EP1984029A2 - Methods of identifying and treating patients likely to benefit from omega-3 fatty acid therapy for dementia, vascular dementia, parkinson's dementia, alzheimer's disease, and/or mild cognitive impairment - Google Patents

Abstract

A method of identifying a patient likely to benefit from omega-3 fatty acid therapy for dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment includes identifying a patient-having abnormal brain activity by conducting one or more baseline scans of the patients brain, administering a first dosage regimen of omega-3 fatty acids to the patient and, thereafter conducting one or more assessment scans of the patient's brain, comparing the one or more assessment scans with the one or more baseline scans to determine any improvement in the patient's brain activity, and selecting any patient having an improvement in brain activity to receive omega-3 fatty acid therapy for the treatment or prevention of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment.

Description

METHODS OF IDENTIFYING AND TREATING PATIENTS LIKELY TO

BENEFIT FROM OMEGA-3 FATTY ACID THERAPY FOR DEMENTIA,

VASCULAR DEMENTIA, PARKINSON'S DEMENTIA, ALZHEIMER'S DISEASE,

AND/OR MILD COGNITIVE IMPAIRMENT

RELATED APPLICATION DATA

[0001] This application claims priority from Provisional Application No. 60/773,920, which was filed on February 16, 2006. The contents of this priority application are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

[0002] The present invention relates to methods for identifying patients who are likely to benefit from therapy with a therapeutically effective dose of omega-3 fatty acids to treat or prevent dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment (MCI). The present invention also relates to methods of treating patients who are likely to benefit from omega-3 fatty acid therapy with a therapeutically effective dose of one or more active agents including omega-3 fatty acids to treat or prevent Alzheimer's disease, dementia, and/or MCI. The present invention also relates to a diagnostic test to identify patients who are likely to benefit from omega-3 fatty acid therapy.

2. Description of the Related Art

[0003] Alzheimer's disease and other dementias are traditionally defined by neuropathology; however, increasing evidence has clarified the fallibility of such an approach. While there is clearly a tendency for Alzheimer's disease patients to show increased levels of cerebral amyloid, there is a broad overlap in cerebral amyloid

RPP/195671.2 burden between Alzheimer's disease patients and patients with normal aging who do not have clinical evidence of dementia. Moreover, while a small percentage of patients with genetic defects in processing of amyloid clearly do develop dementia at an earlier age than is typical for senile dementia (e.g., under the age of 65 years), the current consensus from many lines of evidence is that soluble oligimers of amyloid, rather than the fully aggregated product seen in tissue sections, are more likely responsible for neurotoxic effects of the disease. Furthermore, especially in populations with increased or increasing life expectancy, pure dementia of any type is much less common than a mixed pattern, most often a combination of Alzheimer's disease and cerebrovascular disease. Hence, the often touted "clinically accurate" diagnosis of Alzheimer's disease is generally in error and a majority of dementia patients actually have mixed dementia.

[0004] Vascular dementia has traditionally been diagnosed in patients who have suffered from cerebral stroke. As a result of a large vessel infarct, a substantial part of the brain will be damaged, with subsequent memory loss and/or partial paralysis as a result. With the advancement of imaging technologies, forms of dementia that previously were not associated with cerebral vascular conditions have been identified: (1 ) signs of small scale lacunar infarcts due to microstrokes, which are often not recognized as such; (2) gradual oxygen starvation of parts of the brain due to advancement of atherosclerosis of small cerebral vessels which can be observed as extensive periventricular white matter lesions. These forms of dementia can be diagnosed only by imaging technology.

[0005] The extent to which a patient's brain abnormality manifests itself with respect to clinical signs of dysfunction (e.g., Alzheimer's disease, any of the forms of dementia and/or MCI) may be initially evaluated using tests such as the abbreviated

RPP/l 95671.2 ² mental test score (AMTS) and the mini mental state examination (MMSE). If a patient's score on one of these tests is below a certain level (typically, below 6 on the AMTS₁ or below 24 on the MMSE), further evaluation may be required. This further evaluation may include blood tests to rule out treatable conditions, such as vitamin deficiencies, as well as neuroimaging. Neuroimaging approaches to categorizing abnormal patients include, but are not limited to, cortical radioactive brain uptake (CRBU), correlative brain regional activity (COBRA), positron emission tomography (PET), single photon emission computed tomography (SPECT), computed tomography (CT), magnetic resonance imaging (MRI)₁ and stimulated acoustic emission (SAE). SPECT and PET in particular are generally known to be over 85% accurate. Brain SPECT is even more reliable when basal metabolic images are compared to stimulated perfusion images acquired either simultaneously or sequentially within any time interval which is relatively short (weeks to months) in comparison to the usual course of significant changes in the disease(s). Another practical advantage of the three dimensional aspect of SPECT or PET images is their resolution of separate brain regions which show evidence of one or the other of the mixed pathologies usually found in dementia patients, e.g., some areas of neurodegenerative disease characterized by more adequate stimulated perfusion than metabolism (typically in the hippocampal and parietooccipital areas bilaterally in early Alzheimer's disease), and some areas of cerebrovascular disease characterized by more adequate metabolism than stimulated perfusion. [0006] Additional advantages of defining brain abnormality by neuroimaging criteria include the ease of quantifying such criteria, e.g., the Cortical Metabolic index (CMi) and Cortical Perfusion index (CPi) and their excellent correlation with cerebral function as measured by standard neuropsychological tests and the ability to use

RPP/195671.2 3 such quantification and good functional correlation to assess the effect of drug or other dementia therapy.

[0007] It is clear that the imaging abnormalities seen in dementia are sensitive and can be used to detect the earliest signs of dementia in patients who are either asymptomatic or have only minimal or minor symptoms, i.e., the stage most often referred to as MCI. The consensus opinion is that patients treated at earlier stages of disease are more likely to have robust and sustained responses than those treated later in the course of the disease.

[0008] Although a few treatments exist for patients suffering from dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or MCI, e.g., central cholinesterase inhibitors such as donepezil (ARICEPT^®), non-steroidal antiinflammatory drugs (NSAIDs), and anti-Parkinson's medications, nearly all known treatments have only limited effectiveness, if any. These treatments appear to have the primary effect of decreasing the rate of disease progression, but actual improvements in the disease state are unusual, particularly in groups of patients of statistically significant size. Accordingly, there is still a need for methods and compositions for treating and/or preventing dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or MCI, as well as methods and compositions for slowing the progression of these conditions. In addition, there is a need for methods of identifying patients that will be more likely to be successfully treated with therapeutics for dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or MCI.

[0009] Ornega-3 fatty acids are known to be important for brain development. Two omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been found to be particularly important. Marine oils, e.g., fish oils, are a

RPP/l 95671.2 ⁴ good source of EPA and DHA, which have been found to regulate lipid metabolism. Omega-3 fatty acids seem to be well-tolerated, without giving rise to any severe side effects.

[00010] One form of omega-3 fatty acid is a concentrate of omega-3, long chain, polyunsaturated fatty acids from fish oil containing DHA and EPA that is sold under the trademark Omacor^®. Such a form of omega-3 fatty acid is described, for example, In U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,594, the disclosures of which are incorporated herein by reference.

