Journal of Parkinson's disease最新文献

BackgroundType 2 diabetes mellitus (DM) can influence the phenotype and progression of Parkinson's disease (PD), as both conditions share inflammation as a common pathogenic mechanism.ObjectiveTo explore peripheral inflammatory indices that reflect the impact of DM on PD.MethodsWe analyzed 52 drug-naïve PD patients with DM and 182 without DM, along with age- and sex-matched healthy control (HC) with and without DM in a 1:1 ratio. Clinical features were evaluated, including the Hoehn and Yahr (H&Y) scale and the Unified Parkinson's Disease Rating Scale (UPDRS). Peripheral inflammatory markers included the count of leukocyte subpopulations, high-density lipoprotein-cholesterol (HDL-C), and markers derived from these including neutrophil-to-HDL-C ratio (NHR), monocyte-to-HDL-C ratio (MHR), and lymphocyte-to-HDL-C ratio (LHR).ResultsThere were no significant differences in age, sex, or disease duration between PD with DM and PD without DM group. The PD with DM group showed more symmetric motor features (p = 0.007) compared to the PD without DM group. NHR, MHR, and LHR were elevated in the PD with DM group compared to the other groups. Notably, MHR was highest in the PD with DM group, followed by the HC with DM group and the PD without DM group, and HC without DM group (9.73 vs. 8.30 vs. 7.63 vs. 6.46, p < 0.001). MHR positively correlated with clinical scales, including H&Y and UPDRS, across all PD patients (p < 0.05 for all).ConclusionsOur study suggests that MHR effectively reflects the peripheral inflammatory status related to both PD and diabetes.

Diagnosing α-synucleinopathies and assessing target engagement in trials is hindered by the lack of reliable biomarkers. Here, we introduce a first-in-kind quantitative, highly sensitive, and disease-specific diagnostic assay, named Seeding Amplification ImmunoAssay (SAIA), developed and validated to detect synucleinopathy-linked disorders. To this end, we used wide range of specimens, including 38 brain homogenates (BH) and 559 cerebrospinal fluid (CSF) samples from subjects with diverse synucleinopathy disorders, non-synucleinopathy diseases, idiopathic REM sleep behavior disorder (iRBD), and controls. SAIA generated robust results detecting disease-related α-synuclein seeds in BH samples at attogram levels, as referenced to preformed fibrils of α-synuclein. Furthermore, we conducted side-by-side comparisons between SAIA and a traditional Seeding Amplification Assay (SAA), which revealed high concordance. Further, SAIA distinguished synucleinopathies from non-synucleinopathies and controls with sensitivities and specificities ranging between 80-100% and area under the curve values exceeding 0.9. SAIA also accurately identified 24/24 (100%) iRBD cases, considered a prodromal state of PD, with 100% sensitivity and 80% specificity. Further optimization of SAIA through timepoint analyses revealed that shorter incubation times enhanced the assay's specificity for distinguishing MSA from PD highlighting the potential for improved differentiation between specific synucleinopathies. In conclusion, SAIA represents a novel, high-throughput method to screen, diagnose, and monitor synucleinopathy disorders in living subjects, offering significant improvements over existing methods through its quantitative output, shorter incubation time, and simplified workflow, features that enhance its suitability for clinical trial applications.

The Parkinson pandemic continues to spread. Almost 12 million individuals now have the disease, nearly double the estimate from just six years ago. Its human-made nature is also increasingly clear as more studies tie environmental toxicants to the disease. Chief among these are certain pesticides, the dry-cleaning chemicals trichloroethylene and perchloroethylene, and air pollution. An etiological role for these toxicants-inhaled or ingested-is also consistent with the emerging brain- and body-first models of Parkinson's disease.To address the pandemic will require a "PLAN" that (1) Prevents the disease; (2) Learns why it starts; (3) Amplifies the voices of persons with the disease and their caregivers; and (4) Navigates the frontier of new treatments. Reducing or eliminating toxicants will help slow its rise. Learning why the disease begins will require investigating exposures, interactions of the environment with genes, and modifiers. Amplifying the voices of those affected can raise awareness, improve care, and change the disease's course. Vastly expanding the scale and scope of research funding will accelerate efforts to prevent the disease and find more effective therapies. If successfully implemented, such a plan will translate to bold "0-10-100" goals by 2035. The goals include a 0% rise in the global incidence of Parkinson's, a 10-fold increase in research funding and in the proportion devoted toward prevention, and 100% of individuals having access to levodopa and receiving appropriate care. The results will lay the foundation for even greater ambitions, including the fall of Parkinson's disease.

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.