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Parkinson's disease (PD), recognized as the second most prevalent neurodegenerative disease in the aging population, presents a significant challenge due to the current lack of effective treatment methods to mitigate its progression. Many pathogenesis of PD are related to lysosomal dysfunction. Moreover, extensive genetic studies have shown a significant correlation between the lysosomal membrane protein TMEM175 and the risk of developing PD. Building on this discovery, TMEM175 has been identified as a novel potassium ion channel. Intriguingly, further investigations have found that potassium ion channels gradually close and transform into hydrion "excretion" channels in the microenvironment of lysosomes. This finding was further substantiated by studies on TMEM175 knockout mice, which exhibited pronounced motor dysfunction in pole climbing and suspension tests, alongside a notable reduction in dopamine neurons within the substantia nigra compacta. Despite these advancements, the current research landscape is not without its controversies. In light of this, the present review endeavors to methodically examine and consolidate a vast array of recent literature on TMEM175. This comprehensive analysis spans from the foundational research on the structure and function of TMEM175 to expansive population genetics studies and mechanism research utilizing cellular and animal models.A thorough understanding of the structure and function of TMEM175, coupled with insights into the intricate mechanisms underpinning lysosomal dysfunction in PD dopaminergic neurons, is imperative. Such knowledge is crucial for pinpointing precise intervention targets, thereby paving the way for novel therapeutic strategies that could potentially alter the neurodegenerative trajectory of PD., Competing Interests: Declaration of Competing Interest The authors have declared that no competing interests exist, (Copyright © 2024. Published by Elsevier B.V.)

Background: Parkinson's disease (PD) is viewed as a progressively deteriorating neurodegenerative disorder, the exact etiology of which remains not fully deciphered to this date. The gut microbiota could play a crucial role in PD development by modulating the human immune system., Objective: This study aims to explore the relationship between gut microbiota and PD, focusing on how immune characteristics may both directly and indirectly influence their interaction., Methods: Utilizing cumulative data from genome-wide association studies (GWAS), our research conducted a two-sample Mendelian randomization (MR) analysis to clarify the association between the gut microbiome and PD. Additionally, by employing a two-step MR approach, we assessed the impact of gut microbiota on PD development via immune characteristics and quantified HLA-DR mediation effect on plasmacytoid dendritic cells (pDCs)., Results: We discovered significant associations between PD and microbiota, comprising one class, one order, two families, and two genera. Furthermore, we explored the extent to which HLA-DR on pDCs mediates the effect of Butyrivibrio gut microbiota on PD., Conclusion: Our study emphasizes the complex interactions between the gut microbiota, immune characteristics, and PD. The relationships and intermediary roles identified in our research provide important insights for developing potential therapies that target the gut microbiome to alleviate symptoms in PD patients., (© 2024. Fondazione Società Italiana di Neurologia.)

Introduction: Morphological abnormalities of erythrocytes/red blood cells (RBCs), e.g., increased acanthocytes, in Parkinson's disease (PD) have been reported previously, although the underlying mechanisms remain to be characterized. In this study, the potential roles of α-synuclein (α-syn), a protein critically involved in PD and highly abundant in RBCs, were studied in PD patients as well as in a PD mouse model., Methods: Transgenic [PAC-Tg (SNCA A53T ), A53T] mice overexpressing A53T mutant α-syn and SNCA knockout mice were employed to characterize the effect of α-syn on RBC morphology. In addition to A53T and SNCA knockout mice, the morphology of RBCs of PD patients was also examined using scanning electron microscopy. The potential roles of α-syn were further investigated in cultured RBCs and mice., Results: Morphological abnormalities of RBCs and increased accumulation of aggregated α-syn on the RBC membrane were observed in PD patients. A similar phenomenon was also observed in A53T mice. Furthermore, while mice lacking α-syn expression showed a lower proportion of acanthocytes, treating RBCs derived from SNCA knockout mice with aggregated α-syn resulted in a higher percentage of acanthocytes. In a follow-up proteomic investigation, several major classes of proteins were identified as α-syn-associated proteins on the RBC membrane, seven of which were calcium-binding proteins. Applying aggregated α-syn to the RBC membrane directly induced extracellular calcium influx along with morphological changes; both observations were adequately reversed by blocking calcium influx., Conclusions: This study demonstrated that α-syn plays a critical role in PD-associated morphological abnormalities of RBCs, at least partially via a process mediated by extracellular calcium influx., 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. Production and hosting by Elsevier B.V.)

Objective: Evidence of abnormal α-synuclein (α-Syn) deposition in the brain is required for definitive diagnosis of synucleinopathies, which remains challenging. The seed amplification assay (SAA) is an innovative technique that can detect the seeding activity of misfolded α-Syn, enabling the amplification and detection of minute quantities of pathogenic α-Syn aggregates. This study aimed to evaluate oral mucosa α-Syn SAA as possible diagnostic and prodromal biomarkers for synucleinopathies., Methods: A total of 107 Parkinson's disease (PD) patients, 99 multiple system atrophy (MSA) patients, 33 patients with isolated rapid eye movement sleep behavior disorder (iRBD) and 103 healthy controls (HC) were included. The SAA was applied to detect the seeding activity of α-Syn from oral mucosa. A combination of morphological, biochemical, and biophysical methods was also used to analyze the fibrils generated from the oral mucosa α-Syn SAA., Results: Structured illumination microscopy images revealed the increased α-Syn species in oral mucosa of PD, MSA, and iRBD patients than in HCs. Oral mucosa α-Syn SAA distinguished patients with PD from HC with 67.3% sensitivity and 90.3% specificity. Oral mucosa was α-Syn SAA positive in 53.5% MSA patients and 63.6% iRBD patients. Furthermore, the α-Syn fibrils generated from MSA demonstrated greater resistance to proteinase K digestion and exhibited stronger cytotoxicity compared to those from PD patients., Conclusion: Oral mucosa α-Syn seeding activity may serve as novel non-invasive diagnostic and prodromal biomarkers for synucleinopathies. The α-Syn aggregates amplified from the oral mucosa of PD and MSA exhibited distinct biochemical and biophysical properties. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Parkinson's disease is the second most common neurodegenerative disorder, exhibiting an upward trend in prevalence. We aimed to investigate the prevalence of Parkinson's disease, temporal trends between 1980 and 2023, and variations in prevalence by location, age, sex, survey period, sociodemographic index (SDI), human development index (HDI), and study characteristics (sample size, diagnostic criteria, and data source)., Methods: In this systematic review and meta-analysis we searched PubMed, Cochrane, Web of Science, Embase, Scopus, and Global Health for observational studies that reported Parkinson's disease prevalence in the general population from database inception to Nov 1, 2023. We included studies if they were original observational investigations, had participants from the general population or community-based datasets, and provided numerical data on the prevalence of Parkinson's disease either with 95% CIs or with sufficient information to calculate 95% CIs. Studies were excluded if they were conducted in a specific population, had a sample size smaller than 1000, or were review articles, case reports, protocols, meeting abstracts, letters, comments, short communications, posters, and reports. The publication characteristics (first author and publication year), study location (countries, WHO regions, SDI, and HDI), survey period, study design, diagnostic criteria, data source, participant information, and prevalence data were extracted from articles using a standard form. Two authors independently evaluated eligibility, and discrepancies were resolved through discussion with the third author. We used random effect models to pool estimates with 95% CIs. Estimated annual percentage change (EAPC) was calculated to assess the temporal trend in prevalence of Parkinson's disease. The study was registered with PROSPERO, CRD42022364417., Findings: 83 studies from 37 countries were eligible for analysis, with 56 studies providing all-age prevalence, 53 studies reporting age-specific prevalence, and 26 studies providing both all-age and age-specific prevalence. Global pooled prevalence of Parkinson's disease was 1·51 cases per 1000 (95% CI 1·19-1·88), which was higher in males (1·54 cases per 1000 [1·17-1·96]) than in females (1·49 cases per 1000 [1·12-1·92], p=0·030). During different survey periods, the prevalence of Parkinson's disease was 0·90 cases per 1000 (0·48-1·44; 1980-89), 1·38 cases per 1000 (1·17-1·61; 1990-99), 1·18 cases per 1000 (0·77-1·67; 2000-09), and 3·81 cases per 1000 (2·67-5·14; 2010-23). The EAPC of Parkinson's disease prevalence was significantly higher in the period of 2004-23 (EAPC 16·32% [95% CI 6·07-26·58], p=0·0040) than in the period of 1980-2003 (5·30% [0·82-9·79], p=0·022). Statistically significant disparities in prevalence were observed across six WHO regions. Prevalence increased with HDI or SDI. Considerable variations were observed in the pooled prevalence of Parkinson's disease based on different sample sizes or diagnostic criteria. Prevalence also increased with age, reaching 9·34 cases per 1000 (7·26-11·67) among individuals older than 60 years., Interpretation: The global prevalence of Parkinson's disease has been increasing since the 1980s, with a more pronounced rise in the past two decades. The prevalence of Parkinson's disease is higher in countries with higher HDI or SDI. It is necessary to conduct more high-quality epidemiological studies on Parkinson's disease, especially in low SDI countries., Funding: National Nature Science Foundation of China., Translation: For the Chinese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Early and precise diagnosis of α-synucleinopathies is challenging but critical. In this study, we developed a molecular beacon-based assay to evaluate microRNA-containing extracellular vesicles (EVs) in plasma. We recruited 1203 participants including healthy controls (HCs) and patients with isolated REM sleep behavior disorder (iRBD), α-synucleinopathies, or non-α-synucleinopathies from eight centers across China. Plasma miR-44438-containing EV levels were significantly increased in α-synucleinopathies, including those in the prodromal stage (e.g., iRBD), compared to both non-α-synucleinopathy patients and HCs. However, there are no significant differences between Parkinson's disease (PD) and multiple system atrophy. The miR-44438-containing EV levels negatively correlated with age and the Hoehn and Yahr stage of PD patients, suggesting a potential association with disease progression. Furthermore, a longitudinal analysis over 16.3 months demonstrated a significant decline in miR-44438-containing EV levels in patients with PD. These results highlight the potential of plasma miR-44438-containing EV as a biomarker for early detection and progress monitoring of α-synucleinopathies.

