WO2016135707A1 - Diagnostic de trouble dépressif majeur, de déficience cognitive légère, et de la maladie d'alzheimer et d'autres troubles neurologiques et psychiatriques - Google Patents

Diagnostic de trouble dépressif majeur, de déficience cognitive légère, et de la maladie d'alzheimer et d'autres troubles neurologiques et psychiatriques Download PDF

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WO2016135707A1
WO2016135707A1 PCT/IB2016/051093 IB2016051093W WO2016135707A1 WO 2016135707 A1 WO2016135707 A1 WO 2016135707A1 IB 2016051093 W IB2016051093 W IB 2016051093W WO 2016135707 A1 WO2016135707 A1 WO 2016135707A1
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autoantibodies
subject
folate
fra
sample
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PCT/IB2016/051093
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Juan A. Ruiz
JR. Harold O. KOCH
Lori W. BARRENTINE
Jane Durga
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Nestec S.A.
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    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/564—Immunoassay; Biospecific binding assay; Materials therefor for pre-existing immune complex or autoimmune disease, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
    • 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
    • G01N33/82—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving vitamins or their receptors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2814—Dementia; Cognitive disorders
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2814—Dementia; Cognitive disorders
    • G01N2800/2821—Alzheimer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/30—Psychoses; Psychiatry
    • G01N2800/304—Mood disorders, e.g. bipolar, depression

Definitions

  • MDD Major Depressive Disorder
  • a neuropsychiatric condition that afflicts anywhere from 10 to 20% of the population. The most common age of onset is between 30 and 40 years, with a later peak between 50 and 60 years of age. In the United States, MDD is a contributing cause to the majority of the approximately 30,000 annual deaths by suicide. Diagnosis and severity of MDD are based on a clinician assessment of a defined set of specific signs and symptoms experienced by the subject during one or more major depressive episodes (See, e.g., American Psychiatric Association (2013), Diagnostic and statistical manual of mental disorders: DSM-5, Washington, D.C. American Psychiatric Association). This subjective diagnostic method relies on the subject's self-reported experiences and observed behavior.
  • MCI mild cognitive impairment
  • MCI is considered to be a clinical stage distinct from normal aging and dementia. Diagnosis of MCI can involve a comprehensive clinical assessment including clinical observation, neuroimaging, blood tests and neuropsychological testing, similar to that used for diagnosing Alzheimer's disease. MCI can be diagnosed if there is evidence of: a cognitive or memory complaint by the individual and/or a family member; cognitive or memory impairment for age; a change in functional abilities; generally preserved activities of daily life, possibly with increased difficulty; and an absence of dementia.
  • ADRD Alzheimer's disease and related disorders
  • MCI Folstein Mini- Mental State Examination
  • AD Alzheimer's disease
  • AD is an age-related, non-reversible brain disorder that develops over a period of years.
  • the symptoms of AD gradually lead to behavior and personality changes, a decline in cognitive abilities such as decision-making and language skills, and problems recognizing family and friends.
  • AD ultimately leads to a severe loss of mental function. These losses are related to the worsening breakdown of the connections between certain neurons in the brain and their eventual death.
  • AD is one of a group of disorders called dementias that are characterized by cognitive and behavioral problems. It is the most common cause of dementia among people age 65 and older.
  • Cerebral folate deficiency is defined as any neurological syndrome associated with low cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF) levels, the active folate metabolite, in the presence of normal folate metabolism outside the nervous system. CFD can result from either disturbed folate transport or from increased folate turnover within the central nervous system (CNS).
  • CSF cerebrospinal fluid
  • MTHF 5-methyltetrahydrofolate
  • CFD can result from either disturbed folate transport or from increased folate turnover within the central nervous system (CNS).
  • CNS central nervous system
  • the present invention provides a method for aiding in the diagnosis of a risk for major depressive disorder (MDD) and/or the risk of inadequate response to antidepressant treatments in a subject.
  • the method comprises detecting or quantitating the level or amount of autoantibodies to folate receptor alpha (FRa) in a sample from the subject; and diagnosing the subject as having a risk for MDD by the presence of autoantibodies to folate receptor alpha (FRa).
  • detecting or quantitating comprises performing an immunoassay with a folate receptor as an antigen.
  • detecting or quantitating comprises using a homogeneous mobility shift assay (HMSA).
  • HMSA homogeneous mobility shift assay
  • the present invention provides a method for treating a subject having MDD.
  • the method comprises detecting or quantitating the level of autoantibodies to folate receptor alpha (FRa) in a sample from the subject; and administering a treatment comprising a therapeutically effective amount of a folate containing formulation and a therapeutically effective amount of an antidepressant drug to the subject to ameliorate at least one symptom of MDD if the presence of autoantibodies to FRa is detected or determined.
  • FRa folate receptor alpha
  • the sample is selected from the group of whole blood, serum, plasma, urine, saliva and cerebral spinal fluid (CSF).
  • the sample is a serum sample.
  • the sample is a cerebral spinal fluid (CSF) sample.
  • the subject has lower than normal levels of MTHF in CSF. The subject may have normal levels of MTHF in whole blood.
  • the subject is resistant to at least one antidepressant drug, which can be, for example, a selective serotonin reuptake inhibitor (SSRI) or selective
  • the autoantibodies to folate receptor alpha (FRa) comprise blocking autoantibodies and/or binding autoantibodies.
  • the binding autoantibodies can be IgG antibodies and/or IgM antibodies against FRa.
  • the level or amount of autoantibodies can be in a range of from about 0 to 74 pg/ml in the sample. In some instances, the level or amount of autoantibodies can be in a range of from about 75 to 160 pg/ml in the sample. In other instances, the level or amount of autoantibodies is in a range of from about 161 to 260 pg/ml in the sample. In yet other instances, the level or amount of autoantibodies is in a range of from about 261 to 742 pg/ml in the sample.
  • the method further comprises treating the subject with a folate containing formulation and an antidepressant drug.
  • the antidepressant drug can be a selective serotonin reuptake inhibitor (SSRI) or selective norepinephrine reuptake inhibitor (S RI).
  • the presence or level of autoantibodies is correlated to the
  • the present invention provides a method for aiding in the diagnosis of a risk for mild cognitive impairment (MCI) or Alzheimer' s disease and related dementias (ADRD) in a subject.
  • the method comprises detecting or quantitating autoantibodies to folate receptor alpha (FRa) in a sample from the subject; and diagnosing the subject as having a risk for MCI or ADRD by the presence of autoantibodies to folate receptor alpha (FRa).
  • detecting or quantitating comprises performing an immunoassay with a folate receptor as an antigen.
  • detecting or quantitating comprises using a homogeneous mobility shift assay (HMSA).
  • HMSA homogeneous mobility shift assay
  • the present invention provides a method for treating a subject having MCI.
  • the method comprises detecting or quantitating autoantibodies to folate receptor alpha (FRa) in a sample from the subject; and administering a treatment comprising a therapeutically effective amount of a folate containing formulation to the subject to ameliorate at least one symptom of MCI if the presence of autoantibodies to FRa is determined.
  • FRa folate receptor alpha
  • the sample is a member selected from the group of whole blood, serum, plasma, urine, saliva and cerebral spinal fluid (CSF).
  • the sample is a serum sample.
  • the sample is a cerebral spinal fluid (CSF) sample.
  • the subject has lower than normal levels of MTHF in CSF.
  • the subject can have normal levels of MTHF in whole blood.
  • the level of MTHF can be determined according to any method recognized by those of ordinary skill in the art.
  • the autoantibodies to folate receptor alpha (FRa) comprise blocking autoantibodies and/or binding autoantibodies.
  • the binding autoantibodies can be IgG autoantibodies and/or IgM autoantibodies.
  • the level or amount of autoantibodies can be in a range of from about 0 to 74 pg/ml in the sample. In some instances, the level or amount of autoantibodies can be in a range of from about 75 to 160 pg/ml in the sample. In other instances, the level or amount of autoantibodies is in a range of from about 161 to 260 pg/ml in the sample. In yet other instances, the level or amount of autoantibodies is in a range of from about 261 to 742 pg/ml in the sample.
  • the method further comprises treating the subject with a folate containing formulation.
  • the method further comprises treating the subject with a folate containing formulation that includes vitamin B i2 and other B-vitamins, and an intracellular antioxidant such as N-acetyl-cysteine and a drug such as an acetylcholinesterase inhibitor and/or memantine (e.g., an NMD A antagonist drug).
  • an intracellular antioxidant such as N-acetyl-cysteine
  • a drug such as an acetylcholinesterase inhibitor and/or memantine (e.g., an NMD A antagonist drug).
  • the presence or level of autoantibodies is correlated to a cognitive or memory test scale.
  • the treatment further comprises a therapeutic effective amount of an acetylcholinesterase inhibitor or memantine drug. In other aspects, the treatment further comprises a therapeutic effective amount of an acetylcholinesterase inhibitor and a memantine drug (e.g., an NMDA antagonist drug).
  • the sample is a member selected from the group of whole blood, serum, plasma, urine, saliva and cerebral spinal fluid (CSF). In some embodiments, the sample is a serum sample. In other embodiments, the sample is a cerebral spinal fluid (CSF) sample.
  • the autoantibodies to folate receptor alpha comprise blocking autoantibodies and/or binding autoantibodies.
  • the binding autoantibodies can be IgG antibodies and/or IgM antibodies.
  • detecting or quantitating comprises performing an immunoassay with a folate receptor as an antigen. In other aspects, detecting or quantitating comprises using a homogeneous mobility shift assay (HMSA).
  • HMSA homogeneous mobility shift assay
  • the present invention provides a method for treating a subject having ADRD, the method comprising: detecting or quantitating autoantibodies to folate receptor alpha (FRa) in a sample from the subject; and administering a treatment comprising a therapeutically effective amount of a folate containing compound to the subject to ameliorate at least one symptom of ADRD if the presence of autoantibodies to FRa is determined.
  • FRa folate receptor alpha
  • the treatment further comprises a therapeutic effective amount of an acetylcholinesterase inhibitor or memantine drug (e.g., an MDA antagonist drug). In other aspects, the treatment further comprises a therapeutic effective amount of an acetylcholinesterase inhibitor and a memantine drug.
  • a therapeutic effective amount of an acetylcholinesterase inhibitor or memantine drug e.g., an MDA antagonist drug.
