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Lewy body dementias (LBD) are the second most common dementia. Several genes have been associated with LBD, but little is known about their contributions to LBD pathophysiology. Each gene may transcribe multiple RNA, and LBD brains have extensive RNA splicing dysregulation. Hence, we completed the first transcriptome-wide transcript-level differential expression analysis of post-mortem LBD brains for gaining more insights into LBD molecular pathology that are essential for facilitating discovery of novel therapeutic targets and biomarkers for LBD. We completed transcript-level quantification of next-generation RNA-sequencing data from post-mortem anterior cingulate (ACC) and dorsolateral prefrontal cortices (DLPFC) of people with pathology-verified LBD (LBD = 14; Controls = 7) using Salmon . We identified differentially expressed transcripts (DET) using edgeR and investigated their functional implications using DAVID . We performed transcriptome-wide alternative splicing analysis using DRIMseq . We identified 74 DET in ACC and 96 DET in DLPFC after Benjamini-Hochberg false discovery rate (FDR) correction (5%). There were 135 and 98 FDR-corrected alternatively spliced genes in ACC and DLPFC of LBD brains, respectively. Identified DET may contribute to LBD pathology by altering DNA repair, apoptosis, neuroplasticity, protein phosphorylation, and regulation of RNA transcription. We confirm widespread alternative splicing and absence of chronic neuroinflammation in LBD brains. Transcript-level differential expression analysis can reveal specific DET that cannot be detected by gene-level expression analyses. Therapeutic and diagnostic biomarker potential of identified DET, especially those from TMEM18, MICB, MPO, and GABRB3 , warrant further investigation. Future LBD blood-based biomarker studies should prioritise measuring the identified DET in small extracellular vesicles.

A 75-year-old Chinese American man presented to behavioral neurology clinic for a second opinion of dementia with Lewy body disease (DLB). The clinical manifestations met the criteria for a probable DLB diagnosis. Yet, in-depth evaluation unveiled clinical history, family history, and neuroimaging evidences that suggested a diagnosis of behavioral variant frontotemporal dementia (FTD). A heterozygous pathogenic variant in the microtubule-associated protein Tau ( MAPT ) was identified through genetic testing and confirmed the diagnosis of autosomal dominant MAPT -related FTD. This case is the first reported instance of MAPT -related FTD presenting with well-formed visual hallucinations in an elderly Chinese American.

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 <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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Single-nucleus RNA-sequencing (snRNA-seq) has revealed new levels of cellular organization and diversity within the human brain. However, full-length mRNA isoforms are not resolved in typical snRNA-seq analyses using short-read sequencing that cannot capture full-length transcripts. Here we combine standard 10x Genomics short-read snRNA-seq with targeted PacBio long-read snRNA-seq to examine isoforms of genes associated with neurological diseases at the single-cell level from prefrontal cortex samples of diseased and nondiseased human brain, assessing over 165,000 cells. Samples from 25 postmortem donors with Alzheimer's disease (AD), dementia with Lewy bodies (DLB), or Parkinson's disease (PD), along with age-matched controls, were compared. Analysis of the short-read libraries identified shared and distinct gene expression changes across the diseases. The same libraries were then assayed using enrichment probes to target 50 disease-related genes followed by long-read PacBio sequencing, enabling linkage between cell type and isoform expression. Vast mRNA isoform diversity was observed in all 50 targeted genes, even those that were not differentially expressed in the short-read data. We also developed an informatics method for detection of isoform structural differences in novel isoforms versus the reference annotation. These data expand available single-cell datasets of the human prefrontal cortical transcriptome with combined short- and long-read sequencing across AD, DLB, and PD, revealing increased mRNA isoform diversity that may contribute to disease features and could potentially represent therapeutic targets for neurodegenerative diseases., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Liu et al.)

The formation of amyloid-β (Aβ) aggregates in brain is a neuropathological hallmark of Alzheimer's disease (AD). However, there is mounting evidence that Aβ also plays a pathogenic role in other types of dementia and that specific post-translational Aβ modifications contribute to its pathogenic profile. The objective of this study was to test the hypothesis that distinct types of dementia are characterized by specific patterns of post-translationally modified Aβ variants. We conducted a comparative analysis and quantified Aβ as well as Aβ with pyroglutamate (pGlu3-Aβ and pGlu11-Aβ), N-truncation (Aβ(4-X)), isoaspartate racemization (isoAsp7-Aβ and isoAsp27-Aβ), phosphorylation (pSer8-Aβ and pSer26-Aβ) or nitration (3NTyr10-Aβ) modification in post mortem human brain tissue from non-demented control subjects in comparison to tissue classified as pre-symptomatic AD (Pre-AD), AD, dementia with Lewy bodies and vascular dementia. Aβ modification-specific immunohistochemical labelings of brain sections from the posterior superior temporal gyrus were examined by machine learning-based segmentation protocols and immunoassay analyses in brain tissue after sequential Aβ extraction were carried out. Our findings revealed that AD cases displayed the highest concentrations of all Aβ variants followed by dementia with Lewy bodies, Pre-AD, vascular dementia and non-demented controls. With both analytical methods, we identified the isoAsp7-Aβ variant as a highly abundant Aβ form in all clinical conditions, followed by Aβ(4-X), pGlu3-Aβ, pGlu11-Aβ and pSer8-Aβ. These Aβ variants were detected in distinct plaque types of compact, coarse-grained, cored and diffuse morphologies and, with varying frequencies, in cerebral blood vessels. The 3NTyr10-Aβ, pSer26-Aβ and isoAsp27-Aβ variants were not found to be present in Aβ plaques but were detected intraneuronally. There was a strong positive correlation between isoAsp7-Aβ and Thal phase and a moderate negative correlation between isoAsp7-Aβ and performance on the Mini Mental State Examination. Furthermore, the abundance of all Aβ variants was highest in APOE 3/4 carriers. In aggregation assays, the isoAsp7-Aβ, pGlu3-Aβ and pGlu11-Aβ variants showed instant fibril formation without lag phase, whereas Aβ(4-X), pSer26-Aβ and isoAsp27-Aβ did not form fibrils. We conclude that targeting Aβ post-translational modifications, and in particular the highly abundant isoAsp7-Aβ variant, might be considered for diagnostic and therapeutic approaches in different types of dementia. Hence, our findings might have implications for current antibody-based therapies of AD., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Consent for publication: All the authors have approved publication., (© 2024. The Author(s).)

Background: Glucocerebrosidase 1 (GBA1) mutations are associated with reduced survival in Parkinson's disease but their effect on survival in dementia with Lewy bodies (DLB) is unclear., Objective: To assess the impact of GBA1 mutations on survival among Ashkenazi Jews with DLB, while controlling for APOE status., Methods: One hundred and forty participants from Tel Aviv Medical Center, Israel were genotyped for GBA1 mutations and APOE polymorphisms. Survival rates and follow-up cognitive screening scores were analyzed., Results: GBA1 mutation carriers had a two-fold increased risk of death (HR = 1.999), while APOE status did not independently affect survival. In a subset of patients with available clinical data (N = 63), carriers of the APOE ε4 allele showed faster cognitive deterioration, while GBA1 mutation carriers also declined more rapidly albeit not significantly., Conclusion: Understanding the genetic effects on survival and progression is crucial for patient counseling and inclusion in clinical trials., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

