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Abstract Background Reactive astrogliosis has been demonstrated to have a role in Parkinson’s disease (PD); however, astrocyte-specific plasma glial fibrillary acidic protein (GFAP)’s correlation with PD progression remains unknown. We aimed to determine whether plasma GFAP can monitor and predict PD progression. Methods A total of 184 patients with PD and 95 healthy controls (HCs) were included in this prospective cohort study and followed-up for 5 years. Plasma GFAP, amyloid-beta (Aβ), p-tau181, and neurofilament light chain (NfL) were measured at baseline and at 1- and 2-year follow-ups. Motor and non-motor symptoms, activities of daily living, global cognitive function, executive function, and disease stage were evaluated using the Unified Parkinson’s Disease Rating Scale (UPDRS) part III, UPDRS-I, UPDRS-II, Montreal Cognitive Assessment (MoCA), Frontal Assessment Battery (FAB), and Hoehn and Yahr (H&Y) scales at each visit, respectively. Results Plasma GFAP levels were higher in patients with PD (mean [SD]: 69.80 [36.18], pg/mL) compared to HCs (mean [SD]: 57.89 [23.54], pg/mL). Higher levels of GFAP were observed in female and older PD patients. The adjusted linear mixed-effects models showed that plasma GFAP levels were significantly associated with UPDRS-I scores (β: 0.006, 95% CI [0.001–0.011], p = 0.027). Higher baseline plasma GFAP correlated with faster increase in UPDRS-I (β: 0.237, 95% CI [0.055–0.419], p = 0.011) and UPDRS-III (β: 0.676, 95% CI [0.023–1.330], p = 0.043) scores and H&Y stage (β: 0.098, 95% CI [0.047–0.149], p < 0.001) and faster decrease in MoCA (β: − 0.501, 95% CI [− 0.768 to − 0.234], p < 0.001) and FAB scores (β: − 0.358, 95% CI [− 0.587 to − 0.129], p = 0.002). Higher baseline plasma GFAP predicted a more rapid progression to postural instability (hazard ratio: 1.009, 95% CI [1.001–1.017], p = 0.033). Conclusions Plasma GFAP might be a potential biomarker for monitoring and predicting disease progression in PD.

Abstract Background The progression of sleep disturbances remains unclear in patients with early multiple system atrophy (MSA). We aimed to explore the frequency, severity, and coexistence of 2-year longitudinal changes of sleep disturbances including REM sleep behavior disorder (RBD), excessive daytime sleepiness (EDS), and Parkinson’s disease-related sleep problems (PD-SP) in early MSA. Methods MSA patients with a disease duration

Abstract Background Patients with amyotrophic lateral sclerosis (ALS) demonstrate great heterogeneity in the age at onset (AAO), which is closely related to the course of disease. However, most genetic studies focused on the risk of ALS, while the genetic background underlying AAO of ALS is still unknown. Methods To identify genetic determinants influencing AAO of ALS, we performed genome-wide association analysis using a Cox proportional hazards model in 2,841 patients with ALS (Ndiscovery = 2,272, Nreplication = 569) in the Chinese population. We further conducted colocalization analysis using public cis-eQTL dataset, and Mendelian randomization analysis to identify risk factors for AAO of ALS. Finally, functional experiments including dual-luciferase reporter assay and RT-qPCR were performed to explore the regulatory effect of the target variant. Results The total heritability of AAO of ALS was ~ 0.24. One novel locus rs10128627 (FRMD8) was significantly associated with earlier AAO by ~ 3.15 years (P = 1.54E-08, beta = 0.31, SE = 0.05). This locus was cis-eQTL of NEAT1 in multiple brain tissues and blood. Colocalization analysis detected association signals at this locus between AAO of ALS and expression of NEAT1. Furthermore, functional exploration supported the variant rs10128627 was associated with upregulated expression of NEAT1 in cell models and patients with ALS. Causal inference suggested higher total cholesterol, low-density lipoprotein, and eosinophil were nominally associated with earlier AAO of ALS, while monocyte might delay the AAO. Conclusions Collective evidence from genetic, bioinformatic, and functional results suggested NEAT1 as a key player in the disease progression of ALS. These findings improve the current understanding of the genetic role in AAO of ALS, and provide a novel target for further research on the pathogenesis and therapeutic options to delay the disease onset.

BackgroundCystatin C (CysC) levels in amyotrophic lateral sclerosis (ALS) have been found changes, however, the associations between serum CysC levels and the progression and survival of ALS remain largely unknown.MethodsA total of 1,086 ALS patients and 1,026 sex-age matched healthy controls (HCs) were enrolled in this study. Serum CysC, other renal function, and metabolic parameters were measured. Correlation analysis and binary logistic regression were used to explore the factors related to serum CysC. Kaplan–Meier curve and Cox regression model were used for survival analysis.ResultsCysC levels were significantly higher in ALS patients compared to HCs (0.94 vs. 0.85 mg/L, p

Abstract Objectives High visit‐to‐visit blood pressure variability (BPV) was found to be associated with cognitive decline in the elderly. This study aimed to investigate the impact of visit‐to‐visit BPV on cognition in patients with early‐stage Parkinson's disease (PD). Design This is a retrospective analysis of a prospective cohort. Setting and participants A total of 297 patients with early‐stage PD (103 mild cognitive impairments [PD‐MCI] and 194 normal cognitions [PD‐NC] at baseline) were included from the Parkinson's Progression Markers Initiative study. Methods Variation independent of mean (VIM) of the first year was used as the indicator of BPV. The Montreal Cognitive Assessment (MoCA) was used to assess global cognition. Patients were divided into PD‐MCI and PD‐NC according to the MoCA score at baseline. Longitudinal cerebrospinal fluid (Aβ‐42, Aβ, α‐synuclein, neurofilament light protein, tau phosphorylated at the threonine 181 position, total tau, glial fibrillary acidic protein) and serum (neurofilament light protein) biomarkers were assessed. The Bayesian linear growth model was used to evaluate the relationship between baseline BPV and the rate of change in cognition and biomarkers. Results Higher systolic VIM of the first year was related to a greater rate of decline in MoCA score in the following years in PD‐MCI (β = −.15 [95% CI −.29, −.01]). No association was found between BPV and biomarkers. Conclusion and implications Higher systolic VIM predicted a steeper decline in cognitive tests in PD‐MCI independently from the mean value of blood pressure, orthostatic hypotension, and supine hypertension.

Abstract We modified the original Unified Multiple System Atrophy Rating Scale (UMSARS) for remote video-based visits by excluding ocular motor dysfunction, increased tone, and body sway, resulting in a 23-item UMSARS (mUMSARS-23). The mUMSARS-23 demonstrated excellent reliability and strong validity when compared to the original scale, making it a promising tool for conducting video-based virtual assessments in patients with multiple system atrophy.

