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Genetic variants and epigenetic features both contribute to the risk of Alzheimer's disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as a hub of both the genetic and epigenetic effects, in Caribbean Hispanics (CH) and generalized the findings to Non-Hispanic Whites (NHW). First, we conducted a genome-wide, sliding-window-based association with AD, in 7,155 CH and 1,283 NHW participants. Next, using data from the dorsolateral prefrontal cortex in 179 CH brains, we tested the cis- and trans-effects of AD-associated CGS on brain DNA methylation to mRNA expression. For the genes with significant cis- and trans-effects, we investigated their enriched pathways. We identified six genetic loci in CH with CGS dosage associated with AD at genome-wide significance levels: ADAM20 (Score = 55.19, P = 4.06 × 10-8), the intergenic region between VRTN and SYNDIG1L (Score = - 37.67, P = 2.25 × 10-9), SPG7 (16q24.3) (Score = 40.51, P = 2.23 × 10-8), PVRL2 (Score = 125.86, P = 1.64 × 10-9), TOMM40 (Score = - 18.58, P = 4.61 × 10-8), and APOE (Score = 75.12, P = 7.26 × 10-26). CGSes in PVRL2 and APOE were also significant in NHW. Except for ADAM20, CGSes in the other five loci were associated with CH brain methylation levels (mQTLs) and CGSes in SPG7, PVRL2, and APOE were also mQTLs in NHW. Except for SYNDIG1L (P = 0.08), brain methylation levels in the other five loci affected downstream mRNA expression in CH (P

Microsatellite repeat expansion disease loci can exhibit pleiotropic clinical and biological effects depending on repeat length. Large expansions in C9orf72 (100s-1000s of units) are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). However, whether intermediate expansions also contribute to neurodegenerative disease is not well understood. Several studies have identified intermediate repeats in Parkinson's disease patients, but the association was not found in autopsy-confirmed cases. We hypothesized that intermediate C9orf72 repeats are a genetic risk factor for corticobasal degeneration (CBD), a neurodegenerative disease that can be clinically similar to Parkinson's but has distinct tau protein pathology. Indeed, intermediate C9orf72 repeats were significantly enriched in autopsy-proven CBD (n = 354 cases, odds ratio = 3.59, p = 0.00024). While large C9orf72 repeat expansions are known to decrease C9orf72 expression, intermediate C9orf72 repeats result in increased C9orf72 expression in human brain tissue and CRISPR/cas9 knockin iPSC-derived neural progenitor cells. In contrast to cases of FTD/ALS with large C9orf72 expansions, CBD with intermediate C9orf72 repeats was not associated with pathologic RNA foci or dipeptide repeat protein aggregates. Knock-in cells with intermediate repeats exhibit numerous changes in gene expression pathways relating to vesicle trafficking and autophagy. Additionally, overexpression of C9orf72 without the repeat expansion leads to defects in autophagy under nutrient starvation conditions. These results raise the possibility that therapeutic strategies to reduce C9orf72 expression may be beneficial for the treatment of CBD.

Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10(-12)), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10(-8)), and 2p22 at SOS1 (rs963731; P=1.76 × 10(-7)). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10(-7)) and MAPT H1c (17q21; rs242557; P=7.91 × 10(-6)). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein).

Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.

Objective: Essential tremor is among the most prevalent neurological diseases. Diagnosis is based entirely on neurological evaluation. Historically, there were few postmortem brain studies, hindering attempts to develop pathologically based criteria to distinguish essential tremor from control brains. However, an intensive effort to bank essential tremor brains over recent years has resulted in postmortem studies involving >200 brains, which have identified numerous degenerative changes in the essential tremor cerebellar cortex. Although essential tremor and controls have been compared with respect to individual metrics of pathology, there has been no overarching analysis to derive a combination of metrics to distinguish essential tremor from controls. We asked whether there is a constellation of pathological findings that separates essential tremor from controls, and how well that constellation performs. Methods: Analyses included 100 essential tremor brains from the essential tremor centralized brain repository and 50 control brains. A standard tissue block from the cerebellar cortex was used to quantify 11 metrics of pathological change. Three supervised classification algorithms were investigated, with data divided into training and validation samples. Results: Using three different algorithms, we illustrate the ability to correctly predict a diagnosis of essential tremor, with sensitivity and specificity >87%, and in the majority of situations, >90%. We also provide a web‐based application that uses these metric values, and based on specified cutoffs, determines the likely diagnosis. Interpretation: These analyses set the stage for use of pathologically based criteria to distinguish clinically diagnosed essential tremor cases from controls, at the time of postmortem. [ABSTRACT FROM AUTHOR]