  • FIG. 1 shows the distribution of propensity scores in age and gender matched TRD cases with controls.
  • FIGS. 2A-2C provide analysis results for the TRD study cases.
  • FIG. 2A shows matching cases and controls in six sub-classes based on the propensity scores.
  • FIG. 2B shows the full data of the Chi-square test for deviance to detect effect-modification.
  • FIG. 2C shows the matched data of the Chi-square test for deviance to detect effect-modification.
  • FIG. 3 shows the distribution of propensity scores in age and gender matched NAC cases with controls.
  • FIGS. 4A-4C provide analysis results for the NAC study cases.
  • FIG. 4A shows matching cases and controls in six sub-classes based on the propensity scores.
  • FIG. 4B shows the full data of the Chi-square test for deviance to detect effect-modification.
  • FIG. 4C shows the matched data of the Chi-square test for deviance to detect effect-modification. DETAILED DESCRIPTION OF THE INVENTION I. INTRODUCTION
  • the present invention is based, in-part, on the surprising discovery of molecular markers of major depressive disorder, mild cognitive impairment and Alzheimer' s disease and other disorders.
  • Provided herein are methods for diagnosing MDD or MCI or ADRD or CFD based on the presence or level of circulating autoantibodies against folate receptor a (FRa) in a sample, such as a serum sample from a subject.
  • FRa folate receptor a
  • FRa folate receptor a
  • individuals with MDD or MCI or ADRD or CFD can develop or have blocking and/or binding autoantibodies to FRa.
  • These autoantibodies are polyclonal and may be blocking autoantibodies, binding autoantibodies, or both.
  • the autoantibodies can interfere with folate transport across the blood-brain barrier. These biomarkers are indicative of MDD or MCI or ADRD or CFD. In certain instances, the autoantibodies are correlated to man-made disease scoring scales or indexes such as the HAMD scale, and cognitive or memory test scales. In certain aspects, the methods described herein include features that are significantly more than correlating a nature-based principle and a disease state.
  • the L-5-methyltetrahydrofolate dose is tailored for patients suffering from depression, schizophrenia, MCI, MDD, ADRD or CFD who need higher L-5-methyltetrahydrofolate intake caused by genetic polymorphisms (like for instance MTHFR C677T) or due to blocked L-5-methyltetrahydrofolate passage at the blood-brain barrier. Dose escalation of L-5-methyltetrahydrofolate is warranted if there are confounding effects such as the severity of the indication, polymorphisms or the amount and type of autoantibodies.
  • dose escalation is warranted if blocked folate transfer across the blood-brain barrier is due to FRa-autoantibodies, or a patient history of bad food habits or diseases leading to nutritional deficiencies amongst others systemic folate deficiency (like fast food overconsumption, alcoholism, hidden celiac disease, and the like).
  • a subject carrying one or more polymorphisms associated with brain folate deficiency may require a dose of L-methylfolate that is about 2 to 4 times higher than a subject without the polymorphism(s).
  • a subject carrying one or more polymorphisms associated with brain folate deficiency e.g., MTHFR C677T
  • also has autoantibodies against FRa then an even higher dose of L- methylfolate should be administered to the subject to impact brain folate levels.
  • subjects with the autoantibodies may have unmetabolized folic acid.
  • L-5-methyltetrahydrofolate will bind to the FRa attached to choroid epithelial cells.
  • the low-affinity high capacity transporter RFCl will also be enabled to transport methylfolate to the CNS across the blood-brain barrier.
  • membrane attached FRa antigen can complex with these antibodies and the natural route of FRa-mediated transport is blocked.
  • transport of methylfolate across the blood-brain barrier via RFCl occurs at plasma concentrations significantly above the physiological nanomolar range.
  • administration of high doses of 5-methyltetrahydrofolate can achieve the principle of therapy for CFD syndromes due to FRa-autoantibodies or due to FRa gene mutations wherein higher doses are needed.
  • the presence and or titer of the autoantibodies assist or aid in the diagnostic of a variety of diseases.
  • the methods of treating is influenced by the presence of the autoantibodies and other factors or conditions that affect folate brain levels, such as for example, one-carbon polymorphisms (e.g., MTHFR 677C ⁇ T or 1298A ⁇ C or others).
  • unmetabolized folic acid can also be an indicator.
  • a patient needs more folate to reach the brain (and effectively be part of the normal treatment regimen) when autoantibodies are present, when unmetabolized folic acid is present then when just dealing with a genetic polymorphism alone.
  • detection, presence or levels of autoantibodies, unmetabolized folic acid and polymorphisms help increase diagnosis and prognosis of a variety of folate-associated diseases.
  • the methods are useful in a variety of indications including, but not limited to, neuropsychiatric and neurological diseases and disorders (e.g.
  • autism schizophrenia
  • hearing loss noise induced or age-related
  • tinnitus macular degeneration
  • visual disturbances anosmia, migraine, headache, inflammation linked diseases, myelination related diseases (e.g., multiple sclerosis), epilepsy and seizures in general, sleep disturbances, insomnia, irritability associated with neuropsychiatric disorders, metabolic diseases, including diabetic peripheral neuropathy and neuropathy in general, renal diseases, lung diseases, and or thyroid diseases.
  • depression is a clinical symptom, and can include, but not limited to, major depressive disorder (including single episode and recurrent), unipolar depression, treatment-refractory depression, resistant depression, anxious depression and dysthymia (also referred to as dysthymic disorder).
  • major depressive disorder including single episode and recurrent
  • unipolar depression including single episode and recurrent
  • treatment-refractory depression including single episode and recurrent
  • resistant depression including single episode and recurrent
  • anxious depression also referred to as dysthymic disorder
  • depression can encompass any major depressive disorder, dysthymic disorder, mood disorders due to medical conditions with depressive features, mood disorders due to medical conditions with major depressive-like episodes, substance-induced mood disorders with depressive features and depressive disorder not otherwise specific as defined by their diagnostic criteria, as listed in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) or any later edition thereof, or the World Health Organization's International Statistical Classification of Diseases and Related Health Problems (ICD-10).
  • major depressive disorder includes a mental/mood condition characterized by two or more major depressive episodes. Symptoms of MDD may include fatigue, feelings of worthlessness or guilt, impaired concentration or indecisiveness, insomnia or hypersomnia, markedly diminished interest or pleasure in almost all activities, restlessness, recurring thoughts of death or suicide, and significant weight loss or gain (5% weight change). Diagnostic criteria for MDD and depressive episodes are list in the DSM-IV and are useful for assessing a subject.
  • depression is evaluated by a clinician using, e.g., the criteria listed in the DSM-IV or efficacy measures (neuropsychological assessments) such as the Hamilton Depression Rating Scale (HAMD-28, HAMD-21 or HAMD-7), the Clinical Global Impression (CGI) Scale, the Montgomery -Asberg Depression Rating Scale (MADRS), the Beck Depression Inventory (BDI), the Zung Self-Rating Depression Scale, the Wechsler Depression Rating Scale, the Raskin Depression Rating Scale, the Inventory of Depressive Symptomatology (IDS), and the Quick Inventory of Depressive Symptomatology (QIDS).
  • measurable lessening of depression includes any clinically significant decline in a measurable marker or symptom, such as measuring markers for depression in the blood or CSF e.g., red blood cell folate, serum folate, serum MTHF, or assessing the degree of depression, e.g., using a neuropsychological assessment.
  • a score of 0-7 on HAMD-7 is typically considered to be normal. Scores of 20 or higher indicate moderate, severe, or very severe depression. Questions 18-21 may be recorded to give further information about the depression (such as whether diurnal 1 variation or paranoid symptoms are present), but are not necessary part of the scale. Thus, a reduction of symptoms can be considered clinically relevant if, e.g., the HAMD score is decreased to under, e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, or 6.
  • MCI cognitive impairment
  • MCI includes a brain function syndrome or condition that is characterized by symptoms including problems with memory, language, thinking and judgment that are greater than normal age-related changes.
  • MCI Mini-Mental State Examination
  • neurological examinations e.g., neurological examinations, neuropsychological evaluations, and evaluations of medical history can be performed by a clinician to assess a subject and aid in the evaluation of possible MCI. There may be a higher likelihood of MCI to progress to an Alzheimer' s disease-related disorder.
  • ADRD Alzheimer's disease
  • AD Alzheimer's disease
  • AD is an age-related, non-reversible brain disorder that develops over a period of years.
  • the symptoms of AD gradually lead to behavior and personality changes, a decline in cognitive abilities such as decision-making and language skills, and problems recognizing family and friends.
  • AD ultimately leads to a severe loss of mental function or dementia. These losses are related to the worsening breakdown of the connections between certain neurons in the brain and their eventual death.
  • Cognitive, functional, global and caregiver based assessments of Alzheimer' s disease and related disorders can performed to evaluate an individual' s overall condition.
  • useful cognitive assessments include the Alzheimer's Disease Assessment Scale, cognitive subsection (ADAS-cog), Blessed information-memory- concentration test (BIMC), clinical dementia rating scale (CDR), and mini-mental state examination (MMSE).
  • useful function assessment tools include, but are not limited to, the function assessment questionnaire (FAQ), instrumental activity of daily living (IADL), physical self-maintenance scale (PSMS), and progressive deterioration scale (PDS).
  • Non- limiting global assessment tools include the clinical global impression of change (CGIC), clinical interview-based impression (CIBI) and global deterioration scale (GDS).
  • Useful caregiver-based assessments include the behavioral pathology in Alzheimer' s disease rating scale (BEHAVE-AD) and neuropsychiatry inventory (NPI). Additional methods for assessing cognitive impairment in patients suspected of having Alzheimer' s disease are described, for example, in Cordell et al., Alzheimer' s & Dementia, 2013, 9: 141-150.
  • acetylcholinesterase inhibitor or "AChEI” is used herein to refer to a drug that enhances function of cholinergic neurons by inhibiting the catabolic enzyme acetylcholinesterase (AChE).
  • the term encompasses reversible, pseudo-reversible and irreversible AChEIs as well as AChEIs that selectively inhibit AChE, and AChEIs, that are less selective (e.g., also target butyrylcholinesterase, BuChE).
  • AChEIs useful in the methods of the present invention are reversible or pseudo-reversible.
