RECENT DATA ON THE NATURAL HISTORY OF ALZHEIMER S DISEASE: RESULTS FROM THE REAL.FR STUDY

Transcription

1 RECENT DATA ON THE NATURAL HISTORY OF ALZHEIMER S DISEASE RECENT DATA ON THE NATURAL HISTORY OF ALZHEIMER S DISEASE: RESULTS FROM THE REAL.FR STUDY F. CORTES, S. GILLETTE-GUYONNET, F. NOURHASHEMI, S. ANDRIEU, C. CANTET, B. VELLAS, THE REAL.FR GROUP Service de Médecine Interne et Gérontologie Clinique, Pavillon JP Junod, 170 avenue de Casselardit Toulouse (France) (F Cortes, S Gillette-Guyonnet, F Nourhashemi, C Cantet, B Vellas) and Unité Inserm 558, 37 allée Jules Guesdes, Toulouse (France) (F Cortes, S Gillette-Guyonnet, F Nourhashemi, S Andrieu, C Cantet, B Vellas), Correspondence and proofs to: Name: Cortes Frederic, Address : Service de médecine interne et gérontologie clinique, Service du Pr Vellas, Pavillon JP Junod, Hôpital La Grave- Casselardit, 170 avenue de Casselardit31300 Toulouse cedex 9-France, Tel.: ,Fax: , cortes.fr@chu-toulouse.fr Abstract: Objectives: This paper aims to present the changes observed in the evolution of Alzheimer s disease (AD) in the cohort REAL.FR after one year by taking account new treatments and improved management. Methods: Four hundred and ninety-eight patients recruited for the REAL.FR study were followed for one year with a standardized case report filled for each patient every 6 months. Changes in the status of these patients were evaluated on various levels: cognitive, functional, behavioural, global, nutritional, social, medical and caregiver burden. Specific treatments were also recorded. Results: A high proportion of patients received specific treatment for AD throughout the year (86%), mainly acetylcholinesterase inhibitors (AChEI). As expected we observed statistically significant changes in cognitive function (MMS : -1.93±3.74, p< and ADAS-cog : +2.40±3.74, p<0.0001), an overall loss of autonomy (ADL :-0.56±1.05, p< and IADL : -1.00±1.46, p<0.0001), worsening of behavioral disturbances (NPI : +1.85±14.83, p=0.0047) and a deterioration of general status (CDR- SB : +1.63±2.55, p<0.0001). Even if the MNA score decreased not significantly, the loss was close to the threshold of significativity (MNA : -0.31±3.07, p=0.0531). Conclusion: We observed a statistically significant change for the worse in most parameters. However, it appears that this deterioration had been relatively slowed by non-pharmacological management and the specific AD treatments. This resulted in stability or improvement of the condition in 63.4% of patient at 1 year. The management proposed (including prescription of AChEI) seemed to have a real impact on the course of the disease during this first year of follow-up. Introduction At the present time, Alzheimer s (AD) disease is the subject of numerous studies, but paradoxically concerning its natural history little information is available which takes into account the advent of new treatments and improved management. Alzheimer s disease is known to be a progressive disease characterised by gradual cognitive decline and loss of autonomy, leading to total dependence of the patient and the onset of behavioural disturbances (1) which sometimes have major effects on the life of the patient and of the caregiver. These problems are the result of a neurodegenerative process which particularly affects the cholinergic system (2). Because of the increasing importance of AD, efficient management of patients must be initiated and so our present knowledge of the natural history of the disease must be improved. In particular, it is necessary to take account of the influence of the treatments which have recently become available, with first of all the three drugs indicated for mild to moderate forms of the disease: donepezil (Aricept), rivastigmine (Exelon) and galantamine (Reminyl). These have proved their efficacy and tolerability in clinical trials, where they were found to slow the progression of the disease by inhibiting acetylcholine degradation (3,4,5,6,7). More recently, a new drug for the more severe forms of the disease has been developed: memantine (Ebixa) which acts as a non-specific NMDA receptor antagonist, maintaining glutamatergic transmission and thus reducing neuronal degradation, leading to improvement of the patients condition (8). In the course of AD, we should not overlook the progress achieved in patient management through better knowledge of the