The spectrum of synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), is characterized by α-synuclein (αSyn) pathology, which serves as the definitive diagnostic marker. However, current diagnostic methods primarily rely on motor symptoms that manifest years after the initial neuropathological changes, thereby delaying potential treatment. The symptomatic overlap between PD and MSA further complicates the diagnosis, highlighting the need for precise and differential diagnostic methods for these overlapping neurodegenerative diseases. αSyn misfolding and aggregation occur before clinical symptoms appear, suggesting that detection of pathological αSyn could enable early molecular diagnosis of synucleinopathies. Recent advances in seed amplification assay (SAA) offer a tool for detecting neurodegenerative diseases by identifying αSyn misfolding in fluid and tissue samples, even at preclinical stages. Extensive research has validated the effectiveness and reproducibility of SAAs for diagnosing synucleinopathies, with ongoing efforts focusing on optimizing conditions for detecting pathological αSyn in more accessible samples and identifying specific αSyn species to differentiate between various synucleinopathies. This review offers a thorough overview of SAA technology, exploring its applications for diagnosing synucleinopathies, addressing the current challenges, and outlining future directions for its clinical use., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Clinical distinction between dementia with Lewy bodies (DLB) and late-onset Alzheimer's disease (AD) is difficult, while several features might affect the analyses of biomarkers. This study aimed to verify associations of anthropometric and demographic features with cerebrospinal fluid biomarkers, their ratios, and restructured traditional regression formulas in patients with DLB and AD, as well as in cognitively healthy controls. Consecutive outpatients with DLB were paired with outpatients with AD according to sex, dementia stage, and cognitive status, and with controls according to sex and age to investigate associations of sex, age, dementia duration, total sleep time, body mass index, alcohol use, smoking, sanitation, and APOE-ε4 alleles on the measurement of cerebrospinal fluid α-synuclein, biomarker ratios, and restructured traditional regression formulas involving amyloid-β (Aβ 42 ,Aβ 40 ,Aβ 38 ), tau, and phospho-tau Thr 181 . Overall, 81 participants were included with DLB (n = 27;11 APOE-ε4 +) or AD (n = 27;12 APOE-ε4 +), and controls (n = 27;4 APOE-ε4 +); two thirds were women. Cerebrospinal fluid evidence of amyloidosis and tauopathy was more prevalent among women with AD, while Aβ 42 /Aβ 38 could also discriminate men with DLB from men with AD. Restructured traditional regression formulas had higher diagnostic accuracy for women with AD. Aging, higher body mass index, and APOE-ε4 alleles were associated with amyloidosis in DLB, while only in AD were higher body mass index associated with lower tau pathology load, and more alcohol use associated with higher phospho-tau Thr 181 /Aβ 42 . These findings confirm the effects of anthropometric and demographic features on cerebrospinal fluid biomarkers, and also differences in aberrant amyloidosis and tauopathy between DLB and AD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Dementia with Lewy bodies (DLB) is the second most common age-related neurocognitive pathology after Alzheimer's disease. Animal models characterizing this disease are lacking and their development would ameliorate both the understanding of neuropathological mechanisms underlying DLB as well as the efficacy of pre-clinical studies tackling this disease., Methods: We performed extensive phenotypic characterization of a transgenic mouse model overexpressing, most prominently in the dorsal hippocampus (DH) and frontal cortex (FC), wild-type form of the human α-synuclein gene (mThy1-hSNCA, 12 to 14-month-old males). Moreover, we drew a comparison of our mouse model results to DH- and FC- dependent neuropsychological and neuropathological deficits observed in a cohort of patients including 34 healthy control subjects and 55 prodromal-DLB patients (males and females)., Results: Our study revealed an increase of pathological form of soluble α-synuclein, mainly in the FC and DH of the mThy1-hSNCA model. However, functional impairment as well as increase in transcripts of inflammatory markers and decrease in plasticity-relevant protein level were exclusive to the FC. Furthermore, we did not observe pathophysiological or Tyrosine Hydroxylase alterations in the striatum or substantia nigra, nor motor deficits in our model. Interestingly, the results stemming from the cohort of prodromal DLB patients also demonstrated functional deficits emanating from FC alterations, along with preservation of those usually related to DH dysfunctions., Conclusions: This study demonstrates that pathophysiological impairment of the FC with concomitant DH preservation is observed at an early stage of DLB, and that the mThy1-hSNCA mouse model parallels some markers of this pathology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) are neurodegenerative disorders characterized by the accumulation of α-synuclein aggregates. α-synuclein forms droplets via liquid-liquid phase separation (LLPS), followed by liquid-solid phase separation (LSPS) to form amyloids, how this process is physiologically-regulated remains unclear. β-synuclein colocalizes with α-synuclein in presynaptic terminals. Here, we report that β-synuclein partitions into α-synuclein condensates promotes the LLPS, and slows down LSPS of α-synuclein, while disease-associated β-synuclein mutations lose these capacities. Exogenous β-synuclein improves the movement defects and prolongs the lifespan of an α-synuclein-expressing NL5901 Caenorhabditis elegans strain, while disease-associated β-synuclein mutants aggravate the symptoms. Decapeptides targeted at the α-/β-synuclein interaction sites are rationally designed, which suppress the LSPS of α-synuclein, rescue the movement defects, and prolong the lifespan of C. elegans NL5901. Together, we unveil a Yin-Yang balance between α- and β-synuclein underlying the normal and disease states of PD and DLB with therapeutical potentials., (© 2024. The Author(s).)

Genome-wide association studies have successfully identified many genetic risk loci for dementia, but exact biological mechanisms through which genetic risk factors contribute to dementia remains unclear. Integrating CSF proteomic data with dementia risk loci could reveal intermediate molecular pathways connecting genetic variance to the development of dementia. We tested to what extent effects of known dementia risk loci can be observed in CSF levels of 665 proteins [proximity extension-based (PEA) immunoassays] in a deeply-phenotyped mixed memory clinic cohort [n = 502, mean age (standard deviation, SD) = 64.1 (8.7) years, 181 female (35.4%)], including patients with Alzheimer's disease (AD, n = 213), dementia with Lewy bodies (DLB, n = 50) and frontotemporal dementia (FTD, n = 93), and controls (n = 146). Validation was assessed in independent cohorts (n = 99 PEA platform, n = 198, mass reaction monitoring-targeted mass spectroscopy and multiplex assay). We performed additional analyses stratified according to diagnostic status (AD, DLB, FTD and controls separately), to explore whether associations between CSF proteins and genetic variants were specific to disease or not. We identified four AD risk loci as protein quantitative trait loci (pQTL): CR1-CR2 (rs3818361, P = 1.65 × 10-8), ZCWPW1-PILRB (rs1476679, P = 2.73 × 10-32), CTSH-CTSH (rs3784539, P = 2.88 × 10-24) and HESX1-RETN (rs186108507, P = 8.39 × 10-8), of which the first three pQTLs showed direct replication in the independent cohorts. We identified one AD-specific association between a rare genetic variant of TREM2 and CSF IL6 levels (rs75932628, P = 3.90 × 10-7). DLB risk locus GBA showed positive trans effects on seven inter-related CSF levels in DLB patients only. No pQTLs were identified for FTD loci, either for the total sample as for analyses performed within FTD only. Protein QTL variants were involved in the immune system, highlighting the importance of this system in the pathophysiology of dementia. We further identified pQTLs in stratified analyses for AD and DLB, hinting at disease-specific pQTLs in dementia. Dissecting the contribution of risk loci to neurobiological processes aids in understanding disease mechanisms underlying dementia., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Mutations in the LRRK2 gene are the most common genetic cause of Parkinson disease but are believed to play no significant role in Lewy body disease (LBD)., Objectives: As the frequency of G2019S LRRK2 mutation is extremely high in North African patients with Parkinson disease, we postulate that the high prevalence of LBD in North Africa might be due to the same mutation because LBD and Parkinson disease share many clinical, pathological, and genetic features., Methods: We screened patients with LBD or prodromal LBD for the G2019S mutation of LRRK2., Results: A total of 162 patients were tested for the mutation, which was present in 5 of the 47 patients with North African ancestors. This is a much higher prevalence (10.6%) than in healthy North African subjects (1.45%) but lower than in North African patients with Parkinson disease (36% to 39%). Carriers tended to develop more often orthostatic hypotension and swallowing problems., Conclusions: Where previous studies in European and North American patients found no link between LRRK2 mutations and LBD, we found an LRRK2 mutation associated with Lewy body disease, namely the G2019S mutation that might be restricted to patients with North African ancestors. Our study illustrates the need to introduce ethnic diversity as stratifying factor in the analysis of genetic causes of neurodegenerative disorders. The current development of disease-modifying drugs modulating LRRK2 kinase activity could justify to screen North African patients with LBD for the G2019S LRRK2 mutation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Lewy body dementia (LBD) is a neurodegenerative disorder characterized by the accumulation of Lewy bodies, which primarily composed of misfolded alpha-synuclein (αS). The development of LBD and APOE4 subtypes is thought to be associated with disorders of lipid metabolism. In this study, we investigated the causal relationship between serum lipids, liposomes and LBD using a two-sample Mendelian randomization (TSMR) method., Methods: A TSMR analysis of genome-wide association study (GWAS) data for 8 serum lipids, 179 lipidomes components, LBD and its subtypes was performed, using inverse variance weighted as the primary outcome. To ensure robustness, the sensitivity analyses including MR Pleiotropy RESidual Sum and Outlier, Cochran's test, leave-one-out method and funnel plots were performed., Results: In this study, we found that low-density lipoprotein cholesterol (LDL-C) (OR=1.45, 95% CI=1.19-1.77, P<0.001) and remnant cholesterol (RC) (OR=2.64, 95% CI=1.64-4.28, P<0.001) had significant positive causal effects on LBD, and RC also had a positive effect on LBD in carriers of the APOE4 gene. The results of lipidome analysis showed that phosphatidylcholine (PC) (O-16:0&#95;20:4) levels (OR=0.86, 95% CI=0.75-0.98, P=0.02) and PC (O-18:1&#95;20:4) levels (OR=0.76, 95% CI=0.65-0.89, P <0.001) had negative causal effects on LBD, whereas phosphatidylinositol (PI) (18:1&#95;20:4) levels had a positive causal effect on LBD (OR=1.19, 95% CI=1.02-1.39, P=0.03). For LBD with APOE4 carriers, high levels of PC (16:1&#95;18:0) and PC (O-18:2&#95;18:1) had a significant positive effect, while high levels of PC (O-16:1&#95;18:0), phosphatidylethanolamine (PE) (O-18:2&#95;18:1), sphingomyelin (SM) (d38:2), and triacylglycerol (TAG) (56:5) significantly reduced the risk. No heterogeneity and horizontal pleiotropy were observed in sensitivity analysis., Conclusion: Elevated LDL-C and RC levels are significant risk factors for LBD, with RC also impacting APOE4-carrying LBD. Glycerophospholipids play a crucial role in the pathogenesis of LBD, but the specific components that play a role differ from those with the APOE4 carries. These findings highlight the importance of lipid metabolism in LBD and APOE4 subtypes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Fu, Pan, Yu, Liu, Shen, Ma and Jiang.)