  • AChEIs useful in the methods and compositions of the present invention include, but are not limited to, tacrine (THA; l,2,3,4-tetrahydro-9-aminoacridine hydrochloride), donepezil, galantamine, rivastigmine, huperzine A, zanapezil, ganstigmine, phenserine,
  • NMDA antagonist drugs is used to refer to drugs, that can suppress the normal triggering of NMDA receptor-mediated neuronal firings.
  • Preferred NMDA antagonist drugs of the invention are 1-aminocyclohexane derivatives such as memantine and neramexane. These compounds also have 5HT 3 antagonist activity and/or neuronal nicotinic receptor antagonist activity.
  • sample includes any biological specimen obtained from an individual.
  • Suitable samples for use in the present invention include, without limitation, whole blood, plasma, serum, cerebrospinal fluid, saliva, urine, stool, tears, any other bodily fluid, tissue samples (e.g., biopsy), and cellular extracts thereof (e.g., red blood cellular extract).
  • the sample is a blood, plasma, serum, urine, saliva or cerebrospinal fluid (CSF) sample.
  • CSF cerebrospinal fluid
  • the use of samples such as plasma, serum, saliva, urine and CSF is well known in the art (see, e.g., Hashida et al., J. Clin. Lab. Anal., 1 1 :267-86 (1997)).
  • samples such as whole blood, plasma, serum, saliva, urine or CSF samples can be diluted prior to the analysis of marker levels.
  • the term "marker” or “biomarker” includes any biochemical marker, serological marker, protein markers, genetic marker, metabolic markers, or other clinical characteristic that can be used in the selection of therapy for depression, in the prediction of the probable course and outcome of depression, and/or in the prediction of the likelihood of recovery from the disorder.
  • the markers are utilized in combination with one or more (e.g., a plurality of) statistical analyses to aid or provide a prognosis of depression in an individual.
  • the markers are used to aid or provide a prediction of therapeutic response to a treatment (e.g., antidepressant drug monotherapy) in an individual diagnosed with depression (e.g., major depressive disorder).
  • the present invention relies, in part, on determining the presence (or absence) or level (e.g., concentration) of an autoantibody against folate receptor a in a sample obtained from an individual.
  • detecting the presence of an autoantibody includes determining the presence of each marker of interest by using any quantitative or qualitative assay known to one of skill in the art.
  • qualitative assays that determine the presence or absence of a particular trait, variable, genotype, and/or biochemical or serological substance e.g., protein or antibody
  • quantitative assays that determine the presence or absence of protein, antibody, or activity are suitable for detecting each marker of interest.
  • the term "detecting the level of an autoantibody” includes determining the level of each marker of interest by using any direct or indirect quantitative assay known to one of skill in the art. In certain instances, quantitative assays that determine, for example, the relative or absolute amount of protein, antibody, or activity are suitable for detecting the level of each marker of interest. One skilled in the art will appreciate that any assay useful for detecting the level of a marker is also useful for detecting the presence or absence of the marker. [0055]
  • the term "individual,” “subject,” or “patient” are used interchangeably and typically includes humans, but also includes other animals such as, e.g., other primates, rodents, canines, felines, equines, ovines, porcines, and the like.
  • antidepressant or “antidepressant drug” includes any pharmaceutical agent which treats depression.
  • antidepressant drug administered to the subject in accordance with the methods described herein can be any conventional pharmaceutical agent which treats depression.
  • antidepressant drug administered to the subject in accordance with the methods described herein can be any conventional pharmaceutical agent which treats depression.
  • antidepressant drugs include, but are not limited to, selective serotonin reuptake inhibitors (SSRIs), serotonin and dopamine reuptake inhibitors (SDRIs), serotonin-norepinephrine reuptake inhibitors (S RIs), serotonin-noradrenaline-dopamine reuptake inhibitors
  • SSRIs selective serotonin reuptake inhibitors
  • SDRIs serotonin and dopamine reuptake inhibitors
  • S RIs serotonin-norepinephrine reuptake inhibitors
  • drug monotherapy includes a treatment regimen that includes the use of one therapeutic agent (e.g., drug) during the course of therapy.
  • the agent can be any therapeutic agent (e.g., drug) during the course of therapy.
  • the agent can be any therapeutic agent (e.g., drug) during the course of therapy.
  • the agent can be any therapeutic agent (e.g., drug) during the course of therapy.
  • the agent can be any therapeutic agent (e.g., drug) during the course of therapy.
  • the agent can be
  • adjunctive therapy includes a treatment regimen that includes another therapeutic agent (e.g., drug) used together with another therapeutic agent (e.g., drug) during the course of therapy.
  • the adjunctive agent can be administered once or repeatedly during the course of therapy and given simultaneously or subsequently to the primary agent.
  • treatment refers to preventing the progression of the disease, altering the course of the disorder (for example, but are not limited to, slowing the progression of the disorder), partially reversing a symptom of the disorder or reducing one or more symptoms and/or one or more biochemical markers in a subject, preventing one or more symptoms from worsening or progressing, promoting recovery, and/or improving prognosis.
  • the terms “effective amount,” “amount effective” and “therapeutically effective amount” include an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, these terms include an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts.
  • the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose.
  • the dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.
  • a preparation can be administered in a "prophylactically effective amount"; that is, an amount effective for prevention of a disease or condition.
  • the term "memory test scale” or “cognitive or memory test scale” includes a neuropsychological test designed to measure different cognitive or memory functions in a subject.
  • cognitive or memory tests useful for diagnosing MCI include the Williams Scale for the Measurement of Memory, Wechsler Memory Scale, Rivermead Behavior Memory Test, Wechsler Adult Intelligence Scale, Mattice Dementia Rating Scale (DRS), the Everyday Memory Questionnaire, Free and Cued and Selective Reminding Test, Rey Auditory Verbal Learning Test, California Verbal Learning Test, Hopkins Verbal Learning Test (HVLT), Trail Making test, Boston Naming Test, Stroop Color Word Test, Cambridge Neuropsychological Test Automated Battery (CANTAB), Motor Control Task (MT) test, Pattern Recognition Memory (PRM) test, Paired Associates Learning (PAL) test, Spatial Working Memory (SWM) test, and other tests to evaluate episodic memory (i.e., the ability to learn and retain new information), executive functions (e.g., set-shifting
  • Cerebral folate deficiency (CFD) syndrome is a neurodevelopmental disorder typically caused by folate receptor autoantibodies that interfere with folate transport across the blood-brain barrier.
  • CFD Cerebral folate deficiency
  • the serum or plasma blood levels of folate are typically normal, but a sample of cerebral spinal fluid indicates decreased levels of folate.
  • the present invention provides methods comprising measuring the presence (or absence) or level of autoantibodies to FRa in a sample, e.g., blood, serum, plasma, urine, saliva or CSF sample, from a subject.
  • a sample e.g., blood, serum, plasma, urine, saliva or CSF sample
  • the subject can be a human subject.
  • the subject is suspected of or has MDD.
  • the subject has one or more MTHFR S Ps (e.g., one or more MTHFR C677T mutations).
  • the subject has impaired or blocked folate transport at the blood- brain barrier.
  • the subject is suspected of or has MCI.
  • the subject is suspected of or has ADRD.
  • the subject can have or is suspected of having cerebral folate deficiency syndrome, or the subject can have or is suspected of having sub-normal cerebral folate level e.g., a neurological syndrome or condition characterized by having lower levels of 5-methyltetrahydrofolate (5MTHF) in the cerebrospinal fluid and normal levels of folate in the blood and plasma.
  • 5MTHF 5-methyltetrahydrofolate
  • the subject has normal folate levels in serum, plasma and/or whole blood compared to a healthy subject, yet has a lower than normal level of 5-methyltetrahydrofolate (5MTHF) in cerebrospinal fluid.
  • the serum autoantibody titer can be used to predict the CSF methylfolate level. The level of CSF methylfolate can then be used to administer the necessary dose of methylfolate.
  • the CSF methylfolate levels are stratified depending on age, sex, indication and combinations thereof.
  • the method provided herein includes measuring the presence or level of blocking autoantibody, the presence or level of binding IgG autoantibody, the presence or level of binding IgM autoantibody, and any combination thereof.
  • Levels of autoantibodies to FRa can be detected by any known methods in the art. Autoantibodies to FRa can be detected using immunoassays as described in, e.g., Ramaekers et al, N Eng J Med, 352: 1985-91, 2005, Molloy et al., N Engl J Med, 361(2): 152-160, 2009, U.S. Pat. No. 7,846,672 and U.S. Pat. App. No.
  • recombinant or purified folate receptor a or apo-FRa i.e., FRa without bound folate
  • the test sample serum or plasma
  • the complexed autoantibodies are detected using a detectable, labeled secondary antibody against human IgG or IgM and, in some instances, a colorimetric reaction.
  • the test sample can be pre-treated to remove endogenous folate, such as by treating with acid/charcoal.
  • autoantibodies against FRa can be detected using a homogenous mobility shift assay (HMSA).
  • HMSA homogenous mobility shift assay
  • Autoantibodies against FRa can be detected by using fluorescently labeled folate receptor and FIPLC on a size exclusion column.
  • the presence of complexes comprising labeled FRa and FRaAuAb can be monitored by fluorescence and compared to free labeled FRa.
  • Autoantibodies against FRa can be detected using a homogenous mobility shift assay (FEVISA) as disclosed in U.S. Patent No. 8,574,855, U. S. Patent Pub. No.
  • FEVISA homogenous mobility shift assay
  • the present invention provides a method for determining the presence or level of an autoantibody to FRa in a sample, the method comprising: (a) contacting a fluorescently labeled folate receptor with the sample to form a labeled complex with the autoantibody; (b) subjecting the labeled complex to size exclusion chromatography to separate the labeled complex from free labeled folate receptor and to detect an amount of the labeled complex and an amount of free labeled folate receptor; and (c) comparing the amount of the labeled complex and the amount of the free labeled folate receptor detected in step (b) to a standard curve of known amounts of the autoantibody, thereby determining the presence or level of the autoantibody.
  • mass spectrometry can be used, e.g., the biological sample is infused directly into the mass spectrometer which provides both separation and detection of autoantibodies to FRa.