Background and Objectives: Cognitive impairments are common in idiopathic REM sleep behavior disorder (iRBD), in which the cholinergic degeneration of nucleus basalis of Meynert (NBM) may play an important role. However, the progressive changes of NBM, the relationship between progressive NBM degeneration and progression of cognitive impairments, and whether degeneration of the NBM can predict cognitive decline in patients with iRBD remain unclear. This study aimed to investigate the cross-sectional and longitudinal microstructural alterations in the NBM of patients with iRBD using free-water imaging and whether free water in the NBM is related to cognitive, mood, and autonomic function., Methods: We compared the baseline free-water values in the NBM between 59 healthy controls (HCs), 57 patients with iRBD, 57 patients with Parkinson disease (PD) with normal cognition (PD-NC), and 64 patients with PD with cognitive impairment (PD-CI). Thirty patients with iRBD and 40 HCs had one longitudinal data. In patients with iRBD, we explored the associations between baseline and longitudinal changes of free-water values in the NBM and clinical characteristics and whether baseline free-water values in the NBM could predict cognitive decline., Results: IRBD, PD-NC, and PD-CI groups had significantly increased free-water values in the NBM compared with HCs, whereas PD-CI had higher free-water values compared with iRBD and PD-NC. In patients with iRBD, free-water values in the NBM were progressively elevated over follow-up and correlated with the progression of cognitive impairment and depression. Free-water values in the NBM could predict cognitive decline in the iRBD group. Furthermore, we found that patients with iRBD with cognitive impairment had higher relative change of free-water value in the NBM compared with patients with iRBD with normal cognition over follow-up., Discussion: This study proves that free-water values in the NBM are elevated cross-sectionally and longitudinally and are associated with the progression of cognitive impairment and depression in patients with iRBD. Moreover, the free-water value in the NBM can predict cognitive decline in patients with iRBD. Whether free-water imaging of the NBM has the potential to be a marker for monitoring progressive cognitive impairment and predicting the conversion to dementia in synucleinopathies needs further investigation.

Aims: Parkinsonian tremor (PT) is regulated by numerous neurophysiological components across multiple temporospatial scales. The dynamics of tremor fluctuation are thus highly complex. This study aimed to explore the effects of different medications on tremor complexity, and how the underlying factors contribute to such tremor complexity., Methods: In this study, 66 participants received a 2-mg dose of benzhexol or a pre-determined dose of levodopa at two study visits in a randomized order. Before and after taking the medications, tremor fluctuation was recorded using surface electromyography electrodes and accelerometers in resting, posture, and weighting conditions with and without a concurrent cognitive task. Tremor complexity was quantified using multiscale entropy., Results: Tremor complexity in resting (p = 0.002) and postural condition (p < 0.0001) was lower when participants were performing a cognitive task compared to a task-free condition. After taking levodopa and benzhexol, participants had increased (p = 0.02-0.03) and decreased (p = 0.03) tremor complexity compared to pre-medication state, respectively. Tremor complexity and its changes as induced by medications were significantly correlated with clinical ratings and their changes (β = -0.23 to -0.39; p = 0.002-0.04), respectively., Conclusion: Tremor complexity may be a promising marker to capture the pathophysiology underlying the development of PT, aiding the characterization of the effects medications have on PT regulation., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Background: Levodopa could induce orthostatic hypotension (OH) in Parkinson's disease (PD) patients. Accurate prediction of acute OH post levodopa (AOHPL) is important for rational drug use in PD patients. Here, we develop and validate a prediction model of AOHPL to facilitate physicians in identifying patients at higher probability of developing AOHPL., Methods: The study involved 497 PD inpatients who underwent a levodopa challenge test (LCT) and the supine-to-standing test (STS) four times during LCT. Patients were divided into two groups based on whether OH occurred during levodopa effectiveness (AOHPL) or not (non-AOHPL). The dataset was randomly split into training (80%) and independent test data (20%). Several models were trained and compared for discrimination between AOHPL and non-AOHPL. Final model was evaluated on independent test data. Shapley additive explanations (SHAP) values were employed to reveal how variables explain specific predictions for given observations in the independent test data., Results: We included 180 PD patients without AOHPL and 194 PD patients with AOHPL to develop and validate predictive models. Random Forest was selected as our final model as its leave-one-out cross validation performance [AUC&#95;ROC 0.776, accuracy 73.6%, sensitivity 71.6%, specificity 75.7%] outperformed other models. The most crucial features in this predictive model were the maximal SBP drop and DBP drop of STS before medication (ΔSBP/ΔDBP). We achieved a prediction accuracy of 72% on independent test data. ΔSBP, ΔDBP, and standing mean artery pressure were the top three variables that contributed most to the predictions across all individual observations in the independent test data., Conclusions: The validated classifier could serve as a valuable tool for clinicians, offering the probability of a patient developing AOHPL at an early stage. This supports clinical decision-making, potentially enhancing the quality of life for PD patients., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Background and Purpose: The ventral pallidum (VP) regulates involuntary movements, but it is unclear whether the VP regulates the abnormal involuntary movements in Parkinson's disease (PD) patients who have levodopa-induced dyskinesia (LID). To further understand the role of the VP in PD patients with LID (PD-LID), we explored the structural and functional characteristics of the VP in such patients using multimodal magnetic resonance imaging (MRI)., Methods: Thirty-one PD-LID patients, 39 PD patients without LID (PD-nLID), and 28 healthy controls (HCs) underwent T1-weighted MRI, quantitative susceptibility mapping, multi-shell diffusion MRI, and resting-state functional MRI (rs-fMRI). Different measures characterizing the VP were obtained using a region-of-interest-based approach., Results: The left VP in the PD-LID group showed significantly higher intracellular volume fraction (ICVF) and isotropic volume fraction (IsoVF) compared with the PD-nLID and HC groups. Rs-MRI revealed that, compared with the PD-nLID group, the PD-LID group in the medication 'off' state had higher functional connectivity (FC) between the left VP and the left anterior caudate, left middle frontal gyrus and left precentral gyrus, as well as between the right VP and the right posterior ventral putamen and right mediodorsal thalamus. In addition, the ICVF values of the left VP, the FC between the left VP and the left anterior caudate and left middle frontal gyrus were positively correlated with Unified Dyskinesia Rating Scale scores., Conclusion: Our multimodal imaging findings show that the microstructural changes of the VP (i.e., the higher ICVF and IsoVF) and the functional change in the ventral striatum-VP-mediodorsal thalamus-cortex network may be associated with pathophysiological mechanisms of PD-LID., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: Alpha-synuclein seed amplification assays (α-syn SAAs) are promising diagnostic methods for Parkinson's disease (PD) and other synucleinopathies. However, there is limited consensus regarding the diagnostic and differential diagnostic performance of α-syn SAAs on biofluids and peripheral tissues., Methods: A comprehensive research was performed in PubMed, Web of Science, Embase and Cochrane Library. Meta-analysis was performed using a random-effects model. A network meta-analysis based on an ANOVA model was conducted to compare the relative accuracy of α-syn SAAs with different specimens., Results: The pooled sensitivity and specificity of α-syn SAAs in distinguishing PD from healthy controls or non-neurodegenerative neurological controls were 0.91 (95% confidence interval [CI] 0.89-0.92) and 0.95 (95% CI 0.94-0.96) for cerebrospinal fluid (CSF); 0.91 (95% CI 0.86-0.94) and 0.92 (95% CI 0.87-0.95) for skin; 0.80 (95% CI 0.66-0.89) and 0.87 (95% CI 0.69-0.96) for submandibular gland; 0.44 (95% CI 0.30-0.59) and 0.92 (95% CI 0.79-0.98) for gastrointestinal tract; 0.79 (95% CI 0.70-0.86) and 0.88 (95% CI 0.77-0.95) for saliva; and 0.51 (95% CI 0.39-0.62) and 0.91 (95% CI 0.84-0.96) for olfactory mucosa (OM). The pooled sensitivity and specificity were 0.91 (95% CI 0.89-0.93) and 0.50 (95% CI 0.44-0.55) for CSF, 0.92 (95% CI 0.83-0.97) and 0.22 (95% CI 0.06-0.48) for skin, and 0.55 (95% CI 0.42-0.68) and 0.50 (95% CI 0.35-0.65) for OM in distinguishing PD from multiple system atrophy. The pooled sensitivity and specificity were 0.92 (95% CI 0.89-0.94) and 0.84 (95% CI 0.73-0.91) for CSF, 0.92 (95% CI 0.83-0.97) and 0.88 (95% CI 0.64-0.99) for skin and 0.63 (95% CI 0.52-0.73) and 0.86 (95% CI 0.64-0.97) for OM in distinguishing PD from progressive supranuclear palsy. The pooled sensitivity and specificity were 0.94 (95% CI 0.90-0.97) and 0.95 (95% CI 0.77-1.00) for CSF and 0.94 (95% CI 0.84-0.99) and 0.86 (95% CI 0.42-1.00) for skin in distinguishing PD from corticobasal degeneration., Conclusions: α-Synuclein SAAs of CSF, skin, saliva, submandibular gland, gastrointestinal tract and OM are promising diagnostic assays for PD, with CSF and skin α-syn SAAs demonstrating higher diagnostic performance., (© 2023 European Academy of Neurology.)

