Parkinson's Disease Disorders Research Articles

New Multiomic Studies Shed Light on Cellular Diversity and Neuronal Susceptibility in Parkinson's Disease.

Parkinson's disease is a complex neurodegenerative disorder characterized by degeneration of dopaminergic neurons, with patients manifesting varying motor and nonmotor symptoms. Previous studies using single-cell RNA sequencing in rodent models and humans have identified distinct heterogeneity of neurons and glial cells with differential vulnerability. Recent studies have increasingly leveraged multiomics approaches, including spatial transcriptomics, epigenomics, and proteomics, in the study of Parkinson's disease, providing new insights into pathogenic mechanisms. Continued advancements in experimental technologies and sophisticated computational tools will be essential in uncovering a network of neuronal vulnerability and prioritizing disease modifiers for novel therapeutics development. © 2025 International Parkinson and Movement Disorder Society.

Step Width Haptic Feedback for Gait Stability in Spinocerebellar Ataxia: Preliminary Results.

Wider step width and lower step-to-step variability are linked to improved gait stability and reduced fall risk. It is unclear if patients with spinocerebellar ataxia (SCA) can learn to adjust these aspects of gait to reduce fall risk. The aims were to examine the possibility of using wearable step width haptic biofeedback to enhance gait stability and reduce fall risk in individuals with SCA. Thirteen people with SCA type 3 performed step width training (single session) using real-time feedback. Step width increased post-training (19.3 cm, interquartile range [IQR] 16.3-20.2 cm) and at retention (16.6 cm, IQR 16.2-21.1 cm), compared to baseline (11.0 cm, IQR 5.2-15.2 cm; P < 0.001). Step width variability decreased during post-training (19.7%, IQR 17.4%-26.2%) and at retention (22.3%, IQR 18.6%-30.2%), compared to baseline (44.5%, IQR 28.5%-71.2%; P < 0.001). Crossover steps, another mark of instability, decreased after training (P < 0.031). These pilot results suggest that patients with SCA can use a novel, wearable biofeedback system to improve their gait stability. © 2025 International Parkinson and Movement Disorder Society.

A smart tool for non expert clinicians for the dissemination of the MDS criteria for progressive supranuclear palsy.

Due to the variety of clinical phenotypes and the massive clinical overlap with other neurodegenerative diseases, the diagnosis of Progressive Supranuclear Palsy (PSP) remains a major challenge. Notwithstanding, early and reliable clinical diagnosis of PSP is highly warranted for estimation of prognosis, appropriate allocation to therapeutic trials and development of new diagnostic tools. As reliable biomarkers are lacking, PSP diagnosis relies on the application of the clinical criteria promoted by the International Parkinson and Movement Disorder Society (MDS). Despite providing a framework including all the main PSP cornerstones (ocular dysfunction and postural instability, akinesia and cognitive dysfunction), the application of the MDS PSP criteria is complex and not straightforward to apply in a clinical setting. Herein we propose a practical tool, including a video-guided slide-set and a smartsheet, to disseminate the MDS PSP clinical criteria among healthy practitioners and increase confidence in non expert clinicians towards suspicion and diagnosis of PSP. The video-guided slide set may serve as a teaching resource for both general neurologists and practitioners, while the smartsheet may represent a valid support in attributing the degree of diagnostic certainty and phenotype based on the identified clinical features. Application of our tool may improve early recognition of patients in primary and secondary care and determine a prompt referral to third level movement disorder centers for consideration in clinical trials testing disease-modifying treatments.

Prospective Multicenter Evaluation of the MDS "Suggestive of PSP" Diagnostic Criteria.

