WO2023064794A1 - Procédés et systèmes de prévention prophylactique, de ralentissement de l'évolution ou de traitement de l'angiopathie amyloïde cérébrale, de la maladie d'alzheimer et/ou d'un accident vasculaire cérébral aigu - Google Patents

Procédés et systèmes de prévention prophylactique, de ralentissement de l'évolution ou de traitement de l'angiopathie amyloïde cérébrale, de la maladie d'alzheimer et/ou d'un accident vasculaire cérébral aigu Download PDF

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WO2023064794A1
WO2023064794A1 PCT/US2022/077947 US2022077947W WO2023064794A1 WO 2023064794 A1 WO2023064794 A1 WO 2023064794A1 US 2022077947 W US2022077947 W US 2022077947W WO 2023064794 A1 WO2023064794 A1 WO 2023064794A1
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patient
beta
high density
caa
perivascular
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PCT/US2022/077947
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English (en)
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Hollis Bryan BREWER
Michael M. MATIN
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Hdl Therapeutics, Inc.
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Priority claimed from US17/571,225 external-priority patent/US20220202857A1/en
Application filed by Hdl Therapeutics, Inc. filed Critical Hdl Therapeutics, Inc.
Publication of WO2023064794A1 publication Critical patent/WO2023064794A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/02—Arrangements for diagnosis sequentially in different planes; Stereoscopic radiation diagnosis
    • A61B6/03—Computed tomography [CT]
    • A61B6/037—Emission tomography
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/50—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications
    • A61B6/501—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications for diagnosis of the head, e.g. neuroimaging or craniography
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/52—Devices using data or image processing specially adapted for radiation diagnosis
    • A61B6/5211—Devices using data or image processing specially adapted for radiation diagnosis involving processing of medical diagnostic data
    • A61B6/5217—Devices using data or image processing specially adapted for radiation diagnosis involving processing of medical diagnostic data extracting a diagnostic or physiological parameter from medical diagnostic data
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/08—Detecting organic movements or changes, e.g. tumours, cysts, swellings
    • A61B8/0808—Detecting organic movements or changes, e.g. tumours, cysts, swellings for diagnosis of the brain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/52—Devices using data or image processing specially adapted for diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/5215—Devices using data or image processing specially adapted for diagnosis using ultrasonic, sonic or infrasonic waves involving processing of medical diagnostic data
    • A61B8/5223—Devices using data or image processing specially adapted for diagnosis using ultrasonic, sonic or infrasonic waves involving processing of medical diagnostic data for extracting a diagnostic or physiological parameter from medical diagnostic data
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4836—Diagnosis combined with treatment in closed-loop systems or methods
    • A61B5/4839—Diagnosis combined with treatment in closed-loop systems or methods combined with drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4709—Amyloid plaque core protein
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • 63/262,423 titled “Methods for Prophylactically Preventing, Slowing the Progression of, or Treating Cerebral Amyloid Angiopathy, Alzheimer's Disease and/or Acute Stroke”, filed on October 12, 2021, and United States Patent Provisional Application No. 63/135,001, titled “Methods for Treating Lipid-Related Dysfunction in Lupus Patients”, filed on January 8, 2021.
  • United States Patent Application Number 17/571,225 is also a continuation-in-part application of United States Patent Application No. 17/315,509, titled “Methods for Preserving and Administering Pre-Beta High Density Lipoprotein Having a Predetermined Minimum Level of Degradation” and filed on May 10, 2021, which is a continuation application of United States Patent Application Number 17/021,883, of the same title, filed on September 15, 2020, and issued as United States Patent No.
  • United States Patent Application Number 17/571,225 is also a continuation-in-part application of United States Patent Application No. 17/012,410, titled “Systems for Removing Air from the Fluid Circuits of a Plasma Processing System” and filed on September 4, 2020, which is a continuation application of United States Patent Application No. 16/198,672, titled “Systems and Methods for Priming Fluid Circuits of a Plasma Processing System”, filed on November 21, 2018, and issued as United States Patent No. 11,027,052 on June 8, 2021, which, in turn, relies on United States Provisional Patent Application No. 62/589,919, entitled “Systems and Methods for Causing Regression of Arterial Plaque” and filed on November 22, 2017, for priority.
  • United States Patent Application Number 17/571,225 is also a continuation-in-part application of United States Patent Application No. 17/012,396, titled “Systems for Removing Air from the Fluid Circuits of a Plasma Processing System”, filed on September 4, 2020, and issued as United States Patent Number 11,400,188 on August 2, 2022, which is a continuation application of United StatesPatent Application No. 16/198,672, titled “Systems and Methods for Priming Fluid Circuits of a Plasma Processing System”, filed on November 21, 2018, and issued as United States Patent No. 11,027,052 on June 8, 2021, which, in turn, relies on United States Provisional Patent Application No. 62/589,919, entitled “Systems and Methods for Causing Regression of Arterial Plaque” and filed on November 22, 2017, for priority.
  • United States Patent Application Number 17/571,225 is also a continuation-in-part application of United States Patent Application No. 16/698, 193, titled “Methods for Treating Lipid- Related Diseases Including Xanthomas, Carotid Artery Stenoses, and Cerebral Atherosclerosis” and filed on November 27, 2019, which relies on United States Patent Provisional Application Number 62/773,388, titled “Methods for Treating Cholesterol Related Diseases” and filed on November 30, 2018, for priority.
  • United States Patent Application No. 16/698,193 is also a continuation-in-part application of United States Patent Application Number 16/409,543, titled “Methods for Prophylactically Preventing, Slowing the Progression of, or Treating Cerebral Amyloid Angiopathy, Alzheimer's Disease and/or Acute Stroke” and filed on May 10, 2019, which relies on United States Provisional Patent Application Number 62/700,804, titled “Methods for Prophylactically Preventing, Slowing the Progression of, or Treating Cerebral Amyloid Angiopathy, Alzheimer's Disease and/or Acute Stroke” and filed on July 19, 2018 and United States Provisional Patent Application Number 62/670,615, of the same title and filed on May 11, 2018, for priority.
  • United States Patent Application Number 16/409,543 is also a continuation-in-part application of United States Patent Application Number 15/909,765, titled “Methods for Prophylactically Preventing, Slowing the Progression of, or Treating Alzheimer's Disease” and filed on March 1, 2018, which relies on United States Provisional Patent Application Number 62/537,581, titled “Methods for Treating Cholesterol-Related Diseases” and filed on July 27, 2017, United States Provisional Patent Application Number 62/516,100, entitled “Methods for Treating Cholesterol -Related Diseases” and filed on June 6, 2017, and United States Provisional Patent Application Number 62/465,262, entitled “Method for Treating Familial Hypercholesterolemia” and filed on March 1, 2017, for priority.
  • United States Patent Application Number 15/909,765 is also a continuation-in-part application of United States Patent Application Number 15/876,808, titled “Methods for Treating Cholesterol -Related Diseases” and filed on January 22, 2018, which, in turn, relies on United States Provisional Patent Application Number 62/516,100, titled “Methods for Treating Cholesterol- Related Diseases” and filed on June 6, 2017, United States Provisional Patent Application Number 62/465,262, titled “Method for Treating Familial Hypercholesterolemia” and filed on March 1, 2017, and United States Provisional Patent Application Number 62/449,416, titled “Method for Treating Familial Hypercholesterolemia” and filed on January 23, 2017, for priority.
  • United States Patent Application No. 16/698,193 is also a continuation-in-part application of United States Patent Application Number 16/225,210, entitled “Methods for Preserving and Administering Pre-Beta High Density Lipoprotein Extracted from Human Plasma”, filed on December 19, 2018, and issued as United States Patent No. 10,821,133 on November 3, 2020, which relies on United States Provisional Patent Application Number 62/611,098, titled “Methods for Treating Cholesterol -Related Diseases” and filed on December 28, 2017, for priority.
  • United States Patent Application No. 16/698,193 is also a continuation-in-part application of United States Patent Application Number 16/198,672, titled “Systems and Methods for Priming Fluid Circuits of a Plasma Processing System”, filed on November 21, 2018, and issued as United States Patent No. 11,027,052 on June 8, 2021, which relies on United States Provisional Patent Application Number 62/589,919, titled “Systems and Methods for Causing Regression of Arterial Plaque” and filed on November 22, 2017, for priority.
  • United States Patent Application No. 16/698,193 is also a continuation-in-part application of United States Patent Application Number 16/046,830, titled “Methods for Treating Cholesterol- Related Diseases Using Administered Solutions Having Increased Pre-Beta HDL Particles” and filed on July 26, 2018, which relies on United States Provisional Patent Application Number 62/537,581, titled “Method for Treating Cholesterol-Related Diseases” and filed on July 27, 2017, for priority.
  • United States Patent Application No. 16/046,830 is also a continuation-in-part application of United States Patent Application Number 15/909,765, entitled “Methods for Prophylactically Preventing, Slowing the Progression of, or Treating Alzheimer’s Disease”, and filed on March 1, 2018, which, in turn, relies on United States Provisional Patent Application Number 62/537,581, entitled “Method for Treating Cholesterol -Related Diseases” and filed on July 27, 2017, United States Provisional Patent Application Number 62/516,100, entitled “Methods for Treating Cholesterol -Related Diseases” and filed on June 6, 2017, and United States Provisional Patent Application Number 62/465,262, entitled “Method for Treating Familial Hypercholesterolemia” and filed on March 1, 2017, for priority.
  • United States Patent Application Number 17/571,225 is also a continuation-in-part application of United States Patent Application No. 16/409,543, titled “Methods for Prophylactically Preventing, Slowing the Progression of, or Treating Cerebral Amyloid Angiopathy, Alzheimer's Disease and/or Acute Stroke” and filed on May 10, 2019, which relies on United States Provisional Patent Application Number 62/700,804, titled “Methods for Prophylactically Preventing, Slowing the Progression of, or Treating Cerebral Amyloid Angiopathy, Alzheimer's Disease and/or Acute Stroke” and filed on July 19, 2018 and United States Provisional Patent Application Number 62/670,615, of the same title and filed on May 11, 2018, for priority.
  • United States Patent Application Number 17/571,225 is also a continuation-in-part application of United States Patent Application No. 16/046,830, tilted “Methods for Treating Cholesterol -Related Diseases Using Administered Solutions Having Increased Pre-Beta HDL Particles” and filed on July 26, 2018, which relies on United States Provisional Patent Application Number 62/537,581, entitled “Method for Treating Cholesterol-Related Diseases” and filed on July 27, 2017, for priority.
  • United States Patent Application Number 17/571,225 is also a continuation-in-part application of United States Patent Application No. 15/909,765, entitled “Methods for Prophylactically Preventing, Slowing the Progression of, or Treating Alzheimer's Disease” and filed on March 1, 2018, which relies on United States Provisional Patent Application Number 62/465,262, entitled “Method for Treating Familial Hypercholesterolemia” and filed on March 1, 2017, United States Provisional Patent Application Number 62/516,100, entitled “Methods for Treating Cholesterol-Related Diseases” and filed on June 6, and United States Provisional Patent Application Number 62/537,581, entitled “Methods for Treating Cholesterol-Related Diseases” and filed on July 27, 2017, for priority.
  • United States Patent Application Number 17/571,225 is also a continuation-in-part application of United States Patent Application Number 15/876,808, titled “Methods for Treating Cholesterol -Related Diseases”, and filed on January 22, 2018, which, in turn, relies on United States Provisional Patent Application Number 62/516,100, entitled “Methods for Treating Cholesterol -Related Diseases” and filed on June 6, 2017, United States Provisional Patent Application Number 62/465,262, entitled “Method for Treating Familial Hypercholesterolemia” and filed on March 1, 2017, and United States Provisional Patent Application Number 62/449,416, entitled “Method for Treating Familial Hypercholesterolemia” and filed on January 23, 2017, for priority.
  • the method of the present specification provides for either an isolated or a successively repeated treatment procedure for selective removal of lipid from HDL to create a pre-beta HDL particle while leaving LDL particles substantially intact and the administration of the pre-beta HDL particle to an individual having an acute stroke, or cerebral cognitive impairment with Alzheimer’s disease, in order to treat, delay, halt and stabilize, reverse or improve the progression of the disease or pathophysiologic process that leads to the symptoms related to acute stroke or Alzheimer’s disease.
  • Cerebral Amyloid Angiopathy is an aging-related condition caused by deposits of amyloid proteins in the wall or perivascular space (such as in the intramural peri-arterial drainage (IPAD) System/Perivascular Pathway) of blood vessels in a brain.
  • Low levels of CAA may usually be harmless, however, severe CAA may lead to the protein deposits causing the blood vessels to crack, in which case the blood can leak out and damage the brain.
  • Amyloids are similar to the deposits in the brain that cause Alzheimer’s disease (AD).
  • the factors known to increase risks of CAA include advancing age, an accompanying presence of AD, and some type of genes. Specifically, the gene known as Apolipoprotein E is considered to be a risk factor for CAA.
  • CAA is also estimated to be the cause of 30-40% of hemorrhagic strokes. Differential diagnosis may be performed to determine the probability of CAA in a patient. Imaging tests like CT scans or MRI scans can show whether a bleeding occurred in the outer part of the brain (the cortex) where CAA is usually most severe. This can help distinguish CAA from hemorrhagic strokes caused by high blood pressure, which tend to occur in deep sections of the brain. In addition, a kind of MRI scan called gradient-echo MRI can show whether there have been other tiny areas of bleeding that are also in the typical locations for CAA.
  • amyloid proteins in the arteries and blood vessels of the brain may also result in Hereditary CAA (HCAA) or Hereditary Cerebral Hemorrhage with Amyloidosis (HCHWA).
  • HCAA Hereditary CAA
  • HCHWA Hereditary Cerebral Hemorrhage with Amyloidosis
  • the amyloid deposits known as plaques, damage brain cells, eventually causing cell death and impairing various parts of the brain.
  • CAA amyloid beta peptide deposits within small to medium-sized blood vessels of the brain and leptomeninges. It is believed that vascular amyloid deposits in sporadic CAA are biochemically similar to the material comprising senile plaques in Alzheimer’s disease (AD).
  • AD Alzheimer’s disease
  • CAA occurs either in association with AD or as a certain familial syndrome such as familial hypercholesterolemia.
  • the ratio of certain amyloid peptides in plasma or cerebrospinal fluid, particularly beta amyloid peptides 42 and 40, may be used as an indicator of the presence of CAA and/or AD in a patient.
  • a healthy individual may have levels, in the plasma, of beta amyloid peptide 42 of approximately 19.6 pg/ml and of beta amyloid peptide 40 of approximately 276.7 pg/ml, for a ratio of beta amyloid peptide 42 to beta amyloid peptide 40 of approximately 0.073.
  • a patient with CAA or AD may have levels, in the plasma, of beta amyloid peptide 42 of approximately 13.2 pg/ml and of beta amyloid peptide 40 of approximately 244.3 pg/ml, for a ratio of beta amyloid peptide 42 to beta amyloid peptide 40 of approximately 0.057. Therefore, CAA and AD patients present with a decreased ratio of beta amyloid peptide 42 to beta amyloid peptide 40 in the plasma compared to individuals without CAA or AD.
  • amyloid beta peptides produced in the brain, a significant amount of amyloid beta peptides may be produced in the periphery. These peripherally produced amyloid beta peptides may be produced in the liver or outside of the liver and are present in the plasma peripheral to the brain. The peripherally produced amyloid beta peptides are sufficiently small to travel through the patient’s circulatory system, cross the blood brain barrier, and then become stuck or deposited in the brain, forming amyloid plaques and causing cerebrovascular disease as discussed above.
  • AD Alzheimer’s disease
  • AD Alzheimer's disease
  • AD is determined using results from several tests to arrive at a differential diagnosis. Thus, there is no definitive diagnosis for AD. Research has indicated that familial hypercholesterolemia is an early risk factor for AD. It is theorized that LDL receptors are involved in increasing the risk of AD. It has been observed that certain individuals are predisposed to AD, as demonstrated by family history or by genetic testing. Given that there is no established treatment for AD once lesions are formed, it would be desirable to provide a prophylactic way to treat AD or prevent the onset of AD altogether.
  • AD Cerebral Amyloid Angiopathy
  • CAA amyloid-beta
  • vascular dementia creates changes in cognitive functioning (which is why it is sometimes referred to as “vascular cognitive impairment”) that is usually a result of a stroke that blocks major brain blood vessels.
  • hemorrhagic stroke One form of acute stroke, as mentioned above, is hemorrhagic stroke.
  • CAA occurs due to deposits of protein in the wall of blood vessels in the brain.
  • protein deposits cause the blood vessel wall to crack, resulting in leakage of blood, which damages the brain and causes hemorrhagic stroke.
  • Ischemic stroke occurs when there is a blockage in an artery leading to the brain, and may be a secondary condition caused by a hemorrhagic stroke.
  • ischemic stroke occurs when diseased or damaged cerebral arteries become blocked by the formation of a blood clot within the brain.
  • Cerebral thrombosis thrombotic stroke
  • Large-vessel thrombosis is the term used when the blockage is in one of the brain’s larger blood-supplying arteries such as the carotid or middle cerebral, while small-vessel thrombosis involves one (or more) of the brain’s smaller, yet deeper, penetrating arteries.
  • This latter type of stroke is also called a lacuner stroke.
  • An embolic stroke is also caused by a clot within an artery, but in this case the clot (or emboli) forms somewhere other than in the brain itself.
  • the present specification discloses a method for delaying a progression of, stabilizing, or improving symptoms related to cerebral amyloid angiopathy (CAA) in a patient, comprising: monitoring a pathophysiological change indicative of CAA in a patient; based on said monitoring, determining if at least one of amyloid plaque, Tau oligomers, or other oligomers is present in a perivascular space/IP D System/Perivascular Pathway of the patient in excess of a predetermined threshold; based on a presence of the at least one of the amyloid plaque, the Tau oligomers, or the other oligomers in the perivascular space/IPAD System/Perivascular Pathway of the patient, determining a treatment protocol for the patient, wherein the treatment protocol comprises, at least in part, administering to the patient a high density lipoprotein composition derived from mixing a blood fraction with a lipid removing agent and administering to the patient a CETP inhibitor.
  • CAA cerebral amyloid angiopathy
  • the high density lipoprotein composition is adapted to facilitate a drainage of at least one of soluble beta amyloids, soluble Tau oligomers, or other soluble oligomers.
  • the method further comprises determining an amount of at least one of the amyloid plaque, the Tau oligomers, or the other oligomers in the perivascular space/IPAD System/Perivascular Pathway.
  • the method further comprises using diagnostic imaging to determine at least one of the presence or the extent of the at least one of the amyloid plaque, the Tau oligomers, or the other oligomers in the perivascular space/IPAD System/Perivascular Pathway of the patient.
  • the drainage is facilitated via the patient’s intramural peri-arterial drainage (IPAD) pathway.
  • IPD intramural peri-arterial drainage
  • the high density lipoprotein composition is derived by: obtaining the blood fraction from the patient, wherein the blood fraction has high-density lipoproteins; mixing the blood fraction with the lipid removing agent to yield pre-beta high-density lipoproteins; separating the pre-beta high-density lipoproteins; and delivering the pre-beta high-density lipoproteins to the patient.
  • the method further comprises: connecting the patient to a device for withdrawing blood; withdrawing blood from the patient; and separating blood cells from the blood to yield the blood fraction containing high density lipoproteins and low density lipoproteins.
  • the pre-beta high density lipoproteins have an increased concentration of prebeta high density lipoproteins relative to the high density lipoproteins from the blood fraction prior to mixing.
  • the pre-beta high density lipoproteins have a concentration of alpha high density lipoproteins in addition to pre-beta high density lipoproteins from the blood fraction prior to mixing.
  • the high density lipoprotein composition derived from mixing the blood fraction with the lipid removing agent is delivered to the patient via infusion therapy in a dosage ranging from 1 mg/kg to 250 mg/kg.
  • the high density lipoprotein composition derived from mixing the blood fraction of the patient with the lipid removing agent is delivered to the patient via infusion therapy at a rate of 999 mL/hour +/- 100 mL/hr.
  • the pathophysiological change is indicated by an accumulation of plaque in the perivascular space/IPAD System/Perivascular Pathway of the patient resulting in cerebral amyloid angiopathy.
  • the method further comprises determining a severity of CAA in the patient using at least one of global functioning, cognitive functioning, activities of daily living, or behavioral assessments.
  • the patient experiences a decrease in an accumulation of the at least one of the amyloid plaque, the Tau oligomers, or other oligomers in the perivascular space/IPAD System/Perivascular Pathway.
  • a rate of degeneration of the patient after administering to the patient the high density lipoprotein composition and the CETP inhibitor, a rate of degeneration of the patient’s physiological and/or cognitive parameters indicative of CAA decreases.
  • a rate of degeneration of the patient’s physiological and/or cognitive parameters indicative of CAA slows down relative to a rate of degeneration of the patient’s physiological and/or cognitive parameters indicative of CAA before administering to the patient the high density lipoprotein composition and the CETP inhibitor.
  • the patient’s physiological and/or cognitive symptoms indicative of CAA improve relative to the patient’s physiological and/or cognitive symptoms indicative of CAA before administering to the patient the high density lipoprotein composition and the CETP inhibitor.
  • the high density lipoprotein composition is derived by: obtaining a blood fraction from an individual other than the patient, wherein the blood fraction has high-density lipoproteins; mixing the blood fraction with the lipid removing agent to yield pre-beta high-density lipoproteins; separating the pre-beta high-density lipoproteins; and delivering the pre-beta high- density lipoproteins to the patient.
  • the lipid removing agent is at least one of phenols, hydrocarbons, amines, ethers, esters, alcohols, halohydrocarbons, halocarbons, di-isopropyl ether (DIPE), diethyl ether (DEE), n-butanol, ethyl acetate, di chloromethane, chloroform, isoflurane, sevoflurane, perfluorocyclohexanes, trifluoroethane, cyclofluorohexanol, or combinations thereof.
  • DIPE di-isopropyl ether
  • DEE diethyl ether
  • n-butanol ethyl acetate
  • di chloromethane chloroform
  • isoflurane sevoflurane
  • perfluorocyclohexanes trifluoroethane
  • cyclofluorohexanol or combinations thereof.
  • the CETP inhibitor is administered to the patient in a dose ranging from 1 mg to 1000 mg or any increment therein.
  • the CETP inhibitor is administered to the patient at any time interval that will achieve the desired therapeutic outcome.
  • the CETP inhibitor is administered to the patient in a dose ranging selected from one of 30 mg/day, 100 mg/day, or 500 mg/day.
  • the present specification also discloses a method for delaying a progression of, stabilizing, or improving symptoms related to cerebral amyloid angiopathy (CAA) in a patient, comprising: monitoring a pathophysiological change indicative of CAA in a patient; based on said monitoring, determining if at least one of amyloid plaque, Tau oligomers, or other oligomers is present in a perivascular space/IPAD System/Perivascular Pathway of the patient in excess of a predetermined threshold; based on a presence of the at least one of the amyloid plaque, the Tau oligomers, or the other oligomers in the perivascular space/IPAD System/Perivascular Pathway of the patient, determining a treatment protocol for the patient, wherein the treatment protocol comprises, at least in part, administering to the patient a CETP inhibitor.
  • CAA cerebral amyloid angiopathy
  • the method further comprises determining an amount of at least one of the amyloid plaque, the Tau oligomers, or the other oligomers in the perivascular space/IPAD System/Perivascular Pathway.
  • the method further comprises using diagnostic imaging to determine at least one of the presence or the extent of the at least one of the amyloid plaque, the Tau oligomers, or the other oligomers in the perivascular space/IPAD System/Perivascular Pathway of the patient.
  • the drainage is facilitated via the patient’s intramural peri-arterial drainage (IPAD) pathway.
  • IPD intramural peri-arterial drainage
  • the pathophysiological change is indicated by an accumulation of plaque in the perivascular space/IPAD System/Perivascular Pathway of the patient resulting in cerebral amyloid angiopathy.
  • the method further comprises determining a severity of CAA in the patient using at least one of global functioning, cognitive functioning, activities of daily living, or behavioral assessments.
  • the patient experiences a decrease in an accumulation of the at least one of the amyloid plaque, the Tau oligomers, or other oligomers in the perivascular space/IPAD System/Perivascular Pathway.
  • a rate of degeneration of the patient after administering to the patient the CETP inhibitor, a rate of degeneration of the patient’s physiological and/or cognitive parameters indicative of CAA decreases.