Objective: Levodopa administration can induce or worsen orthostatic hypotension (OH) in patients with Parkinson's disease (PD). Understanding of acute OH post levodopa (AOHPL) is important for rational drug use in PD patients. Primary objective of this study was to investigate the incidence of AOHPL in PD patients. The secondary objectives were a) hemodynamic character of AOHPL; b) risk factors of AOHPL; c) relationship between motor responsiveness and blood pressure (BP) change., Methods: 490 PD inpatients underwent acute levodopa challenge test (LCT). Supine-to-standing test (STS) was done 4 times during LCT, including before levodopa and every hour post levodopa intake within 3 h. Patients were classified into two groups, AOHPL and non-AOHPL. A comprehensive set of clinical features scales was assessed, including both motor (e.g., motor response, wearing-off) and nonmotor symptoms (e.g., autonomic dysfunction, neuropsychology)., Results: 33.1% PD patients had OH before drug, 50.8% the same subjects had AOHPL during levodopa effectiveness. PD patients who had better response to levodopa likely to have lower standing mean artery pressure (MAP) and severer systolic BP drop after levodopa intake. BP increased when the motor performance worsened and vice versa. Beneficial response was a risk factors of AOHPL (OR = 1.624, P = 0.017)., Conclusions: AOHPL was very common in PD patients. We suggested that PD patients with risk factors should monitor hemodynamic change during LCT to avoid AOHPL following the introduction or increase of oral levodopa. The fluctuations of BP were complicated and multifactorial, likely caused by the process of PD and levodopa both., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work. There is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the submitted manuscript., (Copyright © 2023. Published by Elsevier Ltd.)

Background: The accumulation of α-synuclein (α-syn), an essential step in PD development and progression, is observed not only in neurons but also in glia, including astrocytes. The mechanisms regulating astrocytic α-syn level and aggregation remain unclear. More recently, it has been demonstrated that a part of α-syn spreading occurs through extracellular vesicles (EVs), although it is unknown whether this process is involved in astrocytes of PD. It is known, however, that EVs derived from the central nervous system exist in the blood and are extensively explored as biomarkers for PD and other neurodegenerative disorders., Methods: Primary astrocytes were transfected with A53T α-syn plasmid or exposed to α-syn aggregates. The level of astrocyte-derived EVs (AEVs) was assessed by nanoparticle tracking analysis and immunofluorescence. The lysosomal function was evaluated by Cathepsin assays, immunofluorescence for levels of Lamp1 and Lamp2, and LysoTracker Red staining. The Apogee assays were optimized to measure the GLT-1 + AEVs in clinical cohorts of 106 PD, 47 multiple system atrophy (MSA), and 103 healthy control (HC) to test the potential of plasma AEVs as a biomarker to differentiate PD from other forms of parkinsonism., Results: The number of AEVs significantly increased in primary astrocytes with α-syn deposition. The mechanism of increased AEVs was partially attributed to lysosomal dysfunction. The number of α-syn-carrying AEVs was significantly higher in patients with PD than in HC and MSA. The integrative model combining AEVs with total and aggregated α-syn exhibited efficient diagnostic power in differentiating PD from HC with an AUC of 0.915, and from MSA with an AUC of 0.877., Conclusions: Pathological α-syn deposition could increase the astrocytic secretion of EVs, possibly through α-syn-induced lysosomal dysfunction. The α-syn-containing AEVs in the peripheral blood may be an effective biomarker for clinical diagnosis or differential diagnosis of PD., (© 2023. Ruijin Hospital, Shanghai Jiao Tong University.)

The current study aimed to investigate the clinical characteristics of Parkinson's disease (PD) patients with concomitant periodic limb movements in sleep (PLMS). The clinical data of 36 PD patients who underwent polysomnography (PSG) in Beijing Tiantan Hospital from October 2018 to July 2022 were collected. Unified Parkinson's Disease Rating Scale 3.0 and Hoehn & Yahr (H-Y) stage were used to evaluate the disease severity. Patients were divided into two groups: the PLMS+group periodic limb movements in sleep index [(PLMSI)≥15 times/h] and the PLMS-group (PLMSI<15 times/h), using the PLMSI 15 times/h as the cut-off value. The clinical characteristics between the two groups were compared. There were 15 patients (42%) in the PLMS+group and 21 patients (58%) in the PLMS-group, among which 12 patients (12/15) in the PLMS+group and 9 patients (42.9%) in the PLMS-group had rapid eye movement sleep behavior disorder (RBD). The rate of RBD in PLMS+group was higher than that in PLMS-group ( P <0.05). There was statistically significant difference in the blood folate level between the PLMS-group and PLMS+group [6.20 (5.14, 11.70) ng/ml vs 4.41 (3.07, 5.64) ng/ml] ( P< 0.01). Folate deficiency was more common in the PLMS+group, while no statistically significant differences were found in homocysteine and ferritin levels (both P >0.05). Four patients in the PLMS+group had falling experience, while 14.3% (3/21) patients in the PLMS-group had falling experience. Patients in the PLMS+group were more likely to fall. The PLMS+group had higher arousal index according to PSG [PLMS-group: 11.90 (9.10, 15.80) times/h; PLMS+group: 21.50 (19.35, 29.90) times/h] ( P< 0.05). No statistically significant differences in other sleep parameters were detected between the two groups (all P >0.05). Meanwhile, the apnea-hypopnea index (AHI) in both groups was higher than normal (<5 times/h), of which the PLMS-group was 9.80 (4.70, 22.20) times/h and the PLMS+group was 8.20 (1.70, 11.15) times/h, indicating that PD patients were more likely to experience sleep apnea and hypopnea. PD patients with PLMS had lower folate level, higher risk for falls, higher sleep arousal index, more sleep fragmentation, and higher prevalence of RBD.

Objectives: To evaluate the difference of tau burden between patients with progressive supranuclear palsy (PSP) and healthy controls (HCs) or other neurodegenerative diseases using tau-positron emission tomography (PET) imaging., Methods: A systematic search on PubMed, Embase, and Web of Science databases was performed for tau-PET studies in PSP patients, up to April 1, 2022. Standardized mean differences (SMDs) of tau tracer uptake were calculated using random-effects models. Subgroup analysis based on the type of tau tracers, meta-regression, and sensitivity analysis were conducted., Results: Twenty-seven studies comprising 553 PSP, 626 HCs, and 406 other neurodegenerative diseases were included. Compared with HCs, PSP patients showed elevated tau binding in basal ganglia, midbrain, dentate nucleus, cerebellar white matter, and frontal lobe with decreasing SMD (SMD: 0.390-1.698). Compared with Parkinson's disease patients, increased tau binding was identified in the midbrain, basal ganglia, dentate nucleus, and frontal and parietal lobe in PSP patients with decreasing SMD (SMD: 0.503-1.853). PSP patients showed higher tau binding in the subthalamic nucleus (SMD = 1.351) and globus pallidus (SMD = 1.000), and lower binding in the cortex and parahippocampal gyrus than Alzheimer's disease patients (SMD: - 2.976 to - 1.018). PSP patients showed higher midbrain tau binding than multiple system atrophy patients (SMD = 1.269)., Conclusion: Tau PET imaging indicates different topography of tau deposition between PSP patients and HCs or other neurodegenerative disorders. The affinity and selectivity of tracers for 4R-tau and the off-target binding of tracers should be considered when interpreting the results., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Introduction: Emerging evidence suggests that cerebral small vessel disease (CSVD) may worsen cognitive functions in Parkinson's disease (PD). However, the effect of microbleeds on cognitive function in patients with PD remains unknown. This study explored the association between the presence, number and location of microbleeds with dementia in PD patients., Methods: This cross-sectional study included 431 patients with PD from Beijing Tiantan Hospital from May 2016 to August 2019. Cognition assessments (MMSE, MoCA) were performed for these patients. MRI imaging sequences were obtained and reviewed independently by two well-trained readers who were blind to all clinical data. Spearman's correlation analysis and logistic regression model analysis were further used for the assessments., Results: An association between cerebral microbleeds with cognitive ability and dementia in PD patients was revealed. A significance was observed between the total number of microbleeds and two widely used scores of cognitive assessments (Spearman R = - 0.120 to MMSE with a p = 0.016, and - 0.117 to MoCA with a p = 0.020). In detail, infratentorial microbleeds were associated with the level of cognition in PD patients (Spearman R = - 0.099 to MMSE with a p = 0.049, and - 0.116 to MoCA with a p = 0.021). Furthermore, logistic regression analysis results also confirmed such correlations between the number of microbleeds and cognitive ability after adjusting for age, cholesterol level, Hamilton Anxiety Scale, Hamilton Depression Scale, and white matter hyperintensity Fazekas score (OR 3.28, p = 0.035, 95% CI 1.090-9.892)., Conclusions: The occurrence of microbleeds, especially in the infratentorial locations, may worsen the cognitive function of PD patients and result in dementia. Management of cerebral vascular disease could be beneficial to patients with PD., (© 2022. The Author(s) under exclusive licence to Belgian Neurological Society.)

