Alzheimer Disease: Dubois B

Gillette Guyonnet S, Abellan Van Kan G, Andrieu S, Aquino JP, Arbus C, Becq JP, Berr C, Bismuth S, Chamontin B, Dantoine T, Dartigues JF, Dubois B, Fraysse B, Hergueta T, Hanaire H, Jeandel C, Lagleyre S, Lala F, Nourhashemi F, Ousset PJ, Portet F, Ritz P, Robert P, Rolland Y, Sanz C, Soto M, Touchon J, Vellas B. · Gerontopole, Pole Geriatrie Gerontologie, Hopital La Grave-Casselardit, Toulouse. · J Nutr Health Aging. · Pubmed #18810298 No free full text.

Abstract: Alzheimer's disease (AD) is the most frequent form of dementia and according to the most recent estimation it affects nearly 27 million people in the world. The onset of the disease is generally insidious. It is becoming increasingly evident that the underlying pathophysiological mechanisms are active long before the appearance of the clinical symptoms of the disease. In the current context, it is important to develop strategies to delay the onset of cognitive decline. Delaying the onset by 5 years would reduce the prevalence by half at term, and a delay of 10 years would reduce it by three-quarters. The effectiveness of currently suggested preventive approaches remains to be confirmed, but certain strategies could be applied straight away to at-risk subjects. We propose that a health-promoting memory consultation should be set up for elderly persons who have attended a specialized memory consultation and in whom the diagnosis of dementia and of AD in particular, has not been established by standardized tools. Through this consultation, they would be offered full multidimensional investigation of all aspects of their health status, follow-up could be organized, general practitioners in private practice could be made more conscious of this population and the elderly could be made more aware of the risk factors to which they are exposed. The development of an information policy for the elderly would meet a present need. In our reflection, we must take into account the question of how to give this preventive consultation its due place in the healthcare pathway of the elderly person in order to ensure coordinated follow-up with all the other health professionals involved. The principle of the health-promoting memory consultation is undergoing validation in a large French multicentre preventive trial in 1200 frail elderly persons aged 70 years followed for three years, the Multidomain Alzheimer Preventive Trial (MAPT).

Robert PH, Berr C, Volteau M, Bertogliati-Fileau C, Benoit M, Guerin O, Sarazin M, Legrain S, Dubois B, Anonymous00075. · Centre Mémoire de Ressources et de Recherche, CHU de Nice, INSERM JE 2441, Nice, France. · Am J Geriatr Psychiatry. · Pubmed #18757769 No free full text.

Abstract: OBJECTIVE: Apathy is one of the most common behavioral symptoms in mild cognitive impairment (MCI). The aim of the authors' study was to examine the influence of the apathy dimensions, i.e., emotional blunting, lack of initiative, and lack of interest, on the risk of developing of Alzheimer disease (AD) in patients with MCI. DESIGN: Longitudinal study. SETTING: Fourteen French memory clinics. PARTICIPANTS: Apathy was assessed in 214 MCI patients. The main endpoint considered was the development of AD during the 3-year follow-up. MEASUREMENTS: The neuropsychiatric evaluation included the Goldberg anxiety scale and the Montgomery and Asberg Depression Rating Scale; apathy was assessed with the Apathy Inventory. RESULTS: After 3 years, 59 patients (27.2%) had developed AD. The risk of conversion to AD was significantly higher for patients with lack of interest. Using Cox analyses, controlling for age, gender and education, the difference between survival curves was significant for lack of interest. CONCLUSIONS: Lack of interest, a mild behavioral sign, could be an indicator of potential decline in MCI patients and underlines the importance of checking the cognitive status of these patients.

Colliot O, Chételat G, Chupin M, Desgranges B, Magnin B, Benali H, Dubois B, Garnero L, Eustache F, Lehéricy S. · Cognitive Neuroscience and Brain Imaging Laboratory, Centre National de la Recherche Scientifique, UPR640-LENA, Université Pierre et Marie Curie-Paris 6, Hôpital de la Pitié-Salpêtrière, Paris, France. · Radiology. · Pubmed #18458242 links to  free full text

Abstract: PURPOSE: To prospectively evaluate the accuracy of automated hippocampal volumetry to help distinguish between patients with Alzheimer disease (AD), patients with mild cognitive impairment (MCI), and elderly controls, by using established criteria for patients with AD and MCI as the reference standard. MATERIALS AND METHODS: The regional ethics committee approved the study and written informed consent was obtained from all participants. The study included 25 patients with AD (11 men, 14 women; mean age +/- standard deviation [SD], 73 years +/- 6; Mini-Mental State Examination (MMSE) score, 24.4 +/- 2.7), 24 patients with amnestic MCI (10 men, 14 women; mean age +/- SD, 74 years +/- 8; MMSE score, 27.2 +/- 1.4) and 25 elderly healthy controls (13 men, 12 women; mean age +/- SD, 64 years +/- 8). For each participant, the hippocampi were automatically segmented on three-dimensional T1-weighted magnetic resonance (MR) images with high spatial resolution. Segmentation was performed by using recently developed software that allows fast segmentation with minimal user input. Group differences in hippocampal volume were assessed by using Student t tests. To obtain robust estimates of P values, the correct classification rate, sensitivity, and specificity, bootstrap methods were used. RESULTS: Significant hippocampal volume reductions were detected in all groups of patients (-32% in AD patients vs controls, P < .001; -19% in MCI patients vs controls, P < .001; and -15% in AD patients vs MCI patients, P < .01). Individual classification on the basis of hippocampal volume resulted in 84% correct classification (sensitivity, 84%; specificity, 84%) between AD patients and controls and 73% correct classification (sensitivity, 75%; specificity, 70%) between MCI patients and controls. CONCLUSION: This automated method can serve as an alternative to manual tracing and may thus prove useful in assisting with the diagnosis of AD.

