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BackgroundTo date, no medication has slowed the progression of Parkinson's disease (PD). Preclinical, epidemiological, and experimental data on humans all support many benefits of endurance exercise among persons with PD. The key question is whether there is a definitive additional benefit of exercising at high intensity, in terms of slowing disease progression, beyond the well-documented benefit of endurance training on a treadmill for fitness, gait, and functional mobility. This study will determine the efficacy of high-intensity endurance exercise as first-line therapy for persons diagnosed with PD within 3 years, and untreated with symptomatic therapy at baseline.MethodsThis is a multicenter, randomized, evaluator-blinded study of endurance exercise training. The exercise intervention will be delivered by treadmill at 2 doses over 18 months: moderate intensity (4 days/week for 30 min per session at 60-65% maximum heart rate) and high intensity (4 days/week for 30 min per session at 80-85% maximum heart rate). We will randomize 370 participants and follow them at multiple time points for 24 months. The primary outcome is the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor score (Part III) with the primary analysis assessing the change in MDS-UPDRS motor score (Part III) over 12 months, or until initiation of symptomatic antiparkinsonian treatment if before 12 months. Secondary outcomes are striatal dopamine transporter binding, 6-min walk distance, number of daily steps, cognitive function, physical fitness, quality of life, time to initiate dopaminergic medication, circulating levels of C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF). Tertiary outcomes are walking stride length and turning velocity.DiscussionSPARX3 is a Phase 3 clinical trial designed to determine the efficacy of high-intensity, endurance treadmill exercise to slow the progression of PD as measured by the MDS-UPDRS motor score. Establishing whether high-intensity endurance treadmill exercise can slow the progression of PD would mark a significant breakthrough in treating PD. It would have a meaningful impact on the quality of life of people with PD, their caregivers and public health.Trial registrationClinicalTrials.gov NCT04284436 . Registered on February 25, 2020.

Cognitive impairment is a common non-motor symptom in Parkinson's Disease (PD) and an important source of patient disability and caregiver burden. The timing, profile and rate of cognitive decline varies widely among individuals with PD and can range from normal cognition to mild cognitive impairment (PD-MCI) and dementia (PDD). Beta-amyloid and tau brain accumulation, oxidative stress and neuroinflammation are reported risk factors for cognitive impairment. Traumatic brain injury and pesticide and tobacco exposure have also been described. Genetic risk factors including genes such as COMT, APOE, MAPT and BDNF may also play a role. Less is known about protective factors, although the Mediterranean diet and exercise may fall in this category. Nonetheless, there is conflicting evidence for most of the factors that have been studied. The use of inconsistent criteria and lack of comprehensive assessment in many studies are important methodological issues. Timing of exposure also plays a crucial role, although identification of the correct time window has been historically difficult in PD. Our understanding of the mechanism behind these factors, as well as the interactions between gene and environment as determinants of disease phenotype and the identification of modifiable risk factors will be paramount, as this will allow for potential interventions even in established PD.

Abstract Background To date, no medication has slowed the progression of Parkinson’s disease (PD). Preclinical, epidemiological, and experimental data on humans all support many benefits of endurance exercise among persons with PD. The key question is whether there is a definitive additional benefit of exercising at high intensity, in terms of slowing disease progression, beyond the well-documented benefit of endurance training on a treadmill for fitness, gait, and functional mobility. This study will determine the efficacy of high-intensity endurance exercise as first-line therapy for persons diagnosed with PD within 3 years, and untreated with symptomatic therapy at baseline. Methods This is a multicenter, randomized, evaluator-blinded study of endurance exercise training. The exercise intervention will be delivered by treadmill at 2 doses over 18 months: moderate intensity (4 days/week for 30 min per session at 60–65% maximum heart rate) and high intensity (4 days/week for 30 min per session at 80–85% maximum heart rate). We will randomize 370 participants and follow them at multiple time points for 24 months. The primary outcome is the Movement Disorders Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) motor score (Part III) with the primary analysis assessing the change in MDS-UPDRS motor score (Part III) over 12 months, or until initiation of symptomatic antiparkinsonian treatment if before 12 months. Secondary outcomes are striatal dopamine transporter binding, 6-min walk distance, number of daily steps, cognitive function, physical fitness, quality of life, time to initiate dopaminergic medication, circulating levels of C-reactive protein (CRP), and brain-derived neurotrophic factor (BDNF). Tertiary outcomes are walking stride length and turning velocity. Discussion SPARX3 is a Phase 3 clinical trial designed to determine the efficacy of high-intensity, endurance treadmill exercise to slow the progression of PD as measured by the MDS-UPDRS motor score. Establishing whether high-intensity endurance treadmill exercise can slow the progression of PD would mark a significant breakthrough in treating PD. It would have a meaningful impact on the quality of life of people with PD, their caregivers and public health. Trial registration ClinicalTrials.gov NCT04284436 . Registered on February 25, 2020.