  • a rate of degeneration of the patient’s physiological and/or cognitive parameters indicative of CAA slows down relative to a rate of degeneration of the patient’s physiological and/or cognitive parameters indicative of CAA before administering to the patient the CETP inhibitor.
  • the patient’s physiological and/or cognitive symptoms indicative of CAA improve relative to the patient’s physiological and/or cognitive symptoms indicative of CAA before administering to the patient the CETP inhibitor.
  • the CETP inhibitor is administered to the patient in a dose ranging from 1 mg to 1000 mg.
  • the CETP inhibitor is administered to the patient at any time interval that will achieve the desired therapeutic outcome.
  • the CETP inhibitor is administered to the patient in a dose ranging selected from one of 30 mg/day, 100 mg/day, or 500 mg/day.
  • the present specification also discloses a method for delaying a progression of, stabilizing, or improving symptoms related to cerebral amyloid angiopathy (CAA) in a patient, comprising: monitoring a pathophysiological change indicative of CAA in a patient; based on said monitoring, determining if at least one of amyloid plaque, Tau oligomers, or other oligomers is present in a perivascular space/IPAD System/Perivascular Pathway of the patient in excess of a predetermined threshold; and, based on a presence of the at least one of the amyloid plaque, the Tau oligomers, or the other oligomers in the perivascular space/IPAD System/Perivascular Pathway of the patient, determining a treatment protocol for the patient, wherein the treatment protocol comprises, at least in part, administering to the patient a high density lipoprotein composition derived from mixing a blood fraction with a lipid removing agent.
  • CAA cerebral amyloid angiopathy
  • the high density lipoprotein composition is adapted to facilitate a drainage of at least one of soluble beta amyloids, soluble Tau oligomers, or other soluble oligomers.
  • the method further comprises determining an amount of at least one of the amyloid plaque, the Tau oligomers, or the other oligomers in the perivascular space/IPAD System/Perivascular Pathway.
  • the method further comprises using diagnostic imaging to determine at least one of the presence or the extent of the at least one of the amyloid plaque, the Tau oligomers, or the other oligomers in the perivascular space of the patient.
  • the drainage is facilitated via the patient’s intramural peri-arterial drainage (IPAD) pathway.
  • IPD intramural peri-arterial drainage
  • the lipid removing agent is at least one of phenols, hydrocarbons, amines, ethers, esters, alcohols, halohydrocarbons, halocarbons, di-isopropyl ether (DIPE), diethyl ether (DEE), n-butanol, ethyl acetate, di chloromethane, chloroform, isoflurane, sevoflurane, perfluorocyclohexanes, trifluoroethane, cyclofluorohexanol, or combinations thereof.
  • DIPE di-isopropyl ether
  • DEE diethyl ether
  • n-butanol ethyl acetate
  • di chloromethane chloroform
  • isoflurane sevoflurane
  • perfluorocyclohexanes trifluoroethane
  • cyclofluorohexanol or combinations thereof.
  • the present specification also discloses a method for delaying the progression of, stabilizing, or improving symptoms related to cerebral amyloid angiopathy (CAA) in a patient, comprising: monitoring a pathophysiological change indicative of CAA or a potential future onset of CAA, in the patient; based on said monitoring, determining if amyloid plaque, and/or Tau oligomers, and/or other oligomers is present in a perivascular space/IPAD System/Perivascular Pathway of the patient; based on the determination of the presence of amyloid plaque, and/or Tau oligomers, and/or other oligomers in the perivascular space/IPAD System/Perivascular Pathway of the patient, determining a treatment protocol for the patient, wherein the treatment protocol comprises, at least in part, administering to the patient a high density lipoprotein composition derived from mixing a blood fraction having unmodified high density lipoproteins with a solvent to yield pre-beta high density lipoproteins, wherein the
  • the solvent is at least one of phenols, hydrocarbons, amines, ethers, esters, alcohols, halohydrocarbons, halocarbons, di-isopropyl ether (DIPE), diethyl ether (DEE), n- butanol, ethyl acetate, dichloromethane, chloroform, isoflurane, sevoflurane, perfluorocyclohexanes, trifluoroethane, cyclofluorohexanol, or combinations thereof.
  • DIPE di-isopropyl ether
  • DEE diethyl ether
  • n- butanol ethyl acetate
  • dichloromethane chloroform
  • isoflurane sevoflurane
  • perfluorocyclohexanes trifluoroethane
  • cyclofluorohexanol or combinations thereof.
  • administering the pre-beta high density lipoproteins to the patient facilitates a drainage of soluble oligomers.
  • the method further comprises: connecting the patient to a device for withdrawing blood; withdrawing blood from the patient; and separating blood cells from the blood to yield the blood fraction containing low density lipoproteins and the high density lipoproteins.
  • the method further comprises delivering the high density lipoprotein composition to the patient via infusion therapy in a dosage ranging from 1 mg/kg to 250 mg/kg.
  • the method further comprises delivering the high density lipoprotein composition to the patient via infusion therapy at a rate of 999 mL/hour +/- 100 mL/hr.
  • the present specification also discloses a method for delaying a progression of, stabilizing, or improving symptoms related to Alzheimer’s Disease (AD) in a patient, comprising: monitoring a pathophysiological change indicative of AD in a patient; based on said monitoring, determining if amyloid plaque, and/or Tau oligomers, and/or other oligomers is present in a perivascular space/IPAD System/Perivascular Pathway of the patient; determining an extent of amyloid plaque, and/or Tau oligomers, and/or other oligomers in said perivascular space/IPAD System/Perivascular Pathway ; and, based on the presence of amyloid plaque, and/or Tau oligomers, and/or other oligomers in the perivascular space/IPAD System/Perivascular Pathway of the patient, determining a treatment protocol for the patient, wherein the treatment protocol comprises administering to the patient a high density lipoprotein composition derived from mixing a blood fraction with a lipid removing agent
  • diagnostic imaging is used to determine the presence and extent of amyloid plaque, and/or Tau oligomers, and/or other oligomers in the perivascular space/IPAD Sy stem/Peri vascular Pathway of the patient.
  • the high density lipoprotein composition is derived by obtaining the blood fraction from the patient, wherein the blood fraction has high-density lipoproteins; mixing the blood fraction with the lipid removing agent to yield pre-beta high-density lipoproteins; separating the pre-beta high-density lipoproteins; and delivering the pre-beta high-density lipoproteins to the patient.
  • the method further comprises connecting the patient to a device for withdrawing blood; withdrawing blood from the patient; and separating blood cells from the blood to yield the blood fraction containing high density lipoproteins and low density lipoproteins.
  • the pre-beta high density lipoproteins have an increased concentration of prebeta high density lipoproteins relative to the high density lipoproteins from the blood fraction prior to mixing.
  • the pre-beta high density lipoproteins have a concentration of alpha high density lipoproteins in addition to pre-beta high density lipoproteins from the blood fraction prior to mixing.
  • the pathophysiological change is indicated by an accumulation of plaque in the perivascular space/IPAD System/Perivascular Pathway of the patient resulting in cerebral amyloid angiopathy.
  • the high density lipoprotein composition derived from mixing the blood fraction with the lipid removing agent is delivered to the patient via infusion therapy in a dosage ranging from 1 mg/kg to 250 mg/kg.
  • the high density lipoprotein composition derived from mixing the blood fraction of the patient with the lipid removing agent is delivered to the patient via infusion therapy at a rate of 999 mL/hour +/- 100 mL/hr.
  • the method further comprises determining a severity of CAA or AD in the patient using at least one of global functioning, cognitive functioning, activities of daily living, or behavioral assessments.
  • the patient experiences a decrease in an accumulation of the at least one of the amyloid plaque, the Tau oligomers, or other oligomers in the perivascular space/IPAD System/Perivascular Pathway.
  • a rate of degeneration of the patient after administering to the patient the high density lipoprotein composition, a rate of degeneration of the patient’s physiological and/or cognitive parameters indicative of CAA decreases or indicative of AD stabilizes and does not experience a further decrease.
  • a rate of degeneration of the patient after administering to the patient the high density lipoprotein composition, a rate of degeneration of the patient’s physiological and/or cognitive parameters indicative of CAA or AD, slows down relative to a rate of degeneration of the patient’s physiological and/or cognitive parameters indicative of CAA or AD before administering to the patient the high density lipoprotein composition.
  • the patient’s physiological and/or cognitive symptoms indicative of CAA or AD improve relative to the patient’s physiological and/or cognitive symptoms indicative of CAA or AD before administering to the patient the high density lipoprotein composition.
  • the high density lipoprotein composition is derived by obtaining a blood fraction from an individual other than the patient, wherein the blood fraction has high-density lipoproteins; mixing the blood fraction with the lipid removing agent to yield pre-beta high-density lipoproteins; separating the pre-beta high-density lipoproteins; and delivering the pre-beta high- density lipoproteins to the patient.
  • the present specification also discloses a method for delaying the progression of, stabilizing, or improving symptoms related to Alzheimer’s Disease (AD) in a patient, comprising: monitoring a pathophysiological change indicative of AD, or a potential future onset of AD, in the patient; based on said monitoring, determining if amyloid plaque, and/or Tau oligomers, and/or other oligomers is present in a perivascular space/IPAD System/Perivascular Pathway of the patient; based on the determination of the presence of amyloid plaque, and/or Tau oligomers, and/or other oligomers in the perivascular space/IPAD System/Perivascular Pathway of the patient, determining a treatment protocol for the patient, wherein the treatment protocol comprises administering to the patient a high density lipoprotein composition derived from mixing a blood fraction, having unmodified high density lipoproteins, with a lipid removing agent to yield prebeta high density lipoproteins, wherein the pre-beta high density
  • the composition is derived by obtaining the blood fraction from the patient; mixing the blood fraction with the lipid removing agent to yield the pre-beta high-density lipoproteins; separating the pre-beta high-density lipoproteins; and delivering the pre-beta high- density lipoproteins to the patient.
  • the method further comprises connecting the patient to a device for withdrawing blood; withdrawing blood from the patient; and separating blood cells from the blood to yield the blood fraction containing low density lipoproteins and the high density lipoproteins.
  • the composition is derived by obtaining the blood fraction from an individual other than the patient; mixing the blood fraction with the lipid removing agent to yield the pre-beta high-density lipoproteins; separating the pre-beta high-density lipoproteins; and delivering the prebeta high-density lipoproteins to the patient.
  • the present specification also discloses a method for impacting hippocampal volume indicative of Alzheimer’s Disease (AD) in a patient, comprising: determining if amyloid plaque, and/or Tau oligomers, and/or other oligomers is present in a perivascular space/IPAD Sy stem/Peri vascular Pathway of the patient; determining a volume of a hippocampus of the patient; and, based on the determination of the presence of amyloid plaque, and/or Tau oligomers, and/or other oligomers in the perivascular space/IPAD System/Perivascular Pathway of the patient and the volume of the hippocampus of the patient, determining a treatment protocol for the patient, wherein the treatment protocol comprises administering to the patient a high density lipoprotein composition derived from mixing a blood fraction of the patient with a lipid removing agent.
  • AD Alzheimer’s Disease
  • the present specification also discloses a method for impacting hippocampal volume indicative of Alzheimer’s Disease (AD) in a person with Down syndrome, comprising: determining if amyloid plaque, and/or Tau oligomers, and/or other oligomers are present in a perivascular space/IPAD System/Perivascular Pathway of the person with Down syndrome; determining a volume of a hippocampus of the person with Down syndrome; and, based on the determination of the presence of amyloid plaque, and/or Tau oligomers, and/or other oligomers in the perivascular space/IPAD System/Perivascular Pathway of the person with Down syndrome and the volume of the hippocampus of the person with Down syndrome, determining a treatment protocol for the person with Down syndrome, wherein the treatment protocol comprises administering to the person with Down syndrome a high density lipoprotein composition derived from mixing a blood fraction of the person with Down syndrome with a lipid removing agent.
  • AD Alzheimer’s Disease
  • an increase in the hippocampal volume of a patient results in improved cognitive function.
  • the present specification also discloses a method for delaying a progression of, halting and stabilizing, or reversing and improving symptoms related to Alzheimer’ s Disease (AD) in a patient, comprising: monitoring a pathophysiological change indicative of AD in a patient; based on said monitoring, determining if amyloid plaque is present in a perivascular space/IPAD Sy stem/Peri vascular Pathway of the patient; determining an extent of amyloid plaque in said perivascular space/IPAD System/Perivascular Pathway ; and, based on the presence of amyloid plaque in the perivascular space/IPAD System/Perivascular Pathway of the patient, determining a treatment protocol for the patient, wherein the treatment protocol comprises administering to the patient a high density lipoprotein composition derived from mixing a blood fraction with a lipid removing agent.
  • AD Alzheimer’ s Disease
  • diagnostic imaging is used to determine the presence and extent of amyloid plaque in the perivascular space/IPAD System/Perivascular Pathway of the patient.
  • the high density lipoprotein composition is derived by obtaining the blood fraction from the patient, wherein the blood fraction has high-density lipoproteins; mixing the blood fraction with the lipid removing agent to yield pre-beta high-density lipoproteins; separating the pre-beta high-density lipoproteins; and delivering the pre-beta high-density lipoproteins to the patient.
  • the method further comprises connecting the patient to a device for withdrawing blood; withdrawing blood from the patient; and separating blood cells from the blood to yield the blood fraction containing high density lipoproteins and low density lipoproteins.
  • the pre-beta high density lipoproteins have an increased concentration of prebeta high density lipoproteins relative to the high density lipoproteins from the blood fraction prior to mixing.
  • the pathophysiological change is indicated by an accumulation of plaque in the perivascular space/IPAD System/Perivascular Pathway of the patient resulting in cerebral amyloid angiopathy.
  • the high density lipoprotein composition derived from mixing the blood fraction with the lipid removing agent is delivered to the patient via infusion therapy in a dosage ranging from 1 mg/kg to 250 mg/kg.
  • the high density lipoprotein composition derived from mixing the blood fraction of the patient with the lipid removing agent is delivered to the patient via infusion therapy at a rate of 999 mL/hour or another rate determined best for the patient.
  • the method further comprises determining a severity of AD in the patient using at least one of global functioning, cognitive functioning, activities of daily living, or behavioral assessments.
  • the patient experiences a halt in further accumulation or a decrease in the accumulation of amyloid plaque in the perivascular space/IPAD System/Perivascular Pathway .
  • a rate of degeneration of the patient stabilizes and does not experience a further decrease.
  • a rate of degeneration of the patient’s physiological and/or cognitive parameters indicative of AD slows down relative to a rate of degeneration of the patient’s physiological and/or cognitive parameters indicative of AD before administering to the patient the high density lipoprotein composition.
  • the patient’s physiological and/or cognitive symptoms indicative of AD improve relative to the patient’s physiological and/or cognitive symptoms indicative of AD before administering to the patient the high density lipoprotein composition.
  • the high density lipoprotein composition is derived by obtaining the blood fraction from an individual other than the patient, wherein the blood fraction has high-density lipoproteins; mixing the blood fraction with the lipid removing agent to yield pre-beta high-density lipoproteins; separating the pre-beta high-density lipoproteins; and delivering the pre-beta high- density lipoproteins to the patient.
  • the present specification also discloses a method for delaying the progression of, halting and stabilizing, or reversing and improving symptoms related to Alzheimer’s Disease (AD) in a patient, comprising: monitoring a pathophysiological change indicative of AD, or a potential future onset of AD, in the patient; based on said monitoring, determining if amyloid plaque is present in a perivascular space/IPAD System/Perivascular Pathway of the patient; based on the determination of the presence of amyloid plaque in the perivascular space/IPAD System/Perivascular Pathway of the patient, determining a treatment protocol for the patient, wherein the treatment protocol comprises administering to the patient a high density lipoprotein composition derived from mixing a blood fraction, having unmodified high density lipoproteins, with a lipid removing agent to yield pre-beta high density lipoproteins, wherein the pre-beta high density lipoproteins have an increased concentration of pre-beta high density lipoprotein relative to the unmodified high
  • the composition is derived by obtaining the blood fraction from the patient; mixing the blood fraction with the lipid removing agent to yield the pre-beta high-density lipoproteins; separating the pre-beta high-density lipoproteins; and delivering the pre-beta high- density lipoproteins to the patient.
  • the method further comprises connecting the patient to a device for withdrawing blood; withdrawing blood from the patient; and separating blood cells from the blood to yield the blood fraction containing low density lipoproteins and the high density lipoproteins.
  • the composition is derived by obtaining the blood fraction from an individual other than the patient; mixing the blood fraction with the lipid removing agent to yield the pre-beta high-density lipoproteins; separating the pre-beta high-density lipoproteins; and delivering the prebeta high-density lipoproteins to the patient.
  • the present specification also discloses a method for improving an impairment of cognitive function indicative of Alzheimer’s Disease (AD) in a patient, comprising: determining if amyloid plaque is present in a perivascular space/IPAD System/Perivascular Pathway of the patient; determining an extent or severity of cognitive impairment in the patient using at least one of a global, cognitive, functional or behavioral assessment test; and, based on the determination of the presence of amyloid plaque in the perivascular space/IPAD System/Perivascular Pathway of the patient and said extent or severity of cognitive impairment in the patient, determining a treatment protocol for the patient, wherein the treatment protocol comprises administering to the patient a high density lipoprotein composition derived from mixing a blood fraction of the patient with a lipid removing agent.
  • AD Alzheimer’s Disease
  • the method further comprises determining an extent of amyloid plaque in the perivascular space/IPAD System/Perivascular Pathway and determining the treatment protocol based at least in part on the determined extent of amyloid plaque.
  • the high density lipoprotein composition comprises pre-beta high density lipoproteins having an increased concentration of pre-beta high density lipoprotein relative to high density lipoproteins from the blood fraction prior to mixing.
  • the composition is derived by: obtaining the blood fraction from the patient; mixing said blood fraction with the lipid removing agent to yield pre-beta high-density lipoproteins; separating said pre-beta high-density lipoproteins; and delivering said pre-beta high- density lipoproteins to said patient.
  • the AD is indicated by at least one of homozygous familial hypercholesterolemia, heterozygous familial hypercholesterolemia, ischemic stroke, coronary artery disease, acute coronary syndrome, or peripheral arterial disease.
  • periodically monitoring changes comprises monitoring changes within a period of three to six months.
  • the mixing the blood fraction with a lipid removing agent yields pre-beta high density lipoprotein that has an increased concentration of pre-beta high density lipoprotein relative to total protein.
  • the present specification also discloses a method for delaying a progression of, stabilizing, or improving symptoms related to Cerebral Amyloid Angiopathy (CAA) in a patient, comprising: monitoring a pathophysiological change indicative of CAA in a patient; based on said monitoring, determining if amyloid plaque is present in a perivascular space/IPAD System/Perivascular Pathway of the patient; determining an extent of amyloid plaque in said perivascular space/IPAD System/Perivascular Pathway ; and, based on the presence of amyloid plaque in the perivascular space/IPAD System/Perivascular Pathway of the patient, determining a treatment protocol for the patient, wherein the treatment protocol comprises administering to the patient a high density lipoprotein composition derived from mixing a blood fraction with a lipid removing agent.
  • diagnostic imaging is used to determine the presence and extent of amyloid plaque in the perivascular space/IPAD System/Perivascular Pathway of the patient.
  • the high density lipoprotein composition is derived by obtaining the blood fraction from the patient, wherein the blood fraction has high-density lipoproteins; mixing the blood fraction with the lipid removing agent to yield pre-beta high-density lipoproteins; separating the pre-beta high-density lipoproteins; and delivering the pre-beta high-density lipoproteins to the patient.
  • the method further comprises connecting the patient to a device for withdrawing blood; withdrawing blood from the patient; and separating blood cells from the blood to yield the blood fraction containing high density lipoproteins and low density lipoproteins.
  • the pre-beta high density lipoproteins have an increased concentration of prebeta high density lipoproteins relative to the high density lipoproteins from the blood fraction prior to mixing.
  • the pre-beta high density lipoproteins have a concentration of alpha high density lipoproteins in addition to pre-beta high density lipoproteins from the blood fraction prior to mixing.
  • the pathophysiological change is indicated by an accumulation of plaque in the perivascular space/IPAD System/Perivascular Pathway of the patient resulting in CAA.
  • the high density lipoprotein composition derived from mixing the blood fraction with the lipid removing agent is delivered to the patient via infusion therapy in a dosage ranging from 1 mg/kg to 250 mg/kg.
  • the high density lipoprotein composition derived from mixing the blood fraction of the patient with the lipid removing agent is delivered to the patient via infusion therapy at a rate of 999 mL/hour +/- 100 mL/hr.
  • the patient experiences a decrease in the accumulation of amyloid plaque in the perivascular space/IPAD System/Perivascular Pathway .
  • a rate of degeneration of the patient’s physiological parameters indicative of CAA stabilizes and does not experience a further decrease.
  • a rate of degeneration of the patient’s physiological parameters indicative of CAA slows down relative to a rate of degeneration of the patient’s physiological parameters indicative of CAA before administering to the patient the high density lipoprotein composition.
  • the patient’s physiological symptoms indicative of CAA improve relative to the patient’s physiological symptoms indicative of CAA before administering to the patient the high density lipoprotein composition.
  • the high density lipoprotein composition is derived by obtaining the blood fraction from an individual other than the patient, wherein the blood fraction has high-density lipoproteins; mixing the blood fraction with the lipid removing agent to yield pre-beta high-density lipoproteins; separating the pre-beta high-density lipoproteins; and delivering the pre-beta high- density lipoproteins to the patient.
  • the method further comprises delaying a progression of, stabilizing, or improving symptoms related to Cerebral Amyloid Angiopathy (CAA) in a patient, the symptoms comprising Hereditary Cerebral Amlyoid Angiopathy (HCAA).
  • CAA Cerebral Amyloid Angiopathy
  • HCAA Hereditary Cerebral Amlyoid Angiopathy
  • the method further comprises delaying a progression of, stabilizing, or improving symptoms related to Cerebral Amyloid Angiopathy (CAA) in a patient, the symptoms comprising Hereditary Cerebral Hemorrhage With Amyloidosis (HCHWA).
  • CAA Cerebral Amyloid Angiopathy
  • HSHWA Hereditary Cerebral Hemorrhage With Amyloidosis
  • the present specification also discloses a method for delaying the progression of, stabilizing, or improving symptoms related to Cerebral Amyloid Angiopathy (CAA) in a patient, comprising: monitoring a pathophysiological change indicative of CAA, or a potential future onset of CAA, in the patient; based on said monitoring, determining if amyloid plaque is present in a perivascular space/IPAD System/Perivascular Pathway of the patient; based on the determination of the presence of amyloid plaque in the perivascular space/IPAD System/Perivascular Pathway of the patient, determining a treatment protocol for the patient, wherein the treatment protocol comprises administering to the patient a high density lipoprotein composition derived from mixing a blood fraction, having unmodified high density lipoproteins, with a lipid removing agent to yield pre-beta high density lipoproteins, wherein the pre-beta high density lipoproteins have an increased concentration of pre-beta high density lipoprotein relative to the unmodified high
  • the composition is derived by obtaining the blood fraction from the patient; mixing the blood fraction with the lipid removing agent to yield the pre-beta high-density lipoproteins; separating the pre-beta high-density lipoproteins; and delivering the pre-beta high- density lipoproteins to the patient.
  • the method further comprises connecting the patient to a device for withdrawing blood; withdrawing blood from the patient; and separating blood cells from the blood to yield the blood fraction containing low density lipoproteins and the high density lipoproteins.
  • the composition is derived by obtaining the blood fraction from an individual other than the patient; mixing the blood fraction with the lipid removing agent to yield the pre-beta high-density lipoproteins; separating the pre-beta high-density lipoproteins; and delivering the prebeta high-density lipoproteins to the patient.
  • the present specification also discloses a method for improving symptoms related to Hemorrhagic Stroke (HS) in a patient, comprising: monitoring a condition indicative of HS in a patient; based on said monitoring, determining if amyloid plaque is present in a perivascular space/IPAD System/Perivascular Pathway of the patient; determining an extent of amyloid plaque in said perivascular space/IPAD System/Perivascular Pathway; and, based on the presence of amyloid plaque in the perivascular space/IPAD System/Perivascular Pathway of the patient, determining a treatment protocol for the patient, wherein the treatment protocol comprises administering to the patient a high density lipoprotein composition derived from mixing a blood fraction with a lipid removing agent.
  • HS Hemorrhagic Stroke
  • diagnostic imaging is used to determine the presence and extent of amyloid plaque in the perivascular space/IPAD System/Perivascular Pathway of the patient.
