Citations

AbstractIntroductionClinicopathological correlations differ by sex in Lewy body dementia (LBD). However, previous studies have focused on pathological staging systems that place less emphasis on regional pathologies.MethodsWe included 357 people (131 female, 226 male) with a high likelihood of LBD based on pathology from the Brain Bank for Neurodegenerative (Jacksonville, FL). Sex differences for regional Lewy body, senile plaque, and neurofibrillary tangle counts and their associations with clinical LBD diagnosis were assessed.ResultsFemales were less likely to have a clinical LBD diagnosis; they had more Lewy bodies, neurofibrillary tangles, and senile plaques in various regions than males (all p’s < 0.05). A higher likelihood of clinical LBD diagnosis was associated with more middle frontal, cingulate, and entorhinal Lewy body pathology, and more so for males than for females (all p’s < 0.045).DiscussionSex differences for clinicopathological correlations in LBD also occur at the regional pathology level. Females have a higher frequency of clinical misdiagnosis than males.Highlights Females have a higher risk of clinical underdiagnosis for Lewy body dementia (LBD) than males. Regional pathology counts differ by sex for people with a high likelihood of LBD. Regional pathology association with clinical LBD diagnosis differs by sex. Regional Lewy body counts have a stronger association with LBD phenotype for males.

AbstractBackgroundLewy body dementia (LBD) is the second most prevalent dementia in the United States after Alzheimer’s disease (AD). Recent studies have implicated rare mutations in two lipid transport genes, ABCA1 and ATP8B4, in Alzheimer’s disease. Substantial co‐pathology and shared risk factors indicate an intersectional genetic architecture between LBD and AD; therefore, we investigated the association of rare mutations in ABCA1 and ATP8B4 with LBD. Additionally, we examined rare mutations in 25 genes involved in ABCA1‐related lipid‐specific pathway with risk of developing LBD.MethodWe annotated rare missense and loss‐of‐function (LOF) mutations in ABCA1 and ATP8B4 genes, using Ensembl Variant Effect Predictor, in previously published whole‐genome sequence data from 2,591 LBD cases and 4,027 healthy controls of European ancestry. To test the association with LBD risk, we applied the optimized sequence kernel association test (SKAT‐O), followed by single‐variant association test (Fisher’s exact test), and multiple testing (Bonferroni correction). Additionally, we evaluated rare coding variants of 25 genes in ABCA1‐related positive regulation of the cholesterol efflux pathway (GO: 0010875) by performing single‐gene burden and gene‐set burden analyses.ResultsWe found a significant enrichment of rare ABCA1 missense mutations in LBD (SKAT‐O p = 2.68E‐02). However, no significant associations were found between LBD and ABCA1 LOF, and ATP8B4 LOF or missense mutations. Interestingly, the single‐variant analysis identified two ABCA1 missense variants, c.5398A>C; p.N1800H (Fisher’s test: p‐value = 1.16E‐04) and c.3544G>A; p.A1182T (p‐value = 4.29E‐02), with the p.N1800H substitution surviving Bonferroni multiple testing. The p.N1800H variant is reported to be pathogenic, and it was observed in twelve LBD patients and one control, with an odds ratio of 18.48 (95%CI = 2.4‐142.8). This mutation is reported to be pathogenic, in our LBD cohort, six out of twelve ABCA1 p.N1800H carriers also carry the APOE ε4 risk allele. However, neither a single‐gene burden nor a gene‐set burden analysis in 25 genes in the positive regulation of the cholesterol efflux pathway revealed any significant associations with LBD.ConclusionOur findings reveal significant enrichment of ABCA1 missense mutations in LBD emphasizing the genomic complexity surrounding LBD and AD.

