WO2006034542A1 - Diagnostics de la maladie d'alzheimer et de la deficience cognitive legere - Google Patents

Diagnostics de la maladie d'alzheimer et de la deficience cognitive legere Download PDF

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Publication number
WO2006034542A1
WO2006034542A1 PCT/AU2005/001485 AU2005001485W WO2006034542A1 WO 2006034542 A1 WO2006034542 A1 WO 2006034542A1 AU 2005001485 W AU2005001485 W AU 2005001485W WO 2006034542 A1 WO2006034542 A1 WO 2006034542A1
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Prior art keywords
alzheimer
mci
disease
diagnosis
acetylcholine
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PCT/AU2005/001485
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English (en)
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Zeinab Khalil
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The National Ageing Research Institute Inc.
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Priority claimed from AU2004905592A external-priority patent/AU2004905592A0/en
Application filed by The National Ageing Research Institute Inc. filed Critical The National Ageing Research Institute Inc.
Publication of WO2006034542A1 publication Critical patent/WO2006034542A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
    • A61K49/0006—Skin tests, e.g. intradermal testing, test strips, delayed hypersensitivity

Definitions

  • the present invention relates to methods for diagnosis of Alzheimer's disease and/or MCI in patients and diagnostic kits for use in such methods.
  • Alzheimer's disease is a disorder associated with enormous personal cost and trauma. For example, in later stages of the disease it is common for sufferers to experience memory loss to an extent that even immediate family and close friends can no longer be recognised. This is an incredibly traumatic scenario not only for the sufferer but for their carers, upon whom greater dependancy is placed as the disease progresses.
  • Mild Cognitive Impairment is a risk state or indicator for progression to Alzheimer's disease.
  • MCI is a transition state between the cognitive changes associated with the ageing process and those of a more serious nature that are associated with Alzheimer's.
  • the disorder can be divided into two broad subtypes, amnestic MCI, which significantly affects memory, and nonamnestic MCI, which does not. Both subtypes are characterised by impaired language, attention and visuospatial function.
  • the effective use of therapeutic agents to halt or at least slow progression of the disease is of course contingent upon accurate disease diagnosis.
  • diagnosis of Alzheimer's disease has been fraught with difficulty as the diagnosis is based upon behavioural characteristics common to many other forms of dementia. While it is possible for various scans and tests to be conducted, an Alzheimer's disease diagnosis is currently only made after elimination of other forms of dementia and brain disorder. Conclusive Alzheimer's disease diagnosis is presently only possible following post-mortem autopsy.
  • accurate diagnosis of MCI is particularly difficult as there will always be difficulty in determining whether memory impairment is greater than normal or whether memory or cognitive changes are related to normal memory.
  • Alzheimer's and MCI diagnostic methods that will serve to provide an accurate diagnosis of the disorders at an early stage so that therapeutic regimes presently available, and those which will become available over the next years, can be adopted to halt or at least slow progression of the disease. It is with these factors in mind that the present invention has been conceived. It is well recognised that the pathology of Alzheimer's disease is associated with a reduction in brain cell number and the presence in the brain of neurofibrillary tangles and amyloid plaques, resulting in disorganisation of the neural network. The amyloid or senile plaques are formed by deposition in the brain of amyloid ⁇ protein (A ⁇ 4).
  • a ⁇ 4 amyloid ⁇ protein
  • MCI is likely to be associated with the early stages of the same progression.
  • a method of Alzheimer's disease diagnosis and/or diagnosis of MCI in a patient comprising: (i) dermally administering to the patient an amount of an endothelial acting vasodilating agent effective to induce local microvascular dilation in a normal patient; and
  • the endothelial activating vasodilating agent is selected from substance P, bradykinin and serotonin.
  • a particularly preferred endothelial acting vasodilating agent is acetylcholine.
  • Administration of the endothelial acting vasodilating agent may be topical, by injection or by electrophoresis. Preferably administration is by electrophoresis.