The recent Movement Disorders Society (MDS)-progressive supranuclear palsy (PSP) diagnostic criteria conceptualized three clinical diagnostic certainty levels: "suggestive of PSP" for sensitive early diagnosis based on subtle clinical signs, "possible PSP" balancing sensitivity and specificity, and "probable PSP" highly specific for PSP pathology. The aim of this study was to prospectively validate the criteria against long-term clinical follow-up and characterize the diagnostic certainty increase over time. Patients with "possible PSP" or "suggestive of PSP" diagnosis and clinical follow-up were recruited in two German multicenter longitudinal observational studies (ProPSP and DescribePSP). The cumulative percentage of patients longitudinally increasing diagnostic certainty was assessed over up to 2.5 years of follow-up. The sample size per arm required to detect 30% attenuated rate in diagnostic certainty increase in trials was estimated over multiple time intervals. Of 254 patients with available longitudinal data, 61 patients had low diagnostic certainty at baseline (48 suggestive of PSP, 13 possible PSP) and multiple clinical visits (median: 3, range: 2-4). The cumulative percentage of patients increasing diagnostic certainty progressed with follow-up duration (30.4% at 6 months, 51.7% at 1 year, 80.4% at 2.5 years). The sample size required to detect 30% reduction in diagnostic certainty increase rate within 1 year was 163, slightly smaller than that required using the PSP rating scale. Most "suggestive of PSP" patients increased diagnostic certainty upon longitudinal follow-up, providing the first prospective multicenter validation of MDS-PSP diagnostic criteria. Our data support the design of trials tailored for these early-stage patients, suggesting the PSP rating scale and the diagnostic certainty increase rate as potential endpoint measures. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Effect of a Wrist Harmonic Liquid Tremor Absorber-Damping on the Upper Extremity Essential Tremor.

Essential tremor (ET) is a common type of tremor. Previous research has shown that wearable orthoses and biomechanical loading methods can suppress tremors. This study aims to investigate the effect of a harmonic liquid dampener on upper extremity ET. The study involved 9 women and 5 men from a neurology outpatient clinic. A 285-g liquid-based harmonic dampening wristband was used. Tremors were recorded from the wrist along the x-y-z axes using a vibrometer, and the Bain-Findley Rating Scale (BFRS) was employed for assessment. BFRS scores significantly improved after the wristband was used (mean difference 35.64, P = 0.001, Cohen's d effect size =2.979). The tremor amplitude decreased significantly along the x-axis (Cohen's d: 1.35, P = 0.001), y-axis (Cohen's d: 3.232, P = 0.001), and z-axis (Cohen's d: 3.321, P = 0.001). The liquid-filled harmonic dampening wristband shows promise as a new, effective treatment option for ET patients. © 2025 International Parkinson and Movement Disorder Society.

Automated Detection of Isolated REM Sleep Behavior Disorder Using Computer Vision.

Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is, in most cases, an early stage of Parkinson's disease or related disorders. Diagnosis requires an overnight video-polysomnogram (vPSG), however, even for sleep experts, interpreting vPSG data is challenging. Using a 3D camera, automated analysis of movements has yielded high accuracy. We aimed to replicate and extend prior work using a conventional 2D camera. The dataset included 172 vPSG recordings from a clinical sleep center, 81 patients with iRBD and 91 non-RBD healthy controls (63 with a range of other sleep disorders and 28 healthy sleepers). An optical flow computer vision algorithm automatically detected movements during rapid eye movement (REM) sleep, from which features of rate, ratio, magnitude and velocity of movements, and ratio of immobility were extracted. Patients with iRBD exhibited an increased number of shorter movements and immobility periods. Accuracies for detecting iRBD ranged from 84.9% (with 2 features) to 87.2% (with 5 features). Combining all 5 features but only analyzing short (0.1-2 second duration) movements achieved the highest accuracy at 91.9%. Of the 11 patients with iRBD without noticeable movements during vPSG, 7 were correctly identified. This work improves prior art by using a 2D camera routinely used in sleep laboratories and improving performance by adding only 3 features. This approach could be implemented in clinical sleep laboratories to facilitate and improve the diagnosis of iRBD. Coupled with automated detection of REM sleep, it should also be tested in the home environment using conventional infrared cameras to detect and/or monitor RBD. ANN NEUROL 2025.

TDP-43 Cryptic RNAs in Perry Syndrome: Differences across Brain Regions and TDP-43 Proteinopathies.