  • the autoantibodies to FRa can be optionally separated (e.g., prior to detection) from a biological sample by gas chromatography (GC), e.g., when interfaced with mass spectrometry (GC-MS), and/or high performance liquid chromatography (HPLC), and/or capillary electrophoresis (CE).
  • GC gas chromatography
  • HPLC high performance liquid chromatography
  • CE capillary electrophoresis
  • Nanostructure-initiator mass spectrometry laser-desorption/ionization mass spectrometry, e.g., matrix assisted laser desorption/ionization (MALDI) mass spectrometry, surface-enhanced laser
  • MALDI matrix assisted laser desorption/ionization
  • LC-MS liquid chromatography-mass spectrometry
  • GC-MS gas chromatography-mass spectrometry
  • HPLC-MS high performance liquid chromatography-mass spectrometry
  • capillary electrophoresis-mass spectrometry capillary electrophoresis-mass spectrometry
  • tandem mass spectrometry e.g., MS/MS, MS/MS/MS, ESI-MS/MS, etc.
  • Blocking autoantibodies to FRa refer to autoantibodies that block (e.g., sterically hinder or prevent) the binding of folic acid or folate to folate receptor a.
  • Methods for detecting blocking autoantibodies include an assay that uses radiolabeled folic acid.
  • the assay can include the steps of incubating the individual's sample, e.g., serum, that is free of folate with solubilized, purified folate receptors and adding radiolabeled folic acid, e.g., [ 3 H]folic acid. If the blocking autoantibodies are present in the sample, [ 3 H]folic acid will be prevented from binding the folate receptor.
  • the method comprises incubating the sample with solubilized apo-folate receptor and [ 3 H]folic acid such that the folic acid can bind to the folate receptor, removing free [ 3 H]folic acid by adsorption to dextran-coated charcoal, and measuring receptor-bound radioactivity in the supernatant fraction.
  • the amount of blocking autoantibody can be determined because it is inversely proportional to the amount of radioactivity bound to the receptor.
  • An exemplary embodiment of a method of measuring the level of blocking autoantibodies to FRa is found in, e.g., Ramaekers et al, N Eng J Med, 352: 1985-91, 2005.
  • Binding autoantibodies to FRa refers to autoantibodies that specifically bind to folate receptor a.
  • a FRa epitope is recognized by a binding autoantibody against FRa.
  • An exemplary embodiment of a method for measuring the level of binding autoantibodies is an ELISA assay using purified or recombinant folate receptors as the immobilized antigen. Secondary antibodies known to those of ordinary skill in the art can be used to determine whether the autoantibody is an IgG or IgM antibody type.
  • the level or amount of autoantibodies detected in an individual' s sample is from about 0 to about 1000 pg/ml, e.g., about 0 pg/ml-about 900 pg/ml, about 50 pg/ml-about 1000 pg/ml, about 0 pg/ml-about 100 pg/ml, about 0 pg/ml-about 74 pg/ml, about 75 pg/ml-about 160 pg/ml, about 161 pg/ml-about 260 pg/ml, about 261 pg/ml-about 1000 pg/ml, about 0 pg/ml-about 250 pg/ml, about 251 pg/ml-about 500 pg/ml, or about 501 pg/ml-about 1000 pg/ml.
  • kits for diagnosing MDD or MCI or ADRD or CFD in a subject by measuring the level of blocking and/or binding autoantibodies to FRa in a sample taken from the subject.
  • the subject may be suspected of having MDD or MCI or ADRD or CFD. If the presence of blocking and/or binding (e.g., IgG binding autoantibodies and/or IgM binding autoantibodies) is determined, the subject is determined to have MDD or MCI or ADRD or CFD.
  • blocking and/or binding e.g., IgG binding autoantibodies and/or IgM binding autoantibodies
  • the presence or level of autoantibodies is correlated to a depression criteria or scale.
  • the level of autoantibodies to FRa can correspond to a value or value range on a depression scale such as the HAMD-28 scale and the like.
  • the level of autoantibodies represents a score indicating major depressive disorder.
  • the presence or level of autoantibodies is correlated to a cognitive or memory test scale.
  • the level of autoantibodies determined using the method provided herein can represent a value or value range corresponding to MCI on a cognitive or memory test scale.
  • the level of autoantibodies can represent a value or value range corresponding to ADRD on a cognitive or memory test scale.
  • the present invention is based, in part, on the surprising discovery that subjects with MDD or MCI or ADRD have a statistically higher probability or incidence of having blocking and/or binding autoantibodies to FRa compared to normal subjects who do not have MDD or MCI or ADRD.
  • the test subject and normal (control) subject can be age- matched and gender-matched.
  • the test subject and normal (control) subject can be age-matched and gender-matched.
  • the method for aiding the diagnosis of MDD or MCI or ADRD includes using a statistical algorithm to process the information obtained from detecting or quantitating the presence (or absence) or level of the autoantibodies.
  • the statistical algorithms independently comprise one or more learning statistical classifier systems.
  • statistical algorithms advantageously provide improved sensitivity, specificity, negative predictive value, positive predictive value, and/or overall accuracy for diagnosing MDD or MCI or ADRD.
  • the term "statistical algorithm” or “statistical process” includes any of a variety of statistical analyses used to determine relationships between variables.
  • the variables can be the presence or level of at least one marker of interest and/or the assessment of at least one psychological measure. Any number of markers and/or psychological measures can be analyzed using a statistical algorithm described herein. For example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more biomarkers and/or psychological measures can be included in a statistical algorithm. In one embodiment, logistic regression is used. In another embodiment, linear regression is used.
  • the statistical algorithms of the present invention can use a quantile measurement of a particular marker within a given population as a variable.
  • Quantiles are a set of "cut points" that divide a sample of data into groups containing (as far as possible) equal numbers of observations. For example, quartiles are values that divide a sample of data into four groups containing (as far as possible) equal numbers of observations. The lower quartile is the data value a quarter way up through the ordered data set; the upper quartile is the data value a quarter way down through the ordered data set.
  • Quintiles are values that divide a sample of data into five groups containing (as far as possible) equal numbers of observations.
  • the present invention can also include the use of percentile ranges of marker levels (e.g., tertiles, quartile, quintiles, etc.), or their cumulative indices (e.g., quartile sums of marker levels, etc.) as variables in the algorithms (just as with continuous variables).
  • percentile ranges of marker levels e.g., tertiles, quartile, quintiles, etc.
  • cumulative indices e.g., quartile sums of marker levels, etc.
  • the present invention involves detecting or determining the presence, absence or level of autoantibodies using quartile analysis.
  • the level of autoantibodies is defined as being in the first quartile ( ⁇ 25%), second quartile (25-50%), third quartile (51%- ⁇ 75%), or fourth quartile (75-100%) in relation to a reference database of samples. These quartiles may be assigned a quartile score of 1, 2, 3, and 4, respectively.
  • autoantibodies that are not detected in a sample are assigned a quartile score of 0 or 1
  • autoantibodies that are detected (e.g., present) in a sample is assigned a quartile score of 4.
  • quartile 1 represents samples with the lowest autoantibody levels
  • quartile 4 represent samples with the highest autoantibody levels.
  • the reference database of samples can include a large spectrum of patients with MDD, MCI or ADRD. From such a database, quartile cut-offs can be established.
  • Statistical algorithms can be trained and tested using a cohort of samples (e.g., serological samples) from healthy individuals, MDD patients, non-MDD patients, MCI patients, non-MCI patients, AD patients, non-AD patients, ADRD patients and/or non-ADRD patients.
  • Samples from patients diagnosed with MDD can be stratified according to HAMD-28 score. Samples from patients diagnosed with MDD using a published criteria such as the HAMD-28 diagnostic criteria are suitable for use in training and testing the statistical algorithms described herein. Samples from healthy individuals can include those that were not identified as MDD, MCI, ADRD or AD samples.
  • One skilled in the art will know of additional techniques and diagnostic criteria for obtaining a cohort of patient samples that can be used in training and testing the statistical algorithms described herein.
  • sensitivity refers to the probability that a method, system, or code of the invention gives a positive result when the sample is positive, e.g., having MDD, MCI or ADRD. Sensitivity is calculated as the number of true positive results divided by the sum of the true positives and false negatives. Sensitivity essentially is a measure of how well a method, system, or code of the invention correctly identifies those with MDD, MCI or
  • the statistical algorithms can be selected such that the sensitivity is at least about 60%, and can be, for example, at least about 65%, 70%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.
  • the term "specificity" refers to the probability that a method, system, or code of the invention gives a negative result when the sample is not positive, e.g., not having MDD, MCI or ADRD. Specificity is calculated as the number of true negative results divided by the sum of the true negatives and false positives. Specificity essentially is a measure of how well a method, system, or code of the invention excludes those who do not have MDD, MCI or ADRD from those who have the disease.
  • the statistical algorithms can be selected such that the specificity is at least about 70%, for example, at least about 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.
  • negative predictive value refers to the probability that an individual identified as not having MDD, MCI or ADRD actually does not have the disease. Negative predictive value can be calculated as the number of true negatives divided by the sum of the true negatives and false negatives. Negative predictive value is determined by the characteristics of the method, system, or code as well as the prevalence of the disease in the population analyzed.
  • the statistical algorithms can be selected such that the negative predictive value in a population having a disease prevalence is in the range of about 70% to about 99% and can be, for example, at least about 70%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.
  • Positive predictive value refers to the probability that an individual identified as having MDD, MCI or ADRD actually has the disease. Positive predictive value can be calculated as the number of true positives divided by the sum of the true positives and false positives. Positive predictive value is determined by the
  • the statistical algorithms can be selected such that the positive predictive value in a population having a disease prevalence is in the range of about 80% to about 99% and can be, for example, at least about 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.
  • Predictive values including negative and positive predictive values, are influenced by the prevalence of the disease in the population analyzed.
  • the statistical algorithms can be selected to produce a desired clinical parameter for a clinical population with a prevalence of MDD, MCI or ADRD.
  • statistical algorithms can be selected for MDD, MCI or ADRD prevalence of up to about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%), 60%), 65%), or 70%, which can be seen, e.g., in a clinician's office such as a
  • the presence (or absence) or level of autoantibodies can be substantially equal to or similar to a control subject who has MDD.
  • the control subject who has MDD is diagnosed using a Hamilton Depression Rating Scale or memory test.
