WO2012048871A1

WO2012048871A1 - Memantine for improving cognitive performance in subjects

Info

Publication number: WO2012048871A1
Application number: PCT/EP2011/005123
Authority: WO
Inventors: Frank Tennigkeit
Original assignee: Merz Pharma GmbH and Co KGaA
Current assignee: Merz Pharma GmbH and Co KGaA
Priority date: 2010-10-12
Filing date: 2011-10-12
Publication date: 2012-04-19
Anticipated expiration: 2013-04-12

Abstract

Memantine for use in improving cognitive performance in a subject by administering an effective amount of memantine to said subject, characterized in that the subject is not suffering from a disorder being or being accompanied by a cognitive condition ranging in severity from mild cognitive impairment (MCI), age-associated memory impairment (AAMI) to dementia.

Description

MEMANTINE FOR IMPROVING COGNITIVE PERFORMANCE IN SUBJECTS

FIELD OF THE INVENTION

[0001] The present invention relates to a use of memantine for improving cognitive performance of a subject with subjective cognitive impairment.

BACKGROUND OF THE INVENTION

[0002] Memantine (1-amino-3,5-dimethyl adamantine) is a systemically-active uncompetitive NMDA receptor antagonist having moderate affinity for the receptor and strong voltage dependency and rapid blocking/unblocking kinetics. Memantine has been shown to be useful in alleviation of various progressive neurodegenerative disorders such as dementia in patients with moderate to severe Alzheimer's disease, Parkinson's disease, and spasticity (see, e.g., U. S. Patents No. 5,061 ,703; 5,614,560, and 6,034,134). Memantine is approved for the treatment of moderate to severe Alzheimer's disease (AD) by the FDA and the EMA.

[0003] Memantine has been used to treat age-associated memory impairment, diagnosed by a standardized memory test and the MMSE („A double-blind, placebo- controlled trial of memantine in age-associated memory impairment (memantine in AAMI)", Ferris, S. et al., Int J Geriatr Psychiatry 2007; 22(5):448-55). In this study, the patients were given a daily dose of 20 mg/day. For example the criteria for a diagnosis of AAMI include objective evidence of memory problems below the norm compared with healthy young adults (Crook et al. Dev. Neuropsychol. 1986; 2:261- 76.).

[0004] Memantine has also been used to improve cognition in patients with mild cognitive impairment (MCI) and moderate cognitive impairment diagnosed by the MMSE and a cognitive testing battery (Memantine Improves Cognition in Patients With Mild Cognitive Impairment: Presented at the 9th International Conference on Alzheimer's and Parkinson's Diseases (ADPD); Presentation title: Open-Label, Control-Group Study to Evaluate Effectiveness of Akatinol Memantine in Patients With Non-Dementia Cognitive Impairments. Abstract P413).

[0005] Memantine has further been used to improve cognition in patients with cognitive impairment in moderate to severe Alzheimers disease (Reisberg et al. NEJM 2003; 348(14):1333-41 , Winblad et al. Dement Geriatr Cogn Disord 2007; 24(1):20-7.).

[0006] Subjective cognitive impairment (SCI) is defined by subjective complaints of memory and/or other cognitive problems (e.g. attention, learning aptitude, concentration, language and speed of information processing) and is defined in accordance with Reisberg et al, Alzheimers & Dementia 2010; 6(1): 11-24.

[0007] SCI can be a prodromal form of mild cognitive impairment (MCI) and dementia. The latter cognitive disorders are characterized by memory and/or other cognitive impairments, objectively measured by psychometric tests (e.g. the Mini- Mental State Examination and others, for details see Petersen et al. Neurology 2001 ; 56(9): 1133-42) and below defined norm values. MCI is defined (among other criteria) by "impairment on objective cognitive tasks; and/or evidence of decline over time on objective cognitive tasks. "(Winblad et al. J. Int. Med. 2004; 256:240-246). [0008] Criteria for the diagnosis of Alzheimers dementia also include "clinical and neuropsychological evaluation" (McKhann et al. Neurology 1984; 34(7):939-44.).

[0009] Subjects with SCI or SMI have a higher probability to progress to MCI and dementia compared to normal control subjects (Reisberg et al., Alzheimers & Dementia 2010; 6(1):11-24; Jessen et al. Arch. Gen. Psych. 2010; 67(4):414 - 422).