Background: Degeneration of the substantia nigra (SN) may contribute to levodopa-induced dyskinesia (LID) in Parkinson's disease (PD), but the exact characteristics of SN in LID remain unclear., Objective: To further understand the pathogenesis of patients with PD with LID (PD-LID), we explored the structural and functional characteristics of SN in PD-LID using multimodal magnetic resonance imaging (MRI)., Methods: Twenty-nine patients with PD-LID, 37 patients with PD without LID (PD-nLID), and 28 healthy control subjects underwent T1-weighted MRI, quantitative susceptibility mapping, neuromelanin-sensitive MRI, multishell diffusion MRI, and resting-state functional MRI. Different measures characterizing the SN were obtained using a region of interest-based approach., Results: Compared with patients with PD-nLID and healthy control subjects, the quantitative susceptibility mapping values of SN pars compacta (SNpc) were significantly higher (P = 0.049 and P = 0.00002), and the neuromelanin contrast-to-noise ratio values in SNpc were significantly lower (P = 0.012 and P = 0.000002) in PD-LID. The intracellular volume fraction of the posterior SN in PD-LID was significantly higher compared with PD-nLID (P = 0.037). Resting-state fMRI indicated that PD-LID in the medication off state showed higher functional connectivity between the SNpc and putamen compared with PD-nLID (P = 0.031), and the functional connectivity changes in PD-LID were positively correlated with Unified Dyskinesia Rating Scale total scores (R = 0.427, P = 0.042)., Conclusions: Our multimodal imaging findings highlight greater neurodegeneration in SN and the altered nigrostriatal connectivity in PD-LID. These characteristics provide a new perspective into the role of SN in the pathophysiological mechanisms underlying PD-LID. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background and Purpose: The monoamine oxidase type B inhibitors plus channel blockers (MAO-BIs plus) are a new class of antiparkinsonian drug with additional mechanisms of action for their property as ion channel blockers. The present study aimed to compare the efficacy and safety of MAO-BIs plus and conventional MAO-BIs, as well as their corresponding doses, as adjuvant therapy to levodopa in the treatment of Parkinson's disease (PD)., Method: Randomized controlled trials enrolling PD patients treated with selegiline, rasagiline, safinamide or zonisamide as adjuvant therapy to levodopa were identified. Bayesian network meta-analysis was conducted., Results: Thirty-one randomized controlled trials comprising 7142 PD patients were included. Compared with levodopa monotherapy, the combination therapy of MAO-BIs and levodopa was significantly more effective, with a mean difference of 2.74 (1.26-4.18) on the Unified Parkinson's Disease Rating Scale (UPDRS) III score change for selegiline, 2.67 (1.45-3.87) for safinamide, 2.2 (0.98-3.64) for zonisamide and 2.04 (1.24-2.87) for rasagiline. No significant difference was detected amongst MAO-BIs. The surface under the cumulative ranking results showed that safinamide 100 mg and rasagiline 1 mg ranked first in improving UPDRS III and UPDRS II, respectively. Zonisamide 100 mg ranked first in reducing OFF time. For safety outcomes, rasagiline was associated with a higher incidence of adverse events than placebo and safinamide. MAO-BIs plus had a higher probability of being safer agents compared to conventional MAO-BIs., Conclusions: Monoamine oxidase type B inhibitors plus, conventional MAO-BIs and the corresponding doses are similar in efficacy in PD treatment. MAO-BIs plus might be safer than conventional MAO-BIs. Head-to-head comparisons are needed for further investigation., (© 2022 European Academy of Neurology.)

Background and Purpose: Axial postural abnormalities, mainly involving the spinal deformities, are disabling symptoms of Parkinson's disease (PD). However, the prevalence of axial postural abnormalities in PD and their clinical correlates remain unclear. The present study aimed to conduct a systematic review and meta-analysis of the prevalence of overall and subtypes of axial postural abnormalities in PD., Methods: PubMed, Embase, Web of Science and Cochrane databases were searched up to 31st March, 2022. We identified studies that reported the prevalence of axial postural abnormalities in PD. The pooled estimate of prevalence was calculated using a random effect model. Subgroup analysis and meta-regression were performed., Results: There were 19 studies met the inclusion criteria. The overall prevalence of axial postural abnormalities in PD was 22.1% (95% CI 19.7-24.5%). The prevalence of each subtype of axial postural abnormalities was 19.6% for scoliosis (95% CI 10.6-28.7%), 10.2% for camptocormia (95% CI 7.7-12.7%), 8% for Pisa syndrome (95% CI 4.7-11.4%), and 7.9% for antecollis (95% CI 3.9-11.9%). Subgroup analysis showed that the measuring method of axial postural abnormalities exerted significant effects on prevalence estimates. Axial postural abnormalities in PD were associated with older age, longer disease duration, higher H-Y stage, greater levodopa equivalent daily dose, more severe motor symptoms, motor fluctuations, and akinetic-rigid subtype., Conclusions: Axial postural abnormalities, which include scoliosis, camptocormia, Pisa syndrome, and antecollis, are not uncommon in patients with PD. Future research on axial postural abnormalities should be based on uniform diagnostic criteria and measuring methods., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Introduction: Impaired gait is observed in patients with Parkinson's disease (PD) in both single-task (ST) and dual-task (DT) conditions. Non-motor symptoms (NMSs), another vital symptom future experienced along the PD disease trajectory, contribute to gait performance in PD. However, whether DT gait performance is indicative of NMS burden (NMSB) remains unknown. This study investigated correlation between NMS and DT gait performance and whether NMSB is reflected in the DT effects (DTEs) of gait parameters in PD., Methods: Thirty-three idiopathic PD participants were enrolled in this study; the median H-Y staging was 2.5. NMSB was assessed by Non-motor Symptoms Scale (NMSS). Spatiotemporal gait parameters under ST and DT conditions were evaluated by wearable sensors. Gait parameters under ST and DT conditions and DTEs of gait parameters were compared across NMSB groups. The associations between NMS and DTEs of gait parameters were analyzed by correlation analysis and linear regression models., Results: Compared to PD patients with mild-moderate NMSB, the severe-very severe NMSB group showed slower gait speed and shorter stride length under both ST and DT conditions (p < 0.05). DT had significantly negative effect on gait parameters in PD patients, including gait speed, stride length, and gait cycle duration (p < 0.05). PD patients with mild-moderate NMSB showed larger DTEs of cadence and bilateral gait cycle duration (p < 0.05). DTEs of bilateral gait cycle duration and swing phase on the more affected (MA) side were significantly correlated with NMSS scores (∣rSp∣ ≥ 0.3, p < 0.05). Gait cycle duration on the less affected (LA) side explained 43% of the variance in NMSS scores, when accounting for demographic and clinical confounders (β =  - 1.095 95% CI - 4.061 ~  - 0.058, p = 0.044; adjusted R 2  = 0.434)., Conclusion: DT gait performance could reflect NMSB in PD patients at early stage, and gait cycle duration is a valuable gait parameter to further investigate and to provide more evidence for PD management., (© 2022. Fondazione Società Italiana di Neurologia.)

Background: Early diagnosis of Parkinson's disease (PD) could significantly improve outcomes for patients and future disease-modifying treatments. Several studies have revealed that α-synuclein levels in peripheral erythrocytes are associated with PD, but the diagnostic value in early PD is still unknown., Methods: This study included both cross-sectional and longitudinal design. The subjects included 45 patients with early PD and 79 age-matched healthy controls. Participants were re-examined with repeated blood collection and clinical assessments after 3 years. The electrochemiluminescence assay was used to measure total and oligomeric α-synuclein levels respectively. The diagnostic value of erythrocytic α-synuclein for early PD was determined by receiver operator characteristic (ROC) curve. Correlations between RBC α-synuclein levels and changes over 3 years in clinical characteristic scores were further investigated with a linear regression., Results: Total and oligomeric α-synuclein levels in erythrocyte were significantly increased in early PD groups compared with control group (Total α-synuclein, p < 0.001; Oligomer, p < 0.001). Levels of total and oligomeric α-synuclein in erythrocytes were correlated with MDS-UPDRS III scores in early PD (Total α-synuclein, p = 0.008; Oligomer, p = 0.037). After adjusting for age, gender and dopaminergic medication, an association was found between higher erythrocytic oligomeric α-synuclein levels at baseline and greater increase in MDS-UPDRS III scores over 3 years (p = 0.007)., Conclusion: Our study suggests that total and oligomeric α-synuclein in erythrocyte were elevated even in the initial motor stage of PD. Higher erythrocytic oligomeric α-synuclein levels at baseline predicts a faster clinical decline over time in patients with early PD., (Copyright © 2022. Published by Elsevier Ltd.)

Introduction: Emerging evidence has suggested that lipid metabolism is correlated with Parkinson's disease (PD) onset and progression. However, the effect of lipid metabolism on motor performance in PD patients is still unknown. This study estimated the association between lipid profiles and the severity of motor performance in PD., Methods: This cross-sectional study enrolled 279 idiopathic PD patients from the Department of Neurology of Beijing Tiantan Hospital from May 2016 to August 2018. Serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (Apo-A1), and apolipoprotein B (Apo-B) levels were detected in fast serum samples. Motor performance was assessed by Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) total scores and subscores in these patients. The associations of lipid profiles with motor performance were analyzed using multivariable linear regression models., Results: Compared to males, females with PD exhibited significantly higher serum TC, LDL-C, HDL-C, Apo-A1, and Apo-B levels. When accounting for covariates, lower serum TG levels were significantly associated with higher MDS-UPDRS III total scores and gait/postural instability subscores. Additionally, the univariate linear regression model showed that in males with PD, serum HDL-C or Apo-A1 levels were significantly associated with tremor subscores., Conclusion: Lower serum TG levels were associated with more severe motor performance in patients with PD and TG may be a potential predictive biomarker for motor performance in PD patients., (© 2022. The Author(s).)

Objective: To investigate the risk factors of motor complications in female patients with Parkinson's disease (PD) and the correlation between the occurrence of motor complications and sex hormone levels., Methods: According to the occurrence and types of motor complications, 103 female PD patients were divided into two groups: patients with or without the wearing-off phenomenon, patients with or without dyskinesia. Binary logistic regression analysis was performed respectively to screen for the risk factors of the wearing-off phenomenon and dyskinesia in female PD patients., Results: Among 103 female PD patients, 44 (42.72%) had motor complications. Patients with the wearing-off phenomenon and patients with dyskinesia had higher prolactin levels than patients without the wearing-off phenomenon and patients without dyskinesia, respectively. However, the difference was no longer significant when the two groups were corrected for multiple comparisons (P < 0.0028). Multivariate analysis found that younger age at onset and higher Hoehn-Yahr (H&Y) stage were identified as independent risk factors for the wearing-off phenomenon and younger age of onset was an independent risk factor for dyskinesia in female PD patients (P < 0.05)., Conclusion: Female PD patients have a higher incidence of motor complications. Younger age of onset and higher H&Y stage were the risk factors of the wearing-off phenomenon, and younger onset age was the risk factor of dyskinesia in female PD patients. There may be a certain correlation between the occurrence of motor complications and sex hormone levels in female PD patients, which requires further verification., (© 2022. Fondazione Società Italiana di Neurologia.)

