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Drugs & Aging 1999 Mar; 14 (3): 197-230 1170-229X/99/0003-0197/$17.00/0 © Adis International Limited. All rights reserved.

Memory Assessment in Studies of Cognition-Enhancing Drugs for Alzheimer’s Disease Martine Simard and Robert van Reekum Department of Psychiatry, Baycrest Centre for Geriatric Care, North York, Ontario, Canada, and Division of Geriatric Psychiatry, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Methodology of the Literature Review . . . . . . . . . . . . . . . . . . . . 2. Memory Function in Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . 2.1 Short Term or Working Memory . . . . . . . . . . . . . . . . . . . . . . 2.2 Long Term Memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Metamemory: Insight About Memory . . . . . . . . . . . . . . . . . . 2.4 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Assessment of Memory in Drug Trials . . . . . . . . . . . . . . . . . . . . . . 3.1 Specific Neuropsychological Tests . . . . . . . . . . . . . . . . . . . . 3.2 Clinical Scales and General Observational Measures . . . . . . . . . 4. Conclusions and Suggestions for Memory Assessment in Future Research

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197 198 199 199 201 203 203 204 205 216 222

There is an increasing number of cognition-enhancing drugs for Alzheimer’s Disease (AD) and, consequently, drug trials represent a growing field of interest in research. As memory dysfunction is generally the first and most severe cognitive impairment in AD, the choice of memory testing to be used in these studies is of great importance. It should reflect an understanding of memory systems being assessed with neuropsychological tests and the fact that some tests can be more appropriate than others to show benefit with certain classes of cognitionenhancing drugs. Severe deterioration of episodic and semantic memory occurs very early in the AD process while working memory shows a gradual deterioration over time. Some aspects of working and implicit memory can be spared in the mild to moderate stages of AD. Tests of working, episodic, semantic and implicit memory are used as outcomes in trials with acetylcholinesterase inhibitors, drugs with other neurotransmitter strategies, metabolic enhancers and drugs which may impact upon a variety of CNS processes. The clinical scales and observational measures are largely used in trials of cognition-enhancing drugs for AD (46.66% of all the studies reviewed). The Digit Span test, the Rey Auditory Verbal Learning Test, the Buschke Selective Reminding Test and the verbal fluency tasks are the most sensitive memory

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tests, whereas the most sensitive scales are the Sandoz Clinical Assessment– Geriatric, the Gottfried-Bräne-Steel scale and the Blessed Dementia Scale. Finally, we suggest that future investigations should use sensitive memory tests, together with behavioural and psychiatric scales, rather than general observational evaluations.

There is growing interest in the field of cognitionenhancing drugs for Alzheimer’s Disease (AD) and related dementias, and research is abundant and growing rapidly. Much of the hope for these drugs is related to the possibility that memory function may be improved, or at least sustained, in these disorders. Although it has been argued that memory function is but one of many potential outcomes of importance for these drugs,[1] it is also evident that memory itself is not a single function or outcome, but rather is a complex set of systems which vary in their degree of impairment in AD and are likely to vary in terms of their response to cognition-enhancing drugs. Hence, the choice of memory testing to be used in assessing drug efficacy should reflect an understanding of the aspect of memory being assessed with the test; some tests are more likely to show benefit with particular classes of cognition-enhancing drugs. The principal aims of this article are to provide a guide to choosing the most appropriate measures for trials of cognition-enhancing drugs in AD, and to allow readers of such research to be fully aware of issues of measurement in these studies. We initially summarise research into memory, especially as related to minimal-to-moderate AD, in an effort to orient the reader to the various aspects of memory, their nomenclature and testing paradigms, and the evidence of dysfunction of each aspect in these early stages of AD (at which most present drug research is targeted). The main focus of this article is the memory assessments used in trials of cognitionenhancing drugs. However, a close analysis of those studies with generally good results[1] shows that almost half of them did not use specific memory tests, but rather general cognitive scales or observational evaluations including some memory assessment. As a result, after reviewing the specific memory tests, we will also examine cognitive © Adis International Limited. All rights reserved.

scales or observational evaluations. The conclusion suggests guidelines for assessment of memory in future investigations of cognition-enhancing drugs. Our approach could be susceptible to some authors’ bias compared with the meta-analysis approach that quantifies evidence. Nonetheless, we think that a detailed review of memory assessments used in drug trials, adopting a psychometric sensitivity point of view, can be helpful in targeting successes and flaws of neuropsychological and clinical instruments used to test the efficacy of drugs. This article is an introduction to the subject and we invite interested readers to consult original papers. Unfortunately, reviews of clinical trials with cognition-enhancing drugs are in danger of becoming rapidly out of date because of the exponential expansion of research in this particular field. For this reason, an update on the subject is recommended every 1 or 2 years. 1. Methodology of the Literature Review To obtain information on memory functioning in AD, abstracts in Medline and Psychological Abstracts over the past 5 to 8 years were searched using the following terms: memory and AD, priming, metamemory, awareness, early diagnosis and AD, prognosis and AD. The most pertinent papers related to AD were retained. Where appropriate, reviews and older papers were also used. To choose the drug trials in AD with the most promising evidence of efficacy, we used as our basis a previous literature review by our group.[1] In this paper,[1] we outlined that immediate use is supported for tacrine and further investigation is strongly supported for hydergine, nicergoline, nimodipine, selegiline (deprenyl) and pyritinol. In addition, promising evidence of efficacy exists for desferrioxamine (deferoxamine), indomethacin, Drugs & Aging 1999 Mar; 14 (3)

Memory Assessment in Alzheimer’s Disease

acetyl-L-carnitine, antagonic-stress formulation (a natural compound),[1] teniloxazine, desmopressin, thyroid-releasing hormone (TRH), estradiol, choline/ lecithin, besipirdine, linopirdine, posatirelin (a TRH analogue) and alaproclate. Other drugs have also been included; a recent trial with propentofylline is analysed because this drug has been recently submitted to the US Food and Drug Administration (FDA), and trials with donepezil and α-tocopherol (vitamin E) were included because these drugs are now available. Of these trials, we included those that were randomised, published and focused on AD. The results of nonrandomised trials with drugs previously mentioned[2-12] are otherwise available upon request to the first author. Papers using animal models or models of disease are not discussed in this review. 2. Memory Function in Alzheimer’s Disease In the cognitive field of memory research, there are 2 major theoretical approaches: the unitary approach and the multiple systems approach. The unitary or processing theorists consider that observed dissociations between memory tasks are the result of between-task variations in requirements for processing operations. The multiple systems theorists assume that different types of memory involve distinct processes operating by their own rules, sometimes on different neuroanatomical bases. We will adopt the multisystems approach[13-17] instead of the unitary approach[18-20] to describe memory deficits encountered in AD. This theoretical orientation is strongly supported by neuropsychological and pathological evidence of memory dissociation syndromes in patients with amnesia[14,21,22] and in patients with other pathologies.[23-24] 2.1 Short Term or Working Memory

The description of short term memory functioning will be done in the working memory model framework.[25,26] Working memory is the system necessary for holding and manipulating information while performing miscellaneous tasks includ© Adis International Limited. All rights reserved.

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ing learning, reasoning and comprehending.[25] The central executive system (CES) is the central component of this model.[15,26-28] The CES has a high degree of complexity and a limited capacity. It is assumed to be an attentional controller which has, among other roles, the role of coordinating and scheduling the performance of 2 or more concurrent activities.[15,26] For example, the CES is active when someone is driving while talking to a passenger in the car. This latter function of the CES, measured with a dual task paradigm,[15,28-31] has been shown to be impaired in patients with minimal[32] and, to a greater extent, mild[29,30,32] AD. [We define ‘minimal impairment’ as having Mini-Mental State Examination (MMSE) scores ≥24; 17-23 for mild.] The CES is also active when someone has to monitor information when performing a mental operation, as can be measured with the Digit Span (DS) subtest of the Wechsler Adult Intelligence Scale (WAIS).[33] The DS subtest also involves the functioning of the articulatory loop (see below).[27] In AD, the progressive deterioration (see table I) of performance on the DS subtest[27,34,35] is generally attributed to an impairment of the CES.[27] Another component of the working memory model is the visuospatial sketchpad (VSSP), which maintains information under a visuospatial code.[16,26] The VSSP is principally of use to remember the spatial positions of objects and its action lasts a few seconds. It intervenes when, for example, an individual visually follows the track of a moving target or when trying to remember the exact location of an object by photographic memory (mental imagery) without the help of verbal strategies. The functioning of the VSSP, as measured by the Corsi’s blocks test, is altered in patients with, even mild, AD.[15] The last and most studied component of the working memory model is the articulatory loop. The function of this system is to maintain phonologically encoded material in primary memory through short term storage and to translate, when applicable, visually presented material into verbal material.[15,27] The articulatory loop system comprises 2 subsystems, a passive phonological buffer Drugs & Aging 1999 Mar; 14 (3)

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Table I. Summary of memory functions in Alzheimer’s disease (AD) Memory system

Tests or paradigms

Changes in minimal AD

mild AD

moderate AD

Dual task Digit span

↓ ↓

↓↓ ↓

? ↓↓

Visuospatial sketchpad

Corsi’s blocks test

↓↓

↓↓

↓↓↓

Articulatory loop

Recency effect Phonological similarity effect Word length effect

↔ ↔ ↔

↔ ↔ ↔

↓ ? ?

Episodic memory

Encoding Free recall Cued recall Recognition

↓↓↓ ↓↓↓ ↓↓ ↓↓

↓↓↓ ↓↓↓ ↓↓↓ ↓↓

↓↓↓ ↓↓↓ ↓↓↓ ↓↓↓

Source memory

Recall of contexts of learning

↔

↔

↔

Semantic memory

Category fluency tasks Pyramids and palm trees test

↓↓± ↓±

↓↓± ↓↓±

↓↓↓ ↓↓↓

Autobiographical memory

Autobiographical incidents schedule: childhood early adult life late adult life

↓ ↓↓ ↓↓↓

↓ ↓↓ ↓↓↓

? ? ?

Personal semantic memory schedule: childhood early adult life late adult life

↓ ↓↓ ↓↓↓

↓ ↓↓ ↓↓↓

? ? ?

Subtests of the Rivermead behavioural memory test

↓↓

↓↓

?

Pursuit-rotor task Mirror reading task

↔ ↔

↔ ↔

↔ ↔

data-driven processes

Word identification tasks Incomplete picture tasks Word-stem completion tasks

↔ ↔ ↔±

↔ ↔ ↔±

↔ ↔ ↔±

conceptually-driven processes

Word-stem completion tasks

↓↓±

↓↓±

↓↓±

Comparisons of patient’s self-report and caregiver ratings Concordance between patient’s subjective description of abilities and objective measures Accuracy of patient’s performance predictions Combined methods

↓

↓↓

↓↓↓

↓

↓↓

↓↓↓

↓ ↓

↓↓ ↓↓

↓↓↓ ↓↓↓

Working memory Central executive system

Long-term memory Explicit memory

Personal semantic memory

Prospective memory

Implicit memory Skill learning Verbal priming

Metamemory Awareness of memory (self-monitoring)

↓ = mild deficit; ↓↓ = moderate deficit; ↓↓↓ = severe deficit; ↔ = preserved; ± = heterogeneity/variability of results; ? = not tested.

or store and an articulatory rehearsal mechanism. The articulatory loop plays a role when, for example, someone keeps repeating a phone number in order to be able to redial it. Another example involves trying to recall a list of groceries by first recollecting the last items of the list. The function© Adis International Limited. All rights reserved.

ing of the articulatory loop is spared in patients with early stages of AD, as measured by repetition of digits, and by the presence of phonological similarity, length and recency effects on tests of verbal learning.[15] However, recent findings[36] suggest that the recency effect is disrupted in moderate AD. Drugs & Aging 1999 Mar; 14 (3)


2.2 Long Term Memory

The taxonomy of long term memory with multiple systems will be described around the concept of explicit versus implicit memory.[37,38] Explicit memory involves conscious recollection for personally experienced events. Tests that require recall or recognition of information acquired in a given spatiotemporal context can be classified as explicit memory tasks.[38] Implicit memory refers to priming effects in memory; that is, the extent to which prior exposure to stimulus material facilitates the recall of further material, but in a manner that need not involve conscious recollection.[36,37] 2.2.1 Explicit Memory

Within the framework of the explicit memory concept[37,38] other distinctions can be drawn. These distinctions are not pure in the sense that the various systems are clearly related; for example, to place an item into semantic memory first requires processing through episodic memory. Nonetheless, classifying explicit memory into systems is helpful as dissociations are seen in explicit memory in many neurological syndromes. The most important distinctions concern the dualistic concepts of episodic/ semantic memory[13,39,17] and of autobiographical/ personal semantic memory.[22,40,41] Another aspect of explicit memory will be briefly presented: prospective memory. This kind of memory, contrasting with retrospective memory, refers to the conscious recollection that certain actions will need to be performed at a future date. Episodic/Semantic Memory

Episodic memory represents memory for personally experienced events stored in spatiotemporal and emotional contexts.[42] Processes taking place in episodic memory are the following: encoding, retrieval (with free and cued recall as well as the recognition paradigm) and consolidation. Typically, episodic memory is in action whenever an individual learns new information in a given context and tries to remember it at least 15 minutes later. Functioning of episodic memory is principally assessed in the laboratory with methods such as: © Adis International Limited. All rights reserved.

