WO2016072842A1

WO2016072842A1 - Method for preventing, reducing the risk of, or treating behavioral frontotemporal dementia

Info

Publication number: WO2016072842A1
Application number: PCT/NL2014/050767
Authority: WO
Original assignee: N.V. Nutricia
Priority date: 2014-11-05
Filing date: 2014-11-05
Publication date: 2016-05-12

Abstract

The invention pertains to the use of one or more of uridine and cytidine, or salts, phosphates, acyl derivatives or esters thereof in the manufacture of a product for treating, preventing or reducing the risk of occurrence of behavioral frontotemporal dementia, or behavioral symptoms thereof.

Description

METHOD FOR PREVENTING, REDUCING THE RISK OF, OR TREATING BEHAVIORAL FRONTOTEMPORAL DEMENTIA

The invention is in the field of medical nutrition and more particularly relates to a composition for treating, preventing or reducing the risk of occurrence of behavioral major or mild frontotemporal neurocognitive disorder [F D] or frontotemporal dementia [FTD]. It particularly relates to treating or reducing behavioral

symptomatology in behavioral FTD patients or prodromal behavioral FTD patients. BACKGROUND OF THE INVENTION

During the last decennium, uridine, choline and omega-3 fatty acids such as DHA have attracted attention as active components in treating cognitive dysfunction and age- associated memory impairment (AAMI), see e.g. WO2007/089703 (Massachusetts Institute of Technology) and WO 2009/002165 (N.V. Nutricia). These compounds are rate-limiting precursors for membrane phosphatide synthesis. According to the above applications, by improving the membrane phosphatide synthesis, it is believed to improve cognitive or memory function. The effects on membrane phospholipids have been associated with enhancement in specific pre- and post-synaptic proteins. WO 2013/066165 and WO 2013/066167 (N.V. Nutricia) disclose a product comprising (i) one or more of uridine and cytidine, or salts, phosphates, acyl derivatives or esters thereof , and (ii) a lipid fraction comprising at least one of docosahexaenoic acid 5 (22:6; DHA), eicosapentaenoic acid (20:5; EPA) and docosapentaenoic acid (22:5; DP A), or esters thereof, recognition and executive functions like speed of information processing, cognitive and mental flexibility, attention, scanning, and cognitive set shifting can be improved, in particular in a Alzheimer's or dementia patient. WO 2012/125020 discloses a similar product for use in the prevention or treatment of neurotrauma, traumatic brain injury, cerebral palsy and spinal cord injury. In the art, focus of attention has been on subjects suffering from or at immediate risk of developing dementia and/or Alzheimer's Disease [AD]. The neurodegeneration in these patients is commonly associated with the formation of protein agglomerates, which manifest themselves as amyloid plagues or Lewy bodies. However, in the art there is also a need to address other clinical forms of dementia, such as frontotemporal dementia which is distinguished from Alzheimer's disease and Lewy body dementia based on the fact that it does not manifest with amyloid plaques, neurofibrillary tangles, or Lewy bodies. As addressed in the experimental part of the application, tools such as Frontal Assessment Battery exist that help distinguishing (behavioral) FTD from Alzheimer- type Dementia ('DAT').

The symptoms of FTD fall into two clinical patterns that involve either (1) changes in behavior, or (2) problems with language. The first type, the behavioural variant of frontotemporal dementia (or 'behavioral frontotemporal dementia' or 'bvFTD') features behavior that can be either impulsive (disinhibited) or bored and listless (apathetic) and includes inappropriate social behavior; lack of social tact; lack of empathy;

distractability; loss of insight into the behaviors of oneself and others; an increased interest in sex; changes in food preferences; agitation or, conversely, blunted emotions; neglect of personal hygiene; repetitive or compulsive behavior, and decreased energy and motivation. Approximately 60% of patients with any form of FTD have the behavioural variant of FTD. The second type, the progressive non-fluent aphasia, primarily features symptoms of language disturbance, including difficulty making or understanding speech, often in conjunction with the behavioral type's symptoms.

Spatial skills and memory remain intact. There is considerable overlap between progressive nonfluent aphasia and corticobasal degeneration. Approximately 20 % of FTD patients have this variant.

SUMMARY OF THE INVENTION

The inventors have observed that a product comprising (i) one or more of uridine and cytidine, or salts, phosphates, acyl derivatives or esters thereof, and optionally (ii) a lipid fraction comprising at least one of docosahexaenoic acid (22:6; DHA),

eicosapentaenoic acid (20:5; EPA) and docosapentaenoic acid (22:5; DP A), or esters thereof, upon administration can prevent, treat or reduce the occurrence of behavioral frontotemporal dementia, or behavioral symptoms thereof. The product is particularly useful for treating or reducing behavioral symptomatology in behavioral FTD patients or 'prodromal behavioral FTD patients' who are at increased risk of developing bvFTD. Throughout the application, 'frontotemporal dementia' (FTD) and 'frontotemporal neurocognitive disorder' (F D) are terms which are used interchangeably, in accordance with the way both terms are practiced synonymously in the field, and both FTD and FND encompass both major and mild forms. The invention relates to the behavioral variant of (major and mild) FTD or FND, i.e. 'bvFTD' or 'bvFND' .

Reference is made to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), which is the 2013 update to the American Psychiatric Association's (APA) classification and diagnostic tool. In the United States the DSM serves as a universal authority for psychiatric diagnosis.

LIST OF PREFERRED EMBODIMENTS

In a first aspect, the invention pertains to the use of the aforementioned components (i) and optionally (ii) in the manufacture of a product for treating, preventing or reducing the risk of occurrence of behavioral frontotemporal dementia, or symptoms thereof. The product is particularly useful for treating or reducing behavioral symptomatology in behavioral FTD patients or 'prodromal behavioral FTD patients' who are at increased risk of developing bvFTD. Alternatively, the invention pertains to a method for treating, preventing or reducing the risk of occurrence of behavioral frontotemporal dementia, or symptoms thereof, in a subject, said method comprising administering to said subject a product comprising the aforementioned components (i) and optionally (ii). The product is particularly useful for treating or reducing behavioral symptomatology in behavioral FTD patients or

'prodromal behavioral FTD patients' who are at increased risk of developing bvFTD. The prodromal stage of bvFTD is characterized by both cognitive and behavioral features, clinically identified by (1) cognitive profiling, (2) the presence of

behavioral/psychiatric symptoms in the absence of memory complaints, or (3) a combined approach of cognitive, behavioral, and neuroimaging features.