Abstract Purpose This study examined occupational histories in neuropathologically confirmed cases of multiple system atrophy to identify environmental associations of potential relevance to disease causation. Methods 270 neuropathologically confirmed cases of multiple system atrophy obtained from the Mayo Clinic brain bank for neurodegenerative disorders in Jacksonville, Florida, were included in this case-control study. Demographic and disease information was collected from medical records. Information regarding occupational history was collected retrospectively from medical records and published obituaries. Proportions of employment by occupational sector were compared to United States census data. Results The most common prior occupations in patients were healthcare (15.2%), education (15.2%), administration (14.8%), clerical (10.7%), petroleum industry (8.9%), business ownership (8.5%), and metal industry (7.8%). When comparing patients to United States census data, significant differences were identified for electrical (5.6% vs. 0.4%, P < 0.001), education (15.2% vs. 2.3%, P < 0.001), real estate (4.4% vs. 0.7%, P < 0.001), metal industry (7.8% vs. 3.0%, P < 0.001), information technology (4.1% vs. 1.8%, P = 0.011), clerical (10.7% vs. 5.5%, P = 0.001), and petroleum industry (8.9% vs. 5.6%, P = 0.024). Conclusions Electrical engineers and electricians, educators, real estate agents, workers in the metal industry, information technologists, clerical staff, and workers in the petroleum industry were significantly overrepresented in our series of multiple system atrophy patients as compared to population data. We hypothesize that these occupational associations may signify environmental exposures increasing disease risk in genetically susceptible individuals. We cannot exclude a potential selection bias in patients willing to donate their brains to an academic center in order to contribute to scientific knowledge.

Mutations in the PINK1 and PRKN genes are the most frequent genetic cause of early-onset Parkinson disease. The pathogenic p.R275W substitution in PRKN is the most frequent substitution observed in patients, and thus far has been characterized mostly through overexpression models that suggest a possible gain of toxic misfunction. However, its effects under endogenous conditions are largely unknown. We used patient fibroblasts, isogenic neurons, and post-mortem human brain samples from carriers with and without PRKN p.R275W to assess functional impact. Immunoblot analysis and immunofluorescence were used to study mitophagy activation, and mitophagy execution was analyzed by flow cytometry of the reporter mitoKeima. The functional analysis was accompanied by structural investigation of PRKN p.R275W. We observed lower PRKN protein in fibroblasts with compound heterozygous p.R275W mutations. Isogenic neurons showed an allele-dose dependent decrease in PRKN protein. Lower PRKN protein levels were accompanied by diminished phosphorylated ubiquitin and decreased MFN2 modification. Mitochondrial degradation was also allele-dose dependently impaired. Consistently, PRKN protein levels were drastically reduced in human brain samples from p.R275W carriers. Finally, structural simulations showed significant changes in the closed form of PRKN p.R275W. Our data suggest that under endogenous conditions the p.R275W mutation results in a loss-of-function by destabilizing PRKN.

Aggregated α-synuclein (α-SYN) proteins, encoded by the SNCA gene, are hallmarks of Lewy body disease (LBD), affecting multiple brain regions. However, the specific mechanisms underlying α-SYN pathology in cortical neurons, crucial for LBD-associated dementia, remain unclear. Here, we recapitulated α-SYN pathologies in human induced pluripotent stem cells (iPSCs)–derived cortical organoids generated from patients with LBD with SNCA gene triplication. Single-cell RNA sequencing, combined with functional and molecular validation, identified synaptic and mitochondrial dysfunction in excitatory neurons exhibiting high expression of the SNCA gene, aligning with observations in the cortex of autopsy-confirmed LBD human brains. Furthermore, we screened 1280 Food and Drug Administration–approved drugs and identified four candidates (entacapone, tolcapone, phenazopyridine hydrochloride, and zalcitabine) that inhibited α-SYN seeding activity in real-time quaking-induced conversion assays with human brains, reduced α-SYN aggregation, and alleviated mitochondrial dysfunction in SNCA triplication organoids and excitatory neurons. Our findings establish human cortical LBD models and suggest potential therapeutic drugs targeting α-SYN aggregation for LBD.