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.

Observational and genetic studies have reported the relationship between dyslexia and Alzheimer's disease (AD). Until now, the causal effect of dyslexia on AD risk has remained unclear. We conducted a two-sample univariable Mendelian randomization (MR) analysis to determine the causal association between dyslexia and the risk of AD, vascular dementia (VD), Lewy body dementia (LBD), and frontotemporal dementia (FTD) and its four subtypes. First, we selected 42 dyslexia genetic variants from a large-scale genome-wide association studies (GWAS) dataset and extracted their corresponding GWAS summary statistics from AD, VD, LBD, and FTD. Second, we selected four MR methods, including inverse-variance weighted (IVW), weighted median, MR-Egger, and MR-PRESSO. Heterogeneity, horizontal pleiotropy, and leave-one-out sensitivity analysis were then used to evaluate the reliability of all causal estimates. We also conducted multivariable MR (MVMR) and mediation analysis to assess the potential mediating role of cognitive performance (CP) or educational achievement (EA) on the causal association between dyslexia and AD. Two MVMR methods, including MV IVW and MV-Egger, and two-step MR were used to perform the analysis. Using IVW, we found a significant causal association between increased dyslexia and increased risk of AD (OR = 1.15, 95% CI: 1.04-1.28, P = 0.006), but not VD, LBD, FTD, or its four subtypes. MR-PRESSO further supported the statistically significant association between dyslexia and AD (OR = 1.15, 95% CI: 1.05-1.27, P = 0.006). All sensitivity analyses confirmed the reliability of causal estimates. Using MV IVW and mediation analysis, we found no causal relationship between dyslexia and AD after adjusting for CP but not EA, CP mediated the total effect of dyslexia on AD with a proportion of 46.32%. We provide genetic evidence to support a causal effect of increased dyslexia on increased risk of AD, which was largely mediated by CP. Reading activity may be a potential intervention strategy for AD by improving cognitive function., (© 2024. The Author(s).)

Background: The term rapidly progressive dementia (RPD) with Lewy bodies (rpDLB) is used for DLB patients who develop a rapidly progressive neurological syndrome and have reduced survival. Here, we characterise the clinical, neuropathological, and molecular characteristics of a large rpDLB neuropathological series., Methods: We included all RPD patients with a disease duration < 4 years submitted to our prion disease referral centre between 2003 and 2022 who showed Lewy body pathology (LBP) in limbic or neocortical stages as primary neuropathological diagnosis, had no systemic condition justifying the rapid deterioration and were previously neurologically unimpaired. Clinical features were retrieved and compared with Creutzfeldt-Jakob disease (CJD) and rapidly progressive Alzheimer's disease (rpAD) cohorts. Neuropathological and genetic (whole exome sequencing, APOE genotyping, and C9orf72 repeat expansion analysis) characteristics of rpDLB patients were systematically investigated. We scored semi-quantitatively the LBP load and performed a α-synuclein (αSyn) RT-QuIC seeding amplification assay (SAA) on cerebrospinal fluid (CSF) and tenfold serially diluted brain homogenates from different brain areas in rpDLB patients and typical long-lasting Lewy body disease (LBD) with dementia patients as control group., Results: RpDLB patients were older (p = 0.047) and presented more cognitive fluctuations (p = 0.005), visual hallucinations (p = 0.020), neuropsychiatric symptoms (p = 0.006) and seizures (p = 0.032), and fewer cerebellar (p < 0.001) and visual (p = 0.004) signs than CJD ones. Delirium onset was more common than in both CJD (p < 0.001) and rpAD (p = 0.008). Atypical LBD signs (pyramidal, myoclonus, akinetic mutism) were common. All tested patients were positive by CSF αSyn SAA. Concomitant pathologies were common, with only four cases showing relatively "pure" LBP. LBP load and αSyn seeding activity measured through αSyn RT-QuIC SAA were not significantly different between rpDLB patients and typical LBD. We found a likely pathogenic variant in GBA in one patient., Conclusions: Our results indicate that: 1) rpDLB exhibits a distinct clinical signature (2) CSF αSyn SAA is a reliable diagnostic test; 3) rpDLB is a heterogeneous neuropathological entity that can be underlain by both widespread pure LBP, or multiple copathologies 4) rpDLB is likely not sustained by distinct αSyn conformational strains; 5) genetic defects may, at least occasionally, contribute to the poor prognosis in these patients., (© 2024. The Author(s).)

Lewy body diseases (LBD) comprise a group of complex neurodegenerative conditions originating from accumulation of misfolded alpha-synuclein (α-syn) in the form of Lewy bodies. LBD pathologies are characterized by α-syn deposition in association with other proteins such as Amyloid β (Aβ), Tau, and TAR-DNA-binding protein. To investigate the complex interactions of these proteins, we constructed 2 novel transgenic overexpressing (OE) C. elegans strains (α-syn A53T ;Tau pro-agg (OE) and α-syn A53T ;Aβ1-42;Tau pro-agg (OE)) and compared them with previously established Parkinson's, Alzheimer's, and Lewy Body Dementia disease models. The LBD models presented here demonstrate impairments including uncoordinated movement, egg-laying deficits, altered serotonergic and cholinergic signaling, memory and posture deficits, as well as dopaminergic neuron damage and loss. Expression levels of total and prone to aggregation α-syn protein were increased in α-syn A53T ;Aβ 1-42 but decreased in α-syn A53T ;Tau pro-agg animals when compared to α-syn A53T animals suggesting protein interactions. These alterations were also observed at the mRNA level suggesting a pre-transcriptional mechanism. miRNA-seq revealed that cel-miR-1018 was upregulated in LBD models α-syn A53T , α-syn A53T ;Aβ 1-42 , and α-syn A53T ;Tau pro-agg compared with WT. cel-miR-58c was upregulated in α-syn A53T ;Tau pro-agg but downregulated in α-syn A53T and α-syn A53T ;Aβ 1-42 compared with WT. cel-miR-41-3p and cel-miR-355-5p were significantly downregulated in 3 LBD models. Our results obtained in a model organism provide evidence of interactions between different pathological proteins and alterations in specific miRNAs that may further exacerbate or ameliorate LBD pathology., (© 2024. The Author(s).)

