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At least 19 recordsLinked to original sources

PubMed2026

Elucidating shared genetic signals between type 2 diabetes and three neurodegenerative dementia phenotypes.

Type 2 diabetes (T2D) and dementia frequently co-occur, yet the biological mechanisms underlying this comorbidity remain incompletely understood. Here, we systematically investigate shared genetic signals between T2D and three forms of neurodegenerative dementia (Alzheimer disease, Lewy body dementia, and sporadic frontotemporal dementia) using large-scale genome-wide association studies of clinically diagnosed individuals. We identify five genomic regions harboring shared association signals between T2D and at least one dementia subtype. Among these, the APOE locus was common to all dementia subtypes, whereas the remaining four loci (GBA, CRY2/PEX16/MAPK8IP1, INO80E, and NSF) were each shared exclusively between T2D and one dementia subtype. Integrating multi-omics data across several disease-relevant tissues and orthogonal lines of functional evidence, we prioritize 26 candidate genes through which these shared genetic loci potentially mediate their effect. Pathway enrichment highlights lipid and lipoprotein regulatory biology as a central shared axis. Mendelian randomization analyses using genetically regulated gene expression in relevant tissues indicate pleiotropic mechanisms with divergent phenotypic consequences. Our findings identify shared genetic loci between T2D and neurodegenerative dementia, revealing systemic metabolic-neurodegenerative trade-offs and highlighting key genes that underpin the comorbidity, providing a framework for improved understanding of age-related multi-morbidity.

Alzheimer disease↗

PubMed1979

Lewy bodies in the presence of Alzheimer's disease.

Large numbers of Lewy bodies in the substantia nigra were found in a case of Alzheimer's disease. Parkinsonian symptoms were not recognized. The patient appears to be an example of an association recognized by Woodard but not yet understood. The case is discussed in the context of reported relationships between Parkinson's disease or "Lewy body disease" and dementia, on the one hand, and reports linking various forms of psychoses with an unusually high incidence of Lewy bodies, on the other.

Aged↗

PubMed1976

Parkinson's disease: distribution of Lewy bodies and monoamine neuron system.

A systematic study of the central and peripheral nervous systems in 3 cases of Parkinson's disease has demonstrated that Lewy bodies are present in 27 nuclei. Of these 20 nuclei (12 pigmented and 8 unpigmented) are involved in 2 or all 3 cases. It is noticed that the distribution of Lewy bodies in Parkinson's disease described here corresponds surprisingly well to that of monoamine (dopamine, noradrenaline and serotonin) cell bodies demonstrated in rats by the histochemical fluorescence method. This correlation is similar to that of Alzheimer's neurofibillary changes in postencephalitic Parkinsonism as described by Ishii. Inasmuch as these viewpoints are also in agreement with preciously reported biochemical data on Parkinsonism, it is suggested that Parkinsonism (idiopathic and postencephalitic) should represent a system degeneration of monoamine neuron systems.

Biogenic Amines↗

PubMed1977

Dense core vesicles around the Lewy body in incidental Parkinson's disease: an electron microscopic study.

In a case of Lewy body disease incidentally found at autopsy, numerous dense core vesicles 80--200 nm in diameter, were seen in the neuronal perikarya of the locus caeruleus. They were particularly numerous in the vicinity of the Lewy bodies. The change seems to occur at the early stage of Lewy body production and may represent an additional morphologic clue to abnormal catecholamine metabolism in Parkinson's disease.

Aged↗

PubMed2025

Structural variants linked to Alzheimer's disease and other common age-related clinical and neuropathologic traits.

