Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. We thank Drs. D. Stephen Snyder and Marilyn Miller from NIA who are ex-officio ADGC members. EADI. This work has been developed and supported by the LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease) including funding from MEL (Metropole européenne de Lille), ERDF (European Regional Development Fund) and Conseil Régional Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. The generation and management of GWAS genotype data for the Rotterdam Study (RS-I, RS-II, RS-III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the

Introduction We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development.

BackgroundThere is no consensus about which hippocampal subfields become atrophic earliest in the course of Alzheimer's disease (AD).MethodsThirty AD patients, 41 mild cognitive impairment (MCI) patients, and 38 healthy controls (HCs) underwent cerebral magnetic resonance imaging (with an automated segmentation protocol for the volumetric analysis of hippocampal subfields) and a test of immediate and delayed recall of a 15-word list.ResultsThe volumes of the presubiculum and subiculum presented the most remarkable reduction in the patient's groups. In the MCI group, only the volumes of presubiculum and subiculum predicted performance on the memory tests. In AD patients, the volumes of all hippocampal subfields (with the notable exception of the CA1) predicted memory scores.ConclusionsOur data point to a prevalent atrophy of the presubicular-subicular complex from the early phases of AD. This finding is consistent with neuropathological observations in AD patients and probably reflects the severe degeneration of the perforant pathway while penetrating the hippocampus through the subicular field in its course from the entorhinal cortex to the dentate gyrus.

Anosognosia is the lack of awareness or the underestimation of a specific deficit in sensory, perceptual, motor, affective or cognitive functioning due to a brain lesion. This self-awareness deficit has been studied mainly in stroke hemiplegic patients, who may report no deficit, overestimate their abilities or deny that they are unable to move a paretic limb. In this review, a detailed search of the literature was conducted to illustrate clinical manifestations, pathogenetic models, diagnostic procedures and unresolved issues in anosognosia for motor impairment after stroke. English and French language papers spanning the period January 1990-January 2007 were selected using PubMed Services and utilizing research words stroke, anosognosia, awareness, denial, unawareness, hemiplegia. Papers reporting sign-based definitions, neurological and neuropsychological data and the results of clinical trials or historical trends in diagnosis were chosen. As a result, a very complex and multifaceted phenomenon emerges, whose variable behavioural manifestations often produce uncertainties in conceptual definitions and diagnostic procedures. Although a number of questionnaires and diagnostic methods have been developed to assess anosognosia following stroke in the last 30 years, they are often limited by insufficient discriminative power or a narrow focus on specific deficits. As a consequence, epidemiological estimates are variable and incidence rates have ranged from 7 to 77% in stroke. In addition, the pathogenesis of anosognosia is widely debated. The most recent neuropsychological models have suggested a defect in the feedforward system, while neuro-anatomical studies have consistently reported on the involvement of the right cerebral hemisphere, particularly the prefrontal and parieto-temporal cortex, as well as insula and thalamus. We highlight the need for a multidimensional assessment procedure and suggest some potentially productive directions for future research about unawareness of illness.