Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis

Funder: QingLan Research Project of Jiangsu for Outstanding Young TeachersFunder: Project funded by Postdoctoral Science Foundation of Xuzhou Medical UniversityFunder: Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) for Xuzhou Medical UniversityAbstract: We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population

Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia

The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA\xe2\x80\x99s relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration

Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once

Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once

Physical aggression among patients with dementia, neuropathologically confirmed post-mortem

ObjectiveTo investigate the prevalence of physical aggression among patients with dementia of different types and to analyze potential differences in clinical traits, in terms of singular or repetitive behavior and occurrence in early or late stage of the disease. We also aimed at examining against whom the physical aggression was exerted.MethodsWe included 281 cases with a neuropathological dementia diagnosis from the brain bank at the Department of Pathology, Lund University, for this retrospective medical records review. The study covers cases with a post-mortem examination performed between 1967 and 2013.ResultsOf the 281 patients studied, 97 (35%) patients had a history of exerting physical aggression during the course of their disease. The patients with frontotemporal dementia exerted physical aggression earlier in the course of their disease than Alzheimer's disease patients. The most frequent victims of the patients' physical aggression were health staff and other patients. The aggression also affected family members as well as (to the demented patient) unknown people. The frequency of the physical aggression differed among the different diagnostic groups; frontotemporal dementia patients exhibiting a higher physical aggression frequency score than did Alzheimer's disease patients.ConclusionsThe patterns of manifested physical aggression thus differ between the frontotemporal dementia and Alzheimer's disease patient groups in this study. Knowledge about such differences may be of value in decision making in patient care

Police Interactions Among Neuropathologically Confirmed Dementia Patients: Prevalence and Cause

Objective:The aim of this study was to investigate and compare the prevalence and recurrence of police interaction (PI) with patients diagnosed with dementia. We also aimed to study the reason behind the PI, the time of occurrence of PI, and potential consequences of the PI.Methods:For this retrospective medical records’ review, we included 281 cases with a neuropathologic dementia diagnosis from the Department of Pathology, Region Skane/Lund University, between 1967 and 2013. The diagnoses were Alzheimer disease, frontotemporal lobar degeneration, vascular dementia, and mixed dementia. A prerequisite was that extensive clinical investigation and follow-up had been conducted at the Department of Geriatric Psychiatry in Lund.Results:Of the 281 patients studied, 50 (18%) had a history of interacting with the police during the course of their disease. Frontotemporal dementia patients had a relatively higher prevalence of PI and more often due to criminal behavior. The recurrence of PIs differed among the groups; frontotemporal dementia patients exhibited a higher PI recurrence compared with the other groups.Conclusions:The patterns of PIs differ between the frontotemporal dementia and Alzheimer disease patients. Knowledge about such differences may be of value for the police, the judiciary system, and the society in general

Age-related incidence and family history in frontotemporal dementia: data from the Swedish Dementia Registry.

OBJECTIVES: Frontotemporal dementia (FTD) is considered to be a mainly early-onset neurodegenerative disorder with a strong hereditary component. The aim of the study was to investigate age-related incidence and family history in FTD compared to other dementia disorders, especially Alzheimer's disease (AD). METHODS: The Swedish Dementia Registry (SveDem) registers all new cases of dementia diagnosed by the participating centres, including data on demographics, diagnosis, and investigations used. Data for the period 2008-2011 were extracted and compared with age-related population data on a regional and national level. RESULTS: There were 20 305 patients registered in SveDem during 2008-2011, whereof 352 received a diagnosis of FTD. Mean age at diagnosis for FTD was 69.6 years and almost 70% of FTD cases were 65 years or older at the time of diagnosis. Both FTD and AD showed an increased incidence with age, which reached a maximum in the age group 80-84 years at 6.04 and 202 cases per 100 000 person-years, respectively. The proportion of cases with a positive family history was significantly lower in FTD than in AD. CONCLUSIONS: Contrary to general opinion within the field, data from SveDem show that the incidence of FTD increases with age, and that the majority of cases are diagnosed after the age of 65 years. In addition, data from SveDem might suggest that the importance of hereditary factors in general is similar in FTD and AD. The recognition of these findings has important consequences for the diagnosis, treatment and care of patients with FTD

Original Article Somatic complaints in frontotemporal dementia

Abstract: Frontotemporal dementia (FTD) is associated with a broad spectrum of clinical characteristics. The objective of this study was to analyze the prevalence of unexplained somatic complaints in neuropathologically verified FTD. We also examined whether the somatic presentations correlated with protein pathology or regional brain pathology and if the patients with these somatic features showed more depressive traits. Ninety-seven consecutively neuropathologically verified FTLD patients were selected. All 97 patients were part of a longitudinal study of FTD and all medical records were systematically reviewed. The somatic complaints focused on were headache, musculoskeletal, gastro/urogenital and abnormal pain response. Symptoms of somatic character (either somatic complaints and/or abnormal pain response) were found in 40.2%. These patients did not differ from the total group with regard to gender, age at onset or duration. Six patients showed exaggerated reactions to sensory stimuli, whereas three patients showed reduced response to pain. Depressive traits were present in 38% and did not correlate with somatic complaints. Suicidal behavior was present in 17 patients, in 10 of these suicidal behavior was concurrent with somatic complaints. No clear correlation between somatic complaints and brain protein pathology, regional pathology or asymmetric hemispherical atrophy was found. Our results show that many FTD patients suffer from unexplained somatic complaints before and/or during dementia where no clear correlation can be found with protein pathology or regional degeneration. Somatic complaints are not covered by current diagnostic criteria for FTD, but need to be considered in diagnostics and care. The need for prospective studies with neuropathological follow up must be stressed as these phenomena remain unexplained, misinterpreted, bizarre and, in many cases, excruciating