%0 Journal Article %J J Alzheimers Dis %D 2017 %T Cognitive Event-Related Potential, an Early Diagnosis Biomarker in Frail Elderly Subjects: The ERP-MAPT-PLUS Ancillary Study. %A Bennys, Karim %A Gabelle, Audrey %A Berr, Claudine %A De Verbizier, Delphine %A Andrieu, Sandrine %A Vellas, Bruno %A Touchon, Jacques %X

BACKGROUND: By analyzing brain synaptic function, cognitive event-related potentials (ERPs) could provide powerful and innovative tools for early Alzheimer's disease (AD) diagnosis.

OBJECTIVE: We investigated the relevance of the ERP-P300 component as a potential diagnosis marker in elderly subjects at risk of developing AD.

METHODS: ERP-P300 was analyzed on 85 subjects recruited from the Multidomain Alzheimer Preventive Trial (MAPT). PET-AV45 brain imaging was available from 36 subjects.

RESULTS: Two ERP-P300 subgroups were identified according to their PET-AV45 status: PET-Aβ positive (n = 15) and PET-Aβ negative (n = 21). In the amyloid positive group, we observed a highly significant increase in P3b latency in parietal brain regions (p = 0.0052). P3b in parietal regions correctly categorized 69.4% elderly subjects from the P300-PET Aβ positive group. Combined analysis of parietal P3b latencies and category fluency correctly classified 75% subjects from the P300-PET Aβ positive group.

CONCLUSIONS: The P300 ERP presents good predictive measure of brain amyloid load and has the potential to be used as a screening instrument for preclinical AD. The incorporation of P3b latency may be used as an adjunctive tool with neuropsychological assessment (i.e., verbal category fluency) as a specific and sensitive method for preclinical assessment of AD.

%B J Alzheimers Dis %V 58 %P 87-97 %8 2017 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/28372327?dopt=Abstract %R 10.3233/JAD-161012 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Effect of Early Referral to Specialist in Dementia on Institutionalization and Functional Decline: Findings from a Population-Based Study. %A Pimouguet, Clément %A Le-Goff, Mélanie %A Rizzuto, Debora %A Berr, Claudine %A Leffondré, Karen %A Pérès, Karine %A Dartigues, Jean François %A Helmer, Catherine %K Activities of Daily Living %K Cognition Disorders %K Community Health Planning %K Dementia %K Disability Evaluation %K Female %K Finland %K Follow-Up Studies %K Humans %K Institutionalization %K Male %K Psychiatric Status Rating Scales %K Referral and Consultation %K Specialization %X

BACKGROUND: Although early diagnosis has been hypothesized to benefit both patients and caregivers, until now studies evaluating the effect of early dementia diagnosis are lacking.

OBJECTIVE: To investigate the influence of early specialist referral for dementia on the risk of institutionalization and functional decline in Activity of Daily Living (ADL).

METHODS: Incident dementia cases were screened in a prospective population-based cohort, the Three-City Study, and initial specialist consultation for cognitive complaint was assessed at dementia diagnosis. Proportional hazard regression and illness-death models were used to test the association between specialist referral and, respectively, institutionalization and functional decline.

RESULTS: Only one third of the incident individuals with dementia had consulted a specialist for cognitive problems early (36%). After adjustment on potential confounders (including cognitive and functional decline) and competing risk of death, participants who had consulted a specialist early in the disease course presented a higher rate of being institutionalized than those who did not (Hazard Ratio = 2.00, 95% Confidence Interval (CI): 1.09- 3.64). But early specialist referral was not associated with further functional decline (HR = 1.09, 95% CI: 0.71- 1.67).

CONCLUSIONS: Early specialist referral in dementia is associated with increased risk of institutionalization but not with functional decline in ADL. These findings suggest that early care referral in dementia may be a marker of concern for patients and/or caregivers; subsequent medical and social care could be suboptimal or inappropriate to allow patients to stay longer at home.

%B J Alzheimers Dis %V 49 %P 819-28 %8 2016 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26484926?dopt=Abstract %R 10.3233/JAD-150574 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Evaluation of a Genetic Risk Score to Improve Risk Prediction for Alzheimer's Disease. %A Chouraki, Vincent %A Reitz, Christiane %A Maury, Fleur %A Bis, Joshua C %A Bellenguez, Celine %A Yu, Lei %A Jakobsdottir, Johanna %A Mukherjee, Shubhabrata %A Adams, Hieab H %A Choi, Seung Hoan %A Larson, Eric B %A Fitzpatrick, Annette %A Uitterlinden, Andre G %A De Jager, Philip L %A Hofman, Albert %A Gudnason, Vilmundur %A Vardarajan, Badri %A Ibrahim-Verbaas, Carla %A van der Lee, Sven J %A Lopez, Oscar %A Dartigues, Jean-François %A Berr, Claudine %A Amouyel, Philippe %A Bennett, David A %A van Duijn, Cornelia %A DeStefano, Anita L %A Launer, Lenore J %A Ikram, M Arfan %A Crane, Paul K %A Lambert, Jean-Charles %A Mayeux, Richard %A Seshadri, Sudha %X