Cognitive impairment is a common non-motor symptom in Parkinson’s Disease (PD) and an important source of patient disability and caregiver burden. The timing, profile and rate of cognitive decline varies widely among individuals with PD and can range from normal cognition to mild cognitive impairment (PD-MCI) and dementia (PDD). Beta-amyloid and tau brain accumulation, oxidative stress and neuroinflammation are reported risk factors for cognitive impairment. Traumatic brain injury and pesticide and tobacco exposure have also been described. Genetic risk factors including genes such as COMT, APOE, MAPT and BDNF may also play a role. Less is known about protective factors, although the Mediterranean diet and exercise may fall in this category. Nonetheless, there is conflicting evidence for most of the factors that have been studied. The use of inconsistent criteria and lack of comprehensive assessment in many studies are important methodological issues. Timing of exposure also plays a crucial role, although identification of the correct time window has been historically difficult in PD. Our understanding of the mechanism behind these factors, as well as the interactions between gene and environment as determinants of disease phenotype and the identification of modifiable risk factors will be paramount, as this will allow for potential interventions even in established PD.

Objective: The aim of this study is to determine if the University of Pennsylvania’s Smell Identification Test (UPSIT) is an accurate diagnostic tool for olfactory dysfunction in Parkinson’s disease (PD). Method: We included 138 non-demented PD subjects and 175 control subjects matched by gender. Smell identification was tested using UPSIT. Results: The mean number of UPSIT items correctly identified by controls was 27.52±5.88; the mean score for PD subjects was 19.66±6.08 (p=

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Long-term longitudinal data on outcomes in sporadic Parkinson's Disease are limited, especially from cohorts with extensive biological characterization. Recent advances in biomarkers characterization of Parkinson's Disease necessitate an updated examination of long-term progression within contemporary cohorts like the Parkinson's Progression Markers Initiative, which enrolled individuals within 2 years of clinical diagnosis of Parkinson's Disease. Our study leverages the Neuronal Synuclein Disease framework, which defines the disease based on biomarker assessed presence of neuronal alpha-synuclein and dopamine deficit, rather than based on conventional clinical diagnostic criteria. In this study we aimed to provide a comprehensive long-term description of disease progression using the integrated biological and clinical staging system framework. We analyzed data from 344 participants from the sporadic Parkinson's Disease cohort in the Parkinson's Progression Markers Initiative, who met Neuronal Synuclein Disease criteria. We assessed 11-year progression in a spectrum of clinical measures. We used Cox proportional hazards models to assess the association between baseline stage and time to key outcomes, including survival, postural instability (Hoehn & Yahr ≥ 3), loss of independence (Schwab & England < 80%), cognitive decline, and domain-based milestones such as walking and balance, motor complications, autonomic dysfunction, and activities of daily living. Additional analyses were completed to account for death and participant dropout. Biomarker analysis included dopamine transporter binding measures, as well as serum urate, neurofilament light chain and CSF amyloid-beta, phosphorylated tau and total tau. At baseline, despite the cohort consisting of individuals within 2 years of clinical diagnosis, there was clear separation of participants in Neuronal Synuclein Disease Stages (23% Stage 2b, 67% Stage 3, 10% Stage 4). At 11 years, data were available for 153 participants; 35 participants had died over the follow up period. Of retained participants, 59% presented normal cognition, 24% had evidence of postural instability and mean Schwab & England score was 78.5. Serum neurofilament light chain consistently increased over time. No other biofluids had a consistent change in trajectory. Of importance, baseline Neuronal Synuclein Disease Stage predicted progression to clinically meaningful milestones. This study provides data on longitudinal, 11-year progression in Neuronal Synuclein Disease participants within 2 years of clinical diagnosis. We observed better long-term outcomes in this contemporary observational study cohort. It highlights the heterogeneity in the early Parkinson's Disease population as defined by clinical diagnostic criteria and underscores the importance of shifting from clinical to biologically and functionally based inclusion criteria in the design of new clinical trials.