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• learning and recall of lists of words or paragraphs, presented either orally or visually • learning and recall of abstract drawings • facial recognition tests. Patients with AD show encoding and retrieval deficits in free and cued recall situations,[27,35,43-49] together with recognition deficits,[17,44] very early in the course of the disease (see table I).[17,35,45,47-49] As a component of episodic memory, source memory[13,50,51] refers to the capacity to remember the learning context of a fact or the source of some knowledge. An individual can learn information, for example, from a friend, at a conference, from a journal article or from a book. These are all possible learning sources. Assessing source memory typically follows 2 steps: (i) learning and recall of facts acquired in different contexts, and (ii) recall of the contexts in which the recollected facts were learned.[46] Some data have demonstrated that patients with mild AD have spared performance on tests assessing source memory,[46] even though they are severely impaired on the content of the episode (see table I).[46,51] Semantic memory refers to the capacity to actualise crystallised knowledge (facts, ideas and concepts) stored using semantic organisation (semantic network) and conceptualisation processes. All semantic memory material must first be registered in episodic memory before being transferred into semantic knowledge. Semantic or Category Fluency tasks (animals, vegetables, clothes, etc.), the Vocabulary subtest of the WAIS[33] and the Pyramids and Palm Trees test[52] are good examples of semantic memory tasks. Some data indicate that semantic memory is disrupted very early[53] in the course of the disease, in both minimal[47,52] and mild[17,48] stages of AD. However, there is heterogeneity in the results,[17,48,54] with some patients showing severe impairment on all semantic memory tests while others performed variably on specific tests.[48] The semantic network might also be more impaired in patients with AD with a worse prognosis[53] or a worse performance in episodic memory (see table I).[17] Drugs & Aging 1999 Mar; 14 (3)

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Autobiographical/Personal Semantic Memory

The term autobiographical memory is used to focus attention upon a individual’s record of his/ her own personal experiences (recent and remote), as opposed to his/her performance on standard laboratory tests such as free recall.[40] The Autobiographical Incidents Schedule,[40] the questionnaire of Flicker et al.[55] and the Autobiographical Fluency Task[56] can assess autobiographical memory performance. Patient groups with minimal[32] and mild[32,41,57] AD were found to be impaired on autobiographical memory (see table I). Patients in the minimal and mild stages show a temporal gradient, with stronger deficits for recent events (late adult) than for events of childhood and early adult life.[32,57] The personal semantic memory concept refers to old and overlearned personal autobiographical memories or factual knowledge about a person’s own past.[22,40] One’s own name, date of birth and parents’ names are all examples of information belonging to personal semantic memory. The Personal Semantic Memory Schedule[40] and the Autobiographical Fluency Task[56] are good tests of personal semantic memory. Patients in the minimal[32] and mild[32,41] stages of AD were impaired on personal semantic tasks covering childhood, early adult and late adult life (see table I). Nevertheless, patients with minimal AD had the tendency to be less impaired than patients with mild AD on questions about childhood.[32] Prospective Memory

Prospective memory (remembering to carry out actions in the future) is an important aspect of cognition which is necessary for people to function in their everyday lives.[58] There are also retrospective aspects to prospective memory in that planning of any action is an episodic event.[59] The Rivermead Behavioural Memory (RBM) Test[60] contains subtests measuring prospective memory, such as: • remembering an appointment • remembering a belonging • remembering to deliver a message. © Adis International Limited. All rights reserved.

Simard & van Reekum

Studies on prospective memory use different applications or variations of the RBM test. Prospective memory has been shown to be impaired early in the course of AD (see table I).[58,61] 2.2.2 Implicit Memory

Within the implicit memory framework, subdivisions can be made relative to skill learning[45,62-64] and repetition priming.[45,47,65-67] Skill Learning

Skill learning refers to our motor and perceptual learning capacity, measured respectively with pursuit-rotor[45,62] and mirror-reading[45,64] tasks. In the pursuit-rotor task, patients have to maintain contact between a stylus held in the preferred hand and a small metallic disk on a rotating turntable.[45] In the mirror-reading task, patients must read words presented in backwards order. To observe skill learning effects, the time of execution for each task must improve with practice. Patients in the mild and moderate stages of AD showed preserved performance on skill learning measured with pursuit-rotor[44,61,63] and mirror-reading[45,64] tasks (see table I). Repetition Priming

Repetition priming is change in speed or accuracy of processing words or pictures as a result of previous exposure to these words or pictures, when compared with an appropriate baseline measure.[67] Within the repetition priming framework, the instructions given to individuals during the study phase of stimuli are very important. Both study phase and instructions are called the orienting task. The taxonomy of repetition priming that will be used in this article will follow the dichotomy of data-driven/ conceptually-driven processes[68] instead of the dichotomy of word-form/structural-description.[69] Data-driven versus conceptually-driven processes can refer to the type of instructions given during the orienting task and/or to the nature of the stimulus presented. Furthermore, tasks of repetition priming usually fall into 2 categories: word identification/incomplete-picture and word-stem completion tasks. Although there is some agreement about the spared performance of patients with mild Drugs & Aging 1999 Mar; 14 (3)


and moderate AD when compared with controls on data-driven (perceptual) process tasks using wordidentification[45,47,65,67] or incomplete-picture[70] paradigms, there is controversy on the results related to conceptually-driven process tasks using word-stem completion (see table I).[45,47,65,67] Deweer et al.[45] suggested the following reasons for the discrepancies between studies on the wordstem completion tasks: (i) non-similarity of items between study and test phases would explain failure on the word-stem completion tasks[65,67] and, on the contrary, the perceptual similarity of items between the 2 phases would account for preserved performance on word-stem completion tasks; [45,46] (ii) in contrast to other authors,[65-67] Deweer et al.[45] suggest that word-stem completion tasks involve both data-driven and conceptual processes, and the use of perceptual/data-driven instructions[45,47] on word-stem completion might improve the performance in priming for patients with AD.[45,47] Consequently, the contradictory results found on wordstem completion tasks may be explained, at least in part, by the nature of the task itself together with the nature of the orienting task. However, Fleischman et al.,[67] believe that causes for discrepancies need to be thoroughly explored. 2.3 Metamemory: Insight About Memory

Metamemory is awareness for memory deficits, and involves self-monitoring of memory functioning. It is a relatively new field of research for patients with AD, most of the data having been collected in the last decade. Various methodologies have been used to study awareness of memory and other cognitive deficits in patients with AD: (i) comparisons of patient self-report and caregiver ratings; (ii) concordance between patient’s subjective description of abilities and objective measures; (iii) accuracy of patient’s performance predictions on specific cognitive tasks; and (iv) combined methods.[71] Most of the results indicate that patients with AD have an impairment of metamemory associated with the severity of dementia, but a few studies have found deficits of metamemory in mild and moderate AD (see table I).[71] Memory for re© Adis International Limited. All rights reserved.

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cent events would be more sensitive to an alteration of metamemory than memory for remote events.[71] 2.4 Overview

Sections 2.1 to 2.3 have described what is known to be impaired in memory functioning of patients with minimal to moderate AD. According to this review, some components of working memory have been shown to be altered in early AD, including the VSSP and the CES. The functioning of the CES in particular, as measured by the dual task, is impaired in minimal, and to a greater extent, in mild stages of AD. However, the CES is not fully described theoretically[28] and, as a consequence, several aspects of its functioning remain to be investigated in patients with AD as well as in healthy people. In long term explicit memory, episodic memory, as measured by learning with recall and recognition paradigms, is severely impaired very early in the disease process. Whereas deterioration of episodic memory occurs in every patient with early AD, semantic memory and semantic network, by contrast, may deteriorate only in patients with mild AD with a more severe prognosis of dementia and/ or worse episodic memory performance. Autobiographical and personal semantic memory are also affected in patients with minimal and mild AD. Deterioration of autobiographical and personal semantic memory, however, shows a temporal gradient, with memory for recent events of the late adult period being the most affected in autobiographical memory (patients with minimal and mild AD) and memory for late adult and early adult periods being the most altered in personal semantic memory (patients with minimal AD only). Although there are very few studies on prospective memory, some data indicate that this type of memory is altered early in the disease process. It could, however, be important to adequately assess this type of memory because data coming from a pilot study with 4 patients (with mild to moderate AD) show that a cognitive remediation programme might improve performance on some prospective Drugs & Aging 1999 Mar; 14 (3)

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memory tasks.[61] These results suggest therefore that prospective memory could be a sensitive target to some form of intervention. In long term implicit memory, there are contradictory results on word-stem completion tasks that might be explained in part by the theoretical debate around definitions of word-stem completion tasks, the nature of presented items and orienting tasks. This area of cognitive research would benefit from agreement among different authors on the definition of terms that they refer to in their studies and from a clarification of requirements for each task. Despite these controversial issues, a majority of studies seem to have reached a consensus in finding impairment on conceptually driven, word-stem completion tasks in patients with mild and moderate AD. Metamemory is also damaged early in the process of the disease, and its worsening follows the severity of dementia. It should be noted that studies on metamemory present some weaknesses, including the lack of objective tests and the fact that results of these studies are largely dependent on caregiver reports. Unfortunately, the degree of awareness is not assessed in caregivers. We have also described what is known to be spared in memory functioning of patients with minimal to moderate AD. In studies on working memory, the articulatory loop is spared in patients with mild AD. Some studies on long term explicit memory have shown that patients with mild AD, with better prognosis and better episodic memory functioning than other patients, might have spared semantic network and memory. Source memory seems to also be spared in patients with mild AD, although this statement is dependent upon the data of only one study. Studies on long term implicit memory report that performance on skill learning and data-driven or perceptual repetition priming tasks may be preserved even in moderate stages of AD. The main problem with the latter studies, is that it is not know what happens, in the severe stages, to memory systems found to be spared in mild and moderate stages. Indeed, few of the stud© Adis International Limited. All rights reserved.

Simard & van Reekum

ies mentioned in this review were longitudinal investigations (with some exceptions)[30,54]. From the point of view of research into cognitionenhancing drugs, the aspects of memory functioning that are most affected early in the course of AD may be the most relevant as treatment targets. Some tests used to assess each aspect of memory, and the response to these tests in non-medicated persons with AD, are discussed above and summarised in table I. It is also obvious that some aspects of memory are relatively well preserved early in the course of AD, and as such these aspects of memory are less likely to be improved by cognitionenhancing drugs. Certainly, failure to improve these aspects of memory with cognition-enhancing drugs should not be seen as evidence of treatment nonresponse. We now review the research into cognitionenhancing drugs published to date to examine the evidence for treatment response in the various aspects of memory. As a prelude to this discussion, table II summarises the possible neuroanatomical and neurochemical substrates of memory systems. 3. Assessment of Memory in Drug Trials Tables III, IV, V and VI present the results of memory testing in randomised clinical trials of cognition-enhancing drugs, arranged by therapeutic strategy. Memory testing in these trials used: (i) neuropsychological testing paradigms; (ii) clinical scales such as the Alzheimer Disease Assessment Scale (ADAS), the Sandoz Clinical Assessment– Geriatric (SCAG) or the Gottfried-Bräne-Steel scale (GBS); and (iii) general observational measures (including a general cognitive assessment) which are subjective in nature and not psychometrically structured [e.g. the Clinical InterviewBased Impression of Change (CIBIC) or the Clinical Global Impression of Change (CGIC)]. Almost half (21 of 45) of the trials discussed have used primarily observational measures, or clinical scales, as the cognitive outcomes of interest instead of using specific neuropsychological tests for memory. Drugs & Aging 1999 Mar; 14 (3)


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Table II. Possible neuroanatomical and neurochemical substrates of memory systems Memory system

Possible neuroanatomical substrate

Possible neurotransmitter involvements

Working memory Central executive system

Frontal lobes (prefrontal areas)[31,72-74]

Dopamine[75] Noradrenaline (norepinephrine)[76] Others?