Freezing of gait is a debilitating symptom in advanced Parkinson's disease and responds heterogeneously to treatments such as deep brain stimulation. Recent studies indicated that cortical dysfunction is involved in the development of freezing, while evidence depicting the specific role of the primary motor cortex in the multi-circuit pathology of freezing is lacking. Since abnormal beta-gamma phase-amplitude coupling recorded from the primary motor cortex in patients with Parkinson's disease indicates parkinsonian state and responses to therapeutic deep brain stimulation, we hypothesized this metric might reveal unique information on understanding and improving therapy for freezing of gait. Here, we directly recorded potentials in the primary motor cortex using subdural electrocorticography and synchronously captured gait freezing using optoelectronic motion-tracking systems in 16 freely-walking patients with Parkinson's disease who received subthalamic nucleus deep brain stimulation surgery. Overall, we recorded 451 timed up-and-go walking trials and quantified 7073 s of stable walking and 3384 s of gait freezing in conditions of on/off-stimulation and with/without dual-tasking. We found that (i) high beta-gamma phase-amplitude coupling in the primary motor cortex was detected in freezing trials (i.e. walking trials that contained freezing), but not non-freezing trials, and the high coupling in freezing trials was not caused by dual-tasking or the lack of movement; (ii) non-freezing episodes within freezing trials also demonstrated abnormally high couplings, which predicted freezing severity; (iii) deep brain stimulation of subthalamic nucleus reduced these abnormal couplings and simultaneously improved freezing; and (iv) in trials that were at similar coupling levels, stimulation trials still demonstrated lower freezing severity than no-stimulation trials. These findings suggest that elevated phase-amplitude coupling in the primary motor cortex indicates higher probabilities of freezing. Therapeutic deep brain stimulation alleviates freezing by both decoupling cortical oscillations and enhancing cortical resistance to abnormal coupling. We formalized these findings to a novel 'bandwidth model,' which specifies the role of cortical dysfunction, cognitive burden and therapeutic stimulation on the emergence of freezing. By targeting key elements in the model, we may develop next-generation deep brain stimulation approaches for freezing of gait., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Depression is one typical mood disorder in Parkinson's disease (DPD). The alterations in the resting-state brain activities are believed to be associated with DPD. These resting-state activities are regulated by neurophysiological components over multiple temporal scales. The multiscale dynamics of these spontaneous fluctuations are thus complex, but not well-characterized., Objective: To characterize the complexity of the spontaneous blood-oxygen-level-dependent (BOLD) of fMRI in DPD. We hypothesized that (1) compared to non-depression PD (NDPD), the complexity in DPD would be lower; and (2) the diminished complexity would be associated with lower connections/communications between brain regions., Methods: Twenty-nine participants (10 in DPD and 19 in NDPD) who were naïve to medications completed a resting-sate functional MRI scan. The BOLD complexity within each voxel was calculated by using multiscale entropy (MSE). The complexity of the whole brain and each of the 90 regions parcellated following automated-anatomical-labeling template was then obtained by averaging voxel-wised complexity across all brain regions or within each region. The level of connections of regions with diminished complexity was measured by their own global functional connectivity (FC)., Results: As compared to NDPD patients, the whole-brain complexity and complexity in 18 regions were significantly lower in DPD (F > 16.3, p < 0.0005). Particularly, in eight of the 18 regions, lower complexity was associated with lower global FC (Beta = 0.333 ~ 0.611, p = 0.000 ~ 0.030)., Conclusion: The results from this pilot study suggest that the resting-state BOLD complexity may provide critical knowledge into the pathology of DPD. Future studies are thus warranted to confirm the findings of this study., (© 2022. The Author(s).)

Introduction: With the levodopa threshold effect for dyskinesia observed, threshold dosage of levodopa was identified in the general Parkinson's disease (PD) population. While early-onset PD (EOPD) and late-onset PD (LOPD) differ in the pathogenesis and clinical manifestations, threshold dosage of levodopa for individualized treatment remains unestablished. The objective of this study was to propose threshold dosage of levodopa in EOPD and LOPD patients, respectively., Methods: Data on demographic and clinical and treatment measures were collected in 539 PD patients. Patients were divided into different onset groups using 50 as the cut-off age. We used univariable and multivariable analysis to screen for risk factors for dyskinesia. Receiver operating characteristic curve was used to determine the levodopa threshold dosages for dyskinesia., Results: The prevalence of dyskinesia was 47.7% (53/111) in the EOPD group and 24.1% (103/428) in the LOPD group. Risk factors identified for dyskinesia include high levodopa daily dose and levodopa responsiveness for EOPD patients and high levodopa daily dose, long levodopa treatment duration, low body weight, use of entacapone, and high Hoehn-Yahr stage in off state for LOPD patients. The daily levodopa threshold dosages were 400 mg or 5.9 mg/kg for EOPD and 450 mg or 7.2 mg/kg for LOPD., Conclusion: EOPD patients had lower levodopa threshold dosage comparing with LOPD patients. Treatment of EOPD requires stricter levodopa dose control to delay the onset of dyskinesia., (© 2021. Fondazione Società Italiana di Neurologia.)

Background: Immune system dysfunction, including higher levels of peripheral monocytes and inflammatory cytokines, is an important feature of Parkinson's disease (PD) pathogenesis, although the mechanism underlying the process remains to be investigated. In the central nervous system, it is well-known that α-synuclein (α-syn), a key protein involved in PD, activates microglia potently, and it is also reported that α-syn exists in the peripheral system, especially in erythrocytes or red blood cells (RBC) at exceedingly high concentration. The current study focused on the possibility that RBC-derived α-syn mediates the sensitization of peripheral monocytes in PD patients., Methods: The hyperactivation of monocytes was assessed quantitatively by measuring mRNA levels of typical inflammatory cytokines (including IL-1β, IL-6 and TNF-α) and protein levels of secreted inflammatory cytokines (including pro-inflammatory cytokines: IL-1β, IL-6, TNF-α, IL-8, IFN-γ, IL-2, and IL-12p70 and anti-inflammatory cytokines: IL-4, IL-10, and IL-13). Western blot, nanoparticle tracking analysis and electron microscopy were used to characterize RBC-derived extracellular vesicles (RBC-EVs). Inhibitors of endocytosis and leucine-rich repeat kinase 2 (LRRK2), another key protein involved in PD, were used to investigate how these two factors mediated the process of monocyte sensitization by RBC-EVs., Results: Increased inflammatory sensitization of monocytes was observed in PD patients and PD model mice. We found that α-syn-containing RBC-EVs isolated from PD model mice or free form oligomeric α-syn induced the inflammatory sensitization of THP-1 cells, and demonstrated that endocytosis was a requirement for this pathophysiological pathway. Furthermore, the hyperactivation of THP-1 cells induced by RBC-EVs was associated with increased LRRK2 production and kinase activity. The phenomenon of inflammatory sensitization of human monocytes and increased LRRK2 were also observed by the treatment of RBC-EVs isolated from PD patients., Conclusions: Our data provided new insight into how hyperactivation of monocytes occurs in PD patients, and identified the central role played by α-syn-containing RBC-EVs in this process., (© 2022. The Author(s).)

Objective: Whether perivascular space (PVS) visible on magnetic resonance imaging (MRI) represents glymphatic dysfunction and whether this imaging marker is pathologic in Parkinson's disease (PD) have been controversial. The objective was to determine whether PVS visible on MRI is independently associated with cognitive decline in patients with PD, and to test whether pathologic proteins in the CSF (such as Aβ 42 ) mediate the pathologic role of PVS., Methods: A total of 341 patients with Parkinson's disease from Parkinson's Progression Marker Initiative (PPMI) cohort was included in the present study. PVS in the basal ganglia (BG-PVS) and centrum semiovale were evaluated with a semiquantitative scale. Changes in the Montreal Cognitive Assessment (MoCA) score and the absolute MoCA score at the 3-year assessment were considered the main cognitive outcome. A multivariable linear regression model was used to test the association between PVS and cognitive decline. A mixed linear model and path analysis were used to test the interaction among PVS, CSF biomarkers and cognitive decline., Results: BG-PVS was associated with cognitive decline in patients with PD at the 3-year follow-up independent of age, baseline cognition, motor and nonmotor function, presynaptic dopaminergic deficiency, and CSF biomarkers. The interaction between BG-PVS and Aβ 42 /tTau, Aβ 42 /pTau, and Aβ 42 levels was significantly predictive of 3-year cognitive decline. Path analysis confirmed that CSF Aβ 42 /tTau levels partially mediated the pathologic effect of BG-PVS on cognitive outcome in PD., Conclusions: BG-PVS is independently associated with cognitive decline in PD, and this association may be partially mediated by toxic CSF proteins., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Cognitive impairment is a clinical feature of multiple system atrophy (MSA). However, the prevalence and factors influencing the prevalence of cognitive impairment and dementia in MSA patients remain unclear., Objective: We aim to provide an estimate of the prevalence of cognitive impairment and dementia in patients with MSA and to evaluate the possible effect of demographic, clinical and methodological factors on the prevalence., Methods: We systematically searched the PubMed, Embase, and Web of science databases to identify studies that report the prevalence of cognitive impairment or dementia in MSA published up to February 2022. We computed the estimates of the pooled prevalence using random-effects models. Heterogeneity was investigated by subgroup analyses and meta-regression. Differences between MSA patients with and without cognitive impairment in demographic and clinical features were explored., Results: A total of 23 studies comprising 2064 MSA patients were included in meta-analysis. The pooled prevalence of cognitive impairment in MSA patients was 37% (95% CI: 29% -45%), the prevalence of dementia was 11% (95% CI: 7% -15%). The subgroup analyses showed the prevalence of dementia in pathologically-confirmed MSA was 7% (95% CI: 0% -12%), in clinically diagnosed MSA was 14% (95% CI: 10% -18%). Cognitive impairment in MSA patients was associated with older age, lower education, longer disease duration and more severe motor symptoms., Conclusion: Cognitive impairment is a common non-motor symptom in MSA. Dementia can develop in a few patients with MSA as well, but usually in the late stage.

