Parkinsonism & related disorders最新文献

Background: Chorea affects quality of life and functional independence in most adults with Huntington disease (HD). Vesicular monoamine transporter 2 (VMAT2) inhibitors, tetrabenazine, deutetrabenazine, and valbenazine, are pharmacological agents used to manage HD-related chorea. This systematic review evaluates the safety and efficacy of these agents in individuals with HD.

Methods: This review was conducted in accordance with PRISMA guidelines and registered with PROSPERO, CRD42024581306. A comprehensive literature search was performed for studies published up to July 3, 2025. Eligible studies included randomized controlled trials, cohort studies, and case-control studies. Two reviewers independently performed data extraction and risk-of-bias assessment.

Results: Three randomized trials met eligibility criteria and were included in the final analysis. All three VMAT2 inhibitors significantly reduced Unified Huntington Disease Rating Scale Total Maximal Chorea scores. Clinical Global Impression-Improvement Scale for tetrabenazine and both Patient Global Impression of Change and Clinician Global Impression of Change ratings for deutetrabenazine and valbenazine favored active treatment. Deutetrabenazine modestly improved 36-Item Short Form Health Survey physical functioning and Swallowing Disturbance Questionnaire scores. Tetrabenazine was associated with higher adverse event (AE) rates; whereas valbenazine and deutetrabenazine demonstrated better tolerability.

Discussion: This systematic review shows VMAT2 inhibitors significantly reduce chorea severity in HD. While tetrabenazine showed the greatest reduction in chorea scores, valbenazine and deutetrabenazine provided broader benefits on functional outcomes and improvement scales. Tetrabenazine had the highest rate of AEs, whereas deutetrabenazine demonstrated favorable tolerability, with fewer complications. Valbenazine demonstrated an intermediate safety profile. These differences should guide individualized treatment decisions in clinical practice.

Background: Istradefylline, a selective adenosine A_2A receptor antagonist, is approved as an adjunct to levodopa in Parkinson's disease, but its long-term effects on clinically meaningful outcomes are unclear.

Objective: We aimed to compare the association of istradefylline versus catechol-O-methyltransferase (COMT) inhibitors with mortality, treatment escalation, and disease progression in levodopa-treated Parkinson's disease.

Methods: We conducted a nationwide cohort study emulating a target trial using the DeSC claims database in Japan. Patients aged ≥50 years with levodopa-treated Parkinson's disease between 2014 and 2023 were included. Strategies were initiation of istradefylline versus COMT inhibitors. Primary outcomes were all-cause mortality, levodopa-equivalent daily dose (LEDD) escalation to ≥1100 mg, and dementia or psychosis. Secondary outcomes were fractures, cardiovascular events, pneumonia, and depression. Intention-to-treat and per-protocol effects were estimated using Cox models with propensity score-based overlap weighting.

Results: We identified 3190 istradefylline and 7986 COMT inhibitor initiators. In intention-to-treat analysis, istradefylline was associated with lower risks of mortality (hazard ratio [HR] 0.91; 95 % CI 0.84-0.99) and LEDD escalation (HR 0.83; 95 % CI 0.73-0.94). Associations were stronger in per-protocol analysis (mortality: HR 0.84, 95 % CI 0.72-0.97; LEDD escalation: HR 0.71, 95 % CI 0.59-0.84). Istradefylline was linked to higher fracture risk (intention-to-treat HR 1.13, 95 % CI 1.02-1.25; per protocol HR 1.23, 95 % CI 1.07-1.41). No differences were observed for dementia, psychosis, or other outcomes.

Conclusions: Istradefylline was associated with reduced mortality and treatment escalation but increased fracture risk compared with COMT inhibitors, supporting further evaluation of adenosine A_2A antagonists.

Background: Parkinson's disease (PD) is a neurodegenerative disorder in which age is the strongest risk factor, but the role of cardiovascular disease (CVD) remains unclear. This study examines the impact of CVD history on PD onset and progression.

Methods: We conducted a cross-sectional analysis using data from the Parkinson's Progression Markers Initiative (PPMI), involving 1109 participants (924 PD patients and 185 healthy controls). The correlation of CVD history with PD and its progression (motor and non-motor symptoms assessed with Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS I-IV), autonomic dysfunction assessed with Scales for Outcomes in PD-Autonomic Dysfunction (SCOPA-AUT), and cognitive impairment assessed with Montreal Cognitive Assessment (MoCA)) was evaluated using regression models.

Results: Participants had a mean age of 62.84 ± 9.64 years (61 % male), with no significant group differences in CVD history (P = 0.382). CVD history was not associated with PD occurrence, even after matched comparison. PD participants were predominantly early-stage with a mean follow-up of 4.84 ± 4.67 years. CVD history showed no association with autonomic or cognitive outcomes but was associated with a higher risk of motor complications (MDS-UPDRS IV: OR:3.34, 95 %CI:1.38-8.63, P = 0.009), with no effects on other MDS-UPDRS categories; progression-based analyses likewise showed no impact on autonomic or cognitive function (P > 0.05).

Conclusions: CVD history does not independently predict PD incidence or autonomic or cognitive progression but may increase the risk of motor complications. These findings should be interpreted cautiously due to the predominance of early-stage PD patients and small subgroup sizes, and require further validation.

Introduction: Parkinson's disease (PD) is a common neurodegenerative disease. Abnormal iron metabolism is closely associated with PD risk. This study aimed to identify key iron metabolism-related genes (IMRGs) in the substantia nigra (SN) that affect PD progression.

Methods: Differences in iron metabolism scores between PD and control groups were compared. After differential expression analysis and weighted gene co-expression network Analysis, differentially expressed-IMRGs (DE-IMRGs) were identified from IMRGs, differentially expressed genes (DEGs), and module genes. Key genes were obtained from a protein-protein interaction network, machine learning, and receiver operating characteristic curves. Correlations between key genes and nomograms, Gene Set Enrichment Analysis, immune infiltration, potential drug prediction, and consensus clustering were explored. In vitro experiments were conducted to verify the identified key genes.

Results: Iron metabolism scores differed significantly between the PD and control groups. In total, 1128 DEGs and 597 module genes were obtained, intersected with 522 IMRGs, and 23 DE-IMRGs were acquired. Eight candidate key genes were identified, followed by the identification of two key genes, Fatty Acid 2-Hydroxylase (FA2H)‌ and ‌Cytochrome P450 Family 1 Subfamily A Member 2 (CYP1A2). The nomograms of the two key genes possessed high precision for predicting PD, and 102 and 15 drugs involving CYP1A2 and FA2H were searched, respectively. The proportions of the five immune cells showed obvious differences between the PD and control groups, and CYP1A2 and FA2H were significantly correlated with many immune cells. In vitro experiments revealed that FA2H reduced 6-OHDA-stimulated SH-SY5Y cell viability and enhanced apoptosis.

Conclusion: Iron metabolism in the SN is important in the progression of PD, and two IMRGs, CYP1A2 and FA2H, are involved in the pathogenesis of PD.