Articulatory loop: verbal rehearsal phonological buffer

Left middle and inferior frontal gyri[77,78] Left supramarginal gyrus[79]

Visuospatial sketchpad: ‘what’ system ‘where’ system

Temporal-occipital lobes and prefrontal areas[80] Parietal-occipital lobes and prefrontal areas[80-82]

Episodic memory General

Acetylcholine[36] Others? Unknown

Medial temporal lobes and diencephalic midline or limbic Acetylcholine[83] system[14,23,24,84-86]

Encoding and consolidation

Hippocampus, parahippocampal gyrus, entorhinal area, amygdala, mammillary bodies, septum, anterior and dorsal-medial thalamic nuclei; cingulate gyri and orbito-frontal regions

Catecholamines (encoding)[87] Vasopressin (encoding)[87]

Retrieval

Frontal regions

Catecholamines[87]

Semantic memory General

Neocortex[14,23,85]

Unknown

Anterior and posterior temporal lobes (except medial structures)[88-91] Parietal and occipital lobes[92] Brain stem mesencephalic structure[93]

Unknown

Left primary motor cortex Left supplementary motor area Left pulvinar thalamus[63]

Unknown

Occipital lobes[65] Medial temporal lobes[66]

Non-acetylcholine[83] Unknown

Autobiographical memory General (retrograde memory for personal events)

Implicit memory Skill learning

Verbal priming: data-driven processes conceptually-driven processes

In section 3.1 we discuss the application of specific neuropsychological tests which assess the memory systems described previously. Section 3.2 then discusses the clinical scales and general observational measures used in these trials. 3.1 Specific Neuropsychological Tests 3.1.1 Working Memory

Approximately one-third of the trials have used tests of working memory. These include studies on selegiline, acetyl-L-carnitine, tacrine, choline/ lecithin, TRH and teniloxazine, and have assessed the effects of these drugs on: (i) the functioning of the CES and the articulatory loop, using the DS © Adis International Limited. All rights reserved.

subtest of the WAIS and (ii) the functioning of the VSSP using various tests [the Corsi’s blocks test, the Complex Visual Search test, various cancellation tasks, the Trail Making Test–A (TMT–A), the Barbizet-Cany’s 7/24 immediate recall, a short term memory test for figures, and a sequential visual memory test]. The DS subtest of the WAIS[33] has been the test of working memory which has been the most frequently used in drug trials (see tables III, IV and VI). Four studies of selegiline 10 mg/day have reported significant improvement on the DS subtest after 3 months,[106-109] whereas only 2 studies showed no improvement or deterioration with dosages of 10 to 15 mg/day after 1 to 15 months.[110,111] Three studDrugs & Aging 1999 Mar; 14 (3)

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Table III. Results of trials with acetylcholinesterase inhibitors in treatment of Alzheimer’s disease Drugs and study

No. of No. of participants dropouts

Neuropsychological tests

Results (duration; dosage)

Global assessment Orientation test Names learning test Alzheimer’s deficit scale The New York University memory test WAIS MMSE

↑ all stages (3 wks; 150-200mg) ↑ all stages (3 wks; 150-200mg) ↑ only stages 3-4 (3 wks; 150-200mg) ↑ all stages (3 wks; 150 to 200mg) ? ? ?

ADAS-cog

↓ 4 points, 26% (6 wks; 40 or 80mg) ↓ 4 points, 9% placebo = placebo (6 wks; 40 or 80mg) = placebo (6 wks; 40 or 80mg)

Tacrine Summers et al.[94]

Davis et al.[95]

17

2

215

28

CGIC MMSE Farlow et al.[96]

Minthon et al.[97]

Wilcock et al.[98]

Knapp et al.[99]

468

106

17

79

663

0

38

384

ADAS-cog CGIC clinician-rated caregiver-rated

↑ (6-12 wks; 80mg)

Vocabulary Paired associates (verbal learning test, immediate recall) DS Simple visual reaction time Choice visual reaction time

= b (6/14/24 wks; 75-125mg) = b (6/14/24 wks; 75-125mg)

MMSE Kendrick battery object learning task CAMCOG DS Logical memory (Wechsler): immediate recall delayed recall

= placebo (12 wks; 150mg) ↑ vs placebo (12 wks; 150mg) ↑ vs placebo (12 wks; 150mg) = placebo (12 wks; 150mg)

CIBIC ADAS-cog

↑ vs placebo (30 wks; 120 or 160mg) ↑ vs placebo (30 wks; 120 or 160mg) ↑ 40% (30 wks; 160mg) ↑ vs placebo (30 wks; 160mg) ↑ (30 wks; 160mg)

GDS MMSE Maltby et al.[100]

53

21

BSRT (with parallel forms): verbal (words) visual (objects) word recognition word recall MMSE Face recognition Symbol digit modalities DS: forward

↑ (12 wks; 80mg) ↑ (6-12 wks; 80mg)

= b (6/14/24 wks; 75-125mg) = b (6/14/24 wks; 75-125mg) = b (6/14/24 wks; 75-125mg)

= placebo (12 wks; 150mg) = placebo (12 wks; 150mg)

= placebo/b (3/6/9mo; 100mg) = placebo/b (3/6/9mo; 100mg) = placebo/b (3/6mo; 100mg) = placebo/b (3/6mo; 100mg) = placebo/b (3/6/9mo; 100mg) = placebo/b (3/6mo; 100mg) = placebo/b (3/6/9mo; 100mg)

backward Verbal fluency Word stem completion

= placebo/b (3/6/9mo; 100mg) ↓ vs placebo (6mo) = placebo/b (3/6mo; 100mg) = placebo/b (3/6mo; 100mg) = placebo/b (3/6mo; 100mg)

MMSE Mattis dementia rating scale Cognitive difficulties score

= b (days 28-56; mean of 114mg) = b (days 28-56; mean of 114mg) = b (days 28-56; mean of 114mg)

Tacrine/lecithin Chatellier et al.[101]

67

© Adis International Limited. All rights reserved.

7

Drugs & Aging 1999 Mar; 14 (3)


207

Table III. Contd Drugs and study Gauthier et al.[102]

No. of No. of participants dropouts 52

3



MMSE

↑ (4 wks; 85mg) = b (38 wks; 100mg) ↓ (38 wks; 100mg) ↓ (38 wks; 100mg)

3MS or modified MMSE Hierarchic dementia scale Eagger et al.[103]

89

24

MMSE Abbreviated Mental Test Score CANTAB attentional battery 5-choice localisation test ability to follow a simple rule and to reverse it paired associative learning visual recognition memory complex visual search short-term memory attentional shifting test

↑ (13 wks; 150mg) ↑ (13 wks; 150mg) ↑ (placebo phase) ↑ (13 wks; 150mg) ↑ (13 wks; 150mg) = b (13 wks; 150mg) = b (13 wks; 150mg) = b (13 wks; 150mg) = b (13 wks; 150mg) = b (13 wks; 150mg)

Tacrine/estradiol Schneider et al.[104]

51

5

ADAS-cog CIBIC CIC MMSE

Rogers & Friedhoff[105]

161

20

ADAS-cog CGIC MMSE CDR-SB

↑ (30 wks; 80/120/160mg) only for ERT + tacrine group ↑ (30 wks; 80/120/160mg) only for ERT + tacrine group ↑ (30 wks; 80/120/160mg) only for ERT + tacrine group = placebo (30 wks; 80/120/160mg) ↑ 2.5 points (3/9/12 wks; 5mg) ↓ placebo (3/9/12 wks) = b (12 wks); 5mg: failure rate 11%; placebo: failure rate 20% ↑ (1/3/6/9/12 wks; 5mg) = placebo (12 wks; 1/3mg) = b (12 wks; 1/3/5mg)

3MS = modified Mini-Mental State Examination; ADAS-cog = Alzheimer Disease Assessment Scale – cognitive; b = baseline; BSRT = Buschke Selective Reminding Test; CAMCOG = Camdex cognitive estimation; CANTAB = Cambridge Neuropsychological Test Automated Battery; CDR-SB = Clinical Dementia Rating scale – Sum of the Boxes; CGIC = Clinical Global Impression of Change; CIBIC = Clinician Interview-Based Impression of Change; CIC = Caregiver Impression of Change; DS = Digit Span; ERT = estrogen replacement therapy; GDS = Global Deterioration Scale; MMSE = Mini-Mental State Examination; mo =months; WAIS = Wechsler Adult Intelligence Scale; wks = weeks; ↑ indicates improvement; = indicates no difference compared with; ↓ indicates deterioration; ? indicates unknown.

ies of acetyl-L-carnitine have also demonstrated significant improvement on the DS subtest with dosages of 1000 to 3000 mg/day.[106,130,132] However, 3 trials of tacrine 75 to 150 mg/day,[97,98,100] and trials of choline/lecithin[113] and TRH,[134] showed no improvement, or deterioration, in performance on the DS subtest. The development of cancellation tasks,[135,136] the TMT-A,[137] the Corsi’s blocks test[138] and the Barbizet-Cany’s 7/24 test,[139] precede the elaboration of the working memory model of Baddeley,[25,26] including the VSSP subsystem. Nonetheless, these tests, together with the Complex Visual Search test © Adis International Limited. All rights reserved.

and a sequential visual memory test, are considered in the present paper as tests of the VSSP. They measure visuospatial short term retention, visual scanning and tracking and also, in the case of the Corsi’s blocks test, retention of temporal and spatial sequences. In Baddeley’s model,[25,26] these functions are managed by the VSSP. The Corsi’s blocks test has been otherwise related to the functioning of the VSSP,[15,140-142] as well as a modified version of the Barbizet Cany’s 7/24.[141,142] Cancellation tasks with letters or pictures have been the most common way of measuring the functioning of the VSSP in the present review. Studies with selegilDrugs & Aging 1999 Mar; 14 (3)

208

Simard & van Reekum

Table IV. Results of trials with strategies other than acetylcholinesterase inhibitors in treatment of Alzheimer’s disease Drugs and study

No. of participants

No. of dropouts


Results

Selegiline (deprenyl) Campi et al.[106]

40

0

Falsaperla et al.[107]

40

0

Monteverde et al.[108]

40

4

Piccinin et al.[109]

20

?

