Combined Physiotherapy and Cognitive Behavioral Therapy for Functional Movement Disorders: A Randomized Clinical Trial.

Importance: Functional movement disorders (FMDs) are frequent and disabling neurological disorders with a substantial socioeconomic impact. Few randomized studies have analyzed the effectiveness of combined physiotherapy and psychotherapy in patients' quality of life. Objective: To assess the efficacy of multidisciplinary treatment (physiotherapy plus cognitive behavioral therapy) in FMDs. Design, Setting, and Participants: This was a parallel, rater-blinded, single-center, randomized clinical trial. Recruitment took place from June 2022 to April 2023, and follow-up visits were performed at months 3 and 5, concluding in October 2023. Participants were recruited from a national referral center for movement disorders: the Movement Disorders Unit from the Hospital Universitario Virgen Rocio in Seville, Spain. Patients had to be 18 years or older with a confirmed FMD diagnosis and capable of giving consent to participate. Patients who did not meet eligibility criteria or refused to participate were excluded. Any uncontrolled psychiatric disorder was considered an exclusion criterion. Interventions: Patients were randomly assigned, in a ratio of 1:1 to multidisciplinary treatment (physiotherapy plus cognitive behavioral therapy), or a control intervention (psychological support intervention). Main Outcomes and Measures: Primary outcomes: between-group differences in changes from baseline to month 3 and month 5 in patients' quality of life (EQ-5D-5L score: EQ Index and EQ visual analog scale [EQ VAS]; and 36-Item Short-Form Survey Physical Component Summary [SF-36 PCS] and SF-36 Mental Component Summary [MCS]). Linear mixed models were applied, controlling by baseline severity and applying Bonferroni correction. Results: Of 70 patients screened with an FMD, 40 were enrolled (mean [SD] age, 43.5 [12.8] years; age range, 18-66 years; 32 female [80%]; mean [SD] age at FMD onset, 38.4 [12.1] years), and 38 completed all the follow-up visits and were included in the analysis for primary outcomes. Multidisciplinary treatment improved SF-36 PCS with a mean between-group difference at 3 months of 4.23 points (95% CI, -0.9 to 9.4 points; P = .11) and a significant mean between-group difference at 5 months of 5.62 points (95% CI, 2.3-8.9 points; P < .001), after multiple-comparisons adjustment. There were no significant differences in other quality-of-life outcomes such as SF-36 MCS (mean between-group difference at 3 and 5 months: 0.72 points; 95% CI, -5.5 to 7.0 points; P = .82 and 0.69 points; 95% CI, 2.3-8.9 points; P = .83, respectively), EQ VAS (9.34 points; 95% CI, -0.6 to 19.3 points; P = .07 and 13.7 points; 95% CI, -1.7 to 29.0 points; P = .09, respectively) and EQ Index (0.001 point; 95% CI, -0.1 to 0.1 point; P = .98 and 0.08 points; 95% CI, 0-0.2 points; P = .13, respectively). At months 3 and 5, 42% and 47% of patients, respectively, in the multidisciplinary group reported improved health using the EQ-5D system, compared with 26% and 16% of patients, respectively, in the control group. Conclusions and Relevance: Results show that multidisciplinary treatment (physiotherapy plus cognitive behavioral therapy) effectively improves FMD symptoms and physical aspects of patients' quality of life. Further studies must be performed to evaluate the potential cost-effectiveness of this approach in FMD. Trial Registration: ClinicalTrials.gov Identifier: NCT05634486.

Role of ATP10B in Parkinson disease in a cohort from southern Spain.

The ATP10B gene has been proposed to play an important role in the development of early-onset Parkinson's disease (PD). Nevertheless, various studies have presented controversial conclusions regarding the involvement of this gene in PD. Here, we screened 1162 patients with PD, employing a targeted resequencing approach to investigate the putative relevance of this gene in a large independent cohort of these patients from southern Spain. Variations were classified according to the American College of Medical Genetics and Genomics criteria. Association studies were performed using data of a representative healthy Spanish population from the Medical Genome Project. Frequent variants were excluded. A total of 68 variants (rare or very rare) were detected in our cohort. Among ATP10B variant carriers, 12.9 % were putative compound heterozygous carriers; of these, 25 % were patients with early-onset PD. No evidence of a relation between any rare variants of ATP10B and PD risk was observed. Therefore, our results do not support a role for ATP10B in the onset of PD, or in the risk of developing it.

