Parkinsonism & related disorders最新文献

Introduction: Deep brain stimulation (DBS) targeting the posterior subthalamic area (PSA) is a more recent target to manage medication-refractory essential tremor (ET), with some studies suggesting enhanced tremor control and more favorable side-effects profile compared to traditional ventral intermediate nucleus (Vim). This study aims to assess the long-term efficacy and side effect profile of PSA-DBS in ET patients.

Methods: Fourteen ET patients who underwent bilateral PSA-DBS were evaluated using the Fahn-Tolosa-Marin Tremor Rating Scale preoperatively, at 12 months, and at the last follow-up (range 10-63 months). Within the first 6 months postoperatively, systematic monopolar contact testing was performed to determine individual thresholds for tremor suppression and adverse effects. Standardized neurological examinations and blinded video assessments were used to document stimulation-induced side effects.

Results: Tremor was significantly reduced postoperatively, allowing a 59% reduction at 12 months and 39% at last follow-up. Common side effects at last follow-up included dysarthria (93%), ataxia (57%), and gait disturbances (79%), mainly mild to moderate in severity. Additionally, stimulation-induced dyskinesia occurred in 21% of patients. Patient satisfaction remained high, with 85.7% reporting significant improvements.

Conclusions: Bilateral PSA-DBS demonstrates sustained tremor reduction but can frequently present stimulation-induced side-effects, highlighting the importance of careful long-term monitoring and programming adjustments.

Background: The development of non-invasive diagnostic tools for Parkinson's disease (PD) remains an unmet clinical need. Given the contribution by peripheral metabolism and environmental factors toward PD pathogenesis, comprehensive profiling of the plasma phenome could enable early disease detection. Accordingly, this study aimed to develop a non-invasive diagnostic panel for PD, to comprehensively characterize potential environmental triggers of PD pathogenesis, and to delineate the relationship between peripheral metabolism and disease progression.

Methods: We performed quantitative plasma phenome profiling - including metabolomics, lipidomics and bile acid analysis - in two independent cohorts of early PD (n = 226, median disease duration <5 years) comprising predominantly treated and treatment-naive patients, respectively, and healthy controls (HCs; n = 122) to identify PD-associated metabolites. Longitudinal analyses were conducted in a patient subset over a two-year follow-up. Longitudinal analyses (2 years) and trans-omics integration were applied.

Results: Trans-omics integration showed glutathione metabolism dysregulation, with reduced plasma γ-glutamyl peptides and elevated sphingomyelin linked to motor dysfunction; higher baseline γ-glutamyl peptides predicted worse motor prognosis in PD. Reduced sphingosine-1-phosphates (S1Ps) and lysophosphatidic acids (LPAs) were correlated with abated tricarboxylic acid (TCA) cycle and motor deterioration. A three-metabolite panel (pyroglutamic acid, 2-methylbutyrylglycine, α-ketoisovaleric acid), selected via LASSO regression, robustly discriminated early PD from HCs, consistently outperforming clinical indices and lipid/bile acid panels (Discovery AUROC = 0.97 [0.96-0.99]; Validation AUROC = 0.83 [0.75-0.91]).

Conclusion: Our findings demonstrate the clinical utility of plasma metabolites as robust, medication-independent biomarkers for early PD diagnosis, and delineate disease-associated metabolic deficits as potential targets for nutritional/metabolic intervention.

Introduction: Neuroinflammation is increasingly implicated in PD. Peripheral immune alterations are well described, but their link to motor complications, particularly ON-OFF fluctuations, remains unstudied. We hypothesized that such fluctuations act as intermittent stressors, transiently modulating peripheral immunity.

Objective: To investigate the immunological impact of motor fluctuations in PD by analyzing blood transcriptomic signatures during motor state transitions.

Methods: Whole-blood transcriptomic profiling with Clariom D arrays was performed in fluctuating PD (PD-Fluc) patients during OFF and ON dopaminergic states to identify relevant genes and pathways. Four natural killer (NK) cell-related genes were validated by qPCR in an expanded cohort: PD-Fluc, non-fluctuating PD (PD-NonFluc), and controls. Motor status (MDS-UPDRS III) was evaluated before each blood draw.

Results: Transcriptomic analysis identified 737 transcripts differentially expressed in ON vs. OFF states in PD-Fluc patients, with NK cell-related genes among the most prominently downregulated in the ON state. Gene set enrichment analysis (GSEA) further supported the downregulation of NK cell-mediated cytotoxicity pathways. qPCR validation confirmed state-dependent modulation of ADGRG1 and PRF1 genes in PD-Fluc patients, an effect absent in PD-NonFluc patients following dopaminergic treatment. Moreover, the expression levels of these genes were able to discriminate PD-Fluc from PD-NonFluc patients, highlighting their potential as molecular markers for disease stratification.

Conclusion: Motor fluctuations in PD drive dynamic changes in peripheral immunity, including up-regulation of NK cell-related genes in the OFF state, which reflects fluctuating immune activation states. These findings underscore the need for early and sustained control of motor fluctuations to protect neurological and immune integrity.

Introduction: It is believed that anticholinergics alleviate tremor and rigidity in Parkinson's (PD) by counteracting a relative cholinergic overactivity in motor regions, but this remains unclear. This study aimed to investigate possible cholinergic alterations in tremor dominant (TD) PD that may back use of anticholinergics.

Methods: Twelve PD patients [six with TD and six with non-tremor dominant (nTD) phenotype] and six healthy controls (HC) underwent cholinergic positron emission tomography with [¹¹C]-donepezil. Participants were assessed with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale.

Results: We found no increases of [¹¹C]-donepezil binding in cortical or subcortical areas of either PD group compared with HC. Compared with HC, [¹¹C]-donepezil binding was significantly decreased in the thalamus of nTD patients (p = 0.0463) but not in TD patients. This was confirmed by voxel-wise analyses that found further significant decreases in hippocampus, caudate, parahippocampus, cerebellar vermis, and lower part of mesencephalon of nTD PD patients compared with HC (p = 0.000). However, no significant differences in [¹¹C]-donepezil binding were found in the direct comparison between TD and nTD PD patients.

Conclusion: Our study provides evidence that TD PD patients might have relatively preserved cholinergic function in tremor-associated regions. However, anticholinergics should be used with caution when treating parkinsonian tremor due to their side effect profile.

Introduction: There is a scarcity of data and guidelines for therapeutic management of degenerative Parkinsonian syndromes (DPS) patients in their terminal phase. This study aims to describe the evolution of a cohort of DPS patients who were treated by continuous subcutaneous apomorphine infusion (CSAI) through a home-based program (Hospital-at-Home, HaH), after a life-threatening acute medical event.

Methods: This retrospective descriptive exploratory study based on medical records analysis, included 12 Parkinson's disease (PD) and 5 multiple system atrophy (MSA) patients treated by CSAI through a HaH program, during and after they suffered from a life-threatening acute medical event compromising the oral route. Outcomes were the patient's symptoms (pain, rigidity, ability to swallow and communicate), medication, CSAI-side effects and patients trajectory.

Results: CSAI was associated with symptom improvement in 82% of patients (14/17). The treatment was well tolerated, 35 % of patients developed CSAI-related side effects but none warranted CSAI discontinuation.

Conclusion: The findings point toward a potential benefit of CSAI delivered through a HaH program on symptom and comfort improvement in advanced PD and MSA patients. This positive effect was suggested in patients facing a life-threatening event compromising the oral route, whether or not they were in the immediate end-of-life phase.

Background: Orthostatic hypotension (OH) is a frequent autonomic feature of Parkinson's disease (PD), yet its long-term clinical consequences remain insufficiently characterized, particularly regarding falls and major vascular events.

Methods: Adults aged ≥50 years with PD who had a 2018 hospitalization or outpatient visit and received antiparkinsonian medication were included; the first encounter served as the index. Patients with vascular events in the prior 12 months were excluded. Five-year risks were assessed using inverse probability of treatment weighting (IPTW) and propensity score matching (PSM). Logistic regression estimated ORs, negative binomial models assessed fall counts, and OH pharmacotherapy effects were evaluated.

Results: Among 111,368 patients with PD who met the inclusion criteria, 2598 had OH. OH was independently associated with higher 5-year fall risk (adjusted OR 1.35, 95 % CI 1.21-1.51) and more cumulative falls (IRR 1.22, 95 % CI 1.20-1.24). These associations persisted in PSM analyses. In contrast, OH was not associated with major vascular events (adjusted OR 0.99, 95 % CI 0.86-1.14). Traditional cardiovascular risk factors, including hypertension, dyslipidemia, and diabetes, were strongly associated with vascular outcomes. Among patients with OH, pharmacotherapy was associated with higher fall risk (adjusted OR 1.34, 95 % CI 1.10-1.64) but not with vascular events. Findings were consistent across sensitivity analyses.

Conclusions: In this national PD cohort, both OH and its pharmacotherapy increased long-term fall risk but showed no association with major vascular events. These findings indicate distinct outcome profiles of OH, underscoring the need for focused fall-prevention and further evaluation of vascular safety.

Background: Isolated rapid eye movement sleep behavior disorder (iRBD) is a prodromal stage of α-synucleinopathy such as Parkinson's disease (PD). Brain cholinergic alterations have been reported in these diseases, but direct comparisons of terminal density between iRBD and clinically manifest PD have not yet been performed.

Objectives: To assess brain cholinergic terminal density in iRBD using positron emission tomography (PET) with [¹⁸F]-fluoroethoxybenzovesamicol (FEOBV), and to compare findings with both healthy controls and patients with PD.

Methods: Forty-six participants (16 with polysomnography-confirmed iRBD, 12 with PD, and 18 controls) underwent high-resolution PET neuroimaging with FEOBV. Voxel-wise analyses and effect size mapping were conducted to compare the groups, using standardized uptake value ratios (SUVRs). Correlations were performed between whole-cortex SUVR and clinical measures.

Results: Compared to controls, both the iRBD and PD groups exhibited significant cortical cholinergic denervation of similar magnitudes (11-12 %). Effect size mapping revealed very large losses (Cohen's ds < -1.5) in the posterior cortex in both patient groups, predominantly occipital-parietal in iRBD and occipital-temporal in PD. In iRBD, lower cortical uptake was associated with poorer performance on executive and visuospatial tests. Moreover, in iRBD but not in PD, there was a trend toward higher FEOBV uptake in subcortical areas, including brainstem regions.

Conclusions: Cholinergic denervation in iRBD is comparable in extent to that in PD, with subtle topographic distinctions, and correlates with cognitive deficits.