Journal of Parkinson's disease最新文献

BackgroundCognitive dysfunction is one of the most debilitating non-motor symptoms of Parkinson's disease (PD). This study aimed to explore the interplay between altered neurotransmitter activities, including dopamine and acetylcholine, and brain metabolism in cognitive decline in PD.MethodsWe enrolled 172 PD patients (mean ± SD age 69.8 ± 8.6 years; 93 females) who underwent brain magnetic resonance imaging, N-(3-[¹⁸F]fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (¹⁸F-FP-CIT) positron emission tomography (PET), ¹⁸F-fluorodeoxyglucose (FDG) PET, and neuropsychological testing. General linear models and mediation analyses were used to investigate the association between striatal dopamine transporter (DAT) availability or basal forebrain (BF) volume, brain metabolism, and domain-specific cognitive scores.ResultsA significant relationship between caudate dopamine depletion and posterior BF atrophy was found in PD patients. Caudate and putaminal dopamine depletion were associated with altered brain metabolism in regions where PD patients showed decreased metabolism compared with healthy controls, whereas atrophy in the posterior BF was associated with hypometabolism in the lateral prefrontal, orbitofrontal, inferior parietal, and lateral temporal cortices as well as in the precuneus, with a significant interaction between caudate DAT availability and posterior BF volume. Caudate dopamine depletion was associated with visuospatial, memory, and executive dysfunction, whereas posterior BF atrophy was additionally associated with attention. Mediation analyses revealed that visuospatial dysfunction was associated with caudate dopamine depletion or posterior BF atrophy via altered brain metabolism, while executive dysfunction was linked to both directly and through metabolism changes.ConclusionsCaudate dopaminergic and posterior BF cholinergic deficits are interrelated and affect cognition in a domain-specific manner, either directly or through the mediation of altered brain metabolism.

BackgroundReactive astrocytes are one of the pathological features of Parkinson's disease (PD) and are associated with neuroinflammation and neuronal damage.ObjectiveTo explore the causal relationship between reactive astrocyte-related genes and PD through the summary data-based Mendelian randomization (SMR).MethodsWe combined these reactive astrocyte-related Quantitative Trait Loci (QTLs) data with PD genome-wide association study (GWAS) statistics. Using SMR, we explored causal links between gene expression, methylation and protein levels (pQTL) with PD, which were validated through colocalization analysis, replication cohorts and substantia nigra tissue data. The study also explored the causal relationship between DNA methylation and gene expression.ResultsSMR analysis identified 95 mQTLs (corresponding to 44 genes), 9 eQTLs, and 7 pQTLs nominally associated with PD (P-SMR_multi < 0.05 & P-SMR < 0.05, and P-HEIDI > 0.01). There was still a significant causal association between MAPK1 expression and Parkinson's disease risk after FDR correction (OR = 2.085, 95%CI = 1.463 to 2.972, P-HEIDI = 0.225, P-SMR_FDR = 0.013), supported by strong colocalization (PPH4 = 0.987). Similarly, there was a significant association between corrected CTSB protein levels and Parkinson's disease risk (OR = 0.855, 95%CI = 0.791 to 0.925, P-HEIDI = 0.076, P-SMR_FDR = 0.028). The methylation and expression of CLEC3B and PLAU were both nominally associated with the risk of PD. Further analysis revealed that there was also a causal relationship between their methylation and expression.ConclusionsWe identified the MAPK1 gene as a potential causative gene for PD. Its high expression was robustly causally associated with an increased risk of PD and was supported by strong colocalization evidence.