disease and through the development of home help services. The REAL.FR study (Réseau sur la Maladie d Alzheimer Français)has been set up with the aim of studying the natural history of AD by taking all these factors into account. This project is a unique observatory, assessing through longitudinal follow-up in 16 Alzheimer centers in France the long-term impact and tolerance of treatments, modalities of use of services and of management of the sick elderly person, as well as predictors of admission to hospital or to an institution. This paper aims to present the changes observed in the cohort after 1 year by analysing all these parameters and their influence on the course of AD. Material and methods The REAL.FR study is a prospective multicenter study which has recruited throughout France, between 2000 and 2002, 693 patients presenting AD according to the NINCDS- ADRDA and DSM-IV criteria (9,10). The methodology of the study has been described in detail elsewhere (11). Briefly, for inclusion in the study, the patients had to present a mild to moderate form of the disease (score between 12 and 26 on the Mini-Mental State) (12), be ambulatory, living in their own homes and cared for by a clearly identified caregiver. At 86

2 THE JOURNAL OF NUTRITION, HEALTH & AGING inclusion, the patients underwent a full medical examination (CT scan, thyroid tests). We excluded from the study patients with severe AD, those who were institutionalized and those with a concomitant disorder which could affect the short-term prognosis. Data are collected prospectively every 6 months for 4 years during a visit in 1 of the 16 centers participating in the study. A standardized case report form is filled in for each patient by a specially trained, multidisciplinary medical team. The data collected include: 1/ cognitive evaluation with administration of the MMS (12) and the cognitive subscale of the Alzheimer s Disease Assessment Scale (ADAS-cog) (13), 2/ evaluation of the capacity to carry out the activities of daily living, using the Activities of Daily Living scale (ADL) (14) and the Instrumental Activities of Daily Living scale (IADL) (15) for the more complex activities, 3/ evaluation of behavioural disturbance with the Neuropsychiatric Inventory (NPI) (16). 4/ overall evaluation using the Clinical Dementia Rating (CDR) (17) and Reisberg s Global Dementia Scale (GDS) (18). At each visit, all current treatments, in particular specific treatments for AD, are carefully recorded. Nutritional status is also assessed with the Mini-Nutritional Assessment (MNA) (19). Lastly, caregiver burden is measured with the Zarit Burden Interview (20). During follow-up, all events occurring between two visits, in particular admissions to hospital or to institutions, use of new support or home assistance services, changes among the patient s family and friends, are carefully recorded together with deaths, entry to an institution where follow-up is not possible, and other reasons for premature discontinuation such as withdrawal of consent, medical problems of patient or caregiver, or loss to follow-up. Statistical analysis Statistical analysis of the data was carried out with SAS 8.0 software. Bivariate analysis was used to describe the changes at one year in cognitive and non-cognitive parameters in the patients of the cohort. Wilcoxon s non-parametric test was used for quantitative variables and the McNemar test for qualitative variables. For the MMS : deterioration is a loss of 3 points or more in 12 months; improvement is an increase of 3 points or more in 12 months and stable concern patients whose score at 1 year and score at inclusion differed by between 3 and 3, exclusive. For the ADL: deterioration is a loss of 0.5 points or more in 12 months and improvement is a gain of 0.5 points or more in 12 months. For the IADL: deterioration is a loss of 1 point or more in 12 months and improvement is gain of 1 point or more in 12 months. For the NPI: deterioration is an increase of 1 point or more in total score in 12 months and improvement is a decrease of 1 point or more in total score in 12 months. For the measure of weight: deterioration is a loss of 4 % or more of baseline weight in 12 months, improvement is an increase of 4 % or more of baseline weight and stable is a weight at 1 year equivalent to baseline weight ± 4 %. For the MNA: deterioration is a change to poorer