5-items acquisition 5-items recall 10 min 5-items recall 24 hrs Short story acquisition Short story recall 10 min DS forward Word fluency BDS-Part 1 BDS-Part 2 5-items acquisition 5-items recall 10 min 5-items recall 24 hrs Short story acquisition Short story recall 10 min DS forward Word fluency BDS-Part 1 BDS-Part 2 5-items acquisition 5-items recall 10 min 5-items recall 24 hrs Short story acquisition Short story recall 10 min DS forward Word fluency BDS-Part 1 BDS-Part 2 Word fluency DS RAVLT learning

↑ (1/2/3mo; 10mg) ↑ (1/2/3mo; 10mg) ↑ (1/2/3mo; 10mg) ↑ (1/2/3mo; 10mg) ↑ (1/2/3mo; 10mg) ↑ (1/2/3mo; 10mg) ↑ (1/2/3mo; 10mg) ↑ (1/2/3mo; 10mg) ↑ (2/3mo; 10mg) ↑ (1/2/3mo; 10mg) ↑ (2/3mo; 10mg) ↑ (1/2/3mo; 10mg) ↑ (2/3mo; 10mg) ↑ (1/2/3mo; 10mg) ↑ (1/2/3mo; 10mg) ↑ (1/2/3mo; 10mg) ↑ (1/2/3mo; 10mg) ↑ (1/2/3mo; 10mg) ↑ (2/3mo; 10mg) ↑ (1/2/3mo; 10mg) ↑ (1/2/3mo; 10mg) ↑ (1/2/3mo; 10mg) ↑ (1/2/3mo; 10mg) ↑ (1/2/3mo; 10mg) ↑ (1/2/3mo; 10mg) ↑ (1/2/3mo; 10mg) ↑ (1/2/3mo; 10mg) ↑ (3/6mo; 10mg) ↑ (3mo; 10mg) ↑ minimal/placebo (6mo; 10mg) = placebo (3mo; 10mg) ↑ minimal/placebo (6mo; 10mg) = placebo (3mo; 10mg) ↑ minimal/placebo (6mo; 10mg) = placebo (3mo; 10mg) ↑ minimal/placebo (3mo; 10mg) = placebo (6mo; 10mg)

RAVLT long-term recall RAVLT recognition RAVLT confabulations

Burke et al.[110]

39

6


Barbizet-Cany’s 7/24 test: total score long-term recall TMT-A Picture cancellation task right wrong omitted Letter cancellation task right wrong omitted TMT-A WAIS-R DS WAIS-R mental control Symbol digit modalities written raw score oral raw score

= placebo (3/6mo; 10mg) ↑ (3/6mo; 10mg) = placebo (3/6mo; 10mg) = placebo (3-6mo; 10mg) = placebo (3-6mo; 10mg) = placebo (3-6mo; 10mg ↑ (3-6mo; 10mg) = placebo (3-6mo; 10mg) = placebo (3-6mo; 10mg) ↑ (8/15mo; 15mg) = b (2/8/15mo; 15mg) = b (2/8/15mo; 15mg) ↑ (15mo; 15mg) ↑ (8/15mo; 15mg)



209

Table IV. Cont Drugs and study

No. of participants

No. of dropouts

Marin et al.[111]

17

2

Sano et al.[112]

341

?

Choline/lecithin Corona et al.[113]

52

15

Parnetti et al.[114]

126

0


Results

Word fluency Boston naming test WMS logical memory I WMS logical memory II WMS paired associates I WMS paired associates II WMS visual reproduction I WMS visual reproduction II DS Word fluency List learning Delayed recall Delayed recognition MMSE ADAS-cog BDS

= b (2/8/15mo; 15mg) = b (2/8/15mo; 15mg) ↑ (15mo; 15mg) = b (2/8/15mo; 15mg) = b (2/8/15mo; 15mg) ↑ (2mo; 15mg) = b (2/8/15mo; 15mg) = b (2/8/15mo; 15mg) = placebo (1mo; 10mg) = placebo (1mo; 10mg) = placebo (1mo; 10mg) = placebo (1mo; 10mg) = placebo (1mo; 10mg) = b/placebo (15.6mo; 10mg) = b/placebo (12.4mo; 10mg) ↑ b/placebo (20mo; 10mg) with b score of MMSE as a co-variate

DS Sequential visual memory Corsi blocks Corsi supraspan Verbal fluency Story (immediate recall) Recall tests: verbal material visual material auditory material GDS SCAG GBS (Italian version) RAVLT: immediate recall (learning trials) delayed recall MMSE

= b (4 wks; 3g) = b (4 wks; 3g) = b (4 wks; 3g) = b (4 wks; 3g) = b (4 wks; 3g) = b (4 wks; 3g) = b (4 wks; 3g) = b (4 wks; 3g) = b (4 wks; 3g) ↑ 29% treated group (6mo; 1200mg) ↑ (6mo; 1200mg) ↑ (4/6mo; 1200mg) ↑ (6mo; 1200mg) ↑ (6mo; 1200mg) ↑ (4/6mo; 1200mg)

Posatirelin Parnetti et al.[115]

214

?

GBS MMSE

↑ (3mo; 10mg) ↑ trend (3mo; 10mg)

Besipirdine Huff[116]

275

27

ADAS-cog CIBIC

= b (4/8/12 wks; 5/20mg) ↓ vs placebo (4/8/12 wks; 5/20mg) = b/placebo (4/8/12 wks; 5/20mg)

GBS: intellectual function CGIC

↑ (4 wks; 400mg) = placebo (4 wks; 400mg)

Alaproclate Dehlin et al.[117]

43

5

ADAS-cog = Alzheimer Disease Assessment Scale – cognitive; b = baseline; BDS = Blessed Dementia Scale; CGIC = Clinical Global Impression of Change; CIBIC = Clinician Interview-Based Impression of Change; DS = Digit Span; GBS = Gottfried-Bräne-Steen scale; GDS = Global Deterioration Scale; MMSE = Mini-Mental State Examination; mo =months; RAVLT = Rey Auditory Verbal Learning Test; SCAG = Sandoz Clinical Assessment – Geriatric; TMT-A = Trail Making Test-A; WAIS-R = Wechsler Adult Intelligence Scale - Revised; wks = weeks; WMS = Wechsler Memory Scale; ↑ indicates improvement; = indicates no difference compared with; ↓ indicates deterioration.



210

Simard & van Reekum

Table V. Results of trials with metabolic enhancers in treatment of Alzheimer’s disease Drugs and study Hydergine Schneider & Olin[118]

Schneider et al.[119]


308

62

9%



Clinically based ratings (SCAG, Crichton rating scale, BPRS, Clifton rating scale, Parkside behavioural rating scale)

= placebo (12-52 wks; 1.5-9mg)

Clinical global ratings

? (n=1)

Combined neuropsychological measures (WAIS, trail making test, tests of orientation)

↑ (12-52 wks; ≥4mg)

WMS: memory quotient

↑ (3mo; 20mg)

WAIS:

Saletu et al.[120]

112

14

verbal IQ

↑ (3mo; 20mg)

performance IQ

↑ (3mo; 20mg)

full IQ

↑ (3mo; 20mg)

deterioration index

↑ (3mo; 20mg)

digit symbol (score)

↑ (3mo; 20mg)

SCAG

↑ (3mo; 20mg)

SASG

↑ (3mo; 20mg)

MMSE

↑ (8 wks; 30mg) ↑ vs placebo (8 wks)

SCAG

↑ (8 wks; 30mg)

CGIC

↑ (8 wks; 30mg) ↑ vs placebo (8 wks)

Teniloxazine Aguglia et al.[121]

117

1

Memory of figures

↑ (23.1% patients; 45-90 days; 80mg)

Toulouse-Pieron reaction test (attention-concentration):

Propentofylline Marcusson et al.[122]

261

73

no. of wrong symbols

= b (45-90 days; 80mg)

time to complete test

= b (45-90 days; 80mg)

no. of symbols omitted

↑ vs b (45-90 days; 80mg)

GBS

↑ (3/6/12mo; 300mg)

MMSE

↑ (only 12mo; 300mg) = placebo (3mo; 300mg)

SKT

↑ (6/12mo; 300mg)

DS

= placebo (3/6/12mo; 300mg) = placebo (3mo; 300mg)

CGIC:

Pyritinol Knezevic et al.[123]

31


5

item I (severity of dementia)

↑ (6/12mo; 300mg)

item II (global change)

= placebo (3/12mo; 300mg)

CETM

↑ (10 wks; 200mg)

SCAG

= placebo (10 wks; 200mg)

ADAS

= placebo (10 wks; 200mg)

SKT

↑ (10 wks; 200mg and placebo; only descriptive statistics; statistical significance of difference ?)



211

Table V. Contd Drugs and study

Fischhof et al.[124]


162

6



SASS

↑ (10 wks; 200mg and placebo; only descriptive statistics; statistical significance of difference ?)

CGIC

↑ (41% patients; 3mo; 200mg)

SKT

↑ (53.2% patients; 3mo; 200mg)

SCAG

↑ (53.2% patients; 3mo; 200mg)

ADAS = Alzheimer Disease Assessment Scale; b = baseline; BPRS = Brief Psychiatric Rating Scale; CETM = contextual effect upon text memory; CGIC = Clinical Global Impression of Change; DS = Digit Span; GBS = Gottfried-Bräne-Steen scale; IQ = intelligence quotient; MMSE = Mini-Mental State Examination; mo =months; SASG = Self-Assessment Scale – Geriatric; SASS = Self Assessment Scale; SCAG = Sandoz Clinical Assessment – Geriatric; SKT = Syndrom Kurztest; WAIS = Wechsler Adult Intelligence Scale; WMS = Wechsler Memory Scale; wks = weeks; ↑ indicates improvement; = indicates no difference compared with; ↓ indicates deterioration; ? indicates unknown.

ine,[109] acetyl-L-carnitine [132] and teniloxazine[121] have all shown some improvement on their respective cancellation task. Of 2 studies of selegiline using the TMT-A, one demonstrated some improvement after 8 and 15 months with a dosage of 15 mg/day,[110] whereas the other showed no improvement after 3 and 6 months with a dosage of 10 mg/day.[109] A study of teniloxazine[121] used a short term memory test for numbers and reported some improvement after 45 and 90 days with a dosage of 80 mg/day. No improvement has been observed in any of the other tests of VSSP (the Corsi’s blocks test, the Complex Visual Search test, the Barbizet-Cany’s 7/24 immediate recall and a sequential visual memory test) in trials of selegiline,[109] choline/lecithin[113] and tacrine.[103] 3.1.2 Episodic Memory

Several tests of episodic memory have been used in drug trials. The most common ones were, in order of frequency: (i) the Logical Memory subtests of the Wechsler Memory Scale (WMS) [immediate and delayed free recall of orally presented paragraphs or stories]; (ii) the Buschke Selective Reminding Test (BSRT) [learning of a list of words or drawings of objects visually presented with recognition, free and cued recall paradigms]; (iii) the Paired Associates Learning subtest of the WMS (learning a list of semantically related and nonrelated paired words orally presented with a cued recall paradigm); (iv) the Rey Auditory Verbal Learning Test (RAVLT) [learning of a list of words © Adis International Limited. All rights reserved.

orally presented with free recall and recognition paradigms]; (v) the 5-items test (acquisition or learning phase, 10 minutes and 24 hours delayed recall); (vi) the Names Learning test; and (vii) various tests of verbal and visual recall and recognition. Among the 8 trials that have employed the Logical Memory subtest, 6 trials showed improvement. Indeed, 4 trials with selegiline 10 to 15 mg/day demonstrated amelioration on both the immediate and delayed recall assessments after 1 to 15 months of treatment.[110,106-108] Two trials with acetyl-Lcarnitine also showed some improvement on the Logical Memory subtest, although less impressive than the improvement found with selegiline.[106,132] In 1 trial, for example, the improvement of performance occurred only for the immediate recall paradigm after 3 months of treatment.[106] Finally, no improvement has been reported in trials of treatment strategies related to increasing acetylcholine levels. The performance of a group treated with tacrine was not different from that of the placebo group,[98] and a group treated with choline/lecithin did not improve over baseline.[113] Of 5 trials using the BSRT (H. Buschke and E. Grober, personal communication),[143,144] 3 showed improvement in performance of the free recall, the cued recall or the recognition parts of the test. One study with TRH showed a specific improvement in free recall,[134] whereas the other study with TRH reported specific improvement in Drugs & Aging 1999 Mar; 14 (3)

212

Simard & van Reekum

Table VI. Results of trials with drugs affecting putative aetiologic processes and some pathological processes in Alzheimer’s disease Drugs and study

No. of No. of Neuropsychological tests participants dropouts


Desferrioxamine McLauchlan et al.[125]

48

13

Videotaped home behavioral ↓ treatment group (6/12/18/24mo; 125mg) assessment part A-B-C (short ↓↓ no treatment group sequences of everyday behaviours; identification of body parts and left-right orientation; capacity to recognise coins and count change on verbal request)

44

16

ADAS-cog

Indomethacin Rogers et al.[126]

Boston naming test MMSE

↑ (+1.4 ± 4.9% 6mo): sig. diff. from placebo (↓ –13.3 ± 5.6%) ↑ (+4.4 ± 3.7% 6mo): not sig. diff. from placebo (↓ –6.6 ± 5.5%) ↓ (–0.9 ± 4.8% 6mo): sig. diff. from placebo (↓ –13.4 ± 4.4%)

