MILD ALZHEIMER'S DISEASE: A «POSITION PAPER»

08 DELRIEU/c:04 LORD_c 16/06/09 16:13 Page 503 MILD ALZHEIMER'S DISEASE: A «POSITION PAPER» J. DELRIEU 1, T. VOISIN 1, S. ANDRIEU 2, S. BELLIARD 3, J. BELMIN 4, F. BLANCHARD 5, M. CECCALDI 6, J.F. DARTIGUES 7, B. DEFONTAINES 8, S. LEHERICY 9, C. MEKIES 10, O. MOREAUD 11, L. NACCACHE 12, F. NOURHASHEMI 1,2, P.J. OUSSET 1,2, F. PASQUIER 13, P. PAYOUX 14, F. PUISIEUX 15, P. ROBERT 16, J. TOUCHON 17, B. VELLAS 1,2, B. DUBOIS 18 1. Service de médecine interne gériatrique et gérontologie clinique, Gérontopôle, CHU Toulouse, Hôpital Purpan Casselardit, Toulouse, France; 2. Unité INSERM 558, Epidémiologie, CHU Toulouse, France; 3. Centre Mémoire de Ressource et de Recherche, Service de neurologie, CHU Pontchaillou, Rennes ; 4. Centre hospitalier C. Foix J. Rostand, Service de Médecine Interne, Ivry sur Seine, France; 5. Hôpital Sébastopol, Service de Médecine Interne, Reims, France; 6. Hôpital La Timone, Service de Neurologie, Marseille, France; 7. INSERM U897, University Bordeaux II, Bordeaux, France; 8. Hôpital les Invalides, Service Unités Sensori-cognitives, Paris, France; 9. Service de Neuroradiologie, Centre de NeuroImagerie de Recherche CENIR Inserm U610, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; 10. Clinique des Cèdres, Service de Neurologie, Cornebarrieu, France; 11. Service de Neurologie et Neuropsychologie, Centre Hospitalier Universitaire, Laboratoire de Psychologie et Neurocognition, Unité Mixte de Recherche, Université pierre Mendes France, Grenoble, France; 12. Hôpital La Pitié-Salpêtrière, Pôle des Maladies du Système Nerveux, Paris, France; 13. EA2691, Service de Neurologie et Centre de la Mémoire, Lille, France; 14. Unité INSERM 455, Service de Médecine Nucléaire, CHU Purpan, Toulouse, France; 15. Clinique de Gérontologie et service de médecine interne et gériatrie, Hôpital Gériatrique Les Bateliers, Centre Hospitalier Universitaire de Lille, France; 16. Centre mémoire de ressources et de Recherche, CHU de Nice, France; 17. INSERM U888 et Service de Neurologie, CM2R du Languedoc-Roussillon, CHU, Montpellier, France; 18. Centre des Maladies Cognitives et Comportementales et INSERM U610, Hôpital de la Salpêtrière, Paris, France. Abstract: Under the auspices of the Société Française de Gériatrie et Gérontologie, a multi-disciplinary group of specialists in geriatrics, neurology, epidemiology, psychiatry, neuroradiology and nuclear medicine met with the aim of drawing up references on the methods for diagnosing and treating mild Alzheimer's disease. The critical analysis of international literature, conducted by Professor Bruno Vellas for the scientific committee, has served to support study of the latest knowledge in 2008. The multi-disciplinary group met on 14 and 15 May 2008 in order to set out the questions that this study must answer and to allocate draft studies. Thus, it has been possible to conduct a study focused on mild Alzheimer's disease, giving particular attention to diagnostic procedure, specific methods of treatment and the benefits of making a diagnosis. Key words: Alzheimer's, mild dementia, diagnosis, biomarkers, treatment. Preambule Alzheimer's disease (AD) is the commonest cause of dementia and now constitutes a major risk to public health. According to the PAQUID cohort study, the Mini Mental State Examination (MMSE) score at the time of diagnosing dementia in France is on average about 19 (1), so the diagnosis is established at the moderate stage of the disease in the majority of cases. In France, the average time required to establish the diagnosis of dementia (time between the onset of symptoms of the disease and diagnosis) is estimated at 24 months whilst it is estimated as 20 months in Europe and 10 months in Germany, which underlines the current level of late diagnosis (2). The proportion of cases detected in the population in 2003 was estimated at 33% at the mild stage of dementia, whereas it was 46% and 73% respectively for the moderate and severe stages (3). Current diagnostic criteria for AD appear to lack sensitivity (especially at the mild stage), tending to be based more on a process of elimination than any positive process. It is therefore useful to investigate the contribution by current neuropsychological, biological and cerebral imaging tools in the diagnostic process for mild AD. Furthermore, in about 50% of cases (4), the initial symptoms do not alert the patient or relatives (frequent confusion between ageing and dementia), and when patients see a doctor, dementia is not identified by their GP (difficulty in distinguishing Received March 10, 2009 Accepted for publication March 12, 2009 503 between a degenerative condition and cognitive recall with sensory problems or general conditions, poor quality information for practitioners relating to specifics about AD and the treatment to prescribe, etc.). It therefore seems important to provide GPs with information and practical tools to help them to recognise the symptoms that may indicate dementia and to look for the signs requiring referral to a specialist for assessment. In fact, improving the diagnostic process in primary care represents a key step in increasing the number of cases detected in the population. Improvement in practical diagnosis of the disease should be considered in parallel to the development of more effective therapies. Currently, we have symptomatic drug therapies, but several pharmacological approaches, aimed at slowing down progression of the disease, based on adjusting production of the peptide amyloid and its break-down, its polymerisation as well as immunotherapy (active and passive) are currently being studied. It has been shown that during the 9 years preceding the diagnosis of dementia (5), there is a gradual cognitive decline with a continuum between the pre-dementia stage, still known as prodromal, now diluted within the general concept of mild cognitive impairment (MCI), and the other stages of the disease. Thus the mild stage of AD where the symptoms may be underestimated, representing a bridging period of the disease (the patient enters into the dementia stage of the disease where the cognitive impairment impacts on everyday