  • the amount of autoantibody is measure and a standard curve generated. If the control subject with MDD and the test subject have similar levels of autoantibodies against FRa or the test subject has higher levels of autoantibodies than the control subject, and similar scores in the respective depression or cognitive scales, it is determined that the test subject has MDD.
  • the level of autoantibodies is correlated to a scoring scale for MDD, such as HAMD-7, HAMD-17, HAMD-21, HAMD-28 and similar scoring scales.
  • a scoring scale for MDD such as HAMD-7, HAMD-17, HAMD-21, HAMD-28 and similar scoring scales.
  • An algorithm or mathematical computation can be used to assign a specific level of autoantibodies to a particular score on a MDD assessment scale.
  • the level of autoantibodies in patients with MCI or ADRD can be correlated to a scoring scale such as cognitive testing scales.
  • cognitive or memory tests include the Free and Cued and Selective Reminding Test, the Rey Auditory Verbal Learning Test, the California Verbal Learning Test, the Hopkins Verbal Learning Test (HVLT), the Wechsler Memory Scale, the Trail Making test, the Boston Naming Test, the Cambridge Neuropsychological Test Automated Battery (CANTAB), the Motor Control Task (MT) test, the Pattern Recognition Memory (PRM) test, the Paired Associates Learning (PAL) test, the Spatial Working Memory (SWM) test, and other tests to evaluate episodic memory (i.e., the ability to learn and retain new information), executive functions (e.g., set-shifting, reasoning, problem-solving, and planning), language (e.g., naming, fluency, expressive speech and comprehension), visuospatial skills, and/or attention control.
  • executive functions e.g., set-shifting, reasoning, problem-solving
  • test subject has a higher level of autoantibodies compared to a control subject who is healthy or normal. If it is determined that the test subject has a higher level of autoantibodies against FRa compared to a normal subject (control subject), then the test subject is predicted to have a higher risk of having MDD or MCI or ADRD than not having the respective disease.
  • a subject having MDD is more likely to have blocking or binding autoantibodies than a normal subject who does not have MDD.
  • a subject with MDD can be at least two times more likely to express blocking or binding autoantibodies in blood, serum, plasma, saliva, urine or cerebrospinal fluid.
  • the subject with MDD can be more likely to have blocking autoantibodies than a normal subject.
  • the subject with MDD can be more likely to have IgM autoantibodies than a normal subject.
  • a subject having MCI is more likely to have blocking or binding autoantibodies than a normal subject who does not have MCI.
  • a subject with MCI can be at least two times more likely to express blocking or binding autoantibodies in blood, serum, plasma, saliva, urine or cerebrospinal fluid.
  • the subject with MCI can be more likely to having binding IgG autoantibodies than a normal subject.
  • the subject with MCI can be more likely to having binding IgM autoantibodies than a normal subject.
  • a subject having ADRD is more likely to have blocking or binding autoantibodies than a normal subject who does not have ADRD.
  • a subject with ADRD can be at least two times more likely to express blocking or binding autoantibodies in blood, serum, plasma, saliva, urine or cerebrospinal fluid.
  • the subject with ADRD can be more likely to having binding IgG autoantibodies than a normal subject.
  • the subject with ADRD can be more likely to having binding IgM autoantibodies than a normal subject.
  • the methods of the present invention may further comprise presenting the levels of the autoantibodies and/or the diagnosis of the subject to a user (e.g., a clinician such as a psychiatrist, neurologist or general practitioner).
  • a user e.g., a clinician such as a psychiatrist, neurologist or general practitioner.
  • the results of the methods are communicated or stored in a readable format or in a computer database or other suitable machine or device for storing such information.
  • the method may include sending or reporting the results to a clinician.
  • the method also includes recommending or selecting a drug therapy for the subject at risk of having MDD. If the subject has a risk of MDD, a combination or adjunctive therapy of folate and an antidepressant drug can be recommended or administered to the subject in need thereof. In some cases, if the subject is resistant to an antidepressant drug such as a selective serotonin reuptake inhibitor (SSRI) or selective norepinephrine reuptake inhibitor (S RI), a different antidepressant drug is recommended or selected. If adjunctive folate therapy is recommended, a folate containing formulation can be Deplin ® in the case of MDD. Deplin® is a medical food containing L-methylfolate, the fully-reduced, bioactive metabolic form of the vitamin B 9 (folate).
  • SSRI selective serotonin reuptake inhibitor
  • S RI selective norepinephrine reuptake inhibitor
  • a drug therapy comprising a folate containing formulation and optionally, an acetylcholinesterase inhibitor and/or memantine drug can be recommended or administered to the subject in need thereof.
  • a subject diagnosed as having MCI or ADRD can be given a folate formulation monotherapy.
  • administration of a folate containing formulation and an acetylcholinesterase inhibitor is recommended.
  • administration of a folate containing formulation and a memantine drug is recommended.
  • administration of a folate containing formulation, an acetylcholinesterase inhibitor, and a memantine drug is recommended.
  • the folate containing formulation can be CerefolinNAC ® in the case of MCI.
  • CerefolinNAC is a medical food containing L-methylfolate, methylcobalamin (the fully-reduced, bioactive metabolic form of the vitamin B i2 , and N-acetyl-cysteine (an intracellular antioxidant).
  • L- methylfolate is the only active form of folate taken up by the brain.
  • the method includes administering a drug therapy to a subject at risk of having MDD or MCI or ADRD to ameliorate at least one symptom of the disorder.
  • a drug therapy such as a combination drug regimen comprising a medically effective amount of a folate formulation and a therapeutically effective amount of an antidepressant drug can be administered to a patient having MDD.
  • a medically effective amount of a folate formulation can be administered to a patient having MCI.
  • a medically effective amount of a folate formulation can be administered with a therapeutically effective amount of an acetylcholinesterase inhibitor.
  • the folate formulation is administered with a therapeutically effective amount of a memantine drug.
  • the folate formulation is administered with a therapeutically effective amount of an acetylcholinesterase inhibitor.
  • acetylcholinesterase inhibitor and a therapeutically effective amount of a memantine drug.
  • a medically effective amount of a folate formulation can be administered to a patient having ADRD.
  • a medically effective amount of a folate formulation can be administered with a therapeutically effective amount of an acetylcholinesterase inhibitor.
  • the folate formulation is administered with a therapeutically effective amount of a memantine drug.
  • the folate formulation is administered with a therapeutically effective amount of an
  • acetylcholinesterase inhibitor and a therapeutically effective amount of a memantine drug.
  • suitable therapies include acetylcholinesterase inhibitors. These therapies include, for example, donepezil (Aricept), rivastigmine (Exelon), and galantamine
  • a combination therapy or adjunctive therapy of a folate formulation and an antidepressant drug can be recommended, selected or administered.
  • the antidepressant drug is a selective serotonin reuptake inhibitor (SSRI) or a selective norepinephrine reuptake inhibitor (S RI).
  • the combination therapy or adjunctive therapy includes a folate formulation and a SSRI.
  • the combination therapy or adjunctive therapy includes a folate formulation and a SNRI.
  • antidepressant include serotonin reuptake inhibitors (SRIs), serotonin reuptake inhibitors (SSRIs), serotonin and dopamine reuptake inhibitors (SDRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), serotonin-noradrenaline-dopamine reuptake inhibitors (SNDRIs), noradrenergic and specific serotonergic anti-depressants (NASSAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), norepinephrine
  • NRIs noradrenaline reuptake inhibitors
  • MAOIs monoamine oxidase inhibitors
  • SSREs selective serotonin reuptake enhancers
  • melatonergic agonists tryptamines
  • TCAs tricyclic antidepressants
  • SSRIs act to preventing the reuptake of serotonin by the presynaptic neuron, thereby maintaining high levels of serotonin in the synapse.
  • SSRIs include, but are not limited to, the following (trade names in parentheses): alaproclate; amoxapine; citalopram (such as CELEXA®, CIPRAMIL®, EMOCAL®, SEPRAM® and SEROPRAM®);
  • clomipramine dapoxetine
  • duloxetine e.g., CYMBAL TA®
  • escitalopram oxalate e.g., LEXAPRO®, CIPRALEX® and ESERTIA®
  • femoxetine fenfluramine
  • fluoxetine e.g.
  • PROZAC® FONTEX®, SEROMEX®, SERONIL®, SARAFEM®, FLUCTIN® (EUR), and FLUOX® (NZ)
  • fluvoxamine maleate e.g., LUVOX®, FAVERIN®, and DUMYROX
  • indalpine milnacipran
  • norfenfluramine olanzapine
  • paroxetine e.g., PAXIL®
  • SEROXAT® SEROXAT®, AROPAX®, DEROXAT®, REXETIN®, XETANOR®, and PAROXAT®); sertraline (e.g., ZOLOFT®, LUSTRAL® and SERLAIN®); trazodone (e.g., DESYREL®, MOLIPAXIN®, TRITTICO®, THOMBRAN®, TRIALODINE®, TRAZOREL®,
  • sertraline e.g., ZOLOFT®, LUSTRAL® and SERLAIN®
  • trazodone e.g., DESYREL®, MOLIPAXIN®, TRITTICO®, THOMBRAN®, TRIALODINE®, TRAZOREL®
  • SSRIs and/or SRIs include, without limitations, citalopram, R-fluoxetine, nefazodone, imipramine, imipramine N-oxide, desipramine, pirandamine, dazepinil, nefopam, befuraline, fezolamine, cianoimipramine, litoxetine, cericlamine, seproxetine, WY 27587, WY 27866, imeldine, ifoxetine, tiflucarbine, viqualine, apelinaprine, YM 922, S 33005, F 98214TA, OPC 14523, cyanodothepine, tnmipramine, quinupramine, dothiepin, , nitroxazepine, McN 5652, McN 5707, 01 77, Org 6582, Org 6997, Org
  • Non-limiting examples of SNRIs include: venlafaxine (EFFEXOR XR®,
  • EFFEXOR® desvenlafaxine
  • PRISTIQ® desvenlafaxine
  • sibutramine MMIDIA®, REDUCTIL®
  • levomilnacipran FETZIMA®
  • nefazodone SEZONE®
  • milnacipran DALCIPRAN®, IXEL®' SAVELLA®
  • duloxetine CYMBALTA®, YENTRENE®
  • bicifadine a levomilnacipran
  • FETZIMA® levomilnacipran
  • SEZONE® nefazodone
  • milnacipran DALCIPRAN®, IXEL®' SAVELLA®
  • duloxetine CYMBALTA®, YENTRENE®
  • bicifadine bicifadine
  • Bupropion e.g., WELLBUTRIN®
  • SDRI serotonin and dopamine reuptake inhibitor
  • SNDRIs include:
  • Sibutramine (MERID I A®/REDUC TIL® ) .
