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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 31300 Toulouse (France) (F Cortes, S Gillette-Guyonnet, F Nourhashemi, C Cantet, B Vellas) and Unité Inserm 558, 37 allée Jules Guesdes, 31000 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:, E-Mail : [email protected] 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<0.0001 and ADAS-cog : +2.40±3.74,
p<0.0001), an overall loss of autonomy (ADL :-0.56±1.05, p<0.0001 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.
degradation, leading to improvement of the patients' condition(8). In the course of AD, we should not overlook the progress At the present time, Alzheimer's (AD) disease is the subject achieved in patient management through better knowledge of of numerous studies, but paradoxically concerning its natural the disease and through the development of home help services. history little information is available which takes into account The REAL.FR study (Réseau sur la Maladie d'Alzheimer the advent of new treatments and improved management.
Français)has been set up with the aim of studying the natural Alzheimer's disease is known to be a progressive disease history of AD by taking all these factors into account. This characterised by gradual cognitive decline and loss of project is a unique observatory, assessing through longitudinal autonomy, leading to total dependence of the patient and the follow-up in 16 Alzheimer centers in France the long-term onset of behavioural disturbances (1) which sometimes have impact and tolerance of treatments, modalities of use of major effects on the life of the patient and of the caregiver.
services and of management of the sick elderly person, as well These problems are the result of a neurodegenerative process as predictors of admission to hospital or to an institution. This which particularly affects the cholinergic system (2). Because paper aims to present the changes observed in the cohort after 1 of the increasing importance of AD, efficient management of year by analysing all these parameters and their influence on patients must be initiated and so our present knowledge of the the course of AD. natural history of the disease must be improved. In particular, itis necessary to take account of the influence of the treatments Material and methods
which have recently become available, with first of all the threedrugs indicated for mild to moderate forms of the disease: The REAL.FR study is a prospective multicenter study donepezil (Aricept), rivastigmine (Exelon) and galantamine which has recruited throughout France, between 2000 and (Reminyl). These have proved their efficacy and tolerability in 2002, 693 patients presenting AD according to the NINCDS- clinical trials, where they were found to slow the progression of ADRDA and DSM-IV criteria (9,10). The methodology of the the disease by inhibiting acetylcholine degradation (3,4,5,6,7).
study has been described in detail elsewhere (11). Briefly, for More recently, a new drug for the more severe forms of the inclusion in the study, the patients had to present a mild to disease has been developed: memantine (Ebixa) which acts as a moderate form of the disease (score between 12 and 26 on the non-specific NMDA receptor antagonist, maintaining Mini-Mental State) (12), be ambulatory, living in their own glutamatergic transmission and thus reducing neuronal homes and cared for by a clearly identified caregiver. At The Journal of Nutrition, Health & AgingVolume 9, Number 2, 2005 THE JOURNAL OF NUTRITION, HEALTH & AGING inclusion, the patients underwent a full medical examination weight in 12 months, improvement is an increase of 4 % or (CT scan, thyroid tests). We excluded from the study patients more of baseline weight and stable is a weight at 1 year with severe AD, those who were institutionalized and those equivalent to baseline weight ± 4 %. For the MNA: with a concomitant disorder which could affect the short-term deterioration is a change to poorer nutritional status (3 categories: normal nutritional status (score >23.5), at risk of Data are collected prospectively every 6 months for 4 years malnutrition (score 17-23.5) or malnutrition (score <17)), during a visit in 1 of the 16 centers participating in the study. A improvement is a change to better nutritional status and stable standardized case report form is filled in for each patient by a means no change from initial category. For the Zarit scale : specially trained, multidisciplinary medical team. The data deterioration is an increase in burden (4 categories: no or slight collected include: burden (score 0-20), mild to moderate burden (score 20-40), 1/ cognitive evaluation with administration of the MMS (12) moderate to severe burden (score 40-60) or severe burden and the cognitive subscale of the Alzheimer's Disease (score > 60)), improvement is a change of category (lighter) Assessment Scale (ADAS-cog) (13), towards lesser burden and stable is no change from initial 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 Overview of follow-up
Neuropsychiatric Inventory (NPI) (16). During the first year of follow-up, 25 subjects died, 30 4/ overall evaluation using the Clinical Dementia Rating entered an institution and 91 prematurely discontinued follow- (CDR) (17) and Reisberg's Global Dementia Scale (GDS) (18).
up for various reasons (see figure 1).