[0010] The effects of Memantine on SCI and SMI have not yet been studied.

OBJECTS OF THE INVENTION

[0011] One object of the invention is to broaden the hitherto known application spectrum of memantine. This and other objects are solved by the subject application.

SUMMARY OF THE INVENTION

[0012] The instant inventors have discovered that memantine may be used for improving cognitive performance in a subject with subjective cognitive impairment.

[0013] According to a first aspect, the invention relates to memantine for use in improving cognitive performance in a subject by administering an effective amount of memantine to said subject, wherein the subject is not suffering from a disorder being or being accompanied by a cognitive condition being age-associated memory impairment (AAMI), or a cognitive condition ranging in severity from mild cognitive impairment (MCI) to dementia. [0014] In a further embodiment memantine is administered to a subject that is suffering from subjective cognitive impairment (SCI), as defined by Reisberg et al. in Alzheimer's & Dementia (2010), Volume 6, pages 11 to 24, and/or wherein the subject is suffering from subjective memory impairment (SMI) as defined by Jessen et al. in Arch Gen Psychiatry (2010), Volume 67 (No. 4), pages 414 to 422, and/or wherein the subject shows a rating according to the Global Deterioration Scale (GDS) as defined in Reisberg et al. in Am J. Psych 1982, Volume 139, pages 1136 to 1139 of less than 3.

[0015] In another embodiment said subject has no clinical symptoms of Alzheimer Dementia (AD-C) but shows an asymptomatic pathophysioloical manifestation of Alzheimer Dementia (AD-P), diagnosed preclinically by the presence of biomarkers as e.g. defined by Sperling et al. in Alzheimer & Dementia (2011), pages 1 to 13. Within this reference AD-P is defined in three stages, the stages being incorporated herein by reference:

[0016] Stage 1 : The stage of asymptomatic cerebral amyloidosis which is characterized inter alia by high PET amyloid tracer retention and/or low CSF Αβ₄2-

[0017] Stage 2: Amyloid positivity and evidence of synaptic dysfuntion and/or early neurodegeneration characterized inter alia by neuronal dysfunction on FDG- PET/fMRI and/or high CSF tau/p-tau and / or cortical thinning/hippocampal atrophy on sMRI.

[0018] Stage 3: Amyloid positivity and evidence of neureodegeneration and subtle cognitive decline. [0019] In another embodiment said improvement of cognitive performance is or comprises the enhancement of the subject's cognition.

[0020] In a still further embodiment said improvement of cognitive performance is or comprises the enhancement of the subject's memory and/or other cognitive problems (e.g. attention, learning aptitude, concentration, language and speed of information processing).

[0021] In another embodiment said improvement of cognitive performance is or comprises the slowing down or prevention of cognitive worsening in said subject.

[0022] In a further embodiment memantine is administered to said subject in a dose of below 20 mg/day, e.g. 10 mg/day.

[0023] In a still further embodiment, the subject application relates to memantine for use in the treatment of a disorder being or being accompanied by a cognitive condition being age-associated memory impairment (AAMI) or mild cognitive impairment (MCI), wherein memantine is administered to a subject suffering from said disorder in a dose of below 20 mg/day, e.g. 10 mg/day.

[0024] In another embodiment, memantine is administered to said subject in a twice daily dose, or in a single dose.

[0025] In still another embodiment memantine may be co-administered with one or more other compound known to improve brain function, such as, but not limited to ginkgo extract, piracetam, nimodipine, nicergolin, acetylcholine esterase inhibitors, and mixtures of two or more thereof. In another embodiment the acetylcholine esterase inhibitor is selected from donepezil, rivastigmine and galantamine, and combinations of two or more thereof.

[0026] In a further embodiment memantine is in the form of an over-the-counter preparation.

[0027] In one embodiment memantine is in the form of a pharmaceutically acceptable salt.

[0028] In one embodiment the subject is a human being. In another embodiment the subject is at least 6 years and up to 50 years old, e.g. 10 to 50 years or 10 to 30 years old. In another embodiment, the subject is above 50 years to 80 years old.

[0029] In a further embodiment, the present application relates to the use of Memantine for improving cognitive performance in a subject by administering an effective amount of memantine to said subject, characterized in that the subject is not suffering from a disorder being or being accompanied by a cognitive condition being age-associated memory impairment (AAMI), or a cognitive condition ranging in severity from, mild cognitive impairment (MCI) to dementia.