[00011] WO 02/45583 discloses methods of diagnosing a membrane fluidity-related disorder, or a predisposition to a membrane fluidity-related disorder, by acquiring a first proton relaxation measurement for a selected region of the brain of the subject in a magnetic resonance imaging (MRI) procedure; administering to the subject a challenge that alters a physical or chemical property of cell membranes in the brain of the subject; acquiring a second proton relaxation measurement for the selected region of the brain in an MRI procedure after the challenge; and detecting any difference between the first proton relaxation measurement and the second proton relaxation measurement, wherein a difference indicates a membrane fluidity-related disorder. Examples of membrane fluidity-related disorders include bipolar disorder, alcoholism, Alzheimer's disease, major depression, and schizophrenia. The challenge can include administering to the patient an effective amount of a compound such as an omega-3 fatty acid, S-adenosylmethionine, a statin, or a cytidine compound, for an effective length of time. However, there is no disclosure of cerebrovascular effects, and furthermore, there is no disclosure of a means or method to differentiate between the different subtypes of membrane fluidity-related

RPP/195671.2 disorders once the initial diagnosis has been made with the challenge dose of an effective compound, in particular an omega-3 fatty acid..

[00012] U.S. Published Application No. 2006/0166935 discloses use of a fatty acid composition including DHA or derivatives thereof, and EPA or derivatives thereof, for the treatment and/or prevention of amyloidos-related diseases, such as Alzheimer's disease, as well as for the treatment and/or prevention of cognitive dysfunction. The application seeks to prevent and/or delay the formation of amyloid fibrils/plaques in the brain.

[00013] Rapoport discloses the use of PET scans to view incorporation of radiolabeled fatty acids in the human brain, which can be used to identify targets of drugs that affect phospholipid metabolism, such as lithium. ("In Vivo Fatty Acid Incorporation into Brain Phospholipids in Relation to Signal Transduction and Membrane Remodeling," Neurochemical Research 24(11): 1403-15 (1999).) [00014] Nagao discloses the use of three-dimensional fractal analysis of HMPAO SPECT images with multiple isocontour cutoffs to quantify cerebral blood flow distribution in Alzheimer's disease. Results were correlated with functional assessment (MMSE and AD Assessment Scale) (P < 0.0001), and a good separation of normal patients from Alzheimer's patients (P < 0.001). ("Fractal analysis of cerebral blood flow distribution in Alzheimer's disease," J. Nucl. Med. 42(10):1446-50 (2001).)

[00015] Okamoto discloses the use of PET scanning performed by the steady-state method using oxygen-15-labelled O₂ and CO₂ to describe the cerebral circulation and metabolism of vascular dementia, as well as to describe cerebral circulatory metabolism in asymptomatic cerebral infarction and chronic cerebral circulatory insufficiency. Use of DHA supplements as therapeutics was suggested for future

RPP/ 195671.2 ⁶ study, as they were expected to result in improved intellectual function. ("Treatment of Vascular Dementia," Ann. N.Y. Acad. ScL 977:507-512 (2002).) [00016] Yoshikawa discloses the use of fractal analysis to assess heterogeneity of cerebral blood flow using HMPAO SPECT. lsocontour cutoff values of from 35 to 50% were used to obtain a linear regression equation, and the number of voxels having a radioactivity exceeding the cut-off value were transformed into natural logarithms, and these were used to calculate the fractal dimension from the slope of the regression line obtained. Results correlated to functional assessments (MMSE), and the separation of the vascular dementia group from and control groups was significant (P < 0.0001). ("Quantification of the heterogeneity of cerebral blood flow in vascular dementia," J. Neurol. 250(2): 194-200 (2003).) [00017] Puri discloses the use of imaging techniques to assess the changes that occur when treating schizophrenia, depression, and Huntington's disease with eicosapentaenoic acid, such as reversal of cerebral atrophy, and decreased ventricular size. ("Monomodal rigid-body registration and applications to the investigation of the effects of eicosapentaenoic acfd intervention in neuropsychiatry disorders," Prostaglandins, Leυkotrienes and Essential Fatty Acids 71: 177-9 (2004).)

[00018] Sfyroeras, et al. assessed the effect of unilateral carotid angioplasty and stenting (CAS) on cerebral perfusion asymmetry in patients with severe extracranial carotid stenosis by means of technetium Tc 99m hexamethylrpropyleneamine oxime brain single photon emission computed tomography ((99m)Tc-HMPAO SPECT)₁ and defined an asymmetry index. The asymmetry index (Al), a measure of the interhemispheric asymmetry in perfusion, was calculated as [(counts in "healthy" hemisphere-counts in hemisphere with carotid stenosis)/counts in "healthy"

RPP/l 95671.2 ⁷ hemisphere] x 100]. This is one criteria of early to moderate cerebrovascular^' disease, which is typically asymmetrical at first. ("Interhemispheric asymmetry in brain perfusion before and after carotid stenting: a 99mTc-HMPAO SPECT study," J. Endovasc. Ther. 13(6):729-37 (December 2006).)

[00019] Lee, et al., used statistical parametric mapping (SPM) and statistical probabilistic anatomical mapping (SPAM), as applied to basal/acetazolamide Tc- 99m ECD brain perfusion SPECT images of patients with middle cerebral artery (MCA) stenosis, in order to assess the efficacy of endovascular stenting of the MCA. The use of perfusion stimulated SPECT was described, and the authors concluded that it provided a better definition of vascular injury than unstimulated resting perfusion SPECT. The study concluded that voxel-based analysis of basal/acetazolamide brain perfusion SPECT was useful after MCA stent placement, and showed that SPM and SPAM analyses of basal/acetazolamide Tc-99m brain SPECT could be used to evaluate the short-term hemodynamic efficacy of successful MCA stent placement. ( "Statistical parametric mapping and statistical probabilistic anatomical mapping analyses of basal/acetazolamide Tc-99m ECD brain SPECT for. efficacy assessment of endovascular stent placement for middle cerebral artery stenosis." Neuroradiology (Electronically published January 3, 2007).)

[00020] However, none of these references discloses methods of identifying those individuals likely to benefit from omega-3 fatty acid therapy for the treatment or prevention of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or MCI. There is also no disclosure of methods for treating a patient so identified by administering a therapeutically effective amount of one or more active agents including omega-3 fatty acids.

RPP/195671.2 8 [00021] There is a need in the art for methods and compositions for treating or preventing dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or MCI₁ or slowing the progression of these diseases or conditions. There is also a need in the art for methods and compositions for identifying patients who are likely to respond to omega-3 fatty acid therapy for Alzheimer's disease, dementia, and/or MCI.