Alternatively, the invention pertains to a product for use in treating, preventing or reducing the risk of occurrence of behavioral frontotemporal dementia, or symptoms thereof, in a subject, said composition comprising the aforementioned components (i) and optionally (ii). The product is particularly useful for treating or reducing behavioral symptomatology in behavioral FTD patients or 'prodromal behavioral FTD patients' who are at increased risk of developing bvFTD. In the method or use according to the invention, the subject has preferably been diagnosed suffering from behavioral FTD or at increased risk of developing behavioral FTD using well-accepted Frontotemporal Assessment Battery (FAB) or Frontal Behavioral Inventory (FBI). Both are assessed in more detail in the experimental part of the application. The Frontal Behavioral Inventory which can be used in the context of the invention is found at http://www.dementia- assessment.com.au/frontotemporal FBI_test_Nov0907.pdf, its contents herein incorporated by reference and otherwise presented in example 2. FAB which can be used in the context of the invention can be found at http : //www . dementia- assessment, coni.au/frontoteniporal/frontal_fab_scale.pdf otherwise presented in example 3. Reference is also made to Dubois, B. ; Litvan, I.; The FAB: A frontal assessment battery at bedside. Neurology. 55(11): 1621-1626, 2000; and Slachevsky, A; Dubois, B. Frontal Assessment Battery and Differential Diagnosis of Frontotemporal Dementia and Alzheimer Disease. Archives of Neurology. 61(7): 1104-1107, 2004. The subject-matter about FAB in both citations are herewith incorporated by reference. Using FAB and/or FBI, subjects suffering from Alzheimer's disease or Alzheimer-type dementia ('DAT') may thus be excluded from the (prophylactic) treatment of the invention.

In one embodiment, the method or use according to the invention, particularly treating or reducing behavioral symptomatology, preferably involves improving the score in at least 1, more preferably at least 2, even more preferably at least 3, particularly at least 4, most particularly at least 5, 6, 7, 8, 9, 10, 11 symptoms, most preferably all symptoms selected from apathy, aspontaneity, indifference/emotional flatness, inflexibility, disorganization, inattention, personal neglect, loss of insight, logopenia, aphasia and verbal apraxia, comprehension and alien hand in the FBI test as taken by a skilled practisioner (i.e. a clinician-rated score). In one embodiment, the method or use according to the invention, particularly treating or reducing behavioral symptomatology, preferably involves improving the Clinical Global Impression (CGI) score of said subject. According to the art, the Clinical Global Impression Scale is a measure of global functioning, a set of ratings made by a clinician in order to assess the overall severity of an individual's symptoms as well as changes in his or her functioning over time. The CGI was developed for use in NIMH-sponsored clinical trials to provide a brief, stand-alone assessment of the clinician's view of the patient's global functioning prior to and after initiating a study medication. CGI provides an overall clinician-determined summary measure that takes into account all available information, including knowledge of the patient's history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the patient's ability to function. Higher scores on the "Severity" subscale of the GCI indicate a worse condition of the patient. The subscale "Improvement" compares the patient's condition after "x" weeks of treatment with the condition of the patient before onset of treatment and gives a score from 1-7 wherein: l=very much improved since the initiation of treatment; 2=much improved; 3=minimally improved; 4=no change from baseline (the initiation of treatment); 5=minimally worse; 6= much worse; 7=very much worse since the initiation of treatment. Reference is made to Guy W, editor. ECDEU Assessment Manual for Psych opharmacology. Rockville, MD: US Department of Health, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and Mental Health

Administration; 1976, the contents of which is herewith incorporated by reference.

In one embodiment, the method or use according to the invention, particularly treating or reducing behavioral symptomatology, preferably involves improving the RMET (reading the mind in the eyes test) score. The 'Reading the Mind in the Eyes' test is an advanced test of theory of mind, and described in detail in Baron-Cohen S, Wheelwright S, Hill J, Raste Y, Plumb I: "The 'reading the mind in the eyes ' test revised version: a study with normal adults, and adults with asperger syndrome or high-functioning autism. " J Child Psychol Psychiatry 2001;42:241-51, which contents is herewith incorporated by reference. The RMET is used to assess individual differences in social cognition and emotion recognition. The test consists of 36 photographs of actors and actresses showing the facial region around the eyes. The participant is asked to choose which of four words best describes what the person in the photograph is thinking or feeling. These words refer to both basic mental states (for example, 'happy') and complex mental states (for example, 'arrogant'). Completing the instrument requires not only the ability to recognize emotional expressions but also the ability to determine the complex cognitive mental state of an individual based on a partial facial expression. Higher scores on this test indicate better performance and thus better social skills.

In one embodiment, the method or use according to the invention, particularly treating or reducing behavioral symptomatology, preferably involves improving the NPI (NeuroPsychiatric Inventory) score. The purpose of the Neuropsychiatric Inventory (NPI) is to obtain information on the presence of psychopathology in patients with brain disorders. The NPI was developed for application to patients with Alzheimer's disease and other dementias, but it may be useful in the assessment of behavioral changes in other conditions. Ten behavioral and two neurovegetative areas are included in the NPI: Delusions, Hallucinations, Agitation/ Aggression, Depression/Dysphoria, Anxiety, Elation/Euphoria, Apathy/Indifference, Disinhibition, Irritability/Lability, Aberrant motor behavior, Sleep and Nighttime Behavior Disorders, Appetite and Eating

Disorders. The more behavioral disturbances a patients displays the higher the score on the NPI. Reference is made to Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. "The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia" Neurology 1994;44:2308-14, its contents herein incorporated by reference.

In one embodiment, the method or use according to the invention, particularly treating or reducing behavioral symptomatology, preferably involves improving the RMET score, the NPI score and/or the CGI score of said subject.

In the above method or use according to the invention, the product preferably further comprises (ii) a lipid fraction comprising at least one of the omega-3 PUFAs docosahexaenoic acid (22:6; DHA), eicosapentaenoic acid (20:5; EPA) and

docosapentaenoic acid (22:5; DP A), or esters thereof. Preferably at least DHA is present, more preferably DHA and EPA. It is preferred that the aforementioned product further comprises at least one of (iii) choline, or salts or esters thereof ; and (iv) at least one vitamin B selected from the group of vitamin B6, vitamin B 12 and vitamin B9, or equivalents thereof, preferably comprising vitamin B6, B9 and B12. The product preferably comprises both (iii) choline, or salts or esters thereof; and (iv) at least one vitamin B selected from the group of vitamin B6, vitamin B 12 and vitamin B9, or equivalents thereof, preferably all of vitamin B6, B9 and B 12.