Abstract Background Recently, several rare variants of SPTLC1 were identified as disease cause for juvenile amyotrophic lateral sclerosis (ALS) by disrupting the normal homeostatic regulation of serine palmitoyltransferase (SPT). However, further exploration of the rare variants in large cohorts was still necessary. Meanwhile, SPTLC2 plays a similar role as SPTLC1 in the SPT function. Methods To explore the genetic role of SPTLC1 and SPTLC2 in ALS, we analyzed the rare protein-coding variants in 2011 patients with ALS and 3298 controls from the Chinese population with whole exome sequencing. Fisher’s exact test was performed between each variant and disease risk, while at gene level over-representation of rare variants in patients was examined with optimized sequence kernel association test (SKAT-O). Results Totally 33 rare variants with minor allele frequency

ObjectivesMutations in glucocerebrosidase (GBA1) can change the clinical phenotype of Parkinson’s disease (PD). This study aimed to explore the clinical characteristics of freezing of gait (FOG) in PD patients with GBA1 mutations.MethodsA whole-exome sequencing analysis was used to identify the GBA1 mutations (pathogenic or likely pathogenic) and exclude other PD-related gene mutations. A forward binary logistic regression model was conducted to identify the associated factors of FOG. The stepwise multiple linear regression analysis models were used to explore the effect of FOG on quality of life.ResultsThe prevalence of FOG in patients with GBA1 mutations (30/95, 31.6%) was significantly higher than those in patients without GBA1 mutations (152/760, 20%) (p = 0.009). A higher (i.e., worse) Unified PD Rating Scale part III score (OR = 1.126, 95%CI = 1.061–1.194, p

BackgroundMalnutrition is associated with poor survival in some diseases. However, the nutritional status in multiple system atrophy (MSA) is unknown, and the significance of malnutrition for the prediction of mortality in MSA has not been well established.ObjectiveWe aimed to determine the prevalence of malnutrition and the prognostic value of malnutrition in patients with early-stage MSA.MethodsPatients diagnosed with early phase MSA (disease duration

Abstract The electrolyte serves as a key component in organic electrochemical transistors (OECTs) and allows for the modulation of the conductivity of the polymer channel by applying a voltage to the gate electrode. Different from liquid electrolytes in OECTs, the solid electrolyte is beneficial for the integration in the circuit and shows great stability. And considering the fabrication of the device, developing a new solution‐processed solid electrolyte for OECTs is a critical area of research. In this work, the organic–inorganic perovskite is used as the electrolyte to fabricate polymer electrochemical transistors due to its solid‐phase ion migration kinetics. To realize this goal, a separate polyethylene oxide (PEO) layer on top of the poly[2‐methoxy‐5‐(2‐ethylhexyloxy)‐1,4‐phenylenevinylene] (MEH‐PPV) layer plays a crucial role since it can affect the electric field and the ion motion. More importantly, based on this device structure, both a polymer light‐emitting electrochemical transistor and the polymer electrochemical phototransistor are realized. The solution‐processed solid organic–inorganic perovskite electrolytes can enable the development of integration in OECTs, which have significant potential for multifunctional applications.

Abstract. Background:. Essential tremor (ET) and Parkinson's disease (PD) are common movement disorders. ET-PD syndrome is characterized by the occurrence of PD in patients with a previous history of ET, which may be an independent phenotype distinct from PD. This study aims to identify clinical characteristics and subtypes in ET-PD. Methods:. A total of 93 newly diagnosed ET-PD patients and 93 newly diagnosed PD patients matched for age, sex, education, and disease duration of PD were selected using propensity score matching analysis. The K-means cluster analysis was performed for 11 variables derived from the ET-PD group, and cluster profiles were established through statistical analysis of demographic and clinical variables. Results:. The ET-PD group consisted of a high number of patients with a family history of ET exhibiting evident tremor with milder hypokinesia and postural instability symptoms, as compared to the PD group. Through the cluster analysis, two clusters of ET-PD patients were identified. The ET-PD cluster 1 (n = 34) had a shorter ET duration before PD onset, lower number of patients with a family history of ET, higher unified PD rating scale instability scores, higher non-motor symptoms scores (non-motor symptoms scale D1 scores, Hamilton depression scale scores, Hamilton anxiety scale scores, and PD sleep scale-2 scores), and higher Chinese version of the PD questionnaire-39 scores relative to the ET-PD cluster 2 (n = 59). Conclusion:. ET-PD patients had significantly different characteristics for motor symptoms as compared to PD patients, and may be distinctly divided into two clinical subtypes, namely, the ET-PD complex type and the ET-PD simple type.

BackgroundThe 2008 criteria for the diagnosis of multiple system atrophy (MSA) has been widely used for more than 10 years, but the sensitivity is low, particularly for patients in the early stage. Recently, a new MSA diagnostic criteria was developed.ObjectiveThe objective of the study was to assess and compare the diagnostic utility of the new movement disorder society (MDS) MSA criteria with the 2008 MSA criteria.MethodsThis study included patients diagnosed with MSA between January 2016 and October 2021. All patients underwent regular face-to-face or telephonic follow-ups every year until October 2022. A total of 587 patients (309 males and 278 females) were retrospectively reviewed to compare the diagnostic accuracy of the MDS MSA criteria to that of the 2008 MSA criteria (determined by the proportion of patients categorized as established or probable MSA). Autopsy is the gold standard diagnosis of MSA, which is not available in clinical practice. Thus, we applied the 2008 MSA criteria at the last review as the reference standard.ResultsThe sensitivity of the MDS MSA criteria (93.2%, 95% CI = 90.5–95.2%) was significantly higher than that of the 2008 MSA criteria (83.5%, 95% CI = 79.8–86.6%) (P < 0.001). Additionally, the sensitivity of the MDS MSA criteria was maintained robustly across different subgroups, defined by diagnostic subtype, disease duration, and the type of symptom[s] at onset. Importantly, the specificities were not significantly different between the MDS MSA criteria and the 2008 MSA criteria (P > 0.05).ConclusionThe present study demonstrated that the MDS MSA criteria exhibited good diagnostic utility for MSA. The new MDS MSA criteria should be considered as a useful diagnostic tool for clinical practice and future therapeutic trials.

Abstract Background Recently, several rare variants of TP73 were identified as potential disease cause for amyotrophic lateral sclerosis (ALS) in the European population. However, further replication was still necessary, especially in cohorts with different ethnic backgrounds. Methods To explore the genetic role of TP73 in ALS in the Asian population, we analyzed the rare protein-coding variants in 2011 patients with ALS and 3298 controls with whole-exome sequencing. Fisher’s exact test was performed between each variant and disease risk, while at gene level over-representation of rare variants in patients was examined with optimized sequence kernel association test. Results Totally 24 rare variants with minor allele frequency

Abstract Background The progression of motor and non-motor symptoms (NMS) and the sensitivity of each item of the Unified Multiple System Atrophy Rating Scale (UMSARS) to change remain unclear in Chinese patients with early-stage multiple system atrophy (MSA). We investigated the evolution of motor symptoms and NMS in early-stage MSA and the sensitivity of each item included in the UMSARS to change over a 2-year follow-up. Methods Motor symptoms and NMS were recorded at baseline and at 1- and 2-year follow-ups based on the UMSARS and the NMS scale. Generalized estimating equation models were used. The sensitivity of an item included in the UMSARS to change was assessed by calculating a standardized effect using the mean annual change divided by the standard deviation of the change. Results We enrolled 246 consecutive patients with MSA and 97 MSA completed the 2-year follow-up. The mean total UMSARS score increased by 11.90 and 22.54 points at the 1- and 2-year follow-ups, respectively. UMSARS-I items associated with motor functions were more sensitive to change and those associated with autonomic dysfunction showed less sensitivity to change. Items 4 (tremor at rest), 5 (action tremor), and 3 (ocular motor dysfunction) of the UMSARS-II were less sensitive to change. The prevalence and severity of NMS significantly increased over the 2-year follow-up. Conclusions We observed significant progression in motor symptoms and NMS in patients with early-stage MSA. Our results provide useful information to support the revision of the UMSARS.