  • a non-limiting example of a NASSA includes mirtazapine (AVANZA®, ZISPIN®, REMERON®).
  • NRIs include, without limitation, atomoxetine, maprotiline, nisoxetine, reboxetine, viloxazine and TCAs/Tetras (such as AMITRIPTYLINE®, AMOXAPINE®, BUTRIPTYLINE®,
  • MAOIs include: iproclozide, iproniazid, isocarboxazid, nialamide, pargyline, phenelzine, rasagiline, selegiline, toloxatone, tranylcypromine, RIMAs (brofaromine, beta-carbolines (harmaline) and moclobemide).
  • a non-limiting example of a SSRE includes tianeptine (STABLON®, COAXIL®, and TATINOL®).
  • a non-limiting example of a TCA includes desipramine (NORPRAMIN® and PERTOFRANEIS®).
  • Additional antidepressants that can be used in the invention described herein can include, but are not limited to, natural products such as Kava-Kava, and St. John' s Wort; dietary supplements such as s-adenosylmethionine; neuropeptides such as thyrotropin- releasing hormone; compounds targeting neuropeptide receptors such as neurokinin receptor antagonists; and hormones such as triiodothyronine.
  • the antidepressant drug dose can range from 0.1 mg/day to about 1000 mg/day, from about 0.5 mg/day to about 500 mg/day, from about 1 mg/day to about 400 mg/day, from about 5 mg/day to about 300 mg/day, or from about 10 mg/day to about 200 mg/day.
  • One of skill in the art can readily adjust dosage for each different antidepressant drug, depending on a number of factors such as types and/or potency of antidepressants, severity of depression, physical condition of a subject (e.g., ages, genders, and weights), administration routes, other medications taken by a subject, and any combinations thereof.
  • combination therapy comprising the therapeutically effective amount of the folate containing formulation and the therapeutically effective amount of the antidepressant drug is sufficient to increase the degree of improvement in at least one neuropsychological test, e.g., as measured by HAMD-7, HAMD-17, HAMD-21, HAMD-28 or other efficacy measures, by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%), at least about 80%, or at least about 90%, as compared to the degree of improvement obtained in the absence of the combination therapy.
  • HAMD-7 e.g., as measured by HAMD-7, HAMD-17, HAMD-21, HAMD-28 or other efficacy measures, by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%), at least about 80%, or at least about 90%, as compared to the
  • an improvement as measured by HAMD-7, HAMD-17, HAMD-21, or HAMD-28 represents a decreased score or a score closer to a score typicaly for a normal subject.
  • the therapeutically effective amount of the antidepressant drug monotherapy is sufficient to increase the degree of improvement in at least one neuropsychological test, e.g., as measured by HAMD-7, HAMD-17, HAMD-21, HAMD-28, or other efficacy measures, by at least about 1-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold or more, as compared to the degree of improvement obtained in the absence of the combination therapy.
  • the therapeutically effective amount of the folate containing formulation is a higher dose compared to a dose administered to a subject who does not have autoantibodies to FRa.
  • an escalating dose of the folate containing formulation is used to treat MDD if the presence of blocking and/or binding autoantibodies is detected.
  • a subject with MDD and autoantibodies against FRa is given a higher dose of a folate compound than a subject with depression and without autoantibodies.
  • the presence or level of autoantibodies in a subject with MDD can indicate that the subject has a blockage of folate transport or passage across the blood-brain barrier.
  • the subject can be administered a therapeutically effective amount of the folate containing formulation such that the amount of folate in the subject' s cerebrospinal fluid is normal (or substantially equal to the amount in cerebrospinal fluid of a subject who does not have MDD).
  • a method for treating major depressive disorder (MDD) in a subject in need thereof by administering to the subject having circulating autoantibodies to folate receptor alpha (FRa) a therapeutically effective amount of a folate containing formulation and a therapeutically effective amount of an antidepressant drug.
  • the method is for prophylactically treating MDD in a subject in need thereof.
  • the subject can have impaired or blocked folate transport across the blood-brain barrier.
  • the subject can have a MTHFR SNP (e.g., a C677T heterozygous or homozygous SNP) or other SNPs involved or associated in one-carbon metabolism.
  • the subject is has a lower than normal level of MTHF in cerebrospinal fluid. Said subject may have normal levels of MTHF in whole blood.
  • the subject is resistant to at least one antidepressant drug (e.g., a SSRI or a SNRI). In some cases, the subject exhibits at least one symptom of MDD prior to administering the folate containing treatment regimen.
  • a suitable therapy such as an acetylcholinesterase inhibitor can be used,
  • Another suitable therapy is memantine (Namenda ® ), which is prescribed to treat moderate to severe AD symptoms or neramexane.
  • memantine namenda ®
  • Agents used in the treatment of dementia include, but not limited to, Thioridazine, Haloperidol, Risperidone, Cognex ® , Aricept ® , and Exelon ® .
  • a combination therapy of a folate formulation and an acetylcholinesterase inhibitor can be recommended, selected, or administered.
  • a combination therapy used to treat ADRD includes a folate formulation and a memantine drug.
  • a combination therapy used to treat ADRD includes a folate formulation, an
  • acetylcholinesterase inhibitor and a memantine drug.
  • the therapeutically effective amount of the folate containing formulation recommended, selected or administered to a subject having or at risk of having ADRD with autoantibodies against FRa is a higher dose compared to a dose administered to a subject who does not have autoantibodies to FRa.
  • an escalating dose of the folate containing formulation is used to treat ADRD if the presence of blocking and/or binding autoantibodies is detected.
  • a subject with ADRD and autoantibodies against FRa is given a higher dose of a folate compound than a subject with ADRD and without autoantibodies.
  • a method for treating Alzheimer's disease and related diseases in a subject in need thereof by administering to the subject having circulating autoantibodies to folate receptor alpha (FRa) a therapeutically effective amount of a folate containing formulation.
  • the method is for prophylactically treating ADRD in a subject in need thereof.
  • the subject is administered a therapeutically effective amount of a folate containing formulation in combination with an acetylcholinesterase inhibitor and/or memantine drug.
  • the subject can be administered a therapeutically effective amount of a folate containing formulation in combination with an acetylcholinesterase inhibitor.
  • the subject can be administered a therapeutically effective amount of a folate containing formulation in combination with a memantine drug.
  • the subject is administered a therapeutically effective amount of a folate containing formulation in combination with an acetylcholinesterase inhibitor and memantine drug.
  • the subject exhibits at least one symptom of ADRD.
  • the subject suffers from mild cognitive impairment due to Alzheimer's disease.
  • the subject suffers from impaired or blocked folate transport at the blood-brain barrier.
  • MCI may represent a prodromal state to clinical Alzheimer's disease
  • treatments proposed for Alzheimer' s disease such as antioxidants and acetylcholinesterase inhibitors, may be useful in the treatment of MCI.
  • CerefolinNAC® is a medical food containing L-methylfolate, methylcobalamin (the fully-reduced, bioactive metabolic form of the vitamin B i2 , and N-acetyl-cysteine (an intracellular antioxidant), which is useful in its treatment.
  • both the 1-aminocyclohexane derivative (e.g., memantine) or the AChEI (e.g. donepezil) are present in a therapeutically effective amount.
  • the optimal therapeutically effective amount should be determined experimentally, taking into consideration the exact mode of administration, form in which the drug is administered, the indication toward which the administration is directed, the subject involved (e.g., body weight, health, age, sex, and the like), and the preference and experience of the physician or veterinarian in charge.
  • the 1- aminocyclohexane derivatives or AChEIs are administered in suitable form in doses ranging from about 1 to 200 mg per day for each drug.
  • the 1-aminocyclohexane derivatives are preferably administered at doses 5-60 mg/day, and especially 10-40 mg/day; the AChEIs are preferably administered at doses 1-40 mg/day, and especially 5-24 mg/day.
  • the 1-aminocyclohexane derivative which may be used in unit dosage amounts of the invention include, for example, 5 mg, 10 mg, 15 mg, and 20 mg for memantine and 5 mg, 10 mg, 20 mg, 30 mg, and 40 mg for neramexane.
  • Preferred specific amounts of the AChEI which may be used in unit dosage amounts of the invention include, for example, 1.5 mg, 3 mg, 4.5 mg, and 6 mg for rivastigmine, 4 mg, 8 mg and 12 mg for galantamine, and 5 mg and 10 mg for donepezil.
  • a combination therapy of a folate formulation and an acetylcholinesterase inhibitor can be recommended, selected, or administered.
  • a combination therapy used to treat MCI includes a folate formulation and a memantine drug.
  • a combination therapy used to treat MCI includes a folate formulation, an acetylcholinesterase inhibitor, and a memantine drug.
  • the therapeutically effective amount of the folate containing formulation recommended, selected or administered to a subject having or at risk of having MCI with autoantibodies against FRa is a higher dose compared to a dose administered to a subject who does not have autoantibodies to FRa.
  • an escalating dose of the folate containing formulation is used to treat MCI if the presence of blocking and/or binding autoantibodies is detected.
  • a subject with MCI and autoantibodies against FRa is given a higher dose of a folate compound than a subject with cognitive impairment and without autoantibodies.
  • antioxidants useful to treat MCI include, but are not limited to, ubiquinone, aged garlic extract, curcumin, lipoic acid, beta-carotene, melatonin, resveratrol, Ginkgo Biloba extract, vitamin C, vitamin E or the like.
  • a method for treating mild cognitive impairment (MCI) in a subject in need thereof by administering to the subject having circulating autoantibodies to folate receptor alpha (FRa) a therapeutically effective amount of a folate containing formulation is for prophylactically treating mild cognitive impairment in a subject in need thereof.
  • the subject is administered a therapeutically effective amount of a folate containing formulation in combination with an acetylcholinesterase inhibitor and/or memantine drug.
  • the subject can be administered a therapeutically effective amount of a folate containing formulation in combination with an acetylcholinesterase inhibitor.