The product preferably comprises the aforementioned components (i) and (ii); and vitamin B6, B9 and B 12. Most preferably, the product further comprises choline.

DETAILED DESCRIPTION OF THE INVENTION

Internationally recognized guidelines for diagnosing behavioral frontotemporal dementia, abbreviated 'bvFTD', have been established. Reference is made to Rascovsky et al. "Sensitivity of revised diagnostic criteria for the behavioral variant of

frontotemporal dementia" Brain (2011) Sept 134(pt9):2456-77, herewith incorporated by reference. In accordance with these guidelines, a subject is identified as suffering from or at increased risk of bvFTD if he or she shows progressive deterioration of behavior and/or cognition by observation or history, does not exhibit any biomarkers strongly indicative of Alzheimer's Disease or other neurodegenerative process, and shows inability to control or adjust his or her behavior in different social contexts. In that context, the subject has preferably been identified as a patient suffering from bvFTD or a prodromal patient at increased risk of developing bvFTD, preferably by subjecting said subject to FAB and/or FBI. The subject is preferably not diagnosed having Alzheimer's disease or Alzheimer-type dementia or any other degenerative dementias. In one embodiment, the subject has a FBI score of 30 or higher. Additionally or alternatively, the subject has a FAB score of 12 or lower.

The subject of the invention is preferably a subject having a Mini -Mental State

Examination (MMSE) score of 24 or higher, preferably 24 - 26, where FAB and FBI have validity in distinguishing Frontotemporal type dementia from Dementia of the Alzheimer's type ('DAT'). The MMSE is a standardized test developed in the art to distinguish between the various (pre-) stages of dementia. It involves a brief 30-point questionnaire that is used to assess cognition. In the time span of about 10 minutes it samples various functions including memory and orientation. The MMSE test includes simple questions and problems in a number of areas: the time and place of the test, repeating lists of words, language use and comprehension, and basic motor skills. Any score of 27 or higher (out of 30) is interpreted as effectively normal; 20-26 indicates mild dementia; 10-19 moderate dementia, and below 10 severe dementia. It was first introduced by Folstein et al. (Psych Res 12: 189, 1975), and is widely used with small modifications to assess cognition. The MMSE 24 - 26 subject group preferably includes prodromal bvFTD subjects who do not suffer from bvFTD, but have an increased likelihood of developing bvFTD.

In one embodiment, the subject is drug naive.

The subjects targeted are preferably elderly. The 'elderly' are preferably human subjects of at least 50 years of age, more preferably at least 55 years of age.

The method or use according to the invention may also involve assessment of the occurrence of and/or quantify the amount of white matter lesions and/or WMH in said subject using imaging techniques such as MRI and/or diffusion tensor imaging (DTI). This may be assessed in identifying the subject of the invention, and/or monitoring the effects of the intervention.

In one aspect of the present invention, the composition according to the invention may be used as a pharmaceutical product comprising one or more pharmaceutically acceptable carrier materials. Such product may contain the daily dosage in one or more dosage units. The dosage unit may be in a liquid form or in a solid form, wherein in the latter case the daily dosage may be provided by one or more solid dosage units, e.g. in one or more capsules or tablets. The pharmaceutical product, preferably for enteral application, may be a solid or liquid galenical formulation. Examples of solid galenical formulations are tablets, capsules (e.g. hard or soft shell gelatine capsules), pills, sachets, powders, granules and the like which contain the active ingredient together with conventional galenical carriers. Any conventional carrier material can be utilized. The carrier material can be organic or inorganic inert carrier material suitable for oral administration. Suitable carriers include water, gelatine, gum Arabic, lactose, starch, magnesium stearate, talc, vegetable oils, and the like. Additionally, additives such as flavouring agents, preservatives, stabilizers, emulsifying agents, buffers and the like may be added in accordance with accepted practices of pharmaceutical compounding. While the individual active ingredients are suitably administered in a single

composition, they may also be administered in individual dosage units.

In a preferred aspect of the present invention, the product according to the invention may be used as a nutritional product, for example as a nutritional supplement, e.g., as an additive to a normal diet, as a fortifier, to add to a normal diet, or as a complete nutrition. The nutritional product preferably comprises at least one component selected from the group of fats, proteins, and carbohydrates. It is understood that a nutritional product differs from a pharmaceutical product by the presence of nutrients which provide nutrition to the subject to which the composition is administered, in particular the presence of protein, fat, digestible carbohydrates and dietary fibres. It may further contain ingredients such as minerals, vitamins, organic acids, and flavouring agents. Although the term "nutraceutical product" is often used in literature, it denotes a nutritional product with a pharmaceutical component or pharmaceutical purpose.

Hence, the nutritional composition according to the invention may also be used in a nutraceutical product.

The product of the invention is an enteral composition, intended for oral administration. In identifying the (preferred) ingredients here below, the terms 'product' and

'composition' in the context of the invention are used interchangeably.

The composition is preferably administered in liquid form. In one embodiment, the product comprises a lipid fraction and at least one of carbohydrates and proteins, wherein the lipid composition provides between 20 and 50 energy % of the food product. In one embodiment, the food product is a liquid composition containing between 0.8 and 1.4 kcal per ml. In one embodiment, the composition further increases levels of pre- and post-synaptic proteins Synapsin-1 and PSD-95, respectively. In one embodiment, these membrane phospholipids and pre- and post-synaptic proteins are not targeted. Nucleotides/nucleosides

The present composition comprises uridine, cytidine and/or an equivalent thereof, including salts, phosphates, acyl derivatives and/or esters. In terms of uridine, the composition preferably comprises at least one uridine or an equivalent thereof selected from the group consisting of uridine (i.e. ribosyl uracil), deoxyuridine (deoxyribosyl uracil), uridine phosphates (UMP, dUMP, UDP, UTP), nucleobase uracil and acylated uridine derivatives. In one embodiment, cytidine, CMP, citicoline (CDP-choline) may also be applied. Preferably, the present composition comprises an uridine phosphate selected from the group consisting of uridine monophosphate (UMP), uridine diphosphate (UDP) and uridine triphosphate (UTP); and/or a cytidine phosphate (CMP, CDP, CTP, preferably CMP). Most preferably the present composition comprises uridine and/or UMP, preferably at least UMP, as UMP is most efficiently being taken up by the body. Preferably at least 50 weight% of the uridine in the present composition is provided by UMP, more preferably at least 75 weight%, most preferably at least 95 weight%. Doses that must be administered are given as UMP. The amount of uracil sources can be calculated taking the molar equivalent to the UMP amount.