SUMMARY OF THE INVENTION

[00022] The present invention provides a method of identifying a patient likely to benefit from omega-3 fatty acid therapy for dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment, comprising the steps of: identifying a patient having abnormal brain activity by conducting one or more baseline scans of the patient's brain, administering a first dosage regimen of omega-3 fatty acids to the patient identified in said identifying step, thereafter conducting one or more assessment scans of the patient's brain, comparing the one or more assessment scans with the one or more baseline scans to determine any improvement in the patient's brain activity, and selecting any patient having an improvement in brain activity to receive omega-3 fatty acid therapy for the treatment or prevention of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment. [00023] The present invention further provides a method of identifying a patient likely to benefit from omega-3 fatty acid therapy for a brain disorder, including the steps of conducting a basal metabolic scan of the patient's brain, thereafter administering a perfusion stimulating dose of omega-3 fatty acids to the patient, thereafter conducting a stimulated perfusion scan of the patient's brain, and

RPP/195671.2 9 comparing the basal metabolic scan with the stimulated perfusion scan to differentially diagnose a brain disorder that is treatable with omega-3 fatty acids. The method further includes the step of selecting any patient diagnosed with a brain disorder that is treatable with omega-3 fatty acids to receive omega-3 fatty acid therapy for the treatment or prevention of the brain disorder. [00024] The present invention also provides a method for treating or preventing dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment in a patient in need thereof, comprising the steps of: identifying a patient having abnormal brain activity by conducting at least one baseline scan of the patient's brain, then administering a first dosage regimen of omega-3 fatty acids to the patient identified in said identifying step, thereafter conducting at least one assessment scan of the patient's brain, comparing the at least one assessment scan with the at least one baseline scan to determine any improvement in the patient's brain activity, selecting any patient having an improvement in brain activity to receive omega-3.fatty acid therapy for the treatment or prevention of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment, and administering to the patient selected in said selecting step a therapeutically effective dose of one or more active agents including omega-3 fatty acids to treat or prevent dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment. [00025] The present invention further provides a method for treating or preventing a brain disorder in a patient in need thereof, including the steps of conducting a basal metabolic scan of the patient's brain, thereafter administering a perfusion stimulating dose of omega-3 fatty acids to the patient, thereafter conducting a stimulated perfusion scan of the patient's brain, comparing the basal metabolic scan with the

RPP/195671.2 ^{1 0} stimulated perfusion scan to differentially diagnose a brain disorder that is treatable with omega-3 fatty acids, selecting any patient diagnosed with a brain disorder that is treatable with omega-3 fatty acids to receive omega-3 fatty acid therapy for the treatment or prevention of the brain disorder, and administering to the patient selected in said selecting step a therapeutically effective dose of one or more active agents including omega-3 fatty acids to treat or prevent said brain disorder. [00026] The invention also provides a diagnostic test for determining whether a patient is likely to respond to omega-3 fatty acid therapy for the treatment or prevention of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment, comprising the steps of: identifying a patient having abnormal brain activity by conducting at least one baseline scan of the patient's brain, administering a first dosage regimen of omega-3 fatty acids to the patient identified in said identifying step, thereafter conducting at least one assessment scan of the patient's brain, and comparing the at least one assessment scan with the at least one baseline scan to determine any improvement in the patient's brain activity, thereby determining whether the patient is likely to respond to omega-3 fatty acid therapy for the treatment or prevention of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment.

[00027] The invention further provides a diagnostic test for determining whether a patient is likely to respond to omega-3 fatty acid therapy for a brain disorder, including the steps of conducting a basal metabolic scan of the patient's brain, thereafter administering a perfusion stimulating dose of omega-3 fatty acids to the patient, thereafter conducting a stimulated perfusion scan of the patient's brain, and comparing the basal metabolic scan with the stimulated perfusion scan to

RPP/195671.2 1 1 differentially diagnose a brain disorder, thereby determining whether the patient is likely to respond to omega-3 fatty acid therapy for the treatment or prevention of the brain disorder.

[00028] The present invention also provides a method for making a differential diagnosis between impairments associated with blood perfusion anomalies, but not an abnormal metabolic index. These types of anomalies will be referred to as "vascular dementia" for the purposes of the present invention. Impairments associated with both blood perfusion anomalies and an abnormal metabolic index will be referred to as "Alzheimer's disease dementia subtype" for purposes of the present invention.

[00029] The invention also provides a treatment regimen involving agents for the treatment or prevention of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment, alone or in combination therapy as simultaneous or concomitant therapy, or as a fixed dosage form. [00030] In further embodiments, the omega-3 fatty acids are administered in conjunction with one or more additional agents suitable for the treatment or prevention of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment. According to another embodiment, the one or more additional agents are each independently selected from the group consisting of cholinesterase inhibitors, aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), clopidogrel, memantine, antihypertensives, dyslipidemic agents, and anti- Parkinson's medications. The combination may be beneficially provided as a unit dosage form of the omega-3 fatty acids and the one or more additional agents for the treatment or prevention of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment.

RPP/195671.2 12 [00031] In preferred embodiments the omega-3 fatty acids comprise Omacor^® omega-3 fatty acids, as described in U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,594. In other preferred embodiments the pharmaceutical composition(s) comprise omega-3 fatty acids present in a concentration of at least 40% by weight as compared to the total fatty acid content of the composition(s). [00032] In still other preferred embodiments the omega-3 fatty acids comprise at least 50% by weight of EPA and DHA as compared to the total fatty acid content of the composition, and the EPA and DHA are in a weight ratio of EPArDHA of from 99:1 to 1 :99, preferably from 1 :2 to 2:1.

[00033] Other novel features and advantages of the present invention will become apparent to those skilled in the art upon examination of the following or upon learning by practice of the invention.

DESCRIPTION QF THE PREFERRED EMBODIMENTS

[00034] As used herein, "dementia" refers to any disorder of the brain and/or the circulatory system supplying the brain that results in a impairment of and/or a loss of physical and/or mental functioning. The most commonly used criteria for diagnoses of dementia is the DSM-IV (Diagnostic and Statistical Manual for Mental Disorders, published by the American Psychiatric Association). Diagnostic features of dementia include: memory impairment and at least one of the following: aphasia, apraxia, agnosia, and disturbances in executive functioning. Generally, the cognitive impairments must be severe enough to cause impairment in social and occupational functioning, and must represent a decline from a previously higher level of functioning. Several types of dementias or closely-related impairments exist with differing etiologies and symptomologies, including but not limited to: dementia

RPP/ 195671.2 ^{1 3} coexisting with degenerative diseases such as Alzheimer's disease, Pick's disease, and Parkinson's disease; vascular dementia associated with lacunar multi-infarct small vessel disease, multi-vessel cortical or subcortical infarcts, single large vessel cortical or subcortical infarcts, Binswager's disease, or leukoaraiosis; vascular cognitive impairment associated with lacunar multi-infarct small vessel disease, multi-vessel cortical or subcortical infarcts, single large vessel cortical or subcortical infarcts, Binswager's disease, or leukoaraiosis; anoxic dementia caused by cardiac arrest; traumatic dementia such as dementia pugilistica; infectious dementia associated with AIDS or Creutzfeldt-Jakob Disease; and toxic dementia such as alcoholic dementia. Some embodiments of the present invention are intended to include "dementia" in its broadest sense, and other embodiments are intended to include any one or more of the individual types of dementias or closely-related impairments included in the above list.