  • the high density lipoprotein composition is derived by obtaining the blood fraction from the patient, wherein the blood fraction has high-density lipoproteins; mixing the blood fraction with the lipid removing agent to yield pre-beta high-density lipoproteins; separating the pre-beta high-density lipoproteins; and delivering the pre-beta high-density lipoproteins to the patient.
  • the method further comprises connecting the patient to a device for withdrawing blood; withdrawing blood from the patient; and separating blood cells from the blood to yield the blood fraction containing high density lipoproteins and low density lipoproteins.
  • the pre-beta high density lipoproteins have an increased concentration of prebeta high density lipoproteins relative to the high density lipoproteins from the blood fraction prior to mixing.
  • the pre-beta high density lipoproteins have a concentration of alpha high density lipoproteins in addition to pre-beta high density lipoproteins from the blood fraction prior to mixing.
  • the condition is indicated by an accumulation of plaque in the perivascular space/IPAD Sy stem/Peri vascular Pathway of the patient resulting in HS.
  • the high density lipoprotein composition derived from mixing the blood fraction with the lipid removing agent is delivered to the patient via infusion therapy in a dosage ranging from 1 mg/kg to 250 mg/kg.
  • the high density lipoprotein composition derived from mixing the blood fraction of the patient with the lipid removing agent is delivered to the patient via infusion therapy at a rate of 999 mL/hour +/- 100 mL/hr.
  • the patient experiences a decrease in the accumulation of amyloid plaque in the perivascular space/IPAD System/Perivascular Pathway.
  • a rate of degeneration of the patient after administering to the patient the high density lipoprotein composition, a rate of degeneration of the patient’s physiological parameters indicative of HS stabilizes and does not experience a further decrease.
  • a rate of degeneration of the patient after administering to the patient the high density lipoprotein composition, a rate of degeneration of the patient’s physiological parameters indicative of HS, slows down relative to a rate of degeneration of the patient’s physiological parameters indicative of HS before administering to the patient the high density lipoprotein composition.
  • the patient’s physiological symptoms indicative of HS improve relative to the patient’s physiological symptoms indicative of HS before administering to the patient the high density lipoprotein composition.
  • the high density lipoprotein composition is derived by obtaining the blood fraction from an individual other than the patient, wherein the blood fraction has high-density lipoproteins; mixing the blood fraction with the lipid removing agent to yield pre-beta high-density lipoproteins; separating the pre-beta high-density lipoproteins; and delivering the pre-beta high- density lipoproteins to the patient.
  • the present specification also discloses a method for improving symptoms related to Hemorrhagic Stroke (HS) in a patient, comprising: monitoring a condition indicative of HS, or a potential future onset of HS, in the patient; based on said monitoring, determining if amyloid plaque is present in a perivascular space/IPAD System/Perivascular Pathway of the patient; based on the determination of the presence of amyloid plaque in the perivascular space/IPAD System/Perivascular Pathway of the patient, determining a treatment protocol for the patient, wherein the treatment protocol comprises administering to the patient a high density lipoprotein composition derived from mixing a blood fraction, having unmodified high density lipoproteins, with a lipid removing agent to yield pre-beta high density lipoproteins, wherein the pre-beta high density lipoproteins have an increased concentration of pre-beta high density lipoprotein relative to the unmodified high density lipoproteins.
  • HS Hemorrhagic Stroke
  • the composition is derived by obtaining the blood fraction from the patient; mixing the blood fraction with the lipid removing agent to yield the pre-beta high-density lipoproteins; separating the pre-beta high-density lipoproteins; and delivering the pre-beta high- density lipoproteins to the patient.
  • the method further comprises connecting the patient to a device for withdrawing blood; withdrawing blood from the patient; and separating blood cells from the blood to yield the blood fraction containing low density lipoproteins and the high density lipoproteins.
  • the composition is derived by obtaining the blood fraction from an individual other than the patient; mixing the blood fraction with the lipid removing agent to yield the pre-beta high-density lipoproteins; separating the pre-beta high-density lipoproteins; and delivering the prebeta high-density lipoproteins to the patient.
  • FIG. 1 is a flow chart delineating the steps of treating cholesterol and amyloid deposit related diseases using the treatment systems and methods in accordance with embodiments of the present specification;
  • FIG. 2 is a schematic representation of a plurality of components used in accordance with some embodiments of the present specification to achieve the processes disclosed herein;
  • FIG. 3 is a pictorial illustration of an exemplary embodiment of a configuration of a plurality of components used in accordance with some embodiments of the present specification to achieve the processes disclosed herein;
  • FIG. 4A is a flowchart describing a plurality of exemplary steps of a therapeutic protocol for treating a patient presenting with cerebral amyloid angiopathy (CAA), in accordance with an embodiment of the present specification;
  • CAA cerebral amyloid angiopathy
  • FIG. 4B is a flowchart describing a plurality of exemplary steps of a therapeutic protocol for treating a patient presenting with cerebral amyloid angiopathy (CAA) using a CETP inhibitor, in accordance with an embodiment of the present specification;
  • CAA cerebral amyloid angiopathy
  • FIG. 4C is a flowchart describing a plurality of exemplary steps of a therapeutic protocol for treating a patient presenting with cerebral amyloid angiopathy (CAA) using a CETP inhibitor and pre-beta HDL particles, in accordance with an embodiment of the present specification;
  • CAA cerebral amyloid angiopathy
  • FIG. 5 is a longitudinal transverse cross-sectional view of a cerebral blood vessel illustrating removal of beta amyloid by transport along a cerebral lymphatic IPAD Sy stem/Peri vascular Pathway, in accordance with an embodiment of the present specification;
  • FIG. 6 is a longitudinal transverse cross-sectional view of a cerebral blood vessel illustrating amyloid accumulation in a cerebral lymphatic IPAD System/Perivascular Pathway of an individual having a high level of the E4 allele, in accordance with an embodiment of the present specification
  • FIG. 7A is a longitudinal transverse cross-sectional view of a cerebral blood vessel of a patient being treated for cerebral amyloid angiopathy (CAA), in accordance with an embodiment of the present specification;
  • CAA cerebral amyloid angiopathy
  • FIG. 7B illustrates a mechanism of removal of beta amyloid molecules by infusing pre-0 HDL particles within the blood vessel of FIG. 7A, in accordance with an embodiment of the present specification
  • FIG. 7C shows modified pre-0 HDL particles flowing through the blood stream of the blood vessel of FIG. 7 A, in accordance with an embodiment of the present specification
  • FIG. 8A is a flowchart describing a plurality of exemplary steps of a therapeutic protocol for treating an AD patient, in accordance with an embodiment of the present specification
  • FIG. 8B is a flowchart describing a plurality of exemplary steps of a therapeutic protocol for treating an AD patient using a CETP inhibitor, in accordance with an embodiment of the present specification
  • FIG. 8C is a flowchart describing a plurality of exemplary steps of a therapeutic protocol for treating an AD patient using a CETP inhibitor and pre-beta HDL particles, in accordance with an embodiment of the present specification;
  • FIG. 9A illustrates plaque in a carotid artery of a patient, in accordance with an example
  • FIG. 9B illustrates plaque in a middle cerebral artery of a patient, in accordance with an example
  • FIG. 9C illustrates an embolus lodged within a central cerebral artery, in accordance with an example
  • FIG. 10A is a flowchart describing a plurality of exemplary steps of a therapeutic protocol for treating a patient of hemorrhagic stroke in the presence of CAA, in accordance with an embodiment of the present specification
  • FIG. 10B is a flowchart describing a plurality of exemplary steps of a therapeutic protocol for treating a patient of hemorrhagic stroke in the presence of CAA using a CETP inhibitor, in accordance with an embodiment of the present specification.
  • FIG. 10C is a flowchart describing a plurality of exemplary steps of a therapeutic protocol for treating a patient of hemorrhagic stroke in the presence of CAA using a CETP inhibitor and pre-beta HDL particles, in accordance with an embodiment of the present specification.
  • the present specification relates to methods and systems for treating cholesterol-related diseases. Some embodiments of the present specification monitor changes in one or more atheroma areas and volumes in a patient, regularly over a period of time. Atheroma areas and volumes are monitored using known imaging techniques, for lipid-containing degenerative material in stenosis. [0185] In accordance with embodiments of the present specification, based on the results of the monitoring, treatment is provided if accumulated lipid-containing degenerative material is identified to be present and above a threshold value. The treatment is repeated each time the atheroma areas and volumes are monitored, at pre-defined time intervals, and accumulated lipid- containing degenerative material is identified to be present and above the threshold.
  • Embodiments of the present specification treat the condition through systems, apparatuses and methods useful for removing lipid from a-High Density Lipoprotein (a-HDL) particles derived primarily from plasma of the patient thereby creating pre-beta HDL particles with reduced lipid content, particularly reduced cholesterol content.
  • a-HDL a-High Density Lipoprotein
  • Embodiments of the present specification create these pre-beta HDL particles with reduced lipid content without substantially modifying LDL particles.
  • Embodiments of the present specification modify original a-HDL particles to yield prebeta HDL particles that have an increased concentration of pre-0 HDL relative to the original HDL.
  • pre-0 HDL dramatically increases the selective removal of cholesterol from lipid-loaded macrophages, wherein the cholesterol is associated with an increased risk of Alzheimer’s disease (AD).
  • Pre-0 HDL has also been shown to regress atherosclerosis and atheroma volumes, in addition to markers of inflammation. Additionally, pre-0 HDL has a higher functional capacity than native HDL to transport proteins.
  • Apo A-l (contained within pre-0 HDL particles) levels are significantly lower in AD patients and are highly correlated to the severity of the AD as measured by Mini Mental State (MMSE) scores of AD patients.
  • MMSE Mini Mental State
  • HDL has been found to be a transport vehicle for A0.
  • Native HDL has been shown to facilitate removal of soluble A0 and attenuate CAA in a novel bioengineered human vessel model of AD. Therefore, embodiments of the present specification utilize the pre-beta HDL particles that have an increased concentration of pre-0 HDL relative to the original HDL to remove A0 for treatment of the progression of AD.
  • the newly formed derivatives of HDL particles are administered to the patient to enhance cellular cholesterol efflux and treat cardiovascular diseases and/or other lipid-associated diseases, including Atheroembolic Renal Disease (AERD).
  • AERD Atheroembolic Renal Disease
  • the regular periodic monitoring and treatment process renders the methods and systems of the present specification more effective in treating cardiovascular diseases including Homozygous Familial Hypercholesterolemia (HoFH), Heterozygous Familial Hypercholesterolemia (HeFH), Ischemic stroke, Coronary Artery Disease (CAD), Acute Coronary Syndrome (ACS), peripheral arterial disease (PAD), Renal Arterial Stenosis (RAS), Cerebral Amyloid Angiopathy (CAA), Hereditary CAA, Hereditary cerebral hemorrhage with amyloidosis, Hemorrhagic Stroke (HS), and for treating the progression of cerebral cognitive impairment such as Alzheimer’s Disease and/or vascular dementia.
  • Homozygous Familial Hypercholesterolemia Homozygous Familial Hypercholesterolemia (HoFH), Heterozygous Familial Hypercholesterolemia (HeFH), Ischemic stroke, Coronary Artery Disease (CAD), Acute Coronary Syndrome (ACS), peripheral arterial disease (PAD
  • any administration protocol of the HDL composition that is disclosed with respect to one indication (i.e. Alzheimer's disease) may be used with any of the other indications (i.e. CAA, HS) unless stated otherwise.
  • each of the words “comprise”, “include”, “have”, “contain”, and forms thereof are not necessarily limited to members in a list with which the words may be associated. Thus, they are intended to be equivalent in meaning and be open- ended in that an item or items following any one of these words is not meant to be an exhaustive listing of such item or items, or meant to be limited to only the listed item or items. It should be noted herein that any feature or component described in association with a specific embodiment may be used and implemented with any other embodiment unless clearly indicated otherwise.
  • fluid may be defined as fluids from animals or humans that contain lipids or lipid containing particles, fluids from culturing tissues and cells that contain lipids and fluids mixed with lipid-containing cells.
  • decreasing the amount of lipids in fluids includes decreasing lipids in plasma and particles contained in plasma, including but not limited to HDL particles.
  • Fluids include, but are not limited to: biological fluids; such as blood, plasma, serum, lymphatic fluid, cerebrospinal fluid, peritoneal fluid, pleural fluid, pericardial fluid, various fluids of the reproductive system including, but not limited to, semen, ejaculatory fluids, follicular fluid and amniotic fluid; cell culture reagents such as normal sera, fetal calf serum or serum derived from any animal or human; and immunological reagents, such as various preparations of antibodies and cytokines from culturing tissues and cells, fluids mixed with lipid- containing cells, and fluids containing lipid-containing organisms, such as a saline solution containing lipid-containing organisms.
  • a preferred fluid treated with the methods of the present specification is plasma.
  • lipid may be defined as any one or more of a group of fats or fat-like substances occurring in humans or animals.
  • the fats or fat-like substances are characterized by their insolubility in water and solubility in organic solvents.
  • the term "lipid” is known to those of ordinary skill in the art and includes, but is not limited to, complex lipid, simple lipid, triglycerides, fatty acids, glycerophospholipids (phospholipids), true fats such as esters of fatty acids, glycerol, cerebrosides, waxes, and sterols such as cholesterol and ergosterol.
  • extraction solvent or “lipid removing agent” may be defined as one or more solvents used for extracting lipids from a fluid or from particles within the fluid. This solvent enters the fluid and remains in the fluid until removed by other subsystems. Suitable extraction solvents include solvents that extract or dissolve lipid, including but not limited to phenols, hydrocarbons, amines, ethers, esters, alcohols, halohydrocarbons, halocarbons, and combinations thereof.
  • Suitable extraction solvents are ethers, esters, alcohols, halohydrocarbons, or halocarbons which include, but are not limited to di-isopropyl ether (DIPE), which is also referred to as isopropyl ether, diethyl ether (DEE), which is also referred to as ethyl ether, lower order alcohols such as butanol, especially n-butanol, ethyl acetate, dichloromethane, chloroform, isoflurane, sevoflurane (1,1, 1,3, 3,3- hexafluoro-2- (fluoromethoxy) propane-d3), perfluorocyclohexanes, trifluoroethane, cyclofluorohexanol, and combinations thereof.
  • DIPE di-isopropyl ether
  • DEE diethyl ether
  • ethyl ether diethyl ether
  • lower order alcohols such as butan
  • patient refers to animals and humans, which may be either a fluid source to be treated with the methods of the present specification or a recipient of derivatives of HDL particles and or plasma with reduced lipid content.
  • HDL particles encompasses several types of particles defined based on a variety of methods such as those that measure charge, density, size and immuno-affinity, including but not limited to electrophoretic mobility, ultracentrifugation, immunoreactivity and other methods known to one of ordinary skill in the art.
  • Such HDL particles include but are not limited to the following: a-HDL, pre-0 HDL (including pre-01 HDL, pre-02 HDL and pre- 03HDL), HDL2 (including HDL2a and HDL2b), HDL3, VHDL, LpA-I, LpA-II, LpA-I/LpA-II (for a review see Barrens et al.
  • HDL particles may be modified in numerous ways including but not limited to changes in one or more of the following metabolic and/or physico-chemical properties (for a review see Barrens et al., Biochemica Biophysica Acta 1300; 73-85,1996); molecular mass (kDa); charge; diameter; shape; density; hydration density; flotation characteristics; content of cholesterol; content of free cholesterol; content of esterified cholesterol; molar ratio of free cholesterol to phospholipids; immuno-affinity; content, activity or helicity of one or more of the following enzymes or proteins: ApoA-I, ApoA-II, ApoD, ApoE, ApoJ, ApoA-IV, cholesterol ester transfer protein (CETP), lecithin; cholesterol acyltransferase (LCAT); capacity and
  • blockage due to lipid content is measured in a percentage and is used to refer to the extent of physical blockage in an artery.
  • FIG. 1 is a flow chart illustrating an exemplary process of treating lipid-related diseases including cerebral diseases, such as, but not limited to stroke conditions such as CAA, Hemorrhagic stroke, Hereditary CAA, Hereditary cerebral hemorrhage with amyloidosis, and for treating the progression of cerebral cognitive impairment such as Alzheimer’s Disease in accordance with some embodiments of the present specification.
  • cerebral diseases such as, but not limited to stroke conditions such as CAA, Hemorrhagic stroke, Hereditary CAA, Hereditary cerebral hemorrhage with amyloidosis, and for treating the progression of cerebral cognitive impairment such as Alzheimer’s Disease in accordance with some embodiments of the present specification.
  • a subject or a patient who is diagnosed with a cerebral disease is monitored for one or more atheroma areas and/or volumes via a diagnostic procedure.
  • advanced medical imaging techniques such as, but not limited to Computer Tomography (CT) angiogram and/or Intravascular Ultrasound (IVUS) may be used to detect areas within the inner layer of artery walls where lipid-containing degenerative material may have accumulated.
  • Accumulated degenerative material may include amyloids, or fatty deposits which may include mostly macrophage cells, or debris, containing lipids, calcium and a variable amount of fibrous connective tissue.
  • Analysis from the imaging techniques may also be used to identify and therefore monitor volumes of lipid-containing degenerative material accumulated within the inner layer of artery walls. Lipid-containing degenerative material and non-lipid- containing degenerative material may swell in the artery wall, thereby intruding into the channel of the artery and narrowing it, resulting in restriction of blood flow.
  • arteries with lipid-containing atheroma lesion/plaque/area/region(s) having an amount or volume of blockage within a predetermined range or as indicated by any of the diagnostic procedures outlined below are identified at 106, the patient is then subjected to the delipidation process.
  • a blood fraction of the patient is obtained.
  • the process of blood fractionation is typically performed by filtration, centrifuging the blood, aspiration, or any other method known to persons skilled in the art. Blood fractionation separates the plasma from the blood.
  • blood is withdrawn from a patient in a volume sufficient to produce about 12ml/kg of plasma based on body weight.
  • the blood is separated into plasma and red blood cells using methods commonly known to one of skill in the art, such as plasmapheresis. Then the red blood cells are stored in an appropriate storage solution or returned to the patient during plasmapheresis. The red blood cells are preferably returned to the patient during plasmapheresis. Physiological saline is also optionally administered to the patient to replenish volume.
  • Blood fractionation is known to persons of ordinary skill in the art, and is performed remotely from the method described in context of FIG. 1.
  • the blood can optionally be combined with an anticoagulant, such as sodium citrate, and centrifuged at forces approximately equal to 2,000 times gravity.
  • the red blood cells are then aspirated from the plasma.
  • the cells are returned to the patient.
  • Low Density Lipoprotein (LDL) is also separated from the plasma. Separated LDL is usually discarded.
  • LDL is retained in the plasma.
  • the blood fraction obtained at step 108 includes plasma with High Density Lipoprotein (HDL), and may or may not include other protein particles.
  • HDL High Density Lipoprotein
  • autologous plasma collected from the patient is subsequently treated via an approved plasmapheresis device.
  • the plasma may be transported using a continuous or batch process.
  • the blood fraction obtained at 108 is mixed with one or more solvents, such as lipid removing agents.
  • the solvents used include either or both of organic solvents sevoflurane and n-butanol.
  • the plasma and solvent are introduced into at least one apparatus for mixing, agitating, or otherwise contacting the plasma with the solvent.
  • the solvent system is optimally designed such that only the HDL particles are treated to reduce their lipid levels and LDL levels are not affected.
  • the solvent system includes factoring in variables such as solvent employed, mixing method, time, and temperature. Solvent type, ratios and concentrations may vary in this step. Acceptable ratios of solvent to plasma include any combination of solvent and plasma.
  • ratios used are 2 parts plasma to 1 part solvent, 1 part plasma to 1 part solvent, or 1 part plasma to 2 parts solvent.
  • a ratio of two parts solvent per one part plasma is used.
  • the present specification uses a ratio of solvent to plasma that yields at least 3% n-butanol in the final solvent/plasma mixture.
  • a final concentration of n- butanol in the final solvent/plasma mixture is 3.33%.
  • the plasma may be transported using a continuous or batch process. Further, various sensing means may be included to monitor pressures, temperatures, flow rates, solvent levels, and the like.
  • the solvents dissolve lipids from the plasma. In embodiments of the present specification, the solvents dissolve lipids to yield treated plasma that contains pre-beta HDL particles with reduced lipid content. The process is designed such that HDL particles are treated to reduce their lipid levels and yield pre-beta HDL particles without destruction of plasma proteins or substantially affecting LDL particles.
  • Energy is introduced into the system in the form of varied mixing methods, time, and speed. At 112, bulk solvents are removed from the pre-beta HDL particles via centrifugation.
  • any remaining soluble solvent is removed via charcoal adsorption, evaporation, or Hollow Fiber Contractors (HFC) pervaporation.
  • the mixture is optionally tested for residual solvent via use of gas chromatography (GC), or similar means.
  • GC gas chromatography
  • the test for residual solvent may optionally be eliminated based on statistical validation.
  • the treated plasma containing pre-beta HDL particles with reduced lipid content which was separated from the solvents at 112, is treated appropriately and subsequently returned to the patient.
  • the pre-beta HDL particles are HDL particles with an increased concentration of pre-beta HDL. Concentration of pre-beta HDL is greater in the pre-beta HDL, relative to the original HDL that was present in the plasma before treating it with the solvent.
  • Embodiments of the present specification utilize the pre-beta HDL particles that have an increased concentration of pre-0 HDL relative to the original HDL to remove A0 for treatment of progression of AD.
  • the resulting treated plasma containing the HDL particles with reduced lipid and increased pre-beta concentration is optionally combined with the patient's red blood cells, if the red cells were not already returned during plasmapheresis, and administered to the patient.
  • One route of administration is through the vascular system, preferably intravenously.
  • the patient is monitored again for changes in the previously monitored atheroma areas and volumes, specifically for lipid or amyloid-containing degenerative material. Therefore, the process is repeated from step 102, as described above.
  • the patient is monitored repeatedly within a period of three to six months.
  • the treatment cycle is also repeated at this frequency until the monitoring suggests substantial or complete removal of lipid or amyloid-related degenerative material that cause cerebral diseases.
  • the atheroma area and volume are monitored to be below threshold, the patient may be considered to have been treated and may not require further repetition of the treatment cycle.
  • frequency of treatment may vary depending on the volume to be treated and the severity of the condition of the patient.
  • a CETP inhibitor is used to increase HDL levels in a patient.
  • a CETP inhibitor is used in conjunction with the delipidation process described throughout the specification. More specifically, a CETP inhibitor is in a class of compounds that inhibit cholesteryl ester transfer protein (CETP), which normally transfers cholesterol from HDL cholesterol to very low density or low density lipoproteins (VLDL or LDL). Inhibition of this process results in higher HDL levels and reduces LDL levels. Thus, in embodiments, the CETP inhibitor is used to increase the plasma level of HDL.
  • CETP cholesteryl ester transfer protein
  • the HDL (wherein the increased levels are created by the delipidation process which generates pre-beta HDL and/or by the use of a CETP inhibitor) will bind to the amyloid that may be present in plasma and/or the perivascular space/IPAD System/Perivascular Pathway.
  • the amyloid When bound to one or both of pre-beta HDL generated by the delipidation process or CETP -inhibited HDL, the amyloid may be transported (now in increased levels) to a site of degradation, thereby decreasing levels of amyloid.
  • the degradation site is the liver.
  • the CETP inhibitor binds to amyloid beta peptides in the peripheral vasculature of the patient, before the amyloid beta peptides have crossed the blood brain barrier and into the brain.
  • a CETP inhibitor is administered to the patient without administering pre-beta HDL particles, resulting in a decrease in flux of amyloid beta peptides into the brain.
  • a CETP inhibitor in administered to the patient in conjunction with the administration of pre-beta HDL particles resulting in a decrease in flux of amyloid beta peptides into the brain (as peripheral amyloid beta peptides are bound by the CETP inhibitor and transported to a degradation site) and an increase in the removal of amyloid beta peptides from the brain (as amyloid beta peptide in the brain is bound by the pre-beta HDL particles, removed from the brain, and transported to a degradation site).
  • the delipidation process of the present specification may be used in a short-term therapeutic approach (boosts), or intermittently, while the use of a CETP inhibitor may be used as a chronic, regular therapeutic approach.
  • a combination therapy comprises the use of a CETP inhibitor as a chronic, regular therapeutic application with an intermittent application of pre-beta HDL particles.