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) Changes in the cohort after 1 year of follow-up. * : patient's or (19). Lastly, caregiver burden is measured with the Zarit caregiver's medical problem, removal… Burden Interview (20). During follow-up, all events occurring between two visits, in Patients recruited - Deceased n = 25 particular admissions to hospital or to institutions, use of new - Institutionalized (follow-up impossible) support or home assistance services, changes among the - Lost to follow-up n = 38 patient's family and friends, are carefully recorded together - Withdrawal of consent n = 34 with deaths, entry to an institution where follow-up is not possible, and other reasons for premature discontinuation suchas withdrawal of consent, medical problems of patient or Discontinous follow-up n = 49 caregiver, or loss to follow-up. Patients who completed the 1st year of follow-up n = 498 Statistical analysis of the data was carried out with SAS 8.0 software. Bivariate analysis was used to describe the changes atone year in cognitive and non-cognitive parameters in the Overall, of the 693 patients initially recruited, 498 were patients of the cohort. Wilcoxon's non-parametric test was used evaluated at 1 year and 49 missed the visit. Table 1 compares for quantitative variables and the McNemar test for qualitative the characteristics at inclusion of patients who prematurely discontinued follow-up (excluding the 25 patients who died) For the MMS : deterioration is a loss of 3 points or more in and of those who were still in the study at 1 year (n = 547).
12 months; improvement is an increase of 3 points or more in Subjects who discontinued follow-up during the first year had a 12 months and stable concern patients whose score at 1 year significantly lower mean MMS score than the patients who and score at inclusion differed by between –3 and 3, exclusive.
completed the year (p=0.0064). Their ability to carry out the For the ADL: deterioration is a loss of 0.5 points or more in 12 activities of daily living was also less (ADL, p=0.0001, IADL months and improvement is a gain of 0.5 points or more in 12 p<0.0001). Overall, these subjects were at a more advanced months. For the IADL: deterioration is a loss of 1 point or more stage of the disease, as shown by the mean CDR-SB score in 12 months and improvement is gain of 1 point or more in 12 which was significantly higher in subjects who left the study months. For the NPI: deterioration is an increase of 1 point or than in those who continued (p=0.0002). These patients were more in total score in 12 months and improvement is a decrease also significantly older (p=0.0017). Lastly, absence of specific of 1 point or more in total score in 12 months. For the measure AD treatment at inclusion significantly increased the risk of of weight: deterioration is a loss of 4 % or more of baseline premature discontinuation during the first year of the study The Journal of Nutrition, Health & AgingVolume 9, Number 2, 2005 RECENT DATA ON THE NATURAL HISTORY OF ALZHEIMER'S DISEASE (OR=0.37, p=0.0002 and 95% CI = 0.22-0.64). ADAS-cog were significantly higher than those obtained atinclusion, with an increase of 2.40 ± 6.10 points (p<0.0001) Comparison of characteristics at inclusion between patients Change in ability to carry out the activities of daily living: followed for 1 year and patients who prematurely discontinued mean scores on the ADL and IADL measured at the end of 1 follow-up (excluding those deceased, n = 25).
year were significantly lower (p<0.0001) than at inclusion,reflecting greater difficulty in carrying out the basic and Parameters at
Discontinuation of follow-up
p student
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 mean ± SD
mean ± SD
basic activities of daily living (figure 2 A). For the morecomplex 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 Age at onset (yr) Age at diagnosis (yr) Changes in autonomy in patients followed for 1 year (n = 498) Age of patient (yr) for each of the items evaluated by the scales for ADL (2A) and IADL (2B). ■ = inclusion; ❑ = 1 year 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 *** : p<0.0001 parameters during the first year of follow-up. Change in behavioural disturbances: the mean NPI score after 1 year was significantly higher than at inclusion, with an Changes in cognitive parameters, autonomy, behavioural increase of 1.85 ± 14.83 (p=0.0047). Behavioural disturbances disturbances, nutritional status and caregiver burden in patients thus significantly worsened in the cohort as a whole, but we did followed for 1 year (n = 498).
not observe a significant increase in the mean number ofproblems (table 2). The various problems assessed by the NPI Mean score at
Mean score
p Wilcoxon
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 NPI (freq x grav) 14.45 ± 14.52 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).