Kinkingnéhun S, Sarazin M, Lehéricy S, Guichart-Gomez E, Hergueta T, Dubois B. · INSERM U610, Paris, France. · Neurology. · Pubmed #18448872 No free full text.

Abstract: OBJECTIVE: To determine whether regional atrophy or neuropsychological factors can predict the rate of decline in patients with mild Alzheimer disease (AD). BACKGROUND: Despite important implications for planning the care and treatment strategy, few prognostic factors of severe AD progression are known. METHODS: Twenty-three patients with mild AD were followed up every 6 months over the course of 3 years. At baseline, patients with AD and 18 controls underwent a neuropsychological battery and a brain MRI. At the end of the 3 years, patients with AD were dichotomized into slow decliners (SLD) or fast decliners (FD) groups on the basis of their decline in Mini-Mental State Examination score over time. We compared baseline cognitive performance and imaging data using voxel-based morphometry (VBM). RESULTS: SLD and FD groups did not differ in age, gender, level of education, mean estimated duration of illness, and standard neuropsychological data at inclusion, except for the Attentional Battery of the Cambridge Neuropsychological Tests Automated Battery (speed processing in shifting condition). VBM comparison between SLD and FD groups demonstrated more gray matter tissue loss in the FD group in the medial occipitoparietal areas, especially in the precuneus, the lingual gyrus, the cuneus, and the surrounding cortex of the parieto-occipital sulcus bilaterally. CONCLUSION: Voxel-based morphometry analysis demonstrated that patients who will have a faster decline at 3 years already had a more extensive cortical atrophy than SLD patients, especially in the medial occipitoparietal areas, which was not yet detected by clinical and neuropsychological assessment.

De Anna F, Attali E, Freynet L, Foubert L, Laurent A, Dubois B, Dalla Barba G. · INSERM Unit 610, Paris, France. · Cortex. · Pubmed #18387559 No free full text.

Abstract: Patients with Alzheimer's disease (AD) suffer from distortions of memory. Among such distortions, intrusions in memory tests are frequently observed. In this study we describe the performance of a group of mild AD patients and a group of normal controls on the recall of three different types of stories: a previously unknown story, a well-known fairy-tale (Cinderella), and a modified well-known fairy-tale (Little Red Riding Hood is not eaten by the wolf). The aim of our study was to test the hypothesis that in patients who tend to produce intrusions, over-learned information interferes with episodic recall, i.e., the retrieval of specific, unique past episodes. AD patients produced significantly more intrusions in the recall of the modified fairy-tale compared to the recall of the two other stories. Intrusions in the recall of the modified fairy-tale always consisted of elements of the original version of the story. We suggest that in AD patients intrusions may be traced back to the interference of strongly represented, over-learned information in episodic memory recall.

Scarmeas N, Brandt J, Blacker D, Albert M, Hadjigeorgiou G, Dubois B, Devanand D, Honig L, Stern Y. · Gertrude H Sergievsky Center, Columbia University Medical Center, New York, NY 10032, USA. · Arch Neurol. · Pubmed #18071039 links to  free full text

Abstract: BACKGROUND: Disruptive behavior is common in Alzheimer disease (AD). There are conflicting reports regarding its ability to predict cognitive decline, functional decline, institutionalization, and mortality. OBJECTIVE: To examine whether the presence of disruptive behavior has predictive value for important outcomes in AD. DESIGN: Using the Columbia University Scale for Psychopathology in Alzheimer Disease (administered every 6 months, for a total of 3438 visit-assessments and an average of 6.9 per patient), the presence of disruptive behavior (wandering, verbal outbursts, physical threats/violence, agitation/restlessness, and sundowning) was extracted and examined as a time-dependent predictor in Cox models. The models controlled for the recruitment cohort, recruitment center, informant status, sex, age, education, a comorbidity index, baseline cognitive and functional performance, and neuroleptic use. SETTING: Five university-based AD centers in the United States and Europe (Predictors Study). PARTICIPANTS: Four hundred ninety-seven patients with early-stage AD (mean Folstein Mini-Mental State Examination score, 20 of 30 at entry) who were recruited and who underwent semiannual follow-up for as long as 14 (mean, 4.4) years. MAIN OUTCOME MEASURES: Cognitive (Columbia Mini-Mental State Examination score, < or = 20 of 57 [approximate Folstein Mini-Mental State Examination score, < or = 10 of 30]) and functional (Blessed Dementia Rating Scale score, parts I and II, > or = 10) ratings, institutionalization equivalent index, and death. RESULTS: At least 1 disruptive behavioral symptom was noted in 48% of patients at baseline and in 83% at any evaluation. Their presence was associated with increased risks of cognitive decline (hazard ratio 1.45 [95% confidence interval (CI), 1.03-2.03]), functional decline (1.66 [95% CI, 1.17-2.36]), and institutionalization (1.47 [95% CI, 1.10-1.97]). Sundowning was associated with faster cognitive decline, wandering with faster functional decline and institutionalization, and agitation/restlessness with faster cognitive and functional decline. There was no association between disruptive behavior and mortality (hazard ratio, 0.94 [95% CI, 0.71-1.25]). CONCLUSION: Disruptive behavior is very common in AD and predicts cognitive decline, functional decline, and institutionalization but not mortality.