BACKGROUND: Alzheimer's disease (AD) is a complex neurodegenerative disorder with substantial genetic influence. While genome-wide association studies (GWAS) have identified numerous risk loci for late-onset AD (LOAD), the functional mechanisms underlying most of these associations remain unresolved. Large genomic rearrangements, known as structural variants (SVs), represent a promising avenue for elucidating such mechanisms within some of these loci. METHODS: By leveraging data from two ongoing cohort studies of aging and dementia, the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP), we performed genome-wide association analysis testing 20,205 common SVs from 1088 participants with whole genome sequencing (WGS) data. A range of Alzheimer's disease and other common age-related clinical and neuropathologic traits were examined. RESULTS: First, we mapped SVs across 81 AD risk loci and discovered 22 SVs in linkage disequilibrium (LD) with GWAS lead variants and directly associated with the phenotypes tested. The strongest association was a deletion of an Alu element in the 3'UTR of the TMEM106B gene, in high LD with the respective AD GWAS locus and associated with multiple AD and AD-related disorders (ADRD) phenotypes, including tangles density, TDP-43, and cognitive resilience. The deletion of this element was also linked to lower TMEM106B protein abundance. We also found a 22-kb deletion associated with depression in ROS/MAP and bearing similar association patterns as GWAS SNPs at the IQCK locus. In addition, we leveraged our catalog of SV-GWAS to replicate and characterize independent findings in SV-based GWAS for AD and five other neurodegenerative diseases. Among these findings, we highlight the replication of genome-wide significant SVs for progressive supranuclear palsy (PSP), including markers for the 17q21.31 MAPT locus inversion and a 1483-bp deletion at the CYP2A13 locus, along with other suggestive associations, such as a 994-bp duplication in the LMNTD1 locus, suggestively linked to AD and a 3958-bp deletion at the DOCK5 locus linked to Lewy body disease (LBD) (P = 3.36 × 10-4). CONCLUSIONS: While still limited in sample size, this study highlights the utility of including analysis of SVs for elucidating mechanisms underlying GWAS loci and provides a valuable resource for the characterization of the effects of SVs in neurodegenerative disease pathogenesis.

Humans↗

PubMed2026

Synaptic vesicle glycoprotein 2A PET imaging in parkinsonian α-synucleinopathies: a systematic review.

Synaptic dysfunction is increasingly recognized as an early and biologically relevant component of α-synucleinopathies. However, conventional imaging biomarkers mainly assess dopaminergic dysfunction, glucose metabolism, or structural damage rather than presynaptic density itself. Synaptic vesicle glycoprotein 2A (SV2A) PET enables in vivo assessment of presynaptic terminal integrity and may provide complementary information in Parkinson's disease (PD), Parkinson's disease dementia/dementia with Lewy bodies (PDD/DLB), and multiple system atrophy (MSA). This systematic review synthesized the available evidence on SV2A-targeted PET in parkinsonian α-synucleinopathies, focusing on regional imaging patterns, clinical associations, longitudinal findings, and methodological determinants of interpretation. Seventeen reports were included. In PD, the most recurrent finding was reduced SV2A binding in the substantia nigra, although additional involvement of brainstem, caudate, striatal, thalamic, raphe, or cortical regions was reported in selected cohorts. In PDD/DLB, abnormalities appeared broader and more cortical, with evidence of association between cortical SV2A binding and cognitive performance. In MSA, one study suggested a distinct infratentorial and cerebellar pattern with potential relevance for phenotypic stratification. SV2A PET is a promising research biomarker for biological characterization of synucleinopathies. However, the field remains limited by small cohorts, methodological heterogeneity, variable quantification strategies, limited longitudinal evidence, and potential cohort overlap. Multicentre validation and harmonized protocols are required before clinical translation.

Humans↗

PubMed2026

Causal Effects Between Neurodegenerative Diseases, Metabolites, and Brain Volume.

INTRODUCTION/OBJECTIVE: Neurodegenerative diseases such as Alzheimer's disease (AD), Lewy dody dementia (LBD), and Parkinson's disease (PD) are linked to changes in brain volume. However, causal evidence on how these diseases affect brain volume and whether metabolites mediate these causal effects remains limited. METHODS: We applied mediation Mendelian randomization analysis using GWAS summary statistics. The inverse variance-weighted method was used to assess causal effects and identify potential metabolite mediators. RESULTS: The MR analyses indicated that bilateral thalamus and putamen volumes (FDR < 0.05) had causal effects on PD. AD and LBD showed causal effects on bilateral thalamus and hippocampus (FDR < 0.01), with LBD specifically showing a causal effect on bilateral putamen (FDR < 0.05). Mediation analyses revealed that AD had a genetically predicted association with Nervonoy- L-carnitine and 1-linoleoyl-2-arachidonoyl-GPC (p-value = 0.04 and 0.01, respectively). Moreover, Nervonoy-L-carnitine was suggestively negatively associated with hippocampus volume (p-value = 0.03 and 0.02, respectively). 1-linoleoyl-2-arachidonoyl-GPC exhibited a negative genetically predicted association with hippocampus volume (p-value < 0.05). Additionally, LBD showed a negative genetically predicted association on the ratio of retinol to linoleoyl-arachidonoyl- glycerol (p-value = 0.02), and a positive genetically predicted association on Nervonoy-L-- carnitine (p-value < 0.05) and 1-linoleoyl-2-arachidonoyl-GPC (p-value = 0.03). DISCUSSION: These results suggest that AD and LBD affect brain regions through causal pathways. The involvement of specific metabolites highlights potential mechanisms linking neurodegeneration to brain volume. CONCLUSION: Nervonoylcarnitine and 1-linoleoyl-2-arachidonoyl-GPC may mediate the predicted effects of AD and LBD on hippocampal volumes, while the ratio of retinol to linoleoyl-arachidonoyl- glycerol mediates only LBD.