  • Embodiments of the present specification create a natural, functional pre-0 HDL, which contain ApoA-I. Normally, pre-0 HDL comprises only 5% of the total HDL in circulation. Embodiments of the present specification describe processes that dramatically increase this ratio to over 80% of the total HDL in circulation. It has been observed that pre-0 HDL derived in accordance with the disclosed methods reduce plaques in coronary arteries of patients with heart disease to a three times greater extent in about seven short weeks than is seen in 2.5 years for statin therapy. In addition, pre-0 HDL substantially reduces inflammation. Furthermore, pre-0 HDL is more efficient than native HDL in removing A0 for treatment of progression of AD.
  • FIG. 2 illustrates an exemplary embodiment of a system and its components used to achieve the methods of the present specification.
  • the figure depicts an exemplary basic component flow diagram defining elements of the HDL modification system 200.
  • Embodiments of the components of system 200 are utilized after obtaining a blood fraction from a patient or another individual (donor).
  • the plasma, separated from the blood is brought in a sterile bag to system 200 for further processing.
  • the plasma may be separated from blood using a known plasmapheresis device.
  • the plasma may be collected from the patient into a sterile bag using standard apheresis techniques.
  • the plasma is then brought in the form of a fluid input to system 200 for further processing.
  • system 200 is not connected to the patient at any time and is a discrete, stand-alone system for delipi dating plasma and creating pre-beta HDL particles.
  • the patient’s plasma is processed by system 200 and brought back to the patient’s location to be reinfused back into the patient.
  • the system may be a continuous flow system that is connected to the patient in which both plasmapheresis and delipidation are performed in an excorporeal, parallel system and the delipidated plasma product is returned to the patient.
  • a fluid input 205 (containing blood plasma) is provided and connected via tubing to a mixing device 220.
  • a solvent input 210 is provided and also connected via tubing to mixing device 220.
  • valves 215, 216 are used to control the flow of fluid from fluid input 205 and solvent from solvent input 210 respectively.
  • the fluid input 205 contains any fluid that includes HDL particles, including plasma having LDL particles or devoid of LDL particles, as discussed above.
  • solvent input 210 can include a single solvent, a mixture of solvents, or a plurality of different solvents that are mixed at the point of solvent input 210. While depicted as a single solvent container, solvent input 210 can comprise a plurality of separate solvent containers. Embodiments of types of solvents that may be used are discussed above.
  • Mixer 220 mixes fluid from fluid input 205 and solvent from solvent input 210 to yield a fluid-solvent mixture.
  • mixer 220 is capable of using a shaker bag mixing method with the input fluid and input solvent in a plurality of batches, such as 1, 2, 3 or more batches.
  • An exemplary mixer is a Barnstead Labline orbital shaker table. In alternative embodiments, other known methods of mixing are utilized.
  • mixer 220 includes shaker table 222. Once formed, the fluid-solvent mixture is directed, through tubing and controlled by at least one valve 215a, to a separator 225.
  • separator 225 is capable of performing bulk solvent separation through gravity separation in a funnel-shaped bag.
  • the fluid-solvent mixture separates into a first layer and second layer.
  • the first layer comprises a mixture of solvent and lipid that has been removed from the HDL particles.
  • the first layer is transported through a valve 215b to a first waste container 235.
  • the second layer comprises a mixture of residual solvent, pre-beta HDL particles, and other elements of the input fluid.
  • the composition of the first layer and the second layer would differ based upon the nature of the input fluid.
  • the second layer is transported through tubing to a solvent extraction device 240.
  • a pressure sensor 229 and valve 230 is positioned in the flow stream to control the flow of the second layer to solvent extraction device 240.
  • valves 215, 216 to enable the flow of fluid from input containers 205, 210 may be timed using mass balance calculations derived from weight determinations of the fluid inputs 205, 210 and separator 225.
  • the valve 215b between separator 225 and first waste container 235 and valve 230 between separator 225 and solvent extraction device 240 open after the input masses (fluid and solvent) substantially balances with the mass in separator 225 and a sufficient period of time has elapsed to permit separation between the first and second layers.
  • valve 215b between separator 225 and first waste container 235 is opened or valve 230 between separator 225 and solvent extraction device 240 is opened.
  • valve 215b between separator 225 and first waste container 235 is open just long enough to remove all of the first layer and some of the second layer, thereby ensuring that as much solvent as possible has been removed from the fluid being sent to solvent extraction device 240.
  • an infusion grade fluid (“IGF”) may be employed via one or more inputs 260 which are in fluid communication with the fluid path 221 leading from separator 225 to solvent extraction device 240 for priming.
  • IGF infusion grade fluid
  • saline is employed as the infusion grade priming fluid in at least one of inputs 260.
  • 0.9% sodium chloride (saline) is employed.
  • glucose may be employed as the infusion grade priming fluid in any one of inputs 260.
  • a glucose input 255 and one or more saline inputs 260 are in fluid communication with the fluid path 221 leading from separator 225 to solvent extraction device 240.
  • a plurality of valves 215c and 215d are also incorporated in the flow stream from glucose input 255 and saline input 260 respectively, to the tubing providing the flow path 221 from separator 225 to solvent extraction device 240.
  • IGF such as saline and/or glucose are incorporated into embodiments of the present specification in order to prime solvent extraction device 240 prior to operation of the system.
  • saline is used to prime most of the fluid communication lines and solvent extraction device 240. If priming is not required, the IGF inputs are not employed. Where such priming is not required, the glucose and saline inputs are not required. Also, one of ordinary skill in the art would appreciate that the glucose and saline inputs can be replaced with other primers if required by the solvent extraction device 240.
  • solvent extraction device 240 is a charcoal column designed to remove the specific solvent used in solvent input 210.
  • An exemplary solvent extraction device 240 is an Asahi Hemosorber charcoal column, or the Bazter/Gambro Adsorba 300C charcoal column or any other charcoal column that is employed in blood hemoglobin perfusion procedures.
  • a pump 250 is used to move the second layer from separator 225, through solvent extraction device 240, and to an output container 245.
  • pump 250 is a rotary peristaltic pump, such as a Masterflex Model 77201-62.
  • the first layer is directed to waste container 235 that is in fluid communication with separator 225 through tubing and at least one valve 215b. Additionally, other waste, if generated, can be directed from the fluid path connecting solvent extraction device 240 and output container 245 to a second waste container 255.
  • a valve 215f is included in the path from the solvent extraction device 240 to the output container 245.
  • a valve 215g is included in the path from the solvent extraction device 240 to the second waste container 255.
  • gravity is used, wherever practical, to move fluid through each of the plurality of components.
  • gravity is used to drain input plasma 205 and input solvent 210 into mixer 220.
  • mixer 220 comprises a shaker bag and separator 225 comprises a funnel bag
  • fluid is moved from the shaker bag to the funnel bag and, subsequently, to first waste container 235, if appropriate, using gravity.
  • the output fluid in output container 245 is subjected to a solvent detection system, or lipid removing agent detection system, to determine if any solvent, or other undesirable component, is in the output fluid.
  • a solvent sensor is only employed in a continuous flow system.
  • the output fluid is subjected to sensors that are capable of determining the concentrations of solvents introduced in the solvent input, such as n-butanol or di-isopropyl ether. The output fluid is returned to the bloodstream of the patient and the solvent concentrations must be below a predetermined level to carry out this operation safely.
  • the sensors are capable of providing such concentration information on a real-time basis and without having to physically transport a sample of the output fluid, or air in the headspace, to a remote device.
  • the resultant separated pre-beta HDL particles are then introduced to the bloodstream of the patient.
  • molecularly imprinted polymer technology is used to enable surface acoustic wave sensors.
  • a surface acoustic wave sensor receives an input, through some interaction of its surface with the surrounding environment, and yields an electrical response, generated by the piezoelectric properties of the sensor substrate.
  • molecularly imprinted polymer technology is used.
  • Molecularly imprinted polymers are plastics programmed to recognize target molecules, like pharmaceuticals, toxins or environmental pollutants, in complex biological samples.
  • the molecular imprinting technology is enabled by the polymerization of one or more functional monomers with an excess of a crosslinking monomer in presence of a target template molecule exhibiting a structure similar to the target molecule that is to be recognized, i.e. the target solvent.
  • the target solvent such as n-butanol
  • cyclic voltammetry is based on varying the applied potential at a working electrode in both the forward and reverse directions, at a predefined scan rate, while monitoring the current. One full cycle, a partial cycle, or a series of cycles can be performed. While platinum is the preferred electrode material, other electrodes, such as gold, silver, iridium, or graphite, could be used. Although, cyclic voltammetric techniques are used, other pulse techniques such as differential pulse voltammetry or square wave voltammetry may increase the speed and sensitivity of measurements.
  • Embodiments of the present specification expressly cover any and all forms of automatically sampling and measuring, detecting, and analyzing an output fluid, or the headspace above the output fluid.
  • automated detection can be achieved by integrating a mini-gas chromatography (GC) measuring device that automatically samples air in the output container, transmits it to a GC device optimized for the specific solvents used in the delipidation process, and, using known GC techniques, analyzes the sample for the presence of the solvents.
  • GC gas chromatography
  • suitable materials for use in any of the apparatus components as described herein include materials that are biocompatible, approved for medical applications that involve contact with internal body fluids, and in compliance with U.S. PVI or lSO 10993 standards. Further, the materials do not substantially degrade from, for instance, exposure to the solvents used in the present specification, during at least a single use.
  • the materials are sterilizable either by radiation or ethylene oxide (EtO) sterilization.
  • EtO ethylene oxide
  • Such suitable materials are capable of being formed into objects using conventional processes, such as, but not limited to, extrusion, injection molding and others.
  • Materials meeting these requirements include, but are not limited to, nylon, polypropylene, polycarbonate, acrylic, polysulfone, poly vinylidene fluoride (PVDF), fluoroelastomers such as VITON, available from DuPont Dow Elastomers L.L.C., thermoplastic elastomers such as SANTOPRENE, available from Monsanto, polyurethane, polyvinyl chloride (PVC), polytetrafluoroethylene (PTFE), polyphenylene ether (PFE), perfluoroalkoxy copolymer (PF A), which is available as TEFLON PFA from E.I. du Pont de Nemours and Company, and combinations thereof.
  • PVDF poly vinylidene fluoride
  • VITON available from DuPont Dow Elastomers L.L.C.
  • thermoplastic elastomers such as SANTOPRENE, available from Monsanto, polyurethane, polyvinyl chloride (PVC), polytetrafluoro
  • Valves 215, 215a, 215b, 215c, 215d, 215e, 215f, 215g, 216 and any other valve used in each embodiment may be composed of, but are not limited to, pinch, globe, ball, gate or other conventional valves.
  • the valves are occlusion valves such as Aero Associates' Model 955 valve.
  • the present specification is not limited to a valve having a particular style.
  • the components of each system described in accordance with embodiments of the present specification may be physically coupled together or coupled together using conduits that may be composed of flexible or rigid pipe, tubing or other such devices known to those of ordinary skill in the art.
  • FIG. 3 illustrates an exemplary configuration of a system used in accordance with some embodiments of the present specification to achieve the processes disclosed herein.
  • a configuration of basic components of the HDL modification system 300 is shown.
  • a fluid input 305 is provided and connected via tubing to a mixing device 320.
  • a solvent input 310 is provided and also connected via tubing to a mixing device 320.
  • valves 316 are used to control the flow of fluid from fluid input 305 and solvent from solvent input 310.
  • the fluid input 305 preferably contains any fluid that includes HDL particles, including plasma having LDL particles or devoid of LDL particles, as discussed above.
  • solvent input 310 can include a single solvent, a mixture of solvents, or a plurality of different solvents that are mixed at the point of solvent input 310. While depicted as a single solvent container, solvent input 310 can comprise a plurality of separate solvent containers. The types of solvents that are used and preferred are discussed above.
  • the mixer 320 mixes fluid from fluid input 305 and solvent from solvent input 310 to yield a fluid-solvent mixture.
  • mixer 320 is capable of using a shaker bag mixing method with the input fluid and input solvent in a plurality of batches, such as 1, 2, 3 or more batches.
  • mixer 320 includes shaker table 322. Once formed, the fluid-solvent mixture is directed, through tubing and controlled by at least one valve 321, to a separator 325.
  • separator 325 is capable of performing bulk solvent separation through gravity separation in a funnel-shaped bag.
  • the fluid-solvent mixture separates into a first layer and second layer.
  • the first layer comprises a mixture of solvent and lipid that has been removed from the HDL particles.
  • the second layer comprises a mixture of residual solvent, pre-beta HDL particles, and other elements of the input fluid.
  • the composition of the first layer and the second layer would differ based upon the nature of the input fluid.
  • the second layer is transported through tubing to a solvent extraction device 340.
  • a pressure sensor 326 and valve 327 is positioned in the flow stream to control the flow of the second layer to the solvent extraction device 340.
  • a glucose input 330 and saline input 350 is in fluid communication with the fluid path leading from the separator 325 to the solvent extraction device 340.
  • a plurality of valves 331 is also preferably incorporated in the flow stream from the glucose input 330 and saline input 350 to the tubing providing the flow path from the separator 325 to the solvent extraction device 340.
  • Glucose and saline are incorporated into the present specification in order to prime the solvent extraction device 340 prior to operation of the system. Where such priming is not required, the glucose and saline inputs are not required. Also, one of ordinary skill in the art would appreciate that the glucose and saline inputs can be replaced with other primers if the solvent extraction device 340 requires it.
  • the solvent extraction device 340 is preferably a charcoal column designed to remove the specific solvent used in the solvent input 310.
  • An exemplary solvent extraction device 340 is an Asahi Hemosorber charcoal column.
  • a pump 335 is used to move the second layer from the separator 325, through the solvent extraction device 340, and to an output container 315.
  • the pump is preferably a peristaltic pump, such as a Masterfl ex Model 77201-62.
  • the first layer is directed to a waste container 355 that is in fluid communication with separator 325 through tubing and at least one valve 356. Additionally, other waste, if generated, can be directed from the fluid path connecting solvent extraction device 340 and output container 315 to waste container 355.
  • an embodiment of the present specification uses gravity, wherever practical, to move fluid through each of the plurality of components.
  • gravity is used to drain the input plasma 305 and input solvent 310 into the mixer 320.
  • the mixer 320 comprises a shaker bag and separator 325 comprises a funnel bag
  • fluid is moved from the shaker bag to the funnel bag and, subsequently, to the waste container 355, if appropriate, using gravity.
  • the present specification preferably comprises configurations wherein all inputs, such as input plasma and input solvents, disposable elements, such as mixing bags, separator bags, waste bags, solvent extraction devices, and solvent detection devices, and output containers are in easily accessible positions and can be readily removed and replaced by a technician.
  • the delipidation systems illustrated in FIGS. 2 and 3, including the shaker tables 222 and 322 are configured to reduce a time required to complete a delipidation process, relative to delipidation systems of the prior art, by a range of 1% to 50%.
  • the delipidation systems illustrated in FIGS. 2 and 3, including the shaker tables 222 and 322 are configured to increase a percentage of delipidation of alpha HDL to pre-beta HDL relative to delipidation systems of the prior art.
  • shaker tables 222 and 322 are configured to increase a percentage of delipidation of alpha HDL to pre-beta HDL up to at least 90%, relative to delipidation systems of the prior art which are configured to provide a percentage of delipidation of alpha HDL to pre-beta HDL of approximately 66%.
  • kits may include an input fluid container (i.e. a high density lipoprotein source container), a lipid removing agent source container (i.e. a solvent container), disposable components of a mixer, such as a bag or other container, disposable components of a separator, such as a bag or other container, disposable components of a solvent extraction device (i.e.
  • an input fluid container i.e. a high density lipoprotein source container
  • a lipid removing agent source container i.e. a solvent container
  • disposable components of a mixer such as a bag or other container
  • disposable components of a separator such as a bag or other container
  • disposable components of a solvent extraction device i.e.
  • a charcoal column an output container
  • disposable components of a waste container such as a bag or other container
  • solvent detection devices and, a plurality of tubing and a plurality of valves for controlling the flow of input fluid (high density lipoprotein) from the input container and lipid removing agent (solvent) from the solvent container to the mixer, for controlling the flow of the mixture of lipid removing agent, lipid, and particle derivative to the separator, for controlling the flow of lipid and lipid removing agent to a waste container, for controlling the flow of residual lipid removing agent, residual lipid, and particle derivative to the extraction device, and for controlling the flow of particle derivative to the output container.
  • input fluid high density lipoprotein
  • lipid removing agent solvent
  • a kit comprises a plastic container having disposable components of a mixer, such as a bag or other container, disposable components of a separator, such as a bag or other container, disposable components of a waste container, such as a bag or other container, and, a plurality of tubing and a plurality of valves for controlling the flow of input fluid (high density lipoprotein) from the input container and lipid removing agent (solvent) from the solvent container to the mixer, for controlling the flow of the mixture of lipid removing agent, lipid, and particle derivative to the separator, for controlling the flow of lipid and lipid removing agent to a waste container, for controlling the flow of residual lipid removing agent, residual lipid, and particle derivative to the extraction device, and for controlling the flow of particle derivative to the output container.
  • Disposable components of a solvent extraction device i.e. a charcoal column
  • the input fluid, the input solvent, and solvent extraction devices may be provided separately.
  • CAA Cerebral Amyloid Angiopathy
  • Cerebral Amyloid Angiopathy is an aging-related condition caused by deposits of amyloid proteins in the wall or perivascular space, intramural peri-arterial drainage (IPAD) system, or perivascular pathway of blood vessels in a brain.
  • the perivascular space comprises fluid-filled structures in the brain around the blood vessels, the perivascular pathway is a waste clearance system in the brain, also not in the blood vessels, and the intramural peri-arterial drainage (IPAD) system is a drainage pathway along the basement membranes in the capillaries and arteries of the blood vessels.
  • CAA Low levels of CAA may usually be harmless, however, severe CAA may lead to the protein deposits causing the blood vessels to crack, in which case the blood can leak out and damage the brain.
  • Amyloids are similar to the deposits in the brain that cause Alzheimer’s disease (AD). Amyloid peptides may be produced in the brain and deposit there, causing disease, and may also be produced peripherally, outside of the brain, cross the blood brain barrier, and become trapped and deposit in the brain, causing disease.
  • the causes known to increase risks of CAA include advancing age, accompanying presence of AD, and some type of genes. Specifically, the gene known as Apolipoprotein E is considered to be a risk factor for CAA.
  • CAA is also estimated to be the cause of 30-40% of hemorrhagic strokes.
  • Differential diagnosis may be performed to determine the probability of CAA in a patient.
  • Imaging tests like CT scans or MRI scans can show whether a bleeding occurred in the outer part of the brain (the cortex) where CAA is usually most severe. This can help distinguish CAA from hemorrhagic strokes caused by high blood pressure, which tend to occur in deep sections of the brain.
  • MRI scan a kind of MRI scan called gradientecho MRI can show whether there have been other tiny areas of bleeding that are also in the typical locations for CAA.
  • a Modified Boston Criteria incorporates cortical superficial siderosis into the radiological diagnosis to determine a probability of CAA.
  • the criteria comprises of combined clinical, imaging and pathological parameters.
  • the criteria has four tiers: o Tier 1 represents definite CAA, and determined during a full post-mortem examination. The examination reveals lobar, cortical, or cortical/subcortical hemorrhage and pathological evidence of severe CAA. o Tier 2 represents probable CAA with supporting pathological evidence. This examination may not be post-mortem.
  • Clinical data and pathological tissue (evacuated hematoma or cortical biopsy specimen) demonstrate a hemorrhage as mentioned above, and some degree of vascular amyloid deposition, indicative of CAA.
  • o Tier 3 represents probable CAA. In this case pathological confirmation is not required. Patients of 55 years or older with an appropriate clinical history are considered. Additionally, MRI findings demonstrate multiple hemorrhages restricted to lobar, cortical, or corticosubcortical regions (cerebellar hemorrhages allowed) of varying sizes/ages without another cause. Alternatively, a single lobar, cortical, or corticosubcortical hemorrhage and focal (three or less sulci) or disseminated (more than three sulci) cortical superficial siderosis without another cause, o Tier 4 represents possible CAA. This is also applicable to patients of 55 years or older age with an appropriate clinical history. Additionally, MRI findings demonstrate a single, (more than three sulci) cortical superficial siderosis without another; or focal or disseminated cortical superficial siderosis without another cause.
  • Apolipoprotein E is a class of proteins involved in the metabolism of fats in the body and is the principal cholesterol carrier in the brain.
  • ApoE is polymorphic, with three major alleles, namely ApoE-c2, ApoE-c3, and ApoE-c4.
  • ApoE-c2 has an allele frequency of approximately 7% to 8% in the general population. This variant of the apolipoprotein binds poorly to cell surface receptors while ApoE-c3 and ApoE-c4 bind relatively well. ApoE-c2 is associated with both increased and decreased risk for atherosclerosis.
  • ApoE-c3 has an allele frequency of approximately 80% in the general population. It is considered the "neutral" ApoE genotype of the three. ApoE-c4 has an allele frequency of approximately 14% in the general population.
  • Beta amyloid (A0) particles are accumulated in the cerebral IPAD System/Perivascular Pathway due to an increased presence of ApoE-c4 particles. As a result, beta amyloid is deposited in the walls of the blood vessel as CAA.
  • a treated plasma that contains pre-beta HDL particles with reduced lipid content is delivered to the patient via infusion therapy.
  • the process is designed such that HDL particles are treated to reduce their lipid levels and yield pre-beta HDL particles without destruction of plasma proteins or substantially affecting LDL particles.
  • the HDL lipoprotein particles are comprised of ApoA-I, phospholipids and cholesterol.
  • ApoA-I Apolipoprotein A-I particles comprise of two sub-fractions, pre-0 HDL and a-HDL, which have pre-beta and alpha electrophoretic mobility, respectively.
  • pre-0 HDL represents ApoA-I molecules complexed with phospholipids.
  • a treated plasma that contains pre-beta HDL particles with reduced lipid content is delivered to the patient via infusion therapy.
  • the pre-beta high density lipoproteins have a concentration of alpha high density lipoproteins in addition to the pre-beta high density lipoproteins from the blood fraction prior to mixing.
  • isolated pre-0 HDL particles are infused into the patient’s blood stream to bind to beta amyloid particles and clear the cerebral IPAD System/Perivascular Pathway.
  • FIG. 4A is a flowchart describing a plurality of exemplary steps of a therapy protocol for treating a CAA patient, in accordance with an embodiment of the present specification.
  • a patient first presents with a pathophysiological change that is consistent with symptoms of CAA. Any of the aforementioned diagnostic techniques may be used in this step.
  • various biomarkers may be used to determine the pathophysiological change. For example, measuring the level of amyloids may be used to assess the extent of a pathophysiological change characteristic of CAA.
  • a patient who is diagnosed with CAA is monitored to determine an extent of accumulation of plaque in the perivascular space/IPAD System/Perivascular Pathway, via at least one diagnostic procedure.
  • advanced medical imaging techniques such as, but not limited to, Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI), may be used.
  • PET Positron Emission Tomography
  • MRI Magnetic Resonance Imaging
  • one or more physiological parameters of the patient are recorded.
  • the one or more physiological parameters are those that may be incidental to determining one or more therapy parameters.
  • the patient’s weight is recorded to determine a dosing range for the patient. It should be appreciated that the physiological parameters may be first recorded prior to step 405.
  • the patient is infused with pre-beta HDL particles in accordance with a therapy protocol.
  • a blood fraction is withdrawn from the patient presenting with the amyloid deposits.
  • a blood fraction is obtained withdrawing blood from a person other than the patient. Therefore, the plasma obtained as a result of the blood fractionation process may be either autologous or non-autologous.
  • the blood fraction is subsequently treated, using the delipidation process described above in context of FIG. 1, to obtain treated plasma containing pre-beta HDL particles.
  • the treated plasma is optionally processed further to generate a product with an increased concentration of isolated pre-0 HDL.
  • the therapy protocol comprises an infusion delivery of pre-beta HDL particles or a concentrated volume of isolated pre-beta particles over a period ranging from 1 hour to 8 hours, and any increment therein, depending upon the concentration of the therapeutic product to be delivered.
  • the dose ranges from 1 mg/kg to 250 mg/kg, and any increment therein, and is administered at an infusion delivery rate of 999 mL/hour +/- lOOml/hour or a rate deemed more appropriate for the patient.
  • the treatment is performed once, or may be repeated at specified frequency or cycle of treatment depending upon a course of therapy.
  • the frequency or cycle of administering the treatment may range from once a week, twice a week, three times per week, daily, once a month, twice a month, three times per month, to at least once in three, six, nine or twelve months.
