Search

Introduction: To apply susceptibility separation on quantitative susceptibility mapping (QSM) images of Parkinson's disease (PD) patients to obtain more accurate images and gain pathophysiological insights., Methods: This retrospective study included subjects who underwent head MRI, including QSM between March 2016 and March 2018. Patients with PD were categorized as having mild cognitive impairment (PD-MCI), or normal cognition (PD-CN); healthy controls (HC) were also enrolled. Susceptibility separation generated positive (QSM+) and negative susceptibility (QSM-) labels. Voxel-based whole-brain susceptibility and atlas-based susceptibility were compared among groups on white matter. Correlations between susceptibility and Montreal Cognitive Assessment (MoCA) scores were analyzed., Results: Overall, 65 subjects (mean age 72 years ±6, 35 men) were included. White-matter regions with significant (P < 0.05) group differences were found for QSM+ (HC > PD-MCI, PD-CN > PD-MCI) and QSM- (PD-MCI > HC, PD-MCI > PD-CN). In the atlas-based analyses, PD-MCI exhibited lower QSM + values (vs. HC; P = 0.002, vs. PD-CN; P = 0.001), and higher QSM-values (vs. HC; P = 0.02, vs. PD-CN; P = 0.03) in the genu of corpus callosum (gCC). QSM+ and QSM-showed significant positive and negative correlations with MoCA (P < 0.05). In the gCC, partial correlation analyses revealed a positive correlation between QSM+ and MoCA (R = 0.458, P < 0.001) and a negative correlation between QSM- and MoCA (R = -0.316, P = 0.01)., Conclusion: QSM utilizing susceptibility separation is valuable for assessing white matter in PD patients, where nerve fiber loss potentially influences cognitive function., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Past studies suggested that Parkinson's disease (PD) patients who engage in physical activity (PA) after diagnosis have slower motor progression. Here, we examine the influence of lifetime PA prior to PD onset on motor, cognitive, and overall functional decline among PD patients., Methods: For 495 participants in the Parkinson's Environment and Gene (PEG) studies, we collected PA-related measures through interviews and quantified these using metabolic equivalents (MET) scores. PD progression was defined as time to a Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) conversion to ≥ 35 points, Hoehn and Yahr (H&Y) ≥ 3, and a 4-point decline in Mini-Mental State Examination (MMSE). We used Cox frailty models to estimate hazard ratios and inverse probability weights to account for heterogeneity by enrollment wave and censoring., Results: For PD patients reporting the highest lifetime strenuous MET-h/wk (highest quartile), we estimated a lower HR for time-to-UPDRS-III-conversion (Q4 vs. Q1: HR = 0.56, 95 % CI = [0.36, 0.87]). Additionally, having engaged in any competitive sport also reduced the risk of reaching a UPDRS-III ≥ 35 points (low vs. none: HR = 0.61, 95 % CI = [0.44, 0.86]; high vs. none: HR = 0.63; 95 % CI = [0.44,0.86]); high levels of sports activities also affected progression on the H&Y scale (high vs. none: HR = 0.73; 95 % CI = [0.46,1.00]). Lifetime PA measures did not affect time-to-MMSE decline., Conclusion: Our study suggests that PD patients who engaged in higher levels of lifetime strenuous PA and competitive sports prior to PD diagnosis experience slower motor and overall functional decline, suggesting that lifetime PA may contribute to a physical reserve advantageous for PD patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: To assess correlative strengths of quantitative electroencephalography (qEEG) and visual rating scale EEG features on cognitive outcomes in only autopsied cases from the Arizona Study of Neurodegenerative Disorders (AZSAND). We hypothesized that autopsy proven Parkinson Disease will show distinct EEG features from Alzheimer's Disease prior to dementia (mild cognitive impairment)., Background: Cognitive decline is debilitating across neurodegenerative diseases. Resting-state EEG analysis, including spectral power across frequency bins (qEEG), has shown significant associations with neurodegenerative disease classification and cognitive status, with autopsy confirmed diagnosis relatively lacking., Methods: Biannual EEG was analyzed from autopsied cases in AZSAND who had at least one rsEEG (>1 min eyes closed±eyes open). Analysis included global relative spectral power and a previously described visual rating scale (VRS). Linear mixed regression was performed for neuropsychological assessment and testing within 2 years of death (n = 236, 594 EEG exams) in a mixed linear regression model., Results: The cohort included cases with final clinicopathologic diagnoses of Parkinson's disease (n = 73), Alzheimer disease (n = 65), and tauopathy not otherwise specified (n = 56). A VRS score of 3 diffuse or frequent generalized slowing) over the study duration was associated with an increase in consensus diagnosis cognitive worsening at 4.9 (3.1) years (HR 2.02, CI 1.05-3.87). Increases in global theta power% and VRS were the most consistently associated with large regression coefficients inversely with cognitive performance measures., Conclusion: Resting-state EEG analysis was meaningfully related to cognitive performance measures in a community-based autopsy cohort. EEG deserves further study and use as a cognitive biomarker., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Sleep problems commonly occur in Parkinson's disease (PD) and significantly affect patients' quality of life. A possible effect on subjective sleep disturbances of monoamine oxidase-B inhibitors (MAOB-Is) has been described., Methods: This prospective, observational, single-centre study involved 45 fluctuating PD patients complaining sleep problems as documented by the PD Sleep Scale -2nd version (PDSS-2 ≥18) starting rasagiline 1 mg/daily or safinamide 100 mg/daily, according to common clinical practice, and maintaining antiparkinsonian therapy unchanged. Polysomnography (PSG), sleep questionnaires (PDSS-2, Epworth Sleepiness Scale - ESS), and motor function were evaluated at baseline (T0) and after 4 months of treatment (T1)., Results: Safinamide was prescribed in thirty patients and rasagiline in fifteen patients. Both drugs induced a significant improvement in Movement Disorder Society Unified PD Rating Scale III scores. Patients treated with rasagiline showed a significant increase in stage 1 (N1) Non-REM sleep compared to T0, with no significant effects on sleep scales. Patients treated with safinamide showed a significant increase in stage 3 of Non-REM sleep and sleep efficiency and a reduction in the rate of periodic limb movements, matching a significant reduction in PDSS-2 and ESS scales compared to T0., Conclusion: This study showed that safinamide, in addition to having a significant effect on PD motor symptoms, like the other MAOB-Is, may exert a specific beneficial effect on subjective and objective sleep, probably driven by its dual mechanism of action, which involves both dopaminergic and glutamatergic neurotransmission., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Tandem gait performance reportedly predicts fall risk in people with Parkinson's disease (PwPD) and help distinguish PwPD from atypical parkinsonism. In a cross-sectional study, we previously showed that tandem gait step-width widens with increasing Hoehn and Yahr (H&Y) staging scores. In this longitudinal study, we aimed to determine if progression in tandem gait deficits is dependent on disease severity in PwPD., Methods: Participants underwent an instrumented tandem gait measurement every 6 months for at least 2 years. The mean and variability of 4 tandem gait parameters were calculated at each visit: step-width, step-length, step-time, and step-velocity. The change in these parameters over time for 3 H&Y groups (stage 1, 2 and 2.5+) compared to aging controls was determined using a random coefficients regression model. The annual percent change in tandem gait parameters was correlated with initial disease features using Kendall's τ B ., Results: 66 participants were analyzed (46 PD, 20 controls). Mean step-width increased over time in an H&Y stage-dependent manner, with H&Y 2 and H&Y 2.5+ experiencing increases of 6% and 10% per year (p = 0.001 and 0.024 respectively). Annual percent-change in step-width was correlated with initial motor Unified Parkinson's Disease Rating Scale (UPDRS) scores (Kendall's τ B  = 0.229), total UPDRS scores (τ B  = 0.249), H&Y scores (τ B  = 0.266) and inversely correlated with Montreal Cognitive Assessment (MoCA) scores (τ B  = -0.209; ps ≤ 0.019)., Conclusion: Tandem gait step-width widens over time more rapidly in more severely affected PD patients. These results suggest that tandem gait should be routinely clinically evaluated and considered in the management of imbalance in PwPD., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tuhin Virmani reports financial support was provided by National Institute of General Medical Sciences. Tuhin Virmani reports financial support was provided by Parkinson's Foundation Inc. Tuhin Virmani reports financial support was provided by University of Arkansas for Medical Sciences. Reid D. Landes reports financial support was provided by National Center for Advancing Translational Sciences. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Evaluation of disease severity in Parkinson's disease (PD) relies on motor symptoms quantification. However, during early-stage PD, these symptoms are subtle and difficult to quantify by experts, which might result in delayed diagnosis and suboptimal disease management., Objective: To evaluate the use of videos and machine learning (ML) for automatic quantification of motor symptoms in early-stage PD., Methods: We analyzed videos of three movement tasks-Finger Tapping, Hand Movement, and Leg Agility- from 26 aged-matched healthy controls and 31 early-stage PD patients. Utilizing ML algorithms for pose estimation we extracted kinematic features from these videos and trained three classification models based on left and right-side movements, and right/left symmetry. The models were trained to differentiate healthy controls from early-stage PD from videos., Results: Combining left side, right side, and symmetry features resulted in a PD detection accuracy of 79 % from Finger Tap videos, 75 % from Hand Movement videos, 79 % from Leg Agility videos, and 86 % when combining the three tasks using a soft voting approach. In contrast, the classification accuracy varied between 40 % and 72 % when the movement side or symmetry were not considered., Conclusions: Our methodology effectively differentiated between early-stage PD and healthy controls using videos of standardized motor tasks by integrating kinematic analyses of left-side, right-side, and bilateral symmetry movements. These results demonstrate that ML can detect movement deficits in early-stage PD from videos. This technology is easy-to-use, highly scalable, and has the potential to improve the management and quantification of motor symptoms in early-stage PD., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Diego L. Guarin reports financial support provided by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number P2CHD101899. David Vaillancourt reports financial support provided by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number 5R01NS058487., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Parkinson's disease (PD) is a stressful neurodegenerative disorder affecting millions worldwide. PD leads to debilitating motor and cognitive symptoms such as tremors, rigidity, and difficulty walking. Current therapies for PD are symptomatic and don't address the root cause. Therefore, there is an urgent need for better management and intensive research into alternative therapies. Mesenchymal stem cell (MSC) therapy is among the leading contenders among these promising avenues. We examined preclinical and clinical evidence demonstrating the neuroprotective, anti-inflammatory, and regenerative properties of the MSCs. This review focuses on the complex pathophysiological mechanisms of PD, as well as the perspectives of MSCs and their derivatives, such as secretomes and exosomes, in the clinical management of PD. We also analyzed the challenges and limitations of each approach, including delivery methods, timing of administration, and long-term safety considerations., Competing Interests: Declaration of competing interest The authors declare that they have approved the final version of the manuscript. They have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article’., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Parkinson's disease (PD) encompasses a range of non-motor symptoms attributed to deficits in various neurotransmitter systems. This study aimed to investigate the associations between cognitive and autonomic symptoms and the degeneration of brainstem monoaminergic nuclei, particularly the serotonergic and noradrenergic nuclei, in a prospective cohort of early PD patients., Methods: Twenty-eight early PD patients (with an average disease duration of approximately three years) underwent baseline [ 18 F]FP-CIT positron emission tomography (PET) scans, Montreal Cognitive Assessment (MoCA), and Composite Autonomic Symptom Scale-31 (COMPASS-31) evaluations, followed by repeat MoCA and COMPASS-31 assessments three years later. Regression models were utilized to analyze both cross-sectional and longitudinal changes in non-motor symptoms relative to baseline degeneration of the noradrenergic locus coeruleus (LC) and serotonergic raphe, normalized by striatal dopaminergic terminal loss., Results: Baseline LC and raphe degeneration in early PD was cross-sectionally associated with poorer MoCA performances. Over the three-year follow-up, gastrointestinal symptoms exhibited progression, while cognitive scores remained stable. Profound baseline degeneration of the LC and raphe, relative to nigrostriatal terminal loss, were predictive of subsequent accelerated deterioration in gastrointestinal symptoms., Conclusion: Brainstem non-dopaminergic dysfunction in early PD is linked to cognitive dysfunction and predicts progression in gastrointestinal symptoms, offering potential indicators for worsening non-motor trajectories., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jung Hwan Shin reports financial support provided by the Ministry of Science and ICT (MSIT), South Korea. Other authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Up to 10 % of Parkinson's disease (PD) populations carry a genetic risk variant, which may not only increase one's chance of developing PD but also affect disease presentation and progression. We hypothesize motor impairment in genetic carriers of PD correlate to different patterns of microstructural changes over time., Design/methods: Data were accessed from the Parkinson's Progression Markers Initiative (PPMI) project. Connectometry analyses were performed for GBA1+ PD, LRRK2+ PD, and sporadic PD correlating white matter structural changes, as measured by quantitative anisotropy (QA), with motor impairment, as measured by MDS-UPDRS III., Results: There was a negative correlation between QA and MDS-UPDRS III in all 3 cohorts at 48 months. In GBA1+ PD (n = 12), the white matter tracts identified were cortical and subcortical, while in the LRRK2+ PD (n = 18) and sporadic PD (n = 45) cohorts white tracts identified were primarily subcortical and within the brainstem., Conclusions: Our findings highlight the association between motor symptom progrerssion and structural connectivity in individuals with GBA1+ PD, LRRK2+ PD, and sporadic PD. Due to the small sample size, larger studies are needed in the future to confirm the findings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Introduction: Patients with Parkinson's Disease (PD) have a distinctive body odor, which was first described by a patient's wife as musky and strong. Later analysis of sebum of patients with PD revealed four volatile organic compounds (VOC) (perillic aldehyde, hippuric acid, eicosane, octadecanal), that differed from healthy subjects, and the patient's wife confirmed that three of them smelled like patients with PD. However, it is unclear whether other people can also perceive this PD body odor and whether it can be artificially recreated. Hence, we aimed to systematically assess whether young women can perceive the PD body odor and whether they can discriminate between the PD body odor and the "artificial PD odor" composed of the four VOCs mentioned above., Methods: T-shirts were collected from 19 people with idiopathic PD and 15 age- and gender-matched healthy participants to represent the PD body odor and the healthy body odor, respectively. The four VOCs were diluted in 1,2-propanediol to prepare the artificial PD body odor. Body odors were rated by 26 young women., Results: PD body odor was perceived as more musty, strong, smelly, and unpleasant compared to healthy and artificial PD body odor. Furthermore, around 80 % of women were able to discriminate PD body odor from artificial PD body odor., Conclusion: Overall, this study confirmed a distinctive body odor quality of patients with PD, which can be perceived by young women. However, the four VOCs, composing the artificial PD body odor, were insufficient to reproduce the body odor from PD patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Since 2021 TH has collaborated on research projects with Sony, Stuttgart, Germany; Smell and Taste Lab, Geneva, Switzerland; Takasago, Paris, France; aspuraclip, Berlin, Germany. He received consultancy fees from Baia Foods, Madrid, Spain; Burghart, Holm, Germany; air-up, Munich, Germany. Other authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: This study aimed to assess the glymphatic function and its correlation with clinical characteristics and the loss of dopaminergic neurons in Parkinson's disease (PD) using hybrid positron emission tomography (PET)-magnetic resonance imaging (MRI) combined with diffusion tensor image analysis along the perivascular space (DTI-ALPS), choroid plexus volume (CPV), and enlarged perivascular space (EPVS) volume., Methods: Twenty-five PD patients and thirty matched healthy controls (HC) participated in the study. All participants underwent 18 F-fluorodopa ( 18 F-DOPA) PET-MRI scanning. The striatal standardized uptake value ratio (SUVR), DTI-ALPS index, CPV, and EPVS volume were calculated. Furthermore, we also analysed the relationship between the DTI-ALPS index, CPV, EPVS volume and striatal SUVR as well as clinical characteristics of PD patients., Results: PD patients demonstrated significantly lower values in DTI-ALPS (t = 3.053, p = 0.004) and larger CPV (t = 2.743, p = 0.008) and EPVS volume (t = 2.807, p = 0.008) compared to HC. In PD group, the ALPS-index was negatively correlated with the Unified Parkinson's Disease Rating Scale III (UPDRS-III) scores (r = -0.730, p < 0.001), and positively correlated with the mean putaminal SUVR (r = 0.560, p = 0.007) and mean caudal SUVR (r = 0.459, p = 0.032). Moreover, the mean putaminal SUVR was negatively associated with the UPDRS-III scores (r = -0.544, p = 0.009)., Conclusion: DTI-ALPS has the potential to uncover glymphatic dysfunction in patients with PD, with this dysfunction correlating strongly with the severity of disease, together with the mean putaminal and caudal SUVR. PET- MRI can serve as a potential multimodal imaging biomarker for early-stage PD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Parkinson's disease (PD) is often accompanied by sleep disturbances, impacting patients' quality of life. While repetitive transcranial magnetic stimulation (rTMS) shows promise in improving self-reported sleep quality, its effects on objective sleep architecture in PD remain understudied. Sleep disturbances, including rapid eye movement (REM) and slow-wave sleep disturbances, correlate with cognitive decline and motor symptoms. This study investigated the effect of low-frequency rTMS targeting the right dorsolateral prefrontal cortex (DLPFC) modifying objective sleep architecture and explored symptom improvement mechanisms in PD patients., Methods: In this randomized, double-blind, sham-controlled trial, 67 PD patients received 10 consecutive days of 1-Hz rTMS over the right DLPFC. Polysomnography assessed sleep microstructure, while electroencephalogram recordings evaluated power spectral density and sleep spindle activity. Clinical scales measured sleep quality, motor symptoms, and cognition at baseline, post-treatment, and 3 months post-rTMS., Results: The rTMS group exhibited improvements in sleep quality, motor symptoms, and cognition post-treatment, persisting at the 3-month follow-up. There was a notable increase in the REM sleep proportion post-rTMS. The rTMS group exhibited elevated low-frequency (0.5-2 Hz) slow-wave electroencephalogram