Perry syndrome (PS) is a rare and fatal hereditary autosomal dominant neurodegenerative disorder caused by mutations in dynactin (DCTN1). PS brains accumulate inclusions positive for ubiquitin, transactive-response DNA-binding protein of 43 kDa (TDP-43), and to a lesser extent dynactin. Little is known regarding the contributions of TDP-43, an RNA binding protein that represses cryptic exon inclusion, in PS. Therefore, we sought to identify the degree of TDP-43 dysfunction in two regions of PS brains. We evaluated the levels of insoluble pTDP-43 and TDP-43-regulated cryptic RNAs and protein in the caudate nucleus and substantia nigra of 7 PS cases, 12 cases of frontotemporal lobar degeneration (FTLD) with TDP-43 pathology, and 11 cognitively healthy controls without TDP-43 pathology. Insoluble pTDP-43 protein levels were detected in PS brains to a similar extent in the caudate nucleus and substantia nigra but lower than those in FTLD brains. The caudate nucleus of PS showed accumulation of eight TDP-43-regulated cryptic RNAs (ACTL6B, CAMK2B, STMN2, UNC13A, KCNQ2, ATG4B, GPSM2, and HDGFL2) and cryptic protein (HDGFL2) characteristic of FTLD. Conversely, only one cryptic target, UNC13A, reached significance in the substantia nigra despite similar pTDP-43 levels. We detected TDP-43 cryptic RNAs and protein in PS caudate nucleus. Given the importance of cryptic exon biology in the development of biomarkers, and the identification of novel targets for therapeutic intervention, it is imperative we understand the consequences of TDP-43 dysfunction across different brain regions and determine the targets that are specific and common to TDP-43 proteinopathies. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

A decade of pyridine-containing heterocycles in US FDA approved drugs: a medicinal chemistry-based analysis.

Heterocyclic scaffolds, particularly, pyridine-containing azaheterocycles, constitute a major part of the drugs approved in the past decade. In the present review, we explored the pyridine ring part of US FDA-approved small molecules (2014-2023). The analysis of the approved drugs bearing a pyridine ring revealed that a total of 54 drugs were approved. Among them, the significant number comprised the anticancer category (18 drugs, 33%), followed by drugs affecting the CNS system (11 drugs, 20%), which include drugs to treat migraines, Parkinsonism disorders, chemotherapeutic-induced nausea, insomnia, and ADHD or as CNS-acting analgesics or sedatives. Next, six drugs (11%) were also approved to treat rare conditions, followed by five drugs that affect the hematopoietic system. The analysis also revealed that drug approval was granted for antibiotics, antivirals, and antifungals, including drugs for the treatment of tropical and sub-tropical diseases. Primary drug targets explored were kinases, and the major metabolizing enzyme was CYP3A4. Further analysis of formulation types revealed that 50% of the approved drugs were tablets, followed by 17% capsules and 15% injections. Elemental analysis showed that most approved drugs contained sulfur, while fluorine was noted in 32 compounds. Therefore, the present review is a concerted effort to cover drugs bearing pyridine rings approved in the last decade and provide thorough discussion and commentary on their pharmacokinetics and pharmacodynamics aspects. Furthermore, in-depth structural and elemental analyses were explored, thus providing comprehensive guidance for medicinal chemists and scientists working in allied science domains.

The RAB32 p.Ser71Arg Variant in Parkinsonisms: Insights from a Large Italian Cohort.

Recently, RAB32 has been identified as possibly linked to Parkinson's disease. We studied the prevalence and clinical correlates of the p.Ser71Arg variant in the RAB32 gene in a large case series of Italian patients with Parkinson's disease or atypical parkinsonism. A single-center cohort with a case-control component (consecutively collected at the Parkinson Institute of Milan between 2002 and 2023) was screened for the RAB32 p.Ser71Arg variant. Detailed clinical characteristics of carriers were reviewed. Healthy control subjects were partners or unrelated caregivers. The variant was detected by a TaqMan polymerase chain reaction assay. A total of 4600 patients (3762 with PD and 838 with atypical parkinsonisms) and 1722 healthy control subjects were consecutively included in the study. We identified 20 new variant carriers that, together with the 8 previously identified, had younger age at onset than noncarriers (51.0 ± 10.7 vs. 58.3 ± 11.0 years, respectively; P = 0.01). All carriers had a good response to dopaminergic therapy and device-aided therapies. Carriers had mild or no cognitive decline and mild or no depressive symptoms; six had impulse control disorders and one a REM behavior disorder. Family history was positive in 55.5% of cases versus 22.0% of patients without the variant (P < 0.001) and was compatible with a dominant pattern of inheritance. The variant was not identified in patients with atypical parkinsonisms. This study confirms that RAB32 is associated with a relatively young adult-onset PD with a favorable therapeutic response. This variant should be included in genetic panels used for the diagnosis of familial and/or relatively young-onset PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Carvacrol Essential Oil as a Neuroprotective Agent: A Review of the Study Designs and Recent Advances.