Sarazin M, Berr C, De Rotrou J, Fabrigoule C, Pasquier F, Legrain S, Michel B, Puel M, Volteau M, Touchon J, Verny M, Dubois B. · INSERM U 610 and Centre des Maladies Cognitives et Comportementales, Hôpital de la Salpêtrière, Paris, France. · Neurology. · Pubmed #17984454 No free full text.

Abstract: OBJECTIVE: To compare the power of tests assessing different cognitive domains for the identification of prodromal Alzheimer disease (AD) among patients with mild cognitive impairment (MCI). BACKGROUND: Given the early involvement of the medial temporal lobe, a precocious and specific pattern of memory disorders might be expected for the identification of prodromal AD. METHODS: A total of 251 patients with MCI were tested at baseline by a standardized neuropsychological battery, which included the Free and Cued Selective Recall Reminding Test (FCSRT) for verbal episodic memory; the Benton Visual Retention Test for visual memory; the Deno 100 and verbal fluency for language; a serial digit learning test and the double task of Baddeley for working memory; Wechsler Adult Intelligence Scale (WAIS) similarities for conceptual elaboration; and the Stroop test, the Trail Making test, and the WAIS digit symbol test for executive functions. The patients were followed at 6-month intervals for up to 3 years in order to identify those who converted to AD vs those who remained stable over time. Statistical analyses were based on receiver operating characteristic curve and Cox proportional hazards models. RESULTS: A total of 59 subjects converted to AD dementia. The most sensitive and specific test for diagnosis of prodromal AD was the FCSRT. Significant cutoff for the diagnosis was 17/48 for free recall, 40/48 for total recall, and below 71% for index of sensitivity of cueing (% of efficacy of semantic cues for retrieval). CONCLUSIONS: The amnestic syndrome of the medial temporal type, defined by the Free and Cued Selective Recall Reminding Test, is able to distinguish patients at an early stage of Alzheimer disease from mild cognitive impairment non-converters.

Ollat H, Laurent B, Bakchine S, Michel BF, Touchon J, Dubois B. · Association pour la Neuro Psycho Pharmacologie, 25 rue de la Plaine, 75020 Paris. · Encephale. · Pubmed #17675917 No free full text.

Abstract: The efficacy of the inhibitors of acetylcholinesterase in Alzheimer's Disease (AD) is moderated and some patients do not respond to these treatments. Sulbutiamine potentializes cholinergic and glutamatergic transmissions, mainly in hippocampus and prefrontal cortex. This multicentric, randomized and double-blind trial evaluates the effects of the association of sulbutiamine to an anticholinesterasic drug in cognitive functions in patients with AD at an early stage (episodic memory, working memory, executive functions, attention). Patients had first donepezil (D) or sulbutiamine (S) during three months. During this period, only attention improved in both groups. During the three following months, a placebo (P) in patients D and donepezil in patients S were added. Compared to entry results, episodic memory decreased in group D + P but improved in group S + D. At the same time the improvement of attention persisted in both groups. Daylife activities only improved in group S + D. In conclusion sulbutiamine can be an adjuvant to treatment in early stage and moderate AD by anticholinesterasic drugs.

Chupin M, Mukuna-Bantumbakulu AR, Hasboun D, Bardinet E, Baillet S, Kinkingnéhun S, Lemieux L, Dubois B, Garnero L. · Department of Clinical and Experimental Epilepsy, Institute of Neurology, UCL, UK. · Neuroimage. · Pubmed #17178234 No free full text.

Abstract: We describe a new algorithm for the automated segmentation of the hippocampus (Hc) and the amygdala (Am) in clinical Magnetic Resonance Imaging (MRI) scans. Based on homotopically deforming regions, our iterative approach allows the simultaneous extraction of both structures, by means of dual competitive growth. One of the most original features of our approach is the deformation constraint based on prior knowledge of anatomical features that are automatically retrieved from the MRI data. The only manual intervention consists of the definition of a bounding box and positioning of two seeds; total execution time for the two structures is between 5 and 7 min including initialisation. The method is evaluated on 16 young healthy subjects and 8 patients with Alzheimer's disease (AD) for whom the atrophy ranged from limited to severe. Three aspects of the performances are characterised for validating the method: accuracy (automated vs. manual segmentations), reproducibility of the automated segmentation and reproducibility of the manual segmentation. For 16 young healthy subjects, accuracy is characterised by mean relative volume error/overlap/maximal boundary distance of 7%/84%/4.5 mm for Hc and 12%/81%/3.9 mm for Am; for 8 Alzheimer's disease patients, it is 9%/84%/6.5 mm for Hc and 15%/76%/4.5 mm for Am. We conclude that the performance of this new approach in data from healthy and diseased subjects in terms of segmentation quality, reproducibility and time efficiency compares favourably with that of previously published manual and automated segmentation methods. The proposed approach provides a new framework for further developments in quantitative analyses of the pathological hippocampus and amygdala in MRI scans.

Dubois B. · CHU Pitié-Salpêtrière, Paris, France. · Encephale. · Pubmed #17099588 No free full text.

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Robert PH, Berr C, Volteau M, Bertogliati C, Benoit M, Sarazin M, Legrain S, Dubois B, Anonymous00781. · Centre Mémoire de Ressources et de Recherche, CHU de Nice, INSERM JE 2441, France. · Clin Neurol Neurosurg. · Pubmed #16567037 No free full text.