ObjectivveThis study aimed to explore the prevalence and clinical correlates of apathy in amyotrophic lateral sclerosis (ALS) in a cohort of Chinese patients.MethodsA total of 1,013 ALS patients were enrolled in this study. Apathy was recorded during face-to-face interviews using Frontal Behavioral Inventory, and other patient characteristics, including depression, anxiety, and cognitive function, were collected using Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HARS), and Chinese version of Addenbrooke’s Cognitive Examination-revised. Health-related quality of life of ALS patients and their caregivers was also evaluated, and the potential factors associated with apathy were explored using forward binary regression analysis. Survival was analyzed using the Cox proportional hazards model.ResultsThe prevalence of apathy in all patients was 28.9%. Patients in the late disease stage had a higher prevalence of apathy than those in the early disease stage. Furthermore, patients with apathy had a lower ALS Functional Rating Scale revised (ALSFRS-R) score, higher HDRS score, HARS score and higher proportion of reported problems in the anxiety/depression. Additionally, their caregivers had higher score of depression and higher Zarit-Burden Interview scores. Multivariate regression analysis revealed that apathy in ALS was associated with the onset region (p = 0.027), ALSFRS-R score (p = 0.007), depression (p = 0.001) and anxiety (p

Objective: The predictive factors for wheelchair dependence in patients with multiple system atrophy (MSA) are unclear. We aimed to explore the predictive factors for early-wheelchair dependence in patients with MSA focusing on clinical features and blood biomarkers. Methods: This is a prospective cohort study. This study included patients diagnosed with MSA between January 2014 and December 2019. At the deadline of October 2021, patients met the diagnosis of probable MSA were included in the analysis. Random forest (RF) was used to establish a predictive model for early-wheelchair dependence. Accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were used to evaluate the performance of the model. Results: Altogether, 100 patients with MSA including 49 with wheelchair dependence and 51 without wheelchair dependence were enrolled in the RF model. Baseline plasma neurofilament light chain (NFL) levels were higher in patients with wheelchair dependence than in those without (P = 0.037). According to the Gini index, the five major predictive factors were disease duration, age of onset, Unified MSA Rating Scale (UMSARS)-II score, NFL, and UMSARS-I score, followed by C-reactive protein (CRP) levels, neutrophil-to-lymphocyte ratio (NLR), UMSARS-IV score, symptom onset, orthostatic hypotension, sex, urinary incontinence, and diagnosis subtype. The sensitivity, specificity, accuracy, and AUC of the RF model were 70.82 %, 74.55 %, 72.29 %, and 0.72, respectively. Conclusion: Besides clinical features, baseline features including NFL, CRP, and NLR were potential predictive biomarkers of early-wheelchair dependence in MSA. These findings provide new insights into the trials regarding early intervention in MSA.

Background: Variants in the annexin A11 gene (ANXA11) have been reported to be associated with amyotrophic lateral sclerosis (ALS). These variants may be involved in the pathogenesis of ALS by causing defects in intracellular protein trafficking. However, the genetic spectrum and clinical characteristics of ALS patients with ANXA11 variants are largely unknown. Methods: Genetic analysis was performed on 1587 Chinese patients with ALS. Eight software packages were used to predict the deleteriousness of missense variants. In addition, we searched PubMed, Embase, and Web of Science for relevant literature and meta-analysed variant frequencies. Results: In our ALS cohort, we identified 20 non-synonymous variants in 29 ALS patients, including one stop-gain, one frameshift, and 18 rare missense variants with seven predicted pathogenic variants. In a literature review of 11 reported studies that included 69 patients, 37 ANXA11 variants were reported, with a frequency of 1.7%, which was similar to that in our cohort (1.8%). Both our cohort and previous reports showed that ANXA11 carriers were more commonly males than females (12/17 vs. 19/31). Patients carrying ANXA11 variants affecting the C-terminal of the protein had earlier disease onset and shorter survival times than those carrying variants affecting the N-terminal. We found a relatively longer median survival time than that previously reported (53.6 months vs. 46.0 months). Additionally, Caucasian ANXA11 carriers were more likely to have cognitive impairment, typically frontotemporal dementia (FTD) than their Asian counterparts (20.0% vs. 14.3%). While more than half of the patients in our cohort had cognitive impairment, none had FTD. Conclusion: In our and previously published cases, ALS-associated ANXA11 variants predominantly affected the N- and C-terminal conserved domains. ANXA11 variant carriers are typically male and cognitively impaired. Our study extends the genotypic and phenotypic spectra of ALS patients with ANXA11 variants. Further expansion of the sample size is needed to analyse the clinical and non-motor symptom characteristics of patients and to deepen the understanding of the pathogenesis of ANXA11-associated ALS.

Abstract The neutrophil-to-lymphocyte ratio (NLR), an inflammatory marker, can predict the prognosis of neurodegenerative diseases. However, the significance of NLR for the prognosis of multiple system atrophy (MSA) has not been reported. We aimed to examine the prognostic significance of NLR in MSA. A total of 169 MSA patients and 163 matched healthy controls (HCs) were enrolled. MSA patients were divided into three groups according to the tertiles of their NLR. Kaplan–Meier survival analysis and Cox regression model were used to assessing the effect of NLR on survival. An independent validation cohort of 56 consecutive patients with probable MSA who met the inclusion criteria was included. The NLR was significantly higher in patients with MSA than that in HCs. The survival duration in patients with MSA in group 3 was shorter than that in patients in the other two groups (P = 0.013). In the multivariable Cox regression model, a higher NLR increased the risk of mortality in patients with MSA after adjusting for confounding factors (HR = 1.922, P = 0.035). Additionally, a higher NLR increased the risk of mortality in MSA with predominant cerebellar ataxia (MSA-C) (HR = 2.398, P = 0.033) and in men (HR = 3.483, P = 0.027). The concordance index for the multivariate Cox regression model was more than 0.7 both in the primary cohort and external validation cohort. Patients with MSA had a higher NLR than did HCs. A high NLR increased the risk of mortality with MSA, especially in MSA-C and in men.

Abstract Objective There is increasing evidence that amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease impacting large-scale brain networks. However, it is still unclear which structural networks are associated with the disease and whether the network connectomics are associated with disease progression. This study was aimed to characterize the network abnormalities in ALS and to identify the network-based biomarkers that predict the ALS baseline progression rate. Methods Magnetic resonance imaging was performed on 73 patients with sporadic ALS and 100 healthy participants to acquire diffusion-weighted magnetic resonance images and construct white matter (WM) networks using tractography methods. The global and regional network properties were compared between ALS and healthy subjects. The single-subject WM network matrices of patients were used to predict the ALS baseline progression rate using machine learning algorithms. Results Compared with the healthy participants, the patients with ALS showed significantly decreased clustering coefficient C p (P = 0.0034, t = 2.98), normalized clustering coefficient γ (P = 0.039, t = 2.08), and small‐worldness σ (P = 0.038, t = 2.10) at the global network level. The patients also showed decreased regional centralities in motor and non-motor systems including the frontal, temporal and subcortical regions. Using the single-subject structural connection matrix, our classification model could distinguish patients with fast versus slow progression rate with an average accuracy of 85%. Conclusion Disruption of the WM structural networks in ALS is indicated by weaker small-worldness and disturbances in regions outside of the motor systems, extending the classical pathophysiological understanding of ALS as a motor disorder. The individual WM structural network matrices of ALS patients are potential neuroimaging biomarkers for the baseline disease progression in clinical practice.