Objective: To evaluate the transcranial sonographic characteristics in patients with Parkinson's disease (PD) with symptoms of restless legs syndrome (RLS). Methods: Patients with diagnosis of definite PD from the Second Affiliated Hospital of Soochow University and 3 other participating hospitals between September 2018 and December 2019 were consecutively enrolled. Concurrent RLS symptoms were determined using Non-motor Symptoms Questionnaire. Transcranial sonography (TCS) and clinical assessments were performed during the same time and the related variables were compared between the two groups using t -test, non-parametric test, Chi-square test and Spearman correlation analysis, respectively. Results: Among 349 patients with PD, the prevalence of RLS symptoms was 22.6%. Compared to patients without RLS symptoms, those with RLS had longer disease duration (43.0 (24.0, 91.0) months vs 37.0 (20.0, 60.0) months, P< 0.05) and higher Hoehn-Yahr stage (2.5 (2.0, 3.0) vs 2.0 (1.5, 2.5), P< 0.01).TCS revealed that patients with RLS symptoms were more likely to have abnormality in the raphe nucleus (21.50% vs 7.78%, χ²=15.9, P< 0.001) and increased third ventricle width ((6.22±1.97) mm vs (5.16±1.90) mm, P< 0.001). No significant differences were found regarding parameters of substantia nigra. Conclusions: Concurrent RLS symptoms are common in PD patients. Abnormal echogenicity of raphe nucleus and increased third ventricle width could be characteristics of TCS in PD patients with RLS symptoms.

Peripheral biomarkers indicative of brain pathology are critically needed for early detection of Parkinson's disease (PD). In this study, using NanoString and digital PCR technologies, we began by screening for alterations in genes associated with PD or atypical Parkinsonism in erythrocytes of PD patients, in which PD-related changes have been reported, and which contain ~ 99% of blood α-synuclein. Erythrocytic CHCHD2 mRNA was significantly reduced even at the early stages of the disease. A significant reduction in protein and/or mRNA expression of CHCHD2 was confirmed in PD brains collected at autopsy as well as in the brains of a PD animal model overexpressing α-synuclein, in addition to seeing a reduction of CHCHD2 in erythrocytes of the same animals. Overexpression of α-synuclein in cellular models of PD also resulted in reduced CHCHD2, via mechanisms likely involving altered subcellular localization of p300 histone acetyltransferase. Finally, the utility of reduced CHCHD2 mRNA as a biomarker for detecting PD, including early-stage PD, was validated in a larger cohort of 205 PD patients and 135 normal controls, with a receiver operating characteristic analysis demonstrating > 80% sensitivity and specificity.

Background: Parkinson disease (PD) is a common movement disorder. Patients with PD have multiple gait impairments that result in an increased risk of falls and diminished quality of life. Therefore, gait measurement is important for the management of PD., Objective: We previously developed a smartphone-based dual-task gait assessment that was validated in healthy adults. The aim of this study was to test the validity of this gait assessment in people with PD, and to examine the association between app-derived gait metrics and the clinical and functional characteristics of PD., Methods: Fifty-two participants with clinically diagnosed PD completed assessments of walking, Movement Disorder Society Unified Parkinson Disease Rating Scale III (UPDRS III), Montreal Cognitive Assessment (MoCA), Hamilton Anxiety (HAM-A), and Hamilton Depression (HAM-D) rating scale tests. Participants followed multimedia instructions provided by the app to complete two 20-meter trials each of walking normally (single task) and walking while performing a serial subtraction dual task (dual task). Gait data were simultaneously collected with the app and gold-standard wearable motion sensors. Stride times and stride time variability were derived from the acceleration and angular velocity signal acquired from the internal motion sensor of the phone and from the wearable sensor system., Results: High correlations were observed between the stride time and stride time variability derived from the app and from the gold-standard system (r=0.98-0.99, P<.001), revealing excellent validity of the app-based gait assessment in PD. Compared with those from the single-task condition, the stride time (F 1,103 =14.1, P<.001) and stride time variability (F 1,103 =6.8, P=.008) in the dual-task condition were significantly greater. Participants who walked with greater stride time variability exhibited a greater UPDRS III total score (single task: β=.39, P<.001; dual task: β=.37, P=.01), HAM-A (single-task: β=.49, P=.007; dual-task: β=.48, P=.009), and HAM-D (single task: β=.44, P=.01; dual task: β=.49, P=.009). Moreover, those with greater dual-task stride time variability (β=.48, P=.001) or dual-task cost of stride time variability (β=.44, P=.004) exhibited lower MoCA scores., Conclusions: A smartphone-based gait assessment can be used to provide meaningful metrics of single- and dual-task gait that are associated with disease severity and functional outcomes in individuals with PD., (©Dongning Su, Zhu Liu, Xin Jiang, Fangzhao Zhang, Wanting Yu, Huizi Ma, Chunxue Wang, Zhan Wang, Xuemei Wang, Wanli Hu, Brad Manor, Tao Feng, Junhong Zhou. Originally published in JMIR mHealth and uHealth (http://mhealth.jmir.org), 19.02.2021.)

Introduction: Emerging evidence has suggested that cerebral small vessel disease (CSVD) may worsen motor function and cognition in Parkinson's disease (PD). However, the effect of CSVD on anxiety and depression in patients with PD remains unknown. This study explored the multi-dimensional effects of CSVD on PD outcomes (motor, cognition, and depression/anxiety)., Methods: This cross-sectional study included 431 patients with PD from Beijing Tiantan Hospital from May 2016 to August 2019. CSVD imaging markers were assessed and the four-point CSVD burden score was calculated. Motor function (MDS-UPDRS III score and subscores), cognition (MMSE, MoCA), anxiety (HAMA), and depression (HAMD) were assessed in these patients. The associations of CSVD with these outcomes were analyzed using the Spearman's correlation and multivariable linear regression models., Results: Motor dysfunction, cognitive impairment, depression, and anxiety were significantly worse in patients with severe CSVD than in those with mild CSVD. Multivariable linear regression showed that CSVD burden was significantly associated with motor dysfunction (MDS-UPDRS III score and rigidity and bradykinesia subscores), impaired cognition, and high levels of depression and anxiety. A marginally significant association was observed between CSVD burden and gait/postural instability in multivariable regression analysis. Among the CSVD imaging markers, white matter hyperintensity, number of lacunes, and microbleeds were positively correlated with the severity of motor, cognitive, and emotional impairments, while the perivascular space in the basal ganglia was only correlated with cognitive impairments., Conclusions: Comorbid CSVD may affect multiple functional domains in patients with PD. Management of cerebrovascular disease may improve PD outcomes., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: The comorbidity of cerebral small vessel disease (CSVD) may worsen gait impairment of Parkinson's disease (PD). However, the evidence remains scarce and controversial, and the mechanism of their potential interaction remains largely unknown. The present study aimed to investigate the overall impact of quantity and location of CSVD on gait/posture function in PD., Methods: This cross-sectional study included 315 consecutive eligible patients with PD from Beijing Tiantan Hospital from May 2016 to August 2018. Associations of gait/posture subscores with the burden score of CSVD and four CSVD imaging markers were assessed using multivariate linear regression models., Results: Burden of CSVD was significantly associated with more severe gait/posture impairment in PD in the unadjusted model (β = 0.521, P = 0.011, 95% CI 0.118-0.923) and in the model adjusted for age, hypertension, ischemic stroke, low-density lipoprotein level, cholesterol level, and cognitive statues (β = 0.448, P = 0.047, 95% CI 0.006-0.891). The presence of lacunes, but not other CSVD markers, was significantly associated with higher gait/posture subscores after the adjustment (β = 0.492, P = 0.041, 95% CI 0.021-0.964), and the number of lacunes in the basal ganglia significantly correlated with the gait/posture subscores in patients with PD (P = 0.012, Spearman r = 0.161)., Conclusions: CSVD and lacunes in the basal ganglia may independently contribute to gait/posture dysfunction in PD. Promoting neurovascular health may preserve some gait/posture function of PD.

Caudate dopaminergic dysfunction is implied in the pathophysiology of patients with Parkinson's disease (PD). Still, connectivity specificities of the caudate nucleus (CN) subdivisions and the effect of dopamine are poorly understood. We collected MRI and neuropsychological data from 34 PD patients and 26 age- and sex-matched healthy elderly individuals (HEs) in this study. Resting-state functional connectivity analysis revealed that compared to the other CN subdivisions, the CN head was more strongly connected to the default mode network (DMN), the CN body to the frontoparietal network (FPN), and the CN tail to the visual network in HEs. PD patients off medication showed reduced connectivity within all these subdivision networks. In PD patients on medication, functional connectivity in the CN head network was significantly improved in the medial prefrontal cortex and in the body network it was improved in the dorsolateral prefrontal cortex. These improvements contributed to ameliorated motivation and cognitive function in PD patients. Our results highlighted the specific alterations and dopamine modulation in these CN subdivision networks in PD, which may provide insight into the pathophysiology and therapeutics of this disease.

Levodopa is widely used to treat Parkinson's disease (PD), and its long-term therapy may induce dyskinesia in a dose-dependent manner. However, the threshold dose with a relatively low risk for dyskinesia has not been determined. Demographic, clinical profiles and detailed information of dopaminergic drugs were recorded for 403 PD patients in treatment with levodopa. Variables were compared between dyskinesia and non-dyskinesia groups. Logistic regression analysis was used to assess the association between levodopa dose-related variables and dyskinesia. Receiver operating characteristic curve and decision tree classification model were used to investigate the cut-off value of levodopa dose to best separate the dyskinesia group from the non-dyskinesia group. Patients with dyskinesia tended to have a lower weight and age at onset, higher percentage of female and wearing-off, longer duration of disease and levodopa treatment, higher H-Y stage and MDS-UPDRS Part III score, and higher levodopa dose and levodopa equivalent dose than those without dyskinesia. After adjusted for demographical and clinical variables, levodopa dose-related factors (daily dose, cumulative dose, and weight-adjusted dose) were still associated with dyskinesia. Both the receiver operating characteristic and decision tree classification analysis indicated that patients who have taken levodopa dose ≤ 400 mg per day may be associated with a reduced risk for dyskinesia. In conclusion, we evaluated the thresholds of levodopa treatment with a relatively low risk for dyskinesia. These data should be considered for prevention and management of dyskinesia in patients with PD.