[00035] "Mild cognitive impairment" or "MCI" refers to the transition stage between the cognitive changes of normal aging and the more serious problem of dementia. MCI can affect many areas of cognition — such as language, attention, reasoning, judgment, reading and writing, and memory. MCI can be divided into two broad subtypes: amnestic MCI, which significantly affects memory; and nonamnestic MCI, which does not affect memory. Other functions may be impaired in either subtype of MCI. Amnestic MCI has been linked to Alzheimer's disease, while nonamnestic MCI may progress to other types of syndromes — such as frontotemporal dementia, primary progressive aphasia, or dementia with Lewy bodies. However, not all patients suffering from MCI develop dementia. These patients may remain stable, or even revert to normal. Some embodiments of the present invention are intended to include "MCI" in its broadest sense, and other embodiments are intended to include

RPP/l 95671.2 14 any one or more of the individual types of MCI or related syndromes included in the above list.

[00036] "Vascular dementia" refers to dementia that is traditionally diagnosed in patients who have suffered from one of many types of cerebral strokes, or who have suffered from multiple cerebral strokes. In the instance of a large vessel infarct, a substantial part of the brain is damaged, with subsequent memory loss and/or partial paralysis as a result. With the advancement of imaging technologies, forms of vascular dementia that previously were not associated with cerebral vascular conditions can be more readily identified, which are also included within the definition of vascular dementia or vascular cognitive impairment. These types of imaging pathologies include signs of small scale lacunar infarcts due to microstrokes, which are often not recognized as such; gradual oxygen starvation of parts of the brain due to advancement of atherosclerosis of small cerebral vessels, which can be observed as extensive periventricular white matter lesions; and subcortical hyperintensities. These forms of vascular dementia and vascular cognitive impairment can be diagnosed only by imaging technology. [00037] Additional symptoms that can be displayed by patients with vascular dementia and/or vascular cognitive impairment include a decrease in executive functioning, which can be detected with various mental examinations, including but not limited to the Brief Executive Assessment (BEA). Individual tests that may comprise the BEA could include but are not limited to FAS verbal fluency, digit symbol, trail making B-A and digit span backwards. Additional tests that would be of value in assessing the degree of impaired executive functioning would measure insistence and persistence of response and/or constructional abilities.

RPP/l 95671.2 15 [00038] The clinical manifestations of impaired executive functioning can be assessed using global assessment scales including but not limited to the Instrumental Activities of Daily Living (IADL). In one of its forms, the IADL comprises of a list of 8 tasks of daily living that require executive functioning to be intact in order to be performed. Tasks that could be part of the IADL include but are not limited to the ability to use the telephone, do laundry, go shopping, prepare food, being responsible for own medications, housekeeping and the ability to handle finances.

[00039] Alzheimer's disease is the most common form of dementia and, according to the National Institutes of Health, it is the fourth leading cause of death in adults. As used herein, "Alzheimer's disease" refers to a neurological disorder characterized by abnormal brain structures such as amyloid plaques and neurofibrillary tangles. It results in slow, progressive memory loss due to a gradual loss and/or impaired functioning of brain cells. Alzheimer's disease significantly affects cognitive capabilities and, eventually, affected individuals become incapacitated. Initially, the dementia may be manifested by barely-noticeable memory deficits. Eventually, the memory loss becomes more severe until it is incapacitating. Other symptoms such as confusion, the inability to articulate words correctly, and hallucinations may also occur. Emotional problems such as easy agitation, poor judgment, and feelings of withdrawal are also common in the early stages of the disease. Without treatment or supervision, death often results from malnutrition or pneumonia. From the initial symptoms, disease progression can last up to 25 years, although typically the duration ranges from eight to 10 years.

[00040] When used herein, the term "brain disorder" may encompass any of the various conditions described above, i.e., dementia, vascular dementia, Parkinson's

RPP/195671.2 16 dementia, Alzheimer's disease, and mild cognitive impairment (MCI), as well as other related conditions.

[00041] The terms "treating" or "treatment" in accordance with the present invention includes relieving the injury giving rise to the disease or condition and may also or alternatively include slowing the progression of the disease or condition.

[00042] According to preferred embodiments of the present invention, patients are identified as being likely to respond to treatment with omega-3 fatty acids for a brain disorder based on either or both of ICMi and ICPi brain scans. As used herein,

"ICMi" refers to the lsocontour Cerebrocortical Metabolic index. As used herein,

"ICPi" refers to the lsocontour Cerebrocortical Perfusion index.

[00043] The ICMi and ICPi are derived by obtaining the ratio between the 60% isocontour for brain activity and the 30% isocontour for total brain activity in a segment of the brain that contains primarily white matter and grey matter, or cerebrocortex, which is the area of the brain that is involved with higher brain processing such as thought and intellectual functioning.

[00044] The segment of the brain which is used to obtain the ICMi and ICPi is approximately horizontal to the long axis of the brain, lying near a line from the most posterior occipital area of the brain to the most anterior frontal portion, being fairly close to the external canthomeatal line that extends from the external opening of the ear to the edge of the eye, and located approximately one third of the distance between the vertex, or top of the brain, to the inferior extent of the cerebellum, or the bottom of the brain. For the purposes of the present invention, this segment shall be referred to as the area of interest.

[00045] The ICMi is obtained using a radiotracer alone. The ICPi is obtained with the use of a perfusion agent, with an omega-3 being the most preferred perfusion

RPP/195671.2 17 agent. Peak activity represents the total amount of radioactivity that is measured following administration of a radiotracer, such as Tc99, and is detected with standard equipment, such as a multichannel analyzer.

[00046] The 60% isocontour is that fraction of radioactivity representing between 60% and 100% of peak activity that is quantified in the area of interest, and is representative of the functioning of neurons primarily of the white and grey matter within this area that are deemed to be responsible for higher brain processes including but not limited to thought, executive functioning, and planning. The 30% isocontour is that fraction of radioactivity representing between 30% and 100% of peak activity that is quantified in the area of interest, and is representative of alt cellular functioning within this area, and includes subcortical regions such as the basal ganglia in addition to regions of white and grey matter. [00047] The ICMi and ICPi may also be expressed as regional indices (e.g., rlCMi and rlCPi), which are defined as activity within a particular brain region of interest, which is then normalized by multiplying by the ratio of the 60% isocontour area to the specific region, i.e., assuming that the specific region's activity is present in the entire area of the 60% isocontour. This is then divided by the same total brain activity at the original ICMi/ICPi level to obtain the regional ICMi/ICPi for the specific region. The uncertainties on these operations follow standard mathematical principles and cause mathematical and statistical limits on what can be done, depending on how robust the original parameter space was. For example, if a very small region is selected, then it will have a very small activity which is only imprecisely measured. One advantage of these regional indices is that they have virtually the same normal range as the ICMi and ICPi, and only slightly higher statistical uncertainties, as long as the regions are of reasonable size with respect to

RPP/195671.2 18 the parametric statistics. Normal ranges for the rlCMi/rlCPi are selected so as to be similar to cardiac ventricular ejection fractions, where indices of about 50% to 72% are considered normal.