spectral density during non-REM sleep. Cognitive enhancement correlated with increased lower delta power, while motor symptom progression correlated with spindle frequency and slow-wave sleep percentage changes., Conclusion: Low-frequency rTMS targeting the right DLPFC holds promise for improving clinical symptoms and modulating sleep architecture in PD. These findings suggest a link between symptom improvement and sleep structure enhancement, highlighting the need for further investigation into the therapeutic potential of rTMS in PD management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The Parkinson Study Group (PSG) gathered North American experts in Parkinson disease during the 9 th  Annual Symposium on "Shaping the Management of Parkinson Disease: Debating Current Controversies". Debaters were tasked with agree or disagree positions to a particular prompt. This is the first in three-part series of "Hype vs. Hope" debates involving current trends and advances in Parkinson disease. With the prompt of "Spreading alpha-synuclein explains cognitive deficits in Parkinson disease," Dr. Kelly Mills, MD, MHS was tasked with the "agree" stance and Dr. Abhimanyu Mahajan, MD, MHS was tasked with the "disagree" stance. The following point-of-view article is an adaptation of this debate., Competing Interests: Declaration of Competing interest Dr. Mills: Dr. Mills has no conflicts of interest to disclose. Dr. Mahajan: Dr. Mahajan has no conflicts of interest to disclose. Dr. Phillips: Dr. Phillips has no conflicts of interest to disclose., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Dysgraphia, a recognized PD motor symptom, lacks effective clinical assessment. Current evaluation relies on motor assessment scales. Computational methods introduced over the past decade offer an objective dysgraphia assessment, considering size, duration, speed, and handwriting fluency. Objective evaluation of dysgraphia may be of help for early diagnosis of PD., Objective: Computerized assessment of dysgraphia in de novo PD patients and its correlation with clinical scales., Methods: We evaluated 38 recently diagnosed, premedication PD patients and age-matched controls without neurological disorders. Participants wrote "La casa de Pamplona es bonita" three times on paper and once on a Wacom tablet under the paper, totaling four phrases. Writing segments of 5-10 s were analyzed. The Wacom tablet captured kinematic data, including mean velocity, mean acceleration, and pen pressure. Data were saved in.svc format and analyzed using specialized software developed by Tecnocampus Mataró. Standard clinical practice data, Hoehn & Yahr staging, and UPDRS scales were used for evaluation., Results: Significant kinematic differences existed; patients had lower mean speed (27 ± 12 vs. 48 ± 18, p < 0.0001) and mean acceleration (7.2 ± 3.9 vs. 15.01 ± 7, p < 0.0001) than controls. Mean speed and mean acceleration correlated significantly with UPDRS III scores (speed: r = -0.52, p < 0.0007; acceleration: r = 0.60, p < 0.0001), indicating kinematic parameters' potential in PD evaluation., Conclusions: Dysgraphia is identifiable in PD patients, even de novo, indicating an early symptom and correlates with clinical scales, offering potential for objective PD patient evaluation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Early differentiation between Parkinson's disease (PD) and Multiple system atrophy (MSA), particularly the parkinsonian subtypes (MSA-P), is challenging due to similar clinical symptoms. We aimed to evaluate Sympathetic skin response (SSR) and Cutaneous silent period (CSP) parameters in patients with MSA-P and PD to identify possible biomarkers that could distinguish the two groups of patients in early stage., Methods: 22 individuals with early-stage MSA-P, 29 with early-stage PD, and 28 healthy controls were recruited from Guangdong Provincial People's Hospital. Demographic data was collected for all participants. Their SSR and CSP were evaluated using clinical electromyography equipment. Data were compared between different groups. The diagnostic accuracy of SSR and CSP parameters was calculated using the ROC curve. Logistic regression was used to produce an integration model to enhance diagnostic utility., Results: Foot amplitude, CSP end latency and duration distinguished MSA-P from PD with the area under the curve (AUC) 0.770, 0.806, and 0.776, respectively. Foot and hand SSR amplitude distinguished PD from HC with the AUC 0.871 and 0.768, respectively. Foot SSR amplitude, hand SSR amplitude, and CSP end latency distinguished MSA-P from HC with the AUC 0.964, 0.872, and 0.812, respectively. The combination of SSR and CSP parameters differentiation between MSA-P and PD, PD and HC with the AUC 0.829 and 0.879, respectively., Conclusions: Analysis of SSR and CSP parameters showed excellent diagnostic accuracy in discriminating patients with early-stage MSA-P from HC and good diagnostic accuracy in discriminating patients with MSA-P from PD with early stages., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Chunge Xie reports financial support was provided by Medical Scientific Research Foundation of Guangdong Province, China. Chunge Xie reports administrative support was provided by Traditional Chinese Medicine Bureau of Guangdong Province, China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Non-motor symptoms and non-motor fluctuations (NMF) in Parkinson's disease (PD) strongly affect health-related quality of life (HRQoL) and disability. The impact of deep brain stimulation (DBS) on NMF remains an area of uncertainty. The aim is to evaluate the impact of DBS on NMF, using the recently validated Non-Motor Fluctuation Assessment (NoMoFa), and to explore the correlation between NMF and motor symptoms, motor complications (MC), and HRQoL post-surgical improvement., Methods: We prospectively evaluated consecutive patients undergoing subthalamic DBS (STN-DBS), at baseline and 6-months after surgery. Assessments included the NoMoFa questionnaire, the MDS-sponsored Unified Parkinson's Disease Rating Scale, and the 39-Item Parkinson's Disease Questionnaire. Pre- and post-surgical NoMoFa scores were compared using the Wilcoxon Signed rank-test. Linear regression analysis evaluated: a) the correlation between NoMoFa scores, motor and MC improvement, correcting for age, disease duration, and dopaminergic therapy reduction; b) the correlation between HRQoL and NMF improvement, correcting for age, disease duration, motor and MC improvement., Results: Twenty patients were evaluated. Total NMF score significantly improved (44.6 %, [IQR = 18.3-100]; p = 0.022), particularly in Off condition (52.0 %, [IQR = 25.4-100]; p = 0.009); we observed strong correlation between NMF and MC improvement (Beta = 0.728; p = 0.006), mainly driven by the mitigation of unpredictable Off (Beta = 0.905; p < 0.001). Even after adjusting for potential confounders, the reduction of NMF independently correlated with increased HRQoL (Beta = 0.714; p = 0.010)., Conclusions: STN-DBS demonstrated strong beneficial effect on NMF, resulting in significant improvement of HRQoL. This underlines the importance of recognizing NMF as a significant factor to be considered in the selection of patients eligible for STN-DBS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Parkinson's disease (PD) presents with a progressive decline in manual dexterity, attributed to dysfunction in the basal ganglia-thalamus-cortex loop, influenced by dopaminergic deficits in the striatum. Recent research suggests that the motor cortex may play a pivotal role in mediating the relationship between striatal dopamine depletion and motor function in PD. Understanding this connection is crucial for comprehending the origins of manual dexterity impairments in PD. Therefore, our study aimed to explore how motor cortex activation mediates the association between striatal dopamine depletion and manual dexterity in PD., Materials and Methods: We enrolled 26 mildly affected PD patients in their off-medication phase to undergo [ 18 F]FDOPA PET/CT scans for evaluating striatal dopaminergic function. EEG recordings were conducted during bimanual anti-phase finger tapping tasks to evaluate motor cortex activity, specifically focusing on Event-Related Desynchronization in the beta band. Manual dexterity was assessed using the Purdue Pegboard Test. Regression-based mediation analysis was conducted to examine whether motor cortex activation mediates the association between striatal dopamine depletion and manual dexterity in PD., Results: Mediation analysis revealed a significant direct effect of putamen dopamine depletion on manual dexterity for the affected hand and assembly tasks (performed with two hands), with motor cortex activity mediating this association. In contrast, while caudate nucleus dopamine depletion showed a significant direct effect on manual dexterity, motor cortex mediation on this association was not observed., Conclusion: Our study confirms the association between striatum dopamine depletion and impaired manual dexterity in PD, with motor cortex activity mediating this relationship., Competing Interests: Declaration of competing interest The author declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To evaluate non-motor symptoms (NMS) occurring during ON pharmacological state and validate a new questionnaire, the Non-motor symptoms-ON scale (NoMoS-ON), exploring ON NMS in Parkinson's disease (PD)., Material and Methods: Patients with PD were evaluated by a new questionnaire, the NoMoS-ON scale, evaluating 17 items related to the main symptoms experienced during the ON state. PD patients who experienced at least one symptom in ON were defined ON-NMS+. Internal consistency and test-retest reliability of NoMoS-ON scale were also assessed., Results: One-hundred and thirty-seven PD patients were consecutively enrolled (79 men and 58 women, age 69.4 ± 9.5 years (mean ± SD)). Seventy-seven patients were ON-NMS+ (56.6 %). PD patients with short disease duration (<7 years) showed the presence of unpleasant NMS: "sleepiness", "light-headedness", "nausea/vomiting". PD patients with longer disease duration experienced pleasant non-motor features including "feel lot of energy", "feel physical well-being". ON-NMS+ were also associated with female gender (OR 2.81, 95%CI 1.37-5.77, p-value 0.005) and with motor fluctuations (OR 2.41, 95%CI 1.20-4.83, p-value 0.013). Cronbach's