Peripheral Inflammation Is Associated with Dopaminergic Degeneration in Parkinson's Disease.

BACKGROUND: Peripheral inflammatory immune responses are suggested to play a major role in dopaminergic degeneration in Parkinson's disease (PD). The neutrophil-to-lymphocyte ratio (NLR) is a well-established biomarker of systemic inflammation in PD. Degeneration of the nigrostriatal dopaminergic system can be assessed in vivo using [123 I]FP-CIT single photon emission computed tomography imaging of striatal dopamine transporter (DAT) density. OBJECTIVES: To assess the relationship between the peripheral immune profile (NLR, lymphocytes, and neutrophils) and striatal DAT density in patients with PD. METHODS: We assessed clinical features, the peripheral immune profile, and striatal [123 I]FP-CIT DAT binding levels of 211 patients with PD (primary-cohort). Covariate-controlled associations between the immune response and striatal DAT levels were assessed using linear regression analyses. For replication purposes, we also studied a separate cohort of 344 de novo patients with PD enrolled in the Parkinson's Progression Markers Initiative (PPMI-cohort). RESULTS: A higher NLR was significantly associated with lower DAT levels in the caudate (primary-cohort: ß = -0.01, p < 0.001; PPMI-cohort: ß = -0.05, p = 0.05) and the putamen (primary-cohort: ß = -0.05, p = 0.02; PPMI-cohort: ß = -0.06, p = 0.02). Intriguingly, a lower lymphocyte count was significantly associated with lower DAT levels in both the caudate (primary-cohort: ß = +0.09, p < 0.05; PPMI-cohort: ß = +0.11, p = 0.02) and the putamen (primary-cohort: ß = +0.09, p < 0.05, PPMI-cohort: ß = +0.14, p = 0.01), but an association with the neutrophil count was not consistently observed (caudate; primary-cohort: ß = -0.05, p = 0.02; PPMI-cohort: ß = 0, p = 0.94; putamen; primary-cohort: ß = -0.04, p = 0.08; PPMI-cohort: ß = -0.01, p = 0.73). CONCLUSIONS: Our findings across two independent cohorts suggest a relationship between systemic inflammation and dopaminergic degeneration in patients with PD. This relationship was mainly driven by the lymphocyte count. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Functional Movement Disorders and Deep Brain Stimulation: A Multi-Center Study.

Background: Functional movement disorders (FMD) are a commonly under-recognized diagnosis in patients with underlying neurodegenerative diseases. FMD have been observed in patients undergoing deep brain stimulation (DBS) for Parkinson's disease (PD) and other movement disorders. The prevalence of coexisting FMD among movement disorder-related DBS patients is unknown, and it may occur more often than previously recognized. Methods: We retrospectively assessed the relative prevalence and clinical characteristics of FMD occurring post-DBS, in PD and dystonia patients (FMD+, n = 29). We compared this cohort with age at surgery-, sex-, and diagnosis-matched subjects without FMD post-DBS (FMD-, n = 29). Results: Both the FMD prevalence (0.2%-2.1%) and the number of cases/DBS procedures/year varied across centers (0.15-3.65). A total of nine of 29 FMD+ cases reported worse outcomes following DBS. Although FMD+ and FMD- manifested similar features, FMD+ showed higher psychiatric comorbidity. Conclusions: DBS may be complicated by the development of FMD in a subset of patients, particularly those with pre-morbid psychiatric conditions.

Peripheral inflammatory immune response differs among sporadic and familial Parkinson's disease.

Peripheral inflammatory immune responses are thought to play a major role in the pathogenesis of Parkinson's disease (PD). The neutrophil-to-lymphocyte ratio (NLR), a biomarker of systemic inflammation, has been reported to be higher in patients with PD than in healthy controls (HCs). The present study was aimed at determining if the peripheral inflammatory immune response could be influenced by the genetic background of patients with PD. We included a discovery cohort with 222 patients with PD (132 sporadic PD, 44 LRRK2-associated PD (with p.G2019S and p.R1441G variants), and 46 GBA-associated PD), as well as 299 HCs. Demographic and clinical data were recorded. Leukocytes and their subpopulations, and the NLR were measured in peripheral blood. Multivariate lineal regression and post-hoc tests were applied to determine the differences among the groups. Subsequently, a replication study using the Parkinson's Progression Markers Initiative cohort was performed which included 401 patients with PD (281 sPD patients, 66 LRRK2-PD patients, 54 GBA-PD patients) and a group of 174 HCs. Patients with sporadic PD and GBA-associated PD showed a significantly lower lymphocyte count, a non-significantly higher neutrophil count and a significantly higher NLR than HCs. The peripheral inflammatory immune response of patients with LRRK2-associated PD did not differ from HCs. Our study supports the involvement of a peripheral inflammatory immune response in the pathophysiology of sPD and GBA-associated PD. However, this inflammatory response was not found in LRRK2-associated PD, probably reflecting different pathogenic inflammatory mechanisms.