Neurodegenerative diseases are commonly classified as proteinopathies that are defined by the aggregation of a specific protein. Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are classified as synucleinopathies since α-synuclein (α-syn)-containing inclusions histopathologically define these diseases. Unbiased biochemical analysis of PD and DLB patient material unexpectedly revealed novel pathological inclusions in the nucleus comprising adenosine-to-inosine (A-to-I)-edited mRNAs and NONO and SFPQ proteins. These inclusions showed no colocalization with Lewy bodies and accumulated at levels comparable to α-syn. NONO and SFPQ aggregates reduced the expression of the editing inhibitor ADAR3, increasing A-to-I editing mainly within human-specific, Alu-repeat regions of axon, synaptic, and mitochondrial transcripts. Inosine-containing transcripts aberrantly accumulated in the nucleus, bound tighter to recombinant purified SFPQ in vitro, and potentiated SFPQ aggregation in human dopamine neurons, resulting in a self-propagating pathological state. Our data offer new insight into the inclusion composition and pathophysiology of PD and DLB., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The mechanisms responsible for neuronal death causing cognitive loss in Alzheimer's disease (AD) and many other dementias are not known. Serum amyloid P component (SAP) is a constitutive plasma protein, which is cytotoxic for cerebral neurones and also promotes formation and persistence of cerebral A β amyloid and neurofibrillary tangles. Circulating SAP, which is produced exclusively by the liver, is normally almost completely excluded from the brain. Conditions increasing brain exposure to SAP increase dementia risk, consistent with a causative role in neurodegeneration. Furthermore, neocortex content of SAP is strongly and independently associated with dementia at death. Here, seeking genomic evidence for a causal link of SAP with neurodegeneration, we meta-analysed three genome-wide association studies of 44 288 participants, then conducted cis -Mendelian randomization assessment of associations with neurodegenerative diseases. Higher genetically instrumented plasma SAP concentrations were associated with AD (odds ratio 1.07, 95% confidence interval (CI) 1.02; 1.11, p = 1.8 × 10 -3 ), Lewy body dementia (odds ratio 1.37, 95%CI 1.19; 1.59, p = 1.5 × 10 -5 ) and plasma tau concentration (0.06 log 2 (ng l -1 ) 95%CI 0.03; 0.08, p = 4.55 × 10 -6 ). These genetic findings are consistent with neuropathogenicity of SAP. Depletion of SAP from the blood and the brain, by the safe, well tolerated, experimental drug miridesap may thus be neuroprotective.

Background: The GPNMB single-nucleotide polymorphism rs199347 and GBA1 variants both associate with Lewy body disorder (LBD) risk. GPNMB encodes glycoprotein nonmetastatic melanoma protein B (GPNMB), a biomarker for GBA1-associated Gaucher's disease., Objective: The aim of this study was to determine whether GPNMB levels (1) differ in LBD with and without GBA1 variants and (2) associate with rs199347 genotype., Methods: We quantified GPNMB levels in plasma and cerebrospinal fluid (CSF) from 124 individuals with LBD with one GBA1 variant (121 plasma, 14 CSF), 631 individuals with LBD without GBA1 variants (626 plasma, 41 CSF), 9 neurologically normal individuals with one GBA1 variant (plasma), and 2 individuals with two GBA1 variants (plasma). We tested for associations between GPNMB levels and rs199347 or GBA1 status., Results: GPNMB levels associate with rs199347 genotype in plasma (P = 0.022) and CSF (P = 0.007), but not with GBA1 status., Conclusions: rs199347 is a protein quantitative trait locus for GPNMB. GPNMB levels are unaltered in individuals carrying one GBA1 variant. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Previous observational investigations suggest that structural and diffusion imaging-derived phenotypes (IDPs) are associated with major neurodegenerative diseases; however, whether these associations are causal remains largely uncertain. Herein we conducted bidirectional two-sample Mendelian randomization analyses to infer the causal relationships between structural and diffusion IDPs and major neurodegenerative diseases using common genetic variants-single nucleotide polymorphism (SNPs) as instrumental variables. Summary statistics of genome-wide association study (GWAS) for structural and diffusion IDPs were obtained from 33,224 individuals in the UK Biobank cohort. Summary statistics of GWAS for seven major neurodegenerative diseases were obtained from the largest GWAS for each disease to date. The forward MR analyses identified significant or suggestively statistical causal effects of genetically predicted three structural IDPs on Alzheimer's disease (AD), frontotemporal dementia (FTD), and multiple sclerosis. For example, the reduction in the surface area of the left superior temporal gyrus was associated with a higher risk of AD. The reverse MR analyses identified significantly or suggestively statistical causal effects of genetically predicted AD, Lewy body dementia (LBD), and FTD on nine structural and diffusion IDPs. For example, LBD was associated with increased mean diffusivity in the right superior longitudinal fasciculus and AD was associated with decreased gray matter volume in the right ventral striatum. Our findings might contribute to shedding light on the prediction and therapeutic intervention for the major neurodegenerative diseases at the neuroimaging level., (© 2024. The Author(s).)

ApoE4 as a risk factor for dementia with Lewy bodies (DLB) is still an issue. We sought to determine the involvement of ApoE4 according to different clinical parameters in our cohort of patients from Strasbourg, France. ApoE genotyping was performed on the AlphaLewyMA cohort. In this cohort, 197 patients were genotyped: 105 DLB patients, 37 Alzheimer's disease (AD) patients, 29 patients with AD/DLB comorbidity, and 26 control subjects (CS). The groups of patients were also classified according to the stage of evolution of the disease: prodromal or demented. We analyzed other parameters in relation to ApoE4 status, such as years of education (YOE) and Alzheimer CSF biomarkers. We observed a higher proportion of ApoE4 carriers in the AD (51.4%) and AD/DLB (72.4%) groups compared to the DLB (25.7%) and CS (11.5%) groups (p < 0.0001). We found a correlation between age at disease onset and YOE in the AD group (p = 0.039) but not in the DLB group (p = 0.056). Interestingly, in the DLB group, the subgroup of patients with high YOE (≥ 11) had significantly more patients with ApoE4 than the subgroup with low YOE (< 11). AD biomarkers did not seem to be impacted by the presence of ApoE4, except for Aβ42: DLB ApoE4-positive demented patients showed a more marked Aβ42 decrease. ApoE4 does not appear to be a risk factor for "pure" DLB patients. These results suggest a strong link between ApoE4 and amyloidopathy and consequently with AD. Trial registration: AlphaLewyMa, Identifier: NCT01876459, date of registration: June 12, 2013., (© 2023. The Author(s), under exclusive licence to American Aging Association.)