Nimodipine Ban et al.[127]

Tollefson[128]

Fischhof[129]

178

227

144

3

32

14

WMS MMSE GDS SCAG CGIC: severity of the illness global improvement BSRT list learning long-term retrieval long-term storage Word fluency Symbol digital modality test SCAG SCAG-cognition Short cognitive performance test CGIC (item 2)

↑ (1/2/3mo; 90mg) ↑ (1/2/3mo; 90mg) ↑ (1/2/3mo; 90mg) ↑ (1/2/3mo; 90mg) ↑ (1/2/3mo; 90mg) ↑ (1/2/3mo; 90mg) = placebo (3mo; 30mg) ↑ vs placebo (3mo; 30mg only) ↑ vs placebo (3mo; 30mg only) ↑ placebo group only (3mo) ↑ placebo group only (3mo) ↑ (3mo; 30mg) placebo = b (3mo) ↑ (3mo; 30mg) placebo = b (3mo) ↑ (3mo; 30mg) placebo = b (3mo) ↑ (3mo; 30mg) placebo = b (3mo)

Acetyl-L-carnitine Campi et al.[106]

40

0

Rai et al.[130]

36

16


5-items acquisition 5-items recall 10 min 5-items recall 24 hrs Short story acquisition Short story recall 10 min DS forward Word fluency BDS-Part 1 BDS-Part 2

↑ (3mo; 1000mg) ↑ (3mo; 1000mg) = b (1/2/3mo; 1000mg) ↑ (3mo; 1000mg) = b (1/2/3mo; 1000mg) ↑ (3mo; 1000mg) ↑ (3mo; 1000mg) = b (1/2/3mo; 1000mg) ↑ (3mo; 1000mg)

Names learning test Digit recall tests Word fluency test

↑ trend only (3/6mo; 2000mg) ↑ trend only (3/6mo; 2000mg) = b = placebo (3/6mo; 2000mg)



213

Table VI. Cond Drugs and study



Livingston et al.[131]a

71

= b (3/6mo) = b (3/6mo) ↓ 3mo; = b 6mo ↓ placebo 3mo; = b 6mo = b (3/6mo) ↓ placebo (3mo); 6mo treated group significant difference from placebo = b (3/6mo) = b (3/6mo) ?

31

MMSE Kendrick object-learning test Word fluency Recognition memory for words

Recognition memory for pictures Modified names learning test CGIC Sano et al.[132]

Parnetti et al.[114]

30

126

3

0

BSRT total recall BSRT delayed recall BSRT delayed recognition WMS: logical memory paired associates visual reproductions Benton visual retention test: recognition Modified MMSE Cancellations: time omission errors Verbal fluency: letter category DS forward DS backward CGIC

= b (6mo; 2500/3000mg) = b (6mo; 2500/3000mg) = b (6mo; 2500/3000mg)

GDS SCAG GBS (Italian version) RAVLT: immediate recall (learning trials) delayed recall MMSE

↑ 15% treated group (6mo;1500mg) ↑ (6mo; 1500mg) = b (4/6mo; 1500mg)

WMS memory quotient WAIS: verbal IQ performance IQ full IQ deterioration index digit symbol (score) SCAG SASG

↑ (3mo; 20mg)

↑ trend only (6mo; 2500/3000mg) = b (6mo; 2500/3000mg) = b (6mo; 2500/3000mg) = b (6mo; 2500/3000mg) = b (6mo; 2500/3000mg) ↑ (6mo; 2500/3000mg) = b (6mo; 2500/3000mg) ↑ trend only (6mo; 2500/3000mg) = b (6mo; 2500/3000mg) ↑ (6mo; 2500/3000mg) = b (6mo; 2500/3000mg) = b (6mo; 2500/3000mg)

= b (6mo; 1500mg) ↑ (6mo; 1500mg) ↑ (4/6mo; 1500mg)

Antagonic stress formulation Schneider et al.[119]

62

9%

↑ (3mo; 20mg) ↑ (3mo; 20mg) ↑ (3mo; 20mg) ↑ (3mo; 20mg) ↑ (3mo; 20mg) ↑ (3mo; 20mg) ↑ (3mo; 20mg)

TRH Lampe et al.[133]

6

?


BSRT: cued recall total Naming test Benton visual recall: number correct 7 other cognitive measures (?)

↑ (p = 0.031; ≤12mg with lecithin) = placebo (p = 0.058; ≤12mg with lecithin) = placebo (p = 0.058; ≤12mg with lecithin) = placebo (p = 0.056; ≤12mg with lecithin) = placebo [(p not reported) ≤12mg with lecithin]


214

Simard & van Reekum

Table VI. Cond Drugs and study


Molchan et al.[134]

10

0

BSRT (6 words): free recall recall consistency Verbal fluency: category letter DS forward + backward


↑ (45 min; 0.5 mg/kg) = b (45 min; 0.5 mg/kg) = b (45 min; 0.5 mg/kg) = b (45 min; 0.5 mg/kg) = b (45 min; 0.5 mg/kg)

Tocopherol (vitamin E) Sano et al.[112]

a

341

?

MMSE ADAS-cog BDS

= b/placebo (15.6mo; 2000 IU) = b/placebo (12.4mo; 2000 IU) ↑ b/placebo (20mo; 2000 IU) with b score of MMSE as a covariate

Dosage not reported in this study.

ADAS-cog = Alzheimer Disease Assessment Scale – cognitive scale; b = baseline; BDS = Blessed Dementia Scale; BSRT = Buschke Selective Reminding Test; CGIC = Clinical Global Impression of Change; DS = Digit Span; GBS = Gottfried-Bräne-Steen scale; GDS = Global Deterioration Scale; IQ = intelligence quotient; min = minutes; MMSE = Mini-Mental State Examination; mo =months; SASG = Self-Assessment Scale – Geriatric; SCAG = Sandoz Clinical Assessment – Geriatric; TRH = thyroid-releasing hormone; WAIS = Wechsler Adult Intelligence Scale; WMS = Wechsler Memory Scale; wks = weeks; ↑ indicates improvement; = indicates no difference compared with; ↓ indicates deterioration; ? indicates unknown.

cued recall.[133] The only trial with nimodipine using the BSRT found improvement in performance on the long term free recall and the recognition parts of the test for the treated group[128] after 3 months of treatment. Finally, no change in performance of the BSRT has been described for a trial with tacrine using both the verbal and the visual forms of the BSRT[100] or for a trial with acetyl-Lcarnitine.[132] The Paired Associates Learning subtest of the WMS has not been very successful in showing any change in performance in treated groups with different drugs. The only improvement that has been reported occurred in a trial with selegiline 15 mg/day, specifically on the Paired Associates part II (delayed recall) and only after 2 months of treatment.[110] The other studies with tacrine[97,103] and acetyl-L-carnitine[132] did not find any change after 6 weeks to 6 months of treatment. The RAVLT[145,146] has been comparatively more useful than the Paired Associates Test in demonstrating change in the episodic memory performance of patients treated with choline/lecithin, acetyl-L-carnitine or selegiline. Indeed, the group treated with choline/lecithin registered better per© Adis International Limited. All rights reserved.

formance on learning and long term recall after 6 months of treatment, whereas the group treated with acetyl-L-carnitine showed improved performance specifically on long term recall after 6 months of treatment.[114] In the trial with selegiline,[109] the change was less impressive than the one found in the former study.[114] The group treated with 10 mg/day improved minimally on the learning, long term recall and recognition parts of the test only after 6 months of treatment.[109] The 5-items test has been used mainly with selegiline, and with one trial of acetyl-L-carnitine. The 3 studies with selegiline have shown improvement in performance on the learning (acquisition), 10 minutes and 24 hours delayed recall parts of the test after 1 to 3 months of treatment with 10 mg/day.[107-108] The acetyl-L-carnitine trial showed less impressive results; improvement occurred particularly on the learning and the 10 minute delayed recall parts of the test after 3 months of treatment.[107] Two out of 3 studies using the Names Learning test have reported improvement. One trial with tacrine[94] and 1 trial with acetyl-L-carnitine[130] have described improvement after 3 to 6 months of Drugs & Aging 1999 Mar; 14 (3)


treatment, whereas another acetyl-L-carnitine trial[131] did not describe any change from baseline after 3 and 6 months of treatment. Various tests of episodic memory for recall and recognition have been used with tacrine, acetyl-Lcarnitine, selegiline and choline/lecithin treatments in addition to the ones previously mentioned. However, only 2 of them have been able to demonstrate improvement: the revised version of the Kendrick Object Learning Task (KOLT)[147] and the Barbizet-Cany’s 7/24 long term recall (visual memory). The performance on the KOLT improved in patients treated with tacrine 150 mg/day for 3 months,[98] but did not show any change after 3 and 6 months of treatment with acetyl-L-carnitine.[131] The Barbizet-Cany’s 7/24 long term recall has been used in only 1 study, a trial of selegiline; improvement was seen after 3 and 6 months of treatment.[109] The Benton Visual Retention Test (BVRT) [148] [TRH and acetyl-L-carnitine trials], the Face Recognition[149] test (a tacrine trial) and the Visual Reproduction of the WMS (selegiline and acetyl-L-carnitine trials) are among the tests of visual memory that have not been able to show any change. Some studies (with tacrine, acetylL-carnitine, selegiline and choline/lecithin) used unspecified verbal and visual recall and recognition tests; no change in performance was found.[103,111,113,131] 3.1.3 Semantic Memory

Three tests have been used to assess semantic memory: verbal fluency tasks,[135,149-151] the Boston Naming Test (BNT)[152-154] and the Vocabulary subtest of the WAIS.[33] Verbal fluency tasks have been the semantic tests most extensively employed. These tasks have shown improvement in 4[106-109] of 6 studies of selegiline 10 mg/day after 1 to 3 months of treatment. Two acetyl-L-carnitine trials[106,132] have also reported some improvement with dosages of 1000 to 3000 mg/day. However, 2 other selegiline trials,[110,111] 1 tacrine trial,[100] 1 choline/lecithin trial,[113] 1 acetyl-L-carnitine trial[130] and 1 TRH trial[134] have demonstrated neither improvement nor deterioration on these tests. Two trials (1 with nimodipine and 1 with © Adis International Limited. All rights reserved.

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acetyl-L-carnitine) have reported deterioration in the placebo group and no improvement or deterioration in the treated group.[128,131] Only 1 of 3 trials using the BNT has reported some improvement; this was after 6 months of treatment with indomethacin, although the improvement was not significantly different from placebo.[126] The other 2 studies (selegiline 10 mg/day and TRH ≤12 mg/day) have registered no improvement on this test.[110,130] The only trial (with tacrine) using the Vocabulary subtest of the WAIS demonstrated neither improvement nor deterioration after 6 to 24 weeks of treatment with 75 to 125 mg/day.[97] 3.1.4 Implicit Memory

Only 1 research group has repeatedly measured the effect of tacrine on the functioning of implicit memory with a word-stem completion task.[100] Neither improvement nor deterioration was found after 3 and 6 months of treatment with 100 mg/day. 3.1.5 Overview

The measures of working memory have shown some improvement in trials with selegiline, acetylL-carnitine and teniloxazine. There was no improvement on these measures in trials with tacrine, choline/lecithin and TRH. Among the measures of working memory, the DS subtest of the WAIS, assessing the functioning of the CES and the Articulatory Loop, has been the most frequently employed and has demonstrated improvement in trials with selegiline and acetyl-L-carnitine. Cancellation tasks, measuring the VSSP, are less often used than the DS subtest but have been useful to show improvement in trials with selegiline, acetyl-Lcarnitine and teniloxazine. Some improvement in performance was found on 2 other tests of the VSSP: the TMT-A (selegiline trial) and a short term memory test for numbers (teniloxazine trial). Several tests of the VSSP have, however, failed to reveal improvement in trials with selegiline, choline/lecithin and tacrine: the Corsi’s Blocks test, the Complex Visual Search test, the BarbizetCany’s 7/24 immediate recall and a sequential visual memory test. These tests are therefore not recDrugs & Aging 1999 Mar; 14 (3)

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ommended for future investigations. The use of measures of working memory has been successful with selegiline [an inhibitor of monoamine oxidase (MAO) B that acts through an increase of catecholamines], with teniloxazine (a metabolic enhancer) and with acetyl-L-carnitine [which has many effects, including cholinergic, neuroprotective, nerve growth factor (NGF) binding, membrane and receptor stabilisation and plasticity].[155] With drugs with other mechanisms of action, such as acetylcholinesterase inhibition (tacrine) and acetylcholine precursor (choline/lecithin), some measures of working memory (DS and cancellation tasks) appear less worthwhile. Certain measures of verbal episodic memory have been very successful in demonstrating improvement in some drug trials but have failed to do so in others. This has been the case for the Logical Memory subtest of the WMS, the BSRT and the Paired Associates of the WMS. The Logical Memory subtest has been useful for trials with selegiline and, to a lesser extent, for trials with acetyl-L-carnitine in detecting improvement in performance, but has failed to show change in trials with tacrine and choline/lecithin, drugs both associated with an increase of acetylcholine. The BSRT has been successful in showing improvement in trials with TRH and nimodipine but has failed to demonstrate improvement in trials with tacrine and acetyl-Lcarnitine. The Paired Associates test, to a lesser extent than the other verbal episodic memory tests, has demonstrated some improvement in a trial with selegiline while showing no change in trials with tacrine and acetyl-L-carnitine. As opposed to the Logical Memory subtest, the BSRT and the Paired Associates, the RAVLT has been successful in showing improvement in trials with choline/lecithin and acetyl-L-carnitine and, to a lesser extent, in a trial with selegiline. The Names Learning test and the KOLT (revised version) have been most useful to demonstrate an improvement in trials with tacrine, while the 5-items test and the Barbizet-Cany’s 7/24 long term recall have been most successful to demonstrate a positive change in trials with selegiline. Several tests of visual episodic memory, such © Adis International Limited. All rights reserved.