alpha was 0.61 and 5 items had adequate item-to-total correlations (r ≥ 0.40). Test-retest reliability was acceptable (intraclass correlation coefficient, ICC = 0.77)., Conclusions: The NoMoS-ON scale is a valid, reproducible and reliable questionnaire capturing the ON NMS in PD. PD patients with disease duration shorter than 7 years showed the presence of unpleasant NMS whereas those with longer disease duration experienced pleasant non-motor features. This could help the physician in the therapy management of PD patients in different phases of their disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To investigate interocular asymmetry (IA) of retinal structure and vessel density in patients with Parkinson's disease (PD) and normal controls (NC)., Methods: Seventy-eight subjects including 40 PD patients and 38 NC had completed optical coherence tomography angiography (OCTA) and neurological examinations for three rating scales (UPDRS-III, MMSE and MoCA). The IA was calculated by the absolute value of difference in right and left eyes. The IA of thickness in macular ganglion cell inner-plexiform layer (GCIPL), peripapillary retinal nerve fiber layer (pRNFL), and vessel density of superficial capillary plexus (SCP), deep capillary plexus (DCP), radial peripapillary capillary (RPC) were obtained from OCTA., Results: The motor-symptom-onset side of eyes showed lower vessel density in parafovea of SCP (51.09 ± 3.46 vs 49.81 ± 4.16, P = 0.03) and superior hemi of perifovea DCP (49.55 ± 5.81 vs 47.33 ± 5.71, = 0.04). The PD patients showed larger IA in thickness of superior half of pRNFL (5.27 [2.67, 10.87] vs 3.08 [1.62, 5.61], P = 0.02) and parafovea GCIPL (2.40[1.25, 6.35] vs 1.40[0.50, 2.45], P = 0.02). No significant interocular asymmetry was found in vessel density between PD and NC. A higher UPDRS-III scale was associated with larger IA in GCIPL (β = 0.093, P = 0.001) and smaller IA in DCP (β = -0.065, P = 0.037)., Conclusion: The motor-symptom-onset side of eyes showed more severe loss of macular vessel density than the other side of eyes. The PD patients showed asymmetrical structural change in GCIPL and pRNFL, which showed the potential as the diagnostic biomarker for PD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Declines in instrumental activities of daily living (IADLs) have been proposed as a prodromal marker of Parkinson's disease (PD). The Cleveland Clinic Virtual Reality Shopping (CC-VRS) platform combines an omnidirectional treadmill with a virtual reality headset to create a virtual grocery store that a user physically walks through and completes a shopping task. The primary aim of this project was to determine the known-group validity of the CC-VRS platform in discriminating IADL performance and to characterize specific motor and cognitive declines responsible for PD-related IADL impairments., Methods: Sixteen individuals with PD and 15 healthy adults completed traditional motor, cognitive, and IADL assessments and the CC-VRS task. Group differences were evaluated using Welch's t-test., Results: There were no between-group differences in traditional performance measures of motor, cognitive, or IADL function. Regarding CC-VRS performance, participants in the PD group completed the task significantly slower than controls (690 vs. 523 sec, respectively). Participants with PD spent 25 % more time walking and turning and were stopped 46 % longer than controls. Average gait speed when viewing the shopping list, a measure of dual-task performance, was significantly slower in the PD group compared to controls (0.26 vs. 0.17 m/s, respectively)., Conclusion: Unlike traditional performance measures of motor, cognitive, and IADL function, the CC-VRS discriminated participants with PD from healthy older adults. For the PD group, motor and dual-task declines contributed to diminished CC-VRS performance. Identifying underlying contributors to IADL declines supports using ecological assessments, such as the CC-VRS, for the routine clinical evaluation of IADLs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Jay L. Alberts and Anson B. Rosenfeldt have authored intellectual property related to the CC-VRS platform., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: We recently identified three distinct Parkinson's disease subtypes: "motor only" (predominant motor deficits with intact cognition and psychiatric function); "psychiatric & motor" (prominent psychiatric symptoms and moderate motor deficits); "cognitive & motor" (cognitive and motor deficits)., Objective: We used an independent cohort to replicate and assess reliability of these Parkinson's disease subtypes., Methods: We tested our original subtype classification with an independent cohort (N = 100) of Parkinson's disease participants without dementia and the same comprehensive evaluations assessing motor, cognitive, and psychiatric function. Next, we combined the original (N = 162) and replication (N = 100) datasets to test the classification model with the full combined dataset (N = 262). We also generated 10 random split-half samples of the combined dataset to establish the reliability of the subtype classifications. Latent class analyses were applied to the replication, combined, and split-half samples to determine subtype classification., Results: First, LCA supported the three-class solution - Motor Only, Psychiatric & Motor, and Cognitive & Motor- in the replication sample. Next, using the larger, combined sample, LCA again supported the three subtype groups, with the emergence of a potential fourth group defined by more severe motor deficits. Finally, split-half analyses showed that the three-class model also had the best fit in 13/20 (65%) split-half samples; two-class and four-class solutions provided the best model fit in five (25%) and two (10%) split-half replications, respectively., Conclusions: These results support the reproducibility and reliability of the Parkinson's disease behavioral subtypes of motor only, psychiatric & motor, and cognitive & motor groups., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Therese Cash received support from NIH (NS097437, NS075321, NS097799, NS124738, NS118146, AT011015). Christina N. Lessov-Schlaggar received support from NINDS NS097437. Erin R. Foster is funded by the National Institutes of Health (NIA R21AG063974, NIA R01AG065214, NIDDK R01DK126826, R01DK064832), the American Parkinson Disease Association (APDA) (ID# 971,949), and the APDA Advanced Parkinson Disease Research Center at Washington University in St Louis, and the Missouri Chapter of the APDA. Peter S. Myers received support from NINDS NS097437. Joshua J. Jackson received support from NINDS NS097437, NIMH AG061162-01, NIDCD DC017522-02S1. Baijayanta Maiti received funding from NINDS K23 NS125107, National Center for Advancing Translational Sciences of the National Institute of Health KL2 TR002346, American Academy of Neurology and American Brain Foundation Clinical Research Training Fellowship in Parkinson's disease, Parkinson Study Group/Parkinson's Disease Foundation Mentored Clinical Research Award, Missouri Chapter of American Parkinson Disease Association, and the Jo Oertli fund and has received honoraria for reviewing grants as a member of the Parkinson Study Group mentoring committee and from the American Academy of Neurology for authorship. Paul T. Kotzbauer received funding from National Institutes of Health NS110436, NS097799, NS075321, NS110456, AG071754, NS123860, NS097437, and from Biogen and has received previous funding and honoraria from AbbVie. Joel S. Perlmutter has received research funding from National Institutes of Health NS075321, NS103957, NS107281, NS092865, U10NS077384, NS097437, U54NS116025, U19 NS110456, AG050263, AG-64937, NS097799, NS075527, ES029524, NS109487, R61 AT010753, (NCATS, NINDS, NIA), R01NS118146, R01AG065214, Department of Defense (DOD W81XWH-217-1-0393), Michael J FoxFoundation, Barnes-Jewish Hospital Foundation (Elliot Stein Family Fund and Parkinson disease research fund), American Parkinson Disease Association (APDA) Advanced Research Center at Washington University, Missouri Chapter of the APDA, Paula and Rodger Riney Fund, Jo Oertli Fund, Huntington Disease Society of America, Murphy Fund, N. Grant Williams Fund and CHDI. He co-directs the Dystonia Coalition, which received the majority of its support through the NIH (grants NS116025, NS065701 from the National Institutes of Neurological Disorders and Stroke, TR 001456 from the Office of Rare Diseases Research at the National Center for Advancing Translational Sciences). Dr. Perlmutter has provided medical legal consultation to Wood, Cooper and Peterson, LLC and to Simmons and Simmons LLP. He serves as Director of Medical and Scientific Advisory Committee of the Dystonia Medical Research Foundation, Chair of the Scientific Advisory Committee of the Parkinson Study Group, Chair of the Standards Committee of the Huntington Study Group (honoraria for this one), member of the Scientific Advisory Board of the APDA, Chair of the Scientific and Publication Committee for ENROLL-HD (honoraria from this one), and member of the Education Committee of the Huntington Study Group (honoraria from this one). Dr. Perlmutter has received honoraria from CHDI, Huntington Disease Study Group, Parkinson Study Group, Beth Israel Hospital (Harvard group), U Pennsylvania, Stanford U. Boston University. Meghan C. Campbell receives research support from NIH (NS097437, NS075321, NS097799, NS124378, AG063974, AT010753, AT010753-S1), the McDonnell Center for Systems Neuroscience, the Mallinckrodt Institute of Radiology at WUSTL, the Neurimaging Labs Innovation Award and has received honoraria from the Parkinson Foundation., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Identifying biomarkers reflecting cellular dysfunctions in early Parkinson's disease patients (ePD) is needed to develop targeted therapeutic strategies. We aimed to determine if cellular energetic dysfunction related to increased brain sodium concentration would be co-located to microstructural alterations and iron deposition in ePD., Methods: We prospectively included 12 ePD (mean disease duration 20.0 ± 10.2 months) and 13 healthy controls (HC), scanned with a 7 T 1 H and 23 Na MRI. Complementary voxel-based and region-based assessments were performed, the latter utilizing a high-resolution multimodal template we created (combining quantitative T 1 maps (qT1), transverse relaxation