Background and objectiveNigrostriatal dopaminergic degeneration is commonly assessed using dopamine transporter (DaT) SPECT. Iron sensitive MRI is a promising technique to assess substantia nigra, yet few studies explored its application in the prodromal stage of alpha-synucleinopathies. Here, we used susceptibility map weighted imaging (SMWI) to assess the swallow tail sign, a radiological marker for substantia nigra integrity, to detect neurodegeneration across the alpha-synucleinopathy continuum.Methods3T-MRI was performed on 115 subjects: 27 overt alpha-synucleinopathies, 34 prodromal alpha-synucleinopathies, 28 Alzheimer's disease and 26 healthy controls. SMWI was obtained with 3D multi-echo gradient-echo imaging. The presence/absence of the swallow tail sign was visually evaluated on SMWI by two neuroradiologists, blinded to the diagnosis. Swallow tail sign's visual assessment was compared across groups to investigate its sensitivity and specificity in identifying alpha-synucleinopathies. Additionally, we compared the SMWI visual analysis sign with both substantia nigra quantitative susceptibility mapping (QSM) and DaT-SPECT.ResultsThe two radiologists' inter-rater agreement was substantial (kappa = 0.8). Visual analysis showed good sensitivity (0.85) and specificity (0.82) in identifying patients with alpha-synucleinopathies. When the subjects were grouped based on DaT-SPECT results, sensitivity increased (0.92), while specificity decreased (0.74). Visual scoring was associated with quantitative substantia nigra MRI assessment obtained with QSM (p < 0.001). Lastly, subjects with the swallow tail sign rated as absent showed significantly lower (p = 0.019) uptake at DaT-SPECT (-1.857 ± 1.343) compared to those with the swallow tail sign rated as present (-0.385 ± 1.850).ConclusionsVisual analysis of SMWI swallow tail sign represents a new and reliable approach for evaluating substantia nigra neurodegeneration across the alpha-synucleinopathy continuum.

BackgroundParkinson's disease (PD) is associated with a high prevalence of cardiovascular dysfunction, a leading cause of mortality in these patients. Autonomic dysfunction, including cardiac autonomic dysfunction (CAD), is increasingly recognized as a significant non-motor symptom in PD and may contribute to adverse cardiac outcomes.ObjectiveTo investigate echocardiographic alterations in PD patients with CAD and evaluate their diagnostic utility for CAD detection.MethodsParticipants were categorized into PD-CAD and PD-nCAD groups based on Cardiovascular Autonomic Reflex Tests. Echocardiographic assessments included standard transthoracic echocardiography and two-dimensional speckle-tracking strain imaging. Multivariable regression was used to identify predictors of PD-CAD. Receiver operating characteristic curves, integrated discrimination improvementResultsA total of 78 participants were included, with a median Hoehn and Yahr stage of 2.00 [IQR 2.00, 2.50]. Among them, 33.33% were classified as having PD-CAD. Impaired systolic function characterized by decreasing left ventricular global longitudinal strain and lower systolic mitral annular velocity were found in PD-CAD group. A model combining LV-GLS, s', and LVMI predicted CAD with AUC = 0.737 (95% CI:0.624-0.850), comparable to conventional autonomic markers.ConclusionSubclinical systolic dysfunction (LV-GLS, s') reflects autonomic-mediated myocardial injury in PD and demonstrates diagnostic potential for CAD identification. Echocardiography may bridge autonomic dysfunction and cardiovascular risk in PD.

Classic accounts of 'kinesia paradoxa' typically involve highly stressful or life-threatening situations, which are difficult to translate to daily life. Here, we describe two patients with parkinsonism who successfully apply self-induced 'arousal-heightening' strategies to improve their mobility. The first patient uses an electronically modified fly swatter to self-deliver a mild electrical shock, enabling him to overcome episodes of freezing of gait. The second patient uses his phone's alarm to alert himself, resulting in improved sit-to-stand transfer. These observations suggest that self-induced arousal-heightening strategies represent a hitherto underexplored compensatory strategy that could help to improve mobility in some individuals with parkinsonism.Plain language summary titleHelping people with Parkinson's disease move more easily using alertness tricks.