Background: Among LRRK2-associated parkinsonism cases with nigral degeneration, over two-thirds demonstrate evidence of pathologic alpha-synuclein, but many do not. Understanding the clinical phenotype and underlying biology in such individuals is critical for therapeutic development. Our objective was to compare clinical and biomarker features, and rate of progression over 4 years follow-up, among LRRK2-associated parkinsonism cases with and without in vivo evidence of alpha-synuclein aggregates., Methods: Data were from the Parkinson's Progression Markers Initiative, a multicenter prospective cohort study. The sample included individuals diagnosed with Parkinson disease with pathogenic variants in LRRK2. Presence of CSF alpha-synuclein aggregation was assessed with seed amplification assay. A range of clinician- and patient- reported outcome assessments were administered. Biomarkers included dopamine transporter SPECT scan, CSF amyloid-beta 1-42 , total tau, phospho-tau 181 , urine bis(monoacylglycerol)phosphate levels, and serum neurofilament light chain. Linear mixed effects models examined differences in trajectory in CSF negative and positive groups., Results: 148 LRRK2-parkinsonism cases (86% with G2019S variant), 46 negative and 102 positive for CSF alpha-synuclein seed amplification assay were included. At baseline, the negative group were older than the positive group (median [interquartile range] 69.1 [65.2-72.3] vs 61.5 [55.6-66.9] years, p<0.001) and a greater proportion were female (28 (61%) vs 43 (42%), p=0.035). Despite being older, the negative group had similar duration since diagnosis, and similar motor rating scale (16 [11-23] vs 16 [10-22], p=0.480) though lower levodopa equivalents. Only 13 (29%) of the negative group were hyposmic, compared to 75 (77%) of the positive group. Lowest putamen dopamine transporter binding expected for age and sex was greater in the negative vs positive groups (0.36 [0.29-0.45] vs 0.26 [0.22-0.37], p<0.001). Serum neurofilament light chain was higher in the negative group compared to the positive group (17.10 [13.60-22.10] vs 10.50 [8.43-14.70]; age-adjusted p-value=0.013). In terms of longitudinal change, the negative group remained stable in functional rating scale score in contrast to the positive group who had a significant increase (worsening) of 0.729 per year (p=0.037), but no other differences in trajectory were found., Conclusion: Among individuals diagnosed with Parkinson disease with pathogenic variants in the LRRK2 gene, we found clinical and biomarker differences in cases without versus with in vivo evidence of CSF alpha-synuclein aggregates. LRRK2 parkinsonism cases without evidence of alpha-synuclein aggregates as a group exhibit less severe motor manifestations and decline may have more significant cognitive dysfunction. The underlying biology in LRRK2-parkinsonism cases without evidence of alpha-synuclein aggregates requires further investigation., Competing Interests: Competing interests The authors report no competing interests.