[0030] In a still further embodiment said use is further characterized by one of the features defined hereinabove.

[0031] In a still further embodiment of said use, the subject shows a rating according to the Global Deteleration Scale (GDS) as defined in Reisberg et al. in Am J. Psych (1982) volume 139, pages 1136 to 1139 of 1 or 2. DETAILED DESCRIPTION OF THE INVENTION

[0032] The present invention relates to memantine for use in improving cognitive performance in a subject by administering an effective amount of memantine to said subject, characterized in that the subject is not suffering from a disorder being or being accompanied by a cognitive condition being age-associated memory impairment (AAMI), or a cognitive condition ranging in severity from mild cognitive impairment (MCI) to dementia.

[0033] The term "subject" encompasses both a human being and an animal. In its broadest definition, the subject is one that is not suffering from a "disorder being or being accompanied by a cognitive condition being age-associated memory impairment (AAMI), or a cognitive condition ranging in severity from mild cognitive impairment (MCI) to dementia".

[0034] The term "disorder being or being accompanied by a cognitive condition being age-associated memory impairment (AAMI), or a cognitive condition ranging in severity from mild cognitive impairment (MCI) to dementia" encompasses any disorder being associated with a cognitive condition as defined above. This definition includes these conditions per se, i.e. as the sole condition under which the subject is suffering. It also includes conditions, where AAMI, MCI or dementia are the result or a side effect of a different, underlying disease, such as Parkinson's disease, Multiple Sclerosis, depression, schizophrenia, bipolar disorder, brain cancer (tumors), aphasia, and stroke. [0035] Within the subject application the condition "mild cognitive impairment (MCI)" is in particular defined/characterized by the symptoms as defined in Petersen et al. in Arch Neurol., 56, pages 303 to 307 (1999). The term "mild cognitive disorder or mild cognitive impairment (MCI)" designates an impairment of the mental performance which exceeds the normal mental impairment depending on age and education of the concerned person. Sometimes, MCI is interpreted as initiated dementia. In one embodiment, said MCI corresponds to GDS stage 3 as defined by Reisberg et al. in Am J. Psych 1982, Volume 139, pages 1136 to 1139.

[0036] The term "age associated memory impairment (AAMI)" is a common condition characterized by mild symptoms of cognitive decline that occur as part of the aging process. Other designations for this condition include "agre related cognitive decline", "age consistent memory impairment", and afe life forgetfulness". The symptoms of AAMI that a person may experience can cause unwarranted fear or anxiety that these may be early signs of Alzheimer's disease or another serious impairment. In particular, the condition "age-associated memory impairment (AAMI)" is defined in accordance with the definition of Crook et al (1986).

[0037] The terms "dementia" and "Alzheimer's disease (AD)" are defined in accordance with WHO. ICD10 Chapter V (F), Geneva: WHO, 1992 and McKhann et al. Neurology 1984; 34(7):939-44, respectively.

[0038] In one embodiment the subject is one that is suffering from subjective cognitive impairment (SCI) as defined in Reisberg et al., Alzheimer's and Dementia (2010), 6, pages 11-24. In one embodiment the condition subjective cognitive impairment is synonymous with a rating of Global Deterioration Scale (GDS) of 2. In a still further embodiment as becomes apparent from the paragraph bridging left and right column of page 13 of Reisberg et al., Alzheimer's and Dementia (2010), 6, pages 11-24, within the determination of the GDS a clinical interview including the Brief Cognitive Rating Scale (BCRS), as defined in Reisberg et al., The Brief Cognitive Rating Scale (BCRS), Psychopharmacol Bull 1988; 24; 629-36 is performed.

[0039] In a further embodiment the subject is suffering from subjective memory impairment (SMI) as defined by Jessen et al. in Arch Gen Psychiatry (2010) 67, pages 414 to 422.

[0040] In a further embodiment the subject has a rating within the Global Deterioration Scale (GDS) as defined by Reisberg et al. in Am J Psych, (1982) 139, pages 1136 to 1139 of lower than 3. Within said reference, the respective GDS ratings are defined as follows, the definition being incorporated herein by reference:

[0041] Stage 1 : No Cognitive Decline

[0042] Clinical characteristics. Patients in stage 1 appear normal clinically; they have no complaints of memory deficit, and a clinical interview does not elicit evidence of memory deficit.