Abstract Idiopathic blepharospasm shows a female predominance in prevalence, whether there are sex-related differences in distributions of nonmotor symptoms (NMSs) and predictors of quality of life are unknown. Four hundred and twenty-five patients with idiopathic blepharospasm were consecutively recruited, and underwent assessments including dystonia severity, mood disturbances, sleep disturbances, cognition, ocular symptoms, and quality of life. Frequencies and distributions of NMSs, and predictors of quality of life in female and male patients were investigated. NMSs existed in majority of male (94.0%) and female (95.8%) patients. The frequencies of depression, cognition dysfunction, and poor sleep quality were higher in female patients, while the frequency of excessive daytime sleepiness was higher in male patients. More female (79.5%) patients had multiple NMS domains affected than male (70.1%) patients (p = 0.040). Quality of life was associated with depression, anxiety and motor severity for female patients (adjusted R2 = 0.367, p

BackgroundAccumulating evidence has suggested that cystatin C is associated with cognitive impairment in patients with neurodegenerative diseases. However, the association between cystatin C and cognitive decline in patients with multiple system atrophy (MSA) remains largely unknown.ObjectivesThe objective was to determine whether cystatin C was independently associated with cognitive decline in patients with early-stage MSA.MethodsPatients with MSA underwent evaluation at baseline and the 1-year follow-up. Cognitive function was evaluated with Montreal cognitive assessment (MoCA). Changes in the MoCA score and the absolute MoCA score at the 1-year assessment were considered the main cognitive outcome. The cystatin C concentrations in patients with MSA and age, sex, and body mass index matched-healthy controls (HCs) were measured. A multiple linear regression model was used to test the association between cystatin C and cognitive decline.ResultsA total of 117 patients with MSA and 416 HCs were enrolled in the study. The cystatin C levels were significantly higher in patients with MSA than in HCs (p

BackgroundThe different clinical characteristics and prognostic values of the motor-nonmotor subtypes of Parkinson’s disease (PD) have been established by previous studies. However, the consistency of motor-nonmotor subtypes in patients with early-stage Parkinson’s disease required further investigation. The present study aimed to evaluate the consistency of motor-nonmotor subtypes across five years of follow-up in a longitudinal cohort.Materials and methodsPatients were classified into different subtypes (mild-motor–predominant, intermediate, diffuse malignant; or tremor-dominant, indeterminate, postural instability and gait difficulty) according to previously verified motor-nonmotor and motor subtyping methods at baseline and at every year of follow-up. The agreement between subtypes was examined using Cohen’s kappa and total agreement. The determinants of having the diffuse malignant subtype as of the fifth-year visit were explored using logistic regression.ResultsA total of 421 patients were included. There was a fair degree of agreement between the baseline motor-nonmotor subtype and the subtype recorded at the one-year follow-up visit (κ = 0.30 ± 0.09; total agreement, 60.6%) and at following years’ visits. The motor-nonmotor subtype had a lower agreement between baseline and follow-up than did the motor subtype. The baseline motor-nonmotor subtype was the determinant of diffuse malignant subtype at the fifth-year visit.ConclusionMany patients experienced a change in their motor-nonmotor subtype during follow-up. Further studies of consistency in PD subtyping methods should be conducted in the future.

Abstract Background Multiple system atrophy (MSA) is an incurable neurodegenerative disease. We aimed to investigate the health‐related quality of life (HRQoL) and the determinants of HRQoL in patients with MSA. Methods The five‐level EuroQol five‐dimensional questionnaire (EQ‐5D‐5L) was used to evaluate patients’ HRQoL. The results of HRQoL were indicated by the EQ‐5D‐5L index values and visual analog scale (EQ VAS) scores. Specific scales were used to measure disease severity, cognition, frontal lobe function, anxiety, depression, fatigue, and sleep disorders. The beta mixture model and the linear regression model were used to explore the determinants of HRQoL in patients with MSA. Results A total of 205 patients with cerebellar variants (MSA‐C; 53.9%) and 175 patients with parkinsonian variants (MSA‐P; 46.1%) were included in this cross‐sectional study. The mean values of the EQ‐5D‐5L index values and EQ VAS scores were .558 and 59.5, respectively. Problem with mobility was the problem reported by the highest proportion of patients (92.1%), followed by problems with usual activities (88.7%), self‐care (81.3%), anxiety/depression (72.1%), and pain/discomfort (53.9%). The determinants of the lower EQ‐5D‐5L index values in patients with MSA were greater disease severity, fatigue, Parkinson's disease‐related sleep problems (PD‐SP), depressive mood, and anxious mood. Greater disease severity, fatigue, and depressive mood were associated with lower EQ VAS scores. Conclusion The problem reported most frequently by Chinese individuals with MSA was mobility. In addition to the greater disease severity of MSA, fatigue, PD‐SP, depression, and anxiety were determinants of poor HRQoL.

ObjectiveCognitive impairment (CI) in patients with cervical dystonia (CD) has been reported in many studies but with inconsistent findings. We investigated the prevalence, characteristics, and clinical factors related to CI in Chinese patients with CD.MethodsSixty-eight patients with CD and 68 healthy controls (HCs) were included in the study. Demographic and clinical data were investigated. A logistic regression analysis was conducted to discriminate the clinical factors associated with CI in patients with CD. A cluster analysis was performed to explore the different characteristics within the group of CD patients with CI.ResultsWe found that 42 (61.76%) patients with CD had CI. The most frequent CI domain was visuospatial function (39.71%), followed by memory (38.24%), attention/working memory (29.41%), language (25.00%), and executive function (23.53%). CD patients with CI were older, less educated, had an older age of onset, more severe motor symptoms and disability, and experienced more pain than CD patients without CI. The presence of CI in patients with CD was associated with less education (OR = 0.802, p = 0.034) and a higher Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) severity subscore (OR = 1.305, p = 0.001). The cluster analysis identified two different subgroups of patients, one with relatively mild cognitive impairment and the other with relatively severe cognitive impairment.ConclusionCI is relatively common in Chinese patients with CD, with the most common CI domain of the visuospatial function. In the present study, CI in patients with CD was associated with less education and more severe motor symptoms, and patients with CI may be further divided into two subgroups based on different extent and domain of cognitive decline.

Abstract Background Cognitive impairment is a common non-motor symptom in patients with Parkinson’s disease (PD). Mild cognitive impairment (MCI) is also prevalent in nondemented PD patients, even in newly diagnosed PD patients. The possible impacts of MCI on brain function activities for PD patients need more investigation, and the potential of emerging technologies for detecting underlying pathophysiology of cognitive signs in PD can be further improved. Method Forty-seven newly diagnosed drug-naïve PD patients (28 PD-MCI patients and 19 PD patients with cognitively unimpaired (PD-CU)) and 28 healthy controls (HCs) underwent resting-state functional MRI. The connectivity patterns of specific networks were investigated through the independent component analysis among PD-MCI, PD-CU and HCs groups. Results The independent component analysis revealed significantly decreased functional connectivity (FC) of the default mode network, visual network and sensorimotor network in the PD-MCI subgroup compared with the HC group. Furthermore, FC of the default mode network was positively correlated with memory scores from the brief visuospatial memory test-revised, and FC of the visual network was positively correlated with visuospatial scores from the clock copying test in the PD-MCI group. In all patients with PD, FC of the sensorimotor network negatively correlated with motor severity scores from the Unified PD Rating Scale (UPDRS) part III. On the other hand, the potential damage was more likely to occur in FC between the sensorimotor network and limbic network, and between the ventral attention network and visual network in all PD patients. Conclusions Newly diagnosed drug-naïve PD-MCI patients showed characteristic damage of FC within the default mode network, visual network and sensorimotor network, and all PD patients presented impaired FC between the sensorimotor network and limbic network, and FC between the ventral attention network and visual network. These network-wide functional aberrations may underline the pathophysiology of PD.