Neurodegenerative diseases were mostly perceived as diseases of ageing populations, but now-a-days, these diseases pose a threat to populations of all age groups despite significant improvements in quality of life. Almost all essential oils (EOs) have been reported to have some neuroprotective abilities and have been used as supplements for good mental health over the centuries. This review highlights the therapeutic potential of one such monoterpene phenolic EO, carvacrol (CV), that has the potential to be used as a main therapeutic intervention for neurodegenerative disorders. Three libraries, Google Scholar, PubMed, and ScienceDirect, were explored for research studies related to the neuroprotective roles of CV. All the research articles from these libraries were sorted out, with the first article tracing back to 2009, and the latest article was published in 2024. The positive effects of CV in the treatment of Alzheimer's and Parkinson's Diseases, multiple sclerosis, ischemia, and behavioural disorders have been supported with evidence. This review not only focused on study designs and the pharmacological pathways taken by CV for neuroprotection but also focused on demographics, illustrating the trend of CV research studies in certain countries and the preferences for the use of in vitro or in vivo models in studies. Our review provides useful evidence about the neuroprotective potential of CV; however, a lack of studies was observed regarding CV encapsulation in proper dosage forms, in particular nanoparticles, which could be further explored for CV delivery to the central nervous system.

Bilateral Lesions in Parkinson's Disease: Gaps and Controversies.

Bilateral lesions of the basal ganglia using termocoagulation or radiation for improving tremor, bradykinesia, and rigidity in people with Parkinson's disease (PD) have been performed starting several decades ago, especially when levodopa and deep brain stimulation (DBS) surgery were not available. However, because of unclear additional benefit compared to unilateral lesion, and particularly to the evidence of increased adverse events occurrence, bilateral lesions were basically abandoned at the end of the 20th century. Therefore, bilateral DBS has become the standard procedure to treat PD. Magnetic resonance imaging-guided focused ultrasound (MRgFUS) is an emerging incisionless technique used to produce therapeutic brain ablation. The positive experiences of unilateral MRgFUS ablation for PD, along with the preliminary favorable outcomes of bilateral thalamic MRgFUS for essential tremor, raise the possibility to eventually reintroduce bilateral lesioning in the management of PD motor features. This possibility has so far only been tested in a few small studies. This article reviews the evidence of bilateral lesioning of the basal ganglia to treat PD, and elaborates on current gaps, controversies, and perspectives of the different available neurosurgical procedures and specifically of MRgFUS ablation. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

α-Synuclein Gene Hypomethylation in LRRK2 Parkinson's Disease Patients.

α-Synuclein (SNCA) gene hypomethylation was reported in idiopathic Parkinson's disease (iPD). Based on a high clinical resemblance between iPD and leucine-rich repeat kinase 2 (LRRK2)-driven Parkinson's disease (L2PD), we investigated the epigenetic status of SNCA in an extensive LRRK2 clinical cohort from Spain. We assessed the methylation levels of 23 CpG sites in the SNCA promoter region using peripheral blood DNA from L2PD patients (n = 151), LRRK2 nonmanifesting carriers (n = 55), iPD patients (n = 115), and healthy control subjects (n = 154) (total: N = 475). Compared with control subjects, we found significant SNCA hypomethylation in 11 of 23 CpGs in L2PD (48%), whereas 22 CpGs (96%) were hypomethylated in iPD. In line with a healthy status, asymptomatic mutation carriers had similar SNCA methylation profiles to control subjects. This study shows for the first time that SNCA hypomethylation occurs in patients with L2PD. Further studies addressing SNCA methylation status in additional worldwide LRRK2 cohorts are warranted. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The First Case of Autosomal Recessive Cerebellar Ataxia with Prominent Paroxysmal Non-kinesigenic Dyskinesia Caused by a Truncating FGF14 Variant in a Turkish Patient.