[00048] The brain scans used in accordance with the invention may be obtained using any scanning technique known to those skilled in the art. Non-limiting examples of acceptable brain scanning techniques include cortical radioactive brain uptake (CRBU), correlative brain regional activity (COBRA), positron emission tomography (PET), single photon emission computed tomography (SPECT), computed tomography (CT), magnetic resonance imaging (MRI), and stimulated acoustic emission (SAE). SPECT and PET scans are presently preferred in accordance with the present invention.

[00049] When using scans for which the lsocontour Cerebrocortical Metabolic index (ICMi) or the lsocontour Cerebrocortical Perfusion index (ICPi) are applicable, the criteria for an abnormal baseline brain scan may include (1) an abnormal ICMi < 50%; (2) an abnormal ICPi < 52%; and/or (3) more than one area of abnormal regional ICMi. Criteria for determining abnormal brain activity differ among scanning techniques, but all criteria are well-known to those of ordinary skill in the art, and are within the scope of the present invention.

[00050] Preferably, the baseline brain scan may be a basal metabolic scan or a stimulated perfusion scan, and more preferably includes at least a stimulated perfusion scan.

[00051] According to one embodiment of the invention, both an ICMi and an ICPi are obtained by conducting both a basal metabolic scan and a stimulated perfusion scan. For example, method of identifying a patient likely to benefit from omega-3 fatty acid therapy for a brain disorder may include the steps of conducting a basal

RPP/19567L2 19 metabolic scan of the patient's brain (e.g., by obtaining an ICMi), then administering a perfusion stimulating dose of omega-3 fatty acids to the patient and conducting a stimulated perfusion scan of the patient's brain (e.g., by obtaining an ICPi), and then comparing the basal metabolic scan with the stimulated perfusion scan in order to differentially diagnose a brain disorder that is treatable with omega-3 fatty acids. [00052] According to one preferred embodiment, the brain disorder that is differentially diagnosed using a baseline basal metabolic scan and a baseline stimulated perfusion scan is a form of vascular dementia. In certain preferred embodiments, a patient having an ICPi that is lower than the ICMi, whether inside or outside of the range that is typically considered abnormal, is considered to have a form of vascular dementia and is selected for treatment using omega-3 fatty acid therapy.

[00053] Accordingly, a patient in whom a brain disorder has been differentially diagnosed may be administered a treatment regimen including administration of όmega-3 fatty acids, and optionally one or more additional agents suitable for the treatment or prevention of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or MCI. In accordance with the therapeutic embodiments of the present invention, the omega-3 fatty acids are preferably administered to a patient identified as being likely to respond to omega-3 fatty acid therapy for dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or MCI in an amount of from about 0.5 to about 8 g/day, more preferably from about 2 to about 6 g/day, and most preferably from about 3 to about 4 g/day. [00054] According to another embodiment of the present invention, patients who are most likely to be suitable candidates for receiving omega-θ fatty acid therapy for dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or

RPP/195671.2 ²O MCI in accordance with the present invention are those who exhibit an abnormal baseline brain scan (by whatever appropriate criteria), and who may optionally also exhibit clinical symptoms of cognitive impairment and/or at least one symptom of a minor stroke, such as transient ischemic attack (TIA). The clinical symptoms may be measured by any of the known mental assessment tests. According to one embodiment, the clinical symptoms include an MMSE < 28.

[00055] The imaging material used to visualize the brain during the scan may be any known imaging material, such as Tc-99m-HMPAO, or fluorodeoxyglucose (FDG). When a stimulated perfusion scan is conducted, the perfusion stimulating agent may be selected from any known perfusion stimulating agents, such as acetazolamide, nitroglycerin, saturated fat, and omega-3 fatty acids. The presently preferred perfusion stimulating agent comprises omega-3 fatty acids. A presently-preferred perfusion stimulating dose of the omega-3 fatty acids is from about 5 to about 15 g, more preferably from about 8 to about 10 g.

[00056] Patients may be selected for further analysis in accordance with the identification step of the present invention if they exhibit abnormal baseline scan results using any appropriate criteria, regardless of whether they exhibit any clinical symptoms of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or MCI. In some embodiments, the patient is asymptomatic. It should be noted that patients having an ICMi of about 40-50% and/or an ICPi of about 42- 52% may not exhibit any clinical symptoms whatsoever, and may therefore be identified as being at risk for dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or MCI early enough in the disease progression for treatment to be more likely to succeed.

RPP/195671.2 21 [00057] According to one embodiment of the present invention, a patient may be identified for further analysis based on an abnormal baseline brain scan, and optionally based on one or more clinical symptoms. Such a patient is then administered a first dosage regimen of omega-3 fatty acids. The first dosage regimen allows the omega-3 fatty acids to stimulate brain perfusion on a long-term or chronic basis, as compared to the short-term or acute perfusion achieved when omega-3 fatty acids are administered as the perfusion agent for the ICPi imaging that may be conducted in accordance with some embodiments of the invention. [00058] The first dosage regimen may be any dose that would likely result in an improved brain scan in a patient who is capable of responding to omega-3 fatty acid therapy for dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or MCI. According to a preferred embodiment, the dosage during the first dosage regimen is from about 0.5 to about 8 g/day, more preferably from about 2 to about 6 g/day, and most preferably from about 3 to about 4 g/day. The period of the first dosage regimen may be of any length that is sufficient to allow a patient to exhibit a response measurable by a brain scan, if the patient is capable of responding to omega-3 fatty acid therapy for dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or MCI. According to a preferred embodiment, the period may last from about 1 to about 12 months, more preferably from about 3 to about 9 months, and most preferably about 6 months. [00059] A second brain scan is conducted following the first dosage regimen in order to assess the effects of the first dosage regimen. This second assessment scan may also be conducted using any of the same or different acceptable brain scanning techniques and agents previously enumerated. The second assessment brain scan may preferably include basal metabolic scan, a stimulated perfusion

RPP/195671.2 22 scan, or both a basal metabolic scan and a stimulated perfusion scan. It is more preferred that the second assessment scan includes at least a stimulated perfusion scan.

[00060] According to a preferred embodiment, the second assessment scan or scans are conducted using the same scanning techniques, imaging agents, and perfusion agents as were used during the baseline brain scan or scans, in order to facilitate comparison between the scans.

[00061] In order to determine whether a patient is a positive-responder to the first dosage regimen of the omega-3 fatty acids, and therefore would likely benefit from omega-3 fatty acid therapy for treating or preventing dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or MCI, or a non-responder to the first dosage regimen who therefore would not likely benefit from omega-3 fatty acid therapy, the results of the baseline scan or scans and the assessment scan or scans are compared. Available clinical response data to drug therapy, if applicable, may also optionally be used in order to facilitate the determination. [00062] In accordance with this aspect of the invention, a "positive response" to the first dosage regimen is intended to include a significant change (p=0.05) in brain activity between the first baseline scan or scans, and the second assessment scan or scans in a population of appropriate patients. An improvement in clinical symptoms, where clinical symptoms were initially present, may additionally be used to determine a positive response.

[00063] In some embodiments, the positive response may include a significant change in global results, a significant change in ICMi, a significant change in ICPi, a significant change in the areas of abnormal regional ICMi, and/or a significant change in the relationship between ICMi and ICPi.