  • Detection of local microvascular blood flow change may preferably be conducted by laser Doppler flowmetry and statistical significance of microvascular dilation reduction relative to dilation detected in a normal patient population may conveniently be established by conducting one-way multivariate analysis of variance (MANOVA).
  • MANOVA multivariate analysis of variance
  • a method of Alzheimer's disease diagnosis and/or MCI diagnosis in a patient comprising: (i) dermally administering to a patient by electrophoresis a saline solution and then after a delay a solution of between 5% v/v and 50% v/v acetylcholine in the saline solution for a period of between 10 seconds and 40 seconds at a current of between 0.1mA and 0.4mA over a skin area of between 0.2cm 2 and 3.0cm 2 ; and (ii) determining local microvascular blood flow following each of saline and acetylcholine administration, by laser Doppler flowmetry;
  • E:S ratio a ratio of microvascular blood flow following acetylcholine administration to microvascular blood flow following saline administration
  • a diagnostic kit when used in diagnostic methods as outlined above there is provided a diagnostic kit for detecting Alzheimer's disease and/or MCI comprising:
  • an electrophoresis administration unit adapted to receive the acetylcholine solution containing electrode chamber.
  • the electrode chamber is additionally adapted for storage of the acetylcholine solution.
  • Figure 1 shows the ratio of endothelial vascular blood flow response to administration of acetylcholine against water, in both control and AD patients.
  • Figure 2 shows the endothelial vascular response to ACh in control and transgenic mice overexpressing amyloid ⁇ protein.
  • Figure 3 shows the ratio of endothelial vascular blood flow response to administration of acetylcholine against saline, in both control and AD patients.
  • Figure 4 shows the ratio of endothelial vascular blood flow response to administration of acetylcholine against saline, in both control and AD patients, where patients under treatment for AD are excluded from the AD patient sample.
  • Figure 5 shows the ration of endothelial vascular blood flow response to administration of acetylcholine against saline, in both control and AD patients, where patients under treatment for AD and who suffer from cardiovascular disease are excluded from the AD patient sample.
  • Figure 6 shows a bar graph of ratio of endothelial response to saline response for different clinically affected patient groups, demonstrating the effect of dementia on E/S ratio.
  • Figure 7 shows a bar graph of ratio of endothelial response to saline response for patient groups with different Mini Mental State Examination (MMSE) scores.
  • MMSE Mini Mental State Examination
  • Figure 8 shows a bar graph of ratio of endothelial response to saline response for patient groups with different levels of cognitive impairment.
  • Figure 9 shows a plot of E:S ratios for normal (control) and MCI affected patients.
  • the present invention relates to a method of diagnosis and diagnostic kits for diagnosis of Alzheimer's disease (AD) and/or Mild Cognitive Impairment (MCI).
  • AD Alzheimer's disease
  • MCI Mild Cognitive Impairment
  • Alzheimer's disease is also intended to imply reference to MCI, where the context is appropriate.
  • This procedure can be also used to monitor the effectiveness of treatment over time.
  • the diagnostic may be performed upon non-symptomatic patients it is more likely that the diagnostic method will be adopted on patients demonstrating some clinical evidence of dementia, preferably at an early stage of dementia onset. It may also be appropriate for patients with a family history of AD to be subjected to the diagnostic method in order that they may have an opportunity to adopt lifestyle practices and whatever treatment options that are available at an early stage, in order to prevent progression of the disease that may be developing, although not yet behaviourally evident. It may also be appropriate for AD patients to be subjected to this testing in order to monitor effectiveness of treatment in improving endothelial microvascular responses in these patients.
  • the diagnostic methods according to the invention involve the dermal administration to the patient of an endothelial acting vasodilating agent.
  • skin is intended to encompass all modes of administration of endothelial acting vasodilating agents to the dermis or skin that will allow the agent or agents concerned to exhibit their pharmacological activity on dermal endothelial cells.