ATX-FGF/SCA27A has been exclusively associated with heterozygous variants in the FGF14 gene, presenting with postural tremor, slowly progressive cerebellar ataxia, and psychiatric and behavioral disturbances. This study describes the first case of ATX-FGF/SCA27A linked to a biallelic frameshift variant in the FGF14 gene. Whole-exome sequencing (WES) was conducted using the Illumina NovaSeq 6000 platform, and the identified variant was confirmed using Sanger sequencing. We report the first case of autosomal recessive FGF14-related cerebellar ataxia caused by a c.75del variant resulting in p.Leu26Serfs*51 truncation of the FGF14 protein. This variant was found in a patient born to consanguineous parents and presented with a complex congenital nonprogressive cerebellar disorder accompanied by neurodevelopmental delay, intellectual disability, and prominent drug-responsive paroxysmal non-kinesigenic dyskinesia. Segregation analysis confirmed that the homozygous variant was inherited from heterozygous parents who developed mild gait ataxia and tremor in their 40s. Biallelic loss-of-function variants in FGF14 are a rare cause of inherited cerebellar ataxia and expand the current genetic spectrum of ATX-FGF14. © 2024 International Parkinson and Movement Disorder Society.

Subthalamic γ Oscillation Underlying Rapid Eye Movement Sleep Abnormality in Parkinsonian Patients.

Abnormal rapid eye movement (REM) sleep, including REM sleep behavior disorder (RBD) and reduced REM sleep, is common in Parkinson's disease (PD), highlighting the importance of further study on REM sleep. However, the biomarkers of REM disturbances remain unknown, leading to the lack of REM-specific neuromodulation interventions. This study aims to investigate the neurophysiological biomarkers of REM disturbance in parkinsonian patients. Ten PD patients implanted with bilateral subthalamic nucleus-deep brain stimulation (STN-DBS) were included in this study, of whom 4 were diagnosed with RBD. Sleep monitoring was conducted 1 month after surgery. Subthalamic local field potentials (LFP) were recorded through sensing-enabled DBS. The neurophysiological features of subthalamic LFP during phasic and tonic microstates of REM sleep and their correlation with REM sleep fragmentation and RBD were analyzed. Differences in subthalamic γ oscillation between phasic and tonic REM correlated positively with the severity of REM sleep fragmentation. Patients with RBD also exhibited stronger γ oscillations during REM sleep compared with non-RBD patients, and both increased β and γ were found before the onset of RBD episodes. Stimulation changes in simulated γ-triggered feedback modulation followed more closely with phasic REM density, whereas an opposite trend was found in simulated β-triggered feedback modulation. Excess subthalamic γ oscillations may contribute to REM instability and RBD, suggesting that γ oscillation could serve as a feedback signal for adaptive DBS for REM sleep disorders. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Membrane vesicles from lactobacillus acidophilus reduce intestinal inflammation and increase 5-HT in the substantia nigra of rats with parkinson's disease.

This study aimed to investigate the role of membrane vesicles (MVs) from the probiotic Lactobacillus acidophilus in reducing intestinal inflammation and increasing 5-hydroxytryptamine (5-HT) and tyrosine hydroxylase (TH) in the substantia nigra in the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease (PD). Twenty healthy male Wistar rats were randomly assigned to four groups (n = 5 per group), including a) control, b) 6-OHDA, c) 6-OHDA+MV, and d) sham groups. PD was induced by bilateral injection of 6-OHDA. Rats in the 6-OHDA+MV group received MV equivalent to 1 × 107 colony-forming units (CFU)/mL 3 d/wk by oral gavage for 4 wk. At the end of 4 wk, all rats were sacrificed; the brain and small intestine were removed for cellular and molecular analysis. The induction of PD by 6-OHDA induced a remarkable decrease in beam-walking (p < 0.0001). In addition, the expression of protein and genes (receptor) of 5-HT (r-5-HT1A) decreased, and that of protein and gene (receptor; GABBR1) of GABA increased in the PD group (p < 0.05 compared with the healthy control group), while MV gavage of 6-OHDA-injected rats controlled these factors in the substantia nigra. In the intestinal tissue, the expression of TLR-4 and α-synuclein gene was significantly increased in the 6-OHDA group compared to the control group (p < 0.0001). MVs might act as potential beneficial tools to reduce intestinal inflammation, control neurological damage associated with PD, and increase 5-HT neurotransmitters. It seems that MVs from L. acidophilus may have therapeutic potential in Parkinson's neurological disorder by controlling the gut-brain axis.

Genetic Analysis of GCA Repeats in the GLS Gene: Implications for Undiagnosed Ataxia and Spinocerebellar Ataxia 3 in Mainland China.

Recent studies have reported that expanded GCA repeats in the GLS gene can cause glutaminase deficiency with ataxia phenotype. However, to data, no studies have investigated the distribution and role of GCA repeats in the GLS gene of Chinese individuals. The aim was to investigate the distribution of GCA repeats in Chinese individuals, including undiagnosed ataxia patients for identifying causal factors, healthy controls for determining the normal range, and ATX-ATXN3 (spinocerebellar ataxia type 3, SCA3) patients for exploring genetic modifiers. We combined whole-genome sequencing (WGS), repeat-primed polymerase chain reaction, capillary electrophoresis (RP-PCR/CE), and ExpansionHunter to screen the GCA repeats in the GLS gene of 349 undiagnosed ataxia individuals, 1505 healthy controls, and 1236 ATX-ATXN3 (SCA3)patients from mainland China. No expanded GCA repeats in the GLS gene were detected across any of the samples. The average number of GCA repeats was 11 (range: 8-31), 12 (range: 6-33), and 11 (range: 6-33) for undiagnosed ataxia patients, healthy controls, and SCA3 patients, respectively. The intermediate repeat size (9 < repeat size ≤ 13) of the nonexpanded GCA allele in the GLS gene was associated with later disease onset in ATX-ATXN3 (SCA3) patients. Abnormal expansions of GLS GCA repeats are rare in the Chinese population. However, intermediate-length normal GCA repeat sizes may influence the age at onset (AAO) in ATX-ATXN3 (SCA3) patients. © 2024 International Parkinson and Movement Disorder Society.

Association between the Amplification Parameters of the α-Synuclein Seed Amplification Assay and Clinical and Genetic Subtypes of Parkinson's Disease.

α-Synuclein seed amplification assay on cerebrospinal fluid (CSF-αSyn-SAA) has shown high accuracy for Parkinson's disease (PD) diagnosis. The analysis of CSF-αSyn-SAA parameters may provide useful insight to dissect the heterogeneity of synucleinopathies. To assess differences in CSF-αSyn-SAA amplification parameters in participants with PD stratified by rapid eye movement (REM) sleep behavior disorder (RBD), dysautonomia, GBA, and LRRK2 variants. Clinical and CSF-αSyn-SAA data from the Parkinson's Progression Marker Initiative dataset were used. CSF-αSyn-SAA parameters included maximum fluorescence (Fmax), time to reach 50% of Fmax (T50), time to threshold (TTT), slope, and area under the curve (AUC). Sporadic PD (n = 371) was stratified according to RBD and dysautonomia (DysA) symptoms. Genetic PD included carriers of pathogenic variants of GBA (GBA-PD, n = 52) and LRRK2 (LRRK2-PD, n = 124) gene. CSF-αSyn-SAA was positive in 77% of LRRK2-PD, 92.3% of GBA-PD, and 93.8% of sporadic PD. The LRRK2-PD cohort showed longer T50 and TTT, and smaller AUC than GBA-PD (P = 0.029, P = 0.029, P = 0.016, respectively) and sporadic PD (P = 0.034, P = 0.033, P = 0.014, respectively). In the sporadic cohort, CSF-αSyn-SAA parameters were similar between PD with (n = 157) and without (n = 190) RBD, whereas participants with DysA (n = 193) presented shorter T50 (P = 0.026) and larger AUC (P = 0.029) than those without (n = 150). CSF-αSyn-SAA parameters vary across genetic and non-genetic PD subtypes at the group level. These differences are mostly driven by the presence of LRRK2 variants and DysA. Significant overlaps in the amplification parameter values exist between groups and limit their use at the individual level. Further studies are necessary to understand the mechanisms of CSF-αSyn-SAA parameter differences. © 2024 International Parkinson and Movement Disorder Society.