  • the course of therapy may range from at least one day, at least one week, at least one month to at least one year.
  • the therapy protocol comprises at least one, and up to three, seven or ten treatments every three, six, nine or twelve months for an annual course of therapy.
  • the at least one treatment may comprise a continuous infusion (IV) of pre-beta HDL particles over a predetermined time period at a rate of 999 mL/hour.
  • the therapy protocol may be titrated or modulated up or down based on a therapeutic endpoint.
  • FIG. 4B is a flowchart describing a plurality of exemplary steps of a therapeutic protocol for treating a patient presenting with cerebral amyloid angiopathy (CAA) using a CETP inhibitor, in accordance with an embodiment of the present specification.
  • a patient first presents with a pathophysiological change that is consistent with symptoms of CAA. Any of the aforementioned diagnostic techniques may be used in this step.
  • various biomarkers may be used to determine the pathophysiological change. For example, measuring the level of amyloids may be used to assess the extent of a pathophysiological change characteristic of CAA.
  • a patient who is diagnosed with CAA is monitored to determine an extent of accumulation of plaque in the perivascular space/IPAD System/Perivascular Pathway, via at least one diagnostic procedure.
  • advanced medical imaging techniques such as, but not limited to, Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI), may be used.
  • PET Positron Emission Tomography
  • MRI Magnetic Resonance Imaging
  • one or more physiological parameters of the patient are recorded.
  • the one or more physiological parameters are those that may be incidental to determining one or more therapy parameters.
  • the patient’s weight is recorded to determine a dosing range for the patient. It should be appreciated that the physiological parameters may be first recorded prior to step 432.
  • the patient is provided with a regimen for using a CETP inhibitor.
  • the dose ranges from 1 mg to 1000 mg, and any increment therein.
  • a patient may be given a CETP inhibitor at any interval that will achieve the desired therapeutic outcome, which includes, but is not limited to twice daily, weekly, biweekly, monthly, every two months, every six months, yearly or any increment therein.
  • a patient is given a CETP inhibitor once daily.
  • a preferred dosage rate is once daily, given orally.
  • a preferred dosage amount of a CETP inhibitor such as evacetrapib, is selected from one of: 30 mg/d, 100 mg/d, or 500 mg/d.
  • the dosage amount may be modified depending upon desired therapeutic outcome.
  • the desired therapeutic outcome may be measured by determining changes in a patient’s mean baseline lipoprotein levels (HDL-C, LDL-C, and triglycerides).
  • the therapy protocol may be titrated or modulated up or down based on a therapeutic endpoint.
  • a CETP inhibitor is used in conjunction with the delipidation process described throughout the specification.
  • the delipidation process of the present specification may be used in a short-term therapeutic approach (boosts), or intermittently, while the use of a CETP inhibitor may be used as a chronic, regular therapeutic approach.
  • boosts short-term therapeutic approach
  • a combination therapy comprises the use of a CETP inhibitor as a chronic, regular therapeutic application with an intermittent application of pre-beta HDL particles.
  • FIG. 4C is a flowchart describing a plurality of exemplary steps of a therapeutic protocol for treating a patient presenting with cerebral amyloid angiopathy (CAA) using a CETP inhibitor and pre-beta HDL particles, in accordance with an embodiment of the present specification.
  • a patient first presents with a pathophysiological change that is consistent with symptoms of CAA. Any of the aforementioned diagnostic techniques may be used in this step.
  • various biomarkers may be used to determine the pathophysiological change. For example, measuring the level of amyloids may be used to assess the extent of a pathophysiological change characteristic of CAA.
  • a patient who is diagnosed with CAA is monitored to determine an extent of accumulation of plaque in the perivascular space/IPAD System/Perivascular Pathway, via at least one diagnostic procedure.
  • advanced medical imaging techniques such as, but not limited to, Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI), may be used.
  • PET Positron Emission Tomography
  • MRI Magnetic Resonance Imaging
  • one or more physiological parameters of the patient are recorded.
  • the one or more physiological parameters are those that may be incidental to determining one or more therapy parameters.
  • the patient’s weight is recorded to determine a dosing range for the patient. It should be appreciated that the physiological parameters may be first recorded prior to step 450.
  • the patient is provided with a regimen for using a CETP inhibitor.
  • the dose ranges from 1 mg to 1000 mg, and any increment therein.
  • a patient may be given a CETP inhibitor at any interval that will achieve the desired therapeutic outcome, which includes, but is not limited to twice daily, weekly, biweekly, monthly, every two months, every six months, yearly or any increment therein.
  • a patient is given a CETP inhibitor once daily.
  • a preferred dosage rate is once daily, given orally.
  • a preferred dosage amount of a CETP inhibitor such as evacetrapib, is selected from one of: 30 mg/d, 100 mg/d, or 500 mg/d.
  • the dosage amount may be modified depending upon desired therapeutic outcome.
  • the desired therapeutic outcome may be measured by determining changes in a patient’s mean baseline lipoprotein levels (HDL-C, LDL-C, and triglycerides).
  • the patient is infused with pre-beta HDL particles in accordance with a therapy protocol.
  • a blood fraction is withdrawn from the patient presenting with CAA.
  • a blood fraction is obtained withdrawing blood from a person other than the patient. Therefore, the plasma obtained as a result of the blood fractionation process may be either autologous or non-autologous.
  • the blood fraction is subsequently treated, using the delipidation process described above to obtain treated plasma containing pre-beta HDL particles.
  • the treated plasma is optionally processed further to generate a product with an increased concentration of isolated pre-0 HDL.
  • the therapy protocol comprises an infusion delivery of pre-beta HDL particles or a concentrated volume of isolated pre-beta particles over a period ranging from 1 hour to 8 hours, and any increment therein, depending upon the concentration of the therapeutic product to be delivered.
  • the dose ranges from 1 mg/kg to 250 mg/kg, and any increment therein, and is administered at an infusion delivery rate of 999 mL/hour +/- lOOml/hour or a rate deemed more appropriate for the patient.
  • the treatment is repeated at specified frequency or cycle of treatment depending upon a course of therapy.
  • the frequency or cycle of administering the treatment may range from once a week, twice a week, three times per week, daily, once a month, twice a month, three times per month, to at least once in three, six, nine or twelve months.
  • the course of therapy may range from at least one day, at least one week, at least one month to at least one year.
  • the therapy protocol comprises at least one, and up to three, seven or ten treatments every three, six, nine or twelve months for an annual course of therapy.
  • the at least one treatment may comprise a continuous infusion (IV) of pre-beta HDL particles over a predetermined time period at a rate of 999 mL/hour.
  • pre-beta HDL particles as described in step 458, is performed on an intermittent basis during chronic administration of a CETP inhibitor, as described in step 456.
  • the therapy protocol may be titrated or modulated up or down based on a therapeutic endpoint.
  • one or more intra-treatment severity level assessments are made using diagnostic and/or physical procedures/tests.
  • the one or more intra-treatment severity level assessments are made at predetermined points in time during the course of therapy. If the intra- treatment severity level assessments show a delay in the onset of additional symptoms, a halting in the worsening of symptoms, or an improvement in the patient’s condition, it is considered to be of therapeutic benefit.
  • the therapeutic amount may be titrated down wherein parameters such as, but not limited to, the dose range, frequency or cycle of treatment and/or course of therapy may be reduced. Alternately, the therapy protocol may be titrated up depending on various factors. Still alternately, if the intra-treatment severity level assessments show or do not show improvement in the patient’s condition, the therapy protocol is not modulated.
  • FIG. 5 is a longitudinal transverse cross-sectional view 505 of a cerebral blood vessel 510 illustrating removal of beta amyloid by transport along the cerebral lymphatic IPAD Sy stem/Peri vascular Pathway, in accordance with an embodiment of the present specification.
  • blood circulates through the lumen 515 of the vessel 510 while Interstitial Fluid (ISF) and solutes, including beta amyloid (A0) 520, are eliminated from the brain through the perivascular drainage pathway 525, which is, effective, the lymphatic drainage of the brain.
  • the E3 allele 530 binds to beta amyloid particles 520, forming modified E3 particles, and thereby transporting beta amyloid particles 520 from the brain along the perivascular drainage pathway 525.
  • Apolipoprotein A-I (ApoA-I) particles 535 and HDL particles 540 as part of the blood circulation 555 through the lumen 515 along with other particles such as, for example, red blood cells 550.
  • FIG. 6 is a longitudinal transverse cross-sectional view 605 of a cerebral blood vessel 610 illustrating amyloid accumulation in cerebral lymphatic perivascular pathways of individuals with an increased presence of the E4 allele, in accordance with an embodiment of the present specification.
  • blood circulates through the lumen 615 of the vessel 610 while beta amyloid (A0) particles 620 are accumulated in the cerebral IPAD System/Perivascular Pathway 625 due to an increased presence of E4 particles 630.
  • beta amyloid 620 is deposited in the walls of the blood vessel 610 as CAA.
  • CAA reflects a failure of elimination of amyloid-beta (A0) from the brain along perivascular lymphatic drainage pathways 625.
  • FIG. 7A is a longitudinal transverse cross-sectional view 705 of a cerebral blood vessel 710 of a patient being treated for cerebral amyloid angiopathy (CAA), in accordance with an embodiment of the present specification.
  • CAA cerebral amyloid angiopathy
  • beta amyloid (A0) particles 720 accumulate in the cerebral IPAD Sy stem/Peri vascular Pathway 725 along with a high presence of E4 particles 730, thereby essentially blocking pathway 725.
  • treated plasma or isolated pre-0 HDL particles 745 are infused into the patient’s blood stream 755 to bind to beta amyloid particles 720 and clear the cerebral IPAD System/Perivascular Pathway 725.
  • Pre- P HDL 745 represents ApoA-I molecules complexed with phospholipids.
  • a blood fraction is obtained.
  • the process of blood fractionation is typically done by filtration, centrifuging the blood, aspiration, or any other method known to persons skilled in the art.
  • Blood fractionation separates the plasma from the blood.
  • blood is withdrawn from a patient in a volume sufficient to produce about 12ml/kg of plasma based on body weight.
  • the blood is separated into plasma and red blood cells using methods commonly known to one of skill in the art, such as plasmapheresis.
  • the red blood cells are stored in an appropriate storage solution or returned to the patient during plasmapheresis.
  • the red blood cells are preferably returned to the patient during plasmapheresis.
  • Physiological saline is also optionally administered to the patient to replenish volume.
  • LDL Low Density Lipoprotein
  • the resultant blood fraction includes plasma with HDL, and may or may not include other protein particles.
  • the process of blood fractionation is performed by withdrawing blood from the patient, and who is being treated by the physician.
  • the process of blood fractionation is performed by withdrawing blood from a person other than the patient. Therefore, the plasma obtained as a result of the blood fractionation process may be either autologous or non-autologous.
  • the autologous or non-autologous plasma obtained is subjected to a delipidation process as described in greater detail above with respect to FIG. 1 but repeated briefly herein.
  • the resultant blood fraction is mixed with one or more solvents, such as lipid removing agents.
  • the solvents used include either or both of organic solvents sevoflurane and n-butanol.
  • the plasma and solvent are introduced into at least one apparatus for mixing, agitating, or otherwise contacting the plasma with the solvent.
  • the solvent system is optimally designed such that only the HDL particles are treated to reduce their lipid levels and LDL levels are not affected.
  • the solvent system includes factoring in variables such as solvent employed, mixing method, time, and temperature.
  • Solvent type, ratios and concentrations may vary in this step.
  • the plasma and solvent are introduced into at least one apparatus for mixing, agitating, or otherwise contacting the plasma with the solvent.
  • the plasma may be transported using a continuous or batch process.
  • the solvents dissolve lipids from the plasma.
  • the solvents dissolve lipids to yield treated plasma that contains pre-beta HDL particles with reduced lipid content.
  • the process is designed such that HDL particles are treated to reduce their lipid levels and yield pre-beta HDL particles without destruction of plasma proteins or substantially affecting LDL particles.
  • the resultant treated plasma containing pre-beta HDL particles with reduced lipid content, which was separated from the solvents, is treated appropriately and may be subsequently returned to the patient in an embodiment.
  • the resultant fluid containing pre-beta HDL particles is further processed, in a second stage, to separate or to isolate pre-0 HDL particles.
  • the second stage occurs in a separate and discrete area from the delipidation process.
  • the second stage processing occurs in-line with the delipidation system, whereby the system may be connected to an affinity column sub-system or ultracentrifugation sub-system.
  • the resultant separated pre-0 HDL particles may then be introduced to the bloodstream of the patient as described below.
  • a presence of non-modified HDL particles 740 is illustrated in the blood stream 755 along with other particles such as, for example, red blood cells 750.
  • the prebeta HDL particles may be HDL particles with an increased concentration of pre-P HDL particles 745. Concentration of pre-P HDL 745 is greater in the pre-beta HDL, relative to the original HDL that was present in the plasma before treating it with the solvent.
  • the resulting treated plasma containing the HDL particles with reduced lipid and increased pre-P concentration is optionally combined with the patient's red blood cells, if the red cells were not already returned during plasmapheresis, and administered to the patient.
  • One route of administration is through the vascular system, preferably intravenously, such as via infusion therapy.
  • FIG. 7B illustrates a mechanism of removal of beta amyloid molecules 720 by infused pre- P HDL particles 745 within the blood vessel 710 of a patient, in accordance with an embodiment of the present specification.
  • pre-P HDL particles 745 With increased concentration of pre-P HDL particles 745 in the patient’s blood stream 755, a relatively higher number of pre-P HDL particles 745 are available to bind to and pull out beta-amyloid particles 720 from the IPAD System/Perivascular Pathway 725.
  • the pre-P HDL particles 745 in the blood stream 755 enter the IPAD System/Perivascular Pathway 725 and bind with beta-amyloid particles 720 to form modified pre-P HDL particles 745’ that re-enter the blood stream 755.
  • FIG. 7C shows a plurality of modified pre-P HDL particles 745’ flowing in the blood stream 755 (in the lumen 715 of the blood vessel 710) and serving to transport the bound beta amyloid 720 to the liver for degradation and subsequent excretion.
  • the infused isolated pre-P HDL particles 745 initiate reverse cholesterol, specifically beta amyloid 720, transport process from the cerebral perivascular pathways 725 to liver.
  • non-modified HDL particles 740 in the blood stream 755 along with other particles such as, for example, red blood cells 750.
  • AD Alzheimer’s Disease
  • CAA CAA
  • Alzheimer’s disease is determined using results from several tests to arrive at a differential diagnosis. Thus, there is no definitive diagnosis for Alzheimer’s disease.
  • treatments and protocols of the present specification are applicable to patients exhibiting presymptomatology of AD, in addition to symptoms related to altered global function, cognitive function, activities of daily living (ADL)/functional impairment, and behavior.
  • patients suffering from AD can be characterized as having early stage (pre-symptomatic)/Stages 1-4, mild, moderate, or severe AD based upon the totality of symptoms.
  • Stage 1 is representative of a class of patients with characteristic pathophysiologic changes of early onset AD but no evidence of clinical impact. These patients are truly asymptomatic with no subjective complaint, functional impairment, or detectable abnormalities on sensitive neuropsychological measures. The characteristic pathophysiologic changes are typically demonstrated by assessment of various biomarker measures.
  • Stage 2 includes the group of patients with characteristic pathophysiologic changes of early onset AD and subtle detectable abnormalities on sensitive neuropsychological measures, but no functional impairment. The emergence of subtle functional impairment signals a transition to Stage 3.
  • Stage 3 is representative of a class of patients with characteristic pathophysiologic changes of early onset AD, subtle or more apparent detectable abnormalities on sensitive neuropsychological measures, and mild but detectable functional impairment.
  • the functional impairment in this stage is not severe enough to warrant a diagnosis of overt dementia.
  • Stage 4 includes a group of patients with overt dementia. This diagnosis is made as functional impairment worsens from that seen in Stage 3. This stage may be refined into additional categories which correspond to mild, moderate, and severe Alzheimer’s disease states as described below.
  • Stages 5, 6, and 7 correspond to increasing degrees of overt dementia and/or cerebral functional impairment. As such, stages 5, 6, and 7 correspond to mild, moderate, and severe AD.
  • a baseline, starting or initial severity level is diagnosed/assessed using at least one physiological diagnostic or advanced medical imaging technique.
  • a baseline, starting or initial severity level is additionally assessed by at least one cognitive measurement or test.
  • a pattern of putatively beneficial effects demonstrated across multiple individual tests may be used to assess impact in early AD or a large magnitude of effect on a single sensitive measure of neuropsychological performance may be used.
  • measuring the level of amyloid peptide may be used to assess a possible treatment benefit.
  • Differential diagnosis and the assessment of the severity level of Alzheimer’s disease may be based on one or more global, cognitive, functional and behavioral measurements, assessments, or tests.
  • global assessment tests may include assessments such as, but not limited to Clinician’s Interview-Based Impression of Change plus caregiver assessment (the CIBIC-plus), and Clinical Dementia Rating-sum of boxes (CDR-SB).
  • assessments such as, but not limited to Clinician’s Interview-Based Impression of Change plus caregiver assessment (the CIBIC-plus), and Clinical Dementia Rating-sum of boxes (CDR-SB).
  • the CIBIC- plus is scored as a seven-point categorical rating, ranging from a score of 1, indicating “markedly improved,” to a score of 4, indicating “no change” to a score of 7, indicating “markedly worse.”
  • the CIBIC-plus has not been systematically compared directly to assessments not using information from caregivers (CIBIC) or other global methods.
  • CDR-SB Clinical Dementia Rating-sum of boxes
  • cognitive tests may include assessments such as, but not limited to, the cognitive subscale of the Alzheimer’s disease Assessment Scale (ADAS-cog) and Mini Mental State Examination (MMSE).
  • assessments such as, but not limited to, the cognitive subscale of the Alzheimer’s disease Assessment Scale (ADAS-cog) and Mini Mental State Examination (MMSE).
  • ADAS-cog Alzheimer’s disease Assessment Scale
  • MMSE Mini Mental State Examination
  • the cognitive subscale of the Alzheimer’s disease Assessment Scale is a multi-factor instrument that has been extensively validated in longitudinal cohorts of Alzheimer’s disease patients.
  • the ADAS-cog examines selected aspects of cognitive performance including elements of memory, orientation, attention, reasoning, language, and praxis.
  • the ADAS-cog scoring range is from 0 to 70, with higher scores indicating greater cognitive impairment.
  • Elderly adults with normal cognitive functionality may score as low as 0 or 1, but it is not unusual for adults not presenting with typical dementia to score slightly higher.
  • the Mini Mental State Examination includes 11 questions regarding orientation, memory, concentration, language, and praxis.
  • the scoring scale ranges from 0 to 30, with a higher score indicating lower impairment.
  • healthy individuals score approximately 29-30 points on the MMSE.
  • a patient with Alzheimer’s disease may typically score in the range of 20- 22 points on the MMSE.
  • functional tests or tests that assess impairment in activities of daily living may include assessments such as, but not limited to, Severe Impairment Battery (SIB), Modified Alzheimer’s disease Cooperative Study-activities of daily living inventory (ADCS-ADL) and Modified Alzheimer’s disease Cooperative Study-activities of daily living inventory for severe Alzheimer’s disease (ADCS-ADL-severe), Progressive Deterioration Scale (PDS), Instrumental Activities of Daily Living (IADL), and the Katz Activities of Daily Living (ADL) index.
  • SIB Severe Impairment Battery
  • ADCS-ADL Modified Alzheimer’s disease Cooperative Study-activities of daily living inventory
  • ADCS-ADL-severe Modified Alzheimer’s disease Cooperative Study-activities of daily living inventory for severe Alzheimer’s disease
  • PDS Progressive Deterioration Scale
  • IADL Instrumental Activities of Daily Living
  • ADL Katz Activities of Daily Living
  • the Severe Impairment Battery (SIB) assessment is a multi-item instrument and has been validated for the evaluation of cognitive function in patients presenting with moderate to severe dementia.
  • the SIB evaluates selective aspects of cognitive performance, including elements of memory, language, orientation, attention, praxis, visuospatial ability, construction, and social interaction.
  • the SIB scoring range is from 0 to 100, with lower scores indicating greater cognitive impairment.
  • the Modified Alzheimer’s Disease Cooperative Study-Activities of Daily Living inventory (ADCS-ADL) consists of a comprehensive battery of ADL questions used to measure the functional capabilities of patients. Each ADL item is rated from the highest level of independent performance to complete loss. The investigator performs the inventory by interviewing a caregiver familiar with the behavior of the patient. A subset of 19 items, including ratings of the patient’s ability to eat, dress, bathe, telephone, travel, shop, and perform other household chores has been validated for the assessment of patients with moderate to severe dementia.
  • the modified ADCS- ADL has a scoring range of 0 to 54, with the lower scores indicative of greater functional impairment.
  • the Modified Alzheimer’s Disease Cooperative Study - Activities of Daily Living Inventory for Severe Alzheimer’s Disease is derived from the Alzheimer’s disease Cooperative Study-Activities of Daily Living Inventory described above, which is a comprehensive battery of ADL questions used to measure the functional capabilities of patients. Each ADL item is rated from the highest level of independent performance to complete loss.
  • the ADCS-ADL-severe is a subset of 19 items, including ratings of the patient’s ability to eat, dress, bathe, use the telephone, get around (or travel), and perform other activities of daily living; it has been validated for the assessment of patients with moderate to severe dementia.
  • the ADCS-ADL- severe has a scoring range of 0 to 54, with the lower scores indicative of greater functional impairment.
  • the investigator performs the inventory by interviewing a caregiver, such as a nurse staff member, who is familiar with the overall functional capability of the patient.
  • the Progressive Deterioration Scale examines activities of daily living (ADL) and instrumental ADL in 11 areas, including the extent to which the patient can leave the immediate neighborhood, the use of familiar household implements, involvement in family finances and budgeting, self-care, and routine tasks.
  • the scoring scale ranges from 0 to 100, wherein a higher score indicating better overall functional capability.
  • IADL Instrumental Activities of Daily Living
  • the Katz Activities of Daily Living (ADL) index is used to assess a patient’s ability to perform ADL independently in six functions of bathing, dressing, toileting, transferring, continence, and feeding. Each function is assigned a score of yes or no for independence in that function, whereby each “yes” answer generates one point. A total score of 6 indicates full functional capability while a score of 2 or less is indicative of severe functional impairment.
  • behavioral and mood tests may include assessments such as, but not limited to, Neuropsychiatric Inventory (NPI) and are employed to determine an extent of depression, anxiety, irritability, and overall mood shifts.
  • NPI Neuropsychiatric Inventory
  • the Neuropsychiatric Inventory evaluates 10 items including delusions, hallucinations, dysphoria, anxiety, agitation, euphoria, apathy, irritability, disinhibition, aberrant motor behavior (pacing and rummaging). Two more items may also be assessed, specifically, night- time behavior and changes in appetite and eating behaviors. The frequency of behavioral disturbances are rated on a four-point scale with the severity rated on three-point scale. A higher total score is indicative of more behavioral problems.
  • diagnostic imaging tests are used to determine the accumulation or regional lesions of plaque in the perivascular space/IPAD System/Perivascular Pathway.
  • the advanced medical imaging techniques are used to both determine the extent of plaque in the perivascular space/IPAD System/Perivascular Pathway and to assess a severity level of Alzheimer’s disease.
  • advanced medical imaging techniques such as, but not limited to, Positron Emission Tomography (PET), Magnetic Resonance Imaging (MRI) and Spinal Fluid Test (Beta Amyloid Fragments), may be used.
  • a specific Amyloid Positron Emission Tomography (PET) Scan also referred to as Amyloid PET imaging, represents a potential major advance in an early diagnosis of Alzheimer’s disease and/or an assessment of the degree of cerebral cognitive impairment.
  • the scan visualizes plaque regions or lesions present in the brain, which are prime suspects in damaging and killing nerve cells in Alzheimer's patients.
  • the scan technique employs radioactive tracers to highlight amyloid protein plaque regions or lesions within the brain, which are a hallmark of Alzheimer's disease.
  • Amyloid PET scanning enables the “illumination” of amyloid plaques on a brain PET scan, enabling accurate detection of plaques in living people.
  • the scan may allow for an earlier diagnosis or assessment of Alzheimer's disease, prior to the presentation of symptomatology.
  • MRI Magnetic Resonance Imaging
  • HDL levels are inversely correlated with the development of AD in epidemiology studies.
  • AD Alzheimerly patients with higher levels of HDL tend to have a higher hippocampal volume; conversely, a lower hippocampal volume has been used as an index of AD disease progression.