Humans↗

PubMed2026

Cholesterol dysregulation in APOE4 astrocytes promotes α-synuclein pathology in miBrains.

The pathological hallmarks of neurodegeneration are the aberrant post-translational modification and aggregation of proteins. Genetic factors, like APOE4, increase the prevalence and severity of tau, amyloid, and α-synuclein pathologies. However, the human brain is largely inaccessible during this process, limiting mechanistic understanding. Here, we developed an iPSC-based 3D model that integrates neurons, glia, myelin, and cerebrovascular cells into a human brain-like tissue ("miBrain"). Single-nucleus RNA sequencing of miBrains confirmed the presence of diverse cell populations and revealed transcriptional responses to α-synuclein pathology. Like the human brain, pathogenic α-synuclein is increased in APOE4/4 miBrains. Combinatorial experiments revealed that endolysosomal dysfunction caused by cholesterol accumulation in APOE4/4 astrocytes impairs the degradation of soluble α-synuclein leading to a pathogenic transformation that seeds α-synuclein inclusions in neurons. Collectively, this study establishes a robust model for investigating protein inclusions in human iPSC-derived brain tissue and highlights the role of astrocytes and cholesterol in APOE4-mediated pathologies.

alpha-Synuclein↗

PubMed2025

A genome-wide association study identifies a novel East Asian-specific locus for dementia with Lewy bodies in Japanese subjects.

BACKGROUND: Dementia with Lewy bodies (DLB) is the second most common type of degenerative dementia in older patients. As with other multifactorial diseases, the pathogenesis results from interactions of environmental and genetic factors. The genetic basis of DLB is not yet fully understood. Recent genomic analyses of DLB in Caucasian cohorts identified genetic susceptibility loci for DLB, but the comprehensive genomic analysis in Asians was still not performed. METHODS: We conducted a genome-wide association study (GWAS) in Japanese subjects (211 DLB cases and 6113 controls) to clarify the genetic architecture of DLB pathogenesis. RESULTS: We identified the East Asian-specific DHTKD1 locus (rs138587229) on chromosome 10 with genome-wide significance (GWS; P = 3.2710-8) and the ICOS/PARD3B locus on chromosome 2 with suggestive significance (P = 3.9510-7) as novel DLB genetic risk loci. We also confirmed the APOE locus (rs429358, P < 5.0 × 10-8), a known risk locus for DLB and Alzheimer's disease in Caucasians. The DHTKD1 locus was associated with the gene expression of SEC61A2 and showed a causal relationship with cholinesterase levels. In a trans-ethnic meta-analysis that included Japanese, UK Biobank, and other Caucasian GWAS, we confirmed the risk for DLB at APOE and SNCA loci with GWS. Transcriptome-wide association analysis identified ZNF155 and ZNF284 in the brain cortex and GPRIN3 in the substantia nigra as putative causal genes for DLB. CONCLUSIONS: This is the first GWAS for DLB in East Asians, and our findings provide new biological and clinical insights into the pathogenesis of DLB.

Aged↗

PubMed2025

Caregiver experiences after the death of a person with dementia with Lewy bodies: A mixed-methods analysis.