Abstract Background The study aimed to appraise the health-related quality of life (HRQoL) measured by the five-level EuroQol-5 dimensions (EQ-5D-5L) in amyotrophic lateral sclerosis (ALS), and to explore the associations between non-motor symptoms (mood changes, cognitive disturbances and sleep disturbances). Methods EQ-5D-5L descriptive scores were converted into a single aggregated “health utility” score. A calibrated visual analog scale (EQ-VAS) was used for self-rating of current health status. Multiple logistic regression analysis was used to explore the factors associated with HRQoL. Results Among the 547 enrolled ALS patients who were assessed using EQ-5D-5L, the highest frequency of reported problems was with usual activities (76.7%), followed by self-care (68.8%) and anxiety/depression (62.0%). The median health utility score was 0.78 and the median EQ-VAS score was 70. Clinical factors corresponding to differences in the EQ-5D-5L health utility score included age of onset, onset region, the ALS Functional Rating Scale-Revised (ALSFRS-R) score, and King’s College stages. Patients with depression, anxiety, and poor sleep had lower health utility scores. Patients with excessive daytime sleepiness and rapid eye movement sleep behavior disorder had lower EQ-VAS scores. Multivariate logistic analysis indicated that ALSFRS-R scores, depression, and anxiety were associated with health utility scores. After adjusting other parameters, ALSFRS-R score, stages, and depression were significantly associated with EQ-VAS scores (P

Abstract The progression of global non-motor symptoms (NMS) in Chinese patients with Parkinson’s disease (PD) has not been explored. We aimed to examine the longitudinal evolution of overall NMS in a 3-year prospective Chinese cohort with early-stage PD. We included 224 patients with early PD who underwent annual evaluation of motor and non-motor symptoms. NMS was assessed using the non-motor symptoms scale (NMSS). We observed an increased number of NMS in the majority of the NMSS domains except mood/apathy and sexual dysfunctions. Significant deterioration was observed in the sleep/fatigue, perceptual problems/hallucinations, attention/memory, gastrointestinal, urinary, and miscellaneous domains during the follow-up (P

BackgroundA growing number of voxel-based morphometry (VBM) studies have demonstrated widespread gray matter (GM) abnormalities in myotonic dystrophy type 1 (DM1), but the findings are heterogeneous. This study integrated previous VBM studies to identify consistent GM changes in the brains of patients with DM1.MethodsSystematic retrieval was conducted in Web of Science, Pubmed, and Embase databases to identify VBM studies that met the inclusion requirements. Data were extracted. The Seed-based d Mapping with Permutation of Subject Images (SDM-PSI) software was used for meta-analysis of voxel aspects.ResultsA total of eight VBM studies were included, including 176 patients with DM1 and 198 healthy controls (HCs). GM volume in patients with DM1 was extensively reduced compared with HCs, including bilateral rolandic operculum, bilateral posterior central gyrus, bilateral precentral gyrus, right insula, right heschl gyrus, right superior temporal gyrus, bilateral supplementary motor area, bilateral middle cingulate gyrus/paracingulate gyrus, left paracentral lobule, and bilateral caudate nucleus. Meta-regression analysis found that regional GM abnormalities were associated with disease duration and Rey-Osterrieth Complex Figure (ROCF)-recall scores.ConclusionDM1 is not only a disease of muscle injury but also a multisystem disease involving brain motor and neuropsychiatric regions, providing a basis for the pathophysiological mechanism of DM1.

PurposeThe study aimed to evaluate the health-related quality of life (HRQoL) measured by the five-level EuroQol-5 dimensions (EQ-5D-5L) in patients with cervical dystonia, and to explore the determinants of HRQoL in patients with cervical dystonia.MethodsEQ-5D-5L health state profiles were converted into a single aggregated “health utility” score. A calibrated visual analog scale (EQ VAS) was used for self-rating of current health status. Multiple linear regression analysis was used to explore the factors associated with HRQoL in cervical dystonia.ResultsA total of 333 patients with cervical dystonia were enrolled in the analysis, with an average age of 44.3 years old. The most common impaired dimension of health was anxiety/depression (73.6%), followed by pain/discomfort (68.2%) and usual activities (48%). The median health utility score was 0.80, and the median EQ VAS score was 70.2. Multivariate linear regression analysis indicated that disease duration and the scores of the Hamilton Depression Rating Scale (HDRS), Pittsburgh sleep quality index (PSQI), Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Part I, and TWSTRS Part III were associated with the health utility scores. After adjusting other parameters, the TWSTRS Part III score and the HDRS score were significantly associated with the EQ VAS scores (p < 0.05).ConclusionThis study evaluated HRQoL in patients with cervical dystonia using the Chinese version of the EQ-5D-5L scale. We found that, besides motor symptoms, non-motor symptoms, including depression, pain, and sleep quality, could be greater determinants of HRQoL in patients with cervical dystonia. Management of non-motor symptoms, therefore, may help improve HRQoL in patients with cervical dystonia.

Abstract Objective To evaluate whether the control status of type 2 diabetes mellitus (DM) influences the progression of Parkinson’s disease (PD). Methods We conducted a prospective cohort study from March 2009 to August 2020. Patients at baseline were categorized into DM and non‐DM groups, and those with DM were further classified into the well and poorly controlled DM groups based on the 7.0% of glycated hemoglobin (HbA1C) levels. Multivariate Cox proportional hazards regression models were used to explore the predictors for PD‐related outcomes by hazard ratios (HRs) and 95% confidence intervals (CIs). Results Of the 379 patients enrolled, 49 (12.9%) had DM, and 22 of DM (44.9%) were poorly controlled. The adjusted HRs were 2.060 (95% CI 1.165‐3.641) for United Rating Scale (UPDRS) III score increased ≥14 in the poorly controlled‐DM group, and 1.066 (95% CI 0.572‐1.986) in the well‐controlled DM group, relative to the non‐DM group (p trend = 0.025), after adjusting for sex, age, age of onset, body mass index, and UPDRS III and Montreal Cognitive Assessment (MoCA) scores at baseline. The adjusted HRs were 2.079 (95% CI 1.212‐3.566) for reaching Hoehn & Yahr stage ≥3 in the poorly controlled DM group, and 0.879 (95% CI 0.413‐1.871) in the well‐controlled DM group, compared with the non‐DM group (p trend = 0.021). Time to death or time to MoCA 3‐point decrease were not significantly different among the three groups. Interpretation Poorly controlled DM is an independent risk factor contributing to motor progression in PD. Our study highlights the importance of adequate control of diabetes in PD.

Abstract Background Facial (lip and jaw) tremor (FT) is associated with Parkinson’s disease (PD) but few studies have been conducted to explore its clinical profile. We performed this study to investigate the prevalence and clinical correlates of FT in PD, and further to evaluate its effect on disease progression. Methods A retrospective, cross-sectional (n = 2224) and longitudinal (n = 674) study was conducted. The presence of FT was based on a ≥ 1 score in the United PD Rating Scale (UPDRS) item 20A. Group comparisons were conducted, followed by a forward binary logistic regression analysis. Inverse probability of treatment weighting (IPTW) based on the propensity score and weighted or unweighted Cox regression models were used to explore the impact of FT on five clinical milestones including death, UPDRS III 11-point increase, Hoehn and Yahr (H&Y) stage reaching 3, dyskinesia development, and Montreal Cognitive Assessment 3-point decrease. Results FT was presented in 403 patients (18.1%), which showed increasing trends with disease duration and H&Y score. Age (P