Cognitive change: the difference between the mean MMS scores after 1 year and those obtained at inclusion revealed asignificant loss of 1.93 ± 3.74 points (p<0.0001). In addition,36.6% of patients showed a clinically significant loss of 3points or more at the end of the year compared with their MMSscore at inclusion (table 3). Similarly, scores at 1 year on the The Journal of Nutrition, Health & AgingVolume 9, Number 2, 2005 THE JOURNAL OF NUTRITION, HEALTH & AGING (respectively 100% and 75%), about 70% of patients who had a Stability, improvement and deterioration of cognitive score of 4 or 5 at inclusion remained stable or improved and parameters, autonomy, behavioural disturbances, nutritional lastly, 5% of patients with a GDS score of 6 at the first visit had status and caregiver burden in patients followed for 1 year 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).
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 NPI (freq x grav) Global change: Figure 4 shows the distribution of patients in the CDR and GDS scales at inclusion and at 1 year. Inaccordance with the inclusion criteria, the majority of patients(77%) had CDR scores of 0.5 or 1 and 62% had scores of 2, 3or 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% hada CDR score of 2 or 3. Table 4 shows the outcome at 1 year ofthe patients according to their CDR or Reisberg's GDS status atinclusion. For the CDR, half of the patients who had a score of0.5 at inclusion showed no change, over 60% of patients whohad a score of 1 or 2 at the first visit remained stable or evenimproved, and 40% of patients with a score of 3 at inclusionhad also improved at 1 year. For Reisberg's GDS, subjects withscores of 2 or 3 at inclusion declined during the year Change in nutritional status: mean weight was stable after 1 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)
GDS score at inclusion
Outcome at 1 year % (n)
The Journal of Nutrition, Health & AgingVolume 9, Number 2, 2005 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), Changes in living arrangements of patients followed for 1 year the loss was close to the threshold of significativity. About 20% (n = 498). ■ = inclusion; ❑ = 1 year of patients presented a clinically significant weight loss (≥ 4%)during this first year of follow-up and in 20.2% the MNA scoredecreased (table 3).
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 Treatments: At inclusion, 80.8% of patients were already receiving specific treatment for AD. Among them, 28.7% hadbeen treated for 1 year or more, 28.9% for 3 to 12 months and23.2% had been treated for less than 3 months. In addition,10.5% of patients started specific AD treatment during theinclusion visit. Of the patients who completed the 1-yearfollow-up, 91.3% were being treated at the beginning of thestudy. At 1 year, 86.8% of patients were treated and had beenfor the entire year, while only 3.2% had never been treated and10% had been treated for less than 12 months. The majority ofpatients in this cohort who were treated throughout the yearwere 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 patientsreceiving such assistance did not change significantly (42.7% atinclusion 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 Medical and social characteristics
57.9%, p=0.2273), surveillance during the day or at night (4% Living arrangements: At inclusion, 28% of patients lived and 4%, p=0.4386) or use of a portable alarm (4.4% then 4.6%, alone at home and at 1 year this percentage was about 26%.
p=0.7963). On the other hand, after 1 year of follow-up, we Both at inclusion and at the end of the year of follow-up, the observed that significantly more patients used day care centers majority of patients lived with a caregiver at home: 69.4% and (1.7% at inclusion and 5.2% at 1 year, p=0.0010), nursing visits then 68%. The caregiver was generally the spouse: 60.3% at at home (16.1% then 24.1%, p<0.0001), physiotherapists (6.6% inclusion and 58.1% at 1 year, rather than another family then 10.1%, p=0.0071), speech therapists (8.9% then 11.9%, member: 8.7% at inclusion and 9.5% at 1 year, while at each p=0.0423) and meal delivery services (5.9% then 9.6%, timepoint 0.4% had a formal caregiver. At 1 year, about 5% p=0.0053) (figure 6). (n=25) of subjects had entered an institution but the majority Caregiver burden: Comparing the scores obtained on the still lived at home (figure 5). Zarit scale completed by the same caregivers at inclusion and at Hospitalisation: About 25% of patients had been admitted to 12 months (table 2), no significant difference was found. The hospital at least once during the year. These admissions were Zarit score remained stable or improved for 84.7% of repeated in 26 subjects (5.7%): 15 patients (3.3%) were caregivers (table 3) and the mean remained greater than 20, hospitalised twice, 10 (2.2%) 3 times and 1 (0.2%) 5 times.
