The pathogenesis of Parkinson's disease

The Lancet, Journal Year: 2024, Volume and Issue: 403(10423), P. 293 - 304

Published: Jan. 1, 2024

Language: Английский

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Autophagy in Parkinson’s Disease

Biomolecules, Journal Year: 2023, Volume and Issue: 13(10), P. 1435 - 1435

Published: Sept. 22, 2023

Parkinson’s disease (PD) is a devastating associated with accumulation of α-synuclein (α-Syn) within dopaminergic neurons, leading to neuronal death. PD characterized by both motor and non-motor clinical symptoms. Several studies indicate that autophagy, an important intracellular degradation pathway, may be involved in different neurodegenerative diseases including PD. The autophagic process mediates the protein aggregates, damaged unneeded proteins, organelles, allowing their clearance, thereby maintaining cell homeostasis. Impaired autophagy cause abnormal proteins. Incomplete or impaired explain neurotoxic aggregates several Indeed, have suggested contribution α-Syn accumulation, death neuroinflammation. In this review, we summarize recent literature on involvement pathogenesis.

Language: Английский

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Overlaps and divergences between tauopathies and synucleinopathies: a duet of neurodegeneration

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: March 26, 2024

Proteinopathy, defined as the abnormal accumulation of proteins that eventually leads to cell death, is one most significant pathological features neurodegenerative diseases. Tauopathies, represented by Alzheimer's disease (AD), and synucleinopathies, Parkinson's (PD), show similarities in multiple aspects. AD manifests extrapyramidal symptoms while dementia also a major sign advanced PD. We other researchers have sequentially shown cross-seeding phenomenon α-synuclein (α-syn) tau, reinforcing pathologies between synucleinopathies tauopathies. The highly overlapping clinical imply shared pathogenic mechanisms two groups disease. diagnostic therapeutic strategies seemingly appropriate for distinct may apply broader spectrum. Therefore, clear understanding overlaps divergences tauopathy synucleinopathy critical unraveling nature complicated associations among In this review, we discuss diverse characteristics tauopathies from aspects genetic causes, manifestations, progression potential common approaches targeting pathology, aim provide timely update setting scheme classification novel insights into development

Language: Английский

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Polygenic scores for disease risk are not associated with clinical outcomes in Parkinson's disease

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 3, 2025

Abstract Polygenic risk scores (PRS) in Parkinson’s disease (PD) are associated with risk. Recently, pathway-specific PRS have been created to take advantage of annotations inking variants biological pathways or cell types. Here, we investigated 8 regions open chromatin using PRS: alpha-synuclein pathway, adaptive immunity, innate lysosomal pathway1, endocytic membrane-trafficking mitochondrial microglial single nucleotide polymorphisms (SNPs), and monocyte SNPs. We analysed 7,402 PD patients across 18 ‘in-person’ cohorts, 6,717 from the online Fox Insight study. did not find any significant associations between PRSs clinical outcomes PD. Though this may be due a lack statistical power limited sample size, it also suggest that genetic architecture sporadic is different genetics progression outcomes.

Language: Английский

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Mild cognitive impairment in Parkinson's disease: current view

Frontiers in Cognition, Journal Year: 2024, Volume and Issue: 3

Published: April 5, 2024

Parkinson's disease (PD), the most common motor movement disorder and second neurodegenerative after Alzheimer's (AD), is often preceded by a period of mild cognitive impairment (MCI), which associated with variety domains including executive function, attention, visuospatial abilities memory. MCI, risk factor for developing dementia, affects around 30% de novo PD patients can increase to 75% more than 10 years. While 30–40% remain in MCI state, up 60% will convert dementia. Characteristic findings are slowing EEG rhythms, frontotemporal hypoperfusion, decreased functional connectivity default mode attentional networks, prefrontal basal-ganglia-cortical circuits, manifests prior clinical symptoms overt brain atrophy. The heterogeneity phenotypes suggests that process multiple neuronal networks neuromodulatory systems may be superimposed Lewy body Alzheimer's-related or other co-pathologies. Sparse neuropathological data PD-MCI revealed heterogenous picture various morphological changes similar diseases. This review highlights essential epidemiological, clinical, neuroimaging PD-MCI, available biomarkers, discusses pathobiological mechanisms involved its development. In view complex pathogenesis, well-designed longitudinal clinico-pathological studies warranted clarify alterations leading PD, supported fluid biomarkers as basis early diagnosis future adequate treatment modalities this debilitating disorder.

Language: Английский

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Clinical and neurochemical correlates of the APOE genotype in early-stage Parkinson’s disease

Neurobiology of Aging, Journal Year: 2023, Volume and Issue: 131, P. 24 - 28

Published: July 19, 2023

Emerging evidence indicates that apolipoprotein E (APOE) genotype may influence Parkinson's disease (PD) course, although clinical and neurochemical correlates have not been completely established. This study aimed to determine the associations of APOE genotypes (ε4 vs. non-ε4) with cerebrospinal fluid (CSF) neurodegeneration biomarkers parameters in early-stage PD patients. One hundred seventy-five patients 89 non-neurodegenerative controls grouped APOE-ε4 carriers (28 PD; 12 controls) non-APOE-ε4 (147 78 were enrolled. CSF levels amyloid-β-42, amyloid-β-40, total 181-phosphorylated tau, scores compared among groups adjusting for main covariates. prevalence was similar controls. had lower amyloid-β-42 than controls, independently from age. also higher "item 5" (attention memory) non-motor symptoms scale carriers, confounding factors. might thus account a more vulnerable subtype characterized by prominent amyloidopathy greater burden early stages. DATA AVAILABILITY: Data are available upon reasonable request.