RPP/195671.2 23 [00064] The improvement in clinical symptoms may be assessed based on (1 ) stabilization of or improvement in scores on mental diagnostic tests (e.g., AMTS and/or MMSE₁ MDRS, ADAS-COG, BEA); and/or (2) personal and/or family and/or physician impression of improvement (e.g., IADL, CIBIC, CIBIC-PLUS). [00065] After comparing the first baseline scan or scans, and the second assessment scan or scans, and optionally any available clinical evidence, if a patient has been determined to exhibit a "positive response" to the first dosage regimen using one or more of the criteria set forth herein and/or any additional appropriate criteria, then that patient has been identified as being likely to benefit from omega-3 acid therapy for dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or MCI, and may be selected to receive such therapy. [00066] Accordingly, a patient exhibiting a "positive response" may be administered a treatment regimen including administration of omega-3 fatty acids, and optionally one or more additional agents suitable for the treatment or prevention of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or MCI. In accordance with the therapeutic embodiments of the present invention, the omega-3 fatty acids are preferably administered to a patient identified as being likely to respond to omega-3 fatty acid therapy for dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or MCI in an amount of from about 0.5 to about 8 g/day, more preferably from about 2 to about 6 g/day, and most preferably from about 3 to about 4 g/day.

[00067] The present invention also provides a method for making a differential diagnosis between vascular dementia and Alzheimer's disease dementia subtype. In embodiments in which the ICMi and ICPi are used, the differential diagnosis may be made based on the understanding of these indices individually in relation to

RPP/195671.2 24 normal subjects, and their relation to each other. Alzheimer's disease typically features comparatively low ICMi and comparatively normal ICPi in the brain regions that are examined. Vascular dementia typically features the reverse pattern, with comparatively normal ICMi and comparatively low ICPi in the brain regions that are examined. Later vascular dementia (or other dementias) typically features larger areas of infarction (e.g., stroke) with comparatively low levels of both ICMi and ICPi. Thus, upon applying this knowledge, a differential diagnosis may be made. [00068] As used herein, the term "omega-3 fatty acids" includes natural or synthetic omega-3 fatty acids, or pharmaceutically acceptable esters, derivatives, conjugates (See, e.g., Zaloga et al., U.S. Patent Application Publication No. 2004/0254357, and Horrobin et al., U.S. Patent No. 6,245,811, the disclosures of which are hereby incorporated by reference), precursors or salts thereof and mixtures thereof. Examples of omega-3 fatty acid oils include but are not limited to omega-3 polyunsaturated, long-chain fatty acids such as a eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and α-linolenic acid; esters of omega-3 fatty acids with glycerol such as mono-, di- and triglycerides; and esters of the omega-3 fatty acids and a primary, secondary or tertiary alcohol such as fatty acid methyl esters and fatty acid ethyl esters. Preferred omega-3 fatty acid oils are long-chain fatty acids such as EPA or DHA, triglycerides thereof, ethyl esters thereof and mixtures thereof. The omega-3 fatty acids or their esters, derivatives, conjugates, precursors, salts and mixtures thereof can be used either in their pure form or as a component of an oil such as fish oil, preferably purified oil concentrates from marine animal origin, e.g. fish or krill. Commercial examples of omega-3 fatty acids suitable for use in the invention include lncromega F2250, F2628, E2251, F2573, TG2162, TG2779, TG2928, TG3525 and E5015 (Croda International PLC, Yorkshire, England), and

RPP/195671.2 25 EPAX6000FA, EPAX5000TG, EPAX4510TG, EPAX2050TG, K85TG, K85EE, K80EE and EPAX7010EE (Pronova Biocare a.s., 1327 Lysaker, Norway). [00069] Preferred compositions include omega-3 fatty acids as recited in U.S. Patent Nos. 5,502,077, 5,656,667 and 5,698,694, which are hereby incorporated herein by reference in their entireties.

[00070] Another preferred composition includes omega-3 fatty acids present in a concentration of at least 40% by weight, preferably at least 50% by weight, more preferably at least 60% by weight, still more preferably at least 70% by weight, most preferably at least 80% by weight, or even at least 90% by weight. Preferably, the omega-3 fatty acids comprise at least 50% by weight of EPA and DHA, more preferably at least 60% by weight, still more preferably at least 70% by weight, most preferably at least 80%, such as about 84% by weight. Preferably the omega-3 fatty acids comprise about 5 to about 100% by weight, more preferably about 25 to about 75% by weight, still more preferably about 40 to about 55% by weight, and most preferably about 46% by weight of EPA. Preferably the omega-3 fatty acids comprise about 5 to about 100% by weight, more preferably about 25 to about 75% by weight, still more preferably about 30 to about 60% by weight, and most preferably about 38% by weight of DHA. All percentages above are by weight as compared to the total fatty acid content in the composition, unless otherwise indicated. The percentage by weight may be based on the free acid or ester forms, although it is preferably based on the ethyl ester form of the omega-3 fatty acids even if other forms are utilized in accordance with the present invention. [00071] The EPAtDHA ratio may be from 99:1 to 1:99, preferably 4:1 to 1 :4, more preferably 3:1 to 1:3, most preferably 2:1 to 1:2. The omega-3 fatty acids may comprise pure EPA or pure DHA.

RPP/l 95671.2 26 [00072] The omega-3 fatty acids can be present in an amount from about 350 mg to about 10 grams, more preferably about 500 mg to about 6 grams, and most preferably from about 750 mg to about 4 grams. This amount may be in one or more dosage forms, preferably one dosage form. The omega-3 fatty acid composition optionally includes chemical antioxidants, such as alpha tocopherol, oils, such as soybean oil and partially hydrogenated vegetable oil, and lubricants such as fractionated coconut oil, lecithin and a mixture of the same. [00073] The most preferred form of omega-3 fatty acids are the Omacor^® omega-3 fatty acids (K85EE, Pronova Biocare A.S., Lysaker, Norway), which preferably comprise the following characteristics (per dosage form):

[00074] Co-administration of omega-3 fatty acids with one or more additional agents suitable for the treatment or prevention of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or MCI is also envisioned in accordance with the present invention. Such additional agents may include, but are not limited to, cholinesterase inhibitors, aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), clopidogrel, memantine, antihypertensive agents, dyslipidemic agents, and anti-Parkinson's medications.

[00075] The daily dosage of omega-3 fatty acids, with or without one or more additional agents suitable for the treatment or prevention of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or MCI, is preferably 1 to 10 dosages, with the preferred number of dosages from 1 to 4 times a day, most preferred 1 to 2 times a day. In combination therapy, the omega-3 fatty acids may

RPP/195671.2 ²⁷ be administered simultaneous to the administration of the one or more additional agents, e.g., as a single fixed dosage pharmaceutical composition or as separate compositions administered at the same time. In other embodiments of combination therapy, the omega-3 fatty acids are administered apart from the administration of the one or more additional agents, but in a concomitant treatment regime. For example, the one or more additional agents may be administered once daily while the omega-3 fatty acids are administered twice daily. One skilled in the art with the benefit of the present disclosure will understand that the precise dosage and schedule for the administration of the omega-3 fatty acids and the one or more additional agents will vary depending on numerous factors, such as, for example, the route of administration and the seriousness of the condition. [00076] In some embodiments, the ingredients for co-administration may be provided in a convenient unit dosage form. The administration route is preferably oral administration, although other forms of administration may be used. [D0077] When administered together, the combination therapy may allow for a greater effect than any expected combined or additive effect of the drugs alone. Further, any undesirable side effects may also be reduced as a result of the lower dosage amount and the reduction in excipients (e.g., surfactants). [00078] The active ingredients of the present invention may be administered with a combination of one or more non-active pharmaceutical ingredients (also known generally herein as "excipients"). Non-active ingredients, for example, serve to solubilize, suspend, thicken, dilute, emulsify, stabilize, preserve, protect, color, ffavor, and fashion the active ingredients into an applicable and efficacious preparation that is safe, convenient, and otherwise acceptable for use.

RPP/l 95671.2 ²⁸ [00079] Excipients may include surfactants, such as propylene glycol monocaprylate, mixtures of glycerol and polyethylene glycol esters of long fatty acids, polyethoxylated castor oils, glycerol esters, oleoyl macrogol glycerides, propylene glycol monolaurate, propylene glycol dicaprylate/dicaprate, polyethylene- polypropylene glycol copolymer, and polyoxyethylene sorbitan monooleate, cosolvents such ethanol, glycerol, polyethylene glycol, and propylene glycol, and oils such as coconut, olive or safflower oils. The use of surfactants, cosolvents, oils or combinations thereof is generally known in the pharmaceutical arts, and as would be understood to one skilled in the art, any suitable surfactant may be used in conjunction with the present invention and embodiments thereof. [00080] In accordance with the present invention, the treatment using omega-3 fatty acids, and optionally the one or more additional agents, is preferably continued over a long period of time, due to the progressive nature of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or MCI. Preferably, treatment extends over at least 3 months, more preferably at least 6 months, and most preferably over a period of at least one year. In accordance with a preferred embodiment, the treatment is at least 5 years, in order to preserve and protect the cognitive function of the patient.

[00081] Those patients identified as being likely to respond to omega-3 fatty acids therapy, regardless of whether they are identified based on a comparison of the results of baseline ICMi and ICPi scans, or based on a comparison of a first baseline scan or scans with a second assessment scan or scans that are conducted following a first trial period during which omega-3 fatty acids are administered, are preferably monitored as they receive the therapeutic dose of omega-3 fatty acids (optionally in combination with the one or more additional agents. The monitoring may include

RPP/195671.2 29 follow-up mental assessments; reviewing reports from family members, caregivers, and/or primary care physicians regarding the patient's clinical symptoms; and/or further brain scanning. Based on the results of the monitoring, it may be beneficial to adjust the dosage of omega-3 fatty acids being administered to the patient, or to include one or more additional agents, in order to optimize the treatment or prevention of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or MCI, or to continue to retard the progression of these conditions.

EXAMPLES

[00082] Particularly preferred embodiments of the present invention will now be described with respect to the information provided in the following patient data charts.

RPP/195671.2 30 TABLE 1 - ICPi < ICMi

<_*>

Group 1: examples of patients dosed with omega-3 fatty acids who demonstrated improvements in symptoms Group 2: examples of baseliπerfirst dosage regimen:assessment, patients are good candidates for therapy Group 3: examples of baseline ICPi < ICMi, patients most likely suffer from vascular dementia Group 4: example where ICMi and ICPi are both in normal range

TECH/486016.1

TABLE 2 - ICPi > ICMi

M M

Group 1: low ICMi and/or ICPi

Group 2: moderate ICMi and ICPi

Group 3: ICMi and ICPi are both in normal range

TECH/486016.1

TABLE 3 - ICPi * ICMi

Group 1: low ICMi and ICPi

Group 2: moderate ICMi and ICPi

Group 3: ICMi and ICPi are both in normal range

TECH/486016.1

[00083] It will, of course, be appreciated that the above description has been given by way of example only and that modifications in detail may be made within the scope of the present invention.

[00084] Throughout this application, various patents and publications have been cited. The disclosures of these patents and publications in their entireties are hereby incorporated by reference into this application, in order to more fully describe the state of the art to which this invention pertains.

[00085] The invention is capable of considerable modification, alteration, and equivalents in form and function, as will occur to those ordinarily skilled in the pertinent arts having the benefit of this disclosure. All references cited herein are hereby incorporated by reference in their entirety.

[00086] While the present invention has been described for what are presently considered the preferred embodiments, the invention is not so limited. To the contrary, the invention is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the detailed description provided above.

RPP/ 195671.2 34

Claims

What is Claimed:

1. A method of identifying a patient likely to benefit from omega-3 fatty acid therapy for dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment, comprising the steps of: identifying a patient having abnormal brain activity by conducting one or more baseline scans of the patient's brain, thereafter administering a first dosage regimen of omega-3 fatty acids to the patient identified in said identifying step, thereafter conducting one or more assessment scans of the patient's brain, comparing the one or more assessment scans with the one or more baseline scans to determine any improvement in the patient's brain activity, and selecting any patient having an improvement in brain activity to receive omega-3 fatty acid therapy for the treatment or prevention of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment.

2. The method of claim 1, wherein the patient does not exhibit apparent symptoms of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment.

3. The method of claim 1 , wherein the one or more baseline scans are selected from one or both of a basal metabolic scan and a stimulated perfusion scan.

RPP/195671.2 35

4. The method of claim 1, wherein the one or more assessment scans are selected from one or both of a basal metabolic scan and a stimulated perfusion scan.

5. The method of claim 1 , wherein the one or more baseline scans includes a stimulated perfusion scan.^"

6. The method of claim 1 , wherein the one or more assessment scans includes a stimulated perfusion scan.

7. The method of claim 1, wherein the one or more baseline scans and the one or more assessment scans are each conducted using a scanning technique independently selected from the group consisting of positron emission tomography (PET) and single photon emission computed tomography (SPECT).

8. A method of identifying a patient likely to benefit from omega-3 fatty acid therapy for a brain disorder, comprising the steps of: conducting a basal metabolic scan of the patient's brain, thereafter administering a perfusion stimulating dose of omega-3 fatty acids to the patient, thereafter conducting a stimulated perfusion scan of the patient's brain, comparing the basal metabolic scan with the stimulated perfusion scan to differentially diagnose a brain disorder that is treatable with omega-3 fatty acids, and

RPP/l 95671.2 36 selecting any patient diagnosed with a brain disorder that is treatable with omega-3 fatty acids to receive omega-3 fatty acid therapy for the treatment or prevention of the brain disorder.

9. The method of claim 8, wherein the patient does not exhibit apparent symptoms of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment.

10. The method of claim 8, wherein the omega-3 fatty acids are administered in a therapeutically effective amount.

11. The method of claim 10, wherein the omega-3 fatty acids are administered along with one or more additional agents suitable for the treatment or prevention of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment.

12. The method of claim 11, wherein the one or more additional agents are each independently selected from the group consisting of cholinesterase inhibitors, aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), clopidogrel, memantine, antihypertensives, dyslipidemic agents, and anti-Parkinson's medications.

