Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

Several magnetic resonance imaging studies have reported hippocampal volume reduction in patients with schizophrenia, but other studies have reported contrasting results. In this review and meta-analysis, the authors aim to clarify whether a reduction in hippocampal volume characterizes patients with schizophrenia by considering illness phase (chronic and first episode) and hippocampus side separately. They made a detailed literature search for studies reporting physical volumetric hippocampal measures of patients with schizophrenia and healthy control (HC) participants and found 44 studies that were eligible for meta-analysis. Individual meta-analyses were also performed on 13 studies of first-episode patients and on 22 studies of chronic patients. The authors also detected any different findings when only males or both males and females were considered. Finally, additional meta-analyses and analyses of variance investigated the role of the factors “illness phase” and “side” on hippocampal volume reduction. Overall, the patient group showed significant bilateral hippocampal volume reduction compared with HC. Interestingly, first-episode and chronic patients showed same-size hippocampal volume reduction. Moreover, the left hippocampus was smaller than the right hippocampus in patients and HC. This review and meta-analysis raises the question about whether hippocampal volume reduction in schizophrenia is of neurodevelopmental origin. Future studies should specifically investigate this issue.

Alzheimer’s disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%¹. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants². Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals—16,036 AD cases and 16,522 controls. Next to variants inTREM2,SORL1andABCA7, we observed a significant association of rare, predicted damaging variants inATP8B4andABCA1with AD risk, and a suggestive signal inADAM10. Additionally, the rare-variant burden inRIN3, CLU, ZCWPW1andACEhighlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.

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.

This article discusses recent evidence supporting the use of action observation therapy and motor imagery practice for rehabilitation of Parkinson's disease. A main question that emerges from the review regards the different effectiveness of these approaches and the possibility of integrating them into a single method to enhance motor behaviour in subjects with Parkinson's disease. In particular, the reviewed studies suggest that action observation therapy can have a positive effect on motor facilitation of patients and that a long-term rehabilitation program based on action observation therapy or motor imagery practice can bring some benefit on their motor recovery. Moreover, the paper discusses how the research on the combined use of action observation and motor imagery for motor improvements in healthy subjects may encourage the combined use of action observation therapy and motor imagery practice for therapeutic aims in Parkinson's disease. To date, this hypothesis has never been experimented.