rate (R2*), quantitative magnetic susceptibility mapping (QSM) images) from 200 subjects. This template allowed a precise multiparametric assessment of sodium concentration, QSM, R 2 *, qT 1 , mean diffusivity, and fractional anisotropy values. A two-sided p-value<0.05 was considered statistically significant after the Bonferroni correction., Results: Relative to HC, ePD showed significantly higher sodium concentration in left Substantia nigra (SN) pars reticulata (46.13 mM ± 3.52 vs 38.60 mM ± 6.10, p = 0.038), a subpart of the SN pars compacta (SNc) and ventral tegmental area, Putamen, Globus Pallidum external, accumbens nucleus and claustrum. Significantly increased QSM and R2* values, and decreased T 1 values, were limited to the Nigrosomes 1 (Nig) and right SNc (all p < 0.05). QSM values in the Nig were significantly correlated to UPDRS-III scores (r = 0.91,p < 0.001)., Conclusion: In ePD, brain sodium accumulation was broad and dissociated from iron accumulation. As with iron accumulation, a sodium-related pathophysiological approach could lead to identifying potential new therapeutic agents and deserves further investigation., Competing Interests: Declaration of competing interest No COI., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Parkinson's disease (PD) presents with decreased heart rate variability (HRV) from its early stages. However, most of its evidence originates from HRV measurements in parasympathetic dominant states. In this study, we aimed to examine whether HRV in sympathetic dominant states during the head-up tilt table test (HUT) serves as a marker of autonomic dysfunction in PD and isolated REM sleep behavior disorder (iRBD)., Methods: We retrospectively assessed 102 patients with PD, 10 patients with iRBD, and 43 healthy controls. We then measured the coefficient of variation of RR intervals as an HRV parameter in sympathetic dominant states (CVRR-S) and parasympathetic dominant states (CVRR-P). Furthermore, we evaluated parameters of cardiac autonomic function, including HUT and the heart-to-mediastinum (H/M) ratio of cardiac metaiodobenzylguanidine scintigraphy., Results: Patients with iRBD and PD at Hoehn and Yahr stage I exhibited a significantly decreased CVRR-S compared to healthy controls (controls vs. iRBD vs. PD; 1.82 ± 0.64 % vs. 1.13 ± 0.41 % vs. 1.15 ± 0.51 %, p < 0.001), although no further deterioration was observed in PD at more severe Hoehn and Yahr stages. CVRR-S showed a significant correlation with the H/M ratio in PD (r = 0.51, p < 0.001). Additionally, receiver operating characteristic (ROC) analysis revealed a larger area under the ROC curve in CVRR-S compared to that in CVRR-P for discriminating PD or iRBD from healthy controls., Conclusion: HRV in sympathetic dominant states shows the potential to be a marker of autonomic dysfunction in iRBD and early-stage PD, aiding in early diagnosis and patient stratification., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Screening for orthostatic hypotension (OH) is integral in Parkinson's disease (PD) management, yet evidence-based guidelines on best practice methods for diagnosing OH in PD are lacking., Methods: We investigated the frequency and correlates of OH, symptomatic OH, and neurogenic OH, in a large consecutively recruited PD cohort (n = 318), and compared the diagnostic performance of the sit-to-stand vs. the supine-to-stand blood pressure (BP) test. We evaluated the utility of continuous BP monitoring and tilt table testing in patients with postural symptoms or falls who were undetected to have OH with clinic-based BP measurements. Disease severity, fluid intake, orthostatic and overactive bladder symptoms, falls, comorbidities and medication history were evaluated., Results: Patients' mean age was 66.1 ± 9.5years, with mean disease duration 7.8 ± 5.5years. OH frequency was 35.8 % based on the supine-to-stand test. OH in PD was significantly associated with older age, lower body mass index, longer disease duration, worse motor, cognitive and overactive bladder symptoms and functional disabilities, falls, and lower fluid intake. A similar profile was seen with asymptomatic OH. Three quarters of OH were neurogenic, with the majority also having supine hypertension. The sit-to-stand test had a sensitivity of only 0.39. One quarter of patients were additionally diagnosed with OH during continuous BP monitoring., Conclusions: The sit-to-stand test substantially underdiagnoses OH in PD, with the important practice implication that supine-to-stand measurements may be preferred. Screening for OH is warranted even in asymptomatic patients. Adequate fluid intake, treatment of urinary dysfunction and falls prevention are important strategies in managing PD patients with OH., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

There is no consensus driven definition of "advanced" Parkinson's disease (APD) currently. APD has been described in terms of emergence of specific clinical features and clinical milestones of the disease e.g., motor fluctuations, time to increasing falls, emergence of cognitive decline, etc. The pathological burden of disease has been used to characterize various stages of the disease. Imaging markers have been associated with various motor and nonmotor symptoms of advancing disease. In this review, we present an overview of clinical, pathologic, and imaging markers of APD. We also propose a model of disease definition involving longitudinal assessments of these markers as well as quality of life metrics to better understand and predict disease progression in those with Parkinson's disease., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sana Aslam reports a relationship with Davis Phinney Foundation that includes: funding grants. Sana Aslam reports a relationship with Barrow Neurological Foundation that includes: funding grants. Ashley Stokes reports a relationship with Eli Lilly and Company that includes: consulting or advisory. Fredric Manfredsson reports a relationship with nVector that includes: equity or stocks. Fredric Manfredsson reports a relationship with CavGene Therapeutics that includes: equity or stocks. Fredric Manfredsson reports a relationship with Neuralina Therapeutics that includes: equity or stocks. Fredric Manfredsson reports a relationship with REGENXBIO Inc that includes: funding grants. Fredric Manfredsson reports a relationship with Aspen Neuroscience that includes: funding grants. Fredric Manfredsson reports a relationship with Seelos Therapeutics that includes: funding grants. Holly Shill reports a relationship with Transposon Therapeutics Inc that includes: funding grants. Holly Shill reports a relationship with Parkinson Study Group that includes: funding grants. Holly Shill reports a relationship with Parkinson's Foundation that includes: funding grants. Holly Shill reports a relationship with National Institute of Neurological Disorders and Stroke that includes: funding grants. Holly Shill reports a relationship with Supernus Pharmaceuticals Inc that includes: funding grants. Holly Shill reports a relationship with The Michael J Fox Foundation that includes: funding grants. Holly Shill reports a relationship with Cavion that includes: funding grants. Holly Shill reports a relationship with Barrow Neurological Foundation that includes: funding grants. Holly Shill reports a relationship with Cerevel Therapeutics Inc that includes: funding grants. Holly Shill reports a relationship with Parkinson Study Group Nq that includes: consulting or advisory. Holly Shill reports a relationship with Biogen that includes: consulting or advisory. Holly Shill reports a relationship with AbbVie Inc that includes: consulting or advisory. Holly Shill reports a relationship with SAGE Therapeutics Inc that includes: consulting or advisory. Holly Shill reports a relationship with Praxis Precision Medicines Inc that includes: consulting or advisory. Holly Shill reports a relationship with KeifeRx that includes: consulting or advisory. Fredric Manfredsson has patent issued to Fredric Manfredsson. Ad-hoc reviewer for PRD. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Although locus coeruleus (LC) has been demonstrated to play a critical role in the cognitive function of Parkinson's disease (PD), the underlying mechanism has not been elucidated. The objective was to investigate the relationship among LC degeneration, cognitive performance, and the glymphatic function in PD., Methods: In this retrospective study, 71 PD subjects (21 with normal cognition; 29 with cognitive impairment (PD-MCI); 21 with dementia (PDD)) and 26 healthy controls were included. All participants underwent neuromelanin-sensitive magnetic resonance imaging (NM-MRI) and diffusion tensor image scanning on a 3.0 T scanner. The brain glymphatic function was measured using diffusion along the perivascular space (ALPS) index, while LC degeneration was estimated using the NM contrast-to-noise ratio of LC (CNR LC )., Results: The ALPS index was significantly lower in both the whole PD group (P = 0.04) and the PDD subgroup (P = 0.02) when compared to the controls. Similarly, the CNR LC was lower in the whole PD group (P < 0.001) compared to the controls. In the PD group, a positive correlation was found between the ALPS index and both the Montreal Cognitive Assessment (MoCA) score (r = 0.36; P = 0.002) and CNR LC (r = 0.26; P = 0.03). Mediation analysis demonstrated that the ALPS index acted as a significant mediator between CNR LC and the MoCA score in PD subjects., Conclusion: The ALPS index, a neuroimaging marker of glymphatic function, serves as a mediator between LC degeneration and cognitive function in PD., Competing Interests: Declarations of competing interest All authors of this manuscript declare no conflicts of interest. Peng Wu reports a relationship with Philips Healthcare that includes: employment., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: In BIPARK-1 and BIPARK-2, addition of once-daily opicapone to levodopa/carbidopa significantly reduced daily "OFF"-time relative to placebo in adults with Parkinson's disease (PD) and motor fluctuations. Diary data from these studies were pooled and analyzed post hoc to characterize "OFF"-times around nighttime sleep and to explore the effects of opicapone 50 mg., Methods: "OFF" before sleep (OBS), "OFF during the nighttime sleep period" (ODNSP), early morning "OFF" (EMO), and duration of nighttime sleep and awake periods were analyzed