All-Cause and Cause-Specific Mortality in Tourette Syndrome and Chronic Tic Disorder.

Tourette syndrome (TS) and chronic tic disorder (CTD) may be associated with an increased risk of mortality, but specific causes of death are poorly understood. In this matched cohort and sibling cohort study, we estimated the risk of all-cause and cause-specific mortality in individuals with TS/CTD, compared with unaffected matched individuals and unaffected full siblings. We identified all individuals diagnosed with TS/CTD in the Swedish National Patient Register who were living in the country between 1973 and 2020 and matched them (1:10) to individuals without TS/CTD from the general population. We also identified their siblings without TS/CTD. All-cause and cause-specific mortality outcomes, based on the International Classification of Diseases codes, were extracted from the Cause of Death Register. Covariates included sociodemographic variables and psychiatric disorders. Risks of mortality were estimated using Cox proportional hazards regression models. We included 10,280 individuals with TS/CTD and 102,800 matched individuals without TS/CTD. In adjusted models, individuals with TS/CTD had an 86% increased hazard of all-cause mortality (hazard ratio: 1.86, 95% confidence interval: 1.65-2.11). The increased risk was observed for both natural (particularly nervous, digestive, and respiratory system diseases) and unnatural causes of death (including suicides and accidents). The sibling comparison showed similar results, indicating that the associations were unlikely to be explained by familial confounding. Individuals with TS/CTD are at increased risk of death due to both natural and unnatural causes. As some of these deaths are potentially preventable, greater focus on the somatic health of individuals with TS/CTD is warranted. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Changes in Action Tremor in Parkinson's Disease over Time: Clinical and Neuroimaging Correlates.

The various symptoms of Parkinson's disease (PD) may change differently over time as the disease progresses. Tremor usually manifests early in the disease, but unlike other motor symptoms, its severity may diminish over time. The cerebral mechanisms underlying these symptom-specific longitudinal trajectories are unclear. Previous magnetic resonance imaging (MRI) studies have shown structural changes in brain regions associated with PD tremor, suggesting that structural changes over time may define clinical trajectories. The aims were to investigate the longitudinal trajectory of PD tremor in relation to bradykinesia and rigidity, and assess whether tremor progression is related to structural changes in tremor-related areas. We used data from the Personalized Parkinson Project: a two-year longitudinal study involving 520 PD patients and 60 healthy controls, who were measured twice clinically and with MRI. Mixed-effects models were used to compare tremor, bradykinesia, and rigidity progression; investigate gray matter changes in tremor-related regions (cerebello-thalamo-cortical circuit and pallidum); and calculate associations between symptom severity and brain structure. Associations across the whole brain were included to assess anatomical specificity. Bradykinesia and rigidity worsened over 2 years, whereas tremor behaved differently: resting tremor severity remained stable, whereas postural and kinetic tremor severity decreased. Attenuation of postural and kinetic tremor was associated with, but not restricted to, atrophy in tremor-related areas. Opposite relationships were observed for bradykinesia and rigidity. Action tremor (postural and kinetic) is an early symptom of PD, which reduces with disease progression. Longitudinal brain atrophy correlates with tremor and other motor symptoms in opposite ways. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Phosphatidylethanolamines are the Main Lipid Class Altered in Red Blood Cells from Patients with VPS13A Disease/Chorea-Acanthocytosis.

VPS13A disease is an ultra-rare disorder caused by loss of function mutations in VPS13A characterized by striatal degeneration and by red blood cell (RBC) acanthocytosis. VPS13A is a bridge-like protein mediating lipid transfer at membrane contact sites. To assess the lipid composition of patient-derived RBCs. RBCs collected from 5 VPS13A disease patients and 12 control subjects were analyzed by mass spectrometry (lipidomics). While we found no significant differences in the overall lipid class level, alterations in certain species were detected: phosphatidylethanolamine species with both longer chain length and higher unsaturation were increased in VPS13A disease samples. Specific ceramide, phosphatidylcholine, and sphingomyelin species were also altered. The presented alterations of particular lipid species in RBCs in VPS13A disease may contribute to (1) the understanding of acanthocyte formation, and (2) future biomarker identification. Lipid distribution seems to play a key role in the pathophysiology of VPS13A disease. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.