Effective prevention of Alzheimer's disease (AD) requires the development of risk prediction tools permitting preclinical intervention. We constructed a genetic risk score (GRS) comprising common genetic variants associated with AD, evaluated its association with incident AD and assessed its capacity to improve risk prediction over traditional models based on age, sex, education, and APOEɛ4. In eight prospective cohorts included in the International Genomics of Alzheimer's Project (IGAP), we derived weighted sum of risk alleles from the 19 top SNPs reported by the IGAP GWAS in participants aged 65 and older without prevalent dementia. Hazard ratios (HR) of incident AD were estimated in Cox models. Improvement in risk prediction was measured by the difference in C-index (Δ-C), the integrated discrimination improvement (IDI) and continuous net reclassification improvement (NRI>0). Overall, 19,687 participants at risk were included, of whom 2,782 developed AD. The GRS was associated with a 17% increase in AD risk (pooled HR = 1.17; 95% CI =   [1.13-1.21] per standard deviation increase in GRS; p-value =  2.86×10-16). This association was stronger among persons with at least one APOEɛ4 allele (HRGRS = 1.24; 95% CI =   [1.15-1.34]) than in others (HRGRS = 1.13; 95% CI =   [1.08-1.18]; pinteraction = 3.45×10-2). Risk prediction after seven years of follow-up showed a small improvement when adding the GRS to age, sex, APOEɛ4, and education (Δ-Cindex =  0.0043 [0.0019-0.0067]). Similar patterns were observed for IDI and NRI>0. In conclusion, a risk score incorporating common genetic variation outside the APOEɛ4 locus improved AD risk prediction and may facilitate risk stratification for prevention trials.

%B J Alzheimers Dis %V 53 %P 921-32 %8 2016 Jun 18 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/27340842?dopt=Abstract %R 10.3233/JAD-150749 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Limiting Factors of Brain Donation in Neurodegenerative Diseases: The Example of French Memory Clinics. %A Le Bouc, Raphael %A Marelli, Cecilia %A Beaufils, Emilie %A Berr, Claudine %A Hommet, Caroline %A Touchon, Jacques %A Pasquier, Florence %A Deramecourt, Vincent %K Autopsy %K Brain %K France %K Health Knowledge, Attitudes, Practice %K Humans %K Neurodegenerative Diseases %K Physicians %K Retrospective Studies %X

Postmortem neuropathological examination of the brain is essential in neurodegenerative diseases, to ensure accurate diagnosis, to obtain an a posteriori critical assessment of the adequacy of clinical care, and to validate new biomarkers, but is only rarely performed. The purpose of this study was to assess factors limiting brain donation, such as reluctance of physicians to seek donation consent, opposition from patients and families, and organizational constraints. We conducted a survey across French memory clinics and major neuropathological centers. Few postmortem examinations were performed annually, as less than one third of the centers had performed at least five autopsies, and 41% had performed none. The main limiting factor was the lack of donation requests made by physicians, as half of them never approach patients for brain donation. Reasons for not seeking donation consent often include discomfort broaching the subject and lack of awareness of the medical and scientific benefit of postmortems (77%), organizational constraints (61%), and overestimation of families' negative reaction (51%). Family refusals represented a second major obstacle, and were often caused by misconceptions. Identifying and addressing these biases early could help improve physicians' rate of making requests and the public's awareness about the importance of brain donation.

%B J Alzheimers Dis %V 49 %P 1075-83 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26756326?dopt=Abstract %R 10.3233/JAD-150825 %0 Journal Article %J J Alzheimers Dis %D 2016 %T Palmomental Reflex a Relevant Sign in Early Alzheimer's Disease Diagnosis? %A Gabelle, Audrey %A Gutierrez, Laure-Anne %A Dartigues, Jean-François %A Ritchie, Karen %A Touchon, Jacques %A Berr, Claudine %K Aged %K Aged, 80 and over %K Alzheimer Disease %K Cohort Studies %K Early Diagnosis %K Female %K Follow-Up Studies %K France %K Humans %K Longitudinal Studies %K Male %K Neuropsychological Tests %K Reflex %X

BACKGROUND: Sophisticated and expensive biomarkers are proposed for the diagnostic of Alzheimer's disease (AD). The amyloid process seems to be early in AD, and brain amyloid load affects the frontal lobe.

OBJECTIVE: To determine if certain simple clinical signs, especially frontal-related signs, could help reach an earlier and better diagnosis.

METHODS: In the frame of the 3-City cohort, we conducted a nested case-control study comparing incident cases of AD to controls matched for age, gender, and education. The standardized neurological exam included extrapyramidal signs (akinesia, rigidity, rest tremor), pyramidal symptoms (spastic rigidity, Babinski reflex), primitive reflexes (snout, palmomental reflex grasping), and tremor (essential, intentional, head) at the time of diagnosis and two years before.

RESULTS: We compared 106 incident AD subjects (mean age at diagnosis 82.2 (SD = 5.9); median MMSE at diagnosis = 23) to 208 matched controls. In patients younger than 80, palmomental reflexes were more frequent in AD than controls, two years before diagnosis (25.0 versus 7.0% , p = 0.03) and at time of diagnosis (30.3 versus 12.3% , p = 0.02). No difference was observed for other signs two years before diagnosis or for patients older than 80.

CONCLUSION: Before diagnosis, the clinical examination of AD patients is not strictly normal; the primitive reflexes appear to be pathological. It might be in connection with the frontal amyloid load at an early stage of the disease. Clinical examination can reveal simple and interesting signs that deserve consideration as well as the other more invasive and expensive biomarkers.

%B J Alzheimers Dis %V 49 %P 1135-41 %8 2016 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/26639955?dopt=Abstract %R 10.3233/JAD-150436