08 DELRIEU/c:04 LORD_c 16/06/09 16:13 Page 504 MILD-STAGE ALZHEIMER'S DISEASE: A «POSITION PAPER» activities). It therefore seems legitimate to pay particular attention to the mild stage of AD. The aim of this article is to provide an overview of the mild dementia stage of AD covering the cognitive, psycho-behavioural, functional and therapeutic areas. This approach hinges on a number of key questions that need to be clarified: - What are the procedures used to diagnose mild AD? - What specific methods are used for treating mild AD? - What are the advantages of diagnosing AD at the mild stage and at which patients is this procedure aimed? Definition of mild dementia According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (6), dementia is mild when the impairment is compatible with retaining some degree of autonomy in everyday activities (washing, dressing, locomotion, feeding). According to CIM-10 (7), the stage is said to be mild when: 1) the degree of memory loss is sufficient to interfere with everyday activities but not incompatible with living independently. The main function affected is the acquisition of new material. For example, the subject has difficulty in registering, retention and recall of elements of everyday and social life, where he has put down items or recently acquired family information. 2) The decline is sufficient to interfere with everyday activities although still allowing independent living. Complex everyday or leisure activities can no longer be carried out. Several global scales taking into account both the cognitive impairment and everyday activities may be used to define the severity of AD such as the Global Deterioration Scale (GDS) and the Clinical Dementia Rating (CDR). Through a semistructured interview with the patient and their next of kin, the CDR (8) allows distinction of 6 domains ( box scores ): memory (M), orientation, judgement and problem-solving, community affairs, home and hobbies, and personal care. Each axis is measured separately, memory being deemed to be the main axis and the others as secondary axes. Where 3 of the secondary axes are rated at a higher or lower score than that for memory, the global CDR score is that of the majority of the secondary axes. Where 3 of the secondary axes are rated identically with memory and 2 differently, the global CDR score is equal to that for memory. The CDR scale is difficult to use in clinical practice because its long and complex assessment usually requires the use of software. The GDS comprises 7 stages numbered 1 to 7, stage 1 corresponding to the absence of any cognitive impairment and stage 7 to a severe dementia stage. Dementia is deemed mild with a global CDR score of 1 (see Table 1) or with a GDS score (9) of 3 or 4. The MMSE (10) may also be a tool used to indicate the severity of dementia. However, the MMSE score is dependent on sociocultural level and is therefore subject to a ceiling effect. For patients who have been diagnosed with dementia, an MMSE score of between about 20 and 26 corresponds to the mild stage. The various stages of AD and especially the mild stage of dementia may therefore be assessed by different scales following a continuum (see Table 2). Cognitive problems are usually associated with loss of autonomy and psychobehavioural problems. The CDR and GDS scales take into consideration functional skills when rating the severity. However, only the GDS scale takes into account psychobehavioural problems in its rating. They are often mentioned in stage 4 and of course at more severe stages. Even if they are less common and less severe than in the more advanced stages, psychobehavioural problems are nevertheless already present in the prodromal and mild stages of dementia. Upon inclusion in the REAL.FR cohort (11), 85.3% of subjects with mild dementia (n=259) presented at least one psychobehavioural symptom during assessment using the Neuro-Psychiatric Inventory (NPI). The most common symptoms at the mild stage are apathy, anxiety, dysphoria as well as problems with feeding and sleeping. The degree of the psychobehavioural symptoms (12) (13) and burden on the caregiver appear to be in direct correlation to the severity of dementia and could therefore be used to define the mild stage, but the scores required to distinguish the various stages have yet to be established. Table 1 Examples of domains assessed by the CDR and rated at 1 Memory Orientation Judgement Community affairs Autonomy Personal care box scores Moderate memory Moderate difficulties Moderate difficulties Incapable of carrying Mild but genuine Requires stimulation (CDR = 1) loss, especially for relating to the sense relating to problem out activities deterioration in recent events, which of time; knows where solving, identifying autonomously away functions carried interferes with the examination is similarities and from home, without out at home; the everyday activities taking place but differences; giving up; appears most difficult jobs may have other on a social level, normal at first sight have been abandoned, orientation problems judgement remains as have the most generally good complex hobbies and interests This data is supplied for information only and does not pre-empt the final score obtained by the algorithm explained previously (there is no need for all the box scores to be 1 in order to obtain a global score of 1) CDR=clinical dementia rating 504

08 DELRIEU/c:04 LORD_c 16/06/09 16:13 Page 505 Table 2 Evaluation of the mild stage of Alzheimer's disease by GDS Degree of deterioration Mild Moderate Global Deterioration Scale (GDS) GDS=3 First signs of impairment apparent. Symptoms in at least 2 of the following areas: - the patient may get lost when going somewhere unfamiliar - work colleagues notice a decline in professional efficiency - the patient can read a chapter of a book but retains little of it - the patient is less able to remember the names of people introduced for the first time - the patient may lose or misplace a valuable item - difficulties in concentrating are apparent at the clinical examination Objective memory loss may only be confirmed through rigorous interview carried out with psychometric tests. Reduced performance in difficult professional or social situations. There is clear denial of the problem by the patient. Symptoms are accompanied by mild to moderate anxiety. GDS=4 Slight impairment during close questioning which manifests itself in the following areas: - The patient has decreased memory of recent events - May reveal gaps in memories of own past - Clear difficulty concentrating on the serial subtraction test - Reduced ability to travel, manage finances Usually, no impairment in the following areas: - Orientation to time and person - Recognising faces and famous people - Ability to get around in familiar places Inability to complete tasks. Denial of problems or unawareness of them is common. Reluctance to engage in activity and avoidance of competitive situations. MMSE 26 MMSE 20 The MMSE (mini-mental score examination) scores are provided as a guideline Figure 1 Progression in cognitive decline based on various stages of Alzheimer's disease (AD) MMSE scores are included in this graph as a guideline; DSM-IV= diagnostic and statistical manual of mental disorders 4th edn, NINCDS-ADRDA= national institute of neurological and communicative disorders and stroke-alzheimer s disease and related disorders association As we have seen before, there is a continuum (see Fig. 1) between the pre-dementia stage and the more advanced stage of AD. It therefore also seems important to define the various stages of the illness in a glossary (14) that we can use later on in this document. Epidemiology of Alzheimer s disease at the mild stage In practice, there are few assessments in Europe (15) on the various stages of severity of AD. Most studies are cohort studies and it is therefore difficult to assess accurately the prevalence and incidence of the disease at the mild stage. There is no population register and therefore no reliable public health indicator. Furthermore, the early stage of the disease is often underestimated due to difficulties in diagnosing it. Generally speaking, the prevalence of AD is 4.8% among people aged over 65 years. The incidence of AD is 11.7 per 1000 persons per year among people aged over 65 years. It increases exponentially with age. Thus, in France, the prevalence of dementia among subjects aged 75 years and over was estimated at 17.8% in 2000 (16). In a Finnish study, conducted among patients aged 75 years and over, in which the severity of the disease was assessed using DSM-III-R criteria, the prevalence of mild dementia was estimated at 8%, moderate dementia at 8.3% and severe dementia at 8.3% in 2003. In the PAQUID cohort (1) (prospective cohort in the general population, 2001) in the 10 year follow-up (1461 subjects), the prevalence of mild dementia (severity assessed according to the MMSE score) was estimated at 4.4%, moderate dementia at 5.6% and severe dementia at 8.3%. During the prospective 10 year follow-up, among patients aged 75 years and over, 32.1% of prevalent dementia was classed as mild (MMSE score of between 19 to 23 inclusive). Prevalence of mild (and very mild) dementia after the age of 75 years is estimated at 7.2% or 315000 patients in mainland France. Nineteen % of patients with mild dementia live in an institution. Of the 41% of patients who do not meet the dependence criteria to qualify for personal assistance to live independently, 52% have mild dementia. 505

08 DELRIEU/c:04 LORD_c 16/06/09 16:13 Page 506 MILD-STAGE ALZHEIMER'S DISEASE: A «POSITION PAPER» GLOSSARY - Mild Cognitive Impairment (MCI): Variable definition but which includes: 1) a subjective disorder affecting memory and/or other cognitive areas and 2) objective impairment of memory and/or other cognitive area 3) with no significant impact on usual activities. Thus, patients with MCI do not meet the generally accepted diagnostic criteria for dementia or AD. - Amnesic MCI: A more specific term to describe a sub-type of MCI, characterised by an amnesic disorder associated with objective memory loss whilst other cognitive areas and usual activities remain. By definition, patients presenting with MCI who do not meet the currently used diagnostic criteria for dementia or AD. - Alzheimer's disease (AD): - Pre-clinical stage: This term refers to the probably long asymptomatic period between the first appearance of cerebral lesions and the first symptoms. It covers subjects with no functional or psychometric impairment but who, during subsequent monitoring, will develop a clinical profile corresponding to the criteria for dementia or AD. - Prodromal or predementia stage: This term refers to the symptomatic period of the disease where the symptoms are not severe enough to meet the currently used diagnostic criteria for dementia or AD. This phase is generally covered by the term MCI. - Probable: This term refers to forms of the disease where the symptoms are severe enough to meet the currently used diagnostic criteria for dementia or AD (no confirmed diagnosis by neuropathological examination). - Certain: Probable AD that meets the histological criteria for AD. - Possible: This term may be used on the basis of a dementia syndrome, where there is no other neurological, psychiatric or systemic disorder likely to cause dementia, and where there is variation in the onset, presentation or progression of the disease. It may be applied where there is a second systemic or cerebral disease likely to produce a dementia syndrome but which is not considered to be the cause of dementia. - Atypical forms: This clinical profile does not strictly meet the currently recognised diagnostic criteria for Alzheimer's disease. This term could therefore cover pure amnesic forms and forms starting with a profile of focal cortical atrophy. - Early stage: This term is used to refer to the mild stage of the disease but is not a strict medical definition. COGNITIVE IMPAIRMENT QUESTIONNAIRE A. Have you felt any change in your memory over the past 6 months? B. Are you under the impression that your memory is functioning less well than that of other people your age? In the past 6 months, have you (more than before; repeat question before each item) 1. BEEN under the impression that you are registering events less well and/or heard your next of kin saying more often I've told you that already? 2. FORGOTTEN an important meeting? 3. LOST your belongings more often and/or for longer than usual? 4. EXPERIENCED more problems with orientation and/or the feeling of not recognising a place that your next of kin have told you that you have visited before? 5. Entirely FORGOTTEN an event even when your next of kin have told you about it and/or when you have looked at photos of it again? 6. HAD the impression of trying to find the words when talking (except for proper nouns) and being forced to use other words, stop talking or to say thing or whatsit more often than usual? 7. CUT BACK on certain activities (or asked for assistance from next of kin) out of fear of making a mistake: personal activities (administrative paperwork, invoices, tax return) or community activities? 8. NOTICED a change in your character with a withdrawal into yourself, reduced contact with others or the feeling of being less interested in things or having less initiative? Examination or monitoring required: score 3 and/or answering yes to question 5 and/or 2 affirmative answers to questions: A, 4, 5, 7, 8. Diagnosing Alzheimer s disease at the mild stage Circumstances of discovery and diagnostic context The reasons why patients with mild AD consult a doctor are very varied. The symptoms may be reported by the patient himself and/or by his friends or family. It may most commonly involve memory loss but also lack of concentration, depression, a change in behaviour, or even language problems. Questioning the subject and an identified companion plays a key part in assessing the impact of the condition on usual activities, lifestyle and where the patient lives, history of the cognitive disorder (how it started and has progressed, change in how the patient functions, etc.) as well as the key nature of the problem (notion of functional decline). Mild Alzheimer's may also be revealed by the progressive onset of a loss of autonomy, weight loss and malnutrition, or even by the onset of falls. In these situations, gerontological assessment, comprising an evaluation of cognitive functions may lead to the diagnosis of dementia. In a study carried out among 1176 GPs in 2004 (17), the common reasons for seeing a doctor were forgetfulness (87.3%), disruption to usual activities (69.63%), disorientation (50.86%), behavioural problems (42.72%) or mood swings (39.75%). Sending GPs a semi-structured questionnaire on cognitive disorder containing questions about memory, language, orientation, activities and behaviour, would provide a more objective view of the key hallmarks of the condition and make referral to specialists more relevant (neurologists, specialist in geriatry, consultation over memory loss, etc.). In fact, this questionnaire (18) is likely to distinguish different cognitive impairment profiles for relatives, subjects with mild cognitive impairment, Alzheimer's patients and subjects with depression. A score above 3 is likely to indicate dementia, especially if the subjects complain of forgetting an entire event, being disorientated or having cut back on their activities and feeling withdrawn into themselves. This questionnaire is only validated for the moment in French. It must be remembered that none of the various above- 506

08 DELRIEU/c:04 LORD_c 16/06/09 16:13 Page 507 mentioned symptoms or grounds for consultation are really specific and if they are present the patient requires precise assessment specifically including assessment of cognitive functions. Diagnostic process The diagnostic criteria for dementia most commonly used in clinical research are the criteria of DSM-IV (6) and National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer s Disease and Related Disorders Association (NINCDS-ADRDA) (19). Diagnosis involves the presence of gradual onset of memory loss combined with impairment in at least one other cognitive domain with an impact on social life or everyday activities. Other pathologies that may be causing cognitive deterioration need to be ruled out. The DSM-IV and NINCDS-ADRDA criteria have been validated by neuropathological testing (independently at the severe stage of the disease) with a diagnostic accuracy ranging from 65% to 95%. The specificity of these criteria compared to other forms of dementia is only 23% to 88%. The recommendations for diagnosing AD, issued by the french agency for healthcare accreditation and evaluation (Agence Nationale d Accréditation et d Evaluation en Santé - ANAES) (20), by the french national health authority (Haute Autorité de Santé - HAS) (21), the American Academy of Neurology (AAN) (22), and EFNS (23) are based on these diagnostic criteria but the different para-clinical tests advocated do vary (see Table 3). Since the publication in 1984 of the NINCDS-ADRDA diagnostic criteria, many advances have been made in understanding the physiopathological processes of the disease. It therefore seems essential to examine the role in diagnosing mild AD of the new para-clinical tests available to us such as the biomarker level in cerebrospinal fluid (CSF), brain MRI (volumetric quantitative and visual qualitative evaluation of the internal temporal structures) and functional nuclear imaging (cerebral perfusion and metabolism, demonstration in vivo of amyloid aggregates). Table 3 Comparison of ANAES, AAN, EFNS and HAS diagnostic processes ANAES AAN EFNS HAS Year 2000 2001 2006 2008 Diagnostic criteria DSM-IV DSM-IIIR/NINCDS-ADRDA DSM-IIIR/NINCDS-ADRDA DSM-IV-TR NINCDS-ADRDA Neuropsychological assessment Episodic memory and other ND Systematic memory+/- Episodic memory and other cognitive areas executive and instrumental cognitive areas functions for mild to moderate dementia Functional assessment IADL ND + IADL or DAD Neuropsychological test(s) MMSE (no professional ND Global assessment + specific MMSE (no professional agreement on other tests) areas/no professional on other tests) agreement on the tests to use agreement Haemogram + + + + Ionogram (calcaemia) + ND + + Glycaemia + ND + + TSH + ND + + SR ND ND + ND TPHA/VDRL CC CC CC CC HIV CC ND CC CC Lyme ND ND CC CC B12 CC + CC CC Folates CC ND CC CC Liver tests CC ND CC CC CSF (Aβ42, Tau and p-tau) - - CC CC CSF (14-3-3) CC CC CC CC Apo-E - - - - APP, presenilin 1 and 2 ND - CC CC CT brain By default By default By default By default MRI brain + + + + MRI/volumetry CC - ND ND SPECT/cerebral blood flow CC - CC CC FDG-PET - - CC CC EEG CC ND CC CC +=recommended, -=not recommended, ND=not discussed, CC=± depending on clinical context; DSM-IV=diagnostic and statistical manual of mental disorders 4th edn, NINCDS- ADRDA=national institute of neurological and communicative disorders and stroke-alzheimer s disease and related disorders association, MMSE=mini-mental state examination, CSF=cerebrospinal fluid, TSH=thyroid-stimulating hormone, SR=sedimentation rate, TPHA/VDRL=treponema pallidum haemagglutination assay/venereal disease research laboratory, APP=amyloid precursor protein, DAD=disability assessment for dementia, ADL=activities of daily living, IADL=instrumental activities of daily living, CT=computed tomography, MRI=magnetic resonance imaging, SPECT=single photon emission computed tomography, FDG-PET=fluorodesoxyglucose positron emission tomography, EEG=electroencephalograph 507