  • Neuroimaging is widely believed to be generally useful for excluding reversible causes of dementia syndrome, such as normal-pressure hydrocephalus, brain tumors, and subdural hematoma, and for excluding other likely causes of dementia, such as cerebrovascular disease, thereby enabling a differential diagnosis of AD.
  • Apolipoprotein E is a class of proteins involved in the metabolism of fats in the body and is the principal cholesterol carrier in the brain.
  • ApoE is polymorphic, with three major alleles, namely ApoE-c2, ApoE-c3, and ApoE-c4.
  • ApoE-c2 has an allele frequency of approximately 7% to 8% in the general population. This variant of the apolipoprotein binds poorly to cell surface receptors while ApoE-c3 and ApoE-c4 bind relatively well. ApoE-c2 is associated with both increased and decreased risk for atherosclerosis.
  • ApoE-c3 has an allele frequency of approximately 80% in the general population. It is considered the "neutral" ApoE genotype of the three. ApoE-c4 has an allele frequency of approximately 14% in the general population.
  • the E4 variant is the largest known genetic risk factor for late-onset sporadic Alzheimer's disease (AD).
  • AD patients have at least one copy of the E4 allele
  • ApoE-c4 is not a definitive determinant of the disease; at least one-third of patients with AD are ApoE-c4 negative and some people with ApoE-c4 homozygotes never develop the disease.
  • studies show that those with two E4 alleles have up to 20 times the risk of developing AD and thus, it can be implicated as at least a contributing factor.
  • the ApoE-c2 allele may serve a protective role in AD.
  • the genotype most at risk for Alzheimer's disease and at an earlier age is ApoE-c4, ApoE-c4.
  • genotype ApoE-c3, ApoE-c3 as a benchmark (allocating a risk factor of 1.0 to the persons who have this genotype), individuals with genotype ApoE-c4, ApoE- E4 have a relative risk factor of 14.9 of developing Alzheimer's disease.
  • Individuals with the ApoE- E3, ApoE-c4 genotype exhibit a relative risk factor of 3.2, while people with the E2 allele and the E4 allele (ApoE-c2, ApoE-c4) have a relative risk factor of 2.6.
  • a treated plasma that contains pre-beta HDL particles with reduced lipid content is delivered to the patient via infusion therapy.
  • the process is designed such that HDL particles are treated to reduce their lipid levels and yield pre-beta HDL particles without destruction of plasma proteins or substantially affecting LDL particles.
  • the HDL lipoprotein particles are comprised of ApoA-I, phospholipids and cholesterol.
  • ApoA-I Apolipoprotein A-I particles comprise of two sub-fractions, pre-0 HDL and a-HDL, which have pre-beta and alpha electrophoretic mobility, respectively.
  • pre-0 HDL represents ApoA-I molecules complexed with phospholipids.
  • pre-0 HDL dramatically increases the selective removal of cholesterol from lipid-loaded macrophages, wherein the cholesterol is associated with an increased risk of Alzheimer’s disease (AD).
  • Pre-0 HDL has also been shown to regress atherosclerosis and atheroma volumes, in addition to markers of inflammation.
  • pre- P HDL has a higher functional capacity than native HDL to transport proteins.
  • Apo A- 1 (contained within pre-P HDL particles) levels are significantly lower in AD patients and are highly correlated to the severity of the AD as measured by Mini Mental State (MMSE) scores of AD patients.
  • MMSE Mini Mental State
  • HDL has been found to be a transport vehicle for A0.
  • Native HDL has been shown to facilitate removal of soluble A0 and attenuate CAA in a novel bioengineered human vessel model of AD. Therefore, embodiments of the present specification utilize the pre-beta HDL particles that have an increased concentration of pre-0 HDL relative to the original HDL to remove A0 for treatment of the progression of AD.
  • a treated plasma that contains pre-beta HDL particles with reduced lipid content is delivered to the patient via infusion therapy.
  • the pre-beta high density lipoproteins have a concentration of alpha high density lipoproteins in addition to the pre-beta high density lipoproteins from the blood fraction prior to mixing.
  • isolated pre-0 HDL particles are infused into the patient’s blood stream to bind to (A0), Tau oligomers, and other soluble oligomer particles and clear the cerebral IPAD System/Perivascular Pathway.
  • a longitudinal transverse cross-sectional view 505 of a cerebral blood vessel 510 illustrating removal of beta amyloid by transport along the cerebral lymphatic IPAD System/Perivascular Pathway is shown, in accordance with an embodiment of the present specification.
  • blood circulates through the lumen 515 of the vessel 510 while Interstitial Fluid (ISF) and solutes, including beta amyloid (A0) 520, are eliminated from the brain through the perivascular drainage pathway 525, which is, effective, the lymphatic drainage of the brain.
  • ISF Interstitial Fluid
  • A0 beta amyloid
  • the E3 allele 530 binds to beta amyloid particles 520, forming modified E3 particles, and thereby transporting beta amyloid particles 520 from the brain along the perivascular drainage pathway 525.
  • Apolipoprotein A-I particles 535 and HDL particles 540 as part of the blood circulation 555 through the lumen 515 along with other particles such as, for example, red blood cells 550.
  • AD is, in some cases, characterized by build-ups of aggregates of the peptide beta-amyloid in the cerebral lymphatic perivascular pathways. As illustrated in Table A, in AD patients the distribution of E2, E3 and E4 alleles is approximately 4%, 60% and 37%, respectively. The isoform ApoE-c4 is not as effective as the alleles at promoting clearance of beta amyloid from the cerebral perivascular drainage pathways. Thus, a skewed abundance of E4 allele is associated with increased vulnerability to AD in individuals with that gene variation and in AD patients is also associated with an increase in the severity of AD and loss of cognitive function.
  • a longitudinal transverse cross-sectional view 605 of a cerebral blood vessel 610 illustrating amyloid accumulation in cerebral lymphatic perivascular pathways of individuals with an increased presence of the E4 allele is illustrated, in accordance with an embodiment of the present specification.
  • blood circulates through the lumen 615 of the vessel 610 while beta amyloid (A0) particles 620 are accumulated in the cerebral IPAD Sy stem/Peri vascular Pathway 625 due to an increased presence of E4 particles 630.
  • beta amyloid 620 is deposited in the walls of the blood vessel 610 as cerebral amyloid angiopathy (CAA).
  • CAA cerebral amyloid angiopathy
  • CAA in AD reflects a failure of elimination of amyloid-beta (A0) from the brain along perivascular lymphatic drainage pathways 625. Failure of elimination of beta amyloid along perivascular pathways may coincide with a reduction in enzymatic degradation of beta amyloid, reduced absorption of beta amyloid into the blood and stiffening of blood vessel walls. Also shown are ApoA-I particles 635 and HDL particles 640 as part of the blood circulation 655 through the lumen 615 along with other particles such as, for example, red blood cells 650.
  • a longitudinal transverse cross-sectional view 705 of a cerebral blood vessel 710 of an AD patient being treated for cerebral amyloid angiopathy (CAA) is shown, in accordance with an embodiment of the present specification.
  • blood circulates through the lumen 715 of the vessel 710 while beta amyloid (A0) particles 720 accumulate in the cerebral IPAD System/Perivascular Pathway 725 along with a high presence of E4 particles 730, thereby essentially blocking pathway 725.
  • beta amyloid (A0) particles 720 accumulate in the cerebral IPAD System/Perivascular Pathway 725 along with a high presence of E4 particles 730, thereby essentially blocking pathway 725.
  • treated plasma or isolated pre-0 HDL particles 745 are infused into the patient’s blood stream 755 to bind to beta amyloid particles 720 and clear the cerebral IPAD System/Perivascular Pathway 725.
  • Pre- P HDL 745 represents ApoA-I molecules complexed with phospholipids.
  • a blood fraction is obtained.
  • the process of blood fractionation is typically done by filtration, centrifuging the blood, aspiration, or any other method known to persons skilled in the art.
  • Blood fractionation separates the plasma from the blood.
  • blood is withdrawn from a patient in a volume sufficient to produce about 12ml/kg of plasma based on body weight.
  • the blood is separated into plasma and red blood cells using methods commonly known to one of skill in the art, such as plasmapheresis.
  • the red blood cells are stored in an appropriate storage solution or returned to the patient during plasmapheresis.
  • the red blood cells are preferably returned to the patient during plasmapheresis.
  • Physiological saline is also optionally administered to the patient to replenish volume.
  • LDL Low Density Lipoprotein
  • the resultant blood fraction includes plasma with HDL, and may or may not include other protein particles.
  • the process of blood fractionation is performed by withdrawing blood from the patient presenting with AD, and who is being treated by the physician.
  • the process of blood fractionation is performed by withdrawing blood from a person other than the patient. Therefore, the plasma obtained as a result of the blood fractionation process may be either autologous or non-autologous.
  • the autologous or non-autologous plasma obtained is subjected to a delipidation process as described in greater detail above with respect to FIG. 1 but repeated briefly herein.
  • the resultant blood fraction is mixed with one or more solvents, such as lipid removing agents.
  • the solvents used include either or both of organic solvents sevoflurane and n-butanol.
  • the plasma and solvent are introduced into at least one apparatus for mixing, agitating, or otherwise contacting the plasma with the solvent.
  • the solvent system is optimally designed such that only the HDL particles are treated to reduce their lipid levels and LDL levels are not affected.
  • the solvent system includes factoring in variables such as solvent employed, mixing method, time, and temperature.
  • Solvent type, ratios and concentrations may vary in this step.
  • the plasma and solvent are introduced into at least one apparatus for mixing, agitating, or otherwise contacting the plasma with the solvent.
  • the plasma may be transported using a continuous or batch process.
  • the solvents dissolve lipids from the plasma.
  • the solvents dissolve lipids to yield treated plasma that contains pre-beta HDL particles with reduced lipid content.
  • the process is designed such that HDL particles are treated to reduce their lipid levels and yield pre-beta HDL particles without destruction of plasma proteins or substantially affecting LDL particles.
  • the resultant treated plasma containing pre-beta HDL particles with reduced lipid content, which was separated from the solvents, is treated appropriately and may subsequently be returned to the patient in an embodiment.
  • the resultant fluid containing pre-beta HDL particles is further processed, in a second stage, to separate or to isolate pre-0 HDL particles.
  • the second stage occurs in a separate and discrete area from the delipidation process.
  • the second stage processing occurs in-line with the delipidation system, whereby the system may be connected to an affinity column sub-system or ultracentrifugation sub-system. The resultant separated pre-0 HDL particles may then be introduced to the bloodstream of the patient as described below.
  • FIG. 7A illustrates the presence of non-modified HDL particles 740 in the blood stream 755 along with other particles such as, for example, red blood cells 750.
  • the pre-beta HDL particles are HDL particles with an increased concentration of pre-0 HDL particles 745. Concentration of pre-0 HDL 745 is greater in the pre-beta HDL, relative to the original HDL that was present in the plasma before treating it with the solvent.
  • the resulting treated plasma containing the HDL particles with reduced lipid and increased pre-0 concentration is optionally combined with the patient's red blood cells, if the red cells were not already returned during plasmapheresis, and administered to the patient.
  • One route of administration is through the vascular system, preferably intravenously, such as via infusion therapy.
  • pre-0 HDL particles 745 the mechanism of removal of beta amyloid molecules 720 by infused pre-0 HDL particles 745 within the blood vessel 710 of an AD patient is illustrated, in accordance with an embodiment of the present specification.
  • a relatively higher number of pre-0 HDL particles 745 are available to bind to and pull out beta-amyloid particles 720 from the IPAD Sy stem/Peri vascular Pathway 725.
  • the pre-0 HDL particles 745 in the blood stream 755 enter the IPAD System/Perivascular Pathway 725 and bind with beta-amyloid particles 720 to form modified pre-0 HDL particles 745’ that re-enter the blood stream 755.
  • modified pre-0 HDL particles 745 flowing in the blood stream 755 (in the lumen 715 of the blood vessel 710) and serving to transport the bound beta amyloid 720 to the liver for degradation and subsequent excretion is shown.
  • the pre-0 HDL particles 745 also pull the E4 particles 730 along with the beta amyloid molecules 720 from the IPAD System/Perivascular Pathway 725.
  • the modified pre-0 HDL particles 745’ are pre-0 HDL 745 binding both beta amyloid 720 and E4 730.
  • the infused isolated pre-0 HDL particles 745 initiate reverse cholesterol, specifically beta amyloid 720, transport process from the cerebral perivascular pathways 725 to liver. Also seen in FIG. 7C are non-modified HDL particles 740 in the blood stream 755 along with other particles such as, for example, red blood cells 750.
  • treated plasma containing pre-beta HDL particles with reduced lipid and/or increased pre-0 concentration is administered to a patient in accordance with a plurality of therapeutic protocols.
  • therapy is based on a level of severity of AD, as described above.
  • the plurality of therapy protocols comprises at least one or any combination of a plurality of therapeutic parameters such as, but not limited to:
  • Dosing range 1 mg/kg to 250 mg/kg, and any increment therein, where a specific fixed dose may be calculated based on one or both of a patient’s weight and the severity of the disease state.
  • Dosing volume the average dosing volume is dependent upon the dose (in mg/kg) and the concentration of the product to be infused into the patient (treated plasma containing pre-beta HDL particles or isolated pre-beta particles).
  • the volume that is returned to the patient is substantially equal to the volume that was removed from the patient prior to the delipidation process.
  • the volume that is returned to the patient is a concentrated volume.
  • the volume delivered to a patient via infusion therapy is dependent upon the preparation of the product, whether it is treated plasma or concentrated, isolated pre-beta and the overall solubility of that product in a buffer or saline.
  • Dosing rate the dose is provided via infusion therapy. It should be noted herein that the rate of infusion is the normal infusion rate for intravenous therapy, or 999 mL/hour and is thus dependent on overall volume and concentration. In an embodiment, the time of infusion ranges from one hour to eight hours.
  • Frequency or cycle of treatment daily, weekly, monthly and annually [0333] Duration or course of therapy: at least one day to at least one year
  • FIG. 8A is a flowchart describing a plurality of exemplary steps of a therapy protocol for treating an AD patient, in accordance with an embodiment of the present specification.
  • a patient first presents with a pathophysiological change that is consistent with early onset AD. Any of the aforementioned diagnostic techniques may be used in this step.
  • various biomarkers may be used to determine the pathophysiological change. For example, measuring the level of amyloid peptide (including 40 and 42) may be used to assess the extent of a pathophysiological change characteristic of AD.
  • the ratio of beta amyloid peptide 42 to beta amyloid peptide 40 is measured to determine and assess the extent of a pathophysiological change characteristic of AD and to assess the efficacy of treatment. Particularly, the ratio of beta amyloid peptide 42 to beta amyloid peptide 40 in plasma and in cerebrospinal fluid is reduced in patients with AD.
  • An AD patient may present with a ratio of beta amyloid peptide 42 to beta amyloid peptide 40 of approximately 0.057, while an individual without AD may have a ratio of 0.073.
  • the patient may present with cerebral amyloid angiopathy (CAA) as detected using imaging and/or biomarker techniques.
  • CAA cerebral amyloid angiopathy
  • CAA patients could present with microbleeds and/or dilated perivascular space/IPAD System/Perivascular Pathways upon imaging and/or biomarker studies relative to individuals without CAA.
  • a change in the incidence in microbleeds and/or size of the perivascular space/IPAD System/Perivascular Pathway may be used to assess efficacy of treatment.
  • a patient who is diagnosed with AD is monitored to determine an extent of accumulation of plaque in the perivascular space/IPAD System/Perivascular Pathway, via at least one diagnostic procedure.
  • advanced medical imaging techniques such as, but not limited to, Positron Emission Tomography (PET), Magnetic Resonance Imaging (MRI) and Spinal Fluid Test (Beta Amyloid Fragments), may be used.
  • the diagnosis and severity level of AD in the patient are additionally assessed based on one or more global, cognitive, functional, and behavioral measurements or tests, as described above.
  • global assessment tests may include assessments such as, but not limited to Clinician’s Interview-Based Impression of Change plus caregiver assessment (the CIBIC-plus), and Clinical Dementia Rating-sum of boxes (CDR-SB).
  • assessments such as, but not limited to Clinician’s Interview-Based Impression of Change plus caregiver assessment (the CIBIC-plus), and Clinical Dementia Rating-sum of boxes (CDR-SB).
  • cognitive tests may include assessments such as, but not limited to, cognitive subscale of the Alzheimer’s disease Assessment Scale (ADAS-cog), and Mini Mental State Examination (MMSE).
  • assessments such as, but not limited to, cognitive subscale of the Alzheimer’s disease Assessment Scale (ADAS-cog), and Mini Mental State Examination (MMSE).
  • ADAS-cog Alzheimer’s disease Assessment Scale
  • MMSE Mini Mental State Examination
  • functional tests may include assessments such as, but not limited to, severe impairment battery (SIB), modified Alzheimer’s disease cooperative study -activities of daily living inventory (ADCS-ADL) and modified Alzheimer’s disease cooperative study activities of daily living inventory for severe Alzheimer’s disease (ADCS-ADL-severe), Progressive Deterioration Scale (PDS), Instrumental Activities of Daily Living (IADL), and Katz activities of daily living (ADL) index.
  • SIB severe impairment battery
  • ADCS-ADL modified Alzheimer’s disease cooperative study -activities of daily living inventory
  • ADCS-ADL-severe modified Alzheimer’s disease cooperative study activities of daily living inventory for severe Alzheimer’s disease
  • PDS Progressive Deterioration Scale
  • IADL Instrumental Activities of Daily Living
  • Katz activities of daily living (ADL) index such as, but not limited to, severe impairment battery (SIB), modified Alzheimer’s disease cooperative study -activities of daily living inventory (ADCS-ADL) and modified Alzheimer’s disease cooperative study activities of daily living inventory for severe Alzheimer’s disease
  • behavioral and mood tests may include assessments such as, but not limited to, Neuropsychiatric Inventory (NPI).
  • NPI Neuropsychiatric Inventory
  • one or more physiological parameters of the patient are recorded.
  • the one or more physiological parameters are those that may be incidental to determining one or more therapy parameters.
  • the patient’s weight is recorded to determine a dosing range for the patient. It should be appreciated that the physiological parameters may be first recorded prior to step 805.
  • the patient is infused with pre-beta HDL particles in accordance with a therapy protocol.
  • a blood fraction is withdrawn from the patient presenting with AD.
  • a blood fraction is obtained withdrawing blood from a person other than the patient. Therefore, the plasma obtained as a result of the blood fractionation process may be either autologous or non-autologous.
  • the blood fraction is subsequently treated, using the delipidation process described above to obtain treated plasma containing pre-beta HDL particles.
  • the treated plasma is optionally processed further to generate a product with an increased concentration of isolated pre-0 HDL.
  • the therapy protocol comprises an infusion delivery of pre-beta HDL particles or a concentrated volume of isolated pre-beta particles over a period ranging from 1 hour to 8 hours, and any increment therein, depending upon the concentration of the therapeutic product to be delivered.
  • the dose ranges from 1 mg/kg to 250 mg/kg, and any increment therein, and is administered at an infusion delivery rate of 999 mL/hour +/- lOOml/hour or a rate deemed more appropriate for the patient.
  • the treatment is repeated at specified frequency or cycle of treatment depending upon a course of therapy.
  • the frequency or cycle of administering the treatment may range from once a week, twice a week, three times per week, daily, once a month, twice a month, three times per month, to at least once in three, six, nine or twelve months.
  • the course of therapy may range from at least one day, at least one week, at least one month to at least one year.
  • the therapy protocol comprises at least one, and up to three, seven or ten treatments every three, six, nine or twelve months for an annual course of therapy.
  • the at least one treatment may comprise a continuous infusion (IV) of pre-beta HDL particles over a predetermined time period at a rate of 999 mL/hour.
  • the therapy protocol may be titrated or modulated up or down based on a therapeutic endpoint.
  • one or more intra-treatment severity level assessments are made using diagnostic and/or cognitive procedures/tests.
  • the one or more intra-treatment severity level assessments are made at predetermined points in time during the course of therapy. If the intra-treatment severity level assessments show a delay in the onset of additional symptoms, a halting in the worsening of symptoms, or an improvement in the patient’s condition, it is considered to be of therapeutic benefit.
  • the therapeutic amount may be titrated down wherein parameters such as, but not limited to, the dose range, frequency or cycle of treatment and/or course of therapy may be reduced.
  • the therapy protocol may be titrated up depending on various factors. Still alternately, if the intra- treatment severity level assessments show or do not show improvement in the patient’s condition, the therapy protocol is not modulated.
  • the therapy protocol is not modulated.
  • the overall volume delivered to the patient via infusion therapy depends on the therapeutic product that is solubilized in a buffer or saline. For example, if the therapeutic product is autologous treated plasma, then the patient will receive a volume of therapeutic product equivalent to the volume that was extracted from the patient. If the therapeutic product is non-autologous treated plasma, the patient may receive a volume of IL as one example. If the therapeutic product is non-autologous isolated, concentrated pre-beta particles, the volume may be much lower.
  • a CETP inhibitor is used to increase HDL levels in a patient.
  • a CETP inhibitor is in a class of compounds that inhibit cholesteryl ester transfer protein (CETP), which normally transfers cholesterol from HDL cholesterol to very low density or low density lipoproteins (VLDL or LDL). Inhibition of this process results in higher HDL levels and reduces LDL levels.
  • CETP inhibitor is used to increase the plasma level of HDL.
  • the HDL (wherein the increased levels are created by the delipidation process which generates pre-beta HDL and/or by the use of a CETP inhibitor) will bind to the amyloid that may be present in plasma and/or the perivascular space/IPAD System/Perivascular Pathway.
  • the amyloid When bound to one or both of pre-beta HDL generated by the delipidation process or CETP -inhibited HDL, the amyloid may be transported (now in increased levels) to its side of degradation, thereby decreasing levels of amyloid.
  • the degradation site is the liver.
  • the CETP inhibitor binds to amyloid beta peptides in the peripheral vasculature of the patient, before the amyloid beta peptides have crossed the blood brain barrier and into the brain.
  • a CETP inhibitor is administered to the patient without administering pre-beta HDL particles, resulting in a decrease in flux of amyloid beta peptides into the brain.
  • a CETP inhibitor in administered to the patient in conjunction with the administration of pre-beta HDL particles resulting in a decrease in flux of amyloid beta peptides into the brain (as peripheral amyloid beta peptides are bound by the CETP inhibitor and transported to a degradation site) and an increase in the removal of amyloid beta peptides from the brain (as amyloid beta peptide in the brain is bound by the pre-beta HDL particles, removed from the brain, and transported to a degradation site).
  • FIG. 8B is a flowchart describing a plurality of exemplary steps of a therapy protocol for treating an AD patient, in accordance with an embodiment of the present specification.
  • a patient first presents with a pathophysiological change that is consistent with early onset AD. Any of the aforementioned diagnostic techniques may be used in this step.
  • various biomarkers may be used to determine the pathophysiological change. For example, measuring the level of amyloid peptide (including 40 and 42) may be used to assess the extent of a pathophysiological change characteristic of AD.
  • the ratio of beta amyloid peptide 42 to beta amyloid peptide 40 is measured to determine and assess the extent of a pathophysiological change characteristic of AD and to assess the efficacy of treatment. Particularly, the ratio of beta amyloid peptide 42 to beta amyloid peptide 40 in plasma and in cerebrospinal fluid is reduced in patients with AD.
  • An AD patient may present with a ratio of beta amyloid peptide 42 to beta amyloid peptide 40 of approximately 0.057, while an individual without AD may have a ratio of 0.073.
  • the patient may present with cerebral amyloid angiopathy (CAA) as detected using imaging and/or biomarker techniques.
  • CAA cerebral amyloid angiopathy
  • CAA patients could present with microbleeds and/or dilated perivascular space/IPAD System/Perivascular Pathways upon imaging and/or biomarker studies relative to individuals without CAA.
  • a change in the incidence in microbleeds and/or size of the perivascular space/IPAD System/Perivascular Pathway may be used to assess efficacy of treatment.
  • a patient who is diagnosed with AD is monitored to determine an extent of accumulation of plaque in the perivascular space/IPAD System/Perivascular Pathway, via at least one diagnostic procedure.
  • advanced medical imaging techniques such as, but not limited to, Positron Emission Tomography (PET), Magnetic Resonance Imaging (MRI) and Spinal Fluid Test (Beta Amyloid Fragments), may be used.