Objective: To characterize DNA methylation (DNAm) differences between sporadic Parkinson's disease (PD) and healthy control (HC) individuals enrolled in the Parkinson's Progression Markers Initiative (PPMI)., Methods: Using whole blood, we characterized longitudinal differences in DNAm between sporadic PD patients (n = 196) and HCs (n = 86) enrolled in PPMI. RNA sequencing (RNAseq) was used to conduct gene expression analyses for genes mapped to differentially methylated cytosine-guanine sites (CpGs)., Results: At the time of patient enrollment, 5,178 CpGs were differentially methylated (2,683 hypermethylated and 2,495 hypomethylated) in PD compared to HC. Of these, 579 CpGs underwent significant methylation changes over 3 years. Several differentially methylated CpGs were found near the cytochrome P450 family 2 subfamily E member 1 (CYP2E1) gene. Additionally, multiple hypermethylated CpGs were associated with the N-myc downregulated gene family member 4 (NDRG4) gene. RNA-Seq analyses showed 75 differentially expressed genes in PD patients compared to controls. An integrative analysis of both differentially methylated sites and differentially expressed genes revealed 20 genes that exhibited hypomethylation concomitant with overexpression. Additionally, 1 gene, cathepsin H (CTSH), displayed hypermethylation that was associated with its decreased expression., Interpretation: We provide initial evidence of alterations in DNAm in blood of PD patients that may serve as potential epigenetic biomarker of disease. To evaluate the significance of these changes throughout the progression of PD, additional profiling at longer intervals and during the prodromal stages of disease will be necessary. ANN NEUROL 2024;95:1162-1172., (© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Parkinson's disease(PD) lacks a biomarker for disease progression. To analyze how cerebrospinal fluid (CSF), glucosylceramide (GlcCer), sphingomyelin (SM), or serum neurofilament light chain (NfL) associate with progression of PD in a retrospective cohort, we used linear mixed-model regressions between baseline biomarkers and change in dopamine transporter brain-imaging (DaTscan©), Montreal cognitive assesment (MoCA), or global composite outcome (GCO) score. In 191 PD patients, biomarkers were not associated with DaTscan or MoCA change over 2.1 years. Higher baseline GlcCer/SM ratio and serum-NfL nonsignificantly associated with increase in GCO score. Results do not support a role for CSF-sphingolipid/serum-NfL to predict cognitive and DaTscan progression in early-PD. Potential prediction of global clinical change warrants further study.

Background: Aging is the strongest risk factor for Parkinson's disease (PD), which is a clinically heterogeneous movement disorder with highly variable age at onset. DNA methylation age (DNAm age) is an epigenetic clock that could reflect biological aging., Objectives: The aim was to evaluate whether PD age at onset is associated with DNAm-age acceleration (difference between DNAm age and chronological age)., Methods: We used the genome-wide Infinium MethylationEPIC array to assess DNAm age in discovery (n = 96) and replication (n = 182) idiopathic PD cohorts and a unique longitudinal LRRK2 cohort (n = 220) at four time points over a 3-year period, comprising 91 manifesting and 129 nonmanifesting G2019S carriers at baseline. Cox proportional hazard regression and multivariate linear regression were used to evaluate the relation between DNAm-age acceleration and PD age at onset, which was highly variable in manifesting G2019S carriers (36-75 years) and both idiopathic PD cohorts (26-77 and 35-81 years)., Results: DNAm-age acceleration remained steady over the 3-year period in most G2019S carriers. It was strongly associated with age at onset in the LRRK2 cohort (P = 2.25 × 10 -15 ) and discovery idiopathic PD cohort (P = 5.39 × 10 -9 ), suggesting that every 5-year increase in DNAm-age acceleration is related to about a 6-year earlier onset. This link was replicated in an independent idiopathic PD cohort (P = 1.91 × 10 -10 ). In each cohort, the faster-aging group has an increased hazard for an earlier onset (up to 255%)., Conclusions: This study is the first to demonstrate that DNAm-age acceleration is related to PD age at onset, which could be considered in disease-modifying clinical trials. Future studies should evaluate the stability of DNAm-age acceleration over longer time periods, especially for phenoconverters from nonmanifesting to manifesting individuals. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

A variety of movement disorders can be associated with hypogonadism. Identification of this association may aid in guiding workup and reaching an accurate diagnosis. We conducted a comprehensive and structured search to identify the most common movement disorders associated with hypogonadism. Only Case Reports and Case Series articles were included. Ataxia was the most common movement disorder associated with hypogonadism, including entities such as Gordon-Holmes syndrome, Boucher-Neuhäuser, Marinesco-Sjögren and Perrault syndrome. Tremor was also commonly described, particularly with aneuploidies such as Klinefelter syndrome and Jacob's syndrome. Other rare conditions including mitochondrial disorders and Woodhouse-Sakati syndrome are associated with dystonia and parkinsonism and either hypo or hypergonadotropic hypogonadism. We also highlight those entities where a combination of movement disorders is present. Hypogonadism may be more commonly associated with movement disorders than previously appreciated. It is important for the clinician to be aware of this association, as well as accompanying symptoms in order to reach a precise diagnosis., Competing Interests: The authors declare that there are no funding sources or conflicts of interest relevant to this work., (© 2021 International Parkinson and Movement Disorder Society.)