08 DELRIEU/c:04 LORD_c 16/06/09 16:13 Page 508 Irrespective of the diagnostic criteria considered, diagnosing AD at the mild stage is a difficult diagnosis to make and requires a detailed assessment of cognitive functions and accurate clinical and paraclinical evaluation. This diagnostic process is best carried out in a specialist context, ideally at memory centres that can carry out a detailed assessment of cognitive functions and has doctors with wide experience in diagnosing this disease. However, within primary care, it is crucial to identify the symptoms of this disease and refer to specialist centres those patients for whom this diagnosis is suspected based on an initial cognitive assessment test that is sufficiently sensitive and specific, easy to carry out and to interpret. Assessment of cognitive functions The MMSE in the consensual form drawn up by the GRECO (Groupe de Recherche et d Evaluations Cognitives) should be used. This standardised test allows an overall assessment of cognitive functions but is, however, not enough on its own to establish the diagnosis of AD. Its interpretation is complex because the thresholds for interpreting the score obtained depend on the level of education and age. Other tests and batteries of tests may be used during an initial consultation (see Table 4). The 5-word test (24) or the Memory Impairment MILD-STAGE ALZHEIMER'S DISEASE: A «POSITION PAPER» Screen (25) (MIS) can also be used during an initial screening by the practitioner at the consultation to assess specifically anterograde verbal memory. However, at the mild stage of AD, it is vital and routine for a professional specialist in neuropsychology to carry out a detailed psychometric analysis. The initial cognitive signs of AD are usually episodic problems with memory and executive functions (30). There is no consensus on the neuropsychological tests to carry out to diagnose AD. However, objective proof of episodic memory loss (loss of recall with non-standard intrusions by enabling behaviours) is indispensable. The differing recall tests distinguish patients with mild AD from healthy subjects with a precision of more than 90% (31). Using a strategy calling upon a specific encoding (e.g. semantic) with clear assessment of free recall and cued recall makes it possible to distinguish AD patients with mild dementia where hippocampal amnesic syndrome is already present, from healthy subjects even if their MMSE scores are identical (32) (33) (34). Among the episodic verbal memory tests comprising cued and differentiated recall, the Grober and Buschke test (35), the California Verbal Learning Test (36) (CVLT) can be carried out during a detailed neuropsychological assessment (see Table 5). Table 4 Advantages and disadvantages of the key tests (non-exhaustive list) and batteries that can be used by the practitioner during an initial consultation Test/Batteries Advantages Disadvantages Mini-mental State Examination (10) - Quick global assessment - Does not allow diagnosis to be made - Useful for carrying out subsequent monitoring - Minimum and maximum effect - Numerous linguistic items Clock Drawing test (26) - Global assessment of cognitive functions - Useful for detecting a dementia syndrome (visio-constructive and executive+++) (sufficiently sensitive) but non-specific for AD - Takes 2 minutes 5-word test (24) - Quick test and easy to conduct - Maximum effect (but possibility of qualitative - Can be carried out by the practitioner during the analysis to assess the benefit of cueing) consultation to screen for AD - Less sensitive / RL-RI 16 for early stages - Sensitivity = 91% and specificity = 87% for AD (regardless of stage) / healthy subjects Memory impairment scale (25) - Quick test - Sensitivity = 60% / healthy subjects - Can be carried out by the practitioner during the consultation to screen for AD - Specificity 96% for AD / healthy subjects Cognitive Disorders Examination (CODEX) (27) - Very short test (3minutes) - Useful for detecting dementia, but non-specific for - Can be carried out by a non-specialist doctor AD - Sensitivity = 92% and specificity = 85% for diagnosing dementia Frontal Assessment Battery (FAB) (28) - Rapid global assessment of executive functions - Sensitivity to dysfunction of frontal lobes but does not allow differential diagnosis AD/FTD (fluency+++) The seven minute screen (29) - Compilation of tests to assess temporal - Specificity not as good as MMSE in cases of orientation, recall memory, clock drawing and depression verbal fluency - Quick - Sensitivity 92.9% and specificity 93.5% for AD/healthy subjects AD = Alzheimer's disease, FTD = fronto-temporal dementia 508