  • the nature of the administration route adopted will of course depend upon the pharmacokinetics of the agent concerned. For example smaller chemical compounds or lipophilic compounds could be absorbed into endothelial cells by direct topical application, in the form of an ointment, oil, salve or the like.
  • Lipophobic compounds may require administration by way of transdermal injection, by electrophoresis (in the case of charged compounds) or with the aid of a lipophilic carrier or liposomes etc. It is to be understood, however, that these modes of administration are mentioned by way of example only. Further details of administration modes and appropriate carriers, diluents, additives and the like are provided in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Co, Easton Pennsylvania, USA, the disclosure of which is included herein in its entirety by way of reference.
  • the amount of endothelial acting vasodilating agent administered may depend upon the nature and activity of the compound concerned, the mode of administration and patient specific factors such as the age, weight, height, sex and general health and well-being of the patient. Other factors material to the amount of endothelial acting vasodilating agent administered to a patient would be apparent to a skilled physician.
  • amounts of from about 0.1ng/kg bodyweight to about l,000 ⁇ g/kg bodyweight are contemplated to be useful in the diagnostic method. More preferably, amounts between about lng/kg bodyweight to about lOO ⁇ g/kg bodyweight and even more preferably amounts of about 10ng/kg bodyweight to about lO ⁇ g/kg bodyweight are envisaged.
  • the amount of the endothelial acting vasodilating agent administered is that which would be effective to induce local microvascular dilation in a normal patient.
  • a normal patient it is intended to mean a patient not suffering from AD, and of generally good health.
  • the normal patient against which the appropriate amount of compound administration should be judged for a patient upon which the diagnostic method is being conducted would be a patient of approximately the same or similar age, weight, height, sex and general state of health as the patient upon which the diagnostic method is being conducted.
  • endothelial acting vasodilating agent it is meant to encompass all physiologically well tolerated agents that can be administered dermally and exhibit detectable endothelial-mediated microvascular dilation in the area local to administration in normal patients, at feasible administration amounts. Such compounds may be known or as yet unidentified, but as long as they meet the requirements outlined herein can be adopted for use in the diagnostic methods according to the invention.
  • Preferred endothelial acting vasodilating agents include substance P, bradykinin and serotonin and a particularly preferred endothelial acting vasodilating agent is acetylcholine (ACh).
  • administration will preferably be by way of electrophoresis in the form of an ACh solution in saline or preferably, distilled water.
  • ACh solution in saline or preferably, distilled water.
  • solutions of between about 5% and about 50% ACh v/v (preferably between about 15% v/v and 40% v/v), in either distilled water or saline are envisaged.
  • physiologically suitable medium it is intended to mean a solvent suitable for administration via electrophoresis to a human patient in combination with ACh, and particularly including, but not necessarily limited to, distilled water and saline solutions.
  • the detection of local microvascular blood flow change following vasodilating agent administration involves the monitoring of microvascular blood flow in the region of administration of the endothelial acting vasodilating agent, both prior to administration and following administration.
  • the microvascular blood flow may be monitored continuously both prior to, during and following administration of the vasodilating agent, or microvascular blood flow may be monitored to detect maximum height of the response flow, for the time period until 50% desensitization or until return to baseline level.
  • microvascular blood flow following administration of the physiologically suitable medium (eg. saline) so as to take into account any effect on microvascular blood flow of the electrophoresis of the medium in determining the blood flow changes attributable to the vasodilating agent.
  • physiologically suitable medium eg. saline
  • the microvascular blood flow is monitored by utilising laser Doppler flowmetry.
  • LDF laser Doppler flowmetry
  • Oberg PA Laser-Doppler flowmetry
  • Biomed Eng 18:125-163 1990 and Johnson JM, The cutaneous circulation.
  • Shephard AP & Oberg PA Laser-Doppler blood flowmetry, pp:121-139, Kluwer Academic, Boston, 1990, the disclosures of which are included herein in their entirety by way of reference.
  • PF-2B Primed Periflux
  • DRT4 Moor Instruments, England
  • Other techniques for monitoring superficial capillary blood flow are also applicable.