The conventional method of one drug being used for one target has not yielded therapeutic solutions for Lewy body dementia (LBD), which is a leading progressive neurological disorder characterized by significant loss of neurons. The age-related disease is marked by memory loss, hallucinations, sleep disorder, mental health deterioration, palsy, and cognitive impairment, all of which have no known effective cure. The present study deploys a network medicine pipeline to repurpose drugs having considerable effect on the genes and proteins related to the diseases of interest. We utilized the novel SAveRUNNER algorithm to quantify the proximity of all drugs obtained from DrugBank with the disease associated gene dataset obtained from Phenopedia and targets in the human interactome. We found that most of the 154 FDA-approved drugs predicted by SAveRUNNER were used to treat nervous system disorders, but some off-label drugs like quinapril and selegiline were interestingly used to treat hypertension and Parkinson's disease (PD), respectively. Additionally, we performed gene set enrichment analysis using Connectivity Map (CMap) and pathway enrichment analysis using EnrichR to validate the efficacy of the drug candidates obtained from the pipeline approach. The investigation enabled us to identify the significant role of the synaptic vesicle pathway in our disease and accordingly finalize 8 suitable antidepressant drugs from the 154 drugs initially predicted by SAveRUNNER. These potential anti-LBD drugs are either selective or non-selective inhibitors of serotonin, dopamine, and norepinephrine transporters. The validated selective serotonin and norepinephrine inhibitors like milnacipran, protriptyline, and venlafaxine are predicted to manage LBD along with the affecting symptomatic issues., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Lewy body dementia (LBD) ranks second among prevalent neurodegenerative dementias. Previous studies have revealed associations of serum lipid measures with several neurodegenerative diseases. Nevertheless, the potential connection between serum lipids and LBD remains undetermined. In this study, Mendelian randomization (MR) analyses were carried out to assess the causal relationships of several serum lipid measures with the risk of developing LBD., Methods: Genome-wide association study (GWAS) data for serum lipids and LBD in European descent individuals were acquired from publicly available genetic summary data. A series of filtering procedures were conducted to identify the genetic variant candidates that are related to serum lipids, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). The causal effects were primarily determined through inverse-variance weighting (IVW)-based analyses., Results: Neither TG (odds ratio [OR] = 1.149; 95% confidence interval [CI], 0.887-1.489; P = 0.293) nor HDL-C (OR = 0.864; 95% CI, 0.718-1.041; P = 0.124) had causal effects on LBD. However, a causal relationship was identified between LDL-C and LBD (OR = 1.343; 95% CI, 1.094-1.649; P = 0.005), which remained significant (OR = 1.237; 95% CI, 1.015-1.508; P = 0.035) following adjustment for HDL-C and TG in multivariable MR., Conclusions: Elevated serum LDL-C increases the risk of LBD, while HDL-C and TG have no significant causal effects on LBD., (© 2024. The Author(s).)

Autosomal dominant variants in LRP10 have been identified in patients with Lewy body diseases (LBDs), including Parkinson's disease (PD), Parkinson's disease-dementia (PDD), and dementia with Lewy bodies (DLB). Nevertheless, there is little mechanistic insight into the role of LRP10 in disease pathogenesis. In the brains of control individuals, LRP10 is typically expressed in non-neuronal cells like astrocytes and neurovasculature, but in idiopathic and genetic cases of PD, PDD, and DLB, it is also present in α-synuclein-positive neuronal Lewy bodies. These observations raise the questions of what leads to the accumulation of LRP10 in Lewy bodies and whether a possible interaction between LRP10 and α-synuclein plays a role in disease pathogenesis. Here, we demonstrate that wild-type LRP10 is secreted via extracellular vesicles (EVs) and can be internalised via clathrin-dependent endocytosis. Additionally, we show that LRP10 secretion is highly sensitive to autophagy inhibition, which induces the formation of atypical LRP10 vesicular structures in neurons in human-induced pluripotent stem cells (iPSC)-derived brain organoids. Furthermore, we show that LRP10 overexpression leads to a strong induction of monomeric α-synuclein secretion, together with time-dependent, stress-sensitive changes in intracellular α-synuclein levels. Interestingly, patient-derived astrocytes carrying the c.1424 + 5G > A LRP10 variant secrete aberrant high-molecular-weight species of LRP10 in EV-free media fractions. Finally, we show that this truncated patient-derived LRP10 protein species (LRP10 splice ) binds to wild-type LRP10, reduces LRP10 wild-type levels, and antagonises the effect of LRP10 on α-synuclein levels and distribution. Together, this work provides initial evidence for a possible functional role of LRP10 in LBDs by modulating intra- and extracellular α-synuclein levels, and pathogenic mechanisms linked to the disease-associated c.1424 + 5G > A LRP10 variant, pointing towards potentially important disease mechanisms in LBDs., (© 2024. The Author(s).)

Objective: Dementia with Lewy bodies (DLB) is the second most common dementia. Advancing our limited understanding of its molecular pathogenesis is essential for identifying novel biomarkers and therapeutic targets for DLB. DLB is an α-synucleinopathy, and small extracellular vesicles (SEV) from people with DLB can transmit α-synuclein oligomerisation between cells. Post-mortem DLB brains and serum SEV from those with DLB share common miRNA signatures, and their functional implications are uncertain. Hence, we aimed to investigate potential targets of DLB-associated SEV miRNA and to analyse their functional implications., Methods: We identified potential targets of six previously reported differentially expressed miRNA genes in serum SEV of people with DLB ( MIR26A1 , MIR320C2 , MIR320D2 , MIR548BA , MIR556 , and MIR4722 ) using miRBase and miRDB databases. We analysed functional implications of these targets using EnrichR gene set enrichment analysis and analysed their protein interactions using Reactome pathway analysis., Results: These SEV miRNA may regulate 4278 genes that were significantly enriched among the genes involved in neuronal development, cell-to-cell communication, vesicle-mediated transport, apoptosis, regulation of cell cycle, post-translational protein modifications, and autophagy lysosomal pathway, after Benjamini-Hochberg false discovery rate correction at 5%. The miRNA target genes and their protein interactions were significantly associated with several neuropsychiatric disorders and with multiple signal transduction, transcriptional regulation, and cytokine signalling pathways., Conclusion: Our findings provide in-silico evidence that potential targets of DLB-associated SEV miRNAs may contribute to Lewy pathology by transcriptional regulation. Experimental validation of these dysfunctional pathways is warranted and could lead to novel therapeutic avenues for DLB.

Dementia with Lewy bodies (DLB) is a significant public health issue. It is the second most common neurodegenerative dementia and presents with severe neuropsychiatric symptoms. Genomic and transcriptomic analyses have provided some insight into disease pathology. Variants within SNCA , GBA , APOE , SNCB , and MAPT have been shown to be associated with DLB in repeated genomic studies. Transcriptomic analysis, conducted predominantly on candidate genes, has identified signatures of synuclein aggregation, protein degradation, amyloid deposition, neuroinflammation, mitochondrial dysfunction, and the upregulation of heat-shock proteins in DLB. Yet, the understanding of DLB molecular pathology is incomplete. This precipitates the current clinical position whereby there are no available disease-modifying treatments or blood-based diagnostic biomarkers. Data science methods have the potential to improve disease understanding, optimising therapeutic intervention and drug development, to reduce disease burden. Genomic prediction will facilitate the early identification of cases and the timely application of future disease-modifying treatments. Transcript-level analyses across the entire transcriptome and machine learning analysis of multi-omic data will uncover novel signatures that may provide clues to DLB pathology and improve drug development. This review will discuss the current genomic and transcriptomic understanding of DLB, highlight gaps in the literature, and describe data science methods that may advance the field.