The present method preferably comprises the administration of uridine (the cumulative amount of uridine, deoxyuridine, uridine phosphates, nucleobase uracil and acylated uridine derivatives) in an amount of (i) 0.1 to 6 g per day, preferably 0.2 to 3 g per day, more preferably 0.4 to 2 g per day, and/or (ii) 0.1 to 6 g per 100 ml (liquid)

composition, preferably 0.2 to 3 g per 100 ml (liquid) composition, more preferably 0.4 to 2 g per 100 ml (liquid) composition. In one embodiment, the above amounts also account for any amounts of cytidine, cytidine phosphates and citicoline incorporated in the composition or method. Uridine and its equivalents are however preferred.

Preferably, the present composition comprises uridine phosphate, preferably uridine monophosphate (UMP). The UMP is very efficiently taken up by the body. Hence, inclusion of UMP in the present composition enables a high effectivity at the lowest dosage and/or the administration of a low volume to the subject.

Omega-3 polyunsaturated fatty acids

The composition preferably comprises at least one co-3 polyunsaturated fatty acid (LC PUFA; having a chain length of 18 and more carbon atoms) selected from the group consisting of docosahexaenoic acid (22:6; DHA), eicosapentaenoic acid (20:5; EPA) and docosapentaenoic acid (22:5 co-3; DP A), preferably at least one of DHA and EPA. Preferably the present composition contains at least DHA, more preferably DHA and EPA. EPA is converted to DPA (co-3), increasing subsequent conversion of DP A to DHA in the brain. Hence, the present composition preferably contains a significant amount of EPA, so to further stimulate in vivo DHA formation. In the context of the invention, 'DPA' is understood to comprise the omega-3 (22:5) DPA only. The DHA, EPA and/or DPA are preferably provided as triglycerides, diglycerides, monoglycerides, free fatty acids or their salts or esters, phospholipids,

lysophospholipids, glycerol ethers, lipoproteins, ceramides, glycolipids or combinations thereof. Preferably, the present composition comprises at least DHA in triglyceride form.

In terms of daily dosage, the present method preferably comprises the administration of 500 to 5000 mg DHA+EPA+DPA (preferably DHA+EPA) per day, more preferably 750 to 4000 mg per day, most preferably 1000 to 3000 mg per day. DHA is preferably administered in an amount of 500 to 5000 mg per day, more preferably 750 to 4000 mg per day, most preferably 1000 to 3000 mg per day. If at all, EPA is preferably administered in an amount of 500 to 5000 mg per day, more preferably 750 to 4000 mg per day, most preferably 1000 to 3000 mg per day. These amounts of EPA apply if it is used alone or in combination with DHA. In terms of unit dosage, the proportion of DHA+EPA+DPA ( preferably DHA+EPA) of the total fatty acids is preferably 5 to 95 weight%, more preferably 10 to 80 weight%, most preferably 15 to 70 weight%. The present composition preferably comprises 5 to 95 weight% DHA based on total fatty acids, preferably 10 to 75 weight% DHA based on total fatty acids, more preferably 10 to 60 weight% DHA based on total fatty acids. The present composition preferably comprises 5 to 95 weight% EPA based on total fatty acids, preferably 10 to 75 weight% EPA, most preferably 15 to 60 weight%, based on total fatty acids.

The ratio of the weights of DHA to EPA is preferably larger than 1, more preferably 2: 1 to 10: 1, more preferably 3 : 1 to 8: 1. The above-mentioned ratios and amounts take into account and optimise several aspects, including taste (too high LCP levels reduce taste, resulting in a reduced compliance), balance between DHA and precursors thereof to ensure optimal effectiveness while maintaining low-volume formulations.

Sources of DHA possible sources of DHA: tuna oil, (other) fish oils, DHA rich alkyl esters, algae oil, egg yolk, or phospholipids enriched with n-3 LCPUFA e.g.

phosphatidylserine-DHA. In one embodiment, the weight ratio co-3/ co-6 in the composition of the invention is preferably in the range 0.3 to 7, preferably in the range 1.4: 1 to 5.9: 1, more preferably in the range 3 : 1 to 5.5 : 1 , most preferably 3 : 1 to 5 : 1 , in particular less than 5: 1. The amount of co-6 LCPUFAs is preferably less than 50, preferably 5 to 40, more preferably 8 to 30 weight% of the fatty acids in the formula.

Choline

The present composition preferably contains choline, a choline salt and/or choline ester. The choline salt is preferably selected from choline chloride, choline bitartrate, or choline stearate. The choline ester is preferably selected from a phosphatidylcholine and lyso-phosphatidyl choline. The present method preferably comprises the administration of more than 50 mg choline per day, preferably 80 to 3000 mg choline per day, more preferably 100 to 2000 mg choline per day, most preferably 150 to 1000 mg choline per day. The present composition preferably comprises 80 mg to 3000 gram choline per 100 ml of the liquid composition, preferably 100 mg to 2000 mg choline per 100 ml, preferably 200 to 1000 mg choline per 100 ml composition, most preferably 200 mg to 600 mg choline per 100 ml. The above numbers are based on choline, the amounts of choline equivalents or sources can be calculated taking the molar equivalent to choline into account. B vitamins

The present combination preferably comprises at least one B complex vitamin. The vitamin B is selected from the group of vitamin Bl (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin or niacinamide), vitamin B5 (pantothenic acid), vitamin B6

(pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine hydrochloride), vitamin B7 (biotin), vitamin B9 (folic acid or folate), and vitamin B12 (various cobalamins).

Functional equivalents are encompassed within these terms.

Preferably, at least one vitamin B is selected from the group of vitamin B6, vitamin B 12 and vitamin B9. Preferably the present composition comprises at least two selected from the group consisting of vitamin B6, vitamin B12 and vitamin B9. In particular, good results have been achieved with a combination comprising vitamin B6, vitamin B 12 and vitamin B9. Their equivalents are considered incorporated. The vitamin B is to be administered in an effective dose, which dose depends on the type of vitamin B used. As a rule of thumb, a suitable minimum or a maximum dose may be chosen based on known dietary recommendations, for instance as recommended by Institute of Medicine (IOM) of the U.S. National Academy of Sciences or by Scientific Committee on Food (a scientific committee of the EU), the information disclosed herein and optionally a limited amount of routine testing. A minimum dose may be based on the estimated average requirement (EAR), although a lower dose may already be effective. A maximum dose usually does not exceed the tolerable upper intake levels (UL), as recommended by IOM. If present in the nutritional composition or medicament, the vitamin B6 is usually present in an amount to provide a daily dosage in the range of 0.1 to 100 mg, in particular in the range of 0.5 to 25 mg, more in particular in the range of 0.5 to 5 mg. The present composition preferably comprises 0.1 to 100 mg vitamin B6 per 100 g (liquid) product, more preferably 0.5 to 5 mg vitamin B6 per 100 g (liquid) product, more preferably 0.5 to 5 mg vitamin B6 per 100 g (liquid) product.