Abstract: OBJECTIVE: To evaluate the relation between apathy and development of dementia in patients with amnestic mild cognitive impairment (MCI). METHODS: Two hundred and fifty-one French-speaking outpatients fulfilling the criteria of amnestic MCI were enrolled. Apathy was assessed with the Apathy Inventory (IA). Neuropsychiatric evaluation also included the Goldberg anxiety scale and the Montgomery and Asberg Depressive Rating Scale (MADRS). The main end point considered after a 1-year follow-up was the development of dementia of Alzheimer type (DAT). RESULTS: At baseline there were 86 (39.8%) subjects presenting at least one symptom of apathy among the 216 included in analysis. After a 1-year follow-up, 22 patients developed DAT. Of the patients with apathy at baseline 13 (15.1%) developed DAT in comparison with 9 (6.9%) of the non-apathetic patients. At the 1-year follow-up, patients developing DAT had a significantly higher frequency of apathetic symptoms (91.7%) than patients without DAT (26.9%). CONCLUSION: Taking into account that apathy is one of the most frequently observed neuropsychiatric symptoms in MCI and in DAT the present study suggests that patients with MCI and apathy should be more closely observed.

Holtzer R, Scarmeas N, Wegesin DJ, Albert M, Brandt J, Dubois B, Hadjigeorgiou GM, Stern Y. · Cognitive Neuroscience Division, Taub Institute, G.H. Gertrude Sergievsky Center and Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York 10032, USA. · J Am Geriatr Soc. · Pubmed #16398891 No free full text.

Abstract: OBJECTIVES: To examine the natural course of depressive symptoms in patients with probable Alzheimer's disease (AD), specifically, the temporal relationship between depressive symptoms, function, and cognitive status. DESIGN: Multicenter cohort study with follow-up of up to 14 years. SETTING: Patients from the two Multicenter Study of Predictors of Disease Course in Alzheimer's Disease (Predictors Study) cohorts were recruited at five sites in the United States and Europe. PARTICIPANTS: Patients diagnosed with probable AD (n=536) enrolled in a longitudinal study (Predictors Study). MEASUREMENTS: Depressive symptoms were evaluated at 6-month intervals using the Columbia Scale for Psychopathology in Alzheimer's Disease. The Modified Mini-Mental State (3MS) and Blessed Dementia Rating Scale (BDRS) were used to assess cognitive status and functional activity, respectively. RESULTS: The prevalence of depressive symptoms was stable over the first 3 years of follow-up, at approximately 40%. There was a significant drop to 28% and 24% in the fourth and fifth years of follow-up, respectively. Time-dependent Cox analysis revealed that functional activity (BDRS) but not cognitive status (3MS) was a significant predictor of the first episode of depressive symptoms during follow-up. Generalized estimating equation analyses showed that AD duration and functional activity but not cognitive status were significantly related to depressive symptoms over the entire follow-up period. CONCLUSION: Depressive symptoms are common in AD, but their prevalence decreases over time. Examination of the temporal relationship between depressive symptoms and risk factors suggests that decline in function but not in cognition precedes the first episode of depressive symptoms in patients with probable AD.

Cowppli-Bony P, Fabrigoule C, Letenneur L, Ritchie K, Alpérovitch A, Dartigues JF, Dubois B. · Unité INSERM U593, université de Bordeaux II, Bordeaux. · Rev Neurol (Paris). · Pubmed #16340916 No free full text.

Abstract: INTRODUCTION: In general medicine lack of time impairs screening for Alzheimer's disease (AD). The five word test (FWT) enables rapid assessment of verbal episodic memory in accordance with Grober and Buschke neuropsychological concept. The main steps of the FWT are: induce specific semantic processing, control of encoding to avoid attention deficits, free and cued recall. Cued recall helps to distinguish a recall impairment from storage impairment which is evocative of AD. OBJECTIVE: Evaluate FWT total score (sum of free and cued recalls), FWT total weighed score which give a higher coefficient for free recalls than cued recalls and present the ability of these two scores for AD screening. METHOD: Evaluation performed with 4116 subjects (of whom 73 MA) aged from 65 years and more, randomly selected in two French towns for the "Three Cities" Study, a population-based cohort. RESULTS: The total score was more specific than sensitive with a maximal sensitivity (Se) at 63 percent with specificity (Sp) at 91.1 percent. The total weighed score significantly increased Se (83.6 percent) with control of specificity (84.9 percent) and positive predictive value (9.1 percent). CONCLUSION: The FWT allows quick screening of patients for whom further neuropsychological evaluation is needed to diagnose AD. The ability of is simple test to screen for AD is improved by a simple weighting procedure: the total weighted score.