Dementia with Lewy bodies (DLB) is a common form of dementia in the elderly population. We performed genome-wide DNA methylation mapping of cerebellar tissue from pathologically confirmed DLB cases and controls to study the epigenetic profile of this understudied disease. After quality control filtering, 728,197 CpG-sites in 278 cases and 172 controls were available for the analysis. We undertook an epigenome-wide association study, which found a differential methylation signature in DLB cases. Our analysis identified seven differentially methylated probes and three regions associated with DLB. The most significant CpGs were located in ARSB (cg16086807), LINC00173 (cg18800161), and MGRN1 (cg16250093). Functional enrichment evaluations found widespread epigenetic dysregulation in genes associated with neuron-to-neuron synapse, postsynaptic specialization, postsynaptic density, and CTCF-mediated synaptic plasticity. In conclusion, our study highlights the potential importance of epigenetic alterations in the pathogenesis of DLB and provides insights into the modified genes, regions and pathways that may guide therapeutic developments., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Although observational studies indicated connections between fatty acids (FAs) and Alzheimer's disease and dementia, uncertainty persists regarding how these relationships extend to dementia with Lewy bodies (DLB)., Objective: To explore the potential causal relationships between FAs and the development of DLB, thus clarifying these associations using genetic instruments to infer causality., Methods: We applied a two-sample Mendelian randomization (MR) and multivariable Mendelian randomization (MVMR) approach. Genetic data were obtained from a DLB cohort, comprising 2,591 cases and 4,027 controls of European descent. Eight FAs, including linoleic acid, docosahexaenoic acid, monounsaturated fatty acid, omega-3 fatty acid, omega-6 fatty acid, polyunsaturated fatty acid, saturated fatty acid, and total fatty acid, were procured from a comprehensive GWAS of metabolic biomarkers of UK Biobank, conducted by Nightingale Health in 2020 (met-d), involving 114,999 individuals. Our analysis included inverse-variance weighted, MR-Egger, weighted-median, simple mode, and weighted-mode MR estimates. Cochran's Q-statistics, MR-PRESSO, and MR-Egger intercept test were used to quantify the heterogeneity and horizontal pleiotropy of instrumental variables., Results: Only linoleic acid showed a significant genetic association with the risk of developing DLB in the univariate MR. The odds ratio for linoleic acid was 1.337 with a 95% confidence interval of 1.019-1.756 (pIVW = 0.036). Results from the MVMR showed that no FAs were associated with the incidence of DLB., Conclusions: The results did not support the hypothesis that FAs could reduce the risk of developing DLB. However, elucidating the relationship between FAs and DLB risk holds potential implications for informing dietary recommendations and therapeutic approaches in DLB.

Background: Neuroinflammation, with altered peripheral proinflammatory cytokine production, plays a major role in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD), while the role of inflammation in dementia with Lewy bodies (DLB) is less known and the results of different studies are often in disagreement., Objective: The present study aimed to investigate the levels of TNFα and IL-6 in serum and supernatants, and the related DNA methylation in patients affected by DLB and AD compared to healthy controls (HCs), to clarify the role of epigenetic mechanisms of DNA promoter methylation on of pro-inflammatory cytokines overproduction., Methods: Twenty-one patients with DLB and fourteen with AD were frequency-matched for age and sex with eleven HCs. Clinical evaluation, TNFα and IL-6 gene methylation status, cytokine gene expression levels and production in serum and peripheral blood mononuclear cell (PBMC) supernatants were performed., Results: In AD and DLB patients, higher serum levels of IL-6 and TNFα were detected than in HCs. Differences in LPS-stimulated versus spontaneous PBMCs were observed between DLB, AD, and HC in the levels of TNFα (p = 0.027) and IL-6 (p < 0.001). Higher levels were also revealed for sIL-6R in DLB (p < 0.001) and AD (p < 0.001) in comparison with HC.DNA hypomethylation in IL-6 and TNFα CpG promoter sites was detected for DLB and AD patients compared to the corresponding site in HCs., Conclusions: Our preliminary study documented increased levels of IL-6 and TNFα in DLB and AD patients to HCs. This overproduction can be due to epigenetic mechanisms regarding the hypomethylation of DNA promoters.

Background: Apolipoprotein E ε4 allele (APOE-ε4) is the main genetic risk factor for late-onset Alzheimer's disease (AD) and may impact cognitive function also via other neuropathological lesions. However, there is limited evidence available from diverse populations, as APOE associations with dementia seem to differ by race. Therefore, we aimed to evaluate the pathways linking APOE-ε4 to cognitive abilities through AD and non-AD neuropathology in an autopsy study with an admixed sample., Methods: Neuropathological lesions were evaluated following international criteria using immunohistochemistry. Participants were classified into APOE-ε4 carriers (at least one ε4 allele) and non-carriers. Cognitive abilities were evaluated by the Clinical Dementia Rating Scale sum of boxes. Mediation analyses were conducted to assess the indirect association of APOE-ε4 with cognition through AD-pathology, lacunar infarcts, hyaline arteriosclerosis, cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), and TAR DNA-binding protein 43 (TDP-43)., Results: We included 648 participants (mean age 75 ± 12 years old, mean education 4.4 ± 3.7 years, 52% women, 69% White, and 28% APOE-ε4 carriers). The association between APOE-ε4 and cognitive abilities was mediated by neurofibrillary tangles (β = 0.88, 95% CI = 0.45; 1.38, p < 0.001) and neuritic plaques (β = 1.36, 95% CI = 0.86; 1.96, p < 0.001). Lacunar infarcts, hyaline arteriosclerosis, CAA, LBD, and TDP-43 were not mediators in the pathway from APOE-ε4 to cognition., Conclusion: The association between APOE-ε4 and cognitive abilities was partially mediated by AD-pathology. On the other hand, cerebrovascular lesions and other neurodegenerative diseases did not mediate the association between APOE-ε4 and cognition., (© 2023. The Author(s).)

Overlapping symptoms and co-pathologies are common in closely related neurodegenerative diseases (NDDs). Investigating genetic risk variants across these NDDs can give further insight into disease manifestations. In this study we have leveraged genome-wide single nucleotide polymorphisms and genome-wide association study summary statistics to cluster patients based on their genetic status across identified risk variants for five NDDs (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Lewy body dementia and frontotemporal dementia). The multi-disease and disease-specific clustering results presented here provide evidence that NDDs have more overlapping genetic aetiology than previously expected and how neurodegeneration should be viewed as a spectrum of symptomology. These clustering analyses also show potential subsets of patients with these diseases that are significantly depleted for any known common genetic risk factors suggesting environmental or other factors at work. Establishing that NDDs with overlapping pathologies share genetic risk loci, future research into how these variants might have different effects on downstream protein expression, pathology and NDD manifestation in general is important for refining and treating NDDs., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Dementia with Lewy bodies and Parkinson's disease dementia are common neurodegenerative diseases that share similar neuropathological profiles and spectra of clinical symptoms but are primarily differentiated by the order in which symptoms manifest. The question of whether a distinct molecular pathological profile could distinguish these disorders is yet to be answered. However, in recent years, studies have begun to investigate genomic, epigenomic, transcriptomic and proteomic differences that may differentiate these disorders, providing novel insights in to disease etiology. In this review, we present an overview of the clinical and pathological hallmarks of Lewy body dementias before summarizing relevant research into genetic, epigenetic, transcriptional and protein signatures in these diseases, with a particular interest in those resolving "omic" level changes. We conclude by suggesting future research directions to address current gaps and questions present within the field., (Copyright © 2023. Published by Elsevier Inc.)

PIWI-interacting RNAs (piRNAs) are small noncoding RNAs that regulate gene expression, yet their molecular functions in neurobiology are unclear. While investigating neurodegeneration mechanisms using human α-syn(A53T) Tg and Aβ Tg ;α-syn(A53T) Tg pan-neuronal overexpressing strains, we unexpectedly observed dysregulation of piRNAs. RNAi screening revealed that knock down of piRNA biogenesis genes improved thrashing behavior; further, a tofu-1 gene deletion ameliorated phenotypic deficits in α-syn(A53T) Tg and Aβ Tg ;α-syn(A53T) Tg transgenic strains. piRNA expression was extensively downregulated and H3K9me3 marks were decreased after tofu-1 deletion in α-syn(A53T) Tg and Aβ Tg ;α-syn(A53T) Tg strains. Dysregulated piRNAs targeted protein degradation genes suggesting that a decrease of piRNA expression leads to an increase of degradation ability in C. elegans. Finally, we interrogated piRNA expression in brain samples from PD patients. piRNAs were observed to be widely overexpressed at late motor stage. In this work, our results provide evidence that piRNAs are mediators in pathogenesis of Lewy body diseases and suggest a molecular mechanism for neurodegeneration in these and related disorders., (© 2023. Springer Nature Limited.)