[0043] Psychometric concomitants. The individual scores on at least 3 of the 5 subtests of the Guild Memory Tests (6) are average or above for the patient^'s age and WAIS vocabulary score.

[0044] Stage 2: Very Mild Cognitive Decline/SCI

[0045] Clinical characteristics. This is the phase of forgetfulness. The patient complains of memory deficit. Most frequently patients in this phase complain of forgetting where familiar objects have been placed and of forgetting names that they formerly knew well. There is no objective evidence of memory deficit in the clinical interview and no objective deficits in employment or social situations. The individual in this phase displays appropriate concern about the symptoms.

[0046] Psychometric concomitants. The patient performs below average for his or her age and WAIS vocabulary score on 3 of the 5 Guild memory subtests.

[0047] Stage 3: Mild Cognitive Decline/MCI

[0048] Clinical characteristics. The earliest clear-cut clinical deficits appear at this stage. However, objective evidence of memory deficit is obtained only through an intensive interview conducted by a trained geriatric psychiatrist. Concentration deficit may be evident on clinical testing. Also, the patient may demonstrate decreased facility in remembering the names of people he or she has just been introduced to. The patient at this stage may read a passage in a book and retain relatively little material.

[0049] Decreased performance becomes manifest in demanding employment and social situations. Coworkers become aware of the patient^'s relatively poor performance. Difficulties in finding words and names may become evident to intimates. The patient may loses or misplace an object of value. Frequently, for the first time the patient may get seriously lost when travelling to an unfamiliar location.

[0050] The subtlety of the clinical symptoms may be increased by the denial that often begins to become manifest in these patients. Mild to moderate anxiety also accompanies the symptoms. The latter is increased if these patients are forced to cope with employment and social demands that they had previously found to be challenging but which, in their present state, they are no longer capable of negotiating.

[0051] Psychometric concomitants. These patients perform one standard deviation or more below average for their age and WAIS vocabulary score on at least 3 of the 5 Guild memory subtests. However, they may still make no errors on the 10- item Mental Status Questionnaire (7).

[0052] In a still further embodiment this subject is of GDS stage 2 or lower, e.g. GDS stage 1 or 2. Again, it is to note that this definition is meant to not include subjects suffering from AAMI.

[0053] In a still further embodiment the subject is of GDS stage 2 and be up to 50 years old, e.g. 6 to 50 or 10 to 30 years old.

[0054] In a still further embodiment, the subject is of GDS stage 2 or lower, and the dosing of memantine is less than 20 mg/day, e.g. 10 mg/day. This definition includes subjects of GDS stage 1 or 2, which are being dosed as defined hereinabove. Again this definition does not include subjects suffering from a disorder being or being accompanied by AAMI.

[0055] The term "improving cognitive performance" as used for the purpose of this application defines the ability of memantine to enhance the cognitive performance of a subject in comparison to placebo or in comparison to the non- administration of memantine. The term "improvement of cognitive performance" means in its broadest meaning an enhancement of the subject's cognition, including but not limited to the enhancement of the subject's memory, attention, learning aptitude, concentration, language and speed of information processing or any combination of two or more thereof. It also encompasses the slowing down or prevention of cognitive worsening in said subject.

[0056] The term "improving cognitive performance" as used within the subject application means that the subject treated gains a subjective impression of change (= improvement) in cognitive functions, such a memory and/or other cognitive problems (e.g. attention, learning aptitude, concentration, language and speed of information processing.

[0057] The above defined "improvement of cognitive performance" may potentially be corroborated by cognitive effects objectively measurable by a neuropsychological testing battery and effects on higher activities of daily living. Examples are computerized testing batteries such as the

[0058] CogState (cf. e.g. Collie A, Maruff P, Darby DG, et al. The effects of practice on the cognitive test performance of neurologically normal individuals assessed at brief test-retest intervals, J Int Neuropsychol Soc. 2003 Mar;9(3):419-28 and Pietrzak RH, Maruff P, Mayes LC, et al. An examination of the construct validity and factor structure of the Groton Maze Learning Test, a new measure of spatial working memory, learning efficiency, and error monitoring, Arch Clin Neuropsychol. 2008 Jul;23(4):433-45),

[0059] CANTAB (Cambridge Neuropsychological Test Automated Battery) (cf. e.g. Sahakian BJ, Owen AM Computerized assessment in neuropsychiatry using CANTAB: discussion paper, J R Soc Med. 1992 Jul;85(7):399-402 and Egerhazi A, Berecz R, Bartok E, Degrell I Automated Neuropsychological Test Battery (CANTAB) in mild cognitive impairment and in Alzheimer's disease, Prog Neuropsychopharmacol Biol Psychiatry. 2007 Apr 13;31(3):746-51. Epub 2007 Jan 16),

[0060] or CDR (Cognitive Drug Research Computerized Assessment System (also abbreviated as COGDRAS)) (cf e.g. Simpson PM, Surmon DJ, Wesnes KA, Wilcock GK The Cognitive Drug Research computerised assessment system for demented patients: a validation study, Int J Geriatr Psychiatry 1991 ; 6: 95-102) computerized testing batteries.

[0061] Furthermore, other testing batteries may be used, such as the

[0062] MMSE (cf e.g. Folstein, M.F., Folstein, S.E., McHugh, P.R. Mini-Mental State: A practical method for grading the cognitive state of patients for the clinician, J. Psychiatr. Research 12, 189-198, 1975),

[0063] ADAS cog (Alzheimer's Disease Assessment Scale) (cf e.g. Rosen, W.G., Mohs, R.C. and Davis, K.L. A New Rating Scale for Alzheimer's Disease, Am. J. Psychiatry 141 , 1356-1364, 1984),

[0064] NTB (cf e.g. Harrison J, Minassian SL, Jenkins L, Black RS, Koller M, Grundman M. A neuropsychological test battery for use in Alzheimer disease clinical trials, Arch Neurol. 2007 Sep;64(9): 1323-9) or the

[0065] Everyday Cognition 39 item version (Ecog 39) (cf e.g. Farias ST, Mungas D, Reed BR, et al. The measurement of everyday cognition (ECog): scale development and psychometric properties, Neuropsychology 2008 Jul;22(4):531-44) battery. [0066] In one embodiment improvement of cognitive performance is thus assessed via the CogState as defined above.

[0067] In one embodiment improvement of cognitive performance is thus assessed via the CANTAB as defined above.

[0068] In one embodiment improvement of cognitive performance is thus assessed via the CDR (COGDRAS) as defined above.

[0069] In one embodiment improvement of cognitive performance is thus assessed via the MMSE as defined above.

[0070] In one embodiment improvement of cognitive performance is thus assessed via the ADAS cog as defined above.

[0071] In one embodiment improvement of cognitive performance is thus assessed via the NTB as defined above.

[0072] In one embodiment improvement of cognitive performance is thus assessed via the Ecog 39 as defined above.

[0073] In all of the above embodiments relating to the assessment of cognitive performance via certain test batteries, the subject to be treated may be one with a rating according to the Global Deteleration Scale (GDS) as defined in Reisberg et al. in Am J. Psych (1982) volume 139, pages 1136 to 1139 of 1 or 2.

[0074] Improvement of cognitive performance can also be assessed based on subjective assessment, e.g. by answering the question "Check the number that best describes how your memory, concentration, or attention problems are now, compared to how it was before you began taking medication"".

[0075] The subject rates the development of his/her memory, concentration or attention problems on a 7-point scale from 1 (very much better) to 7 (very much worse), namely 1 = very much better, 2 = much better, 3 = a little better, 4 = no change, 5 = a little worse, 6 = much worse, 7 = very much worse.

[0076] In the embodiment relating to the assessment of cognitive performance via a subjective assessment as defined above, the subject to be treated may be one with a rating according to the Global Deteleration Scale (GDS) as defined in Reisberg et al. in Am J. Psych (1982) volume 139, pages 1136 to 1139 of 1 or 2.

[0077] In one embodiment, the improvement of cognitive performance is or comprises the enhancement of the subject's cognition.

[0078] The term "cognition" is the scientific term for "the process of thought". Cognition encompasses the ability of the brain to think, to process, communicate and store information, and to solve problems. Cognition is a high level of behavior, preferably unique to humans. The term "cognitive" encompasses functions or processes such as perception, introspection, memory, creativity, communication, concentration, attention, in other words, things which can be performed with the mind.

[0079] In one embodiment, said method comprises the enhancement of the subject's memory and/or other cognitive problems (e.g. attention, learning aptitude, concentration, language and speed of information processing). [0080] In another embodiment, said method is the enhancement of the subject's memory and/or other cognitive problems (e.g. attention, learning aptitude, concentration, language and speed of information processing.

[0081] The term "memory" encompasses an organism's ability to store, retain, and recall information.

[0082] The term "speed information processing" refers to the prediction of how fast an individual can process information in a given amount of time and under given conditions.

[0083] The term "attention" is the cognitive process of selectively concentrating on one aspect of the environment while ignoring other things.

[0084] The term "concentration" is the cognitive process of selectively concentrating on one aspect of the environment for a longer time period while ignoring other things.

[0085] The term "language" is the cognitive process of understanding and communicating thoughts, percepts and other cognitive concepts.

[0086] The term "learning aptitude" refers to the prediction of how well an individual can learn in a given amount of time and under given conditions.

[0087] In a still further embodiment of the improvement of cognitive performance in accordance with the present invention, the "forgetfulness" , also called "forgetting" within a subject to be treated is improved. The term ^u forgetfulness'T forgetting" refers to apparent loss of information already encoded and stored in an individual's long term memory. Stated differently, it is a persistent failure to remember.

[0088] The term "memantine" encompasses 1-amino-3,5-dimethyl adamantane and salts thereof.

[0089] In one embodiment, said memantine is administered to said subject in a dose which is not sufficient to treat a mental disorder or cognitive disorder.

[0090] Accordingly, in one embodiment, said memantine is administered to said subject in a dose which is less than 20 mg/day.

[0091] In one embodiment the dose is 10 mg/day.

[0092] In one embodiment, said memantine is administered to said subject in a daily dose.

[0093] In one embodiment, said memantine is administered to said subject in a single dose.

[0094] In one embodiment, said memantine is administered to said subject in an oral dose.

[0095] In one embodiment, prior to the administration of said memantine to said subject, said subject is not up-titrated with a dose of memantine that exceeds 10 mg/day. [0096] The term "not up-titrated" means that memantine is not administered to the subject prior to the administration of memantine according to the method according to the invention in one or more doses of less than 20 mg/day.

[0097] In one embodiment, a concomitant administration with a medication or medications to said subject is excluded which have an effect on an brain syndrome or mental disorder or cognitive disorder.

[0098] In one embodiment, memantine is the sole compound to be administered to the subject. Accordingly, memantine is not administered to said subject concomitantly to or in combination with a medication which has an effect on a mental disorder or cognitive disorder. In a further embodiment, memantine is not administered to said subject prior to, simultaneously to, or subsequently to said medication.

[0099] In another embodiment, memantine is administered together with other compounds that are capable of improving brain function, including but not limited to ginkgo extract, piracetam, nimodipine, nicergolin and acetylcholine esterase inhibitors, such as those disclosed in EP 1 509 232 A2, e.g. Donepezil, Rivastigmine, Galantamine, and combinations of two or more thereof.

[00100] In another embodiment, memantine is not administered concomitantly to isosorbide dinitrate (ISDN), or in combination with ISDN.

[00101] In another embodiment, memantine is not administered prior to, simultaneously to, or subsequently to ISDN. [00102] In one embodiment, said memantine is administered to said subject in an over-the-counter preparation.

[00103] The term "over-the-counter preparation (OTC)" encompasses a pharmaceutical formulation which is available without prescription.

[00104] The OTC may be prepared by procedures known in the art. For example, memantine can be formulated into tablets, capsules, powders, suspensions, solutions for oral administration, with common and conventional carriers, binders, diluents, and excipients. Inert pharmaceutically acceptable excipients useful to form over-the- counter formulations in accordance with the present invention include starch, mannitol, calcium sulfate, dicalcium phosphate, magnesium stearate, silicic derivatives, and/or sugars such as sucrose, lactose, and glucose. Binding agents include carboxymethyl cellulose and other cellulose derivatives, gelatin, natural and synthetic gums including alginates such as sodium alginate, polyethylene glycol, waxes and the like. Diluents include a suitable oil, saline, sugar solutions such as aqueous dextrose or aqueous glucose, and glycols such as polyethylene or polypropylene glycol. Other excipients include lubricants such as sodium oleate, sodium acetate, sodium stearate, sodium chloride, sodium benzoate, talc, and magnesium stearate, and the like; disintegrating agents including agar, calcium carbonate, sodium bicarbonate, starch, xanthan gum, and the like; and adsorptive carriers such as bentonite and kaolin. Coloring and flavoring agents may also be added to the over-the counter formulations.