Abstract Background Levodopa‐induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2 . Objectives Our goal was to investigate the effects of genetic variants on risk and time to LID. Methods We performed a genome‐wide association study (GWAS) and analyses focused on GBA1 and LRRK2 variants. We also calculated polygenic risk scores (PRS) including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1612 PD patients with and 3175 without LID. Results We found that GBA1 variants were associated with LID risk (odds ratio [OR] = 1.65; 95% confidence interval [CI], 1.21–2.26; P = 0.0017) and LRRK2 variants with reduced time to LID onset (hazard ratio [HR] = 1.42; 95% CI, 1.09–1.84; P = 0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (OR fourth_quartile = 1.27; 95% CI, 1.03–1.56; P = 0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HR third_quartile = 1.38; 95% CI, 1.07–1.79; P = 0.0128; HR fourth_quartile = 1.38; 95% CI = 1.06–1.78; P = 0.0147). Conclusions This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Pregnancy in women with early-onset Parkinson’s disease (PD) is likely to have a higher frequency given the trend toward increasing maternal age, thus resulting in a greater overlap time between childbearing age and PD risk. Deep brain stimulation (DBS) therapy is nowadays offered to PD patients at earlier stage of the disease, when women can still be pre-menopausal. However, few data are available about DBS safety during pregnancy. From a review of the available literature, only one article was published on this topic so far. Therefore, we have developed a clinical consensus on the safety of DBS during pregnancy in PD patients.

Abstract Lewy body dementia and Alzheimer's disease (AD) are leading causes of cognitive impairment, characterized by distinct but overlapping neuropathological hallmarks. Lewy body disease (LBD) is characterized by α-synuclein aggregates in the form of Lewy bodies as well as the deposition of extracellular amyloid plaques, with many cases also exhibiting neurofibrillary tangle (NFT) pathology. In contrast, AD is characterized by amyloid plaques and neurofibrillary tangles. Both conditions often co-occur with additional neuropathological changes, such as vascular disease and TDP-43 pathology. To elucidate shared and distinct molecular signatures underlying these mixed neuropathologies, we extensively analysed transcriptional changes in the anterior cingulate cortex, a brain region critically involved in cognitive processes. We performed bulk tissue RNA sequencing from the anterior cingulate cortex and determined differentially expressed genes (q-value &lt;0.05) in control (n = 81), LBD (n = 436), AD (n = 53) and pathological amyloid cases consisting of amyloid pathology with minimal or no tau pathology (n = 39). We used gene set enrichment and weighted gene correlation network analysis to understand the pathways associated with each neuropathologically defined group. LBD cases had strong upregulation of inflammatory pathways and downregulation of metabolic pathways. The LBD cases were further subdivided into either high Thal amyloid, Braak NFT, or low pathological burden cohorts. Compared to the control cases, the LBD cohorts consistently showed upregulation for genes involved in protein folding and cytokine immune response, as well as downregulation of fatty acid metabolism. Surprisingly, concomitant tau pathology within the LBD cases resulted in no additional changes. Some core inflammatory pathways were shared between AD and LBD but with numerous disease-specific changes. Direct comparison of LBD cohorts versus AD cases revealed strong enrichment of synaptic signalling, behaviour and neuronal system pathways. Females had a stronger response overall in both LBD and AD, with several sex-specific changes. Overall, the results identify genes commonly and uniquely dysregulated in neuropathologically defined LBD and AD cases, shedding light on shared and distinct molecular pathways. Additionally, the study underscores the importance of considering sex-specific changes in understanding the complex transcriptional landscape of these neurodegenerative diseases.

Importance Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement. Objectives To examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy. Design, Setting, and Participants This cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses. Main Outcomes and Measures Clinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET). Results Of the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P &amp;lt; .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P &amp;lt; .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P &amp;lt; .001). Hippocampal MRI volume (Spearman ρ = −0.45; P &amp;lt; .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = −0.74; P &amp;lt; .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02). Conclusions and Relevance Findings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.