Age at symptom onset and death and disease duration in genetic frontotemporal dementia : an international retrospective cohort study

Background: Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72. Methods: In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried. Findings: Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49\ub75 years (SD 10\ub70; onset) and 58\ub75 years (11\ub73; death) in the MAPT group, 58\ub72 years (9\ub78; onset) and 65\ub73 years (10\ub79; death) in the C9orf72 group, and 61\ub73 years (8\ub78; onset) and 68\ub78 years (9\ub77; death) in the GRN group. Mean disease duration was 6\ub74 years (SD 4\ub79) in the C9orf72 group, 7\ub71 years (3\ub79) in the GRN group, and 9\ub73 years (6\ub74) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0\ub745 between individual and parental age at onset, r=0\ub763 between individual and mean family age at onset, r=0\ub758 between individual and parental age at death, and r=0\ub769 between individual and mean family age at death) than in either the C9orf72 group (r=0\ub732 individual and parental age at onset, r=0\ub736 individual and mean family age at onset, r=0\ub738 individual and parental age at death, and r=0\ub740 individual and mean family age at death) or the GRN group (r=0\ub722 individual and parental age at onset, r=0\ub718 individual and mean family age at onset, r=0\ub722 individual and parental age at death, and r=0\ub732 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35\u201362, for age at onset; 61%, 47\u201373, for age at death), and even more by family membership (66%, 56\u201375, for age at onset; 74%, 65\u201382, for age at death). In the GRN group, only 2% (0\u201310) of the variability of age at onset and 9% (3\u201321) of that of age of death was explained by the specific mutation, whereas 14% (9\u201322) of the variability of age at onset and 20% (12\u201330) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11\u201326) of the variability of age at onset and 19% (12\u201329) of that of age at death. Interpretation: Our study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates. Funding: UK Medical Research Council, National Institute for Health Research, and Alzheimer's Society

New insights into the genetic etiology of Alzheimer's disease and related dementias

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

New insights into the genetic etiology of Alzheimer's disease and related dementias

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

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

DATABASE_RF-2011-02351933

In this dataset we provide data from neuropsychological assessments, nutritional assessments (adherence to the Mediterranean Diet ) and anthropometric and physical activity assessments from a sample of an italian elderly subjects.THIS DATASET IS ARCHIVED AT DANS/EASY, BUT NOT ACCESSIBLE HERE. TO VIEW A LIST OF FILES AND ACCESS THE FILES IN THIS DATASET CLICK ON THE DOI-LINK ABOV

Rischio cancerogeno degli idrocarburi policiclici aromatici: classificazioni e interpretazioni del monitoraggio

The polycyclic aromatic hydrocarbons (PAHs) are widespread contaminants characterized by various chemical, physical and toxic properties. The characterization of occupational and environmental exposures and the use of suitable measurements protocols are very significant because their presence in mixtures and environmental persistency. In the past few years, the knowledge concerning carcinogenicity of PAHs have been reviewed, the mechanisms involved are the interaction of PAH's metabolites with DNA and oxidative damages. The main requirement for research concerns lack of knowledge on reference values and occupational exposure's assessment in particular PAHs sampling methods that can lead to combined measurements of vapor and aerosol mixtures. Aims of this study are to describe a possible occupational sources of PAHs providing also an update of mechanism involved in their carcinogenicity and risk calculation as is done in the TEF approach. The classifications provided by International Agencies and Institutions and the limit values adopted have been reviewed and taken into account

Il Medico Competente e le vaccinazioni nel settore della sanità. Evidenze scientifiche e buone prassi

Evidences and good medical practices. Biohazard in healthcare settings is an issue for Occupational Physician (OP), owing to the potential relevant adverse effects for health care workers (HCW) and for the non complete effectiveness of primary prevention. Vaccination represents an effective tool to minimize risk of occupational and nosocomial transmission for many relevant communicable diseases. Implementation of vaccination campaigns may however present some critical aspects. The present study evaluates available scientific evidences and reports an Italian multicenter study (9 Hospitals, 3200 HCW), suggesting good medical practices in vaccination, while highlighting the role of the OP in a multidisciplinary context