corresponding to mild or moderate burden. The Journal of Nutrition, Health & AgingVolume 9, Number 2, 2005 THE JOURNAL OF NUTRITION, HEALTH & AGING depression were present in fewer patients at 1 year than at Changes in use of support services by patients followed for 1 inclusion. This improvement was observed in 38.3% of year (n = 498). ■ = inclusion; ❑ = 1 year *** : p < 0.0001, patients. For behavioural disturbances also, there seemed to be ** : p < 0.01, * p < 0.05.
a slowing of the progression of AD, as the mean NPI scoreincreased by 1.85 ± 14.83 points during the year, whereas otherauthors observed an increase of 3.9 points in 6 months inpatients with mild or moderate AD receiving placebo (24). Inaddition, the mean number of problems presented by thepatients remained stable over the year, with no onset of newproblems in the cohort. Within the cohort, there was a large proportion of patients receiving treatment, mainly AChEIs as they were still at mild tomoderate stages of AD. The large number of treated patientscould partly explain the differences in progression observed. Infact, 86.8% of patients received specific AD treatmentthroughout the year of follow-up, and the impact of thesetreatments, which in clinical trials have been shown to slow thedecline of cognitive function, was partly confirmed in ourresults (5,25,7,26). However, it is impossible to dissociate theeffect 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 Discussion
(p=0.0531) showing that there was a tendency of worseningwith 20.2% of subjects who reported a deterioration. But the As expected, our evaluations of the cognitive aspects of the mean score even remained above 23.5 indicating that the cohort disease demonstrated changes in the status of the patients. The maintained as a whole a good nutritional status. The mean significantly decreased MMS scores and increased ADAS-cog weight did not differ significantly from its value at inclusion scores at the end of the first year of follow-up reflected even if 91.3% of patients who completed 1 year of follow-up alteration of cognitive functions. However, this deterioration were treated with AChEIs after the inclusion visit, which have seems relative if we compare our results with those of the been found capable of inducing weight loss in the course of literature. For the MMS, we observed a decrease of 1.94 ± 3.74 clinical trials (5,27,28). Weight loss is also a characteristic of points over the year, whereas it was 3.6 ± 4.4 points in the AD (29). In most clinical studies of AChEIs, the dose CERAD study (21) of patients not treated for AD recruited escalation phase for each treatment was short, which could between 1987 and 1988 and who had a slightly more advanced explain the frequency and importance of side effects observed, stage of disease at inclusion (MMS: 18.7 ± 4.5) (21). In our weight loss in particular (5,27,28) but in other studies in which study, only 36.6% of patients lost 3 points or more on the the maximum dosage was reached over a longer period there MMS. ADAS-cog scores also differed from baseline results, as were few or no side effects (3,6). In our study, after 1 year of the mean score increased by 2.4 ± 6.1 points during the year follow-up we did not observe any change in the mean weight of whereas in non-treated patients it increased by approximately 5 the cohort. It is probable that the prescription and initiation of points over the same time period (22). In parallel, the loss of AChEI treatment by the practitioners took place over a longer certain abilities measured by the ADL and IADL scales also period than in the clinical trials. But this result may also be a indicated a worsening of the disease. But in this case as well, consequence of the fact that at inclusion the majority of patients the decline in autonomy seemed less pronounced: in our had already been receiving treatment. In fact, 80.8% of them REAL.FR study, decrease in the IADL was – 1.00 ± 1.46, were already treated and the side effects may have already been whereas other authors found a decrease of – 2.06 ± 3.27 in controlled when the final dosage was reached. In addition, time patients who were not treated for AD (23). Overall, the change elapsing since treatment was started had no effect on the risk of of the CDR-SB score and the distribution of patients in the weight loss. Patients who started treatment at the initial visit did Reisberg and CDR scales also reflected deterioration of the not have a significantly greater risk of weight loss than the general condition within the cohort. The NPI scores also others, in spite of effective dosages being reached during the demonstrated a worsening of behavioural disturbances, with an follow-up period. increasing number of patients presenting apathy, aberrant motor Although the status of the patients deteriorated, we have activity and sleep disturbances. In parallel, anxiety and shown that caregiver burden as measured by the Zarit scale did The Journal of Nutrition, Health & AgingVolume 9, Number 2, 2005 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 thereforereflect the worsening of the disease as measured by the various 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° 0101001).