nutritional status (3 categories: normal nutritional status (score >23.5), at risk of malnutrition (score ) or malnutrition (score <17)), improvement is a change to better nutritional status and stable means no change from initial category. For the Zarit scale : deterioration is an increase in burden (4 categories: no or slight burden (score 0-20), mild to moderate burden (score 20-40), moderate to severe burden (score 40-60) or severe burden (score > 60)), improvement is a change of category (lighter) towards lesser burden and stable is no change from initial category. Results Overview of follow-up During the first year of follow-up, 25 subjects died, 30 entered an institution and 91 prematurely discontinued followup for various reasons (see figure 1). Figure 1 Changes in the cohort after 1 year of follow-up. * : patient s or caregiver s medical problem, removal Patients recruited n = 693 Patients who completed the 1st year of follow-up n = Deceased n = 25 - Institutionalized (follow-up impossible) n = 30 - Lost to follow-up n = 38 - Withdrawal of consent n = 34 - Other* n = 19 Discontinous follow-up n = 49 Overall, of the 693 patients initially recruited, 498 were evaluated at 1 year and 49 missed the visit. Table 1 compares the characteristics at inclusion of patients who prematurely discontinued follow-up (excluding the 25 patients who died) and of those who were still in the study at 1 year (n = 547). Subjects who discontinued follow-up during the first year had a significantly lower mean MMS score than the patients who completed the year (p=0.0064). Their ability to carry out the activities of daily living was also less (ADL, p=0.0001, IADL p<0.0001). Overall, these subjects were at a more advanced stage of the disease, as shown by the mean CDR-SB score which was significantly higher in subjects who left the study than in those who continued (p=0.0002). These patients were also significantly older (p=0.0017). Lastly, absence of specific AD treatment at inclusion significantly increased the risk of premature discontinuation during the first year of the study 87

3 RECENT DATA ON THE NATURAL HISTORY OF ALZHEIMER S DISEASE (OR=0.37, p= and 95% CI = ). Table 1 Comparison of characteristics at inclusion between patients followed for 1 year and patients who prematurely discontinued follow-up (excluding those deceased, n = 25). Parameters at Discontinuation of follow-up p student inclusion no yes mean ± SD mean ± SD Total MMS ± ± n = 545 n=121 CDR-SB 6.11 ± ± n=542 n=121 Age at onset (yr) ± ± n=504 n=108 Age at diagnosis (yr) ± ± n=513 n=111 Age of patient (yr) ± ± n=544 n=121 ADL 5.54 ± ± n=547 n=121 IADL 4.51 ± ± 2.21 < n=390 n=96 The results presented below concern the 498 subjects who completed the first year of follow-up. Cognitive and non-cognitive aspects of AD Table 2 shows changes in the cognitive and non-cognitive parameters during the first year of follow-up. Table 2 Changes in cognitive parameters, autonomy, behavioural disturbances, nutritional status and caregiver burden in patients followed for 1 year (n = 498). Parameters Mean score at Mean score Difference p Wilcoxon inclusion at 1 year MMS ± ± 3.74 < ADAS-cog ± ± < CDR-SB 6.21 ± ± ± 2.55 < ADL ± < IADL 4.62 ± ± ± 1.46 < NPI (freq x grav) ± ± ± NPI (n problems) 2.96 ± ± ± Weight ± ± ± MNA ± ± ± Zarit scale ± ± ± ADAS-cog were significantly higher than those obtained at inclusion, with an increase of 2.40 ± 6.10 points (p<0.0001) (table 2). Change in ability to carry out the activities of daily living: mean scores on the ADL and IADL measured at the end of 1 year were significantly lower (p<0.0001) than at inclusion, reflecting greater difficulty in carrying out the basic and instrumental activities of daily living (table 2). Figure 2 shows the items most affected by this gradual loss of function. Concerning the ADL, there was indeed an overall loss for the basic activities of daily living (figure 2 A). For the more complex activities (IADL), we observed an increase in the percentages of dependent subjects after 1 year, whatever the item considered (figures 2 B). Deterioration was observed in 43.8% of patients on the ADL scale and in 59.1% on the IADL (table 3). Figure 2 Changes in autonomy in patients followed for 1 year (n = 498) for each of the items evaluated by the scales for ADL (2A) and IADL (2B). = inclusion; = 1 year *** : p< Change in behavioural