Parkinson's Disease Disorders Research Articles

Multi-headed Ensemble Residual CNN: A Powerful Tool for Fibroblast Growth Factor Prediction

Fibroblast Growth Factor (FGF) performs a significant role in the repair, nervous system, development, and maintenance, making it a promising target for treating neurological diseases such as Parkinson's, stroke, Alzheimer's, and Huntington's disorders. However, the detection of FGF remains challenging due to the high cost and time required by traditional methods. To address this issue, we propose the first sequence-based computational method, FGF-MERCNN, for identifying FGFs using deep learning. Novel datasets were constructed by converting primary sequences into numerical representations through Enhanced Group Amino Acid Composition (EGAAC), Dipeptide Deviation from Expected Mean (DDE), and Group Tripeptide Composition (GTPC). These features were combined and analyzed using several deep learning models, including Convolutional Neural Networks (CNN), Multilayer Perceptrons (MLP), Gated Recurrent Units (GRU), and Multiheaded Ensemble Residual CNN (MERCNN). Among these, the MERCNN model achieved superior performance with accuracies of 88.60% on the training set and 83.68% on the test set, as validated by 5-fold cross-validation. The results of this study represent a significant advancement in FGF detection, offering a faster, cost-effective solution with the potential to improve diagnostic and therapeutic strategies for neurological diseases.

A General Neurologist's Practical Diagnostic Algorithm for Atypical Parkinsonian Disorders: A Consensus Statement.

The most common four neurodegenerative atypical parkinsonian disorders (APDs) are progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal syndrome (CBS), and dementia with Lewy bodies (DLB). Their formal diagnostic criteria often require subspecialty experience to implement as designed and all require excluding competing diagnoses without clearly specifying how to do that. Validated diagnostic criteria are not available at all for many of the other common APDs, including normal pressure hydrocephalus (NPH), vascular parkinsonism (VP), or drug-induced parkinsonism (DIP). APDs also include conditions of structural, genetic, vascular, toxic/metabolic, infectious, and autoimmune origin. Their differential diagnosis can be challenging early in the course, if the presentation is atypical, or if a rare or non-neurodegenerative condition is present. This review equips community general neurologists to make an early provisional diagnosis before, or in place of, referral to a tertiary center. Early diagnosis would allay diagnostic uncertainty, allow prompt symptomatic management, provide disease-specific information and support resources, avoid further pointless testing and treatments, and create the possibility of trial referral. We address 64 APDs using one over-arching flow diagram and a series of detailed tables. Most instances of APDs can be diagnosed with a careful history and neurological exam, along with a non-contrast brain MRI. Additional diagnostic tests are rarely needed but are delineated where applicable. Our diagnostic algorithm encourages referral to a tertiary center whenever the general neurologist feels it would be in the patient's best interest. Our algorithm emphasizes that the diagnosis of APDs is an iterative process, refined with the appearance of new diagnostic features, availability of new technology, and advances in scientific understanding of the disorders. Clinicians' proposals for all diagnostic tests for the APDs, including repeat visits, should be discussed with patients and their families to ensure that the potential information to be gained aligns with their larger clinical goals. We designed this differential diagnostic algorithm for the APDs to enhance general neurologists' diagnostic skills and confidence and to help them address the less common or more ambiguous cases.

18F‐Florzolotau PET Imaging Unveils Tau Pathology in Dementia with Lewy Bodies

AbstractBackgroundDementia with Lewy bodies (DLB) commonly exhibits a complex neuropathology, sharing characteristics with Alzheimer's disease (AD), including tau aggregates. However, studies using the 18F‐AV‐1451 tau tracer have shown inconsistent findings regarding both the extent and topographical distribution of tau pathology in DLB.ObjectivesOur aim was to elucidate the topographical patterns of tau deposition in DLB and to investigate the in vivo pathological distinction between DLB and AD in virtue of the 18F‐Florzolotau positron emission tomography (PET) imaging.MethodsThis cross‐sectional study enrolled patients with DLB (n = 24), AD (n = 43), and cognitively healthy controls (n = 18). Clinical assessments and 18F‐Florzolotau PET imaging were performed. 18F‐Florzolotau binding was quantitatively assessed on PET images using standardized uptake value ratios and voxel‐wise analysis.Results18F‐Florzolotau PET imaging revealed widespread tau deposition across various cortical regions in DLB, uncovering heterogeneous topographical patterns. Among patients, 54.17% showed patterns similar to AD, whereas 16.67% exhibited distinct patterns. Compared to AD, DLB exhibited a unique in vivo neuropathological profile, characterized by a lower tau protein burden, heterogeneous topographical distributions, and a specific role of the medial temporal lobe in tau pathology.Conclusions18F‐Florzolotau PET imaging elucidated tau pathology patterns in DLB, providing valuable insights for future in vivo pathological differentiation and potential disease‐modifying therapies. © 2024 International Parkinson and Movement Disorder Society.

