Journal of Parkinson's disease最新文献

BackgroundGiven the increasing global prevalence of Parkinson's disease (PD) and its complex etiopathogenesis, understanding the role of environmental factors is crucial. Prior investigations suggested a potential link between metal exposure and PD, yet conflicting results emerged.ObjectiveTo identify differences in metal concentrations in whole blood and cerebrospinal fluid (CSF) in PD patients compared to controls.MethodsThe study involved an untreated de novo PD patient cohort from a single-center (n = 102, 38% females, mean age 59.5 (SD 12.5)) and a group of controls with comparable age and sex distribution (n = 127, 35% females, mean age 57.5 (SD 12.4)). Whole blood in all participants and CSF samples in a subgroup (n = 57/55 PD/controls) were collected and concentrations of V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Mo, Cd, Sn, Hg, and Pb, were determined through inductively coupled plasma mass spectrometry.ResultsPD patients exhibited higher concentrations of Hg in both blood and CSF (p = 0.003). Cr concentrations were lower in both blood (p = 0.004) and CSF (p < 0.001) of PD patients. Altered Fe metabolism was evident, with higher blood (p = 0.001) and lower CSF (p = 0.002) Fe concentrations. Other metal alterations in PD included higher Zn (p = 0.008) in blood and lower Co (p < 0.001), Mn (p = 0.006), V (p = 0.009), and Ni (p < 0.001) in CSF.ConclusionsThe findings highlight abnormalities in metal concentrations in biofluids associated with PD, particularly regarding Hg, Cr, and Fe which exhibited alterations in blood and CSF. These findings suggest metal dysregulation in PD, particularly Hg, Cr, and Fe, with potential implications for understanding PD pathogenesis.

BackgroundApathy, defined as a quantitative reduction in goal-directed activity, is a non-motor manifestation that can be present in Parkinson's disease (PD). It seems to be a risk factor for conversion to dementia (PDD) in this population. Amyloid-β deposition also predicts progression to PDD.ObjectiveWe aimed to investigate whether PD patients with apathy showed higher amyloid burden than those without, as well as how these features may influence the rate of progression to dementia.MethodsWe conducted an observational cross-sectional and longitudinal study. Forty-eight PD patients were recruited, including 20 with apathy and 28 without it according to the Starkstein Apathy Scale. They underwent clinical and cognitive evaluations and [¹⁸F]-Flutemetamol PET. The neuropsychological assessment was repeated after 3 years. The predictive value of apathy and amyloid burden for conversion was assessed via logistic regression. Longitudinal trajectories across neuropsychological tests were modeled with linear mixed-effects.ResultsPatients with apathy showed worse performance on several cognitive domains. Using disease duration and global cognition Z-score as covariates, amyloid burden was higher in apathetic vs. non-apathetic patients, mainly in the frontal and temporal cortices. Non-apathetic patients did not have regions with higher amyloid burden in comparison with apathetic patients. After 3 years' follow-up, the conversion rate to worse cognitive state was significantly higher in apathetic (47.4%) vs. non-apathetic (12.0%) patients (p < 0.05). Logistic regression showed that amyloid burden, but not apathy, predicted 3-year cognitive conversion (χ² = 9.95, p < 0.05).ConclusionsApathetic patients exhibit greater amyloid burden and higher cognitive deterioration over time than their non-apathetic counterparts.