disturbances: the mean NPI score after 1 year was significantly higher than at inclusion, with an increase of 1.85 ± (p=0.0047). Behavioural disturbances thus significantly worsened in the cohort as a whole, but we did not observe a significant increase in the mean number of problems (table 2). The various problems assessed by the NPI did not all progress in the same way. In fact, for certain problems the number of patients affected decreased significantly during the year: this was the case for depression (p=0.0186) and anxiety (p=0.0048). On the other hand, apathy (p=0.0196), aberrant motor activity (p<0.0001) and sleep disturbances (p=0.0495) were present in a significantly greater number of patients after 1 year of follow-up (figure 3). Overall worsening of behavioural disturbances (a score increase of 1 point or more) concerned 51.4% of patients, while 38.3% improved (table 3). telephone *** *** *** shopping food preparation *** *** *** housework laundry transportation *** *** treatments money Cognitive change: the difference between the mean MMS scores after 1 year and those obtained at inclusion revealed a significant loss of 1.93 ± 3.74 points (p<0.0001). In addition, 36.6% of patients showed a clinically significant loss of 3 points or more at the end of the year compared with their MMS score at inclusion (table 3). Similarly, scores at 1 year on the 88

4 THE JOURNAL OF NUTRITION, HEALTH & AGING Table 3 Stability, improvement and deterioration of cognitive parameters, autonomy, behavioural disturbances, nutritional status and caregiver burden in patients followed for 1 year (n = 498). Parameters Change Stable Deterioration Improvement % % % MMS ADL IADL NPI (freq x grav) Weight MNA Zarit scale (respectively 100% and 75%), about 70% of patients who had a score of 4 or 5 at inclusion remained stable or improved and lastly, 5% of patients with a GDS score of 6 at the first visit had become worse. In addition, the mean CDR-SB score at the end of the year was significantly higher than at inclusion (p<0.0001) (table 2). Figure 3 Changes in behavioural disturbances measured by the NPI in patients followed for 1 year (n = 498). * : p<0.05, ** : p<0.02, *** : p<0.01. = inclusion; = 1 year Global change: Figure 4 shows the distribution of patients in the CDR and GDS scales at inclusion and at 1 year. In accordance with the inclusion criteria, the majority of patients (77%) had CDR scores of 0.5 or 1 and 62% had scores of 2, 3 or 4 on Reisberg s GDS, indicating mild to moderate AD. At 1 year, the proportions had changed: a larger number of patients (53%) had a score of 5, 6 or 7 on Reisberg s scale and 37% had a CDR score of 2 or 3. Table 4 shows the outcome at 1 year of the patients according to their CDR or Reisberg s GDS status at inclusion. For the CDR, half of the patients who had a score of 0.5 at inclusion showed no change, over 60% of patients who had a score of 1 or 2 at the first visit remained stable or even improved, and 40% of patients with a score of 3 at inclusion had also improved at 1 year. For Reisberg s GDS, subjects with scores of 2 or 3 at inclusion declined during the year 4A % of patients Change in nutritional status: mean weight was stable after 1 Table 4 Outcome of patients followed up for 1 year according to their CDR (4A) and GDS (4B) status at inclusion. CDR score at inclusion Outcome at 1 year % (n) (n = 173) (88) (76) 4.62 (8) 0.58 (1) 1 (n = 186) 6.45 (12) (105) (63) 3.23 (6) 2 (n = 99) 1.01 (1) 8.08 (8) (64) (26) 3 (n = 5) 0 20 (1) 20 (1) 60 (3) 4B GDS score at inclusion Outcome at 1 year % (n) (n = 1) (1) (n = 55) (14) (36) 9.09 (5) (n = 236) 0.85 (2) 2.12 (5) (152) (70) 2.97 (7) 0 5 (n = 159) (9) (106) (43) 0.63 (1) 6 (n = 18) (6) (11) 5.56 (1) 89

5 RECENT DATA ON THE NATURAL HISTORY OF ALZHEIMER S DISEASE year of follow-up compared with its value at inclusion (table 2). Even if the MNA score decreased not significantly (p=0.0531), the loss was close to the threshold of significativity. About 20% of patients presented a clinically significant weight loss ( 4%) during this first year of follow-up and in 20.2% the MNA score decreased (table 3). Figure 5 Changes in living arrangements of patients followed for 1 year (n = 498). = inclusion; = 1 year Figure 4 Changes in the distribution of patients followed up for 1 year (n = 498) on the CDR (4A) and Reisberg s scales (4B). = inclusion; = 1 year Medical