tests and the impact that this could have on caregivers. Theburden related to the task of caregiving is experienceddifferently according to the progression of the patient's disease The REAL.FR group: Principal investigator: Prof. B. Vellas
and depends subjectively on the personal emotional feelings of (Toulouse); Associate investigators: Prof. M. Rainfray, the caregiver (30). The impact of treatments, pharmacological Dr S. Richard-Harston (Bordeaux); Prof. A. Franco, Dr P. Couturier or otherwise, on the progression of AD may explain the (Grenoble); Prof. F. Pasquier, Dr M. Mackowiak, V. Sorel (Lille); stability of the Zarit scores as the worsening of the disease had Dr B. Frigard, Dr H. Idiri, DR Dr K. Gallouj (Lille); Dr B. Michel,L. Margulies (Marseille); Prof. Cl. Jeandel (Montpellier); been slowed, with maintenance of function making the Prof. J. Touchon, Dr F. Portet, Dr S. Lerouge (Montpellier); caregiver's task easier. Various studies have demonstrated that PrProf. Ph. Robert, Dr P. Brocker, C. Bertogliati (Nice); the main cause of increased caregiver burden is increased levels Prof. B. Forette, Dr L. Teillet, Dr L. Lechowski (Paris); of behavioural disturbance (31,32). According to our results, Prof. J. Belmin, Dr. S. Pariel-Madjelssi (Paris); Prof. M. Verny, the behavioural disturbances of the patients in our cohort Dr MA. Artaz (Paris); Prof. F. Forette, Dr AS. Rigaud, Dr F. Latour worsened only very slightly (+ 1.85 ± 14.83 points) and there (Paris); Prof. P. Jouanny, Dr S. Belliard, Dr O. Michel (Rennes); was even an improvement in 38.3% of subjects. This could Dr C. Girtanner, Dr Thomas-Anterion (Saint Etienne); Study explain the stability of the Zarit scores. It is also possible that coordinators: F. Cortes, Dr S. Gillette-Guyonnet, the standardized, regular patient follow-up as part of the Prof. F. Nourhashemi, Dr P.J. Ousset (Toulouse); Epidemiologist:Dr S. Andrieu; Data processing: C. Cantet (Toulouse) REAL.FR study, with 6-monthly visits and evaluations, had aninfluence on the burden experienced by the caregiver, who feltmore 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 Mohs RC, Schmeidler J, Aryan M. Longitudinal studies of cognitive, functional and were still living at home with their spouse, a family member or behavioural change in patients with Alzheimer's disease. Stat Med 2000;19:1401- alone, in spite of worsening of the disorder and an increased Cummings JL, Kaufer D. Neuropsychiatric aspects of Alzheimer's disease: the number of entries into an institution. The high proportion of cholinergic hypothesis revisited. Neurology 1996;47:876-883. patients still living at home may be explained by the slightly 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 greater use made of the various support services, although this donepezil in AD patients. Neurology 2001;57:481-488.
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Sven enterlein

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Preventing and treating seasickness

It Can Happen to Anyone… • Anyone can get seasick. It won't kill you, but for a while you may wish it would. • If you've had motion sickness before, plan ahead and take an OTC drug before embarking. Or get a prescription for The English words "nautical" and "nausea" derive brain incorrectly interprets the distress caused by scopolamine or another powerful antiemetic (antinausea) drug.