Early Changes in the Locus Coeruleus in Mild Cognitive Impairment with Lewy Bodies.

Although neuromelanin-sensitive magnetic resonance imaging (NM-MRI) has been used to evaluate early neurodegeneration in Parkinson's disease, studies concentrating on the locus coeruleus (LC) in pre-dementia stages of dementia with Lewy bodies (DLB) are lacking. The aims were to evaluate NM-MRI signal changes in the LC in patients with mild cognitive impairment with Lewy bodies (MCI-LB) compared to healthy controls (HC) and to identify the cognitive correlates of the changes. We also aimed to test the hypothesis of a caudal-rostral α-synuclein pathology spread using NM-MRI of the different LC subparts. A total of 38 MCI-LB patients and 59 HCs underwent clinical and cognitive testing and NM-MRI of the LC. We calculated the contrast ratio of NM-MRI signal (LC-CR) in the whole LC as well as in its caudal, middle, and rostral MRI slices, and we compared the LC-CR values between the MCI-LB and HC groups. Linear regression analyses were performed to assess the relationship between the LC-CR and cognitive outcomes. The MCI-LB group exhibited a significant reduction in the right LC-CR compared to HCs (P = 0.021). The right LC-CR decrease was associated with impaired visuospatial memory in the MCI-LB group. Only the caudal part of the LC exhibited significant LC-CR decreases in MCI-LB patients compared to HCs on both sides (P < 0.0001). This is the first study that focuses on LC-CRs in MCI-LB patients and analyzes the LC subparts, offering new insights into the LC integrity alterations in the initial stages of DLB and their clinical correlates. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Predictive Modeling and Early Detection of Parkinson's Disease Using Machine Learning

Parkinson's disease is a progressive neurodegenerative disorder that impacts millions of citizens in the USA, mainly targeting the motor system and causing debilitating symptoms such as rigidity, tremors, and bradykinesia. The diagnosis of Parkinson's disease is presently heavily dependent on clinical evaluations and neurological examinations, targeting the detection of motor dysfunction. The principal aim of this study was to use machine learning as a means for early detection and prediction of Parkinson's disease. The dataset utilized for this study was the Parkinson’s Disease Dataset, retrieved from the UCI Machine Learning Repository, which included comprehensive biomedical voice measurements from a cohort of individuals, 23 of whom are diagnosed with Parkinson’s disease and 8 who are healthy controls. This dataset included a set of features extracted from voice recordings. These include parameters like fundamental frequency (pitch), amplitude variation, jitter, shimmer, and several phonation-related measures known to reflect early vocal impairments associated with the disease in question. This research project deployed three credible and proven algorithms, namely, logistic regression, random forest, and the Support Vector Machines. Besides, this study employed a combination of metrics, including accuracy, precision, recall, F1-score, and ROC-AUC, which are more holistic toward the model performance. According to the metric performance results of the three models, several key insights were drawn into the early detection of Parkinson's Disease. Particularly, it was clear that the Random Forest model had superior accuracy and was the most reliable in classifying positive cases and healthy patients, which could be that this model turned out to be most reliable in an early detection setting. In that respect, predictive modeling in Parkinson's Disease is a capability frontier that has the potential to make much difference in clinical decision-making. Supported by Machine Learning algorithms, clinicians can trace the minute patterns in patient data, which are not easily visible through any other diagnostic means. In such cases, early detection of Parkinson's Disorder with vocal biomarkers or motor assessment may afford healthcare professionals opportunities for early interventions that might retard the disease process.

Gut Microbial Metabolites and Future Risk of Parkinson's Disease: A Metabolome-Wide Association Study.

Alterations in gut microbiota are observed in Parkinson's disease (PD). Previous studies on microbiota-derived metabolites in PD were small-scale and post-diagnosis, raising concerns about reverse causality. Our goal was to prospectively investigate the association between plasma microbial metabolites and PD risk within a metabolomics framework. A nested case-control study within the prospective EPIC4PD cohort, measured pre-diagnostic plasma microbial metabolites using untargeted metabolomics. Thirteen microbial metabolites were identified nominally associated with PD risk (P-value < 0.05), including amino acids, bile acid, indoles, and hydroxy acid, although none remained significant after multiple testing correction. Three pathways were implicated in PD risk: valine, leucine, and isoleucine degradation, butanoate metabolism, and propanoate metabolism. PD-associated microbial pathways were more pronounced in men, smokers, and overweight/obese individuals. Changes in microbial metabolites may represent a pre-diagnostic feature of PD. We observed biologically plausible associations between microbial pathways and PD, potentially influenced by individual characteristics. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Glucocerebrosidase deficiency leads to neuropathology via cellular immune activation.