and social characteristics Living arrangements: At inclusion, 28% of patients lived alone at home and at 1 year this percentage was about 26%. Both at inclusion and at the end of the year of follow-up, the majority of patients lived with a caregiver at home: 69.4% and then 68%. The caregiver was generally the spouse: 60.3% at inclusion and 58.1% at 1 year, rather than another family member: 8.7% at inclusion and 9.5% at 1 year, while at each timepoint 0.4% had a formal caregiver. At 1 year, about 5% (n=25) of subjects had entered an institution but the majority still lived at home (figure 5). Hospitalisation: About 25% of patients had been admitted to hospital at least once during the year. These admissions were repeated in 26 subjects (5.7%): 15 patients (3.3%) were hospitalised twice, 10 (2.2%) 3 times and 1 (0.2%) 5 times. Treatments: At inclusion, 80.8% of patients were already receiving specific treatment for AD. Among them, 28.7% had been treated for 1 year or more, 28.9% for 3 to 12 months and 23.2% had been treated for less than 3 months. In addition, 10.5% of patients started specific AD treatment during the inclusion visit. Of the patients who completed the 1-year follow-up, 91.3% were being treated at the beginning of the study. At 1 year, 86.8% of patients were treated and had been for the entire year, while only 3.2% had never been treated and 10% had been treated for less than 12 months. The majority of patients in this cohort who were treated throughout the year were receiving AChEIs and very few were taking Ebixa. Use of support services: At inclusion as at 1 year, patients mainly used home help services and the proportion of patients receiving such assistance did not change significantly (42.7% at inclusion then 45.5%, p=0.1229), nor did use of day hospitals (2.2% then 1.9%, p=0.7389), visits to the doctor (60.5% then 57.9%, p=0.2273), surveillance during the day or at night (4% and 4%, p=0.4386) or use of a portable alarm (4.4% then 4.6%, p=0.7963). On the other hand, after 1 year of follow-up, we observed that significantly more patients used day care centers (1.7% at inclusion and 5.2% at 1 year, p=0.0010), nursing visits at home (16.1% then 24.1%, p<0.0001), physiotherapists (6.6% then 10.1%, p=0.0071), speech therapists (8.9% then 11.9%, p=0.0423) and meal delivery services (5.9% then 9.6%, p=0.0053) (figure 6). Caregiver burden: Comparing the scores obtained on the Zarit scale completed by the same caregivers at inclusion and at 12 months (table 2), no significant difference was found. The Zarit score remained stable or improved for 84.7% of caregivers (table 3) and the mean remained greater than 20, corresponding to mild or moderate burden. 90

6 THE JOURNAL OF NUTRITION, HEALTH & AGING Figure 6 Changes in use of support services by patients followed for 1 year (n = 498). = inclusion; = 1 year *** : p < , ** : p < 0.01, * p < home help day center day hospital nurse visits speech therapist Discussion As expected, our evaluations of the cognitive aspects of the disease demonstrated changes in the status of the patients. The significantly decreased MMS scores and increased ADAS-cog scores at the end of the first year of follow-up reflected alteration of cognitive functions. However, this deterioration seems relative if we compare our results with those of the literature. For the MMS, we observed a decrease of 1.94 ± 3.74 points over the year, whereas it was 3.6 ± 4.4 points in the CERAD study (21) of patients not treated for AD recruited between 1987 and 1988 and who had a slightly more advanced stage of disease at inclusion (MMS: 18.7 ± 4.5) (21). In our study, only 36.6% of patients lost 3 points or more on the MMS. ADAS-cog scores also differed from baseline results, as the mean score increased by 2.4 ± 6.1 points during the year whereas in non-treated patients it increased by approximately 5 points over the same time period (22). In parallel, the loss of certain abilities measured by the ADL and IADL scales also indicated a worsening of the disease. But in this case as well, the decline in autonomy seemed less pronounced: in our REAL.FR study, decrease in the IADL was 1.00 ± 1.46, whereas other authors found a decrease of 2.06 ± 3.27 in patients who were not treated for AD (23). Overall, the change of the CDR-SB score and the distribution of patients in the Reisberg and CDR scales also reflected