Synucleinopathies-related disorders such as Lewy body dementia (LBD) and isolated/idiopathic REM sleep behavior disorder (iRBD) have been associated with neuroinflammation. In this study, we examined whether the human leukocyte antigen (HLA) locus plays a role in iRBD and LBD. In iRBD, HLA-DRB1*11:01 was the only allele passing FDR correction (OR = 1.57, 95% CI = 1.27-1.93, p = 2.70e-05). We also discovered associations between iRBD and HLA-DRB1 70D (OR = 1.26, 95%CI = 1.12-1.41, p = 8.76e-05), 70Q (OR = 0.81, 95%CI = 0.72-0.91, p = 3.65e-04) and 71R (OR = 1.21, 95%CI = 1.08-1.35, p = 1.35e-03). Position 71 (p omnibus  = 0.00102) and 70 (p omnibus  = 0.00125) were associated with iRBD. Our results suggest that the HLA locus may have different roles across synucleinopathies., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

NPC1 encodes a lysosomal protein involved in cholesterol transport. Biallelic mutations in this gene may lead to Niemann-Pick disease type C (NPC), a lysosomal storage disorder. The role of NPC1 in alpha synucleinopathies is still unclear, as different genetic, clinical, and pathological studies have reported contradictory results. This study aimed to evaluate the association of NPC1 variants with the synucleinopathies Parkinson's disease (PD), dementia with Lewy bodies (DLB), and rapid eye movement-sleep behavior disorder (RBD). We analyzed common and rare variants from 3 cohorts of European descent: 1084 RBD cases and 2945 controls, 2852 PD cases and 1686 controls, and 2610 DLB cases and 1920 controls. Logistic regression models were used to assess common variants while optimal sequence Kernel association tests were used to assess rare variants, both adjusted for sex, age, and principal components. No variants were associated with any of the synucleinopathies, supporting that common and rare NPC1 variants do not play an important role in alpha synucleinopathies., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Neurodegenerative diseases are a group of disorders characterized by neuronal cell death causing a variety of physical and mental problems. While these disorders can be characterized by their phenotypic presentation within the nervous system, their aetiologies differ to varying degrees. The majority of previous genetic evidence for overlap between neurodegenerative diseases has been pairwise. In this study, we aimed to identify overlap between the 4 investigated neurodegenerative disorders (Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease) at the variant, gene, genomic locus, gene-set, cell, or tissue level, with specific interest in overlap between 3 or more diseases. Using local genetic correlation, we found 2 loci (TMEM175 and HLA) that were shared across 3 disorders. We also highlighted genes, genomic loci, gene sets, cell types, and tissue types which may be important to 2 or more disorders by analyzing the association of variants with a common factor estimated from the 4 disorders. Our study successfully highlighted genetic loci and tissues associated with 2 or more neurodegenerative diseases., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Abnormalities in the Tri-Carboxylic-Acid (TCA) cycle have been documented in dementia. Through network analysis, TCA cycle metabolites could indirectly reflect known dementia-related abnormalities in biochemical pathways, and key metabolites might be associated with prognosis. This study analyzed TCA cycle metabolites as predictors of cognitive decline in a mild dementia cohort and explored potential interactions with the diagnosis of Lewy Body Dementia (LBD) or Alzheimer's Disease (AD) and APOE-ε4 genotype. We included 145 mild dementia patients (LBD = 59; AD = 86). Serum TCA cycle metabolites were analyzed at baseline, and partial correlation networks were conducted. Cognitive performance was measured annually over 5-years with the Mini-mental State Examination. Longitudinal mixed-effects Tobit models evaluated each baseline metabolite as a predictor of 5-years cognitive decline. APOE-ε4 and diagnosis interactions were explored. Results showed comparable metabolite concentrations in LBD and AD. Multiple testing corrected networks showed larger coefficients for a negative correlation between pyruvate - succinate and positive correlations between fumarate - malate and citrate - Isocitrate in both LBD and AD. In the total sample, adjusted mixed models showed significant associations between baseline citrate concentration and longitudinal MMSE scores. In APOE-ε4 carriers, baseline isocitrate predicted MMSE scores. We conclude that, in mild dementia, serum citrate concentrations could be associated with subsequent cognitive decline, as well as isocitrate concentrations in APOE-ε4 carriers. Downregulation of enzymatic activity in the first half of the TCA cycle (decarboxylating dehydrogenases), with upregulation in the latter half (dehydrogenases only), might be indirectly reflected in serum TCA cycle metabolites' networks., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. and Mitochondria Research Society. All rights reserved. All rights reserved.)

Background: Messenger RNAs (mRNAs) have been reported to be associated with Alzheimer's disease (AD). In this study, we investigated whether plasma-based mRNAs could distinguish AD from cognitively normal controls and other types of dementia, including vascular dementia (VaD), Parkinson's disease dementia (PDD), behavioral variant frontotemporal dementia (bvFTD), and dementia with Lewy body (DLB)., Methods: Plasma mRNA expression was measured in three independent datasets. Dataset 1 (n = 40; controls, 20; AD, 20) was used to identify the differentially expressed mRNAs. Dataset 2 (n = 122; controls: 60; AD: 62) was used to develop a diagnostic AD model using an mRNA panel. Furthermore, we applied the model to Dataset 3 (n = 334; control, 57; AD, 58; VaD, 55; PDD, 54; bvFTD, 55; DLB, 55) to verify its ability to identify AD and other types of dementia., Results: Dataset 1 showed 22 upregulated and 21 downregulated mRNAs. A panel of six mRNAs distinguished AD from the control group in Dataset 2. The panel was used to successfully differentiate AD from other types of dementia in Dataset 3., Conclusions: An AD-specific panel of six mRNAs was created that can be used for AD diagnosis., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Long non-coding RNAs (lncRNAs) have been identified to be involved in the pathogenesis of Alzheimer's disease (AD). In this study, we evaluated whether lncRNAs can be used to discriminate AD patients from controls and patients with other dementias, such as vascular, Parkinson's disease, behavioral variant frontotemporal, and dementia with Lewy body. In this study, we used three datasets to measure the blood lncRNA levels. A pilot study (dataset 1, n = 40; controls, 20; AD, 20) was used to screen for differentially expressed lncRNAs. Dataset 2 (n = 174; controls, 86; AD, 88) was used to identify a lncRNA panel for the diagnostic model. Dataset 3 (n = 333; control, 60; AD, 54; vascular dementia, 53; Parkinson's disease dementia, 55; behavioral variant frontotemporal dementia, 56; and dementia with Lewy body, 55) was used to validate the diagnostic model. In dataset 1, 12 upregulated and 15 downregulated lncRNAs were identified. In dataset 2, a panel of seven lncRNAs was found to have the ability to differentiate AD patients from controls. Finally, this panel was applied to dataset 3 to successfully distinguish AD from other dementias. This study proposes a panel of seven lncRNAs as specific and promising biomarker for AD diagnosis., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Neuropathologically, Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are characterized by the accumulation of insoluble aggregates of α-synuclein (α-syn) in the Lewy bodies (LBs). In addition to full-length α-syn fibrils, C-terminally truncated α-syn is also abundant in the LBs that acts as seeds and facilitates the aggregation of the full-length α-syn in vitro and in vivo and induces toxicity. Hence, identifying molecules that can inhibit the seeding activity of these truncated forms is of great importance. Here, we report the first in vitro selection of aptamers targeting the fibrillar forms of different C-terminally truncated α-syn using systematic evolution by an exponential enrichment method followed by quantitative high-throughput DNA sequencing. We identify a panel of aptamers that bound with high specificity to different truncated forms of α-syn fibrils with no cross-reactivity toward other amyloid fibrils. Interestingly, two of the aptamers (named Apt11 and Apt15) show higher affinity to most C-terminally truncated forms of α-syn fibrils with an evident inhibition of α-syn-seeded aggregation in vitro by Apt11. This inhibition is further confirmed by circular dichroism, Congo red binding assay, and electronic microscopy. Moreover, Apt11 is also found to reduce the insoluble phosphorylated form of α-syn at Ser-129 (pS129-α-syn) in the cell model and also can inhibit α-syn aggregation using RT-QuIC reactions seeded with brain homogenates extracted from patients affected by PD. The aptamers discovered in this study represent potential useful tools for research and diagnostics or therapy toward PD and DLB.