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as the BVRT, the Visual Reproduction subtest of the WMS and the Face Recognition test, have failed to record any improvement in various trials (with acetyl-L-carnitine, selegiline, tacrine and TRH). Measures of semantic memory have been less numerous than measures of episodic memory in the drug trials reviewed in this article. Verbal fluency tasks have been the principal semantic memory tests, with success at showing improvement specifically in trials with selegiline and acetyl-L-carnitine. Verbal fluency tasks failed to demonstrate improvement in trials with tacrine, choline/lecithin and TRH. The BNT and the Vocabulary subtest of the WAIS have been seldom used and proved not to be very helpful in trials with selegiline (BNT), TRH (BNT) and tacrine (Vocabulary). The BNT showed an improvement in performance only in a trial with indomethacin. Finally, a measure of implicit memory, a wordstem completion task, has been used in a trial with tacrine and did not register any change in performance. This result is not surprising since: (i) verbal priming tasks are not acetylcholine-dependent;[83] and (ii) some neuropsychological studies[44,46] have reported preservation of performance on the word-stem completion tasks in patients with mild to moderate AD (see table I and section 2). 3.2 Clinical Scales and General Observational Measures

The clinical and cognitive scales most frequently used in trials of cognition-enhancing drugs are the MMSE,[156] the ADAS,[157] the SCAG,[158] the Self-Assessment Scale–Geriatric (SASG),[159] the Blessed Dementia Scale (BDS),[160] the GBS,[161] the Global Deterioration Scale (GDS),[162] the WAIS and the WMS.[33] The CGIC and the CIBIC are the most frequently used general observational evaluations of cognition and behaviours. 3.2.1 Mini-Mental State Examination (MMSE)

Traditionally, the total score of the MMSE,[156] obtained at the screening evaluation, has been the principal cognitive inclusion/exclusion criterion for drug trials in AD. Furthermore, it has been emDrugs & Aging 1999 Mar; 14 (3)


ployed as an outcome measure for more than half of the drug trials reviewed in this paper. This very short examination contains 7 areas of cognitive evaluation: orientation (for time and place), attention (and calculation), language, ideomotor praxis, constructional praxis and memory. Although the total possible score of the MMSE is 30 (positive scoring system), the maximum score on the memory evaluation is 6. This evaluation involves the immediate recall of 3 words and a few minutes delayed recall of these 3 words. In the present review, the MMSE has been employed in 21 trials with tacrine, donepezil, choline/ lecithin, posatirelin, propentofylline, nimodipine, selegiline, acetyl-L-carnitine, α-tocopherol and indomethacin. Performance on the MMSE improved in 2 of 9 studies with tacrine.[99,103] In 1 trial,[102] the score improved after 4 months of treatment and then decreased significantly after 38 weeks of treatment. Five of these 9 tacrine trials did not register any improvement compared with placebo[95,98,100,104] or baseline[101] after 28 days to 30 weeks of treatment. The data were unavailable in 1 study with tacrine.[94] Trials with choline/lecithin,[114] posatirelin,[115] propentofylline[122] acetyl-L-carnitine[114] and nimodipine[127] showed improvement on the MMSE after 1 to 12 months of treatment. A trial with donepezil reported an improvement in the performance of the treated group after 1 to 9 weeks of treatment, and performance similar to that of the placebo group after 12 weeks of treatment.[105] Trials with selegiline,[112] acetyl-L-carnitine[131,132] and α-tocopherol[112] showed no change compared with baseline or placebo after 3 to 15.6 months of treatment. One trial with nicergoline[120] showed improvement for both the treated and the placebo groups after 8 weeks of treatment, whereas a trial with indomethacin[126] registered deterioration for both the treated and the placebo groups after 6 months of treatment. However, the decrement on the MMSE for the placebo group was significantly more severe than that for the treated group. 3.2.2 Alzheimer Disease Assessment Scale (ADAS)

The original form of the ADAS[157] contained 2 parts: noncognitive behaviour (behavioural/ © Adis International Limited. All rights reserved.

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psychiatric rating scale) and cognitive behaviour (ADAS-cog). The ADAS-cog uses 11 sections to cover 5 general areas of cognition: (i) language (global ratings on spoken language ability, comprehension of spoken language, recall of test instructions and word-finding difficulty in spontaneous speech), comprehension (capacity to follow commands) and naming (objects and fingers); (ii) ideational praxis (ability to fold a letter and put it in an envelope); (iii) constructional praxis (drawing of 4 figures); (iv) orientation (for time, place and person); and (v) memory [learning task with a list of 10 words (3 trials of immediate recall) and a different task of word recognition (with 3 trials of immediate recognition)]. The ADAS-cog has a negative scoring system (the higher the score, the higher the dysfunction) with a possible maximum score of 69. In the present review, the ADAS has been used in 10 trials with tacrine, tacrine/estradiol, donepezil, selegiline, besipirdine, pyritinol, indomethacin and α-tocopherol. The trials with tacrine[95,96,99] and tacrine/estradiol[104] showed some improvement in the treated groups after 6 to 30 weeks of treatment, sometimes accompanied by smaller improvement in the placebo groups.[95,99] The treated groups in trials with donepezil[105] and indomethacin[126] improved minimally after 3 weeks to 6 months (indomethacin) of treatment. Trials with selegiline,[112] besipirdine,[116] pyritinol[123] and αtocopherol[112] did not register improvement in the performance of the treated groups after 4 weeks to 12.4 months of treatment. 3.2.3 Sandoz Clinical Assessment–Geriatric (SCAG)

The original form of the SCAG[158] contains 18 symptom areas and an overall global assessment, all rated on a 7-point format (1 = not present and 7 = severe). Therefore, the scoring system of the SCAG is, like that of the ADAS, negative with a possible minimum score of 19 and a possible maximum score of 126. Fifteen of the symptom areas concern psychiatric and behavioural symptoms, while 3 of 18 symptoms relate more to cognitive functions: mental alertness (concentration capacDrugs & Aging 1999 Mar; 14 (3)

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ity), impairment of recent memory (learning capacity) and disorientation. In the present review, 9 of 10 trials using the SCAG demonstrated improvement. Indeed, trials with choline/lecithin,[114] nicergoline,[119,120] teniloxazine,[121] pyritinol,[124] nimodipine [127,129] acetyl-L-carnitine[114] and antagonic-stress formulation[119] showed improvement in SCAG performance in the treated groups after 1 to 6 months of treatment. One study with pyritinol[123] described no significant difference in the performance of the treated group compared with the placebo group. 3.2.4 Self-Assessment Scale–Geriatric (SASG)

The SASG[159] is the self-assessment version of the SCAG. Use of the SASG is recommended only in patients whose SCAG scores fall within the 1 to 5 scale range; that is, with patients with a global score ≤95.[159] The SASG covers the same areas as the SCAG. In the present analysis, trials with nicergoline,[119] antagonic-stress formulation[119] and pyritinol[123] using the SASG reported improvement after 10 weeks to 12 weeks of treatment. 3.2.5 Blessed Dementia Scale (BDS)

The BDS[160] is, to our knowledge, the oldest scale to be used in trials of cognition-enhancing drugs. It contains 2 main subdivisions: BDS–Part 1 relates to activities of daily living (ADL) with a negative scoring system (0 to 28), and BDS–Part 2 relates to cognition with a positive scoring system (0 to +37). BDS–Part 2 is also called the InformationMemory-Concentration test: 15 points are given for the information test, which measures orientation for time, place and person; 16 points are given for the memory test, which measures the capacity to remember personal semantic, semantic and recent autobiographical events and knowledge; and, finally, 6 points are given for concentration or mental control (months backward, counting 1 to 20 and 20 to 1). Six trials in the present review have used the BDS; all of them found improvement after 1 to 20 months of treatment. The 5 trials with selegiline[106-108,112] and α-tocopherol[112] described improvement in both parts of the scale, whereas the trial with acetyl© Adis International Limited. All rights reserved.

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L-carnitine[106] reported improvement in only the cognitive part (BDS–Part 2) after 3 months of treatment. 3.2.6 Gottfried-Bräne-Steel Scale (GBS)

The GBS[161] contains 4 areas of evaluation: (i) motor functions; (ii) emotional functions; (iii) intellectual functions; and (iv) different symptoms common in dementia (e.g. confusion or restlessness). The intellectual portion (with 11 items) of the scale attempts to assess the level of vigilance of the patient with 3 items devoted to orientation capacity (place, time and person), 1 item to wakefulness capacity, 1 item to concentration capacity, 1 item to inability to increase tempo, 1 item to absent-mindedness, 1 item to long-windedness and 1 item to distractibility. The remaining 2 items concern recent memory (autobiographical memory: capacity to remember the events of the last 24 hours) and distant memory (semantic personal memory and/or autobiographical memory: capacity to remember events and knowledge learned during childhood and youth). Like the ADAS and the SCAG, the scoring system of the GBS is negative with a possible maximum score of 72 and a possible minimum score of 0. In the present review, 5 trials used the GBS. Studies with choline/lecithin,[114] posatirelin,[115] alaproclate[117] and propentofylline[122] reported improvement in performance of treated patients after 1 to 6 months. A trial with acetyl-L-carnitine 1500 mg/day[114] did not report any change after 4 and 6 months of treatment. 3.2.7 Global Deterioration Scale (GDS)

The GDS[162] is a global cognitive deterioration scale for primary degenerative dementia. It defines 6 stages of dementia: stage 1, no cognitive decline; stage 2, very mild cognitive decline; stage 3, mild cognitive decline; stage 4, moderate cognitive decline; stage 5, moderately severe cognitive decline; stage 6, severe cognitive decline. The use of this scale also requires the administration of a detailed psychometric evaluation. Indeed, the original description of the scale by Reisberg and his collaborators[162] gives clinical characteristics and psychometric concomitants for each stage. Drugs & Aging 1999 Mar; 14 (3)


In the present review, use of the GDS in trials lasting 1 to 6 months with tacrine,[99] choline/lecithin,[114] nimodipine[127] and acetyl-L-carnitine[114] showed improvement which was either minimal (with acetylL-carnitine, 15% of the treated group improved after 6 months of treatment)[114] or moderate (with choline/lecithin, 29% of the treated group improved after 6 months of treatment).[114] 3.2.8 Wechsler Adult Intelligence Scale (WAIS) and Wechsler Memory Scale (WMS)

The WAIS and its revised version (WAIS-R)[33] has been developed and validated for healthy adult people, although several of its subtests are often used, together or individually, with patients who are neurologically impaired. This intelligence scale has 2 main components: the verbal subscale and the performance subscale. The WAIS has a positive scoring system with standard scores adjusted for age together with a verbal quotient (VQ), a performance quotient (PQ) as well as an intelligence quotient (IQ) that can be extrapolated. The verbal scale contains subtests measuring semantic memory (vocabulary and information), verbal abstraction (similarities), verbal comprehension and calculation capacities (arithmetic), social judgment (judgment) and verbal working memory (DS forward and backward). The performance scale includes subtests measuring constructional praxis (block design and object assembly), sequential reasoning (image arrangements), visual analysis (image completion) as well as psychomotor speed, visuo-motor and graphic learning (Digit Symbol). The WMS[163,164] and its recent revision, the WMSR,[165] is a validated psychometric instrument devised to thoroughly assess memory capacities. It contains subtests measuring all memory systems and a global memory quotient (MQ) that can be extrapolated. The verbal, performance, intellectual and memory quotients of these instruments have been used as outcomes in trials with nicergoline,[119] antagonicstress formulation[119] and nimodipine (MQ only).[127] All found improvement after 1 to 3 months of treatment. © Adis International Limited. All rights reserved.