descriptively at baseline. Mean changes from baseline to Week 14/15 (end of double-blind treatment) were analyzed using two-sided t-tests in participants with data for both visits., Results: At baseline, 88.3 % (454/514) of participants reported having OBS (34.0 %), ODNSP (17.1 %), or EMO (79.6 %). Those with ODNSP had substantially shorter mean duration of uninterrupted sleep (4.4 h) than the overall pooled population (7.1 h). At Week 14/15, mean decrease from baseline in ODNSP duration was significantly greater with opicapone than with placebo (-0.9 vs. -0.4 h, P < 0.05). In participants with ODNSP at baseline, the decrease in total time spent awake during the night-time sleep period was significantly greater with opicapone than with placebo (-1.0 vs. -0.4 h, P < 0.05), as was the reduction in percent time spent awake during the night-time sleep period (-12.8 % vs. -4.5 %, P < 0.05)., Conclusion: "OFF"-times around nighttime sleep were common in BIPARK-1 and BIPARK-2. Opicapone may improve sleep by decreasing the amount of time spent awake during the night in patients with PD who have night-time sleep period "OFF" episodes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: R. A. Hauser has received speaking fees from Acorda, Amneal Pharmaceuticals, Cerevel, Inhibikase, Kyowa Kirin, Neurocrine Biosciences Ltd., Sunovion and Supernus; has received consulting fees from AbbVie Ltd., Acsel Health, Amneal Pharmaceuticals, Avanex Ltd., Biogen Ltd., BlueRock Therapeutics, EPI-Q, Forsee Pharmaceuticals, Global Kinetics, Inhibikase, Jazz Pharmaceuticals Ltd., KeifeRX, Krog and Partners, Kyowa Kirin, Magnolia Innovation, MDCE Suzhou, MedRhythms, Medsphere Ltd., Merz Ltd., Neurocrine Ltd., Neuroderm, Ovid Therapeutics, PD Neurotechnology Ltd., Pharma Two B, Regenxbio, Revance Ltd., Sage Therapeutics Ltd., Scion NeuroStim, Stoparkinson, Sunovion, Supernus Pharmaceuticals, Tolmar, Tremor Research Group, Tris Pharma Ltd., UCB, and Vivifi Biotech Ltd. R. A. Hauser serves on a scientific advisory board for Stoparkinson and Inhibikase. R. A. Hauser holds stock in Revance Therapeutics Ltd. and has stock options in Enterin, Inhibikase, and Axial Therapeutics. R. A. Hauser has received intellectual property interests from a PD Diary through his University. R. A. Hauser acknowledges a Center of Excellence grant from the Parkinson Foundation. R. A. Hauser's University has received research support from Annovis Bio Inc., Artizan Biosciences, Parkinson's & Movement Disorder Alliance, Inhibikase Therapeutics, AbbVie Inc., Aeon Biopharma, Biogen MA, Bukwang Pharmaceutical Co. Ltd., Cavion Inc., Cerevance Inc., Cerevel Therapeutics, Cynapsus Therapeutics, Enterin Inc., Genentech, Global Kinetics Corporation, Hoffman-La Roche Inc., Impax Laboratories, Integrative Research Laboratories Sweden, Lundbeck Inc., Michael J. Fox Foundation for Parkinson's Research, National Parkinson's Foundation, Neuraly Inc., Neurocrine Biosciences, Neuroderm, Pharma Two B Ltd., Revance Therapeutics, Sage Therapeutics, Sanofi Pharmaceuticals, Scion NeuroStim, SunPharma, and UCB BioPharma. A. Videnovic has served as a consultant to Alexion Pharmaceuticals. P. Soares-da-Silva and J. F. Francisco Rocha are employees of BIAL–Portela & C(a) SA. G. Liang, K. Olson, E. Jen, and O. Klepitskaya are employees of Neurocrine Biosciences., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Individuals with Parkinson's Disease (IwPD) often fail to adjust their voice in different situations, without awareness of this limitation. Clinicians use self-report questionnaires that are typically designed for individuals with General Voice Disorders (GVD) in the vocal assessment of IwPD. However, these instruments may not consider that IwPD have a reduced self-perception of their vocal deficits. This study aimed to compare self-reported vocal symptoms and voice loudness between IwPD and GVD., Methods: 28 IwPD and 26 with GVD completed the Voice Symptom Scale (VoiSS) questionnaire to evaluate their voice self-perception. Vocal loudness (dB) was also assessed. Univariate and multivariate analyses were used to compare the outcomes from these measures between the two groups. Principal Component Analysis and Hierarchical Clustering Analysis were applied to explore data patterns related to voice symptoms., Results: IwPD reported significantly fewer vocal symptoms than those with GVD in all VoiSS questionnaire domains. Multivariate principal component analysis found no significant correlations between VoiSS scores and participant similarities in voice measures. Despite experiencing hypophonia, IwPD scored lower in all VoiSS domains but still fell in the healthy voice range. Hierarchical Clustering Analysis grouped participants into three distinct categories, primarily based on age, vocal loudness, and VoiSS domain scores, distinguishing between PD and GVD individuals., Conclusions: IwPD reported fewer vocal symptoms than GVD. The voice self-assessment seems to be unreliable to assess vocal symptoms in IwPD, at least regarding loudness. New self-report instruments tailored to PD individuals are needed due to their particular voice characteristics., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Gait initiation (GI) includes automatic and voluntary movements. However, research on their impact on the first step in patients with Parkinson's disease (PD) and their relationship to freezing of gait (FOG) is lacking. We examined the effects of automatic movements (anticipatory postural adjustments [APAs]) and voluntary movements (limits of stability [LOS]) on the first step (first-step duration and first-step range of motion), along with their early recognition and prediction of slight FOG., Methods: Twenty-three patients with PD and slight freezing (PD + FOG) and 25 non-freezing patients with PD (PD-FOG) were tested while off medications and compared with 24 healthy controls (HC). All participants completed a 7-m Stand and Walk Test (7 m SAW) and wore inertial sensors to quantify the APAs and first step. LOS was quantified by dynamic posturography in different directions using a pressure platform. We compared differences among all three groups, analysed correlations, and evaluated their predictive value for slight FOG., Results: In PD + FOG, APAs and LOS were worse than those in the PD-FOG and HC groups (p < 0.001), and the first step was worse than that in HC (p < 0.001). APAs were correlated mainly with the first-step duration. APAs and LOS were correlated with the first-step range of motion. APAs have been recognized as independent predictors of FOG, and their combination with LOS enhances predictive sensitivity., Conclusion: APAs and LOS in patients with PD directly affect the first step during GI. In addition, the combination of APAs and LOS helped predict slight FOG., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background and Objectives: With the discovery of the potential role of gait and eye movement disorders in Parkinson's disease (PD) recognition, we intend to investigate the combined diagnostic value of gait and eye movement disorders for PD., Methods: We enrolled some Chinese PD patients and healthy controls and separated them into the training and validation sets based on enrollment time. Performance in five oculomotor paradigms and in one gait paradigm was examined using an infrared eye tracking device and a wearable gait analysis device. We developed and validated a combined model for PD diagnosis via multivariate stepwise logistic regression analysis. Furthermore, subgroup comparisons and multi-model comparison were performed to assess its applicability and advantages., Results: A total of 145 PD patients and 80 healthy controls in China were recruited. The pro-saccade velocity, the trunk-sway max, and the turn mean angular velocity were finally screened out for the model development. Incorporating age factor, the ternary model demonstrated more satisfactory performance on ROC (AUC of 0.953 in the training set and AUC of 0.972 in the validation set), calibration curve, and decision curve. A nomogram was drawn to visualize the model. The combined model outperforms individual models with a broad application and the unique diagnostic value for early detection of PD patients, especially TD-PD patients., Conclusion: We demonstrated the presence of gait and eye movement disorders, as well as the feasibility, applicability, and superiority of employing them together to diagnose PD., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Neurodegenerative diseases share retinal abnormalities. Chromatic pupillometry allows in vivo assessment of photoreceptor functional integrity, including melanopsin-expressing retinal ganglion cells. This exploratory meta-analysis assesses retinal photoreceptor functionality in Alzheimer's vs. Parkinson's disease and conducts an in-depth review of applied pupillometric protocols., Methods: Literature reviews on PubMed and Scopus from 1991 to August 2023 identified chromatic pupillometry studies on Alzheimer's disease (AD; n = 42 patients from 2 studies) and Parkinson's disease (PD; n = 66 from 3 studies). Additionally, a pre-AD study (n = 10) and an isolated REM Sleep Behavior Disorder study (iRBD; n = 10) were found, but their results were not included in the meta-analysis statistics., Results: Melanopsin-mediated post-illumination pupil response to blue light was not significantly impaired in Alzheimer's (weighted mean difference = -1.54, 95% CI: 4.57 to 1.49, z = -1.00, p = 0.319) but was in Parkinson's (weighted mean difference = -9.14, 95% CI: 14.19 to -4.08, z = -3.54, p < 0.001). Other pupil light reflex metrics showed no significant differences compared to controls. Studies adhered to international standards of pupillometry with moderate to low bias. All studies used full-field stimulation. Alzheimer's studies used direct while Parkinson's studies used consensual measurement. Notably, studies did not control for circadian timing and Parkinson's patients were on dopaminergic treatment., Conclusion and Relevance: Results affirm chromatic pupillometry as a useful method to assess melanopsin-related retinal cell dysfunction in Parkinson's but not in Alzheimer's disease. While adhering to international standards, future studies may analyze the effects of local field stimulation, dopaminergic treatment, and longitudinal design to elucidate melanopsin dysfunction in Parkinson's disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The progressive