  • the normal patient population will preferably include at least 5, particularly preferably at least 10, more particularly preferably at least 30 non-Alzheimer's disease sufferers for whom dermal microvascular blood flow change has been determined following administration of an endothelial acting vasodilating agent under the same conditions as those applied to the patient under diagnosis.
  • the comparison of microvascular flow change with that obtained for a normal patient population may be conducted by calculating a ratio of skin endothelial microvascular blood flow following acetylcholine administration to microvascular blood flow following saline administration (E:S ratio), wherein Alzheimer's disease is indicated if E:S ratio is below a threshold value determined by calculating E:S ratios under similar conditions for normal patient (and Alzheimer's disease affected) populations.
  • E:S ratio skin endothelial microvascular blood flow following acetylcholine administration to microvascular blood flow following saline administration
  • Microvascular dilation is of course correlated with increased microvascular blood flow and microvascular constriction is correlated with decreased microvascular blood flow.
  • the electrophoretic administration of acetylcholine in a physiologically suitable medium is conducted for between about 5 seconds and about 2 minutes, preferably between about 10 seconds and about 40 seconds, particularly preferably for approximately 30 seconds.
  • a current of between about 0.05mA and about 0.5mA, preferably between about 0.1mA and about 0.4mA and, particularly preferably, a current of approximately 0.2mA may be utilised for the electrophoresis.
  • the skin area over which an electrophoretic electrode is applied, and across which the acetylcholine will be administered is between about 0.25cm 2 and about 3.0cm 2 , preferably between about 0.2cm 2 and about 3.0cm 2 .
  • an Alzheimer's disease diagnostic kit that may be utilised in relation to the diagnostic methods referred to herein.
  • the diagnostic kit comprises a solution of acetylcholine in a physiologically acceptable medium that is contained within an electrode chamber.
  • the kit may also comprise a physiologically suitable medium (eg. saline).
  • the electrode chamber being compatible with an electrophoresis administration unit so that the acetylcholine containing chamber can easily be placed in position and connected to the electrophoresis administration unit for administration of medium and/or acetylcholine via electrophoresis to the skin of a patient under diagnosis.
  • the medium and/or acetylcholine solution can be supplied and stored within an electrode chamber, such that the chambers are produced at relatively low cost and may be disposable after use. It may also be equipped with appropriate covering means to prevent leakage of the solution therewithin, to ensure sterility of the solution and to protect the solution from other environmental factors (such as light) if necessary.
  • Example 1 Endothelial vascular response to acetylcholine in human AD and control patients
  • Electrophoresis protocol Two Perspex electrode chambers were attached to the middle third of the forearm (2cm apart) by means of a double sided adhesive ring. Each chamber consists of an inner ring with a small hole drilled through the centre to accommodate the placement of a small optical fibre to measure blood flow (blood flux) in the area of the skin directly beneath the probe via a Perimed Periflux (PF-2B) laser Doppler flowmeter, (Stockholm, Sweden). One chamber was filled with 200ul of vehicle (distilled water) and the other was filled with 200ul of 20% ACh (dissolved in distilled water). An indifferent electrode was attached to the volar aspect of the subject's wrist.
  • PF-2B Perimed Periflux
  • a battery-powered electrophoresis Unit (Phoresor II - PM700) was connected to the chamber by alligator clips attached to two parallel metal infusion ports.
  • the Unit provides a direct current for drug electrophoresis.
  • First forearm skin red blood cell flux was recorded immediately before the start of electrophoresis until a stable baseline was achieved.
  • Drug was delivered using an anodal current (0.2 mA for 30 Sec).
  • the blood flux was recorded continuously.
  • the electrophoresis unit was connected to one of the chambers to deliver either vehicle or ACh in a random manner, with a waiting period of 20-30 min between the two stimuli. Blood flow measurements:
  • Basal blood flow as well as the vascular response to ACh was measured using laser Doppler flowmetry (LDF).