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Six trials have used the Digit Symbol subtest of the WAIS. Trials with selegiline,[110] nicergoline[119] and antagonic-stress formulation[119] found improvement after 3 to 15 months of treatment, whereas trials with tacrine[100] and propentofylline[122] did not report any difference between the treated and the placebo groups after 3 to 12 months of treatment. Finally, 1 trial with nimodipine showed deterioration on the Digit Symbol subtest only in the placebo group after 3 months of treatment.[128] 3.2.9 Other Cognitive Scales

Many other cognitive scales have been employed in trials of cognition-enhancing drugs, although most have been used only once. A trial with tacrine using the Mattis Dementia Rating Scale[101] did not show any change after 28 to 56 days of treatment. Another trial with tacrine using the Hierarchic Dementia Scale[102] reported a deterioration in performance after 38 weeks of treatment. A trial with tacrine assessing patients with the Abbreviated Mental Test Score[103] and a trial with nimodipine assessing patients with the Short Cognitive Performance Test[129] showed improvement in performance after 3 months of treatment. Finally, the Syndrom Kurztest (SKT), a European dementia scale used in trials with pyritinol[124] and propentofylline,[122] showed improvement mainly after 3 (pyritinol) to 6 (propentofylline) months of treatment. In another group treated with pyritinol,[123] the performance on the SKT improved in both the treated and placebo groups. 3.2.10 General Observational Evaluations

The CGIC and the CIBIC are the general observational evaluations of cognition and behaviours most frequently used in drug trials. They are subjective in nature and not psychometrically structured or validated. The CIBIC is a global evaluation of change used to determine whether the effects of a drug are important enough to be detected by a skilled and experienced clinical observer during a clinical interview. In this kind of evaluation, every CIBIC rater involved in a drug trial uses their own instruments and questions to evaluate the clinical change, even Drugs & Aging 1999 Mar; 14 (3)

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though guidelines with general areas of cognition that need to be observed are generally provided by the trial sponsors. Usually, at baseline, the clinician interviews the patient and family members and reviews the medical history together with results of former psychometric evaluations to develop a comprehensive impression of the patient’s cognitive abilities and deficits, including behaviours and ADLs. At subsequent visits, the clinician’s evaluation of change in the patient’s condition relative to baseline is based solely on the interchange in the clinician-patient interview; that is, the CIBIC rater has no access to input from family members, clinical staff, scores from psychometric tests or ADLs. The clinician rates the patient on a 7-point scale: 1, very much better; 4, no change; 7, very much worse. The CGIC has the same characteristics as the CIBIC, except that it involves the presence of the caregiver at every assessment to confirm the accuracy of the patient’s statements. In the present review, 14 trials have used either the CGIC, the CIBIC or both. Using the CGIC, 5 trials with tacrine,[96] tacrine/estradiol,[104] pyritinol,[129] and nimodipine[127,129] described improvement, whereas 6 trials with tacrine,[95] donepezil,[105] alaproclate,[117] nicergoline,[120] propentofylline[122] and acetyl-L-carnitine[132] reported no change from baseline or no difference compared with the placebo group after 6 weeks to 12 months of treatment. One research group studying the effects of acetyl-L-carnitine did not report the results of the CGIC, even though it was among their outcomes.[131] Two trials with tacrine[99] and tacrine/ estradiol[104] showed improvement on the CIBIC after 30 weeks of treatment, while a trial with besipirdine[116] did not show any change or deterioration after 4 to 12 weeks of treatment. Various observational and subjective instruments have also been employed in trials with tacrine: the Global Assessment and the Alzheimer’s Deficit Scale,[94] the Camdex Cognitive Estimation (CAMCOG)[98] and the Cognitive Difficulties Score, a self-assessment scale.[101] With the exception of the Cognitive Difficulties Score, all other instruments showed improvement after 3 to 12 © Adis International Limited. All rights reserved.

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weeks of treatment. In addition, the Clinical Dementia Rating Scale–Sum of the Boxes (CDR-SB) has been used in a trial with donepezil; no deterioration was seen after 12 weeks of treatment.[105] 3.2.11 Overview

Among the clinical and cognitive scales, the MMSE and the ADAS-cog, essentially 2 cognitive scales with little memory assessment, have not been very useful in detecting improvement in trials of cognition-enhancing drugs. Indeed, nearly 60% of the trials that used the MMSE failed to find improvement in the performance of the patients. One trial with nicergoline described improvement in both the treated and the placebo groups after 2 months of treatment which might be attributed to a possible practice effect, given the fact that the MMSE has no parallel form of testing. Improvement in the performance of the MMSE took place in trials with choline/lecithin, posatirelin, propentofylline, nimodipine, donepezil (1 to 9 weeks of treatment), 1 of 3 trials with acetyl-L-carnitine and 2 of 9 trials with tacrine. In addition, trials with tacrine, acetyl-L-carnitine, selegiline, α-tocopherol, donepezil (3 months of treatment) and indomethacin did not report any improvement. The ADAS has also not been successful in demonstrating general cognitive improvement. Among the 4 trials with tacrine and tacrine/estradiol that registered improvement in the treated group, 50% showed improvement in performance in the placebo group as well. Trials with donepezil and indomethacin only described minimal improvement, whereas trials with selegiline, besipirdine, pyritinol and α-tocopherol showed no improvement. As a cognitive assessment, the MMSE is very limited: the majority of the measures can be qualified as cerebral posterior ones, neglecting executive functions and working memory alterations. The evaluation of episodic memory, severely altered early in AD, is almost nonexistent. Therefore, in minimal and mild AD the probability of having ceiling effects is strong. The ADAS-cog is more elaborate than the MMSE, but many of the criticisms aimed at the MMSE are also appropriate for the ADAS, in particular those concerning the use Drugs & Aging 1999 Mar; 14 (3)


of posterior measures and the probability of ceiling effects in minimal and mild AD. Unlike the MMSE, the ADAS assesses to a limited extent the capacity of episodic memory. However, the cueing paradigm, of interest for minimal and mild AD (see table I), is not employed and there is no evaluation of the consolidation capacity (with the delayed recall paradigm). Furthermore, the ADAS has no quantitative and thorough evaluation of semantic memory, and no evaluation of working memory, autobiographical memory or personal semantic memory. This lack of measures sensitive to the first stages of the disease, and specifically, the lack of memory system measures in the ADAS, has already been reported by other authors.[166] Those reviewers also mentioned the existence of other scales more appropriate to detect change in AD and emphasised the need to develop new instruments. The SCAG (and the SASG), the BDS, the GBS, the GDS and the performance, verbal, intellectual and memory quotients measured with the WAIS and the WMS were more successful than the MMSE and the ADAS in measuring some improvement in various drug trials. Indeed, 9 of 10 trials with choline/lecithin, nicergoline, teniloxazine, pyritinol, nimodipine, acetyl-L-carnitine and antagonicstress formulation that used the SCAG detected improvement; only 1 trial, with pyritinol, did not find any improvement. The 3 trials with nicergoline, antagonic-stress formulation and pyritinol that used the SASG reported an improvement. However, the SASG is a self-assessment instrument and therefore relies on the awareness capacity of the patient regarding his/her behavioural and cognitive functioning. Table I and section 2 point out that there is a disruption of metamemory functions in the early phases of AD. It is thus possible that expectations and optimism raised by participation in a cognition-enhancing drug trial, together with a deficit of metamemory, could positively influence the patient’s self-rating. The BDS measured improvement in all the studies (with selegiline, α-tocopherol and acetyl-Lcarnitine) in which it has been used. Improvement was also measured in 80% of the trials (with choline/ © Adis International Limited. All rights reserved.

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lecithin, posatirelin, alaproclate and propentofylline) using the GBS, and 100% of the trials (with tacrine, choline/lecithin, nimodipine and acetyl-Lcarnitine) using the GDS. The fact that the BDS, the GBS, the SCAG and the SASG contain an extremely brief memory and/or cognitive assessment is the principal problem of these scales when they are used to assess the efficacy of cognition-enhancing drugs. The total scores (quotients) on the WAIS and the WMS showed improvement in all 3 trials (with nicergoline, antagonic-stress formulation and nimodipine) in which they have been used. The Digit Symbol subtest of the WAIS measures more than 1 cognitive ability (see section 3.2.8) and is usually very sensitive to any brain impairment. This subtest has been used in 6 studies: 3 trials (with selegiline, nicergoline and antagonic-stress formulation) described improvement, 2 trials (with tacrine and propentofylline) reported no improvement, and 1 trial (with nimodipine) showed deterioration in only the placebo group. There are 2 main problems with the use of the WAIS and the WMS in drug trials: (i) VQ, PQ, IQ and MQ, like the other cognitive and clinical scales, do not give specific information about memory systems that are most likely to be affected by the drugs, although they can give a very accurate measure of general cognitive functioning; and (ii) the WAIS and the WMSR do not have parallel forms and, therefore, the repetitive use of these batteries might induce learning or ‘practice’ effects, particularly with ≤3 months between 2 evaluations. Indeed, Little et al.[167] demonstrated the presence of a ‘practice’ effect in an untreated group with mild-to-moderate AD assessed every month during a 6-month period with the same verbal learning test, when compared with a group using parallel forms of the test. The general observational evaluations of cognition and behaviours that are most frequently used in drug trials, the CGIC and the CIBIC, are, like the ADAS, an FDA requirement for drug approval. However, the results reported in the trials using these evaluations are not impressive. Less than half (45.5%) of the trials (with tacrine, tacrine/estradiol, Drugs & Aging 1999 Mar; 14 (3)

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pyritinol and nimodipine) using the CGIC described improvement, and the remainder (with tacrine, donepezil, alaproclate, nicergoline, propentofylline and acetyl-L-carnitine) showed no change. The 3 trials using the CIBIC (with tacrine, tacrine/estradiol and besipirdine) have been more successful: 2 of them (tacrine and tacrine/estradiol) demonstrated improvement. The use of the CIBIC or CGIC evaluations raises some difficulties: (i) the nonpsychometric nature of the instruments themselves is a problem (no sensitivity, validity and interrater reliability data); and (ii) as for the SASG evaluation, reports from the patient may lack validity because of deficits in metamemory. In summary, the scales with the best results in trials of cognition-enhancing drugs are those with a psychiatric assessment (emotional and behavioural) together with a cognitive evaluation that taps into concentration capacity and autobiographical and semantic memory (for example, the BDS, the GBS and the SCAG). However, all the scales and the clinical observational evaluations share the same problem: they do not give information about which aspects of memory are preserved, improved or altered. 4. Conclusions and Suggestions for Memory Assessment in Future Research Although the focus of this article and of the discussion following covers mainly the sensitivity of the outcome instruments to the target symptom (memory), some comments can be made regarding the other possible causes of failure of a given agent to improve the cognitive symptoms of mildly demented patients with AD. First, the drug may be ineffective in AD or may be ineffective at one particular dosage and effective at another dosage. This review has selected compounds that have been previously described[1] as showing some effectiveness. Tables III to VI also give the dosages used in drug trials reviewed in this paper so readers can judge more properly this aspect of the effectiveness of the various agents. Secondly, the design of the study may be poor and/or the results may be underpowered. This review has selected randomised © Adis International Limited. All rights reserved.