nature of Parkinson's disease (PD) affords emphasis on accurate early-stage individual-level assessment of risk and intervention appropriateness. In PD, cognitive impairment (CI) may follow or precede motor symptoms but are generally underdetected. In addition to impeding daily functioning and quality of life, CIs increase the risk for later conversion to dementia, providing a pressing need to develop novel tools to detect and interpret them. Connectome-based predictive modelling (CPM) is an emerging machine-learning approach to individual prediction that holds translational promise due to its noninvasiveness and simple implementation. The aim of this study was to investigate CPM's potential to predict and understand CIs in PD., Methods: Resting-state functional connectivity from 58 patients with PD of varying cognitive status was used to train a CPM-model to predict a global cognitive composite (GCC) score. The model was validated using cross-validation, permutation testing, and internal stability analyses. The combined predictive strength of two brain connectivity networks, positive and negative, directly and inversely correlated with GCC, respectively, was assessed., Results: The model significantly predicted individual GCC scores, r = 0.63, p perm < .05. Separately, the positive and negative networks were similar in performance, rs ≥ .58, ps < .05, but varied in anatomical distribution., Conclusions: This study identified a connectome predictive of cognitive scores in PD, with features overlapping with established and emerging evidence on aberrant connectivity in PD-related CIs. Overall, CPM appears promising for clinical translation in this population, but longitudinal studies with out-of-sample validation are needed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Rest tremor is a movement disorder commonly found in diseases like Parkinson's disease (PD) and essential tremor (ET). Rest tremor typically shows slower progression in PD, but more severe progression in ET. However, the underlying white matter organization of rest tremor behind PD and ET remains unclear., Methods: This study included 57 ET patients (40 without rest tremor (ETWR), 17 with rest tremor (ETRT)), 68 PD patients (34 without rest tremor (PDWR), 34 with rest tremor (PDRT)), and 62 normal controls (NC). Fixel-based analysis was used to evaluate the structural changes of white matter in rest tremor in these different diseases., Results: The fiber-bundle cross-section (FC) of the right non-decussating dentato-rubro-thalamic tract and several fibers outside the dentato-rubro-thalamic pathway in ETWR were significantly higher than that in NC. The fiber density and cross-section of the left nigro-pallidal in PDWR is significantly lower than that in NC, while the FC of bilateral nigro-pallidal in PDRT is significantly lower than that in NC., Conclusion: ET patients with pure action tremor showed over-activation of fiber tracts. However, when superimposed with rest tremor, ET patients no longer exhibited over-activation of fiber tracts, but rather showed a trend of fiber tract damage. Except for the nigro-pallidal degeneration in all PD, PDRT will not experience further deterioration in fiber organization. These results provide important insights into the unique effects of rest tremor on brain fiber architecture in ET and PD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Olfactory dysfunction and REM sleep behavior disorder (RBD) are associated with distinct cognitive trajectories in the course of Parkinson's disease (PD). The underlying neurobiology for this relationship remains unclear but may involve distinct patterns of neurodegeneration. This study aimed to examine longitudinal cortical atrophy and thinning in early-stage PD with severe olfactory deficit (anosmia) without and with concurrent probable RBD., Methods: Longitudinal MRI data over four years of 134 de novo PD and 49 healthy controls (HC) from the Parkinson Progression Marker Initiative (PPMI) cohort were analyzed using a linear mixed-effects model. Patients were categorized into those with anosmia by the University of Pennsylvania Smell Identification Test (UPSIT) score ≤ 18 (AO+) and those without (UPSIT score > 18, AO-). The AO+ group was further subdivided into AO+ with probable RBD (AO+RBD+) and without (AO+RBD-) for subanalysis., Results: Compared to subjects without baseline anosmia, the AO+ group exhibited greater longitudinal declines in both volume and thickness in the bilateral parahippocampal gyri and right transverse temporal gyrus. Patients with concurrent anosmia and RBD showed more extensive longitudinal declines in cortical volume and thickness, involving additional brain regions including the bilateral precuneus, left inferior temporal gyrus, right paracentral gyrus, and right precentral gyrus., Conclusions: The atrophy/thinning patterns in early-stage PD with severe olfactory dysfunction include regions that are critical for cognitive function and could provide a structural basis for previously reported associations between severe olfactory deficit and cognitive decline in PD. Concurrent RBD might enhance the dynamics of cortical changes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We recently proposed a new disease model of Parkinson's disease - the a-Synuclein Origin site and Connectome model. The model posits that the initial pathology starts either in the olfactory bulb or amygdala leading to a brain-first subtype, or in the enteric nervous system leading to a body-first subtype. These subtypes should be distinguishable early in the disease course on a range of imaging, clinical, and neuropathological markers. Here, we review recent original human studies, which tested the predictions of the model. Molecular imaging studies were generally in agreement with the model, whereas structural imaging studies, such as MRI volumetry, showed conflicting findings. Most large-scale clinical studies were supportive, reporting clustering of relevant markers of the body-first subtype, including REM-sleep behavior disorder, constipation, autonomic dysfunction, neuropsychiatric symptoms, and cognitive impairment. Finally, studies of a-synuclein deposition in antemortem and postmortem tissues revealed distribution of pathology, which generally supports the model., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Per Borghammer reports financial support was provided by Lundbeck Foundation. Jacob Horsager reports financial support was provided by Lundbeck Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Parkinson's disease (PD) can be divided into motor subtypes: postural instability/gait difficulty (PIGD), tremor dominant, and indeterminate. This study aimed to assess differences in sleep structure and obstructive sleep apnea (OSA) between the PIGD and non-PIGD subtypes., Methods: PD participants with or without OSA (defined as apnea-hypopnea index (AHI) ≥ 15 events/hour on overnight polysomnography) were included. Patients were separated into two groups: PIGD and non-PIGD. Linear regression was used to explore differences in sleep, AHI, and other respiratory parameters between groups (adjusted for variables determined a priori). Logistic regression adjusted for the same variables was used to determine if the proportion of patients with OSA differed across groups. Subset analyses were performed: subset 1 excluding patients on psychoactive medication; subset 2 excluding patients taking levodopa or dopaminergic agonists (DAs) at nighttime and subset 3 excluding patients on either of the abovementioned drugs., Results: 146 participants were studied. The non-PIGD group had less N3 sleep compared to the PIGD group (12.4% vs 16.9% p = 0.06), reaching significance in subsets 1 and 3. The AHI was significantly lower in the PIGD group (p = 0.047), including when medication effects were removed (p < 0.05). OSA was more frequent in the non-PIGD group, but only significantly in subset 3 (adjusted OR 0.3, p = 0.04)., Conclusion: OSA may be more severe in non-PIGD subtypes, and more frequent, in a subset free of psychoactive medication, and of levodopa and DAs, possibly owing to motor complications and dyskinesia. Future studies are required to confirm this., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AS: none. AB: none. RJK: holds/has recently held research operating funds from Canadian Institutes of Health Research, Fonds de Recherche du Québec – Santé, Bresotec Inc, Signifier Medical Inc and Philips-Respironics. He has received consulting fees from Esai, Powell-Mansfield, and Bresotec Inc. ALL: Advisory board honoraria: Abbvie, Sunovion, Paladin Labs, Merz; Speaker honoraria: Sunovion, Paladin Labs, Abbvie. AR: none. MG: none. MK: Board Member for Biron Soins du sommeil; Research support from Philips for investigator-initiated study., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus (GP) is an established therapy for Parkinson's disease (PD). Novel DBS devices can record local field potential (LFP) physiomarkers from the STN or GP. While beta (13-30 Hz) and gamma (40-90 Hz) STN and GP LFP oscillations correlate with PD motor severity and with therapeutic effects of treatments, STN-GP interactions in electrophysiology in patients with PD are not well characterized., Methods: Simultaneous bilateral STN and GP LFPs were recorded in a patient with PD who received bilateral STN-DBS and GP-DBS. Power spectra in each target and STN-GP coherence were assessed in various ON- and OFF-levodopa and DBS states, both at rest and with voluntary movement., Results: OFF-levodopa and OFF-DBS, beta peaks were present at bilateral STN and GP, coincident with prominent STN-GP beta coherence. Levodopa and dual-target-DBS (simultaneous STN-DBS and GP-DBS) completely suppressed STN-GP coherence. Finely-tuned gamma (FTG) activity at half the stimulation frequency (62.5 Hz) was seen in the STN during GP-DBS at rest. To assess the effects of movement on FTG activity, we recorded LFPs during instructed movement. We observed FTG activity in bilateral GP and bilateral STN during contralateral body movements while on GP-DBS and ON-levodopa. No FTG was seen with STN-DBS or dual-target-DBS., Conclusion: Dual-target-DBS and levodopa suppressed STN-GP coherence. FTG throughout the basal ganglia was induced by GP-DBS in the presence of levodopa and movement. This bilateral STN-FTG and GP-FTG corresponded with the least severe bradykinesia state, suggesting a pro-kinetic role for