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Objective: Although mild cognitive impairment (MCI) is generally considered a risk state for dementia, its prevalence and association with dementia are impacted by the number of tests and cut-points used to assess cognition and define "impairment," and sources of norms. Here, we investigate how these methodological variations impact estimates of incident dementia in adults with bipolar disorder (BD), a vulnerable population with pre-existing cognitive deficits and increased dementia risk. Method: Neuropsychological data from 148 adults with BD and 13,610 healthy controls (HC) were drawn from the National Alzheimer's Coordinating Center. BD participants' scores were standardized against published norms and again using regression-based norms generated from HC within the same catchment area as individual BD patients ("site-specific norms"), varying the number of within-domain tests (one vs. two) and the cut-points (−1 vs. −1.5 SD) used to operationalize MCI. Results: Site-specific norms were more sensitive to incident dementia (88.6%–94.3%) than published norms (74.3%–88.6%), but only when using a "single test" definition of impairment. Specificity (22.1%–74.3%), accuracy (37.8%–68.9%), and positive predictive values (26.1%–38.3%) were overall poor. Applying a "single test" definition of impairment resulted in better negative predictive values using site-specific (92.3%–93.3%) than published norms (83.6%–86.2%), and a substantial increase in relative risk of incident dementia relative to published norms. Conclusions: Neuropsychologists should define "impairment" as scores below −1.0 or −1.5 SD on at least two within-domain measures when using published norms to interpret cognitive performance in adults with BD. [ABSTRACT FROM AUTHOR]

Objective: The aim of the current study is to understand why some individuals avoid developing Parkinson disease (PD) despite being at relatively high genetic risk, using the largest datasets of individual‐level genetic data available. Methods: We calculated polygenic risk score to identify controls and matched PD cases with the highest burden of genetic risk for PD in the discovery cohort (International Parkinson's Disease Genomics Consortium, 7,204 PD cases and 9,412 controls) and validation cohorts (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease, 8,968 cases and 7,598 controls; UK Biobank, 2,639 PD cases and 14,301 controls; Accelerating Medicines Partnership–Parkinson's Disease Initiative, 2,248 cases and 2,817 controls). A genome‐wide association study meta‐analysis was performed on these individuals to understand genetic variation associated with resistance to disease. We further constructed a polygenic resilience score, and performed multimarker analysis of genomic annotation (MAGMA) gene‐based analyses and functional enrichment analyses. Results: A higher polygenic resilience score was associated with a lower risk for PD (β = −0.054, standard error [SE] = 0.022, p = 0.013). Although no single locus reached genome‐wide significance, MAGMA gene‐based analyses nominated TBCA as a putative gene. Furthermore, we estimated the narrow‐sense heritability associated with resilience to PD (h2 = 0.081, SE = 0.035, p = 0.0003). Subsequent functional enrichment analysis highlighted histone methylation as a potential pathway harboring resilience alleles that could mitigate the effects of PD risk loci. Interpretation: The present study represents a novel and comprehensive assessment of heritable genetic variation contributing to PD resistance. We show that a genetic resilience score can modify the penetrance of PD genetic risk factors and therefore protect individuals carrying a high‐risk genetic burden from developing PD. ANN NEUROL 2022;92:270–278 [ABSTRACT FROM AUTHOR]

We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 × 10−16). We also show six risk loci associated with proximal gene expression or DNA methylation. [ABSTRACT FROM AUTHOR]

Letters to the editor are presented in response to the article about the correlation between the variants in gene encoding coenzyme Q2 and the increased risk of multiple-system atrophy, which appeared in the July 18, 2014 issue.

Mutations in TMEM230 have recently been associated to Parkinson's disease (PD). To further understand the role of this gene in the Caucasian population, we interrogated our large repository of next generation sequencing data from unrelated PD cases and controls, as well as multiplex families with autosomal dominant PD. We identified 2 heterozygous missense variants in 2 unrelated PD cases and not in our control database (p.Y106H and p.I162V), and a heterozygous missense variant in 2 PD cases from the same family (p.A163T). However, data presented herein is not sufficient to support the role of any of these variants in PD pathology. A series of unified sequence kernel association tests also failed to show a cumulative effect of rare variation in this gene on the risk of PD in the general Caucasian population. Further evaluation of genetic data from different populations is needed to understand the genetic role of TMEM230 in PD etiology. [ABSTRACT FROM AUTHOR]