Scarmeas N, Brandt J, Albert M, Hadjigeorgiou G, Papadimitriou A, Dubois B, Sarazin M, Devanand D, Honig L, Marder K, Bell K, Wegesin D, Blacker D, Stern Y. · Cognitive Neuroscience Division of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, the Gertrude H. Sergievsky Center, New York, NY 10032, USA. · Arch Neurol. · Pubmed #16216946 links to  free full text

Abstract: BACKGROUND: Delusions and hallucinations are common in Alzheimer disease (AD) and there are conflicting reports regarding their ability to predict cognitive decline, functional decline, and institutionalization. According to all previous literature, they are not associated with mortality. OBJECTIVE: To examine whether the presence of delusions or hallucinations has predictive value for important outcomes in AD. DESIGN, SETTING, AND PARTICIPANTS: A total of 456 patients with AD at early stages (mean Folstein Mini-Mental State Examination [MMSE] score of 21 of 30 at entry) were recruited and followed up semiannually for up to 14 years (mean, 4.5 years) in 5 university-based AD centers in the United States and Europe. Using the Columbia University Scale for Psychopathology in AD (administered every 6 months, for a total of 3266 visit-assessments, average of 7.2 per patient), the presence of delusions and hallucinations was extracted and examined as time-dependent predictors in Cox models. The models controlled for cohort effect, recruitment center, informant status, sex, age, education, a comorbidity index, baseline cognitive and baseline functional performance, behavioral symptoms, and use of neuroleptics and cholinesterase inhibitors. MAIN OUTCOME MEASURES: Cognitive (Columbia MMSE score of < or =20/57 [approximate Folstein MMSE score of < or =10/30]), functional (Blessed Dementia Rating Scale [parts I and II] score of > or =10), institutionalization equivalent index, and death. RESULTS: During the full course of follow-up, 38% of patients reached the cognitive, 41% the functional, 54% the institutionalization, and 49% the mortality end point. Delusions were noted for 34% of patients at baseline and 70% at any evaluation. Their presence was associated with increased risk for cognitive (risk ratio [RR], 1.50; 95% confidence interval [CI], 1.07-2.08) and functional decline (RR, 1.41; 95% CI, 1.02-1.94). Hallucinations were present in 7% of patients at initial visit and in 33% at any visit. Their presence was associated with increased risk for cognitive decline (RR, 1.62; 95% CI, 1.06-2.47), functional decline (RR, 2.25; 95% CI, 1.54-2.27), institutionalization (RR, 1.60; 95% CI, 1.13-2.28), and death (RR, 1.49; 95% CI, 1.03-2.14). CONCLUSIONS: Delusions and hallucinations are very common in AD and predict cognitive and functional decline. Presence of hallucinations is also associated with institutionalization and mortality.

Scarmeas N, Albert M, Brandt J, Blacker D, Hadjigeorgiou G, Papadimitriou A, Dubois B, Sarazin M, Wegesin D, Marder K, Bell K, Honig L, Stern Y. · Cognitive Neuroscience Division of the Taub Institute for Research in Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY 10032, USA. · Neurology. · Pubmed #15911793 No free full text.

Abstract: OBJECTIVE: To examine whether the presence of motor signs has predictive value for important outcomes in Alzheimer disease (AD). METHODS: A total of 533 patients with AD at early stages (mean Folstein Mini-Mental State Examination [MMSE] 21/30 at entry) were recruited and followed semiannually for up to 13.1 years (mean 3) in five University-based AD centers in the United States and European Union. Four outcomes, assessed every 6 months, were used in Cox models: cognitive endpoint (Columbia Mini-Mental State Examination < or = 20/57 [ approximately MMSE < or = 10/30]), functional endpoint (Blessed Dementia Rating Scale > or = 10), institutionalization equivalent index, and death. Using a standardized portion of the Unified PD Rating Scale (administered every 6 months for a total of 3,149 visit-assessments, average 5.9 per patient), the presence of motor signs, as well as of individual motor sign domains, was examined as time-dependent predictor. The models controlled for cohort, recruitment center, sex, age, education, a comorbidity index, and baseline cognitive and functional performance. RESULTS: A total of 39% of the patients reached the cognitive, 41% the functional, 54% the institutionalization, and 47% the mortality endpoint. Motor signs were noted for 14% of patients at baseline and for 45% at any evaluation. Their presence was associated with increased risk for cognitive decline (RR, 1.72; 95% CI, 1.24 to 2.38), functional decline (1.80 [1.33 to 2.45]), institutionalization (1.68 [1.26 to 2.25]), and death (1.38 [1.05 to 1.82]). Tremor was associated with increased risk for reaching the cognitive and bradykinesia for reaching the functional endpoints. Postural-gait abnormalities carried increased risk for institutionalization and mortality. Faster rates of motor sign accumulation were associated with increased risk for all outcomes. CONCLUSIONS: Motor signs predict cognitive and functional decline, institutionalization, and mortality in Alzheimer disease. Different motor sign domains predict different outcomes.

Sarazin M, Stern Y, Berr C, Riba A, Albert M, Brandt J, Dubois B. · INSERM U 610 and Fédération de Neurologie, Centre de Neuropsychologie, Hôpital de la Salpêtrière, 47 Bd de l'Hôpital, 75013 Paris, France. · Neurology. · Pubmed #15781821 No free full text.

Abstract: OBJECTIVE: To determine whether specific cognitive deficits can predict the progression of Alzheimer disease (AD). METHODS: Two hundred fifty-two patients with AD enrolled in the Predictors Study were followed at 6-month intervals for up to 4.5 years with neurologic, cognitive, and psychiatric examinations. Neuropsychological functions were assessed by the Modified Mini-Mental State Examination (mMMSE). Items of mMMSE were divided into five cognitive domains: temporospatial orientation, short-term memory, long-term memory, language, and visuoconstructive functions. Loss of autonomy was assessed by both the Dependency Scale (DS) and the Equivalent Institutional Care (EIC) rating. Cox proportional hazards models, adjusted for age, sex, estimated duration of illness at entry into the study, and presence of extrapyramidal signs and behavioral disturbances, were used to determine the predictive value of each neuropsychological domain on dependency outcomes. RESULTS: Global mMMSE, temporospatial orientation, and short-term memory scores were associated with a greater relative risk of moderate or severe dependency. The visuoconstructive score predicted the development of severe dependency. Long-term memory and language scores were not predictive of the EIC or DS endpoints. CONCLUSIONS: The presence of certain neuropsychological deficits at a patient's initial visit, such as short-term memory, temporospatial orientation, and constructive apraxia, predict more rapid dependency in patients with Alzheimer disease. Neuropsychological items have different weights in term of predictive power, and these effects are independent of the influence of age and disease duration at baseline.

Scarmeas N, Hadjigeorgiou GM, Papadimitriou A, Dubois B, Sarazin M, Brandt J, Albert M, Marder K, Bell K, Honig LS, Wegesin D, Stern Y. · Cognitive Neuroscience Division, Taub Institute for Research in Alzheimer's Disease and the Aging Brain, Gertrude H. Sergievsky Center, and Department of Neurology, New York, NY 10032, USA. · Neurology. · Pubmed #15452286 No free full text.

Abstract: BACKGROUND: Motor signs (MOSIs) are common in Alzheimer disease (AD) and may be associated with rates of cognitive decline, mortality, and cost of care. OBJECTIVE: To describe the progression and identify predictors of individual MOSIs in AD. METHODS: A cohort of 474 patients with AD at early stages was followed semiannually for up to 13.1 years (mean 3.6 years) in five centers in Europe and the United States. MOSIs were rated using a standardized portion of the Unified Parkinson's Disease Rating Scale. Overall, 3,030 visits/assessments of MOSIs (average 6.4/patient) were performed. Prevalence and incidence rates were calculated, and cumulative risk graphs were plotted for individual non-drug-induced MOSI domains. Rates of change over time taking into account potential covariates were also estimated. With use of each MOSI domain as outcome in Cox models, predictors of MOSI incidence were identified. RESULTS: At least one MOSI was detected in 13% of patients at first examination and in 36% for the last evaluation. Total MOSI score increased at an annual rate of 3% of total possible score. Rates of annual change for speech/facial expression (4%), rigidity (2.45%), posture/gait (3.9%), and bradykinesia (3.75%) were of similar magnitude, and their occurrence increased from first (3 to 6%) to last (22 to 29%) evaluation. Tremor was less frequent throughout the course of the disease (4% at first and 7% at last evaluation) and worsened less (0.75% increase/year). CONCLUSIONS: Most motor signs occur frequently and progress rapidly in Alzheimer disease. Tremor is an exception in that it occurs less frequently and advances at slower rates.

Slachevsky A, Villalpando JM, Sarazin M, Hahn-Barma V, Pillon B, Dubois B. · Institut National de la Santé et de la Récherche Médicale E 007 and Fédération de Neurologie, Hôpital de la Salpêtrière, Paris, France. · Arch Neurol. · Pubmed #15262742 links to  free full text

Abstract: BACKGROUND: The different distribution of pathologic features in frontotemporal dementia (FTD) and Alzheimer disease (AD) predicts a predominant dysexecutive syndrome in FTD. The Frontal Assessment Battery (FAB) has previously been validated in diseases associated with a frontal lobe dysfunction. OBJECTIVE: To evaluate the sensitivity of the FAB to differentiate FTD and AD. DESIGN: Comparison study. SETTING: Memory Clinic of the Salpêtrière Hospital, Paris, France. PATIENTS: Twenty-six patients with FTD and 64 patients with AD. MAIN OUTCOME MEASURES: Comparison of FAB and Mini-Mental State Examination (MMSE) scores between patients with FTD and those with AD. RESULTS: The mean +/- SD FAB scores significantly differed between patients with FTD (7.6 +/- 4.2) and those with AD (12.6 +/- 3.7) (P<.001), but not MMSE scores. The FAB correctly identified 78.9% of the patients. These results were maintained in a subgroup of mildly demented patients (MMSE score, > or =24). In these patients, a cutoff score of 12 on the FAB was optimal to differentiate both disorders (sensitivity, 77%; specificity, 87%). CONCLUSIONS: The FAB takes less than 10 minutes to administer and provides an objective measure to distinguish FTD from AD in mildly demented patients.

Dubois B, Albert ML. · Fédération de Neurologie and Inserm E007, Hôpital de la Salpêtrière, Paris, France. · Lancet Neurol. · Pubmed #15039037 No free full text.

Abstract: The concept of mild cognitive impairment (MCI) draws attention to cognitive changes not severe enough to warrant the diagnosis of dementia. As used today, it covers many pathological disorders and characterises a diverse population of patients who attend memory clinics. Our concern is the underlying heterogeneity. We suggest that it will soon be possible (if it is not already) to identify the underlying pathological disorders before the affected patients meet the criteria of dementia, thanks to specific neuropsychological assessments, neuroimaging, and biomarkers. In particular, patients with Alzheimer's disease (AD), the most important subgroup of patients with MCI, can already be identified before appearance of the fully developed clinical dementia syndrome. Accordingly, this paper proposes diagnostic criteria for "prodromal AD".

Cousin E, Hannequin D, Macé S, Dubois B, Ricard S, Génin E, Brun C, Chansac C, Pradier L, Frebourg T, Brice A, Campion D, Deleuze JF. · Aventis Pharma, Evry Genetics Center and Neurodegenerative disease group, Paris Research Center, 13 Quai Jules Guesde, 94400 Vitry-sur-Seine, France. · Neurosci Lett. · Pubmed #14664923 No free full text.