deterioration of the general condition within the cohort. The NPI scores also demonstrated a worsening of behavioural disturbances, with an increasing number of patients presenting apathy, aberrant motor activity and sleep disturbances. In parallel, anxiety and physiotherapist physician surveillance meal delivery portable alarm depression were present in fewer patients at 1 year than at inclusion. This improvement was observed in 38.3% of patients. For behavioural disturbances also, there seemed to be a slowing of the progression of AD, as the mean NPI score increased by 1.85 ± points during the year, whereas other authors observed an increase of 3.9 points in 6 months in patients with mild or moderate AD receiving placebo (24). In addition, the mean number of problems presented by the patients remained stable over the year, with no onset of new problems in the cohort. Within the cohort, there was a large proportion of patients receiving treatment, mainly AChEIs as they were still at mild to moderate stages of AD. The large number of treated patients could partly explain the differences in progression observed. In fact, 86.8% of patients received specific AD treatment throughout the year of follow-up, and the impact of these treatments, which in clinical trials have been shown to slow the decline of cognitive function, was partly confirmed in our results (5,25,7,26). However, it is impossible to dissociate the effect of these medications from that of non-pharmacological management of the patient, which has progressed over recent years thanks to better knowledge of the troubles related to AD. Concerning nutritional status, after 1 year, the mean MNA score decrease was close to the threshold of significativity (p=0.0531) showing that there was a tendency of worsening with 20.2% of subjects who reported a deterioration. But the mean score even remained above 23.5 indicating that the cohort maintained as a whole a good nutritional status. The mean weight did not differ significantly from its value at inclusion even if 91.3% of patients who completed 1 year of follow-up were treated with AChEIs after the inclusion visit, which have been found capable of inducing weight loss in the course of clinical trials (5,27,28). Weight loss is also a characteristic of AD (29). In most clinical studies of AChEIs, the dose escalation phase for each treatment was short, which could explain the frequency and importance of side effects observed, weight loss in particular (5,27,28) but in other studies in which the maximum dosage was reached over a longer period there were few or no side effects (3,6). In our study, after 1 year of follow-up we did not observe any change in the mean weight of the cohort. It is probable that the prescription and initiation of AChEI treatment by the practitioners took place over a longer period than in the clinical trials. But this result may also be a consequence of the fact that at inclusion the majority of patients had already been receiving treatment. In fact, 80.8% of them were already treated and the side effects may have already been controlled when the final dosage was reached. In addition, time elapsing since treatment was started had no effect on the risk of weight loss. Patients who started treatment at the initial visit did not have a significantly greater risk of weight loss than the others, in spite of effective dosages being reached during the follow-up period. Although the status of the patients deteriorated, we have shown that caregiver burden as measured by the Zarit scale did 91

7 RECENT DATA ON THE NATURAL HISTORY OF ALZHEIMER S DISEASE not significantly vary during the first year of follow-up. It increased for only 15.3% of caregivers, which did not therefore reflect the worsening of the disease as measured by the various tests and the impact that this could have on caregivers. The burden related to the task of caregiving is experienced differently according to the progression of the patient s disease and depends subjectively on the personal emotional feelings of the caregiver (30). The impact of treatments, pharmacological or otherwise, on the progression of AD may explain the stability of the Zarit scores as the worsening of the disease had been slowed, with maintenance of function making the caregiver s task easier. Various studies have demonstrated that the main cause of increased caregiver burden