08 DELRIEU/c:04 LORD_c 16/06/09 16:13 Page 509 Table 5 Advantages and disadvantages of the main (non-exhaustive list) tests and batteries that can be used to assess anterograde verbal and/or visual memory with AD Tests/batteries Advantages Disadvantages RL-RI 16 (35) - Distinguishes between impairment in retention or recall - Impossible to assess spontaneous encoding skills - Allows observation of use by patient of the imposed - Impossible to assess benefits associated with specificity encoding strategy (semantic categorisation) of encoding and cueing for recall respectively RI-48 (37) - Sensitivity to assess mild and very mild stages (sensitivity - Allows no conclusions on retention and recall processes = 93% and specificity = 83,8% for mild and very mild AD) (no free recall) CVLT (36) - Allows observation of spontaneous use of encoding - The words are not always familiar to some patients strategies and are not always linked to the categories to - Assesses the sensitivity to interference (learning a second which they belong shopping list) - No monitoring of the encoding strategy Rey Auditory Verbal Learning - Distinguishes between an AD patient and a subject without - No cueing +++ Test (38) dementia MEM III (39) - Diversity of material on offer (recognising faces, family - Integral testing very long and cumbersome scenes, display of logic, etc.) - No parallel version for any re-tests - Recent norms and gauging for each sub-test allowing partial testing of the scale DMS 48 (40) - Specific assessment of visual recognition memory (advantage - No monitoring of encoding +++ for subjects who cannot read or write+++) - Reflects initial AD lesions in the peri-rhinal cortex Rey Complex Figure Test (41) - Assessment of anterograde visual memory (recall memory) - Not a specific memory test and therefore subject to (memory) - Not subject to sociocultural level executive and visio-spatial skills (need correct copy to assess memory) Doors and People test (42) - Assessment of visual and verbal component of anterograde - Entire test very long +++ memory - French version of some sub-tests - Assessment of recall and recognition memory (measures retention and forgetting) - More distractors than in DMS 48 in the visual recognition task CVLT = California verbal learning test Table 6 Advantages and disadvantages of the main (non-exhaustive list) tests and batteries for assessing executive functions Tests/Batteries Advantages Disadvantages Stroop test (43) - Assessment of inhibitor processes - Insufficient standardisation in French - Multiplicity of versions Hayling test (44) - Assessment of automatism inhibitor processes (part B) - Showing any dissociation difficult due to existence - Assessment of initiation skills (part A) of reciprocal causality - Depends on sociocultural level - Insufficient standardisation Verbal fluency (45) - Assessment of mental flexibility - Disturbance difficult to interpret (need to assess (2 minutes) - Standardisation in French according to gender, age and level semantic knowledge) of education - Need for qualitative analysis (cluster description, planning) - Need for categorised and formal word suggestion to assess executive functions Trail Making Test (46) - Assessment of mental flexibility (part B) - Difficult to carry out with patients from low sociocultural (TMT) level Wisconsin Card Sorting - Assessment of decision-making, problem-solving and - Long, complex multiple choice assessment Test (47) (WCST) cognitive flexibility Rey Complex Figure Test - Assessment of planning skills - Requires full visio-spatial skills (copy) Tower of London Test (48) - Assessment of organisation and planning skills - Multiplicity of test versions and pre-requirements - Problems with varying levels of complexity - Length of test - Not subject to sociocultural level Similitudes (49) - Assessment of abstracting and reasoning skills - Depends on sociocultural level for the most difficult items (sub-test de la WAIS) WAIS = weschler adult intelligence scale 509

08 DELRIEU/c:04 LORD_c 16/06/09 16:13 Page 510 MILD-STAGE ALZHEIMER'S DISEASE: A «POSITION PAPER» Table 7 Advantages and disadvantages of the main (non-exhaustive list) tests and batteries for assessing instrumental functions Tests/Batteries Advantages Disadvantages DO 80 (50) - Full assessment of naming pictures - Need to assess semantic knowledge (understanding of words) - Gnosic involvement in naming line drawings +++ - Only validated in french Cube (copy) - Rapid assessment of visio-spatial skills - Subject to patient's sociocultural level (3D retention) Visual Object and Space Perception - Assessment of visio-spatial skills - Length of testing using entire test (8 sub-tests) battery (VOSP) (51) Line orientation judgement test (52) - Assessment of visio-spatial skills - Insufficient standardisation for patients >75 years Line bisection test (53) - Rapid assessment of visio-spatial skills - Low sensitivity mild forms of neglect Bells test (54) - Assessment of visio-spatial skills - Difficult for patients with low visual acuity owing to size of - Qualitative assessment of planning skills stimuli - Standardisation to be completed In most cases, even at the earliest stages of the disease, the memory loss is combined with other impairment of cognitive functions. Thus, a problem with executive functions (see Table 6), language, skills and recognition should be investigated to diagnose AD based on DSM-IV criteria. Furthermore, assessment of instrumental functions (see Table 7) seems vital for the diagnosis of atypical neocortical forms. Impairment of another cognitive area is not required under the new criteria proposed in 2007 (14). The diagnosis of AD is therefore confirmed by the doctor based on the somatic clinical examination and the neuropsychological assessment interpreted according to the case history and clinical context. Biology Blood tests According to HAS, it is recommended requesting by first intention and routinely (regardless of the stage of the disease) a haemogram, a blood ionogram (including calcaemia), glycaemia, and measuring thyroid-stimulating hormone (TSH). Blood tests for syphilis and HIV, vitamin B12 and folate levels, and liver tests should be carried out according to the clinical context (high-risk subjects, etc.). Genotyping and apolipoprotein E are not recommended. In hereditary forms, detecting one of 3 known autosomal dominant mutations (chromosome 21/precursor of amyloid protein, chromosome 14/presenilin 1, chromosome 1/presenilin 2) constitutes a key element in the diagnosis of AD. In fact, looking for genetic mutations seems useful where there is a strong family history of autosomal dominance (in young subjects aged under 60 years, at least 3 cases of AD within 3 generations). Whilst plasma biomarkers for diagnosing AD are currently the subject of research, none is available or validated for clinical practice at present. Cerebrospinal fluid: developing biomarkers for the disease With regard to biomarkers in CSF, many recent studies are aimed at studying their role and diagnostic accuracy in AD. Biomarkers