FTG., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The relationship between mobility and cognition has been studied in the aging population and associations have been also reported in people with Parkinson's disease (PD)., Objective: To compare different aspects of gait and balance between individuals with PD who have normal cognition and those with impaired cognition, using both clinical and instrumented measures., Methods: One-hundred forty-three participants with PD were divided into two groups: 1) normal cognition (n = 71) and 2) impaired cognition (n = 72) based on the Montreal Cognitive Assessment (MoCA) cut-off. Groups were compared using instrumented and clinical measures of gait and balance in the following domains: Sensory Orientation, Anticipatory Postural Adjustments, Automatic Postural Responses and Dynamic Balance for Gait. Instrumented measures were obtained via wearable sensors while performing eight different motor tasks and clinical measures were obtained with the Mini-BESTest., Results: The total Mini-BESTest score was not different between groups. However, the Dynamic Gait domain was worse in individuals with impaired cognition. Among the instrumented measures across domains, all significant group differences were in the Dynamic Gait domain, specifically, dual-task gait speed, dual-task stride length, stance time, and turn velocity., Conclusions: Dynamic balance during gait was more impaired in people with PD who had abnormal cognition than those with normal cognition, for both clinical and instrumented measures. All other balance domains did not differ between groups, for both instrumented and clinical measures., Competing Interests: Declaration of competing interest Natália Mariano Barboza: none. Martina Mancini: none. Suhaila Mahmoud Smaili: none. Fay B. Horak: is employed part-time by APDM, who makes the inertial sensors used to instrument balance and gait in this study. This potential conflict has been reviewed and managed by OHSU. Patricia Carlson-Kuhta: none. Rosie Morris: none. Laurie A. King: none., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Management of PD has largely been affected by COVID-19. Due to the restrictions posed by COVID-19, there has been a shift from in-person to online forms of assessment. This presents a challenge as not all motor symptoms can be assessed virtually. Two of the four cardinal symptoms of PD (rigidity and postural instability) cannot be assessed virtually using the gold-standard Unified Parkinson's Disease Rating Scale (UPDRS-III). As a result, an accurate total motor severity score can not be computed from the remaining subsections. Recently, one study stated that in order for accurate scores to be calculated, only three sections could be absent. Virtually, six sections are unable to be evaluated with online assessments. This inability to compute a total motor severity score may result in poor disease management. Thus, in this study a regression equation was developed to predict total motor severity scores from partial scores., Methods: Total motor severity scores (UPDRS-III) from N = 234 individuals with idiopathic Parkinson's were retrospectively analyzed. In order to conduct a linear regression analysis predictor and outcome variables were created. The variables were then used for the linear regression. The equation was then tested on an independent data set N = 1168., Results: The regression analysis resulted in the equation to predict total motor symptom severity of PD., Conclusions: In conclusion, the developed equation will be very useful for outreach in rural communities, as well as the continued remote management of PD during COVID-19 and beyond., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: The impact of deep brain stimulation (DBS) on speech rhythm and its mechanism remains unclear. We investigated speech rhythm characteristics of patients with Parkinson's disease (PD) treated with subthalamic nucleus (STN) DBS to understand the underlying pathophysiology better., Methods: We enrolled a total of 105 participants and evaluated speech rhythm performances among patients with PD who had undergone STN-DBS (the PD-DBS group), patients with PD treated only with medication (the PD-Med group), patients with cerebellar ataxia (the CA group), and healthy controls (the HC group). Each participant was asked to repeat the syllable/pa/at a comfortable self-chosen steady pace. A widely-used software (the Motor Speech Profile) program performed an acoustic analysis., Results: Compared to the PD-Med and HC groups, speech rate instability (DDKjit) was significantly higher in the PD-DBS and CA groups (p < 0.01). However, after DBS was turned off, the DDKjit of the PD-DBS group improved to a level comparable to that of the PD-Med and HC groups. In contrast to the significantly higher variability of speech volume (DDKcvi) in the CA group, the PD-DBS group showed similar DDKcvi to the PD-Med and HC groups., Conclusions: STN-DBS affects the speech rate stability of patients with PD. Speech rhythm disorders caused by STN-DBS were phenotypically similar to that in CA in terms of interval variability but different regarding amplitude variability. Further studies are warranted to elucidate the underlying pathophysiology of speech rhythm disorders in PD patients treated with DBS., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Transcranial direct current stimulation (tDCS) improves postural response to perturbation in patients with Parkinson's disease (PwPD). However, the influence of baseline characteristics such as clinical/cognitive and postural performance on the response to tDCS remains unclear., Objective: To investigate whether baseline level of postural control (performance during sham condition) and clinical/cognitive characteristics are associated with tDCS-related changes in postural responses to external perturbations in PwPD., Methods: Twenty-four PwPD participated in this study. Clinical assessment included disease severity, disease duration, levodopa equivalent dose and global cognition. Anodal tDCS protocols targeting the primary motor cortex were applied in two separate sessions (at least 2 weeks apart): active (2 mA for 20 min) and sham stimulation. Seven trials with the backward translation of the support base (20 cm/s and 5 cm) were performed after tDCS. Postural outcomes included the recovery time to stable position and onset latency of the medial gastrocnemius (MG). Pearson and Spearman correlation tests were performed., Results: No significant correlations were observed between clinical/cognitive characteristics and tDCS-related changes in postural responses. Negative associations were observed between the baseline level of postural control and tDCS-related changes in postural responses for the recovery time (r = -0.657; p < 0.001) and the MG onset latency (rs = -0.539; p = 0.007). PwPD with worse baseline postural control demonstrated greater improvement after active stimulation., Conclusions: Findings suggest that tDCS-related effects on postural response to perturbation are related to the baseline level of postural control, but not to clinical characteristics in PwPD. Those with worse baseline postural control responded better to tDCS., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: While the concept of prodromal Parkinson's disease (PD) is well established, reliable markers for the diagnosis of this disease stage are still lacking. We investigated the functional connectivity of the putamina in a resting-state functional MRI analysis in persons with at least two prodromal factors for PD, which is considered a high risk for PD (HRPD) group, in comparison to PD patients and controls., Methods: We included 16 PD patients, 20 healthy controls and 20 HRPD subjects. Resting state echo planar images and anatomical T1-weighted images were acquired with a Siemens Prisma 3 T scanner. The computation of correlation maps of the left and the right putamen to the rest of the brain was done in a voxel-wise approach using the REST toolbox. Finally, group differences in the correlation maps were compared on voxel-level and summarized in cluster z-statistics., Results: Compared to both PD patients and healthy controls, the HRPD group showed higher functional connectivity of both putamina to brain regions involved in execution of motion and coordination (cerebellum, vermis, pre- and postcentral gyrus, supplementary motor area) as well as the planning of movement (precuneus, cuneus, superior medial frontal lobe)., Conclusions: Higher functional connectivity of the putamina of HRPD subjects to other brain regions involved in motor execution and planning may indicate a compensatory mechanism. Follow-up evaluation and independent longitudinal studies should test whether our results reflect a dynamic process associated with a prodromal PD state., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Chronotropic incompetence (CI) is broadly defined as the inability of the heart to increase its rate commensurate with increased activity. In this study, we tried to clarify the link between CI and UPDRS part II (off-on), which was calculated by subtracting part II (on) from part II (off), in patients with Parkinson's disease (PD)., Methods: Thirty-six hospitalized patients were examined by using cardiopulmonary exercise testing (CPET) for exercise tolerance (ΔVO2/ΔWR and peak VO2/W) and the presence of CI (ΔHR/ΔWR), and using electrocardiogram for heart rate variability., Results: We originally divided the patients into three groups; Group I (ΔHR/ΔWR x100 <15) (N = 3), Group II (15≥, <60) (N = 28), Group III (>60) (N = 5). Since Group I and III were significantly smaller and older than Group II, we focused and divided into two groups; Group II CI (+), the PD patients with CI (15≤ ΔHR/ΔWR x100 <35), and Group II CI (-), those patients without that (35≤ ΔHR/ΔWR x100 <60). ΔVO2/ΔWR and peak VO2/W in CI (+) patients was lower than CI (-) (P = 0.022 and P = 0.096, respectively). HF power (parasympathetic activity) tends to be decreased, whereas LF/HF ratio (sympathetic activity) was increased in CI (+) patients as compared with CI (-). The UPDRS part II (off-on) of CI (+) patients was significantly higher than CI (-) (P = 0.023)., Conclusions: In PD patients, the difference between 'on' and 'off' in activities of daily living might be predicted by using ΔHR/ΔWR x100 obtained from CPET as an index., (Copyright © 2021 Elsevier Ltd. All rights reserved.)