Mutations in GBA (glucosylceramidase beta), which encodes the lysosomal enzyme glucocerebrosidase (GCase), are the strongest genetic risk factor for the neurodegenerative disorders Parkinson's disease (PD) and Lewy body dementia. Recent work has suggested that neuroinflammation may be an important factor in the risk conferred by GBA mutations. We therefore systematically tested the contributions of immune-related genes to neuropathology in a Drosophila model of GCase deficiency. We identified target immune factors via RNA-Seq and proteomics on heads from GCase-deficient flies, which revealed both increased abundance of humoral factors and increased macrophage activation. We then manipulated the identified immune factors and measured their effect on head protein aggregates, a hallmark of neurodegenerative disease. Genetic ablation of humoral (secreted) immune factors did not suppress the development of protein aggregation. By contrast, re-expressing Gba1b in activated macrophages suppressed head protein aggregation in Gba1b mutants and rescued their lifespan and behavioral deficits. Moreover, reducing the GCase substrate glucosylceramide in activated macrophages also ameliorated Gba1b mutant phenotypes. Taken together, our findings show that glucosylceramide accumulation due to GCase deficiency leads to macrophage activation, which in turn promotes the development of neuropathology.

Study on Pharmacological Treatment of Impulse Control Disorders in Parkinson’s Disease

Parkinson’s disease is neurodegenerative, and additionally, a percentage higher than 60% is represented by the patients with associated psychiatric symptoms, such as anxiety disorders and depression. Due to illness itself and to therapy secondary effects, there is a high risk for these patients to develop impulse control disorders like ICDs: compulsive shopping, pathological gambling binge eating disorder, and hypersexuality. There is high interest in therapy so as to diminish, as much as possible, the associated ICD symptoms. This article presents a study on pharmacological treatment of impulse control disorders in Parkinson disease carried on a sample of patients in hospitals where the authors have their clinical work. This study was carried on for a period of 6 years and is focused on research of different treatment plans. The patients were evaluated by the Hamilton Rating Scale. Statistical analysis of the obtained data (given by the HAM-A scores) is used for data processing. All patients showed a reduction in their impulse behavior. The directions of further research development are mentioned.

Potential Disease-Modifying Effects of Ganglioside GM1 Pulse Treatment on Spinocerebellar Ataxia Type 3, a Parallel-Group, Double-Blind, Randomized, Controlled Trial.

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant inherited neurodegenerative disorder for which there is currently no cure, nor effective treatment strategy. Our aim was to investigate the safety and efficacy of high-dose ganglioside GM1 (ganglioside-monosialic acid) pulse treatment in patients with SCA3. Patients were randomly allocated to receive either high-dose GM1 (400 mg on the first day followed by 200 mg/day), low-dose GM1 (40 mg/day), or placebo (normal saline) for 4 weeks. The primary outcome, assessed by measuring the change in the Scale for the Assessment and Rating of Ataxia (SARA) scores from baseline to 12 weeks post-treatment, is central to evaluating treatment efficacy. Secondary outcomesincluded changes in the International Cooperative Ataxia Rating Scale (ICARS) score, Barthel Index of Activities of Daily Living (ADL), and plasma and cerebrospinal fluid (CSF) GABA levels. Safety was assessed in all treated patients. A total of 48 patients with SCA3 were enrolled in this study. After 12 weeks, data from 43 patients were included in the efficacy analysis (intention-to-treat analysis). The least-squares mean change in the SARA score from baseline to 12 weeks post-treatment was -3.80 (standard error [SE], 0.39; 95% confidence interval [CI], -4.58 to -3.02) in the high-dose GM1 group, 0.34 (SE, 0.40; 95% CI, -0.46 to 1.13) in the low-dose GM1 group, and 0.73 (SE, 0.40; 95% CI, -0.07 to 1.52) in the placebo group, respectively. Secondary outcomes showed improvements in the ICARS score, Barthel Index of ADL, and plasma and CSF GABA levels in the high-dose GM1 group compared to the low-dose GM1 and placebo groups. All treatments were well-tolerated and safe. High-dose GM1 treatment significantly ameliorated ataxic symptoms in patients with SCA3. © 2024 International Parkinson and Movement Disorder Society.

Identification of Novel Genetic Loci Affecting Age at Onset of Parkinson's Disease: A Genome-wide Association Study.

The age at onset (AAO) of Parkinson's disease (PD) varies widely among individuals and significantly influences disease progression and prognosis. However, few genome-wide association studies (GWASs) have investigated genetic variants determining AAO, particularly in East Asian populations. To identify single-nucleotide polymorphisms (SNPs) affecting AAO of PD in Korean patients. We conducted a GWAS on AAO of PD in 1048 Korean patients using sex-adjusted linear regression models. Additionally, we conducted downstream analyses of our primary GWAS results. rs2134545 demonstrated genome-wide significance (β = -2.459; standard error [SE] = 0.851; P = 1.898 × 10-8) and is an intergenic SNP near the ALCAM gene associated with an average AAO reduction of 3.47 years. Additionally, rs4366309 (LYST; MIR1537) demonstrated suggestive significance (β = 2.949; SE = 1.072; P = 8.68 × 10-8) and was associated with an average delay of 3.05 years. The polygenic risk score based on known PD risk loci also affected the AAO for European and Korean PD risk loci, respectively (β = -0.149; P < 0.001 and β = -0.096; P = 0.002). However, the proportion of variance was small (r2 = 0.022 and 0.009, respectively). We identified a novel SNP associated with the AAO of PD near the ALCAM gene, distinct from previously reported PD risk loci. These findings need further functional validation; however, they suggest unique genetic pathways influencing the AAO of PD and highlight the need for further research in diverse populations. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Motor signs and incident dementia with Lewy bodies in older adults with mild cognitive impairment.

Motor signs may herald incident dementia and allow the earlier detection of high-risk individuals and the timely implementation of preventive interventions. The current study was performed to investigate the prognostic properties of motor signs with respect to incident dementia with Lewy bodies (DLB) in older adults with mild cognitive impairment (MCI). Emphasis was placed on sex differences. The specificity of these associations was explored. We analyzed data from the National Alzheimer's Coordinating Center Uniform Data Set. Participants 55 + years old with a diagnosis of MCI were included in the analysis. Those with Parkinson's disease (PD) or other parkinsonian disorders at baseline and those with PD dementia at follow-up were excluded. UPDRS III was used to assess the presence or absence of motor signs in nine domains: hypophonia; masked facies; resting tremor; action/postural tremor; rigidity; bradykinesia; impaired chair rise; impaired posture/gait; postural instability. Αdjusted Cox proportional hazards models featuring sex by motor sign interactions were estimated. Throughout the average follow-up of 3.7 ± 3.1 years, among 4623 individuals with MCI, 2211 progressed to dementia (66 of whom converted to DLB). Masked facies [HR = 4.21 (1.74-10.18)], resting tremor [HR = 4.71 (1.44-15.40)], and bradykinesia [HR = 3.43 (1.82-6.45)] exclusively increased the risk of DLB. The HR of DLB was approximately 15 times greater in women compared to men with masked facies. Impaired posture-gait (approximately 10 times) and resting tremor (approximately 8.5 times) exhibited a similar trend (prominent risk-conferring properties in women compared to men) but failed to achieve statistical significance. Rigidity and hypophonia elevated the risk of other dementia entities, as well. The remaining motor features were not related to incident dementia of any type. Specific motor signs may herald DLB among individuals with MCI. Different associations may exist between masked facies, impaired posture-gait, resting tremor, and incident DLB in men versus women.

Insulin Resistance Is a Modifying Factor for Parkinson's Disease.

Parkinson's disease (PD) is the second most common, and the fastest-growing neurodegenerative disorder with unclear etiology in most cases. Therefore, the identification of non-genetic risk factors for PD pathology is crucial to develop effective preventative or therapeutic strategies. An increasing number of evidence suggests that central insulin resistance might have an essential role in PD pathology. Nevertheless, it is not clear whether insulin resistance arises from external factors/lifestyle, comorbidities such as type 2 diabetes or it can occur in a PD patient's brain independently from peripheral insulin resistance. We aimed to investigate insulin resistance and its role in GBA1mutation-associated PD pathogenesis and phenotype severity. Midbrain organoids, generated from induced pluripotent stem cells (iPSCs) of PD patients carrying the GBA1-N370S heterozygous mutation (GBA-PD) and healthy donors, were exposed to different insulin concentrations to modify insulin signaling function. Transcriptomics analysis was performed to explore insulin signaling gene expression patterns in GBA-PD and to find a potential target for GBA-PD-associated phenotype rescue. The insulin signaling pathway genes show dysregulation in GBA-PD. Particularly, we highlight that a knockdown of FOXO1 mitigates the loss of dopaminergic neurons and cellular death in GBA-PD. Additionally, our findings suggest a promising therapeutic potential of the anti-diabetic drug Pioglitazone in decreasing dopaminergic neuron loss associated with GBA-PD. Local insulin signaling dysfunction plays a substantial role in GBA-PD pathogenesis, exacerbating dopaminergic neuron death. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Focused Ultrasound Pallidothalamic Tractotomy in Cervical Dystonia: A Pilot Study.

