Journal of Parkinson's disease最新文献

BackgroundThe α-synuclein seed amplification assay (αS-SAA) represents a promising strategy for identifying individuals with α-synuclein pathology, empowering development of tailored Parkinson's disease (PD) therapeutics and clinical trial design.ObjectiveTo assess the αS-SAA in cerebrospinal fluid (CSF) from PD patients, non-manifesting carriers (NMCs) and non-manifesting non-carriers (NMNCs) of pathogenic GBA1 and LRRK2 variants.MethodsThis study collected phenotype data from participants in the single-center, longitudinal, natural history BEAT-PD study (TLV-0204-16), which included PD patients and high-risk individuals for whom CSF samples were collected at baseline and 2 years post baseline. Clinical assessments in high-risk individuals enabled calculation of the International Parkinson and Movement Disorder Society probability scores for prodromal PD.ResultsCSF from 98 participants was evaluated, with no differences in age or sex distribution observed between PD and NMC subgroups. All iPD (14/14) and GBA1-PD (14/14) participants were αS-SAA positive at baseline versus only 5/13 LRRK2-PD participants (p < 0.001); 44/45 participants with longitudinal follow-up-maintained baseline αS-SAA status at year 2.LRRK2-PD carriers, all who carried the G2019S variant, with and without positive αS-SAA status were similar in all phenotype characteristics, except for younger age at diagnosis among αS-SAA positive individuals (p = 0.04). Prodromal PD probability scores were higher in αS-SAA positive versus negative GBA1-NMCs (p < 0.001) and NMNCs (p < 0.001).ConclusionsIn LRRK2-PD, αS-SAA was associated with younger age of onset but not with motor or non-motor symptoms. In at-risk participants, αS-SAA-positive status was associated with probability scores for prodromal PD. Longitudinal follow up is required to test if αS-SAA-positivity predicts future conversion to clinical PD.

It is unclear whether Alzheimer disease pathology drives cognitive decline in Parkinson disease (PD) patients carrying GBA1 variants. We evaluated levels of serum phosphorylated tau 217 (p-tau217) in samples from 29 GBA1-PD, 32 idiopathic PD, 20 non-manifesting GBA1 variant carriers (GBA1-NMC) and 31 healthy controls. No differences were detected between PD groups. GBA1-NMCs showed higher levels than healthy controls, which correlated to worse cognition and subthreshold parkinsonism. Serum p-tau217 is not a marker of cognitive decline in GBA1-PD. Whether p-tau217 levels in GBA1-NMCs can predict conversion to PD or are a marker of cognitive decline, irrespective of PD, remains unknown.

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.

BackgroundSuicide risk in Parkinson's disease (PD) remains understudied, with limited exploration of the impact of neuropsychiatric comorbidities and commonly prescribed PD and psychiatric medications.ObjectiveTo investigate the prevalence and correlates of suicide risk in PD.MethodsThis study comprised 129 people with PD (PwP) undergoing screening for clinical trial participation at a movement disorders clinic. Suicide risk and psychiatric diagnoses were assessed with the Mini International Neuropsychiatric Interview (MINI). The Parkinson Anxiety Scale (PAS) and the Beck Depression Inventory-II (BDI-II) were also administered. Logistic regression models were used to identify correlates of suicide risk.ResultsSuicide risk was present in 22.5% of the sample, with 3.9% reporting a lifetime suicide attempt. No associations were found between suicide risk and demographic or PD-related variables. Suicide risk was independently associated with higher PAS score (odds ratio (OR) = 1.17; 95% confidence interval (CI): 1.07-1.29; p = 0.001), higher BDI-II suicidal ideation item score (OR = 32.43; 95% CI: 7.78-135.12; p < 0.001), and benzodiazepine use (OR = 13.88; 95% CI: 2.77-69.57; p = 0.001). Furthermore, the BDI-II suicidal ideation item missed nearly 45% of at-risk individuals identified by the MINI, with only 16 scoring above 0.ConclusionsDespite no documented suicide risk in participants' medical charts or neurologists' referrals, over one-fifth were found to be at risk. Correlates of suicide risk in PD warrant further investigation. This study highlights the importance of screening PwP for suicidality during routine care, and that a one-item screen might not adequately capture at-risk individuals.ClinicalTrials.gov IdentifierNCT03968133.

Compensation strategies are a key element of gait rehabilitation in Parkinson's disease, ideally requiring involvement of specialized therapists. However, access to allied healthcare is not universally guaranteed. We evaluated an online platform to deliver compensation strategies for gait in 25 individuals with Parkinson's in rural Brazil. After three weeks of use, median patient-reported impact of gait impairment on daily activities [rated on visual analogue scale, 0-10] decreased from 7 to 4 (p < 0.001), without reported falls. This suggest that the platform is a safe and effective tool for supporting gait rehabilitation in underserved communities with limited access to healthcare services.

BackgroundPatients with Parkinson's disease (PD) frequently experience a progressive decline in their activities of daily living (ADL), necessitating caregiver support. Discrepancies between patient and caregiver ADL ratings are common and may hinder optimal care.ObjectivesTo quantify patient-caregiver differences in ADL ratings and identify the clinical factors associated with these discrepancies.MethodsWe conducted a cross-sectional study involving 217 patients with PD and their primary caregivers. Both groups independently completed the Activities of Daily Living Questionnaire (ADLQ). Discrepancy (dADLQ) was defined by subtracting the caregiver-rated score from the patient-rated score; its absolute value (δADLQ) reflected the degree of disagreement. Associations with clinical variables, including motor and non-motor symptoms (cognition, mood, sleep, and autonomic function), were examined using multivariate regression.ResultsThe mean ADLQ scores were similar between patients and caregivers, but individual differences varied. The no-discrepancy group was characterized by younger age, shorter disease duration, and lower caregiver burden than those with any discrepancy. Larger δADLQ was associated with more severe motor and non-motor symptoms, as well as increased caregiver burden and depression. The dADLQ scores showed directional associations with patient mood and caregiver burden. Multivariate analysis revealed that δADLQ was independently predicted by greater motor symptom severity and gastrointestinal dysfunction.ConclusionsDiscrepancies in ADL ratings were common in patients with PD and increased with disease severity. They were associated with motor and non-motor symptoms, particularly gastrointestinal dysfunction and mood factors. These findings underscore the importance of integrating both perspectives in clinical assessment, particularly for advanced diseases.Plain language summary titleUnderstanding the Gap Between Patients with Parkinson's Disease and Their Caregivers in Daily Life Abilities.

Gut microbiome alterations are increasingly linked to Parkinson's disease (PD), yet regional signatures remain underexplored. We performed shotgun metagenomic sequencing of stool samples from Egyptian PD patients and healthy controls. PD patients exhibited depletion of short-chain fatty acid-producing taxa, and enrichment of pathobionts. Our findings suggested a pro-inflammatory gut shift in PD and emphasized the need for geographically diverse microbiome studies. While limited in sample size (n = 7 PD patients and n = 6 controls), this pilot addressed a critical gap in African PD microbiome research.