13. The method of claim 12, wherein the omega-3 fatty acids and the one or more additional agents are provided as a unit dosage.

RPP/ 195671.2 37

14. The method of claim 8, wherein a differential diagnosis between Alzheimer's disease and vascular dementia is made based upon comparison of the basal metabolic scan and the stimulated perfusion scan.

15. The method of claim 14 wherein a differential diagnosis for Alzheimer's disease is made if the basal metabolic scan is abnormal in more than 1 area.

16. A method for treating or preventing dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment in a patient in need thereof, comprising the steps of: identifying a patient having abnormal brain activity by conducting at least one baseline scan of the patient's brain, thereafter administering a first dosage regimen of omega-3 fatty acids to the patient identified in said identifying step, thereafter conducting at least one assessment scan of the patient's brain, comparing the at least one assessment scan with the at least one baseline scan to determine any improvement in the patient's brain activity, selecting any patient having an improvement in brain activity to receive omega-3 fatty acid therapy for the treatment or prevention of Alzheimer's disease, dementia, and/or mild cognitive impairment, and administering to the patient selected in said selecting step a therapeutically effective dose of one or more active agents including omega-3 fatty acids to treat or prevent dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment.

RPP/l 95671.2 38

17. The method of claim 16, wherein the patient does not exhibit apparent symptoms of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment.

18. The method of claim 16, wherein the therapeutically effective dose further includes one or more additional agents suitable for the treatment or prevention of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment.

19. The method of claim 16, wherein the one or more additional agents are each independently selected from the group consisting of cholinesterase inhibitors, aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), clopidogrel, memantine, antihypertensives, dyslipidemic agents, and anti-Parkinson's medications.

20. The method of claim 18, wherein the omega-3 fatty acids and the one or more additional agents are provided as a unit dosage.

21. The method of claim 16, wherein the at least one baseline scan includes at least one of a basal metabolic scan and a stimulated perfusion scan.

22. The method of claim 16, wherein the at least one assessment scan includes at least one of a basal metabolic scan and a stimulated perfusion scan.

23. The method of claim 16, wherein the at least one baseline scan includes a stimulated perfusion scan.

RPP/l 95671.2 39

24. The method of claim 16, wherein the at least one assessment scan includes a stimulated perfusion scan.

25. The method of claim 16, wherein the at least one baseline scan and the at least one assessment scan are each conducted using a scanning technique independently selected from the group consisting of positron emission tomography (PET) and single photon emission computed tomography (SPECT).

26. A method for treating or preventing a brain disorder in a patient in need thereof, comprising the steps of: conducting a basal metabolic scan of the patient's brain, thereafter administering a perfusion stimulating dose of omega-3 fatty acids to the patient, thereafter conducting a stimulated perfusion scan of the patient's brain, comparing the basal metabolic scan with the stimulated perfusion scan to differentially diagnose a brain disorder that is treatable with omega-3 fatty acids, selecting any patient diagnosed with a brain disorder that is treatable with omega-3 fatty acids to receive omega-3 fatty acid therapy for the treatment or prevention of the brain disorder, and administering to the patient selected in said selecting step a therapeutically effective dose of one or more active agents including omega-3 fatty acids to treat or prevent said brain disorder.

RPP/l 95671.2 ⁴⁰

27. The method of claim 26, wherein the patient does not exhibit apparent symptoms of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment.

28. The method of claim 26, wherein the omega-3 fatty acids are administered in ^•a therapeutically effective amount.

29. The method of claim 28, wherein the omega-3 fatty acids are administered along with one or more additional agents suitable for the treatment or prevention of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment.

30. The method of claim 29, wherein the one or more additional agents are each independently selected from the group consisting of cholinesterase inhibitors, aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), clopidogrel, memantine, antihypertensives, dyslipidemic agents, and anti-Parkinson's medications.

31. The method of claim 29, wherein the omega-3 fatty acids and the one or more additional agents are provided as a unit dosage.

32. The method of claim 26, wherein a differential diagnosis between Alzheimer's disease and vascular dementia is made based upon comparison of the basal metabolic scan and the stimulated perfusion scan.

RPP/195671.2 41

33. The method of claim 32 wherein a differential diagnosis for Alzheimer's disease is made if the basal metabolic scan is abnormal in more than 1 area.

34. A diagnostic test for determining whether a patient is likely to respond to omega-3 fatty acid therapy for the treatment or prevention of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment, comprising the steps of: identifying a patient having abnormal brain activity by conducting one or more baseline scans of the patient's brain, thereafter administering a first dosage regimen of omega-3 fatty acids to the patient identified in said identifying step, thereafter conducting one or more assessment scans of the patient's brain, and comparing the one or more assessment scans with the one or more baseline scans to determine any improvement in the patient's brain activity, thereby determining whether the patient is likely to respond to omega-3 fatty acid therapy for the treatment or prevention of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment.

35. The diagnostic test of claim 34, wherein the patient does not exhibit apparent symptoms of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment.

36. The diagnostic test of claim 34, wherein the one or more baseline scans include at least one of a basal metabolic scan and a stimulated perfusion scan.

RPP/l 95671.2 42

37. The diagnostic test of claim 34, wherein the one or more assessment scans include at least one of a basal metabolic scan and a stimulated perfusion scan.

38. The diagnostic test of claim 34, wherein the one or more baseline scans include. a stimulated perfusion scan.

39. The diagnostic test of claim 34, wherein the one or more assessment scans include a stimulated perfusion scan.

40. The diagnostic test of claim 34, wherein the one or more baseline scans and the one or more assessment scans are each conducted using a scanning technique independently selected from the group consisting of positron emission tomography (PET) and single photon emission computed tomography (SPECT).

41. The diagnostic test of claim 34, wherein a differential diagnosis between Alzheimer's disease and vascular dementia is made based upon comparison of the one or more baseline scans and the one or more assessment scans.

42. The diagnostic test of claim 41 wherein a differential diagnosis for Alzheimer's disease is made if the one or more baseline scans are abnormal in more than 1 area.

43. A diagnostic test for determining whether a patient is likely to respond to omega-3 fatty acid therapy for a brain disorder, comprising the steps of:

RPP/195671.2 43 conducting a basal metabolic scan of the patient's brain, thereafter administering a perfusion stimulating dose of omega-3 fatty acids to the patient, thereafter conducting a stimulated perfusion scan of the patient's brain, and comparing the basal metabolic scan with the stimulated perfusion scan to differentially diagnose a brain disorder, thereby determining whether the patient is likely to respond to omega-3 fatty acid therapy for the treatment or prevention of the brain disorder.

44. The diagnostic test of claim 43, wherein the patient does not exhibit apparent symptoms of dementia, vascular dementia, Parkinson's dementia, Alzheimer's disease, and/or mild cognitive impairment.

45. The diagnostic test of claim 43, wherein a differential diagnosis between Alzheimer's disease and vascular dementia is made based upon comparison of the basal metabolic scan and the stimulated perfusion scan.

46. The diagnostic test of claim 45 wherein a differential diagnosis for Alzheimer's disease is made if the basal metabolic scan is abnormal in more than 1 area.

RPP/ 195671.2 44