Homocysteine levels, genetic background, and cognitive impairment in Parkinson's disease.

BACKGROUND: Hyperhomocysteinemia is considered an independent risk factor for cognitive impairment. OBJECTIVE: To study the correlation between homocysteine levels and cognitive impairment in patients with PD. METHODS: We conducted a case-control study that included 246 patients with PD, of whom 32 were cognitively impaired. The levels of homocysteine, folate, and vitamin B12 were measured in peripheral blood. Multivariate logistic regression analysis was applied to determine differences in homocysteine levels between PD patients with and without cognitive impairment. A meta-analysis was performed to clarify the role of Hcy levels in PD with cognitive decline. Five polymorphisms in genes involved in Hcy metabolism, including MTHFR rs1801133 and rs1801131, COMT rs4680, MTRR rs1801394, and TCN2 rs1801198, were genotyped. RESULTS: Our case-control study showed that homocysteine levels were associated with cognitive impairment in PD after adjusting for possible confounding factors such as levodopa equivalent daily dose. The results of our meta-analysis further supported the positive association between homocysteine levels and cognition in PD. We found that the MTHFR rs1801133 TT genotype led to higher homocysteine levels in PD patients, whereas the MTHFR rs1801131 CC genotype resulted in higher folate levels. However, the polymorphisms studied were not associated with cognitive impairment in PD. CONCLUSIONS: Increased homocysteine levels were a risk factor for cognitive decline in PD. However, no association was found between polymorphisms in genes involved in homocysteine metabolism and cognitive impairment in PD. Large-scale studies of ethnically diverse populations are required to definitively assess the relationship between MTHFR and cognitive impairment in PD.

Intermediate and Expanded HTT Alleles and the Risk for α-Synucleinopathies.

BACKGROUND: Previous studies suggest a link between CAG repeat number in the HTT gene and non-Huntington neurodegenerative diseases. OBJECTIVE: The aim is to analyze whether expanded HTT CAG alleles and/or their size are associated with the risk for developing α-synucleinopathies or their behavior as modulators of the phenotype. METHODS: We genotyped the HTT gene CAG repeat number and APOE-Ɛ isoforms in a case-control series including patients with either clinical or neuropathological diagnosis of α-synucleinopathy. RESULTS: We identified three Parkinson's disease (PD) patients (0.30%) and two healthy controls (0.19%) carrying low-penetrance HTT repeat expansions whereas none of the dementia with Lewy bodies (DLB) or multisystem atrophy (MSA) patients carried pathogenic HTT expansions. In addition, a clear increase in the number of HTT CAG repeats was found among DLB and PD groups influenced by the male gender and also by the APOE4 allele among DLB patients. HTT intermediate alleles' (IAs) distribution frequency increased in the MSA group compared with controls (8.8% vs. 3.9%, respectively). These differences were indeed statistically significant in the MSA group with neuropathological confirmation. Two MSA HTT CAG IAs carriers with 32 HTT CAG repeats showed isolated polyQ inclusions in pons and basal nuclei, which are two critical structures in the neurodegeneration of MSA. CONCLUSIONS: Our results point to a link between HTT CAG number, HTT IAs, and expanded HTT CAG repeats with other non-HD brain pathology and support the hypothesis that they can share common neurodegenerative pathways. © 2022 International Parkinson and Movement Disorder Society.

CPEB alteration and aberrant transcriptome-polyadenylation lead to a treatable SLC19A3 deficiency in Huntington's disease.

