Movement Disorders最新文献

Background: Chronic musculoskeletal pain often co-occurs with Parkinson's disease (PD); however, whether individuals with chronic pain have a higher risk of developing PD is unclear.

Objectives: To investigate the associations between chronic pain and incident risk of three neurodegenerative parkinsonism categories including PD, multiple system atrophy (MSA), and progressive supranuclear palsy (PSP).

Methods: This study included 355,890 participants (mean [standard deviation] age, 56.51 [8.07] years, 48.40% male) who did not have parkinsonism at baseline from a population-based cohort. Musculoskeletal pain in the hip, neck/shoulder, back, knee, or "all over the body" was assessed. Chronic pain was defined if pain lasted ≥3 months. Participants were categorized into four groups: no chronic pain, having one or two, three or four sites, and pain "all over the body." The diagnosis of PD, MSA, and PSP used self-reports, hospital records, and death registries. Multivariable-adjusted Cox regression was performed for the analyses.

Results: Over a median follow-up of 13.0 years, 2044 participants developed PD, 77 participants developed MSA, and 126 participants developed PSP. In multivariable analyses, there was a dose-response relationship between number of chronic pain sites and incident risk of PD (hazard ratio, 1.15; 95% confidence interval, 1.07-1.23). Participants with one or two pain sites and three or four pain sites had an 11% and 49% increased risk of developing PD, respectively. There were no associations between chronic pain and MSA or PSP.

Conclusions: Chronic musculoskeletal pain was independently associated with PD, suggesting that chronic pain could be used to identify individuals at risk of developing PD. © 2024 International Parkinson and Movement Disorder Society.

Background: The cerebellar cognitive affective syndrome (CCAS) encompasses cognitive and affective symptoms in patients with cerebellar disorders, for which no proven treatment is available.

Objectives: Our primary objective was to study the effect of cerebellar anodal transcranial direct current stimulation (tDCS) on cognitive performance in CCAS patients. Secondary effects on ataxia severity, mood, and quality of life were explored.

Methods: We performed a randomized, double-blind, sham-controlled trial. Thirty-five patients with CCAS were included and received 10 sessions of 20 minutes sham (n = 17) or real (n = 18) tDCS, with a current of 2 mA. Cognitive performance was assessed using executive function subtests of the computerized Test of Attentional Performance (TAP), with the composite as primary endpoint. Secondary outcomes were ataxia severity, mood, and quality of life. Outcomes were evaluated 1, 3, 6, and 12 months post-intervention.

Results: Cerebellar tDCS was well tolerated and no serious adverse events related to the intervention occurred. No significant tDCS effect was found on cognitive performance. Improvement on the TAP was observed in the sham group 1 month post-treatment (estimate = -0.248, 95% CI, -0.49 to -0.01), but not clinically relevant. A positive tDCS effect was observed for ataxia severity 1 month post-treatment (estimate = -0.985, 95% CI, -1.94 to -0.03).

Conclusions: Ten sessions of 20 minutes cerebellar anodal tDCS did not prove efficacious for CCAS-related cognitive impairment, but a significant positive effect of tDCS was found for ataxia severity, aligning with previous findings indicative of tDCS as a therapeutic neuromodulation tool in cerebellar disorders. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: High positivity rate of skin phosphorylated α-synuclein (P-SYN) was observed in Parkinson's disease (PD). Bullous pemphigoid (BP) is one of the most common autoimmune skin diseases associated with PD.

Objectives: Our aim was to investigate whether BP patients might be a targeted risk population for the screening of skin P-SYN.

Methods: Skin P-SYN expression was evaluated by immunohistochemistry in BP patients with/without PD.

Results: Twenty-two BP patients with PD, 24 BP patients without PD, and seven healthy donors were enrolled. Colocalization of P-SYN and PGP9.5 was found in all BP patients, but only one healthy control, whereas BP patients with PD showed higher expression than BP patients without PD (mean ± standard deviation, 10.7 ± 6.7 vs. 7.3 ± 3.2; P = 0.027). Positive expression was mainly observed in basement membrane zone and dermis.

Conclusion: These results indicated BP patients might be a targeted risk population for the screening of skin P-SYN, which was helpful for the detection of PD early. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: Progressive supranuclear palsy (PSP) is a rare and fatal neurodegenerative disorder for which there are currently no disease-modifying treatments. Recent trials of potential therapies had durations of 12 months, which may be insufficient because of nonrandom missingness due to death. Longer durations, incorporating PSP Rating Scale and survival, can reduce the potential for type II error. Selecting efficacy measures more sensitive to disease modification may facilitate identification of treatment effect.

Objective: The objective of this study was to evaluate the simulated phase 3 PSP trial assessing the effect of disease-modifying intervention on a novel combined primary endpoint comprising function (PSP Rating Scale) and survival, the Combined Assessment of Function and Survival (CAFS), and to determine operating characteristics of the CAFS.

Methods: To simulate PSP progression in the trial population, we developed models of PSP Rating Scale and survival using data from published clinical studies. These models were used to define operating characteristics of the CAFS for use in a phase 3 trial.

Results: The sample size determined (N = 384; 1:1 randomization) would provide >80% power to detect significant treatment effects on the CAFS compared with placebo. The CAFS provides good operating characteristics and increased power to detect moderate treatment effects on the PSP Rating Scale. We propose a trial design allowing potential detection of treatment effects at a preplanned interim analysis after participants complete 12 months of treatment, with assessment of effects of treatment (≤24 months) on survival.

Conclusions: Use of the CAFS could provide a comprehensive and robust estimate of the clinical benefit of future therapies. © 2024 UCB. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: Hereditary spastic paraplegia (HSP) is characterized by progressive lower limb weakness and spasticity, with unknown genetic cause in many cases.

Objectives: To identify novel genetic causes of HSP.

Methods: Phenotypic characterization, genetic screening, transcriptome sequencing, and peroneal nerve biopsy were conducted in a Chinese HSP family.

Results: We found a homoplasmic MT-TV (mitochondrial tRNA^Val) mutation, m.1661A > G, present in all affected individuals across four generations of a family with complex HSP. Fourth-generation affected individuals displayed earlier onset, likely due to presumptive anticipation, and greater symptom severity, potentially caused by decreased mitochondrial DNA (mtDNA) copy number. Upregulation of mitochondrial autophagy genes in these patients suggested that MT-TV mutations could lead to reduced mtDNA copy number. Neural biopsies revealed ultrastructural abnormalities in myelin and mitochondria.

Conclusions: The rare MT-TV m.1661A > G mutation is associated with HSP. Variations in mtDNA copy number may play a causal role in differences among clinical phenotypes. © 2024 International Parkinson and Movement Disorder Society.

Advances in genetic technologies and disease modeling have greatly accelerated the pace of introducing and validating molecular-genetic contributors to disease. In dystonia, there is a growing convergence across multiple distinct forms of the disease onto core biological processes. Here, we discuss two of these, the endosome-autophagosome-lysosome pathway and the integrated stress response, to highlight recent advances in the field. Using these two pathomechanisms as examples, we further discuss the opportunities that molecular-genetic grouping of dystonias present to transform dystonia care. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.