Parkinson's disease (PD) is a major human disease associated with degeneration of the central nervous system. Evidence suggests that several endogenously formed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mimicking chemicals that are metabolic conversion products, especially β-carbolines and isoquinolines, act as neurotoxins that induce PD or enhance progression of the disease. We have demonstrated previously that mitochondrially targeted human cytochrome P450 2D6 (CYP2D6), supported by mitochondrial adrenodoxin and adrenodoxin reductase, can efficiently catalyze the conversion of MPTP to the toxic 1-methyl-4-phenylpyridinium ion. In this study, we show that the mitochondrially targeted CYP2D6 can efficiently catalyze MPTP-mimicking compounds, i.e. 2-methyl-1,2,3,4-tetrahydroisoquinoline, 2-methyl-1,2,3,4-tetrahydro-β-carboline, and 9-methyl-norharmon, suspected to induce PD in humans. Our results reveal that activity and respiration in mouse brain mitochondrial complex I are significantly affected by these toxins in WT mice but remain unchanged in Cyp2d6 locus knockout mice, indicating a possible role of CYP2D6 in the metabolism of these compounds both in vivo and in vitro These metabolic effects were minimized in the presence of two CYP2D6 inhibitors, quinidine and ajmalicine. Neuro-2a cells stably expressing predominantly mitochondrially targeted CYP2D6 were more sensitive to toxin-mediated respiratory dysfunction and complex I inhibition than cells expressing predominantly endoplasmic reticulum-targeted CYP2D6. Exposure to these toxins also induced the autophagic marker Parkin and the mitochondrial fission marker Dynamin-related protein 1 (Drp1) in differentiated neurons expressing mitochondrial CYP2D6. Our results show that monomethylamines are converted to their toxic cationic form by mitochondrially directed CYP2D6 and result in neuronal degradation in mice., (© 2019 Chattopadhyay et al.)

Alpha-synuclein (α-SYN) is found in peripheral autonomic neuronal network apart from brain in Parkinson's disease (PD). Nitrated α-SYN is an undesirable modification associated with oxidative and nitrative damage and has been found extensively in brain, gastrointestinal(GI) tract and blood cells in PD. We aim to investigate the presence of nitrated α-SYN in minor salivary gland biopsy in PD. Patients with PD and age-matched controls underwent minor salivary gland biopsy. Motor impairment was assessed by Hoehn-Yahr (H-Y) stage and Unified Parkinson's Disease Rating Scale (UPDRS) Part III in off-state. 11C-methyl-N-2b-carbomethoxy-3b-(4-fluorophenyl) tropane (11C-CFT) DAT-PET scan was performed in all subjects. Immunohistochemical staining for nitrated α-SYN was performed in the minor salivary gland tissues. The minor salivary gland tissues of 8 PD cases and 7 controls with early stage (H-Y stage 1-2) were detected. All PD patients showed asymmetrical and reduction of 11 C-CFT uptake in the caudate, anterior and posterior putamen, while all control subjects showed normal DAT-PET scan. Positive nitrated α-SYN immunostaining was observed in all PD patients (8/8,100%) but not in control subjects (0/7). The results were consistent well with that of DAT-PET. These nitrated alpha-synuclein positive structures were mainly located in the periacinar stroma in PD patients. Our result suggests that nitrated α-SYN exists in the early stage and is probably a promising biomarker for PD. Minor salivary gland is an ideal site for α-SYN nitration detection. Despite of the small number of subjects, attention should be given to α-SYN nitration in PD and more investigations on nitrated α-SYN in different sites and large sample using should be explored in future., (Copyright © 2019. Published by Elsevier B.V.)

Background: Detection of α-synuclein (α-syn) in biological fluids such as saliva may serve as potential biomarker of PD. α-syn pertaining to extracellular vesicles (EVs) has been recently studied in plasma, but not in other biological fluids such as saliva., Aim: 1) To investigate the presence of exosomes in PD saliva; 2) to explore the value of α-syn in salivary EVs as potential biomarker in PD., Methods: Saliva samples were obtained from 74 PD and 60 healthy controls (HCs). The EVs were extracted from saliva by XYCQ EV Enrichment KIT. Western blot and Nanosight 300 were used to validate the existence of exosomes in EVs and to analyze the size of salivary EVs. Salivary EVs α-syn levels, including total α-syn (α-syn Total ), oligomeric α-syn (α-syn Olig ) and phosphorylated-ser129 α-syn (α-syn PS129 ), were measured by Electrochemiluminescence (ECL) assays. Diagnostic value and clinical relevance of salivary EVs α-syn were assessed by Receiver Operator Characteristic (ROC) curve and Spearman correlation., Results: Alix and CD9 positive EVs, representing the presence of exosomes, was detected in PD salivary samples. Size of salivary EVs was about 30-400 nm. The levels of α-syn Olig and α-syn Olig /α-syn Total in the salivary EVs were higher in PD than in HCs (10.39 ± 1.46 pg/ng vs.1.37 ± 0.24 pg/ng, p＜0.001;1.70 ± 0.52 pg/ng vs.0.67 ± 0.26 pg/ng, p＜0.001). There was no significant difference in α-syn Total 、α-syn PS129 、 α-syn PS129 /α-syn Total ratio between PD and HCs (P = 0.723, 0.634, 0.734, respectively). α-syn Olig 2.05 pg/ng distinguished PD from HCs with sensitivity 92% and specificity 86%; α-syn Olig /α-syn Total 0.18 pg/ng differentiated PD from HCs with sensitivity 81% and specificity 71%. No significant correlation between salivary EVs α-syn Olig , α-syn Olig /α-syn Total and disease severity was found., Conclusions: Exosomes are present in PD saliva. The α-syn Olig and α-syn Olig /α-syn Total ratio in salivary EVs may serve as potential diagnostic biomarkers for PD., (Copyright © 2018. Published by Elsevier B.V.)

Parkinson's disease (PD) is a common neurodegenerative disorder. To date, the diagnosis of PD relies mainly on clinical manifestations whereas neuropathological confirmation of the brain is only possible with postmortem studies. Neuronal loss in the substantia nigra pars compacta (SNc) associated with Lewy bodies/neurites is the pathological hallmark feature of PD. The major component of Lewy pathology (LP) is misfolded alpha-synuclein (α-SYN). There is evidence that the distribution of LP is not only limited to the brain but extends to peripheral tissues, including gastrointestinal tract, salivary glands, olfactory mucosa, skin, retina, adrenal gland, and heart. Sensitivity and specificity of α-SYN detection in PD vary greatly among studies due to methodological heterogeneity, such as sampling sites and size, tissue preparation, staining techniques, and antibodies used. Of note, α-SYN has also been found in preclinical and prodromal PD. Further in vivo studies focusing on favorable biopsy sites and standard techniques are needed to get better understanding of α-SYN deposits in preclinical, prodromal, and clinical PD.

Introduction: Glucocerebrosidase (GBA) mutations and leucine-rich repeat kinase 2 (LRRK2) variants are the most common genetic risk factors for late-onset Parkinson's disease (PD). In this study, we aimed to investigate the differences in pre-diagnostic symptoms of PD associated with the variants., Methods: The participants were recruited from 24 centers across China and genotyped for LRRK2 G2385R and R1628P variants and GBA L444P mutation. Participants were surveyed with structural questionnaires for history of environmental exposure and living habits and interviewed to collect the time at onset of each symptoms before diagnosis. We compared the cumulative prevalence and manifestation pattern of symptoms between groups using multiple logistic regression, adjusting age and gender., Results: Total 1799 PD patients were recruited, including 226 patients with LRRK2 G2385R or R1628P variant, 44 with GBA L444P mutation, three with both LRRK2 and GBA mutation, and 1526 idiopathic patients. The cumulative prevalence of non-motor and typical motor symptoms did not differ between groups before diagnosis (P > 0.05). The manifestation sequences of non-motor symptoms were indistinguishable between the LRRK2-carriers, GBA-carriers, and idiopathic PD subjects, and followed the sequence of constipation, hyposmia, sleep disorders, anxiety and depression, sexual dysfunction, urinary incontinency, dizziness and cognition. Slightly higher prevalence of hypomimia and micrographia were detected in the GBA-carriers., Conclusions: The prevalence of pre-diagnostic symptoms is almost indistinguishable between the LRRK2-carriers, GBA-carriers, and idiopathic PD before diagnosis; the sequence of the manifestation of non-motor symptoms largely conforms to the Braak stage for both genetic-related and idiopathic late-onset PD., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

According to epidemiologic studies, smoking appears to downregulate the prevalence of Parkinson's disease (PD), possibly due to antiinflammatory mechanisms via activation of α7 nicotinic acetylcholine receptors (α7 nAChRs). This receptor also appears to play a role in T-cell differentiation. Recently, it has become apparent that the innate immune system participates in PD pathogenesis. The aim of this study was to evaluate the effects of auricular vagus nerve stimulation (aVNS) on substantia nigra (SN) dopaminergic neurodegeneration and the associated neuroinflammation and immune responses in a rat PD model. Adult male Wistar rats were unilaterally administered 6-hydroxydopamine (6-OHDA) to the medial forebrain bundle, followed by aVNS treatment after surgery. Following motor behavioral tests, the expression of tyrosine hydroxylase (TH) in the SN and the levels of inflammatory cytokines in the ventral midbrain were evaluated. In addition, changes in the trends of subsets of CD4+ T lymphocytes in the SN were measured by immunofluorescence staining. Western blotting was used to evaluate the α7 nAChR protein level. Compared with 6-OHDA treats rats, aVNS treatment significantly improved motor deficits, increased TH and α7 nAChR expression, and reduced the levels of inflammatory cytokines (tumor necrosis factor-a (TNF-α) and interleukin-1β (IL-1β)) (p < 0.05). Additionally, aVNS increased the numbers of regulatory T (Treg) cells while decreasing T helper (Th)17 cells. aVNS exerted neuroprotective effects against dopaminergic damage, possibly by suppressing the evolution of inflammation and modulating innate immune responses. Thus, aVNS may be a potential promising therapy in the future.