Language: Английский

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Pathobiology of Cognitive Impairment in Parkinson Disease: Challenges and Outlooks

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 25(1), P. 498 - 498

Published: Dec. 29, 2023

Cognitive impairment (CI) is a characteristic non-motor feature of Parkinson disease (PD) that poses severe burden on the patients and caregivers, yet relatively little known about its pathobiology. deficits are evident throughout course PD, with around 25% subtle cognitive decline mild CI (MCI) at time diagnosis up to 83% developing dementia after 20 years. The heterogeneity phenotypes suggests common neuropathological process, characterized by progressive degeneration dopaminergic striatonigral system many other neuronal systems, results not only in structural but also extensive changes functional network activities neurotransmitter dysfunctions. Modern neuroimaging studies revealed multilocular cortical subcortical atrophies alterations intrinsic connectivities. decreased connectivity (FC) default mode (DMN) bilateral prefrontal cortex affected already before development clinical absence changes. Longitudinal associated frontostriatal limbic affections, white matter microlesions between multiple networks, including thalamo-insular, frontoparietal attention cholinergic forebrain noradrenergic system. Superimposed Alzheimer-related (and concomitant) pathologies due interactions α-synuclein, tau-protein β-amyloid contribute pathogenesis both PD Lewy bodies (DLB). To further elucidate interaction pathomechanisms responsible for well-designed longitudinal clinico-pathological warranted supported fluid sophisticated imaging biomarkers as basis better early future disease-modifying therapies.

Language: Английский

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Association of CSF α‐synuclein seed amplification assay positivity with disease progression and cognitive decline: A longitudinal Alzheimer's Disease Neuroimaging Initiative study

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 20, 2024

Abstract INTRODUCTION Cerebrospinal fluid (CSF) α‐synuclein (α‐syn) seed amplification assay (SAA) is a sensitive and specific tool for detecting Lewy body co‐pathology in Alzheimer's disease. METHODS A total of 1637 cross‐sectional 407 longitudinal CSF samples from the Disease Neuroimaging Initiative (ADNI) were tested with SAA. We examined dynamics amyloid beta (Aβ), α‐syn seeds, phosphorylated tau181 (p‐tau181), along global domain‐specific cognition stable SAA+, SAA−, those who converted to SAA+ SAA−. RESULTS individuals had faster cognitive decline than notably mild impairment, presented earlier symptom onset. conversion was associated Aβ42 positivity but did not impact progression either or p‐tau181 status. Aβ42, p‐tau181, SAA all strong predictors clinical progression, particularly Aβ42. In vitro, kinetic parameters participant demographics, profiles, decline. DISCUSSION These results highlight interplay between their association disease progression. HIGHLIGHTS Seed greater Thirty‐four progressed SAA− that is, ≈ 5% conversion. (Aβ) pathology status biomarkers. Change diagnosis both biomarkers features

Language: Английский

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Unraveling the complex role of MAPT-containing H1 and H2 haplotypes in neurodegenerative diseases

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: May 29, 2024

Abstract A ~ 1 Mb inversion polymorphism exists within the 17q21.31 locus of human genome as direct (H1) and inverted (H2) haplotype clades. This region demonstrates high linkage disequilibrium, but frequency each differs across ancestries. While H1 in all populations shows a normal pattern genetic variability recombination, H2 is enriched European ancestry populations, less frequent African nearly absent East Asian populations. known risk factor for several neurodegenerative diseases, has been associated with many other traits, suggesting its importance cellular phenotypes brain entire body. Conversely, protective these predisposition to recurrent microdeletion syndromes neurodevelopmental disorders such autism. Many single nucleotide variants copy number define H1/H2 haplotypes sub-haplotypes, identifying causal variant(s) specific diseases complex due extended equilibrium. In this review, we assess current knowledge regarding genomic structure, gene expression, phenotypes, disease association. We discuss recent discoveries challenges, evaluate gaps knowledge, highlight understanding effect promote advances precision medicine drug discovery diseases. Graphical

Language: Английский

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Predictors of cognitive impairment in newly diagnosed Parkinson’s disease with normal cognition at baseline: A 5-year cohort study

Frontiers in Aging Neuroscience, Journal Year: 2023, Volume and Issue: 15

Published: Feb. 28, 2023

Background and objective Cognitive impairment (CI) is a substantial contributor to the disability associated with Parkinson’s disease (PD). We aimed assess clinical features explore underlying biomarkers as predictors of CI in patients newly diagnosed PD (NDPD; less than 2 years). Methods evaluated cognitive function status using Montreal Assessment (MoCA) battery neuropsychological tests at baseline subsequent annual follow-up for 5 years from Progression Markers Initiative (PPMI) database. assessed features, apolipoprotein ( APO ) E status, β-glucocerebrosidase GBA mutation cerebrospinal fluid findings, dopamine transporter imaging results. Using diagnosis (combined mild dementia) developed during 5-year outcome measures, we predictive values variables biomarkers. also constructed model logistic regression analysis. Results A total 409 NDPD were enrolled, 232 normal baseline, 94 follow-up. In multivariate analyses, age, current hypertension, MoCA scores, Movement disorder society Unified Rating Scale part III (MDS-UPDRS III) APOE development CI. Predictive accuracy age alone improved by addition (current MDS-UPDRS status; AUC 0.80 [95% 0.74–0.86] vs. 0.71 [0.64–0.77], p = 0.008). domains that had higher frequencies found verbal memory (12.6 16.8%) attention/processing speed (12.7 16.9%), however, no significant difference prevalence was patients. Conclusion NDPD, can be predicted good combining status. Our study underscores need earlier identification our practice.

Language: Английский

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