BackgroundThe role of dietary factors as risk or protective factors for Parkinson's disease (PD) remains debated.ObjectiveThis retrospective case-control study aimed to evaluate the associations between foods identified through a data-driven analysis and PD, and to compare the relevance of dietary versus non-dietary factors as contributors to PD risk.MethodsThe study included 680 PD patients and 612 matched controls recruited from six Italian neurology centers. Dietary data were collected using a validated 77-item food frequency questionnaire, and factor analysis was conducted to identify groups of correlated foods (i.e., factors). Logistic regression models were used to assess the associations between these factors and PD, while non-dietary factors were subsequently included in the model for comparison.ResultsSeven factors were identified, four of which were significantly associated with PD. High consumption of sweets (Factor 1), red meat (Factor 3), and processed meats (Factor 6) was associated with an increased PD risk, whereas a high fruit intake (Factor 2) was protective. These associations remained significant after adjusting for other known non-dietary risk/protective factors. While the increased PD risk associated with dietary factors was weaker than that of non-dietary factors, protective dietary and non-dietary factors showed comparable effects in reducing PD risk.ConclusionsData-driven analysis identified foods potentially influencing PD risk, although non-dietary factors demonstrated a greater impact on PD risk. These findings highlight the need to integrate both diet and lifestyle habits into future PD research and prevention strategies.

BackgroundOccupational pesticide (OcP) exposure and pathogenic GBA1 variants are established risk factors for Parkinson's disease (PD). However, whether they interact to influence disease onset or severity remains uncertain.ObjectiveTo determine the prevalence of OcP exposure and other lifestyle risks in relation to GBA1 status and their interactions on age of onset (AOO) and clinical scores in a well-characterized PD cohort.MethodsWe analyzed 505 people with PD (PwP) enrolled in the Ankara Parkinson's Disease Registry (ANPAR). GBA1 variants were identified using next-generation sequencing; benign or uncertain variants were excluded. Structured, face-to-face interviews collected data on history of OcP exposure, history of head trauma, smoking, coffee and tea consumption habits. PwP with and without GBA1 variants were compared using unadjusted and adjusted tests. General linear models assessed gene-environment interactions on AOO, non-motor, and motor scores.ResultsFifty-two PwP (10.3%) carried pathogenic GBA1 variants. OcP exposure was more common in carriers than non-carriers (36% vs. 22%; adjusted OR 1.98, 95%CI: 1.07-3.67, p = 0.031). No other risk factor differed between groups. Smoking independently delayed AOO, but there were no significant GBA1 × risk/lifestyle factor interactions for AOO or for motor/non-motor scores. Head trauma, coffee, tea, and OcP exposure showed neither main nor interaction effects on severity indices.ConclusionOcP exposure is reported more often by individuals carrying pathogenic GBA1 variants, supporting a gene-environment "dual-hit" model. However, OcPs did not modify AOO or disease severity once PD was manifest.

BackgroundDespite substantial research efforts, advances in Parkinson's disease therapeutics remain largely confined to the management of motor symptoms, with comparatively limited progress in addressing non-motor features, and with no proven success in disease-modifying therapies to date.ObjectivesTo describe recent trends in Parkinson's disease therapeutic trials and to characterize the experimental compounds and targets investigated in drug development programs.MethodsWe conducted a cross-sectional analysis of Parkinson's disease therapeutic clinical trials registered in ClinicalTrials.gov, EUCTR, and CTIS since 2013. For the subset of commercially sponsored medicinal product trials, we further described therapeutic objectives and pharmacological targets.ResultsWe identified 1855 trials, of which 29% were ongoing. Commercial trials predominantly investigated drugs and devices, whereas non-commercial trials more often focused on non-pharmacological interventions. Among 294 commercial medicinal product trials, 166 distinct products representing 146 active compounds were identified, mapped to 52 pharmacological targets, with additional compounds acting through multiple or unclear mechanisms. Dopaminergic approaches dominated (dopamine receptor agents, 18%; dopamine replacement, 15%), followed by aSyn-targeted strategies (10%). Advanced therapies, including cell and gene therapies, were investigated in 8%. Motor symptoms, particularly motor fluctuations, were the most frequent objectives (45%), whereas non-motor symptoms were rarely addressed (8%).ConclusionsThe landscape of Parkinson's disease trials has expanded over the past decade, but progress has largely been limited to incremental improvements in dopaminergic therapies. The continued lack of effective treatments for non-motor symptoms and disease modification suggests a need to rethink current approaches to drug development in Parkinson's disease.