  • Spinal Fluid Test (detection of Beta Amyloid Fragments), is a diagnostic test that requires drawing fluid from the spinal region.
  • a protein "signature" in the spinal fluid of patients with CAA which could represent an important advance in its diagnosis.
  • the signature was found in the cerebrospinal fluid (CSF) of 90% of people with a diagnosis of Alzheimer's disease and 72% of people with mild cognitive impairment (MCI) - a disorder that often progresses to Alzheimer’s.
  • CSF cerebrospinal fluid
  • MCI mild cognitive impairment
  • researchers measured concentrations of three proteins previously identified as potential biological indicators, or biomarkers, for Alzheimer's and MCI: amyloid-beta, tau, and phospho-tau.
  • Alzheimer’s disease was identified in three independent study groups wherein the participants exhibited low levels of the amyloid protein amyloid-beta 1-42, along with high levels of total tau and elevated phospho-tau 181 (P-tau 181).
  • the diagnosis and severity level of AD in the patient are additionally assessed based on one or more global, cognitive, functional, and behavioral measurements or tests, as described above.
  • global assessment tests may include assessments such as, but not limited to Clinician’s Interview-Based Impression of Change plus caregiver assessment (the CIBIC-plus), and Clinical Dementia Rating-sum of boxes (CDR-SB).
  • assessments such as, but not limited to Clinician’s Interview-Based Impression of Change plus caregiver assessment (the CIBIC-plus), and Clinical Dementia Rating-sum of boxes (CDR-SB).
  • cognitive tests may include assessments such as, but not limited to, cognitive subscale of the Alzheimer’s disease Assessment Scale (ADAS-cog), and Mini Mental State Examination (MMSE).
  • assessments such as, but not limited to, cognitive subscale of the Alzheimer’s disease Assessment Scale (ADAS-cog), and Mini Mental State Examination (MMSE).
  • ADAS-cog Alzheimer’s disease Assessment Scale
  • MMSE Mini Mental State Examination
  • functional tests may include assessments such as, but not limited to, severe impairment battery (SIB), modified Alzheimer’s disease cooperative study -activities of daily living inventory (ADCS-ADL) and modified Alzheimer’s disease cooperative study activities of daily living inventory for severe Alzheimer’s disease (ADCS-ADL-severe), Progressive Deterioration Scale (PDS), Instrumental Activities of Daily Living (IADL), and Katz activities of daily living (ADL) index.
  • SIB severe impairment battery
  • ADCS-ADL modified Alzheimer’s disease cooperative study -activities of daily living inventory
  • ADCS-ADL-severe modified Alzheimer’s disease cooperative study activities of daily living inventory for severe Alzheimer’s disease
  • PDS Progressive Deterioration Scale
  • IADL Instrumental Activities of Daily Living
  • Katz activities of daily living (ADL) index such as, but not limited to, severe impairment battery (SIB), modified Alzheimer’s disease cooperative study -activities of daily living inventory (ADCS-ADL) and modified Alzheimer’s disease cooperative study activities of daily living inventory for severe Alzheimer’s disease
  • behavioral and mood tests may include assessments such as, but not limited to, Neuropsychiatric Inventory (NPI).
  • NPI Neuropsychiatric Inventory
  • one or more physiological parameters of the patient are recorded.
  • the one or more physiological parameters are those that may be incidental to determining one or more therapy parameters.
  • the patient’s weight is recorded to determine a dosing range for the patient. It should be appreciated that the physiological parameters may be first recorded prior to step 850.
  • the patient is provided with a regimen for using a CETP inhibitor.
  • the dose ranges from 1 mg to 1000 mg, and any increment therein.
  • a patient may be given a CETP inhibitor at any interval that will achieve the desired therapeutic outcome, which includes, but is not limited to twice daily, weekly, biweekly, monthly, every two months, every six months, yearly or any increment therein.
  • a patient is given a CETP inhibitor once daily.
  • a preferred dosage rate is once daily, given orally.
  • a preferred dosage amount of a CETP inhibitor such as evacetrapib, is selected from one of: 30 mg/d, 100 mg/d, or 500 mg/d.
  • the dosage amount may be modified depending upon desired therapeutic outcome.
  • the desired therapeutic outcome may be measured by determining changes in a patient’s mean baseline lipoprotein levels (HDL-C, LDL-C, and triglycerides).
  • the therapy protocol may be titrated or modulated up or down based on a therapeutic endpoint.
  • a CETP inhibitor is used in conjunction with the delipidation process described throughout the specification.
  • the delipidation process of the present specification may be used in a short-term therapeutic approach (boosts), or intermittently, while the use of a CETP inhibitor may be used as a chronic, regular therapeutic approach.
  • boosts short-term therapeutic approach
  • a combination therapy comprises the use of a CETP inhibitor as a chronic, regular therapeutic application with an intermittent application of pre-beta HDL particles.
  • FIG. 8C is a flowchart describing a plurality of exemplary steps of a therapeutic protocol for treating an AD patient using a CETP inhibitor and pre-beta HDL, in accordance with an embodiment of the present specification.
  • a patient first presents with a pathophysiological change that is consistent with early onset AD. Any of the aforementioned diagnostic techniques may be used in this step.
  • various biomarkers may be used to determine the pathophysiological change. For example, measuring the level of amyloid peptide (including 40 and 42) may be used to assess the extent of a pathophysiological change characteristic of AD.
  • the ratio of beta amyloid peptide 42 to beta amyloid peptide 40 is measured to determine and assess the extent of a pathophysiological change characteristic of AD and to assess the efficacy of treatment. Particularly, the ratio of beta amyloid peptide 42 to beta amyloid peptide 40 in plasma and in cerebrospinal fluid is reduced in patients with AD.
  • An AD patient may present with a ratio of beta amyloid peptide 42 to beta amyloid peptide 40 of approximately 0.057, while an individual without AD may have a ratio of 0.073.
  • the patient may present with cerebral amyloid angiopathy (CAA) as detected using imaging and/or biomarker techniques.
  • CAA cerebral amyloid angiopathy
  • CAA patients could present with microbleeds and/or dilated perivascular space/IPAD System/Perivascular Pathways upon imaging and/or biomarker studies relative to individuals without CAA.
  • a change in the incidence in microbleeds and/or size of the perivascular space/IPAD System/Perivascular Pathway may be used to assess efficacy of treatment.
  • a patient who is diagnosed with AD is monitored to determine an extent of accumulation of plaque in the perivascular space/IPAD System/Perivascular Pathway, via at least one diagnostic procedure.
  • advanced medical imaging techniques such as, but not limited to, Positron Emission Tomography (PET), Magnetic Resonance Imaging (MRI) and Spinal Fluid Test (Beta Amyloid Fragments), may be used.
  • the diagnosis and severity level of AD in the patient are additionally assessed based on one or more global, cognitive, functional, and behavioral measurements or tests, as described above.
  • global assessment tests may include assessments such as, but not limited to Clinician’s Interview-Based Impression of Change plus caregiver assessment (the CIBIC-plus), and Clinical Dementia Rating-sum of boxes (CDR-SB).
  • assessments such as, but not limited to Clinician’s Interview-Based Impression of Change plus caregiver assessment (the CIBIC-plus), and Clinical Dementia Rating-sum of boxes (CDR-SB).
  • cognitive tests may include assessments such as, but not limited to, cognitive subscale of the Alzheimer’s disease Assessment Scale (ADAS-cog), and Mini Mental State Examination (MMSE).
  • assessments such as, but not limited to, cognitive subscale of the Alzheimer’s disease Assessment Scale (ADAS-cog), and Mini Mental State Examination (MMSE).
  • ADAS-cog Alzheimer’s disease Assessment Scale
  • MMSE Mini Mental State Examination
  • functional tests may include assessments such as, but not limited to, severe impairment battery (SIB), modified Alzheimer’s disease cooperative study -activities of daily living inventory (ADCS-ADL) and modified Alzheimer’s disease cooperative study activities of daily living inventory for severe Alzheimer’s disease (ADCS-ADL-severe), Progressive Deterioration Scale (PDS), Instrumental Activities of Daily Living (IADL), and Katz activities of daily living (ADL) index.
  • SIB severe impairment battery
  • ADCS-ADL modified Alzheimer’s disease cooperative study -activities of daily living inventory
  • ADCS-ADL-severe modified Alzheimer’s disease cooperative study activities of daily living inventory for severe Alzheimer’s disease
  • PDS Progressive Deterioration Scale
  • IADL Instrumental Activities of Daily Living
  • Katz activities of daily living (ADL) index such as, but not limited to, severe impairment battery (SIB), modified Alzheimer’s disease cooperative study -activities of daily living inventory (ADCS-ADL) and modified Alzheimer’s disease cooperative study activities of daily living inventory for severe Alzheimer’s disease
  • behavioral and mood tests may include assessments such as, but not limited to, Neuropsychiatric Inventory (NPI).
  • NPI Neuropsychiatric Inventory
  • one or more physiological parameters of the patient are recorded.
  • the one or more physiological parameters are those that may be incidental to determining one or more therapy parameters.
  • the patient’s weight is recorded to determine a dosing range for the patient. It should be appreciated that the physiological parameters may be first recorded prior to step 832.
  • the patient is provided with a regimen for using a CETP inhibitor.
  • the dose ranges from 1 mg to 1000 mg, and any increment therein.
  • a patient may be given a CETP inhibitor at any interval that will achieve the desired therapeutic outcome, which includes, but is not limited to twice daily, weekly, biweekly, monthly, every two months, every six months, yearly or any increment therein.
  • a patient is given a CETP inhibitor once daily.
  • a preferred dosage rate is once daily, given orally.
  • a preferred dosage amount of a CETP inhibitor such as evacetrapib, is selected from one of 30 mg/d, 100 mg/d, or 500 mg/d.
  • the dosage amount may be modified depending upon desired therapeutic outcome.
  • the desired therapeutic outcome may be measured by determining changes in a patient’s mean baseline lipoprotein levels (HDL-C, LDL-C, and triglycerides).
  • the patient is infused with pre-beta HDL particles in accordance with a therapy protocol.
  • a blood fraction is withdrawn from the patient presenting with AD.
  • a blood fraction is obtained withdrawing blood from a person other than the patient. Therefore, the plasma obtained as a result of the blood fractionation process may be either autologous or non-autologous.
  • the blood fraction is subsequently treated, using the delipidation process described above to obtain treated plasma containing pre-beta HDL particles.
  • the treated plasma is optionally processed further to generate a product with an increased concentration of isolated pre-0 HDL.
  • the therapy protocol comprises an infusion delivery of pre-beta HDL particles or a concentrated volume of isolated pre-beta particles over a period ranging from 1 hour to 8 hours, and any increment therein, depending upon the concentration of the therapeutic product to be delivered.
  • the dose ranges from 1 mg/kg to 250 mg/kg, and any increment therein, and is administered at an infusion delivery rate of 999 mL/hour +/- lOOml/hour or a rate deemed more appropriate for the patient.
  • the treatment is repeated at specified frequency or cycle of treatment depending upon a course of therapy.
  • the frequency or cycle of administering the treatment may range from once a week, twice a week, three times per week, daily, once a month, twice a month, three times per month, to at least once in three, six, nine or twelve months.
  • the course of therapy may range from at least one day, at least one week, at least one month to at least one year.
  • the therapy protocol comprises at least one, and up to three, seven or ten treatments every three, six, nine or twelve months for an annual course of therapy.
  • the at least one treatment may comprise a continuous infusion (IV) of pre-beta HDL particles over a predetermined time period at a rate of 999 mL/hour.
  • administration of pre-beta HDL particles, as described in step 842, is performed on an intermittent basis during chronic administration of a CETP inhibitor, as described in step 840.
  • the therapy protocol may be titrated or modulated up or down based on a therapeutic endpoint.
  • ISF interstitial fluids
  • A0 amyloid beta
  • Pre-0 HDL restores vascular wall biology resulting in improvements of tissue perfusion, facilitates the drainage of soluble oligomers, which include, but are not limited to A0 and tau proteins present in the Intramural Peri-Arterial Drainage (IPAD) pathway, improves homeostasis, reduces inflammation, and thereby improves overall neuronal function.
  • soluble oligomers include, but are not limited to A0 and tau proteins present in the Intramural Peri-Arterial Drainage (IPAD) pathway, improves homeostasis, reduces inflammation, and thereby improves overall neuronal function.
  • Embodiments of the present specification provide the ability to turbocharge metabolism and clearance into the circulation of harmful metabolites such as, but not limited to, soluble A0 oligomers, Tau oligomers, and other soluble oligomers from the IPAD pathway and is therefore distinct from current approaches that target parenchymal A0 plaques such as A0 Immunotherapies.
  • the bi-modal neurovascular approach to AD treatment has the potential to slow/halt and even reverse disease progression and improve cognition in patients with mild to moderate AD.
  • Serial treatment with preP-HDL therapy in combination with A0 immunotherapy are likely to succeed where A0 immunotherapies alone have failed, because preP-HDL therapy facilitates clearance of Ap along the IPAD and into general circulation.
  • an AD patient s baseline, starting or initial severity level is diagnosed/assessed and categorized as, one of early onset, mild, moderate or severe as described above.
  • the baseline, starting or initial severity level refers to the severity of AD before the patient is treated with the pre-beta HDL and/or isolated pre-P HDL therapy of the present specification.
  • a CAA patient s baseline, starting or initial severity level is diagnosed/assessed and categorized as, one of early onset, mild, moderate or severe as described above.
  • the baseline, starting or initial severity level refers to the severity of CAA before the patient is treated with the pre-beta HDL and/or isolated pre-P HDL therapy of the present specification.
  • the baseline, starting or initial severity level is diagnosed/assessed using at least one physiological diagnostic or advanced medical imaging technique. In some embodiments, the baseline, starting or initial severity level is additionally assessed by at least one global, cognitive, functional, behavioral measurement or test.
  • Magnetic Resonance Imaging may be considered a neuroimaging examination for diagnosis and assessment of Alzheimer’s disease because it allows for accurate measurement of the 3-dimensional (3D) volume of brain structures, and in particular, the size of the hippocampus and related regions.
  • HDL levels are inversely correlated with the development of AD in epidemiology studies. Elderly patients with higher levels of HDL tend to have a higher hippocampal volume. Lower hippocampal volume has been used as an index of AD disease progression.
  • people with Down syndrome and more specifically as exhibited in children, exhibit a lower hippocampal volume which is associated with cognitive impairment and a higher rate of developing AD than those that do not have Down syndrome.
  • a therapeutic benefit is recognized when the patient’s hippocampal volume is increased.
  • a therapeutic benefit is recognized when a patient is able to maintain or be stabilized in their current state when treated with a therapy protocol of the present specification.
  • a therapeutic benefit is recognized when a patient maintains/stabilizes symptoms when treated with a therapy protocol of the present specification when compared to a placebo.
  • a therapeutic benefit is recognized when a patient shows a delay or halting of worsening of symptoms when treated with a therapy protocol of the present specification when compared to a placebo.
  • a therapeutic benefit is recognized when a patient shows a delay in the rate of progression of symptoms when treated with a therapy protocol of the present specification when compared to a placebo.
  • a therapeutic benefit is recognized when a patient shows an improvement in symptoms when treated with a therapy protocol of the present specification when compared to a placebo.
  • the patient experiences a decrease in the accumulation of amyloid plaque in the perivascular space/IPAD System/Perivascular Pathway.
  • the patient experiences an increase in the ratio of beta amyloid peptide 42 to beta amyloid peptide 40 in plasma relative to the ratio of beta amyloid peptide 42 to beta amyloid peptide 40 in plasma before treatment.
  • the patient experiences an increase in the ratio of beta amyloid peptide 42 to beta amyloid peptide 40 in plasma in a range of 1% to 30%, and preferably by at least 15%, relative to the ratio of beta amyloid peptide 42 to beta amyloid peptide 40 in plasma before treatment.
  • the patient experiences an increase in the ratio of beta amyloid peptide 42 to beta amyloid peptide 40 in cerebrospinal fluid relative to the ratio of beta amyloid peptide 42 to beta amyloid peptide 40 in cerebrospinal fluid before treatment.
  • the patient experiences an increase in the ratio of beta amyloid peptide 42 to beta amyloid peptide 40 in cerebrospinal fluid in a range of 1% to 30%, and preferably by at least 15%, relative to the ratio of beta amyloid peptide 42 to beta amyloid peptide 40 in cerebrospinal fluid before treatment.
  • the patient experiences a decrease in the incidence of microbleeds visualized on imaging and/or biomarker studies relative to the incidence of microbleeds visualized on imaging and/or biomarker studies before treatment, indicative of an improvement in, or stabilization of, symptoms.
  • the patient experiences a decrease in the incidence of microbleeds visualized on imaging and/or biomarker studies by at least 1% relative to the incidence of microbleeds visualized on imaging and/or biomarker studies before treatment, indicative of an improvement in, or stabilization of, symptoms.
  • the patient experiences a decrease in a size of a perivascular space/IPAD System/Perivascular Pathway visualized on imaging and/or biomarker studies relative to a size of a perivascular space/IPAD System/Perivascular Pathway visualized on imaging and/or biomarker studies before treatment, indicative of an improvement in, or stabilization of, symptoms.
  • the patient experiences a decrease in a size of a perivascular space/IPAD System/Perivascular Pathway visualized on imaging and/or biomarker studies by at least 1% relative to a size of a perivascular space/IPAD System/Perivascular Pathway visualized on imaging and/or biomarker studies before treatment, indicative of an improvement in, or stabilization of, symptoms.
  • the rate of progression, level or amount of a patient’s physiological and/or cognitive parameter is unchanged relative to the rate, level or amount of that patient’ s physiological and/or cognitive parameter before therapy treatment.
  • the rate of progression, level or amount of a patient’s physiological and/or cognitive parameter is delayed relative to the rate, level or amount of that patient’ s physiological and/or cognitive parameter before therapy treatment.
  • the rate of progression, level or amount of a patient’s physiological and/or cognitive parameter is modified relative to the rate of progression, level or amount of that patient’s physiological and/or cognitive parameter before therapy treatment.
  • the rate of progression, level or amount of that patient’s physiological and/or cognitive parameter is improved relative to the rate of progression, level or amount of that patient’s physiological and/or cognitive parameter before therapy treatment.
  • the patient experiences an improvement of the Mini-Mental Score Examination (MMSE) score relative to the MMSE score before treatment, indicative of an improvement in, or stabilization of, AD- related symptoms.
  • MMSE Mini-Mental Score Examination
  • the patient experiences an increase of the Mini-Mental Score Examination (MMSE) score in a range of 1-10 points, and preferably by at least 3 points, relative to the MMSE score before treatment, indicative of an improvement in, or stabilization of, AD-related symptoms.
  • MMSE Mini-Mental Score Examination
  • the patient experiences an improvement of the ADAS-cog score indicative of an improvement in, or stabilization of, AD-related symptoms.
  • the patient experiences an improvement of the CIBIC-plus score indicative of an improvement in, or stabilization of, AD-related symptoms.
  • the patient experiences an improvement of the SIB score indicative of an improvement in, or stabilization of, AD-related symptoms.
  • the patient experiences an improvement of the ADCS-ADL score indicative of an improvement in, or stabilization of, AD-related symptoms.
  • the patient experiences an improvement of the ADCS-ADL-severe score indicative of an improvement in, or stabilization of, AD-related symptoms.
  • the patient experiences an improvement of any one of the global, cognitive, functional, or behavioral test scores indicative of an improvement in, or stabilization of, AD-related symptoms.
  • the patient experiences a decrease in the accumulation of amyloid plaque in the perivascular space/IP D System/Perivascular Pathway indicative of an improvement or stabilization of AD- related symptoms.
  • An acute stroke is the sudden interruption of blood supply to the brain. It may be caused either by an abrupt blockage of arteries leading to the brain, in which case it is called Ischemic Stroke (IS); or by bleeding into brain tissue when a blood vessel bursts, when it is known as a Hemorrhagic Stroke (HS).
  • IS Ischemic Stroke
  • HS Hemorrhagic Stroke
  • IS is most commonly caused by narrowing of the arteries in the neck or head.
  • the narrowing of the arteries is often caused by atherosclerosis or gradual cholesterol deposition. If the arteries become too narrow, blood cells may collect and form blood clots.
  • TS Thrombotic Stroke
  • ES Embolic Stroke
  • a TS also referred to as cerebral thrombosis or cerebral infarction, occurs when diseased or damaged cerebral arteries become blocked by the formation of a blood clot within the brain.
  • TS may further be divided into additional categories that correlate to the location of the blockage within the brain:
  • CA Carotid Atherosclerosis
  • CA is said to occur when the blockage is in one of the brain’s larger blood-supplying arteries such as the carotid. Based on one or more tests, CA patients are identified as having plaque in the carotid artery. Sometimes the CA patients are asymptomatic. However, the affected artery may rupture in a manner similar to how plaque can rupture in a coronary artery.
  • FIG. 9A illustrates plaque 902 in a carotid artery 904 of a patient. The illustrated blockage can potentially result in stroke, and is a candidate for therapy in accordance with the embodiments of the present specification.
  • Cerebral atherosclerosis is said to occur when the blockage is in one of the brain’s larger blood-supplying arteries such as the middle cerebral.
  • FIG. 9B illustrates plaque 906 in a middle cerebral artery 908 of a patient. The illustrated plaque deposit can potentially result in a stroke, and is a candidate for therapy in accordance with the embodiments of the present specification.
  • Lacunar Stroke
  • Lacunar stroke is said to occur when one or more of the brain’s smaller but deeper penetrating arteries are blocked. This type of stroke is usually not recognized by patients as it destroys a very small part of the brain. This is sometimes also called arteriosclerosis. An MRI of patient’s brain which has suffered lacunar strokes may appear like Swiss cheese with little holes where these strokes have occurred. These strokes may result in losing function for a long period of time, known as a lacunar state or vascular dementia. Cholesterol plaques are considered to be a major risk factor for these strokes. Therefore patients with these strokes can be treated with the therapy in accordance with embodiments of the present specification.
  • An ES is also caused by a clot in an artery.
  • the clot or emboli
  • emboli forms somewhere other than in the brain itself.
  • these emboli will travel in the bloodstream until they become lodged and cannot travel any farther. This naturally restricts the flow of blood to the brain and results in near-immediate physical and neurological deficits.
  • the embolus formed by the breaking-off of plaque from carotid artery and travels through the circulation to blood vessels in the brain. As the vessels become smaller, the emboli lodge themselves in the vessel wall and restrict blood flow in the brain.
  • FIG. 9C illustrates an embolus 910 lodged within a central cerebral artery 912.
  • the stroke caused by the emboli may result in temporary loss of function, or if the embolus is large, it could result in permanent loss of function. It can be treated by the therapy in accordance with embodiments of the present specification.
  • the embolus can be treated as a symptom of Hemorrhagic Stroke (HS), discussed subsequently herein.
  • HS Hemorrhagic Stroke
  • CAA Cerebral Amyloid Angiopathy
  • the protein deposits cause blood vessels to crack, in which case blood leaks out and damages the brain, resulting in hemorrhagic stroke.
  • AD Alzheimer’s disease
  • the presence of CAA is addressed by instances of the present specification, in a manner similar to therapy and treatment of AD.
  • presence of CAA results in AD in association with hemorrhagic stroke, and may be addressed by embodiments of the present specification.
  • Hemorrhagic stroke is determined by physical examination, and may be confirmed by following diagnostic tests such as imaging.
  • the blood that leaks out of a vessel damaged by CAA can cause the surrounding region of the brain to suddenly stop working properly, resulting in symptoms like weakness or paralysis of the limbs, difficulty speaking, loss of sensation or balance, or even coma. If blood leaks out to the sensitive tissue around the brain, it can cause a sudden and severe headache.
  • Other symptoms sometimes caused by irritation of the surrounding brain are seizures (convulsions) or short spells of temporary neurologic symptoms such as tingling or weakness in the limbs or face.
  • treatments and protocols of the present specification are applicable to patients exhibiting hemorrhagic stroke in the presence of CAA.
  • a baseline, starting or initial severity level of HS is diagnosed/assessed using at least one physiological diagnostic or advanced medical imaging technique. For example, measuring the level of amyloid peptide may be used to assess a possible treatment benefit.
  • diagnostic imaging tests are used to determine the accumulation or regional lesions of plaque in the perivascular space/IPAD System/Perivascular Pathway.
  • the advanced medical imaging techniques are used to both determine the extent of plaque in the perivascular space/IPAD System/Perivascular Pathway and to assess a severity level of Alzheimer’s disease.