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trials and most of them have been placebo-controlled studies. However, this selection does not preclude weaknesses of design in some studies. To allow assessment of the power issue, the number of patients included in the studies together with the number of dropouts are detailed in tables III to VI. For a critical review of the designs used in these drug trials, readers are invited to consult the article of van Reekum et al.[1] Thirdly, the target symptom of the trial (a particular aspect of memory or cognition) may not be impaired in mild AD. Table I and section 2 of the present paper have described the findings related to memory functioning in mildto-moderate AD. In addition, Table II gives an overview of the possible involvement of some neurotransmitters in different memory systems. Future studies of cognition-enhancing drugs should include tests that assess memory systems known to be affected by AD in its minimal, mild and moderate stages (table I and section 2) as well as memory tests that have been shown to be responsive to specific neurotransmitters (see table II), or that have been able to detect improvement in several previous trials (see tables III to VI). Working memory, episodic and semantic memory, autobiographical and personal semantic memory, prospective memory and even metamemory should therefore be evaluation targets in drug trials. Working memory should, in particular, be assessed in trials of drugs producing an increase in catecholaminergic function, with drugs that enhance metabolism and with drugs having multiple effects, such as acetyl-L-carnitine. With acetylcholinesterase inhibitors and acetylcholine agonists, measures of working memory are perhaps less effective. The performance on the Dual Task,[29-31] an experimental test, is actually known to be related to at least 2 catecholaminergic neurotransmitters (see table II) and has been proven to be a sensitive measure in detecting deficits of the CES in minimal to mild AD when compared with healthy controls (see table I and section 2). The DS subtest of the WAIS, which assesses the functioning of the CES and the Articulatory Loop, and cancellation tasks and the TMT-A, which assess some aspects of the Drugs & Aging 1999 Mar; 14 (3)


VSSP, have shown the capacity to detect improvement over time in drug trials (see section 3). Thus, the Dual Task, the DS subtest of the WAIS (or an equivalent measure) and tests of the VSSP such as cancellation tasks or the TMT-A appear to be suitable for future studies. Episodic memory should be evaluated using a number of different paradigms (learning, immediate and delayed recall, free and cued recall, recognition) because its functioning is severely impaired early in the disease process (see table I and section 2) and is also possibly dependent upon many neurotransmitters and processes (see tables II to VI). To achieve a good assessment of change in episodic memory between 2 or more evaluations, it is crucial to use parallel forms of testing because there may be a practice effect over time in patients with mild-to-moderate AD.[167] Among tests of episodic memory, the BSRT[143,144,168] (H. Buschke and E. Grober, personal communication) and the RAVLT[145,146] are most recommended. Both of them use the following paradigms: verbal learning or immediate recall, verbal delayed recall and recognition. Also, both of them have parallel forms (H. Buschke and E. Grober, personal communication).[143-146] The BSRT has been developed[169,170] following the ‘encoding specificity’ paradigm of Tulving and Thompson.[171] The design of the BSRT[143,169,170] (H. Buschke and E. Grober, personal communication) allows coordination of the conditions of encoding and retrieval (with free and cued recall). In order to achieve this coordination, the same semantic cues are used for the encoding phase and for the recall trials.[143,169,170] Variations of the BSRT[169,170] have been elaborated over time. In the Fuld Object Memory Evaluation,[144] 10 common objects are presented in a bag for tactile naming followed by visual naming, if necessary, to guarantee stimulusprocessing. After naming of objects, a distraction of 60 seconds is introduced, followed by 5 short term recall trials and 1 long term recall trial (6 recall trials form)[144] or 1 short-term recall trial, 1 long term recall trial and recognition (2 recall trials form).[168] In another version of the BSRT,[143] 12 items are presented visually and verbally to the pa© Adis International Limited. All rights reserved.

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tient in a 6 recall trials form. The items, according to Buschke,[143] could be pictures, words or objects.[143] The pictures are outline drawings extracted from a standardised set of 260 pictures.[172] Both the BSRT[143] and the Fuld Object Memory Evaluation[144,168] have been proven good detectors and/ or predictors of AD in many studies.[79,168,173-176] Because ceiling effects have been reported in healthy aged controls,[143] other versions of the BSRT have been elaborated: a 4 recall trials form with 16 items (H. Buschke and E. Grober, personal communication) and a form with 64 items covering 16 semantic categories.[50-51] The BSRT and the RAVLT have also been shown to be responsive to manipulation of the cholinergic system,[83] although, in the studies listed here, the effects of choline/lecithin and acetyl-L-carnitine were detected by the RAVLT whereas the BSRT did not detect any change for tacrine and acetyl-L-carnitine. The BSRT has instead detected improvement with TRH and nimodipine. The effects of selegiline have been better revealed by the Logical Memory subtests of the WMS. Among episodic memory tests with a strong visual component, the present review has pointed out the KOLT and the Barbizet-Cany’s 7/24 long term recall as being the most helpful to show some improvement. The KOLT requires patients to look at line drawings of familiar objects and then to recall as many as possible. There are 4 cards in the series, depicting 70 objects. A parallel alternative form of the test is also available.[147] Originally, the KOLT was devised to detect dementia and to follow patients with dementia during treatment.[147,177] However, some psychometric problems have been reported with the KOLT. First, false positive diagnoses of dementia were described in long-stay patients in a psychiatric hospital with no clinical evidence of dementia at baseline and after the 6-week follow-up.[177] This finding raises some doubts about the validity of the instrument to detect dementia and also to measure improvement after treatment. Secondly, in the same study,[177] a practice effect was observed in control patients. A practice effect was also present in the placebo group of Drugs & Aging 1999 Mar; 14 (3)

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the study with acetyl-L-carnitine after 6 months of treatment.[131] Other authors[178] have underlined the weaknesses in the design of the KOLT: some line drawings of objects are ambiguous and the parallel forms of the test are not matched for word frequency of the names of objects.[178] Both the Facial Recognition Test[34] and the BVRT[79] have been previously described as good measures to detect early memory symptoms of AD. Surprisingly, in the present review, these 2 tests failed to show change in trials with tacrine, TRH and acetyl-Lcarnitine. It is of great importance to assess semantic memory, because deterioration of the semantic network and memory, although not unavoidable, may vary from one patient to another in the first stages of the disease (see table I and section 2). Verbal fluency tasks (animals, vegetables, fruits, etc.) have otherwise been proven to be helpful in the detection of the first symptoms of the disease[32,53,79,174,179] and to detect improvement in studies with various drugs (see section 3). However, it appears that, according to our review, verbal fluency tasks are less likely to show improvement in trials with acetylcholinesterase inhibitors or cholinergic agonists. This finding makes some sense, as it has been demonstrated that verbal fluency tasks are not responsive to acetylcholine.[83] Another test of semantic memory largely used in cognitive neuropsychology is the Pyramids and Palm Trees test.[52] This test has been designed to assess nonverbal semantic access or access to visual imagery. It requires patients to match conceptually related pictures (e.g. the target picture of an Egyptian pyramid is presented above drawings depicting a palm tree and a fir tree and the patient is asked to judge which one goes with the pyramid). Six different versions of the test are possible by using either pictures, written or spoken words to change the modality of stimulus or response items. The Pyramids and Palm Trees test has been useful to detect patients among those with early AD and episodic memory deficits who have semantic impairment (see section 2). Evaluation of autobiographical and personal semantic memory is also necessary in drug trials be© Adis International Limited. All rights reserved.

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cause these functions deteriorate following a temporal gradient, early in the disease process (see section 2). No formal or psychometric tests of autobiographical and personal semantic memory have been used in the drug trials analysed in the present review, but it is of interest to underline that some of the clinical scales with the best results (the BDS and the GBS) contain a brief section measuring the functioning of these memory systems. Some instruments can be proposed to the reader who wishes to realise a good evaluation of autobiographical and personal semantic memory: (i) the Autobiographical Incidents Schedule and the Personal Semantic Memory Schedule of Kopelman et al.;[40] (ii) the questionnaire of Flicker et al.[55] developed from the instrument of Squire,[180] containing 20 questions with a 4-choice recognition format pertaining to public events and personalities from the 1950s; and (iii) the Autobiographical Fluency test of Dritschel et al.[56] covering the preschool, primary school, secondary school and postschool periods in which overall demands are similar to those of conventional fluency tasks such as semantic or category generation and letter fluency tasks. The instruments of Kopelman et al.[40] address both episodic and semantic aspects of autobiographical memory over various periods of the patient’s life. They control for age of acquisition and separate episodic from personal semantic memory by eliciting memories for specific events (autobiographical incidents – possible maximum 9 points) and personal semantic information (e.g. names of friends or teachers – possible maximum 21 points) from the same lifetime periods (i.e. preschool, primary school, secondary school, early and recent adult life). In the original paper, Kopelman et al.[40] assessed patients with amnesia and healthy controls matched for age and for estimated premorbid intelligence. They found a good sensitivity and they were able to report an age-related temporal gradient in patients with amnesia, with childhood events and information being recalled better than for the other periods of life. Kopelman and his collaborators also provided evidence of inter-rater reDrugs & Aging 1999 Mar; 14 (3)


liability and validity of the procedure. However, the performance of the healthy controls showed a ceiling effect, particularly in the recent adult life period, in the personal semantic questionnaire and the Autobiographical Incidents questionnaire. No floor or ceiling effects were found in the patient populations.[32,40] The questionnaire of Flicker et al.[55] is a shortened version of the test of Squire[180] that originally contained 30 questions with a 4-choice recognition format. The main problem with this questionnaire (original and shortened versions) is that the questions are referring to international events (e.g. World War II, Vietnam War) or famous personalities with a specifically American perspective. Therefore, the use of this instrument by people from other countries might be more difficult. Dritschel et al.[56] assessed 55 healthy individuals (mean age 45.9 years, range 38 to 55 years) with their Autobiographical Fluency test. They found a temporal gradient, with individuals recalling less easily information (personal semantic memory) and events (autobiographical-episodic memory) from preschool and primary school periods compared with other periods of life. Prospective memory has an important role in the everyday functioning of people. This memory process has been shown to be impaired in the mild stages of AD (table I and section 2). Although none of the drug trials mentioned in this paper have used measures of prospective memory, it would be of interest in the future to do so. Tests that are used in studies of prospective memory are usually subtests of the Rivermaid Behavioural Memory Test (RBMT).[60] The RBMT contains 3 short subtests of prospective memory that are very easy to administer. As with the whole RBMT, the tests of prospective memory are related to everyday life functioning: remember to deliver message, remember to ask for the belonging, ask a question relating to the near future such as an appointment. Four parallel forms of testing are available in various languages. The RBMT has an excellent inter-rater reliability and a good validity. © Adis International Limited. All rights reserved.

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Metamemory is disrupted in the first stages of AD and continues to deteriorate in the moderate and severe stages. To our knowledge, there is no formal instrument for metamemory at the present time. However, the deficits in metamemory registered in the mild stages of AD raise doubts about the reliability of self-assessment measures such as the SASG and the evaluations (for example the CIBIC) in which patients are asked questions about their past or recent events in their life without concurrent input from a reliable caregiver. In the future, efforts should be put into the creation and validation of a metamemory battery or, at least, a metamemory test. Finally, the use of cognitive scales such as the ADAS and the MMSE should be reconsidered in future trials. Indeed, the scales most successful at showing improvement were those more involved with detection of behavioural and psychiatric symptoms, such as the SCAG, the GBS and the BDS. This review suggests that future drug trials choose sensitive memory tests, together with behavioural and psychiatric scales, rather than relying on scales such as the ADAS or the MMSE. Acknowledgements This work was supported by the Alzheimers Society of Canada by a postdoctoral fellowship M.S., and by the KuninLunenfeld Clinical Research Unit, Baycrest Centre for Geriatric Care, North York, Ontario, Canada.

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Correspondence and reprints: Dr Martine Simard, Department of Psychiatry, Baycrest Centre for Geriatric Care, 3560 Bathurst Street, North York, Ontario M6A 2E1, Canada.