If present in the nutritional composition or medicament, the vitamin B12 is usually present in an amount to provide a daily dosage in the range of 0.5 to 100 μg, in particular in the range of 1 to 10 μg, more in particular in the range of 1.5 to 5 μg. The present composition preferably comprises 0.5-100 μg vitamin B12 per 100 g (liquid) product, more preferably 1 to 10 μg vitamin B12 per 100 g (liquid) product, more preferably 1.5 to 5 μg vitamin B 12 per 100 g (liquid) product. The term "vitamin B12" incorporates all cobalamin equivalents known in the art.

If present in the nutritional composition or medicament, the vitamin B9 is usually present in an amount to provide a daily dosage in the range of 50 to 5000 μg, in particular in the range of 100 to 1000 μg, more in particular in the range of 200 to 800 μg. The present composition preferably comprises 50 to 5000 μg folic acid per 100 g (liquid) product, more preferably 100 to 1000 μg folic acid per 100 g (liquid) product, more preferably 200 to 800 μg folic acid per 100 g (liquid) product. Folates include folic acid, folinic acid, methylated, methenylated and formylated forms of folates, their salts or esters, as well as their derivatives with one or more glutamic acid, and all in either reduced or oxidized form.

Phospholipids

It is preferred to incorporate at least one phospholipid in the composition. The term "phospholipid" excludes PC that is already accounted for in the choline fraction. The present composition preferably comprises at least one phospholipid in an amount of 0.01 to 1 gram per 100 ml, more preferably between 0.05 and 0.5 gram per 100 ml, most preferably 80 to 600 mg per 100 ml. The at least one phospholipid is preferably provided for by using lecithin. Vitamins C, E

Vitamin C, or a functional equivalent thereof, may be present in an amount to provide a daily dosage in the range of 20 to 2000 mg, in particular in the range of 30 to 500 mg, more in particular in the range of 75 tol50 mg. In one embodiment, vitamin C , or a functional equivalent thereof, is present in an amount in the range of 20 to 2000 mg, in particular in the range of 30 to 500 mg, more in particular in the range of 75 tol50 mg per 100 ml of the composition. Tocopherol and/or an equivalent thereof (i.e. a compound having vitamin E activity) may be present in an amount to provide a daily dosage in the range of 10 to 300 mg, in particular in the range of 30 to 200 mg, more in particular in the range of 35 to 100 mg, to prevent oxidative damage to the injury site resulting from dietary PUFA. In one embodiment, tocopherol and/or equivalent is present in an amount in the range of 10 to 300 mg, in particular in the range of 30 to 200 mg, more in particular in the range of 35 tolOO mg per 100 ml of the composition. The term "tocopherol and/or an equivalent thereof, as used in this description, comprises tocopherols, tocotrienols, pharmaceutical and/or nutritional acceptable derivatives thereof and any combination thereof. The above numbers are based on tocopherol equivalents, recognized in the art.

Selenium

The present composition preferably contains selenium. The antioxidant activity of selenium advantageously prevents and/or inhibits damages to the brain areas. Preferably the present method provides the administration of a composition comprising 0.01 and 5 mg selenium per 100 ml liquid product, preferably 0.02 and 0.1 mg selenium per 100 ml liquid product. The amount of selenium administered per day is preferably more than 0.01 mg, more preferably 0.01 to 0.5 mg. In view of the above, the composition according to the invention preferably comprises uridine and/or UMP, DHA and optionally EPA (preferably DHA and EPA), choline, folic acid, vitamin B12 and vitamin B6, in any of the aforementioned forms, equivalents or derivatives. The composition preferably comprises uridine and/or UMP, DHA and optionally EPA (preferably DHA and EPA), choline, folic acid, vitamin B 12, vitamin B6, vitamin C, vitamin E, and selenium, in any of the aforementioned forms, equivalents or derivatives. In a further embodiment, the composition also comprises phospholipids.

In one embodiment, the composition according to the invention comprises per daily dosage or per 100 ml of liquid (preferably water) :

-100 - 500 mg, preferably 200 - 400 mg, more preferably about 300 mg EPA,

- 900 - 1500 mg, preferably 950 - 1300 mg, more preferably about 1200 mg DHA,

-200 - 600 mg, preferably 300 - 500 mg, more preferably about 400 mg choline, - 400 - 800 mg, preferably 500 - 700 mg, more preferably about 625 mg UMP (uridine monophosphate),

- 20 - 60 mg, preferably 30 - 50 mg, more preferably about 40 mg vitamin E (alpha- TE),

- 60 - 100 mg, preferably 60 - 90 mg, more preferably about 80 mg vitamin C,

- 40 - 80 μg, preferably 45 - 65 μg, more preferably about 60 μg selenium,

- 1 - 5 μg, preferably 2 - 4 μg, more preferably about 3 μg vitamin B 12,

- 0.5 - 3 mg, preferably 0.5 - 2 mg, more preferably about 1 mg vitamin B6, and

- 200 - 600 μg, preferably 300 - 500 μg, more preferably about 400 μg folic acid.

Preferably, the composition further comprises 50 - 600 mg, preferably 60 - 200 mg, more preferably about 106 mg phospholipids.

The compositions as described above can be used as a nutritional therapy, nutritional support, as a medical food, as a food for special medical purposes or as a nutritional supplement. Such product can be consumed at one, two or three servings of 125 mL per day during recovery and/or rehabilitation in the context of the impairments according to the invention.

Preferably, the composition is enterally administered to the subjects of the invention at least one time per day for a period of at least 3 weeks, preferably at least 4 weeks, more preferably at least 5 weeks, particularly at least 6 weeks.

EXAMPLES Experimental evidence

Introduction: Synaptic dysfunction and loss represent one of the final common pathways of neurodegeneration. Thus, potentially, compounds able to restore synaptic functions could play a significant role in our therapeutic approach to neurodegenerative conditions. The present proof-of-concept study deals with an intervention product as detailed in example lb as an add-on therapy in another neurodegenerative condition, i.e. the behavioural variant of FrontoTemporal Dementia (FTD-bv or bvFTD). Methods: 16 subjects with a diagnosis of FTD-bv according to current criteria were included in the study. Subjects were randomized to receive as an add-on therapy to their current pharmacological regime either intervention product according to example lb 1 u.i.d. or placebo for three weeks and were then switched to the other treatment arm for other three weeks.