  • advanced medical imaging techniques such as, but not limited to, Positron Emission Tomography (PET), Magnetic Resonance Imaging (MRI) and Spinal Fluid Test (Beta Amyloid Fragments), may be used.
  • a specific Amyloid Positron Emission Tomography (PET) Scan also referred to as Amyloid PET imaging, represents a potential major advance in diagnosis of HS and/or an assessment of the degree of impairment.
  • the scan visualizes plaque regions or lesions present in the brain, which are prime suspects in damaging the vessels and causing leakage of blood into the brain.
  • the scan technique employs radioactive tracers to highlight amyloid protein plaque regions or lesions within the brain, which are a hallmark of CAA.
  • Amyloid PET scanning enables the “illumination” of amyloid plaques on a brain PET scan, enabling accurate detection of plaques in living people.
  • the scan may allow for a diagnosis or assessment of HS, prior to the presentation of symptomatology.
  • a treated plasma that contains pre-beta HDL particles with reduced lipid content is delivered to the patient via infusion therapy.
  • the process is designed such that HDL particles are treated to reduce their lipid levels and yield pre-beta HDL particles without destruction of plasma proteins or substantially affecting LDL particles.
  • the HDL lipoprotein particles are comprised of ApoA-I, phospholipids and cholesterol.
  • ApoA-I Apolipoprotein A-I particles comprise of two sub-fractions, pre-0 HDL and a-HDL, which have pre-beta and alpha electrophoretic mobility, respectively.
  • pre-0 HDL represents ApoA-I molecules complexed with phospholipids.
  • a treated plasma that contains pre-beta HDL particles with reduced lipid content is delivered to the patient via infusion therapy.
  • the pre-beta high density lipoproteins have a concentration of alpha high density lipoproteins in addition to the pre-beta high density lipoproteins from the blood fraction prior to mixing.
  • isolated pre-0 HDL particles are infused into the patient’s blood stream to bind to beta amyloid particles and clear the cerebral IPAD Sy stem/Peri vascular Pathway.
  • FIGS. 5, 6, 7A, 7B, and 7C the illustrations for removal of beta amyloid particles in accordance with embodiments of the present specification are explained, and are also applicable to removal of beta amyloid particles in cases of HS when CAA is present.
  • a blood fraction is obtained.
  • the process of blood fractionation is typically done by filtration, centrifuging the blood, aspiration, or any other method known to persons skilled in the art.
  • Blood fractionation separates the plasma from the blood.
  • blood is withdrawn from a patient in a volume sufficient to produce about 12ml/kg of plasma based on body weight.
  • the blood is separated into plasma and red blood cells using methods commonly known to one of skill in the art, such as plasmapheresis.
  • the red blood cells are stored in an appropriate storage solution or returned to the patient during plasmapheresis.
  • the red blood cells are preferably returned to the patient during plasmapheresis.
  • Physiological saline is also optionally administered to the patient to replenish volume.
  • LDL Low Density Lipoprotein
  • the resultant blood fraction includes plasma with HDL, and may or may not include other protein particles.
  • the process of blood fractionation is performed by withdrawing blood from the patient presenting with HS, and who is being treated by the physician.
  • the process of blood fractionation is performed by withdrawing blood from a person other than the patient. Therefore, the plasma obtained as a result of the blood fractionation process may be either autologous or non-autologous.
  • the autologous or non-autologous plasma obtained is subjected to a delipidation process as described in greater detail above with respect to FIG. 1 but repeated briefly herein.
  • the resultant blood fraction is mixed with one or more solvents, such as lipid removing agents.
  • the solvents used include either or both of organic solvents sevoflurane and n-butanol.
  • the plasma and solvent are introduced into at least one apparatus for mixing, agitating, or otherwise contacting the plasma with the solvent.
  • the solvent system is optimally designed such that only the HDL particles are treated to reduce their lipid levels and LDL levels are not affected.
  • the solvent system includes factoring in variables such as solvent employed, mixing method, time, and temperature.
  • Solvent type, ratios and concentrations may vary in this step.
  • the plasma and solvent are introduced into at least one apparatus for mixing, agitating, or otherwise contacting the plasma with the solvent.
  • the plasma may be transported using a continuous or batch process.
  • the solvents dissolve lipids from the plasma.
  • the solvents dissolve lipids to yield treated plasma that contains pre-beta HDL particles with reduced lipid content.
  • the process is designed such that HDL particles are treated to reduce their lipid levels and yield pre-beta HDL particles without destruction of plasma proteins or substantially affecting LDL particles.
  • the resultant treated plasma containing pre-beta HDL particles with reduced lipid content, which was separated from the solvents, is treated appropriately and may subsequently be returned to the patient in an embodiment.
  • the resultant fluid containing pre-beta HDL particles is further processed, in a second stage, to separate or to isolate pre-0 HDL particles.
  • the second stage occurs in a separate and discrete area from the delipidation process.
  • the second stage processing occurs in-line with the delipidation system, whereby the system may be connected to an affinity column sub-system or ultracentrifugation sub-system. The resultant separated pre-0 HDL particles may then be introduced to the bloodstream of the patient as described below.
  • FIG. 10A is a flowchart describing a plurality of exemplary steps of a therapy protocol for treating an HS patient, in accordance with an embodiment of the present specification.
  • a patient first presents with a pathophysiological change that is consistent with potential for HS. Any of the aforementioned diagnostic techniques may be used in this step.
  • various biomarkers may be used to determine the pathophysiological change. For example, measuring the level of amyloid peptide may be used to assess the extent of a pathophysiological change characteristic of HS.
  • the patient may present with cerebral amyloid angiopathy (CAA) as detected using a diagnostic imaging technique.
  • CAA cerebral amyloid angiopathy
  • a patient who is diagnosed with CAA is monitored to determine an extent of accumulation of plaque in the perivascular space/IPAD System/Perivascular Pathway, via at least one diagnostic procedure.
  • advanced medical imaging techniques such as, but not limited to, Positron Emission Tomography (PET), Magnetic Resonance Imaging (MRI) and Spinal Fluid Test (Beta Amyloid Fragments), may be used.
  • one or more physiological parameters of the patient are recorded.
  • the one or more physiological parameters are those that may be incidental to determining one or more therapy parameters.
  • the patient’s weight is recorded to determine a dosing range for the patient. It should be appreciated that the physiological parameters may be first recorded prior to step 1005.
  • the patient is infused with pre-beta HDL particles in accordance with a therapy protocol.
  • a blood fraction is withdrawn from the patient presenting with the CAA.
  • a blood fraction is obtained withdrawing blood from a person other than the patient. Therefore, the plasma obtained as a result of the blood fractionation process may be either autologous or non-autologous.
  • the blood fraction is subsequently treated, using the delipidation process described above to obtain treated plasma containing pre-beta HDL particles.
  • the treated plasma is optionally processed further to generate a product with an increased concentration of isolated pre-0 HDL.
  • the therapy protocol comprises an infusion delivery of pre-beta HDL particles or a concentrated volume of isolated pre-beta particles over a period ranging from 1 hour to 8 hours, and any increment therein, depending upon the concentration of the therapeutic product to be delivered.
  • the dose ranges from 1 mg/kg to 250 mg/kg, and any increment therein, and is administered at an infusion delivery rate of 999 mL/hour +/- lOOml/hour or a rate deemed more appropriate for the patient.
  • the treatment is repeated at specified frequency or cycle of treatment depending upon a course of therapy.
  • the frequency or cycle of administering the treatment may range from once a week, twice a week, three times per week, daily, once a month, twice a month, three times per month, to at least once in three, six, nine or twelve months.
  • the course of therapy may range from at least one day, at least one week, at least one month to at least one year.
  • the therapy protocol comprises at least one, and up to three, seven or ten treatments every three, six, nine or twelve months for an annual course of therapy.
  • the at least one treatment may comprise a continuous infusion (IV) of pre-beta HDL particles over a predetermined time period at a rate of 999 mL/hour.
  • the therapy protocol may be titrated or modulated up or down based on a therapeutic endpoint.
  • one or more intra-treatment severity level assessments are made using diagnostic and/or cognitive procedures/tests.
  • the one or more intra-treatment severity level assessments are made at predetermined points in time during the course of therapy. If the intra-treatment severity level assessments show a delay in the onset of additional symptoms, a halting in the worsening of symptoms, or an improvement in the patient’s condition, it is considered to be of therapeutic benefit.
  • the therapeutic amount may be titrated down wherein parameters such as, but not limited to, the dose range, frequency or cycle of treatment and/or course of therapy may be reduced. Alternately, the therapy protocol may be titrated up depending on various factors. Still alternately, if the intra- treatment severity level assessments show or do not show improvement in the patient’s condition, the therapy protocol is not modulated.
  • FIG. 10B is a flowchart describing a plurality of exemplary steps of a therapy protocol for treating an HS patient, in accordance with an embodiment of the present specification.
  • a patient first presents with a pathophysiological change that is consistent with potential for HS. Any of the aforementioned diagnostic techniques may be used in this step.
  • various biomarkers may be used to determine the pathophysiological change. For example, measuring the level of amyloid peptide may be used to assess the extent of a pathophysiological change characteristic of HS.
  • the patient may present with cerebral amyloid angiopathy (CAA) as detected using a diagnostic imaging technique.
  • CAA cerebral amyloid angiopathy
  • a patient who is diagnosed with CAA is monitored to determine an extent of accumulation of plaque in the perivascular space/IPAD System/Perivascular Pathway, via at least one diagnostic procedure.
  • advanced medical imaging techniques such as, but not limited to, Positron Emission Tomography (PET), Magnetic Resonance Imaging (MRI) and Spinal Fluid Test (Beta Amyloid Fragments), may be used.
  • one or more physiological parameters of the patient are recorded.
  • the one or more physiological parameters are those that may be incidental to determining one or more therapy parameters.
  • the patient’s weight is recorded to determine a dosing range for the patient. It should be appreciated that the physiological parameters may be first recorded prior to step 1050.
  • the patient is provided with a regimen for using a CETP inhibitor.
  • the dose ranges from 1 mg to 1000 mg, and any increment therein.
  • a patient may be given a CETP inhibitor at any interval that will achieve the desired therapeutic outcome, which includes, but is not limited to twice daily, weekly, biweekly, monthly, every two months, every six months, yearly or any increment therein.
  • a patient is given a CETP inhibitor once daily.
  • a preferred dosage rate is once daily, given orally.
  • a preferred dosage amount of a CETP inhibitor such as evacetrapib, is selected from one of: 30 mg/d, 100 mg/d, or 500 mg/d.
  • the dosage amount may be modified depending upon desired therapeutic outcome.
  • the desired therapeutic outcome may be measured by determining changes in a patient’s mean baseline lipoprotein levels (HDL-C, LDL-C, and triglycerides).
  • the therapy protocol may be titrated or modulated up or down based on a therapeutic endpoint.
  • a CETP inhibitor is used in conjunction with the delipidation process described throughout the specification.
  • the delipidation process of the present specification may be used in a short-term therapeutic approach (boosts), or intermittently, while the use of a CETP inhibitor may be used as a chronic, regular therapeutic approach.
  • boosts short-term therapeutic approach
  • a combination therapy comprises the use of a CETP inhibitor as a chronic, regular therapeutic application with an intermittent application of pre-beta HDL particles.
  • FIG. 10C is a flowchart describing a plurality of exemplary steps of a therapeutic protocol for treating a patient of hemorrhagic stroke in the presence of CAA using a CETP inhibitor and pre-beta HDL particles, in accordance with an embodiment of the present specification.
  • a patient first presents with a pathophysiological change that is consistent with potential for HS. Any of the aforementioned diagnostic techniques may be used in this step.
  • various biomarkers may be used to determine the pathophysiological change. For example, measuring the level of amyloid peptide may be used to assess the extent of a pathophysiological change characteristic of HS.
  • the patient may present with cerebral amyloid angiopathy (CAA) as detected using a diagnostic imaging technique.
  • CAA cerebral amyloid angiopathy
  • a patient who is diagnosed with CAA is monitored to determine an extent of accumulation of plaque in the perivascular space/IPAD System/Perivascular Pathway, via at least one diagnostic procedure.
  • advanced medical imaging techniques such as, but not limited to, Positron Emission Tomography (PET), Magnetic Resonance Imaging (MRI) and Spinal Fluid Test (Beta Amyloid Fragments), may be used.
  • one or more physiological parameters of the patient are recorded.
  • the one or more physiological parameters are those that may be incidental to determining one or more therapy parameters.
  • the patient’s weight is recorded to determine a dosing range for the patient. It should be appreciated that the physiological parameters may be first recorded prior to step 1060.
  • the patient is provided with a regimen for using a CETP inhibitor.
  • the dose ranges from 1 mg to 1000 mg, and any increment therein.
  • a patient may be given a CETP inhibitor at any interval that will achieve the desired therapeutic outcome, which includes, but is not limited to twice daily, weekly, biweekly, monthly, every two months, every six months, yearly or any increment therein.
  • a patient is given a CETP inhibitor once daily.
  • a preferred dosage rate is once daily, given orally.
  • a preferred dosage amount of a CETP inhibitor such as evacetrapib, is selected from one of: 30 mg/d, 100 mg/d, or 500 mg/d.
  • the dosage amount may be modified depending upon desired therapeutic outcome.
  • the desired therapeutic outcome may be measured by determining changes in a patient’s mean baseline lipoprotein levels (HDL-C, LDL-C, and triglycerides).
  • the patient is infused with pre-beta HDL particles in accordance with a therapy protocol.
  • a blood fraction is withdrawn from the patient presenting with AD.
  • a blood fraction is obtained withdrawing blood from a person other than the patient. Therefore, the plasma obtained as a result of the blood fractionation process may be either autologous or non-autologous.
  • the blood fraction is subsequently treated, using the delipidation process described above to obtain treated plasma containing pre-beta HDL particles.
  • the treated plasma is optionally processed further to generate a product with an increased concentration of isolated pre-0 HDL.
  • the therapy protocol comprises an infusion delivery of pre-beta HDL particles or a concentrated volume of isolated pre-beta particles over a period ranging from 1 hour to 8 hours, and any increment therein, depending upon the concentration of the therapeutic product to be delivered.
  • the dose ranges from 1 mg/kg to 250 mg/kg, and any increment therein, and is administered at an infusion delivery rate of 999 mL/hour +/- lOOml/hour or a rate deemed more appropriate for the patient.
  • the treatment is repeated at specified frequency or cycle of treatment depending upon a course of therapy.
  • the frequency or cycle of administering the treatment may range from once a week, twice a week, three times per week, daily, once a month, twice a month, three times per month, to at least once in three, six, nine or twelve months.
  • the course of therapy may range from at least one day, at least one week, at least one month to at least one year.
  • the therapy protocol comprises at least one, and up to three, seven or ten treatments every three, six, nine or twelve months for an annual course of therapy.
  • the at least one treatment may comprise a continuous infusion (IV) of pre-beta HDL particles over a predetermined time period at a rate of 999 mL/hour.
  • administration of pre-beta HDL particles, as described in step 1068, is performed on an intermittent basis during chronic administration of a CETP inhibitor, as described in step 1066.
  • the therapy protocol may be titrated or modulated up or down based on a therapeutic endpoint.
  • a CAA patient s baseline, starting or initial severity level is diagnosed/assessed and categorized as, one of early onset, mild, moderate or severe as described above.
  • the baseline, starting or initial severity level refers to the severity of CAA before the patient is treated with the pre-beta HDL and/or isolated pre-0 HDL therapy of the present specification.
  • the baseline, starting or initial severity level is diagnosed/assessed using at least one physiological diagnostic or advanced medical imaging technique.
  • the therapeutic endpoints that are realized with CAA as described above are the same therapeutic endpoints for HS.
  • HCAA Hereditary Cerebral Amyloid Angiopathy
  • HSHWA Hereditary Cerebral Hemorrhage with Amyloidosis
  • HCHWA is a neurological condition in which, like CAA, an abnormal protein (amyloid) builds up in the walls of the arteries of the brain (and less frequently, veins). The amyloid deposits can lead to strokes, seizures, neurological deficits, cognitive decline, and dementia. This disease is also age-related, and may onset from middle-age. This condition can be fatal in one’s sixties with some variations, resulting from continuous neurological decline.
  • CAA Cerebralarcomas syndrome
  • HCAA is an aging-related condition caused by deposits of amyloid proteins in the wall or perivascular space/IPAD System/Perivascular Pathway of blood vessels in a brain.
  • CAA hereditary cerebral amyloid angiopathy
  • the Dutch type of HCAA is the most common form. Stroke is frequently the first sign of the Dutch type and is fatal in about one third of people who have this condition. Survivors often develop dementia and have recurrent strokes. About half of individuals with the Dutch type who have one or more strokes will have recurrent seizures (epilepsy). People with the Flemish and Italian types of HCAA are prone to recurrent strokes and dementia. Individuals with the Piedmont type may have one or more strokes and typically experience impaired movements, numbness or tingling (paresthesias), confusion, or dementia.
  • the first sign of the Icelandic type of HCAA is typically a stroke followed by dementia. Strokes associated with the Icelandic type usually occur earlier than the other types, with individuals typically experiencing their first stroke in their twenties or thirties.
  • Strokes are rare in people with the Arctic type of HCAA, in which the first sign is usually memory loss that then progresses to severe dementia. Strokes are also uncommon in individuals with the Iowa type. This type is characterized by memory loss, problems with vocabulary and the production of speech, personality changes, and involuntary muscle twitches (myoclonus).
  • APP Apolipoprotein
  • CST3 Apolipoprotein
  • ITM2B The APP gene provides instructions for making a protein called amyloid precursor protein. This protein is found in many tissues and organs, including the brain and spinal cord (central nervous system). Mutations in the APP, CST3, or ITM2B gene lead to the production of proteins that are less stable than normal and that tend to cluster together (aggregate). These aggregated proteins form protein clumps called amyloid deposits that accumulate in certain areas of the brain and in its blood vessels. The amyloid deposits, or plaques, damage brain cells, eventually causing cell death and impairing various parts of the brain.
  • amyloid deposits, or plaques damage brain cells, eventually causing cell death and impairing various parts of the brain.
  • a Modified Boston Criteria incorporates cortical superficial siderosis into the radiological diagnosis to determine a probability of CAA, and may also be used for diagnosing HCAA and HCHWA.
  • the criteria comprises of combined clinical, imaging and pathological parameters.
  • the criteria has four tiers: o Tier 1 represents definite CAA, and determined during a full post-mortem examination. The examination reveals lobar, cortical, or corti cal/sub corti cal hemorrhage and pathological evidence of severe CAA. o Tier 2 represents probable CAA with supporting pathological evidence. This examination may not be post-mortem.
  • Clinical data and pathological tissue demonstrate a hemorrhage as mentioned above, and some degree of vascular amyloid deposition, indicative of CAA. o Tier 3 represents probable CAA. In this case pathological confirmation is not required. Patients of 55 years or older with an appropriate clinical history are considered. Additionally, MRI findings demonstrate multiple hemorrhages restricted to lobar, cortical, or corticosubcortical regions (cerebellar hemorrhages allowed) of varying sizes/ages without another cause.
  • a single lobar, cortical, or corticosubcortical hemorrhage and focal (three or less sulci) or disseminated (more than three sulci) cortical superficial siderosis without another cause o Tier 4 represents possible CAA. This is also applicable to patients of 55 years or older age with an appropriate clinical history. Additionally, MRI findings demonstrate a single, (more than three sulci) cortical superficial siderosis without another; or focal or disseminated cortical superficial siderosis without another cause.
  • a treated plasma that contains pre-beta HDL particles with reduced lipid content is delivered to the patient via infusion therapy.
  • the process is designed such that HDL particles are treated to reduce their lipid levels and yield pre-beta HDL particles without destruction of plasma proteins or substantially affecting LDL particles.
  • the HDL lipoprotein particles are comprised of ApoA-I, phospholipids and cholesterol.
  • ApoA-I Apolipoprotein A-I particles comprise of two sub-fractions, pre-0 HDL and a-HDL, which have pre-beta and alpha electrophoretic mobility, respectively.
  • pre-0 HDL represents ApoA-I molecules complexed with phospholipids.
  • a treated plasma that contains pre-beta HDL particles with reduced lipid content is delivered to the patient via infusion therapy.
  • the pre-beta high density lipoproteins have a concentration of alpha high density lipoproteins in addition to the pre-beta high density lipoproteins from the blood fraction prior to mixing.
  • isolated pre-0 HDL particles are infused into the patient’s blood stream to bind to beta amyloid particles and clear the cerebral IPAD System/Perivascular Pathway.
  • isolated pre-0 HDL particles are infused into the patient’s blood stream to bind to beta amyloid particles and clear the cerebral IPAD System/Perivascular Pathway.
  • FIGS. 5, 6, 7A, 7B, and 7C the illustrations for removal of beta amyloid particles in accordance with embodiments of the present specification are explained, and are also applicable to removal of beta amyloid particles in cases of HCAA and HCHWA when CAA is present.
  • the process of a therapy protocol for treating HCAA and HCHWA may be identical to that for treating CAA, as described in FIGS. 4A-4C.

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Abstract

L'invention concerne des systèmes, des appareils et des procédés de prévention prophylactique ou de traitement de l'apparition et/ou de l'évolution de l'angiopathie amyloïde cérébrale (CAA), des états d'accident vasculaire cérébral aigu ou de la maladie d'Alzheimer, comprenant l'administration à un patient de particules de HDL pré-bêta, d'un inhibiteur de CETP ou d'une combinaison à la fois des particules de HDL pré-bêta et d'un inhibiteur de CETP. L'évolution, la stabilisation ou l'amélioration des symptômes liés à ces états sont traitées par surveillance d'un changement pathophysiologique indiquant les états chez un patient, par détermination, sur la base de la surveillance, du fait que la plaque amyloïde est présente ou non dans un espace périvasculaire/un système IPAD/une voie périvasculaire du patient, éventuellement par détermination de l'étendue de la plaque amyloïde dans l'espace périvasculaire/le système IPAD/la voie périvasculaire, et par détermination, sur la base de la présence de la plaque amyloïde dans l'espace périvasculaire/le système IPAD/la voie périvasculaire du patient, d'un protocole de traitement pour le patient.
PCT/US2022/077947 2021-10-12 2022-10-12 Procédés et systèmes de prévention prophylactique, de ralentissement de l'évolution ou de traitement de l'angiopathie amyloïde cérébrale, de la maladie d'alzheimer et/ou d'un accident vasculaire cérébral aigu WO2023064794A1 (fr)

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US17/571,225 US20220202857A1 (en) 2017-01-23 2022-01-07 Systems and methods for reducing low attenuation plaque and/or plaque burden in patients
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070066527A1 (en) * 2005-09-07 2007-03-22 Neurotez, Inc. Leptin as an anti-amyloidogenic biologic and methods for delaying the onset and reducing Alzheimer's disease-like pathology
US20140243414A1 (en) * 2003-03-17 2014-08-28 Japan Tobacco Inc. Pharmaceutical compositions of cetp inhibitors
US20190381070A1 (en) * 2017-01-23 2019-12-19 Hdl Therapeutics, Inc. Methods for Prophylactically Preventing, Slowing the Progression of, or Treating Cerebral Amyloid Angiopathy, Alzheimer's Disease and/or Acute Stroke

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140243414A1 (en) * 2003-03-17 2014-08-28 Japan Tobacco Inc. Pharmaceutical compositions of cetp inhibitors
US20070066527A1 (en) * 2005-09-07 2007-03-22 Neurotez, Inc. Leptin as an anti-amyloidogenic biologic and methods for delaying the onset and reducing Alzheimer's disease-like pathology
US20190381070A1 (en) * 2017-01-23 2019-12-19 Hdl Therapeutics, Inc. Methods for Prophylactically Preventing, Slowing the Progression of, or Treating Cerebral Amyloid Angiopathy, Alzheimer's Disease and/or Acute Stroke

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NICHOLLS STEPHEN J., RUOTOLO GIACOMO, BREWER H. BRYAN, KANE JOHN P., WANG MING-DAUH, KRUEGER KATHRYN A., ADELMAN STEVEN J., NISSEN: "Cholesterol Efflux Capacity and Pre-Beta-1 HDL Concentrations Are Increased in Dyslipidemic Patients Treated With Evacetrapib", JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, ELSEVIER, AMSTERDAM, NL, vol. 66, no. 20, 1 November 2015 (2015-11-01), AMSTERDAM, NL, pages 2201 - 2210, XP093063354, ISSN: 0735-1097, DOI: 10.1016/j.jacc.2015.09.013 *

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