BackgroundDementia with Lewy bodies (DLB) is a common degenerative dementia, but no studies investigate bereaved caregiver experiences.ObjectiveTo investigate the experiences of caregivers three months after the death of persons with DLB using a mixed-methods approach.MethodsDyads of individuals with moderate-advanced DLB and their primary informal caregivers were followed prospectively every 6 months until the person with DLB died. Caregivers completed a study visit with questionnaires and a semi-structured interview ∼3 months later. Spearman correlation coefficients and Wilcoxon rank-sum tests evaluated the relationships of post-death measures with pre-death patient and caregiver variables. Thematic analysis was used to analyze the interviews.ResultsSeventy-three caregivers completed visits (mean 3.5 months post-death). Most of the caregivers were women (82.2%) and spouses (76.7%) or adult children (17.8%). Over 40% had scores indicating risk for clinical depression. Post-death caregiver experiences (depression, quality of life, grief, resilience) correlated with pre-death caregiver experiences. Post-death experiences did not associate with patient characteristics, disease-related symptoms, or healthcare services used in the last 6 months of life. Trajectories for caregiver measures from pre- to post-death visits varied widely. Interview themes included grief and sadness, anger, guilt and regret, relief, appreciation/gratitude, and adjusting to a new normal.ConclusionsThe finding that pre-death caregiving experiences have the strongest association with post-death experiences emphasizes the critical importance of accessible and evidence-based caregiver support before and after the death of a person with DLB. Research is needed to develop interventions for current and bereaved caregivers of individuals with DLB.Trial registration informationNCT04829656 (submitted 2021-03-22).

Caregivers↗

PubMed2026

Missense mutations in the SNCA gene: Molecular mechanisms and clinical implications.

The SNCA gene on chromosome 4 encodes the alpha-synuclein (αSyn) protein, which plays a central role in the pathogenesis of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). While αSyn has established roles in synaptic vesicle dynamics and neuronal signaling, alterations in SNCA regulation and sequence contribute to protein misfolding, aggregation, and loss of function. Alterations in secondary and tertiary structure, as well as protein aggregation, affect biochemical interactions, ultimately leading to pathogenesis. This review outlines the molecular architecture of the SNCA gene, including regulatory regions, alternative splicing, and untranslated regions that influence αSyn expression and isoform diversity. Seven missense mutations of the SNCA gene are discussed in detail from the genomic level, extending to phenotypic presentations. These missense mutations have different effects on the aggregation kinetics and fibril formation. Specific genotype-phenotype correlations are evident, with mutations such as A30P and H50Q commonly resembling idiopathic PD, E46K strongly associated with DLB, and G51D, A53T, and A53E linked to atypical parkinsonism and MSA-like syndromes. Differences in age at onset, disease progression, cognitive involvement, and response to therapy further reflect mutation-specific effects and modifying influences of allelic dosage and epigenetic regulation. Collectively, these findings emphasize the importance of SNCA genetic variation in shaping disease phenotype and progression. Improving the understanding of SNCA genotype-phenotype relationships in future studies may facilitate earlier diagnosis, refine prognostic stratification, and support the development of targeted, disease-modifying therapies for synucleinopathies.

Molecular mechanisms↗

PubMed1976

Presenile dementia with Alzheimer-, Pick- and Lewy-body changes.

An autopsy case of unclassifiable presenil dementia is reported. The outstanding pathological findings were as follows; 1. presence of senile plaques, neurofibrillary changes, Pick bodies, Hirano bodies, granulovacuolar degeneration of neurons, etc. 2. numerous Lewy bodies in the brain stem and diencephalon, 3. peculiar swollen neurons with intracytoplasmic, eosinophilic and argentophilic inclusions ("Lewy-like-bodies") in the cerebral cortices. Detailed study of the last mentioned inclusions indicates that they are almost identical to Lewy bodies, though there are some minor differences, in histochemical and electronmicroscopic findings. Nosologically, this case may represent either a combination of Alzheimer's disease, Pick's disease and idiopathic Parkinsonism with "Lewy-like-bodies" in the cerebral cortices, or a single disease. As far as we know, no similar case been reported.

Aged↗

PubMed2026

Cell-type-specific genetic associations in Lewy body dementia identified using single-cell eQTL-based Mendelian randomization.

BACKGROUND: Lewy body dementia (LBD) is a complex neurodegenerative disorder marked by α-synuclein aggregation and dual impairment of cognitive and motor function.While genome-wide association studies have identified risk loci, the cellular mechanisms linking genetic variation to disease susceptibility remain largely unexplored. METHODS: We performed single-cell transcriptome-wide Mendelian randomization using brain cell-type-specific eQTLs across eight major cell types. Genetic associations were evaluated using inverse-variance weighted models, followed by Bayesian colocalization analysis. Replication was performed in independent stratified LBD cohorts based on APOE ε4 carrier status. Phenome-wide association analysis was included as a supplementary, descriptive assessment of cross-trait associations. RESULTS: Expression of ANKRD65 in excitatory neurons was significantly associated with reduced LBD risk (odds ratio = 0.65, 95 % CI: 0.52-0.81, p = 0.00013). This association passed a false discovery rate of 0.1 and showed strong evidence of colocalization (posterior probability = 0.93). Effect direction was consistent across APOE ε4+ and ε4- LBD subgroups in independent cohorts. No genome-wide significant associations were observed with non-neurological traits in the phenome-wide analysis. CONCLUSIONS: Our findings identify a genetically supported, cell-type-resolved association between ANKRD65 expression in excitatory neurons and LBD risk. This study demonstrates the value of integrating cell-resolved transcriptomic regulation with genetic inference to pinpoint functionally relevant targets in neurodegenerative diseases.