  • LDF is a non-invasive method of measuring skin microvascular blood flow following physiological and pharmacological interventions. LDF allows the continuous measurement of changes in blood flow over time. The results can be recorded on a chart recorder and analysed manually (when the periflux machine is used) or recorded directly onto a computer and analysed off-line using the DRTSOFT software package (when the Moor Instrument is used). Basal blood flow was recorded for 10 to 20 minutes to obtain stable measurements. Responses to ACh were recorded for a maximum of 30 minutes by which time the response had declined to base line. Overall the procedure was completed within 1 hour.
  • Positive Predictability is the proportion of those with a positive test who have AD.
  • Negative Predictability is the proportion of those with a negative test who do not have AD.
  • mice with an average weight of 30g were initially anaesthetised with pentobarbitone sodium (Nembutal 20mg/kg i.p.). Additional doses of anaesthetic (5mg/kg) were administered to ensure that the mice remained under a constant state of surgical anaesthesia. This method of anaesthesia has previously been shown not to alter the basal vasodilation response. At the end of the experiment, the animals were sacrificed by barbiturate overdose.
  • the blister model and ACh perfusion In order to gain access to the microvasculature, a blister was induced on the mice hind footpads using a metal suction cap heated to 4O 0 C and vacuum pressure of approximately 4OkP. Blister induction requires that the animal's feet are secured to the vacuum chamber for 20 min which produces a blister without damage to the microvessels. Once the blister is formed the epidermis is separated from the dermis. The removal of the blister epithelium allows access by superfusion to the extracellular space surrounding nerve terminals. Each mouse foot is secured in a perspex chamber with inlet and outlet ports.
  • Perfusion of Ringer's solution and peptides over the blister is maintained at 4ml/hr by a peristaltic pump (Microperpex S, LKB, Sweden). Both perfusate and body temperature were kept at 37 0 C. An initial equilibration with Ringer's solution for 20 min was allowed before each experiment, during which time a stable baseline was established. Vasodilation and vasoconstriction response to the perfused substance were measured as percentage change in relative blood flux over time, using Laser Doppler flowmetry (Moor Instruments, England) via a probe placed in a central port immediately over the blister base. Blood flux was recorded immediately into a computer containing the DRT4 software.
  • mice Sodium Nitroprusside (SNP; 100 ⁇ M) was perfused at the beginning of each experiment to control for individual variability in smooth muscle reactivity between mice.
  • the vascular response to ACh was examined in Tg mutant (CT100.V717.F) mice while non-Tg mice were used as controls.
  • endothelial cell function was examined using ACh (30 min) while smooth muscle cell function was examined using SNP (10 min).
  • Data (mean + S.E.M.) are presented as percentage change in baseline flux over a 30 min period.
  • Statistical analysis was performed using One-way ANOVA. The data for smooth muscle reactivity as determined by the initial perfusion of SNP was included as a covariate in the statistical analysis.
  • Peripheral markers of vascular nature may be a useful diagnostic adjunct to the clinical detection of those with Alzheimer's disease.
  • the validation sample consisted of 168 cognitively intact healthy volunteers derived from a pre-existing database at the National Ageing Research Institute of 500 healthy older adults. All subjects had skin temperature, medication history, BP, pulse and MMSE performed at time of assessment. A sample of 169 patients with cognitive impairment and early dementia were recruited from an outpatient memory clinic operating at Melbourne Extended Care and Rehabilitation Service. Complete diagnostic information on the type and severity of cognitive impairment was available for this sample. All subjects had a full clinical assessment (Physical exam, blood tests, CT scan, informant history +/- neuropsychological exam) performed by geriatrician or psychogeriatrician.
  • MMSE Mini Mental State Examination
  • Vascular data was calculated as the ratio of endothelial response to saline response for each subject. This ensured the saline response (dependent on individual vascular reactivity to electrophoresis) was incorporated as an internal control in each individual response. MANOVA was used to investigate the differences between different diagnoses and or differing degrees of cognitive impairment (Independent variables) in terms of their effect on endothelial vascular response (Dependent variable).