Huntington's disease (HD) is a hereditary neurodegenerative disorder of the basal ganglia for which disease-modifying treatments are not yet available. Although gene-silencing therapies are currently being tested, further molecular mechanisms must be explored to identify druggable targets for HD. Cytoplasmic polyadenylation element binding proteins 1 to 4 (CPEB1 to CPEB4) are RNA binding proteins that repress or activate translation of CPE-containing transcripts by shortening or elongating their poly(A) tail. Here, we found increased CPEB1 and decreased CPEB4 protein in the striatum of patients and mouse models with HD. This correlated with a reprogramming of polyadenylation in 17.3% of the transcriptome, markedly affecting neurodegeneration-associated genes including PSEN1, MAPT, SNCA, LRRK2, PINK1, DJ1, SOD1, TARDBP, FUS, and HTT and suggesting a new molecular mechanism in neurodegenerative disease etiology. We found decreased protein content of top deadenylated transcripts, including striatal atrophy­linked genes not previously related to HD, such as KTN1 and the easily druggable SLC19A3 (the ThTr2 thiamine transporter). Mutations in SLC19A3 cause biotin-thiamine­responsive basal ganglia disease (BTBGD), a striatal disorder that can be treated with a combination of biotin and thiamine. Similar to patients with BTBGD, patients with HD demonstrated decreased thiamine in the cerebrospinal fluid. Furthermore, patients and mice with HD showed decreased striatal concentrations of thiamine pyrophosphate (TPP), the metabolically active form of thiamine. High-dose biotin and thiamine treatment prevented TPP deficiency in HD mice and attenuated the radiological, neuropathological, and motor HD-like phenotypes, revealing an easily implementable therapy that might benefit patients with HD.

Serum lipid profile among sporadic and familial forms of Parkinson's disease.

Brain cholesterol metabolism has been described as altered in Parkinson's disease (PD) patients. Serum lipid levels have been widely studied in PD with controversial results among different populations and age groups. The present study is aimed at determining if the serum lipid profile could be influenced by the genetic background of PD patients. We included 403 PD patients (342 sporadic PD patients, 30 GBA-associated PD patients, and 31 LRRK2-associated PD patients) and 654 healthy controls (HCs). Total cholesterol, HDL, LDL, and triglycerides were measured in peripheral blood. Analysis of covariance adjusting for sex and age (ANCOVA) and post hoc tests were applied to determine the differences within lipid profiles among the groups. Multivariate ANCOVA revealed significant differences among the groups within cholesterol and LDL levels. GBA-associated PD patients had significantly lower levels of total cholesterol and LDL compared to LRRK2-associated PD patients and HCs. The different serum cholesterol levels in GBA-associated PD might be related to diverse pathogenic mechanisms. Our results support the hypothesis of lipid metabolism disruption as one of the main PD pathogenic mechanisms in patients with GBA-associated PD. Further studies would be necessary to explore their clinical implications.

In vivo cholinergic basal forebrain degeneration and cognition in Parkinson's disease: Imaging results from the COPPADIS study.

INTRODUCTION: We aimed to assess associations between multimodal neuroimaging measures of cholinergic basal forebrain (CBF) integrity and cognition in Parkinson's disease (PD) without dementia. METHODS: The study included a total of 180 non-demented PD patients and 45 healthy controls, who underwent structural MRI acquisitions and standardized neurocognitive assessment through the PD-Cognitive Rating Scale (PD-CRS) within the multicentric COPPADIS-2015 study. A subset of 73 patients also had Diffusion Tensor Imaging (DTI) acquisitions. Volumetric and microstructural (mean diffusivity, MD) indices of CBF degeneration were automatically extracted using a stereotactic CBF atlas. For comparison, we also assessed multimodal indices of hippocampal degeneration. Associations between imaging measures and cognitive performance were assessed using linear models. RESULTS: Compared to controls, CBF volume was not significantly reduced in PD patients as a group. However, across PD patients lower CBF volume was significantly associated with lower global cognition (PD-CRStotal: r = 0.37, p < 0.001), and this association remained significant after controlling for several potential confounding variables (p = 0.004). Analysis of individual item scores showed that this association spanned executive and memory domains. No analogue cognition associations were observed for CBF MD. In covariate-controlled models, hippocampal volume was not associated with cognition in PD, but there was a significant association for hippocampal MD (p = 0.02). CONCLUSIONS: Early cognitive deficits in PD without dementia are more closely related to structural MRI measures of CBF degeneration than hippocampal degeneration. In our multicentric imaging acquisitions, DTI-based diffusion measures in the CBF were inferior to standard volumetric assessments for capturing cognition-relevant changes in non-demented PD.