Abstract Background Abnormal eye movements are common in spinocerebellar ataxias Type 3 (SCA3). We conducted the research to explore the frequency of abnormal eye movements in Chinese patients with SCA3, to compare the demographic and clinical characteristics between SCA3 patients with and without each type of abnormal eye movement, and to explore the correlation between abnormal eye movements and the severity of ataxia. Methods Seventy-four patients with SCA3 were enrolled in this cross-sectional study. Six types of abnormal eye movements including impaired smooth pursuit, increased square-wave jerks (SWJ), gaze-evoked nystagmus (GEN), slowing of saccades, saccadic hypo/hypermetria and supranuclear gaze palsy were evaluated by experienced neurologists. The severity of ataxia was evaluated by Scale for the Assessment and Rating of Ataxia (SARA). Results The prevalence of impaired smooth pursuit, increased SWJ, GEN, slowing of saccades, saccadic hypo/hypermetria and supranuclear gaze palsy in Chinese SCA3 patients was 28.4, 13.5, 78.4, 41.9, 23.0, and 5.4%, respectively. SCA3 patients with GEN had higher scores of International Cooperative Ataxia Rating Scale (ICARS-IV) and total ICARS, and longer length of CAG repeat than patients without GEN. SCA3 patients with slowing of saccades had a longer disease duration, higher scores of ICARS-I, ICARS-II, total ICARS and SARA than patients without slowing of saccades. SCA3 patients with saccadic hypo/hypermetria had higher scores of ICARS-III, ICARS-IV, and SARA than patients without saccadic hypo/hypermetria. The demographic and clinical characteristics did not differ significantly between SCA3 patients with and without impaired smooth pursuit, increased SWJ, or supranuclear gaze palsy. Multivariate linear regression showed that the number of abnormal eye movements (0–6), disease duration, Hamilton Depression Rating Scale-24 (HDRS-24) score, and CAG repeat length were positively correlated with SARA score, whereas Montreal Cognitive Assessment (MoCA) score was negatively correlated with SARA score in SCA3. Conclusions An increased number of abnormal eye movement types correlated with the severity of ataxia in SCA3.

Abstract This study aimed to explore the effect of pre-existing essential tremor (ET) history on the disease progression of Parkinson’s disease (PD). We recruited and followed-up a group of PD patients from March 2009 to July 2020. The ET history of each patient was obtained by retrospective interviews or past medical records. Cox proportional hazards models with inverse probability of treatment weighting (IPTW) were used to estimate the hazard ratio (HR) with 95% confidence intervals (CIs). Of 785 patients who completed the followed-up visits, 61 patients (7.8%) reported a history of pre-existing ET. Cox regression models after IPTW indicated that the positive ET history in patients with PD was protective against time to United PD Rating Scale III 14-point increase (HR = 0.301, 95% CI = 0.134–0.678, P = 0.004), time to akinesia and rigidity 8-point increase (HR = 0.417, 95% CI = 0.218–0.796, P = 0.008), time to conversion to Hoehn and Yahr stage 3 (HR = 0.356, 95% CI = 0.131–0.969, P = 0.043), time to develop dyskinesia (HR = 0.160, 95% CI = 0.037–0.698, P = 0.015), and time to Montreal Cognitive Assessment 3-point decrease (HR = 0.389, 95% CI = 0.160–0.946, P = 0.037), but had no relationship with time to tremor 4-point increase (HR = 1.638, 95% CI = 0.822–3.266, P = 0.161) and time to death (HR = 0.713, 95% CI = 0.219–2.319, P = 0.574). Our study indicated that ET history in patients with PD is associated with a benign prognosis with slower motor and non-motor progression.

Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disorder caused by CAG repeats expansion. There is a paucity of comprehensive clinical analysis in Chinese HD patients due to the low prevalence of HD in Asia. We aimed to comprehensively describe the motor, neuropsychiatric symptoms, and functional assessment in patients with HD from China. A total of 205 HD patients were assessed by the Unified Huntington’s Disease Rating Scale (UHDRS), the short version of Problem-Behavior Assessment (PBA-s), Hamilton Depression Scale (HAMD) and Beck Depression Inventory (BDI). Multivariate logistic regression analysis was used to explore the independent variables correlated with neuropsychiatric subscales. The mean age of motor symptom onset was 41.8 ± 10.0 years old with a diagnostic delay of 4.3 ± 3.8 years and a median CAG repeats of 44. The patients with a positive family history had a younger onset and larger CAG expansion than the patients without a family history (p < 0.05). There was a significant increase in total motor score across disease stages (p < 0.0001). Depression (51%) was the most common neuropsychiatric symptom at all stages, whereas moderate to severe apathy commonly occurred in advanced HD stages. We found lower functional capacity and higher HAMD were independently correlated with irritability; higher HAMD and higher BDI were independently correlated with affect; male sex and higher HAMD were independently correlated with apathy. In summary, comprehensive clinical profile analysis of Chinese HD patients showed not only chorea-like movement, but psychiatric symptoms were outstanding problems and need to be detected early. Our study provides the basis to guide clinical practice, especially in practical diagnostic and management processes.

PurposeSelf-stigma is common in patients with Parkinson's disease (PD) and may lead to social isolation and delayed search for medical help. We conducted a 3-year prospective longitudinal study to investigate the development and evolution of self-stigma in patients with early stage PD and to explore the associated and predictive factors of self-stigma in PD.MethodA total of 224 patients with early stage PD (disease duration

Background: Idiopathic blepharospasm (BSP) is a common adult-onset focal dystonia. Neuroimaging technology can be used to visualize functional and microstructural changes of the whole brain.Method: We used resting-state functional MRI (rs-fMRI) and graph theoretical analysis to explore the functional connectome in patients with BSP. Altogether 20 patients with BSP and 20 age- and gender-matched healthy controls (HCs) were included in the study. Measures of network topology were calculated, such as small-world parameters (clustering coefficient [Cp], the shortest path length [Lp]), network efficiency parameters (global efficiency [Eglob], local efficiency [Eloc]), and the nodal parameter (nodal efficiency [Enod]). In addition, the least absolute shrinkage and selection operator (LASSO) regression was adopted to determine the most critical imaging features, and the classification model using critical imaging features was constructed.Results: Compared with HCs, the BSP group showed significantly decreased Eloc. Imaging features of nodal centrality (Enod) were entered into the LASSO method, and the classification model was constructed with nine imaging nodes. The area under the curve (AUC) was 0.995 (95% CI: 0.973–1.000), and the sensitivity and specificity were 95% and 100%, respectively. Specifically, four imaging nodes within the sensorimotor network (SMN), cerebellum, and default mode network (DMN) held the prominent information. Compared with HCs, the BSP group showed significantly increased Enod in the postcentral region within the SMN, decreased Enod in the precentral region within the SMN, increased Enod in the medial cerebellum, and increased Enod in the precuneus within the DMN.Conclusion: The network model in BSP showed reduced local connectivity. Baseline connectomic measures derived from rs-fMRI data may be capable of identifying patients with BSP, and regions from the SMN, cerebellum, and DMN may provide key insights into the underlying pathophysiology of BSP.

Cognitive impairment (CI) ranging from mild cognitive impairment (MCI) to dementia is a common and disturbing complication in patients with Parkinson’s disease (PD). Numerous studies have focused on neuropathological mechanisms underlying CI in PD, along with the identification of specific biomarkers for CI. Magnetic resonance imaging (MRI), a promising method, has been adopted to examine the changes in the brain and identify the candidate biomarkers associated with CI. In this review, we have summarized the potential biomarkers for CI in PD which have been identified through multi-modal MRI studies. Structural MRI technology is widely used in biomarker research. Specific patterns of gray matter atrophy are promising predictors of the evolution of CI in patients with PD. Moreover, other MRI techniques, such as MRI related to small-vessel disease, neuromelanin-sensitive MRI, quantitative susceptibility mapping, MR diffusion imaging, MRI related to cerebrovascular abnormality, resting-state functional MRI, and proton magnetic resonance spectroscopy, can provide imaging features with a good degree of prediction for CI. In the future, novel combined biomarkers should be developed using the recognized analysis tools and predictive algorithms in both cross-sectional and longitudinal studies.