  • the subject can be administered a therapeutically effective amount of a folate containing formulation in combination with a memantine drug.
  • the subject is administered a therapeutically effective amount of a folate containing formulation in combination with an
  • any art-recognized folate formulation e.g., folate-comprising compound can be selected and/or optionally administered to a human subject determined to have a risk of MDD or MCI or ADRD.
  • the folate formulation comprises L-methylfolate.
  • the folate formulation comprises 6(S)-5-methyltetrahydrofolate (also known as 6(S)-5-MTHF).
  • the folate comprising formulation is Deplin® for MDD and CerefolinNAC® for MCI.
  • Deplin® is a medical food containing L-methylfolate, the fully-reduced, bioactive metabolic form of the vitamin B 9 (folate).
  • CerefolinNAC® is a medical food containing L-methylfolate, methylcobalamin (the fully-reduced, bioactive metabolic form of the vitamin B i2 , and N-acetyl-cysteine (an intracellular antioxidant).
  • L- methylfolate is the active form of folate that can be taken up by the brain.
  • the folate disclosed in US Patent No. 6,441, 168 is used.
  • the folate formulation can include at least one (including at least two, at least three or more) alkaline metal or alkaline earth metal salt of folate, e.g., but not limited to, a calcium salt of folate.
  • the folate formulation is methyl folate, also known as Me- THF, N5 -Methyl -THF, MTHF, 5-MTHF, L-methylfolate, and Levomefolic acid, or a medically acceptable salt thereof (e.g., sodium salt, potassium salt, magnesium salt, calcium salt, glucosamine salt, or galactosamine salt).
  • Methyl folate calcium salt is available by prescription in the United States as DEPLIN® for MDD and CerefolinNAC® for MCI (L- methylfolate calcium salt). Methyl folate calcium salt is also available outside of the United States as METAFOLIN®, BODYFOLIN®, and NUTRIFOLIN®.
  • the folate formulation can include at least one (including at least two, at least three or more) glucosamine salt and/or galactosamine salt of folate (including, e.g., folic acid and reduced folate, e.g., but not limited to, tetrahydrofolate, and derivatives thereof).
  • glucosamine-folate and/or galactosamine-folate and derivatives thereof e.g., disclosed in U.S. Patent No. 7,947,662
  • QUATREFOLIC® Gnosis S.p.A, Milan, IT
  • N-[4-[[[(6S)-2-amino-l,4,5,6,7,8-hexahydro-5-methyl-4-oxo-6- pteridinyl]methyl]amino]benzoyl]-L-glutamic acid, glucosamine salt can be administered to a human subject according to the methods described herein.
  • folates or folate-comprising compounds that can be administered to a subject according to the method provided herein include, but not limited to, the ones described in the U.S. Pat. Nos. 4,336, 185; 6,921,754; and 7,947,662; and U.S. Pat. App. Publication No. : US 2008/0064702, the disclosures of which are incorporated are herein incorporated by reference for all purposes.
  • the effective amount of folate for use in the treatment methods described herein can vary, depending upon the types of folate, severity of depression, cognitive symptoms, presence of FRa autoantibodies, physical conditions of a subject (e.g., ages, genders, weights), the presence or levels of unmetabolized folic acid, polymorphisms related to one- carbon metabolism inflammation and a combination thereof.
  • the therapeutically effective amounts of the folate formulation and antidepressant drug are sufficient to increase the degree of improvement in at least one neuropsychological test, e.g., as measured by HAMD-7, HAMD-17, HAMD-21 or HAMD- 28 or other efficacy measures, by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%), at least about 80%, or at least about 90%, as compared to the degree of improvement obtained in the absence of either drug.
  • HAMD-7, HAMD-17, HAMD-21 or HAMD- 28 or other efficacy measures by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%), at least about 80%, or at least about 90%, as compared to the degree of improvement obtained in the absence of either drug.
  • the therapeutically effective amounts of the folate drug and the antidepressant drug are sufficient to increase the degree of improvement in at least one neuropsychological test, e.g., as measured by HAMD-7, HAMD- 17, HAMD-21, HAMD-28 or other efficacy measures, by at least about 1-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold or more, as compared to the degree of improvement obtained in the absence of either drug.
  • the therapeutically effective amounts of the folate formulation, and optionally, an acetylcholinesterase inhibitor and/or memantine drug are sufficient to increase the degree of improvement in at least one cognitive or memory test by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, as compared to the degree of improvement obtained in the absence of drug therapy.
  • the therapeutically effective amounts of the folate formulation and optionally, the acetylcholinesterase inhibitor and/or memantine drug are sufficient to increase the degree of improvement in at least one cognitive or memory test by at least about 1-fold, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold or more, as compared to the degree of improvement obtained in absence of drug therapy.
  • the therapeutic drugs described herein to treat depression or mild cognitive impairment or Alzheimer's disease or related disorders are administered to a subject by any convenient means known in the art.
  • the methods of the invention can also be used to select a suitable drug for the treatment of depression or MCI or ADRD.
  • the drug combination therapy or adjunctive therapy described herein can be administered alone or as part of a combined therapeutic approach with psychotherapy, psychodynamic therapy, cognitive behavior therapy and combinations thereof.
  • the folate formulation or antidepressant or MCI or ADRD drug described herein can be administered via a single dosage form.
  • the single dosage form can be administered as a single tablet, pill, capsule for oral administration or a solution for parenteral administration.
  • the drug can be administered as separate compositions, e.g., as separate tablets or solutions.
  • the length of time between administrations of a sub-dose of a drug can be adjusted to achieve the desired therapeutic effect.
  • the drugs can be administered concomitantly or sequentially.
  • the antidepressant drug dose can range from 0.1 mg/day to about 1000 mg/day, from about 0.5 mg/day to about 500 mg/day, from about 1 mg/day to about 400 mg/day, from about 5 mg/day to about 300 mg/day, or from about 10 mg/day to about 200 mg/day.
  • One of skill in the art can readily adjust dosage for each different antidepressant drug, depending on a number of factors such as types and/or potency of antidepressants, severity of depression, physical condition of a subject (e.g., ages, genders, and weights), administration routes, other medications taken by a subject, and any
  • a dose of an antidepressant or a pharmaceutically acceptable salt thereof suitable for administration to a human is in the range of about 0.01 to 50 mg per kilogram body weight of the recipient per day, or in the range of 0.1 to 5 mg per kilogram body weight per day.
  • the desired dose can be presented as one single unit dosage form, e.g., containing about 1 mg to about 500 mg, or about 5 mg to about 300 mg.
  • the desired dose can be presented in two, three, four, five or more sub-doses administered at appropriate intervals throughout the day. These sub-doses can be
  • the desired dose of folate can range of about 0.01 to about 50 mg per kilogram body weight of the recipient per day, in the range of about 0.05 to about 5 mg per kilogram body weight per day, or in the range of about 0.1 to about 1 mg per kilogram body weight per day.
  • the desired dose can be presented as one single unit dosage form, e.g., containing about 0.5 mg to about 500 mg, about 5 mg to about 250 mg, about 10 mg to about 100 mg, or about 10 mg to about 50 mg.
  • one single unit dosage form can provide about 1 mg to about 70 mg folate, about 5 mg to about 60 mg folate, or from about 7 mg to about 50 mg folate. In other aspects, one single unit dosage form can provide about 15 mg to about 50 mg folate. In yet other aspects, one single unit dosage form can provide about 20 mg folate.
  • the desired dose can be presented in two, three, four, five or more sub-doses administered at appropriate intervals throughout the day. These sub-doses can be administered in unit dosage forms, for example, containing about 0.1 mg to about 250 mg, about 1 mg to about 100 mg, about 2 mg to about 20 mg, or about 2 mg to about 10 mg.
  • the effective amount of folate administered to a selected human subject for the treatment of depression or MCI or ADRD as described herein is significantly higher than the typical amount taken as a dietary supplement (between 50-600 ⁇ g/day).
  • the effective amount of folate administered to a selected human subject is at least about 2-fold, at least about 5-fold, at least about 10-fold, at least about 25-fold, at least about 50-fold, at least about 100-fold, at least about 250-fold, at least about 500-fold, at least about 1000-fold or more than the typical amount taken as a dietary supplement.
  • the therapeutically effective dose can be in the form of tablets, capsules, emulsions, suspensions, solutions, syrups, sprays, lozenges, powders, and sustained-release formulations.
  • Suitable excipients for oral administration include pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate, and the like.
  • the pharmaceutical composition can be taken with or without ordinary foodstuffs.
  • the pharmaceutically acceptable composition can be delivered via injection. These routes for administration (delivery) include, but are not limited to, subcutaneous or parenteral including intravenous, intraarterial, intramuscular, intraperitoneal, intramyocardial, inhalation, intranasally, and infusion techniques.
  • the pharmaceutical acceptable composition is in a form that is suitable for injection.
  • the pharmaceutical composition is formulated for delivery by a catheter.
  • a pharmaceutical composition When administering a pharmaceutical composition parenterally, it can be generally formulated in a unit dosage injectable form (solution, suspension, emulsion).
  • the pharmaceutical formulations suitable for injection include sterile aqueous solutions or dispersions.
  • the carrier can be a solvent or dispersing medium containing, for example, water, cell culture medium, buffers (e.g., phosphate buffered saline), polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof.
  • the pharmaceutical carrier can be a buffered solution (e.g. PBS).
  • the pharmaceutical composition can be formulated in an emulsion or a gel.
  • combination therapy or adjunctive therapy e.g., antidepressant or MCI drug or ADRD drug together with a folate formulation
  • slow-release or sustained release composition e.g., sustained release or sustained delivery
  • sustained release refers to continual delivery of a therapeutic agent in vivo over a period of time following administration.
  • sustained release can occur over a period of at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 5 hours, at least about 6 hours, at least about 9 hours, at least about 12 hours, at least about 16 hours, at least about 24 hours following administration.
  • sustained release can occur over a period of at least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days following administration.
  • the release of the drug monotherapy from a drug- delivery system can be steady state (zero-order kinetics) with at least about 30% (e.g., including at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95% or more) of the drug compound released between about 3-6 hours post administration, or between about 4-5 hours post administration.
  • the release of the drug compound from a drug-delivery system can be steady state (zero-order kinetics) with substantially full release (e.g., -100%) of the drug released between about 3-6 hours post administration, or between about 4-5 hours post administration.