BackgroundThe rest-activity rhythm (RAR) captures the distribution of rest and activity periods between and within days. Disturbed RAR has been observed in Parkinson's disease (PD), but the contribution of motor and non-motor symptoms to RAR disturbances remains unclear.ObjectiveTo evaluate the extent to which motor and non-motor symptoms account for variations in RAR between people with PD (PwPD).Methods464 PwPD and 105 age-matched controls of the ProPark cohort underwent assessment of motor, psychiatric, sleep, and autonomic function. Participants wore a wrist motion sensor for one week to measure RAR, i.e., relative amplitude, interdaily stability, and intradaily variability. Associations between RAR, and demographic and clinical variables were examined using backward stepwise regression models.ResultsPwPD had lower relative amplitude (p < 0.001), lower interdaily stability (p < 0.001), and higher intradaily variability (p < 0.001), than healthy controls. Motor impairment (β=-0.262, 95% CI = [-0.487,-0.125], R²=6.8%) and the presence of orthostatic hypotension (OH) (β=-0.142, 95% CI = [-0.276,-0.026], R²=1.9%) were associated with lower relative amplitude. Motor impairment (β=0.129, 95% CI = [0.005,0.238], R²=2.5%), the presence of OH (β=0.182, 95% CI = [0.079,0.307], R²=3.6%), and higher age (β=0.158, 95% CI = [0.039,0.277], R²=4.0%) were associated with higher intradaily variability, while female gender (β=-0.196, 95% CI = [-0.318,-0.088], R²=4.7%) was associated with lower intradaily variability. Female gender was linked to higher interdaily stability (β=0.205, 95% CI = [0.071,0.321], R²=4.2%).ConclusionsMore severe motor impairment and having OH are associated with RAR disturbances in PwPD. Future studies are needed to evaluate whether optimizing treatment of motor impairment and OH, both symptomatic and asymptomatic, can improve RAR and increase mobility for PwPD.

SummaryThis study is the first large-scale, head-to-head comparison suggesting that sodium-glucose cotransporter-2 inhibitors (SGLT2is) may offer greater neuroprotection against Parkinson's disease (PD) compared to metformin in patients with type 2 diabetes mellitus (T2DM). Utilizing a 20-year real-world dataset and propensity score matching, we found that SGLT2i users had a 28% lower adjusted hazard ratio (aHR) for PD (0.72; 95% CI, 0.62-0.84) and reduced all-cause mortality. Unlike previous studies suggesting a potential increased PD risk with SGLT2is, our robust study design, stringent exclusion criteria, and competing risk adjustments support a protective association. The findings highlight the need for further prospective research to explore the neuroprotective benefits of SGLT2is, which may justify prioritizing their use in T2DM patients at risk for neurodegeneration.BackgroundType 2 diabetes mellitus (T2DM) is linked to an increased risk of Parkinson's disease (PD), likely mediated by insulin resistance, inflammation, and mitochondrial dysfunction. While metformin has shown neuroprotective effects, sodium-glucose cotransporter-2 inhibitors (SGLT2is) have emerging benefits in neurodegeneration. This study provides the first real-world head-to-head comparison of SGLT2is and metformin on PD risk in T2DM patients.MethodsUsing the TriNetX platform, we analyzed a 20-year dataset (2005-2025) from 142 healthcare organizations, identifying 913,428 T2DM patients (96,018 SGLT2i, 817,410 metformin users). Patients with prior PD, neurodegenerative diseases, or exposure to neuroprotective/neurotoxic antidiabetic drugs were excluded. Propensity score matching (1:1) balanced cohorts across demographic, clinical, and pharmacological variables. Cox proportional hazards models estimated adjusted hazard ratios (aHRs), validated by positive and negative controls.ResultsSGLT2i use was associated with a 28% lower PD risk than metformin (aHR = 0.72; 95% CI, 0.62-0.84; p < 0.0001). Dementia, a positive control, also showed reduced risk (aHR = 0.73; 95% CI, 0.68-0.78; p < 0.0001), reinforcing the neuroprotective effect. Negative controls confirmed specificity. SGLT2i users had significantly lower all-cause mortality (aHR = 0.85; 95% CI, 0.83-0.89; p < 0.0001).ConclusionsThis first large-scale comparison suggests SGLT2is provide superior neuroprotection against PD compared to metformin in T2DM patients, warranting further investigation.

BackgroundFreezing of gait (FOG) is a common and disabling symptom in patients with Parkinson's disease (PD), significantly impairing motor function and quality of life. While traditional deep brain stimulation (DBS) of the subthalamic nucleus (STN) provides some benefits, its efficacy in alleviating FOG remains limited. Combined stimulation of the STN and the substantia nigra pars reticulata (SNr) has recently emerged as a potentially superior approach.ObjectiveTo compare the efficacy of STN-only stimulation and combined STN + SNr stimulation in improving FOG symptoms and quality of life in patients with PD.MethodsThis multicenter, prospective, randomized, crossover study was conducted between May 2020 and May 2024 and enrolled patients with PD and significant FOG. All participants received bilateral DBS electrode implantation. Each subject sequentially underwent both STN-only and combined STN + SNr stimulation conditions according to a randomized crossover schedule, with each stimulation period lasting for six months. Outcome assessments, including the Freezing of Gait Questionnaire (FOG-Q) and the Parkinson's Disease Questionnaire Summary Index (PDQ-SI), were conducted at baseline, 6, 12, and 18 months. Data were analyzed using mixed-model repeated-measures analysis of variance, followed by post hoc Bonferroni-adjusted pairwise comparisons to account for the crossover design.ResultsCompared to STN-only stimulation, combined STN + SNr stimulation resulted in significantly greater improvement in FOG-Q scores and PDQ-SI scores. The benefits were observed at each assessment following the switch to combined stimulation.ConclusionsCombined STN and SNr stimulation was more effective than STN-only stimulation in alleviating FOG symptoms and improving quality of life in patients with PD. This dual-target DBS approach may represent a promising therapeutic strategy for managing refractory FOG in PD.

Parkinson's disease (PD) is a neurological disorder that is characterized by the death of dopaminergic neurons in the substantia nigra. Despite extensive research, the exact cause of PD is unknown, and current treatment options are centered on symptom management rather than disease modification. Most, though not all, epidemiologic studies have demonstrated reduced risk of development of PD among smokers, generating interest in nicotine, a key component of tobacco. Many preclinical investigations have investigated nicotine's neuroprotective properties, especially through its interaction with nicotinic acetylcholine receptors in the central nervous system. Nicotine has been linked to a variety of cellular activities, including neurotransmitter release, neuronal survival, and anti-inflammatory responses. Animal studies in PD models have indicated that nicotine administration can attenuate the degeneration of dopaminergic neurons and ameliorate behavioral abnormalities. Clinical investigations evaluating nicotine as a treatment for PD have yielded mixed results in terms of efficacy. Thus, central questions remain about the effects of nicotine in patients with established PD, and neither nicotine nor smoking are recommended for treatment or prevention of PD. Further research on the multiple proposed mechanisms of nicotine is required, with particular emphasis on elucidating symptomatic versus neuroprotective effects. The aim of this scoping review is to provide a comprehensive discussion of the proposed mechanisms of neuroprotection for nicotine in Parkinson's disease.

BackgroundAlpha-synuclein is associated with neurodegeneration in Parkinson's disease (PD). Recent studies have increasingly recognized incidences of cardiac complaints in PD patients. In particular, the occurrence of arrhythmias in PD patients may indicate potential electrophysiological alterations in the heart. Alpha-synuclein aggregates have been known to have disruptive effects on cell membranes. However, the effect of alpha-synuclein on the heart and sympathetic neuronal tissues remains unknown.ObjectiveThis study investigated the electrophysiological effects of alpha-synuclein aggregates in myocardium and cardiac sympathetic nervous system, potentially reflecting cardiac electrophysiological alteration in PD.MethodsWe measured the in situ sodium and potassium currents from murine ventricular myocardium and stellate ganglia using the loose patch clamp technique. The tissues were exposed to bioactive alpha-synuclein aggregates, and currents were measured under three different conditions: baseline, alpha-synuclein treatment, and wash out.ResultsThe experiments showed that alpha-synuclein aggregates altered the maximum cardiac sodium current (I_Na(Max)) (ANOVA, p < 0.008) and affected its gating properties for channel activation (ANOVA F_2,54 = 6.408, p = 0.003) and inactivation (F_{2, 67} = 6.32, p = 0.003). The alpha-synuclein aggregates also reduced the maximum outward potassium current (I_K(Max)) during channel activation (F_{2, 77} = 6.02, p = 0.002). However, the alpha-synuclein aggregates did not affect the ionic currents in the stellate ganglia.ConclusionsOur results demonstrate that extracellular alpha-synuclein aggregates can inhibit ventricular but not stellate ganglion ionic currents, suggesting a differential sensitivity between the myocardium and the stellate ganglia, and indicating a cardiac-specific toxicity of alpha-synuclein on cardiac electrophysiology.