No clinical trials have been reported on the use of focused ultrasound (FUS) for treating cervical dystonia. We aimed to confirm the efficacy and safety of FUS pallidothalamic tractotomy for cervical dystonia. This was a prospective, open-label, non-controlled pilot study. The primary outcome was defined as a change in the score for the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) from baseline to 6 months after FUS pallidothalamic tractotomy. The secondary outcomes included a change in the neck scale for the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), mood scales including Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Apathy Evaluating Scale (AES), and adverse events. Patients were assessed for TWSTRS, BFMDRS, and adverse events at baseline, 1 week, 1 month, 3 months, and 6 months after treatment. BDI, BAI, and AES were assessed at baseline and 6 months after treatment. Ten patients were enrolled in this study. The mean age of onset of dystonia was 51.6 ± 10.2 years. The TWSTRS at 6 months (29.9 ± 16.0, range: 3-55) was significantly improved by 43.4% (P < 0.001) from baseline. The BFMDRS-Neck scales at 6 months (4.2 ± 2.8) were significantly improved by 38.2% (P < 0.001) from baseline. The BDI, BAI, and AES at 6 months were improved by 23.2%, 10.9%, and 30.3%, respectively from baseline. Reduced hand dexterity in three patients and weight gain in two patients were confirmed at the last evaluation. This study suggests that FUS pallidothalamic tractotomy may be an effective treatment option for patients with cervical dystonia. © 2024 International Parkinson and Movement Disorder Society.

Cerebellar Transcranial Direct Current Stimulation in the Cerebellar Cognitive Affective Syndrome: A Randomized, Double-Blind, Sham-Controlled Trial.

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

Chronic Musculoskeletal Pain and Risk of Incident Parkinson's Disease: A 13-Year Longitudinal Study.

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. 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). 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. 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. 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.

Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients of Bullous Pemphigoid with or without Parkinson's Disease.

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. Our aim was to investigate whether BP patients might be a targeted risk population for the screening of skin P-SYN. Skin P-SYN expression was evaluated by immunohistochemistry in BP patients with/without PD. 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. 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.

Combined Assessment of Function and Survival to Demonstrate the Effect of Treatment on Progressive Supranuclear Palsy.

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. 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. 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. 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. 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.

A Homoplasmic MT-TV Mutation Associated with Mitochondrial Inheritance of Hereditary Spastic Paraplegia.

Hereditary spastic paraplegia (HSP) is characterized by progressive lower limb weakness and spasticity, with unknown genetic cause in many cases. To identify novel genetic causes of HSP. Phenotypic characterization, genetic screening, transcriptome sequencing, and peroneal nerve biopsy were conducted in a Chinese HSP family. We found a homoplasmic MT-TV (mitochondrial tRNAVal) 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. 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.

Emerging Molecular-Genetic Families in Dystonia: Endosome-Autophagosome-Lysosome and Integrated Stress Response Pathways.

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.

Genetic and Epidemiological Insights into RAB32-Linked Parkinson's Disease.

The p.Ser71Arg RAB32 variant was recently associated with Parkinson's disease (PD). The aim was to investigate the presence of RAB32 variants in a large multiethnic group of individuals affected and unaffected by PD. We queried our proprietary database that contains exome/genome sequencing data of >180,000 individuals. Additional PD patients were genotyped, and proximal p.Ser71Arg-associated haplotypes were constructed. p.Ser71Arg was present in 11 PD patients (73% from northern Italy) and in 35 individuals (89% from the Middle East and North Africa [MENA]) aged <50 years without PD-relevant symptoms. It was found in-cis to a set of proximal single-nucleotide polymorphisms. Additional RAB32 variants were comparably frequent in PD and non-PD individuals. The RAB32 p.Ser71Arg variant defines a cluster of PD patients in northern Italy. Globally, it is most prevalent in MENA. Our data indicate that p.Ser71Arg causes PD and that it occurred only once, through a founder event. Other RAB32 variants are unlikely to cause PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.