  • the drug compound can be released from a drug- delivery system at a rate that is slow enough not to overload the intestinal absorption capacity of a patient' s duodenum.
  • a drug delivery system can comprise the drug compound encapsulated in polymer-based particles.
  • the drug-containing polymer-based particles can be filled into capsules or single-dose sachets for additional control of release.
  • Controlled-release (e.g., sustained release) drug delivery systems for different administration methods are known in the art and can be adopted to deliver a combination or adjunctive therapy for the treatment methods described herein. See, e.g., International Pat. App. Nos. WO 2012/1 1 1961 (oral formulation), WO 2012/131678 (injectable formulation); U. S. Pat. App. Nos. US 20140060600A1100A1100A1100A1100, WO 2012/131678 (injectable formulation); U. S. Pat. App. Nos. US
  • a pharmaceutically acceptable carrier includes a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically-acceptable material such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • manufacturing aid e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid
  • solvent encapsulating material involved in carrying or transporting
  • materials which can serve as pharmaceutically-acceptable carriers include: (i) sugars, such as lactose, glucose and sucrose; (ii) starches, such as corn starch and potato starch; (iii) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, methylcellulose, ethyl cellulose, microcrystalline cellulose and cellulose acetate; (iv) powdered tragacanth; (v) malt; (vi) gelatin; (vii) lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc; (viii) excipients, such as cocoa butter and suppository waxes; (ix) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (x) glycols, such as propylene glycol; (xi) polyols, such as glycerin, sorbitol, mannitol and
  • compositions including antimicrobial preservatives, antioxidants, chelating agents, and buffers, can be added.
  • antimicrobial preservatives for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.
  • isotonic agents for example, sugars, sodium chloride, and the like.
  • compositions can also contain auxiliary substances such as wetting or emulsifying agents, pH buffering agents, gelling or viscosity enhancing additives, preservatives, colors, binders, and the like, depending upon the route of administration and the preparation desired.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, gelling or viscosity enhancing additives, preservatives, colors, binders, and the like, depending upon the route of administration and the preparation desired.
  • Standard texts such as "REMINGTON' S PHARMACEUTICAL SCIENCE,” incorporated herein by reference, may be consulted to prepare suitable preparations, without undue experimentation.
  • any vehicle, diluent, or additive used should have to be biocompatible with the antidepressant or a pharmaceutically acceptable salt thereof.
  • compositions can be isotonic, i.e., they can have the same osmotic pressure as blood and lacrimal fluid.
  • the desired isotonicity of the compositions of the composition described herein can be accomplished using sodium chloride, or other pharmaceutically acceptable agents such as dextrose, boric acid, sodium tartrate, propylene glycol or other inorganic or organic solutes.
  • sodium chloride is used in buffers containing sodium ions.
  • Viscosity of the compositions can be maintained at the selected level using a pharmaceutically acceptable thickening agent.
  • a pharmaceutically acceptable thickening agent methylcellulose is used because it is readily and economically available and is easy to work with.
  • suitable thickening agents include, for example, xanthan gum, carboxymethyl cellulose,
  • hydroxypropyl cellulose, carbomer, and the like hydroxypropyl cellulose, carbomer, and the like.
  • concentration of the thickener will depend upon the agent selected. The important point is to use an amount which will achieve the selected viscosity. Viscous compositions are normally prepared from solutions by the addition of such thickening agents.
  • any additives in addition to the antidepressant compound can be present in an amount of 0.001 to 50 wt % solution in phosphate buffered saline, and the active ingredient is present in the order of micrograms to milligrams to grams, such as about 0.0001 to about 5 wt %, about 0.0001 to about 1 wt %, about 0.0001 to about 0.05 wt % or about 0.001 to about 20 wt %, about 0.01 to about 10 wt %, and about 0.05 to about 5 wt %.
  • any therapeutic composition to be administered to a subject with compression and for any particular method of administration, it is preferred to determine toxicity, such as by determining the lethal dose (LD) and LD50 in a suitable animal model e.g., rodent such as mouse; and, the dosage of the composition(s), concentration of components therein and timing of administering the composition(s), which elicit a suitable response.
  • LD lethal dose
  • LD50 LD50
  • suitable animal model e.g., rodent such as mouse
  • compositions described herein can be prepared by mixing the ingredients following generally-accepted procedures.
  • the ingredients can be mixed in an appropriate pharmaceutically acceptable carrier and the mixture can be adjusted to the final concentration and viscosity by the addition of water or thickening agent and possibly a buffer to control pH or an additional solute to control tonicity.
  • the pH can vary from about 3 to about 7.5.
  • the pH of the composition can be about 6.5 to about 7.5.
  • Compositions can be administered in dosages and by techniques well known to those skilled in the medical and veterinary arts taking into consideration such factors as the age, sex, weight, and condition of the particular patient, and the composition form used for administration (e.g., liquid).
  • a subject can also be monitored at periodic time intervals to assess the efficacy of a certain therapeutic regimen.
  • the activation states of certain signal transduction molecules may change based on the therapeutic effect of treatment with one or more of the drugs described herein to treat depression or mild cognitive impairment.
  • the subject can be monitored to assess response and understand the effects of certain drugs or treatments in an individualized approach.
  • subjects who initially respond to a specific drug for depression may become refractory to the drug, indicating that these subjects have developed acquired drug resistance. These subjects can be discontinued on their current therapy and an alternative treatment prescribed in accordance with the methods of the present invention.
  • Example 1 Methods for Diagnosing a Subject with Major Depressive Disorder (MDD).
  • MDD Major Depressive Disorder
  • the pooled effect represents a change in depression state on a validated depression scale of patients with binding autoantibodies (Deplin ® group minus no Deplin ® placebo group).
  • the treatment effect represents a change in depression state on a validated depression scale of patients receiving Deplin ® (patients having autoantibodies minus patient who do not have autoantibodies).
  • This example illustrates that subjects with circulating binding autoantibodies to FRa are predicted to have a drug response to Deplin ® .
  • subject with either blocking autoantibodies or binding autoantibodies are predicted to positively respond to Deplin ® .
  • Example 3 Method for Diagnosing a Subject with Mild Cognitive Impairment (MCI).
  • MCI mild cognitive impairment
  • FRa folate receptor alpha
  • This example provides an age- and gender-matched case-control analysis for the prevalence of autoantibodies to folate receptor alpha (FRa) in individuals with depression or MDD.
  • the FRa autoantibodies included blocking antibodies or binding antibodies (binding IgG or IgM antibodies).
  • the case data was derived from the TRD-1 and TRD-2 (e.g., treatment-resistant depression) studies.
  • the case-group included patients with depression/major depressive disorder at baseline (prior to drug administration), and the control group included age- and gender-matched normal individuals who did not have depression or major depressive disorder.
  • the main objective of the analysis was to test for any differences in prevalence of blocking and binding antibodies between cases and corresponding age- and gender-matched controls. Further, we tested for the difference in prevalence of either binding or blocking antibodies between the cases and the matched controls.
  • FIG. 1 shows the data of matching. Some older control subjects were left unmatched and not included in the analysis. After matching of cases and controls using propensity scores, there was still evidence of possible confounding (FIG. 2C). Next, an unconditional logistic regression was fitted to the matched data to test for the difference in prevalence (in terms of Odds-Ratios (OR)) of antibodies between cases and controls while adjusting for the age and gender. Prevalence for each antibody is given in Table 4.
  • FIGS. 2B and 2C Results for the Chi-square test for deviance to test for effect-modification of age and gender are given in FIGS. 2B and 2C for the full data and the matched data, respectively.
  • This example provides an age- and gender-matched case-control analysis for the prevalence of autoantibodies (blocking antibodies or binding antibodies (e.g., binding IgG and IgM antibodies)) to folate receptor alpha in patients with mild cognitive impairment (MCI) or Alzheimer' s disease and related diseases (ADRD).
  • autoantibodies blocking antibodies or binding antibodies (e.g., binding IgG and IgM antibodies)
  • MCI mild cognitive impairment
  • ADRD Alzheimer' s disease and related diseases
  • the case data was derived from the N-acetylcysteine (NAC) for improving cognitive dysfunction study.
  • NAC N-acetylcysteine
  • the case-group included patients with cognitive impairment at baseline (prior to drug administration), and the control group included age- and gender- matched normal individuals who did not have cognitive impairment.
  • FIGS. 4B and 4C Results for the Chi-square test for deviance to test for effect-modification of age and gender are given in FIGS. 4B and 4C for the full data and the matched data, respectively.
  • FIG. 4A provides matching case and controls in six sub-classes based on propensity scores. Matching prevented effect-modifications that were seen for the IgG binding variable in the full data.
  • FIG. 3 shows the data of matching. Some younger control subjects were left unmatched and not included in the analysis. Prevalence for each antibody is given in Table 9.

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Abstract

La présente invention concerne des procédés pour le diagnostic d'un sujet souffrant de dépression, par exemple, d'un trouble dépressif majeur (MDD), d'une déficience cognitive légère (MCI) ou de maladies liées à la maladie d'Alzheimer (ADRD). La présente invention concerne également des procédés pour recommander ou sélectionner une thérapie de traitement, telle qu'une thérapie de combinaison ou une thérapie d'appoint comprenant une formulation de folate et un antidépresseur pour MDD ou comprenant une formulation de folate et un inhibiteur de l'acétylcholinestérase et/ou de la mémantine pour MCI ou ADRD, pour le sujet.
PCT/IB2016/051093 2015-02-27 2016-02-26 Diagnostic de trouble dépressif majeur, de déficience cognitive légère, et de la maladie d'alzheimer et d'autres troubles neurologiques et psychiatriques WO2016135707A1 (fr)

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EP4413991A1 (fr) * 2023-02-08 2024-08-14 Consejo Superior De Investigaciones Científicas Peptide pour l'amélioration cognitive

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023155893A1 (fr) * 2022-02-17 2023-08-24 The Chinese University Of Hong Kong Approche de correction métabolique pour le traitement du vieillissement accéléré du cerveau induit par l'abus d'alcool
EP4413991A1 (fr) * 2023-02-08 2024-08-14 Consejo Superior De Investigaciones Científicas Peptide pour l'amélioration cognitive

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