Abstract Background Spastic paraplegia type 11 (SPG11) mutations are the most frequent cause of autosomal recessive hereditary spastic paraplegia (ARHSP). We are aiming to identify the causative mutations in SPG11 among families referred to our center with ARHSP in a Chinese population. Methods Targeted next-generation sequencing was performed on the patients to identify disease-causing mutations. Variants were analyzed according to their predicted pathogenicity and their relevance to the clinical phenotypes. The segregation in the family members was validated by Sanger sequencing. Results A total of 12 mutations in SPG11 gene from 9 index cases were identified, including 6 frameshift mutations, 3 missense mutations, 1 nonsense mutation, 1 splicing mutation, and 1 intron deletion mutation. In 6 of these patients, the mutations were homozygous, and the other 3 patients carried two compound heterozygous mutations. Six mutations were novel; 2 were classified as pathogenic, 1 were considered as likely pathogenic, and the other 3 were variants of unknown significance. Additionally, 1 missense heterozygous variant we found was also carried by amyotrophic lateral sclerosis (ALS) patient. Clinically and electrophysiologically, some of our ARHSP patients partially shared various features of autosomal-recessive juvenile amyotrophic lateral sclerosis (ARJALS), including combination of both UMN and LMN degeneration. Conclusions The results contribute to extending of the SPG11 gene mutation spectrum and emphasizing a putative link between ARHSP and ARJALS.

Background: CYLD Lysine 63 Deubiquitinase gene (CYLD) was recently identified to be a novel causative gene for frontal temporal dementia (FTD)-amyotrophic lateral sclerosis (ALS). In the current study, we aimed to (1) systematically screen the mutations of CYLD in a large cohort of Chinese ALS patients, (2) study the genotype–phenotype correlation, and (3) explore the role of CYLD in ALS via rare variants burden analysis.Methods: A total of 978 Chinese sporadic ALS (sALS) patients and 46 familial ALS (fALS) patients were sequenced with whole-exome sequencing and analyzed rare variants in CYLD with minor allele frequency

Background: Subjective cognitive complaints (SCCs), which are associated with a higher risk of cognitive decline, are widespread in the patients with Parkinson's disease (PD). The previous studies have reported inconsistent factors related to SCCs in the patients with late-onset PD (LOPD), and there is limited information on SCCs in the patients with early-onset PD (EOPD).Objective: We aimed to investigate the factors associated with SCCs in the drug-naïve patients with EOPD and LOPD without cognitive impairment.Methods: This cross-sectional study included 332 drug-naïve patients with PD, among whom 134 were EOPD and 198 were LOPD. Motor and non-motor symptoms, such as global objective cognitive status, depression, anxiety, apathy, fatigue, sleep, rapid eye movement sleep behavior disorder, orthostatic hypotension, and excessive daytime sleepiness, were assessed.Results: Twenty-five (18.66%) patients with EOPD and 49 (24.74%) patients with LOPD reported SCCs. A multivariate binary logistic regression analysis revealed that older age at onset [odds ratio (OR) = 1.24, P = 0.002], higher apathy score (OR = 1.13, P = 0.003), and lower scores in the visuospatial/executive abilities (OR = 0.25, P < 0.001) and memory (OR = 0.50, P = 0.024) domains of the Montreal Cognitive Assessment were associated with a higher risk of SCCs in the EOPD group. Higher apathy (OR = 1.06, P = 0.011) and anxiety (OR = 1.14, P < 0.001) scores were associated with SCCs in the LOPD group.Conclusion: Subjective cognitive complaints are only associated with mood disorders in patients with LOPD. In addition, SCCs may reflect subthreshold cognitive impairment in the patients with EOPD.

A loss-of-function variant in Lin-28 Homolog A gene (LIN28A p. R192G, rs558060339) has been identified in two East Asian ancestry patients with early-onset PD (EOPD). Functional studies revealed that such a variant could lead to developmental defects and PD-related phenotype, and the phenotypes could be rescued after correction of the variant. The aim of the study was to screen the variants of LIN28A in Chinese patients with EOPD. A total of 682 EOPD patients were sequenced with whole exome sequencing and the coding and flanking region of LIN28A were analyzed. We identified a rare coding variant, p. P182L, of LIN28A in a Chinese patient with EOPD. Moreover, we also found a 3′-UTR polymorphism (rs4659441) to be associated with an increased risk for PD. However, our rare variant burden analysis did not support a role for LIN28A as a major causal gene for PD.

Objective: To explore the frequency, evolution, associated factors, and risk factors of fatigue over 3-year of prospective follow-up in a cohort of patients with early Parkinson’s disease (PD).Methods: A total of 174 PD patients in the early stage were enrolled and quantitively assessed motor and non-motor symptoms using comprehensive scales including the Fatigue Severity Scale (FSS) annually. Each subject was categorized as PD with and without fatigue based on a cut-off mean value of 4 using FSS. The generalized estimating equation (GEE) was utilized to investigate the associated factors, and the stepwise binary logistic regression model was performed to explore the predictors.Results: The frequency of fatigue was slightly changed (ranging from 35.1 to 40.4%) during the 3-year follow-up. The changed pattern of the frequency of fatigue was similar to that of anxiety. Fatigue was significantly associated with nocturnal sleep disorders (B 2.446, P < 0.001), high Hamilton Anxiety Rating Scale (HAMA) score (B 1.072, P = 0.011), and high Unified PD Rating Scale (UPDRS) III score (B 1.029, P = 0.003) over time. High UPDRS III score [odds ratio (OR) 1.051, P = 0.015] at baseline increased the risk of developing fatigue after 1-year; high LEDD (OR 1.002, P = 0.037) increased the risk of developing fatigue after 2-year; and high LEDD (OR 1.003, P = 0.049) and high HAMA score (OR 1.077, P = 0.042) increased the risk of developing fatigue after 3-year.Conclusion: Our present study provided evidence of the longitudinal evolution of fatigue in patients with early PD and help clinical management of fatigue.

Objective: Vascular risk factors have been reported to be associated with cognitive impairment (CI) in the general population, but their role on CI in multiple system atrophy (MSA) is unclear. This study aimed to explore the relationship between vascular risk factors and CI in patients with MSA.Methods: The clinical data and vascular risk factors were collected. The Montreal Cognitive Assessment tool was used to test the cognitive function of patients with MSA. Binary logistic regression was used to analyze the correlation between vascular risk factors and CI.Results: A total of 658 patients with MSA with a mean disease duration of 2.55 ± 1.47 years were enrolled. In MSA patients, hypertension was recorded in 20.2%, diabetes mellitus in 10.3%, hyperlipidemia in 10.2%, smoking in 41.2%, drinking in 34.8%, and obesity in 9.6%. The prevalence of CI in patients with MSA, MSA with predominant parkinsonism (MSA-P), and MSA with predominant cerebellar ataxia (MSA-C) was 45.0, 45.1, and 44.9%, respectively. In the binary logistic regression model, patients with more than one vascular risk factors were significantly more likely to have CI in MSA (OR = 4.298, 95% CI 1.456–12.691, P = 0.008) and MSA-P (OR = 6.952, 95% CI 1.390–34.774, P = 0.018), after adjusting for age, sex, educational years, disease duration, and total Unified multiple system atrophy rating scale scores.Conclusion: Multiple vascular risk factors had a cumulative impact on CI in MSA. Therefore, the comprehensive management of vascular risk factors in MSA should not be neglected.