Humans↗

PubMed1976

Postural hypotension in idiopathic Parkinson's disease. Etiopathology.

Postural changes in blood pressure were recorded in all 391 patients suffering from Parkinson's syndrome over a period of six years. Intraarterial blood pressure studies were carried out in those with significant postural hypotension. Histological examination of the entire central nervous system and the sympathetic ganglia was performed in six patients suffering from idiopathic Parksinson's disease. Five of the six patients had Lewy bodies in the sympathetic ganglia. Loss of nerve cells was noted in the sympathetic ganglia in those patients that demonstrated postural hypotension. The severity of the lesions in the ganglia correlated with the severity of postural hypotension in idiopathic Parkinson's disease, One case of Shy-Drager syndrome was similarly studied to demonstrate the differences in spinal cord and sympathetic ganglia lesions in the two conditions.

Aged↗

PubMed2024

Genetic evidence for causal association between migraine and dementia: a mendelian randomization study.

BACKGROUND: There is an association between migraine and dementia, however, their causal relationship remains unclear. This study employed bidirectional two-sample Mendelian randomization (MR) to investigate the potential causal relationship between migraine and dementia and its subtypes: Alzheimer's disease (AD), vascular dementia (VaD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB). METHODS: Summary-level statistics data were obtained from publicly available genome-wide association studies (GWAS) for both migraine and five types of dementia. Single nucleotide polymorphisms (SNPs) associated with migraine and each dementia subtype were selected. MR analysis was conducted using inverse variance weighting (IVW) and weighted median (WM) methods. Sensitivity analyses included Cochran's Q test, MR pleiotropy residual sum and outlier (MR-PRESSO) analysis, the intercept of MR-Egger, and leave-one-out analysis. RESULTS: Migraine showed a significant causal relationship with AD and VaD, whereas no causal relationship was observed with all-cause dementia, FTD, or DLB. Migraine may be a potential risk factor for AD (odds ratio [OR]: 1.09; 95% confidence interval [CI]: 0.02-0.14; P = 0.007), while VaD may be a potential risk factor for migraine (OR: 1.04; 95% CI: 0.02-0.06; P = 7.760E-5). Sensitivity analyses demonstrated the robustness of our findings. CONCLUSION: Our study suggest that migraine may have potential causal relationships with AD and VaD. Migraine may be a risk factor for AD, and VaD may be a risk factor for migraine. Our study contributes to unraveling the comprehensive genetic associations between migraine and various types of dementia, and our findings will enhance the academic understanding of the comorbidity between migraine and dementia.

Humans↗

PubMed1976

Vitreous surgery--a summary of past and current concepts.

Explore the source record for details and available documents.

Eye Diseases↗

PubMed1978

The hypothalamus in Parkinson disease.

The hypothalamus was systematically examined in 30 patients with pathologically documented idiopathic parkinsonism. Using Lewy body formation as a marker for nerve cell degeneration, we observed abnormalities in every hypothalamus examined. Of the thirteen hypothalamic nuclei that could be individually identified, none were exempt from Lewy body degeneration. The tuberomamillary nucleus and the lateral and posterior hypothalamic nuclei demonstrated the highest average Lewy body counts (16, 9, and 3, respectively); they were also the most frequently involved nuclei. These findings may aid in interpretation of the autonomic and endocrine abnormalities in patients with Parkinson disease.

Aged↗

PubMed1978

The use of furosemide in the treatment of edema in infants and children.

One hundred thirty-seven courses of furosemide therapy were given to 106 hospitalized pediatric patients with salt and water retention associated with cardiac or renal disease. The diuretic was effective and safe in the pediatric age group when administered acutely as a parenteral medication and over a long-term course by the oral route in the doses and at the time intervals used in this study. On the basis of each kilogram of body weight, the infants with edema as a result of cardiac failure and the children with edema secondary to renal disease responded equally well to furosemide therapy.

Administration, Oral↗