Missense mutations in leucine-rich repeat kinase 2 (LRRK2) are pathogenic for familial Parkinson's disease. However, it is unknown whether levels of LRRK2 protein in the brain are altered in patients with LRRK2-associated Parkinson's disease. Because LRRK2 mutations are relatively rare, accounting for approximately 1% of all Parkinson's disease, we accessioned cases from five international brain banks to investigate levels of the LRRK2 protein, and other genetically associated Parkinson's disease proteins. Brain tissue was obtained from 17 LRRK2 mutation carriers (12 with the G2019S mutation and five with the I2020T mutation) and assayed by immunoblot. Compared to matched controls and idiopathic Parkinson's disease cases, we found levels of LRRK2 protein were reduced in the LRRK2 mutation cases. We also measured a decrease in two other proteins genetically implicated in Parkinson's disease, the core retromer component, vacuolar protein sorting associated protein 35 (VPS35), and the lysosomal hydrolase, glucocerebrosidase (GBA). Moreover, the classical retromer cargo protein, cation-independent mannose-6-phosphate receptor (MPR300, encoded by IGF2R), was also reduced in the LRRK2 mutation cohort and protein levels of the receptor were correlated to levels of LRRK2. These results provide new data on LRRK2 protein expression in brain tissue from LRRK2 mutation carriers and support a relationship between LRRK2 and retromer dysfunction in LRRK2-associated Parkinson's disease brain. [ABSTRACT FROM AUTHOR]

Presents research which demonstrated evidence of caspase-1 activation in the brains of mice and humans with Huntington's disease. Nature of the disease, and its genetic basis; Comparison of transgenic mice with humans who have the disease; Expression of a dominant-negative caspase-1 mutant and its effects; Role of caspase-1 in the disease's pathogenesis; Impact of a caspase inhibitor.

Development of therapeutic approaches that target specific microglia responses in amyotrophic lateral sclerosis (ALS) is crucial due to the involvement of microglia in ALS progression. Our study identifies the predominant microglia subset in human ALS primary motor cortex and spinal cord as an undifferentiated phenotype with dysregulated respiratory electron transport. Moreover, we find that the interferon response microglia subset is enriched in donors with aggressive disease progression, while a previously described potentially protective microglia phenotype is depleted in ALS. Additionally, we observe an enrichment of non-microglial immune cell, mainly NK/T cells, in ALS central nervous system, primarily in the spinal cord. These findings pave the way for the development of microglia subset-specific therapeutic interventions to slow or even stop ALS progression.

Background: Huntington Disease (HD) is a neurodegenerative disorder resulting from the expansion of polyglutamine stretch in the huntingtin protein (Htt). Mutant HTT (mHtt) leads to progressive impairment of several molecular pathways that have been linked to disease pathogenesis. Defects in the production of a number of neurotrophic factors have been described as important determinants contributing to the development of HD. We have previously demonstrated that production of transforming growth factor-β1 (TGF-β1) is also deregulated in HD. Peripheral levels of TGF-β1 were markedly reduced early in the disease and returned to normal levels with disease severity. However, the cause and the biochemical origin of such abnormalities are still unclear., Results: We report here that the abnormal production of peripheral TGF-β1 depends on the changes in the percentage of TGF-β1-producing macrophages along disease course. Variation in the number of TGF-β1-producing macrophages resulted from differential activation state of the same cells, which displayed phenotypic and functional heterogeneity throughout the clinical course of HD. We further demonstrated that, similar to the periphery, the number of TGF-β1-immunoreactive cells in human post-mortem brain with HD, varied with neuropathological changes., Conclusions: Our data indicate that reduced bioavailability of TGF-β1 in the serum of HD subjects is attributable to the variation of the number of TGF-β1-producing macrophages. Macrophages display a differential ability to produce TGF-β1, which reflects diversity in cells polarization throughout the disease course. Besides elucidating the biochemical origin of TGF-β1 fluctuations in HD, our study highlights an interesting parallelism between periphery and central compartment and underlines the potential of TGF-β1 as a possible indicator suitable for prediction of disease onset in HD.