Dementia with Lewy bodies (DLB) is a common form of dementia with known genetic and environmental interactions. However, the underlying epigenetic mechanisms which reflect these gene-environment interactions are poorly studied. Herein, we measure genome-wide DNA methylation profiles of post-mortem brain tissue (Broadmann area 7) from 15 pathologically confirmed DLB brains and compare them with 16 cognitively normal controls using Illumina MethylationEPIC arrays. We identify 17 significantly differentially methylated CpGs (DMCs) and 17 differentially methylated regions (DMRs) between the groups. The DMCs are mainly located at the CpG islands, promoter and first exon regions. Genes associated with the DMCs are linked to "Parkinson's disease" and "metabolic pathway", as well as the diseases of "severe intellectual disability" and "mood disorders". Overall, our study highlights previously unreported DMCs offering insights into DLB pathogenesis with the possibility that some of these could be used as biomarkers of DLB in the future., (© 2022. Crown.)

Objective: To compare event-related oscillations in patients with dementia with Lewy bodies (DLB) who are carriers and non-carriers of glucocerebrosidase (GBA) mutations., Methods: EEG was recorded during a visual oddball task in eight Ashkenazi Jewish DLB patients with the N370S mutation in theGBAgene (GBA-DLB) and eleven DLB non-carriers. The time-frequency power and inter-trial phase clustering were calculated from the Morlet wavelet convolution for the midline electrodes., Results: Task performance and cognitive assessments were comparable between groups. While the within-non-GBA-DLB group analysis revealed delta-band power synchronization relative to the baseline (p = 0.01, Cohen's d = 1.0), the within-GBA-DLB-group analysis detected no event-related changes in power. Both groups showed an increase relative to the baseline in the delta and theta bands inter-trial phase clustering (all p < 0.03, d > 1.3). The between-group analysis revealed that event-related power - but not clustering - was lower in GBA-DLB compared to non-carriers in the delta band at Fz and Cz (p = 0.04, d = -0.9)., Conclusions: GBA-DLB patients showed decreased delta-band power compared to non-carriers despite the similar cognitive performance, whereas inter-trial phase clustering was comparable in both groups., Significance: Preserved inter-trial phase clustering possibly compensates for the impaired power by eliciting the appropriate functional configuration needed for stimulus processing and task performance., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Progressive age is the single major risk factor for neurodegenerative diseases. Cellular aging markers during Parkinson's disease (PD) have been implicated in previous studies, however the majority of studies have investigated the association of individual cellular aging hallmarks with PD but not jointly. Here, we have studied the association of PD with three aging hallmarks (telomere attrition, mitochondrial dysfunction, and cellular senescence) in blood and the brain tissue. Our results show that PD patients had 20% lower mitochondrial DNA copies but 26% longer telomeres in blood compared to controls. Moreover, telomere length in blood was positively correlated with medication (Levodopa Equivalent Daily Dose, LEDD) and disease duration. Similar results were found in brain tissue, where patients with Parkinson's disease (PD), Parkinson's disease dementia (PDD) and Dementia with Lewy Bodies (DLB) showed (46-95%) depleted mtDNA copies, but (7-9%) longer telomeres compared to controls. In addition, patients had lower mitochondrial biogenesis (PGC-1α and PGC-1β) and higher load of a cellular senescence marker in postmortem prefrontal cortex tissue, with DLB showing the highest effect among the patient groups. Our results suggest that mitochondrial dysfunction (copy number and biogenesis) in blood might be a valuable marker to assess the risk of PD. However, further studies with larger sample size are needed to evaluate these findings., (© 2022. The Author(s).)

Importance: Dementia with Lewy bodies (DLB) is a neurodegenerative disease linked to abnormal accumulation of phosphorylated α-synuclein. GBA1 is the gene encoding the lysosomal enzyme glucocerebrosidase (GCase), whose mutations are a risk factor of DLB., Objective: To report all available data exploring the association between GBA1 mutations and DLB., Evidence Review: All publications focused on GCase and DLB in humans between 2003 and 2022 were identified on PubMed, Cochrane and ClinicalTrials.gov., Findings: 29 studies were included and confirmed the strong association between GBA1 mutations and DLB (Odds Ratio [OR]: 8.28). GBA1 mutation carriers presented a more malignant phenotype, with earlier symptom onset, more severe motor and cognitive dysfunctions, more visual hallucinations and rapid eye movement sleep disorder. GBA1 mutations were associated with "purer" neuropathological DLB. No therapeutic recommendations exist and clinical trials targeting GCase are just starting in DLB patients., Conclusions and Relevance: This review reports a link between GBA1 mutations and the DLB phenotype with limited evidence due to the small number of studies., (Copyright © 2022. Published by Elsevier Ltd.)

Purpose of Review: This article describes prodromal α-synucleinopathies., Recent Findings: The pathology underlying α-synucleinopathies, which include Parkinson disease, multiple system atrophy, and dementia with Lewy bodies, begins years before the presence of the full syndrome that is the basis for the clinical diagnosis of each of these disorders. This "prodromal" phase may manifest with various signs or symptoms. In addition to individuals in the prodromal phase, some individuals are asymptomatic but are at risk for α-synucleinopathies owing to genetic predisposition or other risk factors., Summary: Clinicians are increasingly seeing patients in the clinical setting who are prodromal or at risk for α-synucleinopathies, and this article reviews the approach to these patient populations, which includes identifying clinical features, assessment, and counseling., (Copyright © 2022 American Academy of Neurology.)

Background: Isolated rapid eye movement sleep behavior disorder (IRBD) is a well-established clinical risk factor for Lewy body diseases (LBDs), such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB)., Objective: To elucidate whether serum microRNA (miRNA) deregulation in IRBD can antedate the diagnosis of LBD by performing a longitudinal study in different progression stages of IRBD before and after LBD diagnosis and assessing the predictive performance of differentially expressed miRNAs by machine learning-based modeling., Methods: Using genome-wide miRNA analysis and real-time quantitative polymerase chain reaction validation, we assessed serum miRNA profiles from patients with IRBD stratified by dopamine transporter (DaT) single-photon emission computed tomography into DaT-negative IRBD (n = 17) and DaT-positive IRBD (n = 21), IRBD phenoconverted into LBD (n = 13), and controls (n = 20). Longitudinally, we followed up the IRBD cohort by studying three time point serum samples over 26 months., Results: We found sustained cross-sectional and longitudinal deregulation of 12 miRNAs across the RBD continuum, including DaT-negative IRBD, DaT-positive IRBD, and LBD phenoconverted IRBD (let-7c-5p, miR-19b-3p, miR-140, miR-22-3p, miR-221-3p, miR-24-3p, miR-25-3p, miR-29c-3p, miR-361-5p, miR-425-5p, miR-4505, and miR-451a) (false discovery rate P < 0.05). Age- and sex-adjusted predictive modeling based on the 12 differentially expressed miRNA biosignatures discriminated IRBD and PD or DLB from controls with an area under the curve of 98% (95% confidence interval: 89-99%)., Conclusions: Besides clinical diagnosis of IRBD or imaging markers such as DaT single-photon emission computed tomography, specific miRNA biosignatures alone hold promise as progression biomarkers for patients with IRBD for predicting PD and DLB clinical outcomes. Further miRNA studies in other PD at-risk populations, such as LRRK2 mutation asymptomatic carriers or hyposmic subjects, are warranted. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Dementia with Lewy bodies is a neurodegenerative disease, sharing features with Parkinson's and Alzheimer's diseases. We report a case of a patient dementia with Lewy bodies carrying combined PSEN1 and ATP7B mutations. A man developed dementia with Lewy bodies starting at the age of 60 years. CSF biomarkers were of Alzheimer's disease and DaTSCAN was abnormal. Whole-exome sequencing revealed a heterozygous p.Ile408Thr PSEN1 variant and a homozygous p.Arg616Trp ATP7B variant. This case reinstates the need of considering ATP7B mutations when evaluating a patient with parkinsonism and supports p.Ile408Thr as a pathogenic PSEN1 variant., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)