Peripheral Immune Profile and Neutrophil-to-Lymphocyte Ratio in Parkinson's Disease.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) in peripheral blood is a well-established inflammatory marker, but its role in Parkinson's disease (PD) remains unclear. OBJECTIVES: To determine whether a different peripheral immune profile and NLR were present in PD patients. METHODS: We conducted a case-control study that included 377 PD patients and 355 healthy controls (HCs). Leukocytes, subpopulations, and the NLR were measured. Multivariate linear regression analyses were applied to determine the differences between groups and the association between NLR and clinical characteristics in PD. A meta-analysis was performed to clarify the association between NLR and PD. RESULTS: In our case-control study, the NLR was significantly higher in PD patients compared with HCs (2.47 ± 1.1 vs. 1.98 ± 0.91, P < 0.001). No association between NLR and age at onset, disease severity, or disease duration was found. The meta-analysis showed that the NLR was likely to be higher in PD patients. CONCLUSIONS: PD patients had an altered peripheral immune profile and a higher NLR compared with HCs. © 2021 International Parkinson and Movement Disorder Society.

Levodopa-Induced Dyskinesia in Parkinson Disease Specifically Associates With Dopaminergic Depletion in Sensorimotor-Related Functional Subregions of the Striatum.

PURPOSE: To determine whether the development of levodopa-induced dyskinesia (LID) in Parkinson disease (PD) specifically relates to dopaminergic depletion in sensorimotor-related subregions of the striatum. METHODS: Our primary study sample consisted of 185 locally recruited PD patients, of which 73 (40%) developed LID. Retrospective 123I-FP-CIT SPECT data were used to quantify the specific dopamine transporter (DAT) binding ratio within distinct functionally defined striatal subregions related to limbic, executive, and sensorimotor systems. Regional DAT levels were contrasted between patients who developed LID (PD + LID) and those who did not (PD-LID) using analysis of covariance models controlled for demographic and clinical features. For validation of the findings and assessment of the evolution of LID-associated DAT changes from an early disease stage, we also studied serial 123I-FP-CIT SPECT data from 343 de novo PD patients enrolled in the Parkinson Progression Marker's Initiative using mixed linear model analysis. RESULTS: Compared with PD-LID, DAT level reductions in PD + LID patients were most pronounced in the sensorimotor striatal subregion (F = 5.99, P = 0.016) and also significant in the executive-related subregion (F = 5.30, P = 0.023). In the Parkinson Progression Marker's Initiative cohort, DAT levels in PD + LID (n = 161, 47%) were only significantly reduced compared with PD-LID in the sensorimotor striatal subregion (t = -2.05, P = 0.041), and this difference was already present at baseline and remained largely constant over time. CONCLUSION: Measuring DAT depletion in functionally defined sensorimotor-related striatal regions of interest may provide a more sensitive tool to detect LID-associated dopaminergic changes at an early disease stage and could improve individual prognosis of this common clinical complication in PD.

A Modified Progressive Supranuclear Palsy Rating Scale.

BACKGROUND: The Progressive Supranuclear Palsy Rating Scale is a prospectively validated physician-rated measure of disease severity for progressive supranuclear palsy. We hypothesized that, according to experts' opinion, individual scores of items would differ in relevance for patients' quality of life, functionality in daily living, and mortality. Thus, changes in the score may not equate to clinically meaningful changes in the patient's status. OBJECTIVE: The aim of this work was to establish a condensed modified version of the scale focusing on meaningful disease milestones. METHODS: Sixteen movement disorders experts evaluated each scale item for its capacity to capture disease milestones (0 = no, 1 = moderate, 2 = severe milestone). Items not capturing severe milestones were eliminated. Remaining items were recalibrated in proportion to milestone severity by collapsing across response categories that yielded identical milestone severity grades. Items with low sensitivity to change were eliminated, based on power calculations using longitudinal 12-month follow-up data from 86 patients with possible or probable progressive supranuclear palsy. RESULTS: The modified scale retained 14 items (yielding 0-2 points each). The items were rated as functionally relevant to disease milestones with comparable severity. The modified scale was sensitive to change over 6 and 12 months and of similar power for clinical trials of disease-modifying therapy as the original scale (achieving 80% power for two-sample t test to detect a 50% slowing with n = 41 and 25% slowing with n = 159 at 12 months). CONCLUSIONS: The modified Progressive Supranuclear Palsy Rating Scale may serve as a clinimetrically sound scale to monitor disease progression in clinical trials and routine. © 2021 International Parkinson and Movement Disorder Society.