Objective: This study aimed to explore the prevalence and clinical correlates of pathological laughter and crying (PLC) in patients with amyotrophic lateral sclerosis (ALS).Methods: A total of 1,031 ALS patients were enrolled between August 2012 and August 2019. The PLC was recorded by a face-to-face interview. Other characteristics of patients, including depression, anxiety, cognition, and behavior function, were also evaluated. The potential associated factors of PLC were explored using forward binary regression analysis. Survival was analyzed in groups using propensity score matching (PSM) and Cox proportional hazards models.Results: The prevalence of PLC was 11.4% in all patients at baseline. Bulbar-onset and female patients had higher prevalence of PLC. The multivariate regression analysis indicated that PLC in ALS was associated with bulbar onset (p < 0.001), late disease stage (p < 0.001), and higher score in the Hamilton Depression Rating Scale (HDRS) (p = 0.012). The higher score of HDRS was significantly and independently associated with PLC occurrence in bulbar-onset patients (p = 0.032). The late disease stage was related to PLC occurrence in spinal-onset patients (p < 0.001). After comparison with matched pairs by using PSM, PLC at baseline had no impact on survival.Conclusion: PLC was not uncommon in ALS, especially in bulbar-onset and female patients. We highlighted that the emotional state other than cognitive function had possible relationship with PLC in ALS.

Objectives: Estrogen not only plays a key role in the decreased risk of Parkinson’s disease (PD) but also influences its severity. We aimed to explore the effect of the reproductive lifespan on the motor progression of PD female patients in a large prospective cohort study. Methods: A competing risk analysis with a Fine and Gray model on 491 female and 609 male patients with PD was conducted. We regarded the chance of faster motor progression (as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) III increasing by ≥16 points during follow-up) and the chance of death as competing risks. The reproductive lifespan was regarded as the variable of interest, while faster motor progression was set as the primary outcome. Results: In the multivariable competing risk analysis, the male sex was not significantly associated with faster motor progression (subdistribution hazard ratio (SHR) 0.888, 95% CI 0.652–1.209, p = 0.450), while a shorter reproductive lifespan was associated with faster motor progression in women (SHR 0.964, 95% CI 0.936–0.994, p = 0.019). Sensitivity analysis indicated that a shorter reproductive lifespan was also significantly associated with faster motor progression in the 48 female patients who reported menopause after the onset of PD (SHR 0.156, 95% CI 0.045–0.542, p = 0.003). A linear mixed model also revealed the significant main effects of a short reproductive lifespan on the higher UPDRS III score in PD female patients at the last visit (p = 0.026). Conclusions: Our study indicates that a short reproductive lifespan contributes to faster motor progression in PD female patients, which has important implications for understanding the role of endogenous estrogen exposure in female PD and is beneficial to select appropriate patients in clinical trials.

Purpose: Falls are common and are frequently accompanied by injuries in patients with spinocerebellar ataxias type 3 (SCA3). We explored which factors could predict falls in a cohort of patients with SCA3 and developed a nomogram model to predict the first fall in non-fallen patients with SCA3.Method: We conducted a prospective cohort study. Forty-four non-fallen patients with SCA3 were followed up until the first fall or November 5, 2020, whichever came first. Univariate and multivariate Cox proportional hazard regression analyses were applied to explore the predictive factors of falls in patients with SCA3. A nomogram model predicting the no-fall probabilities at 3, 6, 12, and 24 months was formulated based on the results of the multivariate Cox analysis. Internal validation was conducted to assess the discrimination and calibration of the final model using bootstrapping with 1,000 resamples.Results: Multivariate Cox proportional hazard regression showed that the presence of dystonia, hyperreflexia, urinary incontinence, and hidrosis and the number of abnormal eye movements predicted a more rapid progression to falls in patients with SCA3. The nomogram model showed good discrimination with a concordance index of 0.83 and good calibration.Conclusion: Patients with dystonia, hyperreflexia, urinary incontinence, and hidrosis, and more types of abnormal eye movement had a more rapid progression to falls in SCA3.

Objective: We investigated the prevalence, evolution, associated factors, and risk factors of apathy in a cohort of patients with early-stage Parkinson's disease (PD), who underwent a 4-years prospective follow-up.Methods: This study included 188 patients with PD (baseline disease duration

Purpose: This study aimed to identify consistent gray matter volume (GMV) changes in the two subtypes of multiple system atrophy (MSA), including parkinsonism subtype (MSA-P), and cerebellar subtype (MSA-C), by conducting a voxel-wise meta-analysis of whole brain voxel-based morphometry (VBM) studies.Method: VBM studies comparing MSA-P or MSA-C and healthy controls (HCs) were systematically searched in the PubMed, Embase, and Web of Science published from 1974 to 20 October 2020. A quantitative meta-analysis of VBM studies on MSA-P or MSA-C was performed using the effect size-based signed differential mapping (ES-SDM) method separately. A complementary analysis was conducted using the Seed-based d Mapping with Permutation of Subject Images (SDM-PSI) method, which allows a familywise error rate (FWE) correction for multiple comparisons of the results, for further validation of the results.Results: Ten studies were included in the meta-analysis of MSA-P subtype, comprising 136 MSA-P patients and 211 HCs. Five studies were included in the meta-analysis of MSA-C subtype, comprising 89 MSA-C patients and 134 HCs. Cerebellum atrophy was detected in both MSA-P and MSA-C, whereas basal ganglia atrophy was only detected in MSA-P. Cerebral cortex atrophy was detected in both subtypes, with predominant impairment of the superior temporal gyrus, inferior frontal gyrus, temporal pole, insula, and amygdala in MSA-P and predominant impairment of the superior temporal gyrus, middle temporal gyrus, fusiform gyrus, and lingual gyrus in MSA-C. Most of these results survived the FWE correction in the complementary analysis, except for the bilateral amygdala and the left caudate nucleus in MSA-P, and the right superior temporal gyrus and the right middle temporal gyrus in MSA-C. These findings remained robust in the jackknife sensitivity analysis, and no significant heterogeneity was detected.Conclusion: A different pattern of brain atrophy between MSA-P and MSA-C detected in the current study was in line with clinical manifestations and provided the evidence of the pathophysiology of the two subtypes of MSA.

Abstract Photodetectors based on three dimensional organic–inorganic lead halide perovskites have recently received significant attention. As a new type of light-harvesting materials, formamidinium lead iodide (FAPbI3) is known to possess excellent optoelectronic properties even exceeding those of methylammonium lead iodide (MAPbI3). To date, only a few photoconductor-type photodetectors based on FAPbI3 single crystals and polycrystalline thin films in a lateral structure have been reported. Here, we demonstrate low-voltage, high-overall-performance photodiode-type photodetectors in a sandwiched geometry based on polycrystalline α-FAPbI3 thin films synthesized by a one-step solution processing method and post-annealing treatment. The photodetectors exhibit a broadband response from the near-ultraviolet to the near-infrared (330–800 nm), achieving a high on/off current ratio of 8.6 × 104 and fast response times of 7.2/19.5 μs. The devices yield a photoresponsivity of 0.95 AW−1 and a high specific detectivity of 2.8 × 1012 Jones with an external quantum efficiency (EQE) approaching 182% at −1.0 V under 650 nm illumination. The photodiode-type photodetectors based on polycrystalline α-FAPbI3 thin films with superior performance consequently show great promise for future optoelectronic device applications.