Behavioural symptomatology was assessed with the Frontal Behavioral Inventory (FBI) while executive functions deficits were assessed with the Frontal Assessment Battery (FAB), at enrolment, after three weeks, and after six weeks. The FBI is a 24-item questionnaire that measures behaviors such as apathy, indifference, disorganization, inattention, personal neglect, aspontaneity, inflexibility, concreteness, loss of insight, logopenia, verbal apraxia, and alien hand. A 4-point scale (none, mild, moderate, and severe) for each item is used and is dependent on the caregivers response. In the art, the FBI is intended to serve as a quantitative measure to determine the severity of impairment and to possibly assess a change due to therapeutic intervention. The FAB is a brief tool that can be used at the bedside or in a clinic setting to assist in

discriminating between dementias with a frontal dysexecutive phenotype and Dementia of Alzheimer's Type (DAT). The FAB has validity in distinguishing Fronto-temporal type dementia from DAT in mildly demented patients (MMSE > 24). Total score is from a maximum of 18, higher scores indicating better performance. Both FBI and FAB are respected tools in the field, reference is made for instance to pages 18 and 285 of Bruce Milner (editor) "The Human Frontal Lobes: Functions and Disorders (Science and Practice of Neuropsychology" ISBN-10: 1593853297, the contents of which is herewith incorporated by reference.

Moreover all subjects were evaluated with the Clinical Global Impression scale by a physician blinded to the current treatment to evaluate disease burden. According to the art, the Clinical Global Impression Scale (CGI) is a measure of global functioning, a set of ratings made by a clinician in order to assess the overall severity of an individual's symptoms as well as changes in his or her functioning over time. Higher scores on the "Severity" subscale of the GCI indicate a worse condition of the patient. The subscale "Improvement" compares the patient's condition after "x" weeks of treatment with the condition of the patient before onset of treatment and gives a score from 1-7 wherein: l=very much improved since the initiation of treatment; 2=much improved;

3=minimally improved; 4=no change from baseline (the initiation of treatment);

5=minimally worse; 6= much worse; 7=very much worse since the initiation of treatment.

Further, all subjects were evaluated in terms of the RMET (reading the mind in the eyes test and the NPI (NeuroPsychiatric Inventory).

Lastly caregiver quality of life was assessed with the SF-12 self report scale, i.e. the ' Short-Form 12-Item Health Survey' . It is a well-established tool in the field, and includes 2 questions concerning physical functioning; 2 questions on role limitations because of physical health problems; 1 question on bodily pain; 1 question on general health perceptions; 1 question on vitality (energy/fatigue); 1 question on social functioning; 2 questions on role limitations because of emotional problems; and 2 questions on general mental health (psychological distress and psychological well- being).

Results: The intervention product improved the scores on the RMET (reading the mind in the eyes test), the NPI (NeuroPsychiatric Inventory) and the GCI (Clinical Global Impression Scale). All these test showed significant improvement after 12 weeks intervention (RMET p< 0.001; NPI p< 0.001; GCI p<0.005). Compared to baseline, a reduction of behavioural symptomatology was observed, associated with a reduction of clinician-rated global disease burden and an increase of perceived caregiver QoL in the intervention product but not in the placebo groups. Switch from the intervention product to placebo was associated with a worsening of the behavioural symptomatology. No change was observed in FAB scores during the study in either treatment arm. The intervention product was well tolerated by all subjects.

Discussion: In this proof-of-concept study it was shown that the intervention product could represent a useful add-on therapy for behavioral symptomatology in a

convenience sample of 16 FTD patients, in absence of any significant change in executive functions. Example la: Liquid product containing per 125 ml serving:

Fat, g 4.9 Vitamin E (alpha- TE), mg 40

EPA, mg 300 Vitamin C, mg 80

DHA, mg 1200 Selenium, μg 60

Phospholipids, mg 106 Vitamin B 12, μg 3

Choline, mg 400 Vitamin B6, mg 1

UMP (uridine monophosphate), mg 625 Folic acid, μg 400

Abbreviations: EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; TE, tocopherol equivalents.

Example lb: Liquid product containing per 125 ml serving:

Energy, kcal 125 Calcium, mg 100

Protein, g 3.8 Phosphorus, mg 87.5

Carbohydrate, g 16.5 Magnesium, mg 25.0

Fat, g 4.9 Iron, mg 2

EPA, mg 300 Zinc, mg 1.5

DHA, mg 1200 Iodine, μg 16.3

Phospholipids, mg 106 Manganese, mg 0.41

Choline, mg 400 Copper, μg 225

UMP (uridine monophosphate), mg 625 Molybdenum, μg 12.5

Vitamin E (alpha- TE), mg 40 Chromium, μg 8.4

Vitamin C, mg 80 Vitamin A, μg 200

Selenium, μg 60 Thiamin (B l), mg 0.19

Vitamin B 12, μg 3 Riboflavin (B2), mg 0.20

Vitamin B6, mg 1 Niacin (B3), mg NE 2.25

Folic acid, μg 400 Pantothenic acid (B5), mg 0.66

Sodium, mg 125 Vitamin D, μg 0.88

Potassium, mg 187.5 Biotin, μg 5.0

Chloride, mg 156.3 Vitamin K, μg 6.6

Abbreviations: E, niacin equivalents. Example 2: Frontotemporal Behavioral Inventory (FBI)

(source: http://www.dementia- assessment.com.au/frontotemporal/FBI_test_Nov0907.pdf

NAME: AGE: _ DIAGNOSIS: DATE:

CAREGIVER: EXAMINER:

Explain to the caregiver that you are looking for a change in behaviour and personality. Ask the caregiver these questions in the absence of the patient.

Elaborate if necessary. At the end of each question, ask about the extent of the behavioural change, and then score it according to the following: 0 = none, 1 = mild, occasional, 2 = moderate, 3 = severe, most of the time.

1. Apathy: Has s/he lost interest in friends or activities or is s/he interested in seeing people or doing things?

2. Aspontaneity: Does s/he start things on his/her own, or does s/he have to be asked?

3. Indifference / Emotional Flatness: Does s/he respond to occasions of joy or sadness as much as ever, or has s/he lost emotional responsiveness?

4. Inflexibility: Can s/he change his/her mind with reason or does s/he appear stubborn or rigid in thinking lately?

5. Disorganization: Can s/he plan and organize complex activity or is s/he easily distractible, indecisive, or unable to complete a job?