  • Ratio of skin endothelial vascular response to acetylcholine compared to saline response Ratio of skin endothelial vascular response to acetylcholine compared to saline response (ratio E/S).
  • E/S ratios for MCI fell between AD and controls. This is consistent with the pathogenesis of AD. Within individuals with MCI there was an association between E/S ratio and clinical status (as assessed by MMSE). This supports further the idea that blood vessel pathology in the periphery changes as CNS AD load also changes before this load is sufficient to give rise to the clinical syndrome of dementia.
  • the E/S ratio was abnormal in individuals even with very mild MCI (e.g. identified from a subtle decline memory function over the eight years prior to assessment). This suggests that this measure is also sensitive to differentiating normal from abnormal aging.

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Abstract

L'invention concerne une méthode de diagnostic de la maladie d'Alzheimer et/ou de diagnostic de la déficience cognitive légère chez un patient consistant: (i) à administrer par voie dermique au patient une quantité d'un agent de vasodilatation agissant au niveau endothélial efficace pour induire une dilatation microvasculaire locale chez un patient normal; et (ii) à détecter un changement local de l'écoulement sanguin microvasculaire suite à l'administration de l'agent de vasodilatation; la maladie d'Alzheimer et/ou la déficience cognitive légère étant indiquée si la dilatation microvasculaire induite par l'agent de vasodilatation est réduite de manière importante sur le plan statistique par rapport à la dilatation détectée chez une population de patients normaux. L'invention concerne également un kit de diagnostic permettant de détecter la maladie d'Alzheimer et/ou la déficience cognitive légère.
PCT/AU2005/001485 2004-09-27 2005-09-27 Diagnostics de la maladie d'alzheimer et de la deficience cognitive legere WO2006034542A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8057400B2 (en) 2009-05-12 2011-11-15 Angiologix, Inc. System and method of measuring changes in arterial volume of a limb segment
US10238306B2 (en) 2006-02-20 2019-03-26 Everist Genomics, Inc. Method for non-evasively determining an endothelial function and a device for carrying out said method
KR20200117781A (ko) * 2019-04-05 2020-10-14 건국대학교 산학협력단 인지 능력 진단을 위한 정보를 제공하는 방법 및 인지 능력 진단용 바이오 마커 조성물

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WO2003104466A1 (fr) * 2002-01-17 2003-12-18 Socratech, L.L.C. Traitement du dysfonctionnement vasculaire et maladie d'alzheimer

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KHALIL ET AL: "Mechanism of peripheral microvascular dysfunction in transgenic mice over-expressing the Alzheimer's disease amyloid A-beta protein.", JOURNAL OF ALZHEIMER'S DISEASE., vol. 4, 2002, pages 467 - 478 *
KHALIL ET AL: "Mechanisms underlying the vascular activity of beta-amyloid protein fragment (beta A(4)25-35) at the level of skin microvasculature.", BRAIN RESEARCH., vol. 736, 1996, pages 206 - 216 *
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10238306B2 (en) 2006-02-20 2019-03-26 Everist Genomics, Inc. Method for non-evasively determining an endothelial function and a device for carrying out said method
US8057400B2 (en) 2009-05-12 2011-11-15 Angiologix, Inc. System and method of measuring changes in arterial volume of a limb segment
US8657755B2 (en) 2009-05-12 2014-02-25 Angiologix, Inc. System and method of measuring changes in arterial volume of a limb segment
KR20200117781A (ko) * 2019-04-05 2020-10-14 건국대학교 산학협력단 인지 능력 진단을 위한 정보를 제공하는 방법 및 인지 능력 진단용 바이오 마커 조성물
KR102321712B1 (ko) 2019-04-05 2021-11-03 건국대학교 산학협력단 인지 능력 진단을 위한 정보를 제공하는 방법 및 인지 능력 진단용 바이오 마커 조성물

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