is increased levels of behavioural disturbance (31,32). According to our results, the behavioural disturbances of the patients in our cohort worsened only very slightly ( ± points) and there was even an improvement in 38.3% of subjects. This could explain the stability of the Zarit scores. It is also possible that the standardized, regular patient follow-up as part of the REAL.FR study, with 6-monthly visits and evaluations, had an influence on the burden experienced by the caregiver, who felt more supported in facing the difficulties engendered by the progression of their relative s disease. At the end of the first year of follow-up, 94% of subjects were still living at home with their spouse, a family member or alone, in spite of worsening of the disorder and an increased number of entries into an institution. The high proportion of patients still living at home may be explained by the slightly greater use made of the various support services, although this concerned only a limited number of patients (about 10%, excluding nursing visits at home), and by slowing of the progression of AD and stability of caregiver burden, whose increase generally leads to institutionalization (33). Lastly, for patients who prematurely discontinued follow-up in the course of the year, we observed that they were at a more advanced stage of the disease at inclusion. In addition, there were significantly fewer premature withdrawals among the treated patients, which could reflect a protective effect of AChEIs. Our findings demonstrate a slowing of the progression of AD as compared with the data of the literature. This observation may be explained by advances in patient management and by the impact of specific AD medication, which was received by the great majority of subjects in our cohort. This change in disease progression influenced caregiver burden and made it possible to keep patients in their own home. It would thus seem that the impact of present treatment and management on the natural history of AD is important not only to maintain the general status of the patient but also for the family and relatives. These results thus justify diagnosis and appropriate management of dementias of Alzheimer type, allowing stabilization or improvement of the condition in 63.4% of patients at 1 year, while 36.6% showed clinically significant deterioration in spite of overall and pharmacological management. Grant: this work was supported by a grant from the Clinical Research Hospital Program from the French Ministry of Health (PHRC N 98-47N, PHRC N ). The REAL.FR group: Principal investigator: Prof. B. Vellas (Toulouse); Associate investigators: Prof. M. Rainfray, Dr S. Richard-Harston (Bordeaux); Prof. A. Franco, Dr P. Couturier (Grenoble); Prof. F. Pasquier, Dr M. Mackowiak, V. Sorel (Lille); Dr B. Frigard, Dr H. Idiri, DR Dr K. Gallouj (Lille); Dr B. Michel, L. Margulies (Marseille); Prof. Cl. Jeandel (Montpellier); Prof. J. Touchon, Dr F. Portet, Dr S. Lerouge (Montpellier); PrProf. Ph. Robert, Dr P. Brocker, C. Bertogliati (Nice); Prof. B. Forette, Dr L. Teillet, Dr L. Lechowski (Paris); Prof. J. Belmin, Dr. S. Pariel-Madjelssi (Paris); Prof. M. Verny, Dr MA. Artaz (Paris); Prof. F. Forette, Dr AS. Rigaud, Dr F. Latour (Paris); Prof. P. Jouanny, Dr S. Belliard, Dr O. Michel (Rennes); Dr C. Girtanner, Dr Thomas-Anterion (Saint Etienne); Study coordinators: F. Cortes, Dr S. Gillette-Guyonnet, Prof. F. Nourhashemi, Dr P.J. Ousset (Toulouse); Epidemiologist: Dr S. Andrieu; Data processing: C. Cantet (Toulouse) References 1. Mohs RC, Schmeidler J, Aryan M. Longitudinal studies of cognitive, functional and behavioural change in patients with Alzheimer s disease. Stat Med 2000;19: Cummings JL, Kaufer D. Neuropsychiatric aspects of Alzheimer s disease: the cholinergic hypothesis revisited. Neurology 1996;47: Mohs RC, Doody RS, Morris JC, Ieni JR, Rogers SL, Perdomo CA, et al.; "312" Study Group. A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients. Neurology 2001;57: Rogers SL, Doody RS, Pratt RD, Ieni JR. Long-term efficacy and safety of donepezil in the treatment of Alzheimer s disease: final analysis of a US multicenter open-label study. Eur Neuropsychopharmacol 2000;10: Rösler M, Anand R, Cicin-Sain A, Gauthier S, Agid Y, Dal-Bianco P, et al., on behalf of the B303 Exelon Study Group. Efficacy and safety of rivastigmine in patients with Alzheimer s disease: international randomised controlled trial. BMJ 1999;318: Tariot PN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S, Ding C. A 5-month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA- 10 Study Group. Neurology 2000;54: Wilcock GK, Lilienfeld S, Gaens E, on behalf of the Galantamine International-1 Study Group. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: multicenter randomised controlled trial. BMJ 2000;321: Winblad B, Poritis N. Memantine in severe dementia: results of the 9M-Best Study (Benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry 1999;14: McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer s disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984;34: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington DC: APA, Gillette-Guyonnet S, Nourhashemi F, Andrieu S, Cantet C, Micas M, Ousset PJ, et al.; REAL.FR group. The REAL.FR research program on Alzheimer s disease and its management: methods and preliminary results. J Nutr Health Aging 2003;7: Folstein MF, Folstein SE, McHugh PR. Mini-Mental State: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12: Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer s disease. Am J Psychiatry 1984;141: Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW. The index of ADL: A standardized measure of biological and psychosocial function. JAMA 1963;185: Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental activities of daily living. Gerontologist 1969;9:

8 THE JOURNAL OF NUTRITION, HEALTH & AGING 16. Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994;44: Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the staging of dementia. Br J Psychiatry 1982;140: Reisberg B, Ferris SH, de Leon MJ, Crook T. The Global Deterioration Scale for assessment of primary degenerative dementia. Am J Psychiatry 1982;139: Vellas B, Guigoz Y, Garry PJ, Nourhashemi F, Bennahum D, Lauque S, et al. The Mini Nutritional Assessment (MNA) and its use in grading the nutritional state of elderly patients. Nutrition 1999;2: Zarit SH, Reever K, Bach-Peterson J. Relatives of the impaired elderly: Correlates of feelings of burden. Gerontologist 1980;20: Morris JC, Edland S, Clark C, Galasko D, Koss E, Mohs R, et al. The Consortium to Establish a Registry for Alzheimer s Disease (CERAD). Part IV. Rates of cognitive change in the longitudinal assessment of probable Alzheimer s disease. Neurology 1993;43: Stern RG, Mohs RC, Davidson M, Schmeidler J, Silverman J, Kramer-Ginsberg E, et al. A longitudinal study of Alzheimer s disease: measurement, rate and predictors of cognitive deterioration. Am J Psychiatry 1994;151: Green CR, Mohs RC, Schmeidler J, Aryan M, Davis KL. Functional decline in Alzheimer s disease: a longitudinal study. J Am Geriatr Soc 1993;41: Morris JC, Cyrus PA, Orazem J, Mas J, Bieber F, Ruzicka BB, et al. Metrifonate benefits cognitive, behavioral and global function in patients with Alzheimer s disease. Neurology 1998;50: Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff L; Donepezil Study Group. A 24 week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer s disease. Neurology 1998;50: Winblad B, Engedal K, Soininen H, Verhey F, Waldemar G, Wimo A, Wetterholm A-L, Zhang R, Haglund A, Subbiah P and the Donepezil Nordic Study Group. A 1- year, randomised, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology 2001;57: Raskind MA, Peskind ER, Wessel T, Yuan W. Galantamine in AD: A 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology 2000;54: Tariot PN, Cummings JL, Katz IR, Mintzer J, Perdomo CA, Schwam EM, et al. A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer s disease in the nursing home setting. J Am Geriatr Soc 2001;49: White H, Pieper C, Schmader K, Fillenbaum G. Weight change in Alzheimer s disease. J Am Geriatr Soc 1996;44: Tsuji I, Whalen S, Finucane TE. Predictors of nursing home placement in community-based long-term care. J Am Geriatr Soc 1995;4: Coen RF, Swanwick GR, O Boyle CA, Coakley C. Behaviour disturbance and other predictors of carer burden in Alzheimer s disease. Int J Geriatr Psychiatry 1997;12: Donaldson C, Tarrier N, Burns A. Determinants of carer stress in Alzheimer's disease. Int J Geriatr Psychiatry 1998;13: Cohen CA, Gold DP, Shulman KI, Wortley JT, McDonald G, Wargon M. Factors determining the decision to institutionalize dementing individuals: a prospective study. Gerontologist 1993;33: