Pierre Jean Ousset

Neuropsychiatric syndromes in dementia - Results from the European Alzheimer Disease Consortium: Part I

Background/Aims: The aim of this study was to identify neuropsychiatric subsyndromes of the Neuropsychiatric Inventory in a large sample of outpatients with Alzheimer’s disease (AD). Methods: Cross-sectional data of 2,354 patients with AD from 12 centres from the European Alzheimer’s Disease Consortium were collected. Principal component analysis was used for factor analysis. Results: The results showed the presence of 4 neuropsychiatric subsyndromes: hyperactivity, psychosis, affective symptoms and apathy. The subsyndrome apathy was the most common, occurring in almost 65% of the patients. Conclusion: This large study has provided additional robust evidence for the existence of neuropsychiatric subsyndromes in AD.

Consistency of Neuropsychiatric Syndromes across Dementias: Results from the European Alzheimer Disease Consortium

Background/Aims: The aim of this study was to determine the consistency of neuropsychiatric subsyndromes of the Neuropsychiatric Inventory across several clinical and demographic subgroups (e.g. dementia subtypes, dementia severity, medication use, age and gender) in a large sample of outpatients with dementia. Methods: Cross-sectional data of 2,808 patients with dementia from 12 centres from the European Alzheimer’s Disease Consortium were collected. Principal component analysis was used for factor analysis. Subanalyses were performed for dementia subtypes, dementia severity, medication use, age and gender. Results: The results showed the relatively consistent presence of the 4 neuropsychiatric subsyndromes ‘hyperactivity’, ‘psychosis’, ‘affective symptoms’ and ‘apathy’ across the subanalyses. The factor structure was not dependent on dementia subtypes, age and gender but was dependent on dementia severity and cholinesterase use. The factors hyperactivity and affective symptoms were present in all subanalyses, but the presence of the factors apathy and psychosis was dependent on use of cholinesterase inhibitors and dementia severity, respectively. Conclusion: The present study provided evidence of the relative consistency of neuropsychiatric subsyndromes across dementia subtypes, age and gender, thereby stressing the importance of thinking about neuropsychiatric subsyndromes instead of separate symptoms. However, the subsyndromes apathy and psychosis were dependent on use of cholinesterase inhibitors and dementia severity.

Age related cognitive decline: a clinical entity? A longitudinal study of cerebral blood flow and memory performance.

OBJECTIVES: To evaluate the changes in regional cerebral blood flow (rCBF) and memory performance in patients with age related cognitive decline (ARCD) who did and did not become demented during a follow up period. METHODS: Twenty four patients with ARCD were recruited from an outpatient memory clinic, of whom 18 were followed up over a mean period of two years. Eighteen patients with mild to moderate probable Alzheimers disease and 18 aged normal controls were followed up over a mean period of three years. Memory performance and rCBF were evaluated quantitatively at inclusion and during follow up, using single photon emission computed tomography with xenon-133 injection and three subtests of the Wechsler memory scale (logical memory, paired associated learning, and digit span). RESULTS: Patients with ARCD showed decreased rCBF and memory performance at initial evaluation compared with controls. Five of them became demented during the follow up period, with further decline in memory and rCBF. At inclusion, the only feature that distinguished these five patients as a group from the remainder was a pronounced temporoparietal asymmetry. The 13 patients with ARCD who did not become demented still exhibited impaired memory and rCBF at follow up, but without any further decline and no increase in flow asymmetry. CONCLUSIONS: Apart from patients in the preclinical phase of Alzheimers disease, the ARCD category includes non-demented patients who have brain dysfunction that may represent a distinct clinical entity.

The ICTUS Study: A Prospective longitudinal observational study of 1,380 AD patients in Europe. Study design and baseline characteristics of the cohort.

The long-term objective of the ICTUS study is to identify milestones in Alzheimer’s disease (AD) progression and to develop a model to predict disease course in individual AD patients in Europe. The secondary objectives are to describe the patterns of prescribing, and the socioeconomic impact of AD in Europe. Between 2003 and 2005 1,380 patients with probable AD were recruited in specialised (secondary care) clinics in 12 European countries. Their mean age was 76 years and they had a mean of 8.0 ± (SD) 4.6 years of education. Thirty-five percent were male. The mean MMSE score was 20.4 ± (SD) 4.0. Forty-three percent had very mild dementia (CDR 0.5) and 44% had mild dementia (CDR 1). All patients completed baseline evaluation and biannual follow-up is ongoing. The goals of the current study are to describe the specific methods for recruitment in this crosscultural setting and the characteristics of the inception ICTUS cohort, including clinical features, co-morbidity, neuropsychological performance, neuropsychiatric symptoms, functional impairment and social burden.

Methodological Issues in Primary Prevention Trials for Neurodegenerative Dementia

The prevention of neurodegenerative dementias, such as Alzheimers disease, is a public health priority. Due to the large numbers of affected patients, even interventions bringing about a relatively small delay in disease onset could have large public health effects. Randomized controlled trials (RCTs) are required to demonstrate the effectiveness of preventive interventions, but such trials raise specific methodological questions because they are new in the field of neurodegenerative diseases, and require large numbers of elderly subjects and lengthy follow-up periods. We performed a literature search to identify primary prevention RCTs for neurodegenerative dementia. The methodology of the trials was summarized and discussed during two expert meetings. Overall, 39 trials were identified that assessed dementia incidence or cognitive decline as a primary or secondary study outcome. Age was the most common selection criteria for target populations. Follow-up periods ranged from one month to nine years and were longest in studies measuring dementia incidence as an outcome. Results of RCTs have so far been generally negative and conflicting with those of observational studies, perhaps due to methodological issues. Future trials must therefore carefully consider the target population, outcomes and duration of follow-up to be used, and should assess the problem of attrition.

Donepezil decreases annual rate of hippocampal atrophy in suspected prodromal Alzheimer's disease

The purpose of this study was to study the effect of donepezil on the rate of hippocampal atrophy in prodromal Alzheimers disease (AD).

Baisse rapide du Mini Mental State Examination: étude REAL.FR.

Background. - Alzheimers disease is a chronic pathology requiring regular follow-up. The predictive factors of rapid cognitive decline remain unclear. Objectives. - To analyse the baselines characteristics of patients at increased risk of rapid cognitive decline. Methods. - This study presents transversal data on a community-based sample of 340 patients diagnosed with probable Alzheimers disease and followed by REAL.FR group. Rapid cognitive decline was defined as a 3-points or greater loss on the Mini Mental State Examination (MMSE) within six months. Results. - 54 % of patients presented a rapid cognitive decline. Logistic regression analysis showed a positive association between rapid cognitive decline and a MMSE less than or equal to 20 (p<0.003) or a greater BMI (p<0.02) and a tendency towards a negative correlation with anxiety (p = 0.06) and negative correlation with the burden severity (p<0.05). Conclusions. - Patients with a worse cognitive status, a greater BMI and less anxiety or burden were at increased risk of rapid cognitive decline. Future studies should focus on determining etiologies for patients with rapid cognitive loss and help clinicians target these patients for interventions aiming to delay or stabilise the course of this disease

Prediction of Alzheimer’s Disease Dementia: Data from the GuidAge Prevention Trial

In therapeutic trials, it is crucial to identify Alzheimers disease (AD) at its prodromal stage. We assessed the accuracy of the free and cued selective reminding test (FCSRT) compared to other cognitive tests to predict AD dementia in subjects with subjective cognitive decline or mild cognitive impairment. Subjects from the placebo group of the GuidAge trial over 70 years old and without clinical signs of dementia at baseline who completed the 5-year follow-up free of dementia (n = 840) or developed AD dementia (n = 73) were included in our study. Among all the tests, the sum of the 3 free recall of the FCSRT (FCSRT-FR) and the sum of free and cued recall (FCSRT-TR) yielded the best results to predict AD dementia occurrence (all p values <0.05 for comparison of FCSRT-FR ROC and MMSE, CDRsb, and CVF ROCs). FCSRT-FR had an area under the ROC curve of 0.799 (95% CI 0.738-0.85) and the optimal cut-off was 20 (se 68.06% , sp 81.43% , PPV 23.90% , NPV 96,75%). Concerning FCSRT-TR, the AUC was 0.776 and the optimal cut-off was 42 (se 62.5% , sp 82.26% , PPV 23.20% and NPV 96.24%). This study sets the framework for implementing the FCSRT in clinical and therapeutic trials for efficient subject selection.

Évaluation clinique de la démence d'une cohorte de 358 patientspar la version française de l'échelle CDR

PURPOSE A reliable global rating of dementia severity in Alzheimers disease is critical both in clinical and research practice. In this paper, we present the results of the assessment of a cohort of 358 patients using the French version of the Clinical Dementia Rating Scale (CDR). METHODS 358 patients from a multicentric cohort were assessed in a comprehensive way: cognitive (Mini Mental Status Examination), functional (Activities of Daily Living), behavioural (Neuro Psychiatric Inventory) and global (Global Dementia Scale). CDR staging was performed after both patient and caregiver interview. RESULTS 27.6% of the patient had a CDR 0.5 (questionable dementia), 43% CDR 1 (mild dementia), 24.9% CDR 2 (moderate dementia) and 4.5% CDR 3 (severe dementia). All the rating scales were highly correlated with CDR stages (p < 0.0001). The CDR was also correlated with the Global Dementia Scale (p < 0.0001), but a perfect overlap of individual stages was not achieved. CONCLUSIONS CDR staging takes into account the major domains of dementia assessment: cognition, function and behaviour. Staging Alzheimers patients as CDR 0.5 arises the issue of the relationship between very mild dementia and Mild Cognitive Impairment. This study represents the first step of the CDR (French version) validation which is underway in this cohort.

MAPT (multi-domain Alzheimer’s prevention trial): Results at 36 months

Bruno Vellas, Isabelle Carrie, Sophie Guyonnet, Jacques Touchon, Thierry Dantoine, Jean-François Dartigues, Marie Noelle Cufi, Serge Bordes, Yves Gasnier, Philippe Robert, Lawrence Bories, Olivier Rouaud, Francoise Desclaux, Kristel Sudres, Marc Bonnefoy, Alain Pesce, Bertrand Fougere, Julien Delrieu, Catherine Faisant, Françoise Lala, Charlotte Dupuy, Christelle Cantet, Nicola Coley, Sylvie Belleville, Sherry L. Willis, Michael W. Weiner, Pierre Jean Ousset, Sandrine Andrieu, INSERM UMR 1027, Toulouse, France; University of Toulouse III, Toulouse, France; CHU Toulouse, Toulouse, France; CHU Toulouse, Toulouse, France; INSERM UMR 1027, Toulouse, France; CHU Montpellier, Montpellier, France; CHU Limoges, Limoges, France; INSERM U897, Bordeaux, France; Bordeaux University, Bordeaux, France; Memory consultation, CHU Bordeaux, Bordeaux, France; Bordeaux University Hospital, Bordeaux, France; CH Castres, Castres, France; CH Tarbes, Tarbes, France; CHU Nice, Nice, France; CH Foix, Foix, France; Hôpital General, Dijon, France; CH Lavaur, Lavaur, France; CH Montauban, Montauban, France; CHU Lyon SUD, Lyon, France; CH Princesse Grace, Monaco, Monaco; Institute of Aging, University Hospital Toulouse, Toulouse, France; Institut Universitaire de G eriatrie de Montr eal, Montr eal, QC, Canada; Universit e de Montr eal, Montr eal, QC, Canada; Indiana University, Indianapolis, IN, USA; University of California San Francisco, San Francisco, CA, USA; INSERM UMR 1027, Paul Sabatier University, Toulouse, France. Contact e-mail: vellas. b@chu-toulouse.fr