Journal of Parkinson's disease最新文献

BackgroundThe aggregation and spread of α-synuclein within brain are associated with the loss of dopaminergic neurons and the formation of Lewy bodies as seen in Parkinson's disease. Blocking the initiation of α-synuclein aggregation, or the spread of such aggregates, may offer disease-modifying approaches to slow disease progression. Previous studies have demonstrated that modification of aggregation prone proteins, including α-synuclein, with O-linked β-N-acetylglucosamine (O-GlcNAc) reduces their aggregation. Small molecule inhibitors of the enzyme O-GlcNAcase (OGA), which removes O-GlcNAc from proteins, confers neuroprotective benefits in various preclinical disease models of Alzheimer's and Parkinson's diseases.ObjectiveThis study investigates the effects of long-term pharmacological enhancement of O-GlcNAcylation in a transgenic mouse model of Parkinson's disease overexpressing human α-synuclein.MethodsThiamet-G was orally administered to mThy1-hSNCA and wild-type (WT) mice for ten months. Behavioral assessments were conducted to examine changes in locomotion and cognition. Histological analyses were performed to analyze α-synuclein aggregates and dopaminergic neurons in brain sections. Immunoblot and ELISA analyses were performed to analyze O-GlcNAc and soluble α-synuclein using brain lysates, respectively.ResultsThiamet-G increased the level of O-GlcNAc in the brain of both mThy1-hSNCA and WT mice. The levels of total α-synuclein in the brain were unaltered. However, Thiamet-G strongly attenuated the deposition of pS129-immunoreactive α-synuclein aggregates within the substantia nigra, prior to observable neurodegeneration. Thiamet-G also protected against locomotor decline.ConclusionsThese results support OGA inhibition as a therapeutic approach to block the pathological formation of toxic α-synuclein as a disease-modifying treatment against Parkinson's disease.

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.

Bradykinesia and delayed step initiation are central features of Parkinson's disease (PD) and have been linked to reduced movement vigor. Evidence suggests that externally imposed urgency may upregulate vigor and improve motor speed. Previous home-based cueing interventions without time limits improved gait but failed to reduce reaction times, indicating that time constraints may be critical. We conducted a randomized controlled trial to evaluate whether time-constrained, visually guided reaching and stepping exercises enhance response speed in PD. Sixty participants with idiopathic PD (Hoehn & Yahr I-III) completed 24 supervised, home-based sessions using a set of small interactive devices that provided visual and auditory cues and recorded response times. The experimental group trained with time windows adapted during each session to maintain ∼80% success, receiving immediate success/failure feedback, while the control group performed identical tasks without time restrictions. Response times were assessed before and after training with choice stepping and reaching reaction time tasks in a laboratory setting, alongside gait and mobility tests. Repeated measures ANOVA revealed significant group × time interactions favoring the experimental group for both reaching (p < 0.05) and stepping (p < 0.001) reaction times, with medium-to-large effect sizes, whereas controls showed no change. Gait speed improved in both groups, with no additional between-group differences. These findings demonstrate that introducing temporal urgency during reactive training produces meaningful improvements in bradykinesia-related response times in individuals with PD, supporting the integration of time-constrained cueing into scalable home-based rehabilitation. ClinicalTrials.gov: NCT05829915.

Parkinson's disease (PD) involves degeneration of dopaminergic neurons and dysfunction across multiple neurotransmitter systems, contributing to both motor and cognitive impairments. Aerobic exercise improves clinical outcomes; however, its underlying neural mechanisms remain unclear. Using conventional resting-state fMRI combined with Receptor-Enriched Analysis of functional Connectivity by Targets (REACT), we examined molecular-enriched motor network changes following six months of supervised aerobic training in PD. Exercise-related connectivity changes were inversely correlated with baseline PD-healthy control differences, reflecting a partial normalization of PD-altered motor networks. Molecular-enriched analyses revealed selective effects on dopaminergic (FDOPA-enriched) and cholinergic (VAChT-enriched) related networks, with no changes observed in networks associated with serotonergic or noradrenergic systems. These findings provide supporting evidence for potential mechanistic links between aerobic exercise and network reorganization in PD, highlight multisystem effects, and illustrate the utility of molecular-enriched fMRI for probing neurotransmitter-specific interventions.

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.

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.