in CSF (55) (56) would reflect the pathogenic process responsible for the disease, namely aggregation of β amyloid peptides and tau hyperphosphorylation. Enzymelinked immuno assay techniques (ELISA) have been commercialised. In AD, the level of β1-42 amyloid peptide (Aβ42) is reduced in CSF whilst that of β1-40 amyloid peptide (Aβ40) remains normal or very slightly down. In addition the level of total tau (t-tau) and phosphorylated tau (p-tau) proteins in CSF is high compared to healthy subjects (57). The Aβ42/Aβ40 ratio could allow early diagnosis of the disease. The sensitivity and specificity of these 3 markers are higher than 85% for distinguishing AD from the normal subject, Parkinson's disease, cognitive impairment associated with alcohol and psychiatric disorders (58). However, high tau in CSF is not specific to AD (59) and is also found in Lewy body dementia, fronto-temporal dementia and vascular dementia, maybe due to the presence of overlapping of some of these pathologies (see Table 8). These 3 markers do not correlate to the stage of the disease or the time it takes to evolve (60). The biomarker level in CSF does not differ between a mild and moderate stage. Their profile therefore appears similar irrespective of the level of severity of the disease. Thus, the level of Aβ42 is already low at the early stage of the disease and could therefore be used to diagnose AD at the mild dementia stage with equivalent sensitivity and specificity (61). However, the level of p-tau231 appears correlated to the degree of hippocampal atrophy, whilst the level of Aβ42 is in inverse proportion to the amyloid load (62). 510

08 DELRIEU/c:04 LORD_c 16/06/09 16:13 Page 511 Table 8 Sensitivity and specificity of biomarkers in CSF with Alzheimer's disease Study Methodology Sensitivity Specificity Bernd Ibach et al, Participants : AD v. healthy subjects AD v. psychiatric disorders Neurobiology of Ageing - 75 AD - t-tau : 88% - t-tau : 80% 2006 (63) - 39 control subjects - p-tau : 88% - p-tau : 80% - 48 other types of dementia - tau/aβ42 : 81% - tau/aβ42 : 85% - 26 psychiatric disorders - p-tau/aβ42 : 81% - p-tau/aβ42 : 78% AD v. healthy subjects AD v. psychiatric disorders - p-tau : 80% - p-tau : 77% Alessandro Stefani et al, Participants : AD v. vascular dementia AD v. vascular dementia Journal of neurological sciences - 35 AD - Aβ42 : 77% - Aβ42 : 80% 2005 (64) - 31 mixed dementia - 20 vascular dementia Mixed dementia v. vascular dementia Mixed dementia v. vascular dementia - Aβ42 : 95% - Aβ42 : 60% M.Riemenssheider et al, Participants : AD v. FTD AD v. FTD Neurology - 34 FTD - combination of t-tau and Aβ42 : 85% - combination of t-tau et Aβ42 : 85% 2002 (65) - 74 AD - 40 control subjects Harald Hampel et al, Participants : AD v. non AD AD v. non AD Dement Geriatr Cogn Disord - 161 AD - p-tau : 85% - p-tau : 75% 2004 (66) - 206 non AD (other types of dementia and control subjects) AD v. LBD AD v. LBD - p-tau 181 : 94% - p-tau 181 : 64% AD=Alzheimer's disease, FTD=fronto-temporal dementia, LBD=Lewy body dementia A biomarker profile in CSF combining a reduction in Aβ42 with a rise in t-tau and p-tau would be a more specific for diagnosing AD in young subjects (< 65 years) than in older subjects ( 65 years). In fact, although the biomarker profile in CSF is identical in young and elderly subjects with AD, the difference in level compared to healthy subjects appears greater in young subjects (the level of Aβ42 in CSF is not so high, and that of p-tau and t-tau is higher in elderly control subjects than in young control subjects). Indications for using, and benefits of, the biomarker level in CSF in clinical practice: - Atypical forms for increasing confirmation of the diagnosis (atypical progression or discrepancy between various tests) - Diagnostic uncertainty with psychiatric pathologies to record organicity where the biomarker level is positive (histological signature for the disease) - Among young subjects (more specific) Cerebral imaging Structural imaging Carrying out structural brain imaging is crucial (21) to the diagnosis of AD regardless of the stage of the disease. At the mild stage of AD, a brain MRI must be carried out routinely unless contraindicated, in which case cerebral computed tomography is of course preferable. Carrying out a brain MRI fulfils 2 purposes: - The main purpose of this examination is to not fail to identify the presence (diagnostic process by elimination) of large cerebro-vascular lesions or any other so-called curable AD v. FTD AD v. FTD - p-tau 231 : 86% - p-tau 231 : 92% 511 or neurosurgical causes of dementia (intracranial expansive process, normal pressure hydrocephalus, etc.). - The second purpose is to be able to assess more accurately the internal temporal structures (especially the hippocampal formations) so as to assess any atrophy and therefore find additional positive evidence to support the diagnosis of AD. Using MRI to measure (qualitative visual or volumetric quantitative assessment) the structures of the internal temporal lobe (hippocampus, entorhinal cortex and amygdalae) reveals any loss in volume (compared to healthy subjects of the same age) thereby distinguishing AD from healthy subjects as well as other causes of dementia with a specificity and a sensitivity of more than 85% (67) (68). At the mild to moderate stage, the sensitivity and specificity of detection of AD compared to healthy elderly subjects are 85% and 88% respectively. The degree of atrophy of the structures of the internal temporal lobe is proportionate to the severity of the cognitive impairment as well as to the episodic memory performance (69) (see Table 9). The most affected structures are the hippocampus (CA1, subiculum) and the entorhinal cortex. However, atrophy of the hippocampal formations is not specific to AD and is to be found in healthy elderly patients as well as frontotemporal dementia. Nevertheless, MRI with quantitative volumetry of the internal temporal lobe does make it possible to distinguish patients with mild to very mild AD from healthy subjects of the same age (70) (-1.99 DS of hippocampal atrophy for the mild stage compared to healthy subjects). Visual analysis and quantitative volumetry have similar precision (71) (volumetry using a stereological method).