Dystonia is a debilitating hyperkinetic movement disorder, which can be transmitted as a monogenic trait. Here, we describe homozygous frameshift, nonsense, and missense variants in TSPOAP1, which encodes the active-zone RIM-binding protein 1 (RIMBP1), as a genetic cause of autosomal recessive dystonia in 7 subjects from 3 unrelated families. Subjects carrying loss-of-function variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy. Conversely, subjects carrying a pathogenic missense variant (p.Gly1808Ser) presented with isolated adult-onset focal dystonia. In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses. In vitro analysis of the p.Gly1808Ser variant showed larger spike-evoked calcium transients and enhanced neurotransmission, suggesting that RIMBP1-linked dystonia can be caused by either reduced or enhanced rates of spike-evoked release in relevant neural networks. Our findings establish a direct link between dysfunction of the presynaptic active zone and dystonia and highlight the critical role played by well-balanced neurotransmission in motor control and disease pathogenesis.

Objective: Analyze indications for ordering DAT-SPECT scans and the clinical impact of scan results on patients evaluated in a movement disorders practice., Background: DAT-SPECT is FDA approved to evaluate cases of suspected presynaptic dopaminergic deficiency. Little data is available on clinical use and impact of these scans among movement disorders neurologists., Methods: DAT-SPECT scans ordered at the Northwestern University Parkinson's disease (PD) and movement disorders center from 2011-2013 were reviewed. Clinic notes were reviewed for information regarding the indication for ordering each scan, and to assess for any changes in clinical impression or management choices that followed the scan., Results: 83 scans were ordered by four specialists. Scans were commonly ordered to differentiate PD from Essential Tremor (21.7%, n = 18) or from drug-induced parkinsonism (21.7%, n = 18). In 59% (n = 49) of cases, a change in clinical diagnosis or medication regimen occurred within one visit after the scan. The strongest impact was seen for the indication of ET vs. PD in which 72.2% (n = 13) had a change in diagnosis, management, or both., Conclusions: Diagnostic uncertainty in cases of parkinsonism exists even in a tertiary referral center. DAT-SPECT has significant impact on clinical diagnosis and management even in the hands of movement disorders specialists., (© 2015 S. Karger AG, Basel.)

Objective: The aim of this study is to determine the usefulness of the University of Pennsylvania smell identification test (UPSIT), sniffin sticks (SS-16) and brief smell identification test (B-SIT) to assess smell identification in the Mexican population and its accuracy in discriminating subjects with Parkinson's disease (PD)., Methods: We included 199 nondemented PD subjects and 199 control subjects matched by gender. Smell identification was tested using the UPSIT and SS-16. Our group obtained B-SIT data from a previous report., Results: The mean number of UPSIT items correctly identified by controls was 27.3±6; the PD group had a mean score of 19.4±6. UPSIT had a sensitivity of 82% with a specificity of 66% for a cut-off score of ≤25 for detection of PD. The mean number of SS-16 items correctly identified by controls was 10.3±2.2, while the PD group had 7.4±2.8 correct answers. For SS-16, sensitivity was 77.8% and specificity of 71.2% when using a cut-off value of ≤9. Lemon, turpentine and rose had an identification rate below the 25th percentile for all three tests. Odors with an identification rate above the 75th percentile include banana for all three tests, and gasoline, onion and chocolate for UPSIT and B-SIT., Conclusion: The sensitivity and specificity of the smell tests that were evaluated were lower in comparison to other published reports. Cultural biases and smell familiarity may influence the test results. The development of a true cross-culturally adapted smell identification test is warranted may improve test accuracy., (Copyright © 2014. Published by Elsevier B.V.)