Abstract: Polymorphisms in the Nicastrin (NCSTN) gene have recently been associated with familial early-onset Alzheimer's disease (AD). The authors genotyped four NCTSN polymorphisms in a large cohort of 489 AD cases (including 158 sporadic early-onset AD cases and 95 familial early-onset AD cases) and 386 controls but failed to replicate the association between NCSTN haplotype B and AD.

Girardot N, Allinquant B, Langui D, Laquerrière A, Dubois B, Hauw JJ, Duyckaerts C. · Laboratoire de Neuropathologie Raymond Escourolle, CHU Pitié-Salpêtrière, AP-HP & Association Claude Bernard, Paris, Inserm U106, Paris, France. · Neuropathol Appl Neurobiol. · Pubmed #14507337 No free full text.

Abstract: The protein flotillin-1 is associated with the 'lipid rafts', that is, membrane microdomains that are enriched in cholesterol and sphingolipids. We compared flotillin-1 immunoreactivity in the hippocampus, amygdala and isocortex (Brodmann area 22) of six controls and 13 Alzheimer's disease (AD) cases (10 sporadic and three familial). A diffuse labelling of the neuropil was observed in most of the samples. The intensity of this labelling was not correlated with the density of neurofibrillary tangles (NFT) or of senile plaques. Some neuronal cell bodies were diffusely labelled in patients as in controls. Immunostained granular bodies were found in the cell body of a few neurones. The density of neuronal profiles containing large granular bodies (diameter > or =2 microm) was significantly higher in AD cases and was correlated with the density of NFTs in the three regions that were studied. Sections stained by double immunofluorescence methods and examined with confocal microscopy suggested that flotillin-1 accumulated most often in tangle-bearing neurones (76% of flotillin-1-positive neurones contained a NFT). Flotillin-1 immunoreactivity, even when found in a tangle-bearing neurone, was not colocalized with tau protein indicating that the two proteins were not in close contact and probably in different subcellular compartments. Flotillin-1-positive granular bodies were also found in neurones containing Pin1-positive vesicles but were not colocalized with them. Flotillin-1 immunoreactivity was colocalized with cathepsin D, a lysosomal marker. These data indicate that flotillin-1, a marker of rafts, accumulates in lysosomes of tangle-bearing neurones in the course of AD.

Robert PH, Schuck S, Dubois B, Lépine JP, Gallarda T, Olié JP, Goni S, Troy S. · Centre Mémoire de Ressources et de Recherches - PACA, CHU, Nice. · Encephale. · Pubmed #12876552 No free full text.

Abstract: Alzheimer's disease (AD) is a major healthcare challenge due to the increasing longevity of the population. Clinically prominent neuropsychological and neurological impairments, together with behavioral disorders characterize Alzheimer's disease (AD). In the past, behavioural and emotional disturbances received less attention than cognitive symptoms in studies of dementia. The association between cognitive and behavioural symptoms is complicated by the fact that such association could also occur with different patterns during depressive episode without dementia. Because Alzheimer's disease (AD) tends to be under diagnosed, there is an increasing need for accurate neuropsychological screening tools that are easy to administer by psychiatrists. The aim of the present study was to validate, in French, a sensitive and specific screening battery (B2C) designed to improve the discrimination between patients with AD, patients with depression, and healthy elderly subjects. POPULATION AND METHOD: The B2C was administered to 123 ambulatory subjects (mean age 76.4 2.3 years): divided in three groups of subjects. AD subjects were included (n=49) with a Mini-Mental Status Examination (MMSE) score of between 18 and 26, and a confirmed diagnosis (DSM IV) of mild to moderate AD. Subjects were not included if they were receiving treatment with an acetylcholinesterase inhibitor. The depressive group comprised elderly subjects (n=27) with at least two DSM IV criteria for a major depressive episode including the depressive mood criterion and a score of more than 17 on the Montgomery-Asberg Depression Rating Scale (MADRS). The healthy control group (n=47) comprised age-matched subjects with no neurological or psychiatric pathology. The B2C consists of four individual tasks derived from classical neuropsychological tests. Tasks were presented in the following order: temporal orientation test (knowledge of month, date, year, day of the week and time of day), 5 word test (task is originally derived from the Enhanced Cued Recall test), clock drawing test (In this widely used test, the subject had to draw a clock with all the numbers and then draw the clock hands at twenty minutes to four), and the semantic verbal fluency test (the subject was asked to generate as many words as possible from a given category in a fixed time period of 60 seconds). During the pre-study investigator meeting, the test procedure was adapted to ensure uniformity of practice in all centres. The B2C was administered one week to one month after the study inclusion date by a psychologist blinded to the patient groups and who had not participated in the subject's inclusion. Multivariate analysis was performed using a forced model of all four tests. Due to the nature of the dependent variable (AD vs controls and depressive vs control), the chosen discrimination model was a binary logistical regression model. Explanatory variables were limited to the variables of the test battery, and the dependent variable was the subject's status (AD, depressive or control). RESULTS: The mean results for each test are presented in Table II. The time taken to perform the tests was significantly higher (p=0.0001) for the AD group (11.2 minutes) when compared with both the control (7.6 minutes) and depressive group (8.2 minutes). In each of the four subtests, the AD subjects were significantly more impaired than the two other groups. Multivariate analysis was performed using a forced model of all four tests which provided correct classification of a high percentage of subjects (88.5%). The analysis followed a normal distribution and demonstrated that the AD patients were significantly impaired in all four tests of the B2C compared with controls. Depressive, elderly subjects were only impaired in verbal fluency. Multivariate analysis showed that, compared with controls, patients with mild AD were significantly impaired for all four tests. Response operating characteristics (ROC) analysis of the B2C showed: 93.8% sensitivity and 85% specificity for discriminating AD from control patients (table III), and 63% sensitivity and 96% specificity for discriminating AD from depressive patients (table IV). DISCUSSION: The main objective of this study was to demonstrate that the Short Cognitive Evaluation Battery developed in the French language is able to discriminate between patients suffering from AD and healthy elderly subjects. The results clearly demonstrate that AD patients were significantly impaired in all four tests of the B2C compared with the control group. The present study also supports the use of the screening battery for discriminating between AD and depressive subjects. The SCEB was less discriminatory for AD versus depressive patients than for AD versus controls. This could be due to the limited size of the depressive group. The verbal fluency test was the most sensitive for discriminating between AD and depression but this was at the expense of specificity. Other brief screening tests have already been developed in English speaking countries, In French language, the B2C appears to be a highly sensitive and specific tool for discriminating between patients with mild AD and healthy elderly individuals. Furthermore, in combination with clinical evaluation, the B2C could improve the specificity of the difficult discrimination between mild AD and depression. The next step of the validation process will include concurrent validity study and inclusion of a higher number of subjects with depressive symptoms.