Individuals with isolated REM sleep behavior disorder (iRBD) are at high risk of developing α-synucleinopathies, particularly Parkinson's disease (PD) and dementia with Lewy bodies (DLB). With the development of potential neuroprotective treatments for synucleinopathies, including PD, identifying clinical features that can allow for tracking subtle changes in prodromal disease and thereby monitoring risk of phenoconversion in iRBD is paramount. Subtle motor deficits have been suggested to be present in iRBD, making them potentially important clinical markers for predicting future phenoconversion. This review aims to summarize existing literature that has investigated differences in motor function between iRBD and healthy individuals, as well as progression of motor decline in iRBD. 39 eligible studies were included in this review. The results suggest that quantitative motor assessments may be more sensitive to motor impairments in this population than clinical scales. Moreover, dual-tasking tended to unmask subtle motor deficits in individuals with iRBD, particularly in gait, balance, and tapping assessments. Longitudinal studies demonstrate that motor function worsens over time in iRBD, with earliest signs of motor deficits and clear progression in tapping assessments in particular. Larger longitudinal studies that use quantitative methods of motor assessments are needed to better characterize motor progression in iRBD, and confirm the reliability of different motor markers for predicting phenoconversion of iRBD into PD and other synucleinopathies.

Complementary and alternative therapies (CAT) is an umbrella term applied to a diverse set of approaches, with high interest among persons with Parkinson's disease. However, scientific community regards evidence-based medicine as the only acceptable, creating a black and white dichotomy, which is neither epistemologically correct nor workable in daily practice. CAT are heterogeneous, and the label is dynamic as new scientific insights might accrue. Medicine encompasses a wide range of interventions that can be positioned alongside a spectrum of credibility, with many shades of grey between the extremes. We define credibility along three dimensions: the underlying rationale, the scientific rigor, and patient perceptions. By no means this implies we encourage adoption of weakly grounded therapies, or favor exotic treatments over evidence-based approaches. Credibility serves as basis for a nuanced debate in clinical practice, with attention to adverse effects, interactions, and costs. The degree of credibility also informs the need for further research. This offers a practical road forward for open-minded, yet rational decisions by persons with Parkinson's disease, clinicians, funding bodies and relevant stakeholders.

BackgroundParkinson's disease (PD) is a common neurodegenerative disease lacking treatments that modify progressive neuron loss. Terazosin (TZ) increases activity of the glycolytic enzyme phosphoglycerate kinase 1 and could potentially benefit impaired brain bioenergetics in PD. Preclinical data are encouraging, but we lack human data on relationships between TZ dose and measures of TZ target engagement in women and men.ObjectiveThis study evaluated the dose-dependent effects of TZ on brain and systemic bioenergetics and safety and tolerability in neurologically healthy older adults.MethodsWe administered TZ (1, 5, and 10 mg/day) to 18 neurologically healthy 60-85-year-old people. We measured plasma and cerebrospinal fluid TZ concentrations and changes in levels of whole blood ATP, brain ATP with ³¹P magnetic resonance spectroscopy, cerebral metabolic activity with ¹⁸F-FDG PET imaging, and plasma metabolomics. We also assayed tolerability and safety.ResultsTZ crossed the blood-brain barrier, and 5 mg/day increased whole blood ATP and decreased brain ¹⁸F-FDG uptake. TZ 1 mg/day lacked significant effects, and 10 mg/day did not produce additional metabolic benefit compared to 5 mg/day. These effects were similar for both sexes. Mild dizziness occurred in 3 females and 1 male.ConclusionsThese findings in humans align with results from preclinical cell, animal, and epidemiological studies. Our data show that TZ increases markers of energy metabolism with a biphasic dose-response and suggest that 5 mg/day TZ may provide maximal benefit while minimizing adverse consequences of higher doses. These results lay groundwork for clinical trials in people with PD.