This study aims to investigate how the frequency settings of deep brain stimulation (DBS) targeting the subthalamic nucleus (STN) influence the motor symptoms of Parkinson's disease (PD). Stimulation with frequencies less than 100 Hz (mostly 60 or 80 Hz) is considered low-frequency stimulation (LFS) and with frequencies greater than 100 Hz (mostly 130 or 150 Hz) is considered high-frequency stimulation (HFS). We conducted a comprehensive literature review and meta-analysis with a random-effect model. Ten studies with 132 patients were included in our analysis. The pooled results showed no significant difference in the total Unified Parkinson Disease Rating Scale part III (UPDRS-III) scores (mean effect, -1.50; p = 0.19) or the rigidity subscore between HFS and LFS. Compared to LFS, HFS induced greater reduction in the tremor subscore within the medication-off condition (mean effect, 1.01; p = 0.002), while no significance was shown within the medication-on condition (mean effect, 0.01; p = 0.92). LFS induced greater reduction in akinesia subscore (mean effect, -1.68, p = 0.003), the time to complete the stand-walk-sit (SWS) test (mean effect, -4.84; p < 0.00001), and the number of freezing of gait (FOG) (mean effect, -1.71; p = 0.03). These results suggest that two types of frequency settings may have different effects, that is, HFS induces better responses for tremor and LFS induces greater response for akinesia, gait, and FOG, respectively, which are worthwhile to be confirmed in future study, and will ultimately inform the clinical practice in the management of PD using STN-DBS.

Aims: Deep brain stimulation of the subthalamic nucleus (STN-DBS) has become an effective treatment strategy for patients with Parkinson's disease. However, the biological mechanism underlying DBS treatment remains poorly understood., Method: In this study, we investigated how STN-DBS modulated the brain network using a bimodal positron emission tomography (PET)/functional magnetic resonance imaging (fMRI) dataset. We first performed an activation likelihood estimation meta-analysis of 13 PET/SPECT studies concerning STN-DBS effects on resting-state brain activity in Parkinson's disease. Additionally, using a functional connectivity analysis in resting-state fMRI, we investigated whether these STN-DBS-affected regions were functionally connected to constitute an effective network., Results: The results revealed that STN-DBS reduced brain activity in the right thalamus, bilateral caudal supplementary area, and the left primary motor cortex, and it increased brain activity in the left thalamus during rest. Second, these STN-DBS-affected areas were functionally connected within an STN-DBS effective network., Conclusion: Deep brain stimulation of the subthalamic nucleus (STN-DBS) may deactivate the motor cortex as a remote and network effect, affecting the target and the neighboring subcortical areas. These areas may constitute an effective network of STN-DBS modulation. Our results shed light on the mechanisms of STN-DBS treatment from a network perspective and highlight the potential therapeutic benefits of targeted network modulation., (© 2017 John Wiley & Sons Ltd.)

Background: Resting state functional magnetic resonance imaging (rs-fMRI) has been applied to investigate topographic structure in Parkinson's disease (PD). Alteration of topographic architecture has been inconsistent in PD AIM: To investigate the network profile of PD using graph theoretical analysis., Method: Twenty six newly diagnosed PD and 19 age- and gender- matched healthy controls (HC) were included in our analysis. Small-world profile and topographic profiles (nodal degree, global efficiency, local efficiency, cluster coefficient, shortest path length, betweenness centrality) were measured and compared between groups, with age and gender as covariates. We also performed correlation analysis between topographic features with motor severity measured by UPDRS III., Results: Small-world property was present in PD. Nodal degree, global efficiency, local efficiency and characteristic path length consistently revealed disruptive sensorimotor network, and visual network to a less degree in PD. By contrast, default mode network (DMN) and cerebellum in PD showed higher nodal degree, global efficiency and local efficiency, and lower characteristic path length. Global and local efficiency in the midbrain was higher in PD excluding substantia nigra. PD group also exhibited lower cluster coefficient in the subcortical motor network (thalamus and caudate nucleus). No significant correlation was found between topographic properties and motor severity., Conclusion: PD exhibited disruptive sensorimotor and visual networks in early disease stage. DMN, a certain areas in the cerebellum and midbrain may compensate for disruptive sensorimotor and visual network in PD. Disruptive network architecture may be an early alteration of PD pathophysiology but may not serve as a valid biomarker yet., (Copyright © 2017. Published by Elsevier B.V.)

Background/aims: The topological organization of brain functional networks is impaired in Parkinson's disease (PD). However, the altered patterns of functional network hubs in different subtypes of PD are not completely understood., Methods: 3T resting-state functional MRI and voxel-based graph-theory analysis were employed to systematically investigate the intrinsic functional connectivity patterns of whole-brain networks. We enrolled 31 patients with PD (12 tremor dominant [TD] and 19 with postural instability/gait difficulty [PIGD]) and 22 matched healthy controls. Whole-brain voxel-wise functional networks were constructed by measuring the temporal correlations of each pair of brain voxels. Functional connectivity strength was calculated to explore the brain network hubs., Results: We found that both the TD and PIGD subtypes had comprehensive disrupted regions. These mainly involved the basal ganglia, cerebellum, superior temporal gyrus, pre- and postcentral gyri, inferior frontal gyrus, middle temporal gyrus, lingual gyrus, insula, and parahippocampal gyrus. Furthermore, the PIGD subgroup had more disrupted hubs in the cerebellum than the TD subgroup. These disruptions of hub connectivity were not correlated with the HY stage or disease duration., Conclusion: Our results emphasize the subtype-specific PD-related degeneration of brain hubs, providing novel insights into the pathophysiological mechanisms of connectivity dysfunction in different PD subgroups., (© 2017 S. Karger AG, Basel.)

Previous studies showed that the subthalamic nucleus (STN) plays a crucial role in Parkinson's disease (PD) pathophysiology. During rest, PD phenotypes exhibit different STN functional connectivity. STN functional connectivity was examined in 31 PD patients [12 tremor-dominant (TD) and 19 posture instability gait difficulty (PIGD)] and 22 healthy controls (HC). Compared with controls and PIGD patients, the TD patients exhibited higher functional connectivity between the bilateral STN and the left cerebellar anterior lobe. Compared with the TD and HC groups, in the PIGD subgroup functional connectivity was lower between the left putamen and the STN, as well as between the pons and the STN. In the PIGD subgroup, functional connectivity was greater between the STN and bilateral occipital lobe, which positively correlated with PIGD scores in PD patients. Additionally, STN-cerebellum connectivity positively correlated with the tremor score, and STN-putamen connectivity negatively correlated with the PIGD score in PD patients. PD subtypes with distinguished STN functional connectivity might explain the various pathophysiological mechanisms in tremor and gait disorders. Increased coupling between the STN and cerebellum might underlie the neural substrate of PD tremors. Lower functional connectivity between the STN and putamen might underpin PD gait and posture disturbances, while higher functional connectivity between the STN and visual cortex might play a compensatory role., (Copyright © 2016. Published by Elsevier B.V.)

In the present study, we detected the level of oligomeric form of α-synuclein in the red blood cells of ischemic stroke, Parkinson's disease, and normal people and compared the differences to assess the diagnosis potential of α-synuclein in ischemic stroke patients. 86 ischemic stroke, 100 PD, and 102 healthy cases were enrolled in the present study. Total protein amount in the red blood cells were quantified by BCA assay using spectrophotometer. Levels of oligomeric form of α-synuclein were characterized by a sandwich ELISA. Analysis of correlation analysis and receiver operating characteristic curve were conducted. Significant differences were detected in the levels of oligomeric forms of α-synuclein in different samples' blood cells (P < 0.05); the levels of total protein in (188.1 ± 33.9 mmol/L) healthy people were significantly higher than that of PD (147.7 ± 45.0 mmol/L) and ischemic stroke groups (142.9 ± 43.0 mmol/L) (P < 0.05). There was no correlation between the age of patients and level of α-synuclein (R (2) = 0.216 in ischemic stroke group and -0.104 in PD group) and the receiver operating characteristic curve analysis showed a high sensitivity of α-synuclein in discriminating ischemic stroke (sensitivity was 63.7 % and specificity was 9.6 %) and PD (sensitivity was 44.1 % and specificity was 12.5 %) patients from the controls. The levels of oligomeric form of α-synuclein of red blood cells in ischemic stroke and Parkinson's disease patients were both significant higher than normal people. And the level of oligomeric form α-synuclein showed a potential for diagnosis of ischemic stroke in clinic.

Aims: The aim of this study was to investigate the involvement of the ventral intermediate nucleus of thalamus (Vim) in the tremor- and akinetic-/rigid-related networks in Parkinson's disease (PD)., Methods: Tremor-dominant (TD) and akinetic-/rigid-dominant (ARD) PD patients were recruited and scanned by resting-state functional MRI. Functional connectivity from the Vim nucleus was analyzed., Results: In the TD patients, the Vim nucleus exhibited increased connectivity with the cerebellum/dentate nucleus, primary motor cortex (M1), supplementary motor area (SMA), premotor cortex, thalamus, globus pallidus, putamen, and parietal cortex compared with the controls, while the connections between the Vim nucleus and M1 and cerebellum/dentate nucleus had positive correlations with the tremor scores. In the ARD patients, the Vim nucleus only showed enhanced connectivity with the globus pallidus and limbic lobe compared with the controls, and no connectivity showed correlation against the akinetic-rigidity scores. TD patients had increased connectivity with the Vim nucleus in the cerebellum, M1, SMA, thalamus, globus pallidus, putamen, and parietal cortex compared with ARD patients., Conclusions: This study demonstrates that the Vim nucleus has an important role in the tremor-related network, but not in the akinetic-/rigid-related network. Our finding is helpful to explain the selective effect of Vim deep brain stimulation in PD., (© 2016 John Wiley & Sons Ltd.)