BackgroundBoth Mediterranean and ketogenic diets have been proposed as nutritional interventions in Parkinson's disease (PD). Combined approaches may offer maximal benefits.ObjectiveAssess the feasibility, safety and exploratory efficacy of two ketogenic interventions, using a Mediterranean diet base, in individuals with PD (PwP).MethodsIn this Phase II, random-order crossover study, PwP followed two 8-week dietary interventions, separated by an 8-week washout: 1) a high-fat, low-carbohydrate Mediterranean diet (MeDi-KD) and 2) a standard Mediterranean diet supplemented with medium chain triglycerides (MeDi-MCT).ResultsOf 52 participants randomized, 48 started the trial. Forty-one (79%) participants completed at least one, whereas only 33 (63%) completed both intervention phases. There were no intervention-related serious adverse events, nor any significant changes in plasma lipid profiles. Seventy-three percent and 92% of participants reported deviating from the MeDi-KD and MeDi-MCT no more than a few times per month, respectively. Moderate Mediterranean Diet Adherence Screener scores of 6.7 (SD: 1.6) and 7.2 (SD: 2.3) were achieved during the MeDi-KD and MeDi-MCT, respectively, out of a maximum of 14. Fifty percent of participants were in nutritional ketosis ([beta-hydroxybutyrate] ([BHB]) > 0.5 mM) at follow-up for the MeDi-KD, as compared with only 1 (3%) participant following the MeDi-MCT. MDS-UPDRS Part II and IV scores decreased by a mean of -1.4 (SD: 4.2; p = 0.039) and -1.0 (SD: 3.0; p = 0.044) points, respectively, following the MeDi-MCT.ConclusionsWhile both Mediterranean-ketogenic interventions appear safe in the short-term in PwP, their feasibility is called into question by a high study dropout rate (37%) and modest adherence. Preliminary benefits observed in patient-reported motor experiences were paradoxically limited to the MCT-supplemented MeDi, in which ketosis was not reliably achieved. Together, our findings indicate the need to refine behavioral strategies to optimize dietary awareness and adherence in future trials.Trial RegistrationThe trial was registered on ClinicalTrials.gov: NCT05469997.

BackgroundFreezing of gait (FOG) in Parkinson's disease (PD) is a major cause of disability and falls and often responds incompletely to conventional therapy. Rehabilitative interventions including cognitive strategies and sensory cueing are efficacious, but difficulties in learning impair executing these strategies. Transcranial direct current stimulation (tDCS) enhances motor task learning and might enhance the efficacy of rehabilitative interventions.ObjectiveWe assessed whether tDCS can enhance the efficacy of physiotherapy for FOG in PD.MethodsIn a randomized, double-blind, controlled study, anodal tDCS (pre-/motor cortex) or sham-tDCS were delivered combined with a standardized rehabilitative intervention in 24 PD patients with FOG for eight sessions within four weeks. Clinical assessment included walking a Parcourse, timed gait tests, FOG questionary, and clinical scales at baseline, across the interventions with a follow-up 3-months after the last intervention.ResultsNineteen PD patients with FOG completed the study. TDCS combined with physiotherapy reduced FOG, but not more than physiotherapy aloneConclusionCombining tDCS with physiotherapy did not enhance its efficacy in reducing FOG.

Over the past 25 years, a prevailing clinical dogma has held that significant cognitive impairment constitutes a contraindication to the use of Deep Brain Stimulation in Parkinson's disease. Whilst multiple studies, excluding such patients, have repeatedly emphasised the motoric benefits of this approach, less consideration has been given to the consequences of excluding this cohort. However, emerging evidence suggests that Deep Brain Stimulation in Parkinson's Disease patients with moderate cognitive impairment not only allows for significant reductions in dopaminergic therapy (typically alleviating many non-motor symptoms) but also favours survival and reduced admissions into institutional care. These small studies have not demonstrated significantly increased surgical or stimulation related complications in such patients and would suggest that further prospective studies, specifically evaluating this approach are warranted. Indeed, in the absence of a successful disease modifying therapy, exclusion from Deep Brain Stimulation often commits these advanced patients to a trajectory of ineffective pharmacological complexity. Alternative infusion therapies are associated with high discontinuation rates whilst escalating dopaminergic therapy, frequently exacerbates non-motor complications, including orthostatic hypotension, hallucinations, somnolence, and cognitive fluctuations. This flawed treatment strategy further accelerates functional decline, hospitalisation, and institutionalisation. Therefore, a reluctance or failure to offer Deep Brain Stimulation, where appropriate, may inadvertently consign patients to poorer long-term outcomes.

BackgroundAlpha-synuclein can be detected in skin biopsies of individuals with synucleinopathies. However, quantitative data of total and phosphorylated Serine 129 (pS129) alpha-synuclein in skin biopsies are scarce.ObjectiveWe aimed to investigate the biomarker potential of quantitative total and pS129 alpha-synuclein measurements in skin biopsies from people with synucleinopathies and controls.MethodsWe developed and validated AlphaLISA™ immunoassays to determine total and pS129 alpha-synuclein concentrations. Postmortem skin biopsies of Parkinson's disease (PD: n = 18), Dementia with Lewy bodies (DLB: n = 3), Multiple System Atrophy (MSA: n = 5) and control (n = 5) subjects were collected at the cervical vertebra C7. Brain tissues (middle temporal gyrus and substantia nigra) were collected from these same cases. In addition, skin biopsies of controls (n = 20) and PD cases (n = 40) were obtained from the ProPark cohort.ResultsTotal and pSer129 alpha-synuclein could be robustly detected and quantified in all skin samples. We observed a trend towards increased total (+58%, p = 0.055) and pS129 (+131%, p = 0.060) alpha-synuclein skin concentrations in synucleinopathy cases compared to controls. We found no correlations between pS129 alpha-synuclein concentrations in paired brain and skin tissues from the same donors. pS129 alpha-synuclein concentrations were similar for clinical PD cases and controls and there was no correlation with motor symptom severity (UPDRS-III).ConclusionsThese findings highlight that total and pS129 alpha-synuclein can be biochemically quantified in skin biopsies, but warrant further validation and investigation to asses its potential as a diagnostic biomarker in clinical cohorts.