[00105] Accordingly, in one embodiment, said over-the-counter preparation is a tablet, capsule, powder, suspension, or solution. [00106] In one embodiment, said memantine is in the form of a pharmaceutically acceptable salt.

[00107] For the purpose of this disclosure, the term "pharmaceutically acceptable salts" refers to salts of memantine that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., human). Typically, the term "pharmaceutically acceptable salt" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.

[00108] Conversion of memantine to a pharmaceutically acceptable salt thereof is accomplished in conventional fashion by admixture of the base with at least one molecular equivalent of a selected acid in an inert organic solvent. Isolation of the salt is carried out by techniques known to the art such as inducing precipitation with a non-polar solvent (e.g. ether) in which the salt has limited solubility. The nature of the salt is not critical, provided that it is non-toxic and does not substantially interfere with the desired pharmacological activity.

[00109] Examples of pharmaceutically acceptable salts are those formed with hydrochloric, hydrobromic, methanesulfonic, acetic, succinic, maleic, citric acid, and related acids. Further pharmaceutically acceptable salts include, but are not limited to, acid addition salts, such as those made with hydroiodic, perchloric, sulfuric, nitric, phosphoric, propionic, glycolic, lactic, pyruvic, malonic, fumaric, tartaric, benzoic, carbonic, cinnamic, mandelic, ethanesulfonic, hydroxyethanesulfonic, benezenesulfonic, p-toluene sulfonic, cyclohexanesulfamic, salicyclic, p- aminosalicylic, 2-phenoxybenzoic, and 2-acetoxybenzoic acid. [00110] In one embodiment, said pharmaceutically acceptable salt is the hydrochloride.

[00111] In one embodiment, said subject is a human being.

[00112] In one embodiment, said subject is a member of a group of people preparing for oral and/or written examinations.

[00113] In one embodiment, said subject is a member of a group of people attending a school.

[00114] Accordingly, in one embodiment, said subject is a pupil or a student.

[00115] In another embodiment, said subject is a member of a group of people attempting to enhance cognition with regard to complex information such as new technical developments. In one embodiment, said subject did not learn said complex information at school, or said complex information have not been available when said subject visited school.

[00116] Accordingly, in one embodiment, said subject is from 50 to 80 years old, or from 10 to 30 years old.

EXAMPLE

[00117] The following example illustrates the invention without limiting its scope.

[00118] Within this example the efficacy of Memantine for the treatment of subjective cognitive impairment is assessed. The primary objective of this example is to investigate the efficacy and safety of 10 mg/day Memantine in comparison to placebo in the treatment of memory, concentration, or attention problems in patients with subjective cognitive impairment, as measured by a "Patient Global Impression of Change" [PGI-C]-scale.

[00119] For this purpose 300 elderly male and female subjects with complaints of subjective memory, concentration, or attention problems, i.e. which suffer from subjective cognitive impairment, are randomly assigned to one of two treatment groups, i.e. Memantine group vs. placebo group. A daily single dose of 10 mg memantine or the respective placebo is administered to each subject starting at day zero. The active treatment period will last 12 weeks followed by a four weeks safety observation period.

[00120] The subjects are selected according to the following main inclusion criteria:

Age > 50 and < 80;

Subjective worsening of memory, concentration, or attention problems for longer than six months.

[00121] Memantine-HCI immediate release tablets with 10mg memantine-HCI (=8.31 mg memantine) were administered to a first subject group once daily. The dosage form is a 10mg film-coated lactose-free tablets (1 tablet/day) with the following excipients:

Excipients of tablet core: microcrystalline cellulose, sodium croscarmellose,

colloidal anhydrous silica, magnesium stearate. Excipients of tablet coat: Hypromellose, titanium dioxide E171 , Macrogol 400, iron oxide yellow E172.

The general manufacturing procedure for such tablets is described in WO

2006/096194.

[00122] In addition, matching placebo tablets are administered as film coated tablets to the second subject group.

[00123] After a total of 12 weeks intake of placebo/memantine (10 mg/day), the subjects are assessed according to the Patient Global Impression of Change (PGI- C).