08 DELRIEU/c:04 LORD_c 16/06/09 16:13 Page 512 MILD-STAGE ALZHEIMER'S DISEASE: A «POSITION PAPER» Table 9 MRI and Alzheimer's disease at the mild dementia stage Study Methodology Results Gosche KM et al, - Aim: To assess the severity of atrophy of the - All the structures of the internal temporal lobe are significantly Neurology structures of the internal temporal lobe (hippocampus, more atrophied (p <0.001) in AD patients compared to normal 2002 (70) para-hippocampal gyrus, amydala) of AD patients subjects, but the total hippocampal volume is the better deciding according to their stage of progression (CDR) by factor volumetric method compared to control subjects. - The degree of atrophy of the internal temporal lobe - Participants: 126 control subjects, 94 probable AD. compared to healthy subjects is: -1.75 DS for the very mild stage (CDR=0.5), -1.99 for the mild stage (CDR=1) and -2.2 for the moderate stage (CDR=2) Bottino CM et al, - Aim: To assess the precision of the volume - All the measured areas of interest are significantly Int. Psychogeriatr. measurement of the internal temporal structures different (p <0.05) in AD patients compared to MCI and 2002 (67) (hippocampus, amygdalae, para-hippocampal gyrus) normal elderly subjects to distinguish patients with AD, MCI and normal elderly - Measurements for structures of interest on the left-hand subjects side are significantly different (p<0.05) between MCI - Participants : 39 patients with mild to moderate AD, and normal elderly subjects 21 MCI and 20 normal elderly subjects - The accuracy of the volumetric measurement is 88.14% for distinguishing AD patients from control subjects, 81.67% for distinguishing AD patients from MCI and 80.49% for distinguishing MCI patients from control subjects. AD= Alzheimer's disease, CDR=Clinical Dementia rating, MCI=Mild Cognitive Impairment Table 10 Visual assessment of atrophy of the internal temporal lobe (69) Score Width of choroidal fissure Width of temporal horn Height of hippocampal formation 0 Normal Normal Normal 1 Normal Normal 2 3 4 Quantitative volumetric analysis of the hippocampal formations is not routinely available in everyday clinical practice at present. For now, qualitative visual analysis, which is faster, must therefore be given priority, focusing especially on the internal temporal regions (see Table 10). To meet the demands of these 2 aims, the brain MRI must comprise T1 sequences with perpendicular lengthwise crosssections of the hippocampus, axial and/or coronal T2 and/or FLAIR cross-sections to assess lesions in the white matter and cerebrovascular lesions and T2* axial cross-sections to assess microbleeds present with vascular dementia (72). Routine brain MRI comprising: - T2, T2*, FLAIR sequences in axial and/or coronal cross-section (elimination process) - T1 sequences with cross-sections showing the hippocampus (perpendicular lengthwise sections of the hippocampus) and thereby making it possible to carry out a qualitative visual analysis of internal temporal atrophy (positive process) Functional imaging PET (Positron Emission Tomography) and SPECT (Single Photon Emission Computed Tomography) are nuclear imaging scans that make it possible to measure glucidic metabolism (18F-FDG PET) and cerebral perfusion (99mTc-HMPAO, 133Xe, ECD) respectively. More recently, it has become possible to reveal amyloid aggregates in vivo with PET by using PIB (Pittsburgh Compound-B) and FDDNP (2-(1-[6-[(2- [18F]Fluoroethyl(methyl)amino]-2-naphthyl]ethylidene) malononitrile) as radioligand. In everyday clinical practice, SPECT of cerebral perfusion is preferable to PET using FDG or in vivo staining of amyloid plaques, due to its low cost and wider availability, although it is less sensitive and specific. However, SPECT should not be routinely carried out where mild-stage AD is suspected. It appears better to keep it for atypical cases or where there is doubt over the clinical diagnosis. It is also used to distinguish AD and Lewy body dementia with a sensitivity of 88% and a specificity of 85% by using FP-CIT as a radiotracer (73). PET is currently mostly used in clinical research but its subsequent wider availability as well as its encouraging results make it a promising tool for the near future. In fact, PET using 18F-FDG identifies bilateral hypometabolism in the parietotemporal as well as in the posterior cingulate regions (74). It makes it possible to 512

08 DELRIEU/c:04 LORD_c 16/06/09 16:13 Page 513 Table 11 PET in vivo staining of amyloid plaques in Alzheimer's disease Study Methodology Results Hilary A.Archer et al, - Aim: correlation between amyloid load and cerebral atrophy - Correlation between amyloid load in the anterior and Ann. Neurol. - Participants: 9 mild to moderate Alzheimer's posterior cingulate regions and cerebral atrophy 2006 (81) Kerryn E.Pike et al, - Aim: correlation between amyloid load (PIB), - 97% of AD patients, 61% of MCI and 22% of healthy subjects Brain neuropsychological tests with Alzheimer's, MCI and healthy are PIB+ 2007 (82) subjects - Correlation between cerebral amyloid load and episodic - Participants: 31 Alzheimer, 33 MCI and 32 healthy subjects memory loss N.M. Kemppainen et al, - Aim: assess amyloid load and its location in the brain in - Alzheimer v. control subjects : frontal>posterior cingulate Neurology Alzheimer patients/control subjects >parietal>laterotemporal>striatum (p<0.001) 2006 (80) - Participants: 17 Alzheimer, 11 control subjects - SPM analysis PIB= Pittsburgh Compound-B, MCI=mild cognitive impairment, SPM=statistical parametric mapping, AD=Alzheimer s disease distinguish AD from healthy subjects with a sensitivity and a specificity of 85% (75), 86-92% and 80-81% for Lewy body dementia (76) (using the primary visual occipital cortex), 78% and 71% for frontotemporal demential (77) and 75-88% and 18-53% for vascular dementia (78). PET reveals amyloid aggregates (PIB, FDDNP) and shows an increase in retention of radioligand with AD. An increase in the amyloid load is also to be found in some healthy subjects (22% in a sample of healthy elderly subjects around 73 years old) and MCI (79) (in 60% of MCI cases, an identical profile of tracer retention and accumulation is found to that of AD). Retention of radioligand in the AD patient compared to healthy subjects is found mainly in the frontal, posterior cingulate, parietal, lateral temporal and striatal regions (80) (see Table 11). At the mild to moderate stage of the disease, there is a correlation between the amyloid load in the anterior and posterior cingulate regions and cerebral atrophy (81). There is also a correlation between cerebral amyloid load and episodic memory loss (82) (see Table 11). However, there is no correlation between cerebral amyloid load and the degree of severity of the disease, contrary to cerebral metabolism assessed by PET using 18F-FDG. Indications for and role of functional imaging in clinical practice: - Non-routine SPECT of cerebral perfusion to be carried out in atypical cases - PET currently restricted to clinical research Creating a flow chart of diagnostic decisions for mild-stage Alzheimer's disease Figure 2 Flow chart of decisions and role of the various clinical and paraclinical tests in the diagnostic process for mild-stage Alzheimer's disease (also involves seeing a specialist doctor at a memory centre) (Assessment of memory, notably episodic verbal memory using a free, cued and differentiated test of recall as well as executive and instrumental functions) 513