Search

Background: Insulin‐like growth factor 1 (IGF‐1) seems to be involved in the neural circuits associated with social cognition and brain structure. Objectives: To investigate the association of IGF‐1 levels with social cognition and brain structure in Huntington's disease (HD). Methods: We evaluated social cognition using the Ekman test in 22 HD patients and 19 matched controls. Brain structure was assessed using standard volume‐based voxel‐based morphometry and surface‐based cortical thickness pipeline. We analyzed the association of IGF‐1 levels with social cognition and brain structure using adjusted regression analysis. Results: Social cognition was worse in HD patients (P < 0.001), on antidopaminergic drugs (P = 0.02), and with lower IGF‐1 levels (P = 0.04). In neuroimaging analyses, lower IGF‐1 levels were associated with social cognition impairment and atrophy mainly in frontotemporal regions (P < 0.05 corrected). Conclusions: In HD, abnormal IGF‐1 function seems to be associated with brain atrophy leading to clinical deficits in social cognition. [ABSTRACT FROM AUTHOR]

Background and purpose: Recently, some emerging cerebrospinal fluid (CSF) markers have been proposed as diagnostic tools for Alzheimer disease (AD) that can have an effect on disease progression. We analyze the accuracy of these CSF markers for diagnosis of AD in reference to brain amyloid positron emission tomography (PET). We also investigated whether they help in differentiating AD from other dementias and examined their influence in tracing the progression to dementia. Methods: Amyloid‐β (Aβ) 1–42, total tau (t‐tau), phosphorylated tau, Aβ40, Aβ38, beta‐site amyloid precursor protein cleaving enzyme 1 (BACE‐1), neurogranin (ng), phosphorylated neurofilament heavy‐chain, and α‐synuclein (α‐syn) CSF levels were analyzed in 319 subjects, among whom 57 also underwent an amyloid PET scan. We also analyzed longitudinal clinical data from 239 subjects. Results: Emerging CSF markers, especially ng/BACE‐1 ratio (area under the curve = 0.77) and their combinations with core AD CSF markers (all AUCs >0.85), showed high accuracy to discriminate amyloid PET positivity. Subjects with AD had higher CSF BACE‐1, ng, and α‐syn levels than those with non‐AD dementia. CSF t‐tau/α‐syn ratio was higher in subjects with dementia with Lewy bodies than in those with frontotemporal dementia. Most emerging/core AD ratios predicted a faster conversion from mild cognitive impairment (MCI) stage to AD and appeared to be helpful when core AD CSF markers were discordant. In addition, the rate of cognitive decline was associated with all CSF core AD markers, several emerging/core AD two‐marker ratios, and CSF ng levels. Conclusions: These results suggest that emerging biomarkers in conjunction with core AD markers improve diagnosis of AD, are associated with the conversion from MCI into AD, and predict a faster progression of dementia. [ABSTRACT FROM AUTHOR]

Background: Mosaic loss of chromosome Y (mLOY) is a highly common somatic variant among men, and has been associated to higher risk in overall mortality and several types of disease, including Alzheimer's disease (Dumanski et al. 2016). In the present study, we aimed to replicate these findings in both a cross‐sectional and longitudinal setup by determining mLOY phenotype and its associated polygenic risk score (PRS). Method: MADloy R package (González et al. 2020) was used to determine mLOY in germline blood DNA from males in the GR@ACE cohort, composed of AD patients recruited in Fundació ACE (Barcelona, Spain) and population‐based controls recruited from several Spanish centres. Additional MCI patients recruited in Fundació ACE were used to study disease progression. PRS was calculated by additive multiplication of the beta values of 114 genome‐wide significant variants reported in the most relevant mLOY GWAS published to date (Thompson et al. 2019) and their genotypes in our dataset. To ease interpretation of results, PRS per SD units were used. Only individuals with ages 65‐85 were kept for the case‐control and PRS analyses (see Table 1). Statistical analysis was performed by fitting logistic regressions and Cox proportional‐hazards models adjusted by age, APOE and PCs (when needed). Result: mLOY phenotype did not show a significant association with AD in the case‐control setup and showed suggestive results for higher risk of conversion to AD (HR=1.45; p=0.09). However, the mLOY PRS yielded borderline significance in the case‐control dataset (OR=1.08; p=0.09), and statistical significance in MCI to AD conversion (HR=1.22; p=0.01). Importantly, PRS was independent of age, and effects were only observed in male samples, with no effect in conversion to AD or case‐control in the female subset, supporting the validity of our approach. Conclusion: The age‐dependent nature of mLOY and lack of age at sampling information for most controls limited our power to study mLOY phenotype's effect on AD. The mLOY PRS allowed us to overcome these limitations, acting as a male‐specific AD risk factor and providing further evidence of mLOY's impact on AD. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a neurodegenerative disease with an often complex component identifiable by genome‐wide association studies. The most recent large‐scale PD genome‐wide association studies have identified more than 90 independent risk variants for PD risk and progression across more than 80 genomic regions. One major challenge in current genomics is the identification of the causal gene(s) and variant(s) at each genome‐wide association study locus. The objective of the current study was to create a tool that would display data for relevant PD risk loci and provide guidance with the prioritization of causal genes and potential mechanisms at each locus. Methods: We included all significant genome‐wide signals from multiple recent PD genome‐wide association studies including themost recent PD risk genome‐wide association study, age‐at‐onset genome‐wide association study, progression genome‐wide association study, and Asian population PD risk genome‐wide association study. We gathered data for all genes 1 Mb up and downstream of each variant to allow users to assess which gene(s) are most associated with the variant of interest based on a set of self‐ranked criteria. Multiple databases were queried for each gene to collect additional causal data. Results: We created a PD genome‐wide association study browser tool (https://pdgenetics.shinyapps.io/GWASBrowser/) to assist the PD research community with the prioritization of genes for follow‐up functional studies to identify potential therapeutic targets. Conclusions: Our PD genome‐wide association study browser tool provides users with a useful method of identifying potential causal genes at all known PD risk loci from large‐scale PD genome‐wide association studies. We plan to update this tool with new relevant data as sample sizes increase and new PD risk loci are discovered. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA. [ABSTRACT FROM AUTHOR]

Background: The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases.Objectives: To perform the largest PD genome-wide association study restricted to a single country.Methods: We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses.Results: We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls.Conclusions: Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]