Cousin E, Hannequin D, Ricard S, Macé S, Génin E, Chansac C, Brice A, Dubois B, Frebourg T, Mercken L, Benavides J, Pradier L, Campion D, Deleuze JF. · Aventis Pharma, Evry Genetics Center & Neurodegenerative Disease Group, Paris Research Center, 13 Quai Jules Guesde, 94400, Vitry-sur-Seine, France. · Neurosci Lett. · Pubmed #12727304 No free full text.

Abstract: Alzheimer's disease (AD) is a genetically complex neurodegenerative disorder and the leading cause of dementia of the elderly. Recently, Hu et al. suggested that a trinucleotide deletion in intron 13 of the APBB1 gene was a factor protecting against late-onset AD. We report here the results of a case/control study aimed at replicating this association. Our study included 461 AD patients and 397 matched controls. We compared the allele and genotype frequencies of the polymorphism between the two groups but did not find any statistically significant difference (P=0.08 and P=0.09, respectively). By contrast, adjusting for age and sex, we found a slight risk associated with the deletion (odds ratio=1.47, 95% confidence interval=1.05-2.04). Stratification by age showed that the risk effect associated with the deletion concerned subjects aged less than 65 years.

Robert PH, Schuck S, Dubois B, Olié JP, Lépine JP, Gallarda T, Goni S, Troy S, Anonymous00319. · Centre Mémoire, Unité d'Evaluation des Cognitions, Université de Nice-Sophia-Antipolis, Nice, France. · Dement Geriatr Cogn Disord. · Pubmed #12566598 No free full text.

Abstract: Because Alzheimer's disease (AD) tends to be underdiagnosed, there is an increasing need for accurate neuropsychological screening tools that are easy to administer by general practitioners or specialists. The aim of the present study was to validate, in French, a sensitive and specific screening battery designed to improve the discrimination between patients with AD, patients with depression and healthy elderly subjects. The Short Cognitive Evaluation Battery (SCEB) consists of 4 brief tests: temporal orientation, 5-word test, clock-drawing test and a semantic verbal fluency task. The SCEB was administered to 123 ambulatory subjects (mean age 76.4+/-2.3 years): 49 patients with mild AD, 27 patients with depressive symptoms and 47 healthy elderly subjects. The mean time for administration of the test was 11.2 min in the AD group, 8.2 min in the depressive group and 7.2 min in the control group (p < 0.001). Multivariate analysis showed that, compared with controls, patients with mild AD were significantly impaired for all four tests. Response operating characteristics analysis of the SCEB showed: 93.8% sensitivity and 85% specificity for discriminating AD from control patients, and 63% sensitivity and 96% specificity for discriminating AD from depressive patients. In summary, the SCEB appears to be a highly sensitive and specific tool for discriminating between patients with mild AD and healthy elderly individuals. Furthermore, in combination with clinical evaluation, the SCEB could improve the specificity of the difficult discrimination between mild AD and depression.

Dubois B, Touchon J, Portet F, Ousset PJ, Vellas B, Michel B. · Inserm E007 et Fédération de neurologie, Hôpital de la Salpêtrière, Paris. · Presse Med. · Pubmed #12467149 No free full text.

Abstract: OBJECTIVE: Alzheimer's disease (AD) is under-diagnosed in France. Today only an estimated 50% of patients are identified. Diagnosis of AD is particularly difficult because the amnesic syndrome, characteristic of the disease, is often confused with memory dysfunction that is frequent during the process of aging. The improvement in the diagnostic conditions of AD relies on the availability of a simple and reliable tool for screening memory disorders of organic origin. METHOD: The 5-word test studies the recall of a short list, which the physician ensures the patient has registered. Its construction permits the identification of patients exhibiting objective memory disorders. A validation study has been conducted in 86 patients suffering from AD and 126 persons complaining of functional memory disorders. RESULTS: The study has shown the sensitivity (91%) and specificity (87%) of the 5-word test in identifying patients with AD. CONCLUSION: This is a rapid (2 minutes) and simple test that is easy to use in medical practice for the screening of AD.