[00124] The subject rates the development of his/her memory, concentration or attention problems on a 7-point scale from 1 (very much improved) to 7 (very much worsened) to measure the change compared to the baseline situation (day 0).

[00125] The scale presents seven tick boxes which are associated to the numeric values. [00126] It turns out that subjects receiving memantine in a dose of 10 mg/day over 12 weeks show a statistically significant improvement according to the above rating compared to a subject group which receives placebo.

Claims

1. Memantine for use in improving cognitive performance in a subject by administering an effective amount of memantine to said subject, characterized in that the subject is not suffering from a disorder being or being accompanied by a cognitive condition being age-associated memory impairment (AAMI), or a cognitive condition ranging in severity from, mild cognitive impairment (MCI) to dementia.

2. Memantine according to claim 1 , characterized in that the subject is suffering from subjective cognitive impairment (SCI), as defined by Reisberg et al. in Alzheimer's & Dementia (2010), Volume 6, pages 11 to 24, and/or wherein the subject is suffering from subjective memory impairment (SMI) as defined by Jessen et al. in Arch Gen Psychiatry (2010), Volume 67 (No. 4), pages 414 to 422, and/or wherein the subject shows a rating according to the Global Deterioration Scale (GDS) as defined in Reisberg et al. in Am J. Psych (1982), Volume 139, pages 1136 to 1139 of less than 3.

3. Memantine according to claim 1 or 2, wherein the subject shows a rating according to the Global Deteleration Scale (GDS) as defined in Reisberg et al. in Am J. Psych (1982) volume 139, pages 1136 to 1139 of 2.

4. Memantine according to any of the preceding claims, wherein said improvement of cognitive performance is or comprises the enhancement of the subject's cognition.

5. Memantine according to any one of the preceding claims, wherein said improvement of cognitive performance is or comprises the enhancement of the subject's memory, speed of information processing, language, concentration, attention and/or learning aptitude.

6. Memantine according to any of claims 1 to 3, wherein said improvement of cognitive performance is or comprises the slowing down or prevention of cognitive worsening in said subject.

7. Memantine according to any of the preceding claims, wherein said improvement of cognitive performance is assessed via or comprises an assessment via at least one of the following testing batteries: CoqState, CANTAB, CDR, MMSE, ADAS cog, NTB and Ecog39.

8. Memantine according to any one of the preceding claims, wherein said memantine is administered to said subject in a dose which is less than 20 mg/day, or is 10 mg/day.

9. Memantine for use in the treatment of a disorder being or being accompanied by a cognitive condition being age-associated memory impairment (AAMI), or mild cognitive impairment (MCI), wherein memantine is administered to a subject suffering from said disorder in a dose of below 20 mg/day, e.g. 10 mg/day.

10. Memantine according to any one of the preceding claims, wherein said memantine is administered to said subject in a twice daily dose, or in a single dose.

11. Memantine according to any of the preceding claims, wherein memantine is coadministered with one or more other compound known to improve brain function.

12. Memantine according to claim 11 , wherein said compound is selected from ginkgo extract, piracetam, nimodipine, nicergolin and acetylcholine esterase inhibitors.

13. Memantine according to claim 12, wherein the acetylcholine esterase inhibitor is selected from donepezil, rivastigmine, galantamine, and combinations of two or more thereof.

14. Memantine according to any one of the preceding claims, wherein said memantine is administered to said subject in the form of an over-the-counter preparation.

15. Memantine according to any one of the preceding claims, wherein said memantine is in the form of a pharmaceutically acceptable salt.

16. Memantine according to any one of the preceding claims, wherein the subject is a human being.

17. Memantine according to any one of the preceding claims, wherein the subject is above 6 years old, e.g. 10 to 50 years old.

18. Use of Memantine for improving cognitive performance in a subject by administering an effective amount of memantine to said subject, characterized in that the subject is not suffering from a disorder being or being accompanied by a cognitive condition being age-associated memory impairment (AAMI), or a cognitive condition ranging in severity from, mild cognitive impairment (MCI) to dementia.

19. Use according to claim 18, further characterized by one of the features defined in any of claims 2 to 17.

20. Use according to claim 18 or 19, wherein the subject shows a rating according to the Global Deteleration Scale (GDS) as defined in Reisberg et al. in Am J. Psych (1982) volume 139, pages 1136 to 1139 of 1 or 2.