6. Inattention: Does s/he pay attention to what is going on or does s/he seem to lose track or not follow at all?

7. Personal Neglect: Does s/he take as much care of his/her personal hygiene and appearance as usual, or does s/he neglect to wash or change his/her underwear?

8. Loss of Insight: Is s/he aware of any problems or changes in behaviour, or does s/he seem unaware of them or deny them when discussed?

9. Logopenia: Is s/he as talkative as before or has the amount of speech significantly decreased? 10. Aphasia and Verbal Apraxia: Does s/he make language or pronunciation errors or has s/he developed stuttering or grammatical errors recently?

11. Comprehension (Semantic) deficit: Does s/he ask what words mean, has trouble comprehending words, and/or objects, or does s/he know the meaning of words?

12. Alien Hand and/or Apraxia: Has s/he developed clumsiness, stiff hand, inability to use utensils or appliances, or does a hand interfere with the other, or behaves as if it did not belong, or can s/he use both hands as before?

Negative Behavior Score Total of 1 - 12

NAME: DATE:

13. Perseveration, Obsessions (Stereotypy): Does s/he repeat or perseverate actions or remarks? Are there any obsessive routines or behaviours, or has s/he always been a creature of habit?

14. Hoarding: Has s/he started to hoard objects or money excessively or has her/his saving habits remained unchanged?

15. Inappropriateness: Has s/he kept social rules or has s/he said or done things outside what are acceptable? Has s/he been rude, or childish?

16. Excessive jocularity: Has s/he been making jokes excessively or offensively or at the wrong time, or has s/he always had a jocular manner or a quirk sense of humor? 17. Poor Judgment and Impulsivity: Has s/he been using good judgment in decisions, spending or driving, or has s/he acted impulsively, irresponsibly, neglectfully or in poor judgment?

18. Restlessness / Roaming: Has s/he been roaming, pacing, walking, driving excessively or is the activity level normal?

19. Irritability: Has s/he been irritable, short-tempered, or is s/he reacting to stress or frustration as s/he always had?

20. Aggression: Has s/he shown aggression, or shouted at anyone or hurt anyone physically, or is there no change in this respect? 21. Hyperorality/food fads: Has s/he been drinking or eating excessively anything in sight, or developing food fads, a sweet tooth, eating bananas or cookies excessively, or even putting objects in his/her mouth, or has s/he always had a large appetite and the eating habits have not changed? Has s/he lost table manners?

22. Hypersexuality: Has sexual behaviour been unusual or excessive? This could include remarks or undressing, or is there no change in this respect?

23. Utilization Behaviour: Does s/he seem to need to touch, feel, examine, or pick-up objects within reach and sight, or can s/he keep his/her hands to him/herself?

24. Incontinence: Has s/he wet or soiled his or herself, or does s/he have problems that can be explained by urinary infection or childbirth/prostate?

The scoring is intended to capture severity rather than the frequency of abnormalities.

Disinhibition Score Total of 13-24

Cutoff score of 30 distinguishes FTD from other degenerative dementias Total Score:

The caregiver may have a tendency to discuss behaviours that are not related to the questions asked. Although flexibility is desirable, and extra information may be useful, caregivers should be reoriented towards the item by saying, for example, "We were discussing apathy " and then repeating the scripted question. It is advisable to encourage the caregiver, and only if the caregiver does not understand the question shoud the interviewer for example be suggestible; while deviation from the scripted question may be necessary, it should be avoided in general, as it leads to a great deal of extraneous material being discussed.

Example 3. Frontotemporal Assessment Battery (FAB)

(source: http://www.dementia- assessment.com.au/frontotemporal/Frontal_FAB_Scale.pdf)

Purpose

The FAB is a brief tool that can be used at the bedside or in a clinic setting to assist in discriminating between dementias with a frontal dysexecutive phenotype and Dementia of Alzheimer" s Type (DAT). The FAB has validity in distinguishing Fronto-temporal type dementia from DAT in mildly demented patients (MMSE > 24). Total from a maximum of 18, higher scores indicating better performance.

1. Similarities (conceptualization)

"In what way are they alike?"

- A banana and an orange

(In the event of total failure: "they are not alike" or partial failure: "both have peel," help the patient by saying: "both a banana and an orange are fruit"; but credit 0 for the item; do not help the patient for the two following items)

- A table and a chair

- A tulip, a rose and a daisy

Score (only category responses [fruits, furniture, flowers] are considered correct) Three correct: 3 Two correct: 2 One correct: 1 None correct: 0 2. Lexical fluency (mental flexibility)

"Say as many words as you can beginning with the letter„S," any words except surnames or proper nouns."

If the patient gives no response during the first 5 seconds, say: "for instance, snake." If the patient pauses 10 seconds, stimulate him by saying: "any word beginning with the letter„S." The time allowed is 60 seconds.

Score (word repetitions or variations [shoe, shoemaker], surnames, or proper nouns are not counted as correct responses)

> 9 words: 3 6 -9 words: 2 3 -5 words: 1 < 3 words: 0 3. Motor series "Luria" test (programming)

"Look carefully at what I" m doing."

The examiner, seated in front of the patient, performs alone three times with his left hand the series of "fist-edge-palm."

"Now, with your right hand do the same series, first with me, then alone."

The examiner performs the series three times with the patient, then says to him/her: "Now, do it on your own."

Score Patient performs six correct consecutive series alone: 3

Patient performs at least three correct consecutive series alone: 2

Patient fails alone, but performs three correct consecutive series with the examiner: 1

Patient cannot perform three correct consecutive series even with the examiner: 0

4. Conflicting instructions (sensitivity to interference)

"Tap twice when I tap once."

To ensure that the patient has understood the instruction, a series of 3 trials is run: 1-1-1. "Tap once when I tap twice."

To ensure that the patient has understood the instruction, a series of 3 trials is run: 2-2-2. The examiner then performs the following series: 1-1-2-1-2-2-2-1-1-2.

Score No errors: 3 1 -2 errors: 2 > 2 errors: 1

Patient taps like the examiner at least four consecutive times: 0 5. Go-No Go (inhibitory control)

"Tap once when I tap once."

To ensure that the patient has understood the instruction, a series of 3 trials is run: 1-1-1. "Do not tap when I tap twice."

Score No errors: 3 1 -2 errors: 2 > 2 errors: 1

Patient taps like the examiner at least four consecutive times: 0

6. Prehension behaviour (environmental autonomy)

"Do not take my hands."

The examiner is seated in front of the patient. Place the patient" s hands palm up on his knees. Without saying anything or looking at the patient, the examiner brings his own hands close to the patient" s hands and touches the palms of both the patient" s hands, to see if he will spontaneously take them. If the patient takes the examiner" s hands, try again after asking the patient: "Now, do not take my hands."

Score

Patient does not take the examiner" s hands: 3 Patient hesitates and asks what he/she has to do: 2

Patient takes the hands without hesitation: 1

Patient takes the examiner" s hand even after he/she has been told not to do so: 0 Interpreting results

A cut off score of 12 on the FAB has a sensitivity of 77% and specificity of 87% in differentiating between frontal dysexecutive type dementias and DAT

Claims

1. Use of one or more of uridine and cytidine, or salts, phosphates, acyl derivatives or esters thereof in the manufacture of a product for treating, preventing or reducing the risk of occurrence of behavioral frontotemporal dementia (bvFTD), or behavioral symptoms thereof, in a subject.

Use according to claim 1, said product further comprising a lipid fraction comprising at least one of docosahexaenoic acid (22:6; DHA), eicosapentaenoic acid (20:5; EPA) and docosapentaenoic acid (22:5; DP A), or esters thereof.

3. Use according to any one of the preceding claims, said product further

comprising at least one of:

(iii) choline, or salts or esters thereof ; and

(iv) at least one vitamin B selected from the group of vitamin B6, vitamin B12 and vitamin B9, or equivalents thereof, preferably comprising all of vitamin B6, B9 and B12,

4. Use according to any one of the preceding claims, said product further

comprising (iii) choline and (iv) vitamin B6, B9 and B12.

5. Use according to any one of the preceding claims, said product further

comprising one or more selected from the group consisting of vitamin C or its equivalents, vitamin E or its equivalents, and selenium.

6. Use according to any of the preceding claims, wherein said subject has been diagnosed suffering from behavioral FTD or at increased risk of developing behavioral FTD using Frontotemporal Assessment Battery (FAB) or Frontal Behavioral Inventory (FBI).

7. Use according to any of the preceding claims, for treating or reducing behavioral symptomatology in behavioral FTD patients or prodromal behavioral FTD patients who are at increased risk of developing bvFTD. Use according to claim 7, wherein treating or reducing behavioral

symptomatology involves improving the score in at least 1, more preferably at least 2, even more preferably at least 3, particularly at least 4, most particularly at least 5, 6, 7,

8,

9,

10,

11 symptoms, most preferably all symptoms selected from apathy, aspontaneity, indifference/emotional flatness, inflexibility,

disorganization, inattention, personal neglect, loss of insight, logopenia, aphasia and verbal apraxia, comprehension and alien hand in the FBI test as taken by a skilled practisioner.

Use according to claim 7 or 8, wherein treating or reducing behavioral symptomatology involves improving the RMET (reading the mind in the eyes test) score, the NPI (NeuroPsychiatric Inventory) score and/or the CGI (Clinical Global Impression) score of said subject.

Use according to any of the preceding claims, said subject having a Mini-Mental State Examination (MMSE) score of 24 or higher, preferably MMSE 24 - 26.

Use according to any one of the preceding claims, said product being an aqueous composition comprising, per daily dosage or per 100 ml of liquid:

100 - 500 mg EPA,

900 - 1500 mg DHA,

50 - 600 mg phospholipids,

200 - 600 mg choline,

400 - 800 mg UMP (uridine monophosphate),

20 - 60 mg vitamin E (alpha- TE),

60 - 100 mg vitamin C,

40 - 80 μg selenium,

1 - 5 μg vitamin B12,

0.5 - 3 mg vitamin B6, and

200 - 600 μg folic acid.

12. A product for use in treating, preventing or reducing the risk of occurrence of behavioral frontotemporal dementia, or behavioral symptoms thereof, in a subject, said product comprising one or more of uridine and cytidine, or salts, phosphates, acyl derivatives or esters thereof, and optionally a lipid fraction comprising at least one of docosahexaenoic acid (22:6; DHA), eicosapentaenoic acid (20:5; EPA) and docosapentaenoic acid (22:5; DP A), or esters thereof.

13. A method for treating, preventing or reducing the risk of occurrence of behavioral frontotemporal dementia, or behavioral symptoms thereof, in a subject, said method comprising administering to said subject a product comprising one or more of uridine and cytidine, or salts, phosphates, acyl derivatives or esters thereof, and optionally a lipid fraction comprising at least one of

docosahexaenoic acid (22:6; DHA), eicosapentaenoic acid (20:5; EPA) and docosapentaenoic acid (22:5; DP A), or esters thereof.

14. The method according to claim 13, said product further comprising a lipid

fraction comprising at least one of docosahexaenoic acid (22:6; DHA), eicosapentaenoic acid (20:5; EPA) and docosapentaenoic acid (22:5; DP A), or esters thereof.

15. The method according to any one of claims 13 - 14, said product further

comprising at least one of:

(iii) choline, or salts or esters thereof ; and

(iv) at least one vitamin B selected from the group of vitamin B6, vitamin B 12 and vitamin B9, or equivalents thereof, preferably comprising all of vitamin

B6, B9 and B12,

16. The method according to any one of claims 13 - 15, said product further

comprising (iii) choline and (iv) vitamin B6, B9 and B12.

17. The method according to any one of claims 13 - 16, said product further

The method according to any one of claims 13 - 17, wherein said subject has been diagnosed suffering from behavioral FTD or at increased risk of developing behavioral FTD using Frontotemporal Assessment Battery (FAB) or Frontal Behavioral Inventory (FBI).

The method according to any one of claims 13 - 18, for treating or reducing behavioral symptomatology in behavioral FTD patients or prodromal behavioral FTD patients who are at increased risk of developing bvFTD.

The method according to claim 19, wherein treating or reducing behavioral symptomatology involves improving the score in at least 1, more preferably at least 2, even more preferably at least 3, particularly at least 4, most particularly at least 5, 6, 7, 8, 9, 10, 11 symptoms, most preferably all symptoms selected from apathy, aspontaneity, indifference/emotional flatness, inflexibility,

The method according to claim 19 or 20, wherein treating or reducing behavioral symptomatology involves improving the RMET (reading the mind in the eyes test) score, the NPI (NeuroPsychiatric Inventory) score and/or the CGI (Clinical Global Impression) score of said subject.

The method according to any of claims 13 - 21, said subject having a Mini- Mental State Examination (MMSE) score of 24 or higher, preferably MMSE 24 26.

23. The method according to any of claims 13 - 22, said product being an aqueous composition comprising, per daily dosage or per 100 ml of liquid: