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Abstract Our study aimed to investigate the clinical characteristics of PD patients stratified by OH status before and after levodopa challenge to explore the hypothesis that OH might serve as a clinical marker for the body-first subtype of PD. Supine and standing blood pressure were measured in a large cross-sectional cohort of PD patients at the OFF status before and after levodopa challenge test (LCT). Based on OH status, patients were divided into three groups: spontaneous OH (SOH), only levodopa-induced OH (LOH) and non-OH (NOH). Clinical characteristics and associated factors were compared among the groups. A total of 928 patients with a mean age of 62.4 years and average disease duration of 7.9 years were included. There were 224 (24.1%) patients with SOH, 321 (34.6%) with LOH, and 383 (41.3%) with NOH. Compared to NOH, both SOH and LOH were associated with older age, motor fluctuations, and probable rapid eye movement sleep behavior disorder (pRBD). In addition, OH was more associated with cardiovascular and digestive dysfunction, disease severity and worse quality of life. Results of the current study suggest that PD patients developed OH which is more likely to comorbid with RBD, severe autonomic dysfunction and motor fluctuations, consistent with the body-first subtype of PD.

Abstract While numerous single nucleotide variants and small indels have been identified in Parkinson’s disease (PD), the contribution of structural variants (SVs), copy number variants (CNVs), and short tandem repeats (STRs) remains poorly understood. Here we investigated the association using the high-depth whole-genome sequencing data from 466 Chinese PD patients and 513 controls. Totally, we identified 29,561 SVs, 32,153 CNVs, and 174,905 STRs, and found that CNV deletions were significantly enriched in the end-proportion of autosomal chromosomes in PD. After genome-wide association analysis and replication in an external cohort of 352 cases and 547 controls, we validated that the 1.6 kb-deletion neighboring MUC19, 12.4kb-deletion near RXFP1 and GGGAAA repeats in SLC2A13 were significantly associated with PD. Moreover, the MUC19 deletion and the SLC2A13 5-copy repeat reduced the penetrance of the LRRK2 G2385R variant. Moreover, genes with these variants were dosage-sensitive. These data provided novel insights into the genetic architecture of PD.

Abstract Asymptomatic Leucine-Rich Repeat Kinase 2 Gene (LRRK2) carriers are at risk for developing Parkinson's disease (PD). We studied presymptomatic substantia nigra pars compacta (SNc) regional neurodegeneration in asymptomatic LRRK2 carriers compared to idiopathic PD patients using neuromelanin-sensitive MRI technique (NM-MRI). Fifteen asymptomatic LRRK2 carriers, 22 idiopathic PD patients, and 30 healthy controls (HCs) were scanned using NM-MRI. We computed volume and contrast-to-noise ratio (CNR) derived from the whole SNc and the sensorimotor, associative, and limbic SNc regions. An analysis of covariance was performed to explore the differences of whole and regional NM-MRI values among the groups while controlling the effect of age and sex. In whole SNc, LRRK2 had significantly lower CNR than HCs but non-significantly higher volume and CNR than PD patients, and PD patients significantly lower volume and CNR compared to HCs. Inside SNc regions, there were significant group effects for CNR in all regions and for volumes in the associative region, with a trend in the sensorimotor region but no significant changes in the limbic region. PD had reduced volume and CNR in all regions compared to HCs. Asymptomatic LRRK2 carriers showed globally decreased SNc volume and CNR suggesting early nigral neurodegeneration in these subjects at risk of developing PD.

Abstract Introduction Semantic fluency is the ability to name items from a given category within a limited time, which relies on semantic knowledge, working memory, and executive function. Similar to patients with Parkinson's disease (PD), patients with progressive supranuclear palsy (PSP) scored lower than healthy adults in the well‐established semantic fluency test. However, it is unclear how unique are the produced words. This study examined the relationship between semantic fluency and words’ uniqueness in patients with PSP. Methods Twenty‐seven patients with PSP Richardson's syndrome (PSP‐RS), 37 patients with PD, and 41 healthy controls (HC) performed a standard semantic fluency test (animals), and their verbal responses were audio‐recorded. We used the uniqueness to reflect the ability to produce both original and effective work, that is, creativity. Results The PSP‐RS group produced fewer correct words and fewer unique words than the PD and HC groups. Moreover, the correlation between fluency and uniqueness was positive in the HC and PD groups but negative in the PSP‐RS group. Importantly, the actual levodopa dose was positively correlated with the fluency but negatively correlated with the uniqueness in PSP‐RS. The PSP‐RS patients who took a greater dose of levodopa tended to produce more correct words but fewer unique words. Conclusions These results suggested that levodopa may modulate semantic fluency and uniqueness in the early stages of PSP‐RS.

BackgroundWe have shown that genetic factors associating with motor progression of Parkinson’s disease (PD), but their roles in cognitive function is poorly understood. One reason is that while cognitive performance in PD can be evaluated by various cognitive scales, there is no definitive guide indicating which tool performs better.MethodsData were obtained from the Parkinson’s Progression Markers Initiative, where cognitive performance was assessed using five cognitive screening tools, including Symbol Digit Modalities Test (SDMT), Montreal Cognitive Assessment, Benton Judgment of Line Orientation, Modified Semantic Fluency Test, and Letter Number Sequencing Test, at baseline and subsequent annual follow-up visit for 5 years. Genetic data including ApoE and other PD risk genetic information were also obtained. We used SPSS-receiver operating characteristic and ANOVA repeated measures to evaluate which cognitive assessment is the best reflecting cognitive performance in PD at early stage and over time. Logistic regression analyses were used to determine the genetic associations with the rapidity of cognitive decline in PD.ResultsSDMT performed better in detecting mild cognitive impairment at baseline (AUC = 0.763), and SDMT was the only tool showing a steady cognitive decline during longitudinal observation. Multigenetic factors significantly associated with cognitive impairment at early stage of the disease (AUC = 0.950) with IP6K2 rs12497850 more evident, and a significantly faster decline (AUC = 0.831) within 5 years after motor onset, particularly in those carrying FGF20 rs591323.ConclusionSDMT is a preferable cognitive assessment tool for PD and genetic factors synergistically contribute to the cognitive dysfunction in PD.

Background: This study aimed to show a 3-year trajectory of physical performance among Chinese elderly in Beijing communities and explore the associations between new adverse events during the 3-year follow-up period and decreased physical performance. Methods: A longitudinal observational study included baseline data and transitional information of physical performance from 456 community elders (mean age 67.3 ± 4.9 years, female 43.2 %) at a 3-year follow-up. The Mini-Mental State Examination (MMSE) and the Short Physical Performance Battery (SPPB) were used to measure cognition and physical performance, respectively. The number of chronic diseases, cognitive impairment, malnutrition, depression, knee pain, falls, and frailty were the principal independent variables in multivariate logistic regression analysis. Results: The proportion of the elderly with poor physical performance (26.97 %) increased to 42.11 % and the proportion of those with good physical performance (44.96 %) dropped to 30.48 % after the three-year follow-up. As for physical performance transitions, 39.47 % of the elderly progressed to a worsening physical status. After adjustment for covariates, only new onset cognitive impairment (OR: 5.17; 95%CI: 2.01–14.54; P = 0.001) was associated with physical performance deterioration. Conclusion: Cognitive impairment is an independent risk factor for decreased physical performance in elderly people. Active interventions targeted at cognitive impairment could help promote healthy aging.

Abstract REM sleep behavior disorder (RBD) symptoms in Parkinson’s disease (PD) suggest both a clinically and pathologically malignant subtype. However, whether RBD symptoms are associated with alterations in the organization of whole-brain intrinsic functional networks in PD, especially at early disease stages, remains unclear. Here we use resting-state functional MRI, coupled with graph-theoretical approaches and network-based statistics analyses, and validated with large-scale network analyses, to characterize functional brain networks and their relationship with clinical measures in early PD patients with probable RBD (PD+pRBD), early PD patients without probable RBD (PD-pRBD) and healthy controls. Thirty-six PD+pRBD, 57 PD-pRBD and 71 healthy controls were included in the final analyses. The PD+pRBD group demonstrated decreased global efficiency (t = -2.036, P = 0.0432) compared to PD-pRBD, and decreased network efficiency, as well as comprehensively disrupted nodal efficiency and whole-brain networks (all eight networks, but especially in the sensorimotor, default mode and visual networks) compared to healthy controls. The PD-pRBD group showed decreased nodal degree in right ventral frontal cortex and more affected edges in the frontoparietal and ventral attention networks compared to healthy controls. Furthermore, the assortativity coefficient was negatively correlated with Montreal cognitive assessment scores in the PD+pRBD group (r = -0.365, P = 0.026, d = 0.154). The observation of altered whole-brain functional networks and its correlation with cognitive function in PD+pRBD suggest reorganization of the intrinsic functional connectivity to maintain the brain function in the early stage of the disease. Future longitudinal studies following these alterations along disease progression are warranted.

Abstract Purpose Sequential working memory is the ability to maintain and manipulate sequential information at a second time scale. Patients with progressive supranuclear palsy (PSP) or Parkinson's disease (PD) perform poorly in tests that require the flexible arrangement of thoughts or actions. This study investigated whether sequential working memory is differently impaired in patients with PSP versus PD. Method Twenty‐nine patients with PSP Richardson's syndrome (PSP‐RS), 36 patients with PD, and 36 healthy controls (HC) completed 3 well‐established neuropsychological tests, including digit span forward (DST‐F), digit span backward (DST‐B), and adaptive digit ordering tests (DOT‐A). The DST‐F required maintaining digit sequences, and the DST‐B and DOT‐A required maintaining and manipulating digit sequences. Finding The PSP‐RS group scored lower than the PD and HC groups in the DST‐B and DOT‐A but not in the DST‐F, indicating that the ability to manipulate sequences was impaired, but the maintenance ability was preserved in PSP‐RS patients. Moreover, in PSP‐RS, the DST‐B score negatively correlated with the severity of motor symptoms. The actual levodopa dose positively correlated with the DST‐B ordering cost (DST‐F score vs. DST‐B score). The PSP patients who took a greater dose of levodopa tended to have higher DST‐B ordering cost. There was no effect of levodopa on DST‐B or DOT‐A in PD. Conclusion These results suggested that the ability to manipulate sequence was already reduced in patients with PSP‐RS and was worse than in patients with PD.

IntroductionAccurately and objectively quantifying the clinical features of Parkinson's disease (PD) is crucial for assisting in diagnosis and guiding the formulation of treatment plans. Therefore, based on the data on multi-site motor features, this study aimed to develop an interpretable machine learning (ML) model for classifying the “OFF” and “ON” status of patients with PD, as well as to explore the motor features that are most associated with changes in clinical symptoms.MethodsWe employed a support vector machine with a recursive feature elimination (SVM-RFE) algorithm to select promising motion features. Subsequently, 12 ML models were constructed based on these features, and we identified the model with the best classification performance. Then, we used the SHapley Additive exPlanations (SHAP) and the Local Interpretable Model agnostic Explanations (LIME) methods to explain the model and rank the importance of those motor features.ResultsA total of 96 patients were finally included in this study. The naive Bayes (NB) model had the highest classification performance (AUC = 0.956; sensitivity = 0.8947, 95% CI 0.6686–0.9870; accuracy = 0.8421, 95% CI 0.6875–0.9398). Based on the NB model, we analyzed the importance of eight motor features toward the classification results using the SHAP algorithm. The Gait: range of motion (RoM) Shank left (L) (degrees) [Mean] might be the most important motor feature for all classification horizons.ConclusionThe symptoms of PD could be objectively quantified. By utilizing suitable motor features to construct ML models, it became possible to intelligently identify whether patients with PD were in the “ON” or “OFF” status. The variations in these motor features were significantly correlated with improvement rates in patients' quality of life. In the future, they might act as objective digital biomarkers to elucidate the changes in symptoms observed in patients with PD and might be used to assist in the diagnosis and treatment of patients with PD.

Background: Cognitive impairment is common in patients with Parkinson’s disease (PD) and occurs through multiple mechanisms, including Alzheimer’s disease (AD) pathology and the involvement of α-synucleinopathies. We aimed to investigate the pathological biomarkers of both PD and AD in plasma and neuronal extracellular vesicles (EVs) and their association with different types of cognitive impairment in PD patients. Methods: A total of 122 patients with PD and 30 healthy controls were included in this cross-sectional cohort study between March 2021 and July 2023. Non-dementia PD patients were divided into amnestic and non-amnestic groups according to the memory domain of a neuropsychological assessment. Plasma and neuronal EV biomarkers, including α-synuclein (α-syn), beta-amyloid (Aβ), total tau (T-tau), phosphorylated tau181 (p-tau181), and glial fibrillary acidic protein (GFAP), were measured using a single-molecule array and a chemiluminescence immunoassay, respectively. Results: Neuronal EV but not plasma α-syn levels, were significantly increased in PD as compared to healthy controls, and they were positively associated with UPDRS part III scores and the severity of cognitive impairment. A lower plasma Aβ42 level and higher neuronal EV T-tau level were found in the amnestic PD group compared to the non-amnestic PD group. Conclusions: The results of the current study demonstrate that neuronal EV α-syn levels can be a sensitive biomarker for assisting in the diagnosis and disease severity prediction of PD. Both AD and PD pathologies are important factors in cognitive impairment associated with PD, and AD pathologies are more involved in amnestic memory deficit in PD.

ObjectiveTo determine whether the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is associated with cognitive impairment (CI) in community-dwelling Chinese older adults, and to investigate whether this relationship is modified by the Apolipoprotein E (APOE) ɛ4 allele.MethodsThe study is a secondary analysis of 703 participants aged ≥60 years randomly enrolled from the Beijing Longitudinal Study of Aging II prospective cohort. The education-adjusted Mini-Mental State Examination and the Clinical Dementia Rating Scale were used to measure the cognitive performance of the subjects. The main effects and interactions (additive and multiplicative) of the BDNF Met and the APOE ε4 alleles on CI were estimated by logistic regression models.ResultsIn total, 84 out of 703 older adults aged ≥60 years old had CI. No significant difference was observed in the risk of CI between participants with the BDNF Met allele and that of subjects without the BDNF Met allele (p = 0.213; p = 0.164). Individuals carrying both the BDNF Met and APOE ε4 alleles had an almost 1.5-fold increased odds of CI compared with carriers of the BDNF Met allele but without the APOE ε4 allele. The additive association indicated a positive interaction of both BDNF Met and APOE ε4 alleles with wide CIs (p = 0.021; p = 0.018).ConclusionThe results suggest that the APOE ε4 allele may be a potential modifier for the association of the BDNF Val66Met polymorphism with CI in community-dwelling older adults.

BackgroundParkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. Myasthenia gravis (MG) is a rare autoimmune disease caused by antibodies against the neuromuscular junction. PD and comorbid MG are rarely seen.Case presentationHere we report on a patient who was diagnosed with PD and MG. A 74-year-old man had a 4-year history of bradykinesia and was diagnosed with PD. He subsequently developed incomplete palpebral ptosis, apparent dropped head, and shuffling of gait. The results of neostigmine tests were positive. Repetitive nerve stimulation (RNS) showed significant decremental responses at 3 and 5 Hz in the orbicularis oculi. The patient's anti-acetylcholine receptor (anti-AchR) antibody serum level was also elevated. Meanwhile, 9-[18F]fluoropropyl-(+)-dihydrotetrabenazine positron emission tomography–computed tomography (18F-AV133 PET-CT) scan revealed a significant decrease in uptake in the bilateral putamen. After addition of cholinesterase inhibitors, his symptoms of palpebral ptosis and head drop improved greatly and he showed a good response to levodopa.ConclusionAlthough PD with MG is rare, we still need to notice the possibility that a PD patient may have comorbid MG. The underlying mechanism of PD and comorbid MG remains unknown, but an imbalance between the neurotransmitters dopamine and acetylcholine and the immune system are likely to play significant roles in the pathogenesis. In this article, we present our case and a literature review on the co-occurrence of PD and MG, reviewing their clinical features, and discuss the underlying pathogenic mechanism of this comorbidity.

Abstract Genome-wide association studies (GWASs) have identified numerous susceptibility loci for Parkinson’s disease (PD), but its genetic architecture remains underexplored in populations of non-European ancestry. To identify genetic variants associated with PD in the Chinese population, we performed a GWAS using whole-genome sequencing (WGS) in 1,972 cases and 2,478 controls, and a replication study in a total of 8209 cases and 9454 controls. We identified one new risk variant rs61204179 (P combined = 1.47 × 10−9) with low allele frequency, four previously reported risk variants (NUCKS1/RAB29-rs11557080, SNCA-rs356182, FYN-rs997368, and VPS13C-rs2251086), as well as three risk variants in LRRK2 coding region (A419V, R1628P, and G2385R) with genome-wide significance (P

Abstract Background Sarcopenia is common in patients with Parkinson's disease (PD), showing mitochondrial oxidative stress in skeletal muscle. The aggregation of α‐synuclein (α‐Syn) to induce oxidative stress is a key pathogenic process of PD; nevertheless, we know little about its potential role in regulating peripheral nerves and the function of the muscles they innervate. Methods To investigate the role of α‐Syn aggregation on neuromuscular system, we used the Thy1 promoter to overexpress human α‐Syn transgenic mice (mThy1‐hSNCA). hα‐Syn expression was evaluated by western blot, and its localization was determined by confocal microscopy. The impact of α‐Syn aggregation on the structure and function of skeletal muscle mitochondria and neuromuscular junctions (NMJs), as well as muscle mass and function were characterized by flow cytometry, transmission electron microscopy, Seahorse XF24 metabolic assay, and AAV9 in vivo injection. We assessed the regenerative effect of mitochondrial‐targeted superoxide dismutase (Mito‐TEMPO) after skeletal muscle injury in mThy1‐hSNCA mice. Results Overexpressed hα‐Syn protein localized in motor neuron axons and NMJs in muscle and formed aggregates. α‐Syn aggregation increased the number of abnormal mitochondrial in the intramuscular axons and NMJs by over 60% (P

Brain connectivity networks based on functional magnetic resonance imaging (fMRI) have expanded our understanding of brain functions in both healthy and diseased states. However, most current studies construct connectivity networks using averaged regional time courses with the strong assumption that the activities of voxels contained in each brain region are similar, ignoring their possible variations. Additionally, pairwise correlation analysis is often adopted with more attention to positive relationships, while joint interactions at the network level as well as anti-correlations are less investigated. In this paper, to provide a new strategy for regional activity representation and brain connectivity modeling, a novel homogeneous multiset canonical correlation analysis (HMCCA) model is proposed, which enforces sign constraints on the weights of voxels to guarantee homogeneity within each brain region. It is capable of obtaining regional representative signals and constructing covariation and contravariance networks simultaneously, at both group and subject levels. Validations on two sessions of fMRI data verified its reproducibility and reliability when dealing with brain connectivity networks. Further experiments on subjects with and without Parkinson’s disease (PD) revealed significant alterations in brain connectivity patterns, which were further associated with clinical scores and demonstrated superior prediction ability, indicating its potential in clinical practice.

Abstract The chromosome 9 open reading frame 72 (C9ORF72) has been proposed as the causative gene of frontotemporal dementia with parkinsonism (FTDP), but its pathophysiological mechanism of parkinsonism is poorly understood. To explore the roles of striatal motor subdivisions in the pathogenesis of parkinsonism resulting from C9ORF72 repeat expansions in the FTDP, two patients with FTDP from one pedigree and seventeen healthy controls were enrolled. The participants received clinical interviews, physical examinations, genetic testing, [18F]-fluorodeoxyglucose PET/MRI, and [18F]-dihydrotetrabenazine PET/CT. Voxel-wise and region of interest analysis were conducted with respect to gray matter volume, metabolism, and dopamine transport function between patients and controls, focusing on the motor part of the striatum according to the Oxford-GSK-Imanova Striatal Connectivity Atlas. Patient 1 presented with parkinsonism as the initial symptom, while patient 2 exhibited behavior disturbance as the first symptom, followed by parkinsonism within one year. Both patients had the hexanucleotide expansion detected in C9ORF72(>52 repeats). Gray matter volume atrophy, hypometabolism and dopamine dysfunction were observed in the motor areas of the striatum. Of the two patients, marked glucose hypometabolism within the striatal motor subregion was observed in patient 1, with corresponding gray matter atrophy. In addition, presynaptic dopaminergic integrity of patient 2 was deteriorated in the motor subregions which was consistent with gray matter atrophy. These findings imply that parkinsonism in FTDP may be associated with the degeneration and dopaminergic dysfunction of the striatal motor subregion, which might be attributed to C9orf72 repeat expansions.

Measurement(s) electroencephalography (EEG) • electromyography(EMG) • acceleration • skin conductance Technology Type(s) electroencephalography (EEG) • electromyography (EMG) • accelerometer • skin conductance

IntroductionOrthostatic hypotension (OH) frequently accompanies autonomic dysfunction and is an important risk factor for cognitive impairment in Parkinson's disease (PD). However, the association between different cognitive functions and OH in PD patients is not yet fully understood.MethodsThis study aimed to evaluate the scores of different cognitive domains and multiple parameters using different imaging techniques on PD patients with or without OH. A total number of 31 PD patients with OH (n = 20) and without OH (n = 11) were recruited from the Department of Neurology, Beijing Xuanwu Hospital for this study. All patients underwent beat-to-beat non-invasive blood pressure recordings and an active standing test to evaluate neurogenic OH and a global neuropsychological test to assess cognitive function. All patients underwent dynamic cerebral autoregulation (dCA) measurement, brain magnetic resonance imaging (MRI), and brain 18fluorine-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT).ResultsThe results showed that OH patients had poor delayed recall verbal memory when compared with the PD patients without OH (1.75 ± 1.59 vs. 3.10 ± 1.73, p = 0.042). The dCA test indicated a significant difference in the right very low-frequency (VLF) gain between two groups (1.27 ± 0.17 vs. 1.10 ± 0.26, p = 0.045) and the brain 18F-FDG PET/CT indicated a significant difference in the SUV (right medial temporal lobe) to SUV (occipital lobe) ratio (0.60 ± 0.08 vs. 0.67 ± 0.11, p = 0.049). Meanwhile, these two imaging parameters were negatively correlated (p < 0.001). Furthermore, the score of a delayed recall verbal memory in the OH group was positively correlated with the right medial temporal lobe to occipital lobe ratio (p < 0.001) and was negatively correlated with the right VLF gain (p = 0.023).DiscussionPD with OH patients had poor delayed recall memory, which might have been caused by the decreased metabolic dysfunction of specific medial temporal lobe due to the impaired dCA ability.

Objective: Levodopa is the first-line treatment for patients with Parkinson's disease (PD). However, only a few studies have focused on the tolerance of this drug in older patients with PD in the early and middle stages. Therefore, this study aimed to explore the effects of different levodopa doses on blood pressure (BP) in this subpopulation. Methods: This cohort analysis enrolled 83 patients. The levodopa challenge test was used to evaluate drug responsiveness. After at least 12 h following anti-PD drug discontinuation, patients’ BPs were measured in a lying position, after 1 min standing, and after 3 min standing, in “off state” and best “on state.” Results: BP in the 250 mg and 375 mg levodopa/benserazide groups decreased significantly in the lying and standing positions. The 3-min standing-position systolic BP was significantly influenced by the dose of levodopa/benserazide. However, no statistical change was observed in the 125 mg group. The postural-mediated systolic BP disparity was significant at 3 min in the upright position. Nineteen (incidence, 22.9%) and Twenty-five patients (incidence, 30.1%) developed complications of orthostatic hypotension (OH) in the “off state” and best “on state,” respectively. Mild cognitive impairment was a risk factor for OH occurrence in the “off state.” The OH occurrence in the best “on state” was associated with OH in the “off state” and urinary incontinence. Conclusion: Our findings suggest that 250 mg or more of levodopa/benserazide could significantly reduce BP and orthostatic effect in older patients with PD in the early and middle stages. Therefore, they should routinely monitor their BP. Trial registration number: ChiCTR2200055707.

Abstract Background Whether cognitive ageing trajectory is related to common functional deficits independent of initial cognitive function remains inconclusive. We aimed to explore the adverse health effect and potential predictive factors of distinct cognitive trajectories among Chinese older adults. Methods Three thousand five hundred eighty-one community-dwelling older adults who completed three consecutive cognitive function examinations with the Mini-Mental State Examination (MMSE) over 5 years and were without cognitive impairment at enrollment were included. A group-based trajectory model was used to estimate cognitive ageing trajectories. Multivariable-adjusted odds ratio (OR) and 95% confidence intervals (CI) were computed with logistic regression models to identify potential baseline determinants and health effect of cognitive trajectories on various adverse outcomes. Results Two distinct cognitive ageing trajectories were identified with about 5.3% of the study participants ascribed to the rapidly decreasing group. Subjects with rapidly decreasing cognition showed significantly higher odds (OR, 95%CI) of experiencing frailty (4.04, 2.77–5.86), falls (2.01, 1.05–3.70), balance impairment (4.20, 2.75–6.38), high fall risk (5.66, 2.67–11.77) based on the Tinetti total score, disability in activities of daily living (1.76, 1.19–2.56), disability in instrumental activities of daily living (1.52, 1.05–2.19), and motor cognitive risk syndrome (2.24, 1.23–3.98) compared with their steadily decreasing counterparts. Individuals with older age, low education level, no marriage, high score of rapid eye movement behavior disorders, poor physical and cognitive function at baseline were more predisposed to an accelerated cognitive decline. Conclusions Faster cognitive decline was independently associated with higher risk of multiple adverse events. Our findings put more emphasis on a routine and constant surveillance of cognitive function among community-dwelling older adults.

Abstract Background Abnormal activation of immune system is an important pathogenesis of Parkinson’s disease, but the relationship between peripheral inflammation, central microglia activation and dopaminergic degeneration remains unclear. Objectives To evaluate the brain regional microglia activation and its relationship with clinical severity, dopaminergic presynaptic function, and peripheral inflammatory biomarkers related to adaptive immunity. Methods In this case–control study, we recruited 23 healthy participants and 24 participants with early-stage Parkinson’s disease. 18F-PBR06 PET/MR for microglia activation, 18F-FP-DTBZ for dopaminergic denervation, total account of T cells and subpopulations of T helper (Th1/Th2/Th17) cells, and the levels of serum inflammatory cytokines were assessed. Sanger sequencing was used to exclude the mix-affinity binders of 18F-PBR06-PET. Results Compared to healthy controls, patients with Parkinson’s disease had an increased 18F-PBR06-PET standardized uptake value ratio (SUVR) in the putamen, particularly in the ipsilateral side of the motor onset. 18F-PBR06-PET SUVR was positively associated with 18F-FP-DTBZ-PET SUVR in the brainstem and not associated with disease severity measured by Hoehn and Yahr stage, MDS-UPDRS III scores. Patients with Parkinson’s disease had elevated frequencies of Th1 cells and serum levels of IL10 and IL17A as compared to healthy controls. No significant association between peripheral inflammation markers and microglia activation in the brain of PD was observed. Conclusion Parkinson’s disease is associated with early putaminal microglial activation and peripheral phenotypic Th1 bias. Peripheral adaptive immunity might be involved in microglia activation in the process of neurodegeneration in PD indirectly, which may be a potential biomarker for the early detection and the target for immunomodulating therapy.

2- arachidonoylglycerol (2-AG), an abundant endocannabinoid in the brain, regulates diverse neural functions. Here, the authors identified four loss-of-function mutations in dicylglycerol lipase β (DAGLB) from six patients with early onset Parkinsonism. In mice, loss of DAGLB in dopamine neurons reduced neuronal activity and impaired locomotor function and augmentation of 2-AG levels boosted neuronal activity and rescued locomotor deficits.

BackgroundANXA11 mutations were first reported to be associated with amyotrophic lateral sclerosis (ALS) in 2017. Several studies have investigated the prevalence of ANXA11 mutations in different populations, while less is known about the spectrum of phenotypes and the genotype–phenotype correlation with this gene mutation.Case presentationHere, we report a 74-year-old man who was initially diagnosed with progressive supranuclear palsy (PSP) because of repeated falls, slight upward gaze palsy, and mild cognitive dysfunction at the onset. He finally turned out to be ALS with more and more prominent limb weakness and atrophy, together with the evidence of chronic neurogenic change and ongoing denervation on electromyography. Brain magnetic resonance imaging showed extensive cortical atrophy. A missense mutation c.119A > G (p.D40G) on the ANXA11 gene was identified using whole-exome sequencing, which confirmed the diagnosis of ALS. We performed a systematic review of the literature about ALS-relevant cases with ANXA11 mutations and identified 68 affected subjects and 29 variants with the ANXA11 gene. We summarized the phenotypes of ANXA11 mutations and the clinical characteristics of nine patients harboring the ANXA11 p.D40G variant including our case.ConclusionsThe phenotype of ANXA11-related cases is heterogeneous, and most cases showed typical ALS, while some could also have the characteristics of frontotemporal dementia (FTD) and PSP, even inclusion body myopathies (hIBM) occurred in familial ALS (FALS). Our patient presented with ALS with a co-morbid PSP-like symptom (ALS-PSP) phenotype, which has not been reported. Except for our patient, the remaining eight patients with the ANXA11 p.D40G variant presented with a classical ALS phenotype without cognitive impairment.

The well-established semantic fluency test measures the ability to produce a sequence of spoken words from a particular category within a limited period of time. Like patients with Parkinson’s disease (PD), patients with progressive supranuclear palsy (PSP) tend to produce fewer correct words than age-matched healthy adults. This study further examined the difference between patients with PSP and PD in their semantic fluency performance using a graph theory-based approach. Twenty-nine patients with PSP Richardson’s syndrome (PSP-RS), thirty-eight patients with PD, and fifty-one healthy controls (HC) were recruited. All participants completed a standard semantic fluency test (animals). Their verbal responses were recorded, transcripted, and transformed into directed speech graphs. The speech graphs of the PSP-RS group showed higher density, shorter diameter, and shorter average shortest path than those of the PD and HC groups. It indicates that the PSP-RS group produced smaller and denser speech graphs than the PD and HC groups. In the PSP-RS group, moreover, the average shortest paths of the speech graphs correlated with the severity of motor symptoms. This study shows the potential of the graph theory-based approach in distinguishing the semantic fluency performance of nondemented patients with PSP-RS and PD.

ObjectivesTo investigate the association between body fat (BF%) and sarcopenia in older adults with type 2 diabetes mellitus (T2DM) and potential link with increased levels of inflammatory indicators and insulin resistance.MethodsA total of 543 older adults with T2DM were included in this cross-sectional study. Appendicular skeletal muscle (ASM), handgrip strength and gait speed were measured to diagnose sarcopenia according to the updated Asian Working Group for Sarcopenia (AWGS) 2019 criteria. Body composition data were tested using dual-energy X-ray absorptiometry (DEXA). Levels of serum high-sensitive C-reactive protein (hs-CRP), interleukin-6, fasting blood insulin (FINS), hemoglobin A1c (HbA1c), 25-hydroxyvitamin D3 [25(OH) D3] were also determined.ResultsThe prevalence of sarcopenia in all participants was 8.84%, of which 11.90% were male and 5.84% females. The Pearson’s correlation analysis revealed that BF% was negatively correlated with gait speed in men and women (R =-0.195, P=0.001; R = -0.136, P =0.025, respectively). After adjusting for all potential confounders, sarcopenia was positive associated with BF% (male, OR: 1.38, 95% CI: 1.15–1.65, P< 0.001; female, OR: 1.30, 95% CI: 1.07–1.56, P=0.007), and negatively associated with body mass index (BMI) (male, OR: 0.57, 95% CI: 0.44–0.73, P

Abstract Background Sarcopenia, an age-related disease, has been implicated as both a cause and consequence of type 2 diabetes mellitus (T2DM) and a symbol of poor prognosis in older adults with T2DM. Therefore, early detection and effective treatment of sarcopenia are particularly important in older adults with T2DM. We aimed to investigate the prevalence of sarcopenia in Chinese older T2DM patients and explore whether homocysteine and inflammatory indexes could serve as biomarkers and participate in the development process of sarcopenia. Methods T2DM patients aged over 60 years were consecutively recruited from the ward of department of Endocrinology, Xuanwu Hospital between April 2017 and April 2019. Sarcopenia was defined based on the standard of the Asian Working Group of Sarcopenia, including muscle mass, grip strength and gait speed. Logistic regression was used to explore the association between biochemical indicators and sarcopenia. Receiver operating characteristic (ROC) curves were applied to determine the diagnostic effect of these clinical indicators. Results Totally 582 older adults with T2DM were characterized and analyzed in the study. Approximately 8.9% of the older T2DM patients had sarcopenia. After adjusting for age, sex, body mass index (BMI) and hemoglobin A1c (HbA1c), increased concentrations of homocysteine [odds ratio (OR): 2.829; 95% confidence interval (CI), 1.064–7.525] and high-sensitive C-reactive protein (hs-CRP) (OR: 1.021; 95% CI, 1.001–1.042) were independent predictors of sarcopenia; but not interleukin-6. The combination of age, sex, BMI and HbA1c provided a discriminatory effect of sarcopenia with an area under the curve (AUC) of 0.856, when homocysteine was added to the model, the value of the ROC curve was further improved, with an AUC of 0.861. Conclusion In the current study, we demonstrated a positive correlation of homocysteine, hs-CRP with sarcopenia in older adults with T2DM and the relationship remained significant even after adjustment for HbA1c. These biomarkers (homocysteine and hs-CRP) may play important roles in the pathological process of sarcopenia.

Abstract Background The objective was to investigate the individual effect and potential interactions of probable rapid eye movement sleep behavior disorder (pRBD) and sleep insufficiency on fall risk among a Chinese elderly population. Methods Community-dwelling population aged 55 years or above were recruited from the Beijing Longitudinal Study on Aging II cohort from 2010 to 2011. Odds ratio (ORs) and 95% confidence intervals (CIs) were estimated using multivariate logistic regression models. Multiplicative and additive interactions between pRBD and sleep insufficiency were examined using likelihood ratio tests and relative excess risk due to interaction (RERI), respectively. Results Among 6891 included participants, 479 experienced at least once fall. pRBD and sleep insufficiency were both independently associated with elevated fall risk. Compared to the elderly without pRBD or sleep insufficiency, pRBD and sleep insufficiency was each associated with a 2.57-fold (OR = 2.57, 95%CI: 1.46–4.31) and 1.45-fold (OR = 1.45, 95%CI: 1.11–1.88) risk of falls individually, while their coexistence was associated with a less-than-additive 17% (OR = 1.17, 95%CI: 0.43–2.63) increased risk of falls. The combination of these two factors demonstrated evidence of a negative interaction on both multiplicative (ratio of ORs = 0.31, 95%CI: 0.10, 0.86) and additive (RERI = − 1.85, 95%CI: − 3.61, − 0.09) scale. Conclusions Our study has provided robust evidence for the adverse effect of pRBD and sleep insufficiency, as well as their negative interaction on increasing fall risk in a Chinese elderly population.

Abstract Objectives The literature regarding the use of diffusion-tensor imaging-derived metrics in the evaluation of Parkinson’s disease (PD) is controversial. This study attempted to assess the feasibility of a deep-learning-based method for detecting alterations in diffusion kurtosis measurements associated with PD. Methods A total of 68 patients with PD and 77 healthy controls were scanned using scanner-A (3 T Skyra) (DATASET-1). Meanwhile, an additional five healthy volunteers were scanned with both scanner-A and an additional scanner-B (3 T Prisma) (DATASET-2). Diffusion kurtosis imaging (DKI) of DATASET-2 had an extra b shell compared to DATASET-1. In addition, a 3D-convolutional neural network (CNN) was trained from DATASET-2 to harmonize the quality of scalar measures of scanner-A to a similar level as scanner-B. Whole-brain unpaired t test and Tract-Based Spatial Statistics (TBSS) were performed to validate the differences between the PD and control groups using the model-fitting method and CNN-based method, respectively. We further clarified the correlation between clinical assessments and DKI results. Results An increase in mean diffusivity (MD) was found in the left substantia nigra (SN) in the PD group. In the right SN, fractional anisotropy (FA) and mean kurtosis (MK) values were negatively correlated with Hoehn and Yahr (H&Y) scales. In the putamen (Put), FA values were positively correlated with the H&Y scales. It is worth noting that these findings were only observed with the deep learning method. There was neither a group difference nor a correlation with clinical assessments in the SN or striatum exceeding the significance level using the conventional model-fitting method. Conclusions The CNN-based method improves the robustness of DKI and can help to explore PD-associated imaging features.

Background and purposeThe objective cognitive trajectory in patients with post-stroke subjective cognitive complaints (SCC) over time remained unknown. We investigated cognitive outcomes in patients with SCC within 1 year after stroke, and determined factors associated with cognitive recovery.MethodsThis study included 599 patients with a clinical diagnosis of post-stroke SCC and evidence of cognitive deficits including Clinical Dementia Rating Scale (CDR) = 0.5, Montreal Cognitive Assessment (MoCA) score 17 (illiterate) or >20 (primary school) or >24 (junior school or above). Neuropsychological assessment was performed at baseline (2 weeks to 6 months after stroke) and 6-month follow-up visit. Cognitive recovery was operationalized as unimpaired cognition (MoCA score ≥26 and CDR = 0) after 6 months. Factors associated with recovery were defined through logistic regression analysis.ResultsAfter 6 months, 583 patients completed the follow-up with 80 (13.72%) presenting cognitive recovery, among which, 22 (9.48%) cases reported SCC within 2 weeks after stroke, six (10%) at 15–30 days, 13 (15.12%) at 31–60 days, 10 (16.13%) at 61–90 days, five (10.42%) at 91–120 days, nine (23.08%) at 121–150 days, and 15 (26.79%) at 151–180 days. Compared to those reported cognitive complaints at 151–180 days after stroke, patients with early post-stroke SCC had poorer cognitive recovery, which was only significant in individuals with high level of education. Male sex, higher baseline MoCA scores, coffee intake and thalamus lesions were independently associated with high chance of cognitive recovery.ConclusionsAlthough post-stroke SCC contributes to persisting objective cognitive deficits, some patients presented cognitive recovery within 1 year after stroke. Patients with a high education level reporting SCC at earlier stage after stroke had poorer cognitive recovery. Male, higher baseline MoCA scores, coffee intake and thalamus lesions appear to independently predict cognitive recovery.

Background18F-FP-DTBZ has been proven as a biomarker for quantifying the concentration of presynaptic vesicular monoamine transporter 2 (VMAT2). However, its clinical application is still limited.ObjectivesTo evaluate the difference in dopaminergic integrity between patients with Parkinson’s disease (PD) and healthy controls (HC) using 18F-FP-DTBZ PET in vivo and to determine the diagnostic value of standardized uptake value ratios (SUVRs) using the Receiver Operating Characteristic (ROC) curve.MethodsA total of 34 PD and 31 HC participants were enrolled in the PET/MR derivation cohort, while 89 PD and 18 HC participants were recruited in the PET/CT validation cohort. The Hoehn–Yahr Scale and the third part of the MDS-Unified Parkinson’s Disease Rating Scale (MDSUPDRS-III) were used to evaluate the disease staging and severity. All assessments and PET scanning were performed in drug-off states. The striatum was segmented into five subregions as follows: caudate, anterior dorsal putamen (ADP), anterior ventral putamen (AVP), posterior dorsal putamen (PDP), and posterior ventral putamen (PVP) using automatic pipeline built with the PMOD software (version 4.105). The SUVRs of the targeted subregions were calculated using the bilateral occipital cortex as the reference region.ResultsRegarding the diagnostic value, ROC curve and blind validation showed that the contralateral PDP (SUVR = 3.43) had the best diagnostic accuracy (AUC = 0.973; P < 0.05), with a sensitivity of 97.1% (95% CI: 82.9–99.8%), specificity of 100% (95% CI: 86.3–100%), positive predictive value (PPV) of 100% (95% CI: 87.0–100%), negative predictive value (NPV) of 96.9% (95% CI: 82.0–99.8%), and an accuracy of 98.5% for the diagnosis of PD in the derivation cohort. Blind validation of 18F-FP-DTBZ PET imaging diagnosis was done using the PET/CT cohort, where participants with a SUVR of the PDP

Objectives[18F]9-fluoropropyl-(+)-dihydrotetrabenazine ([18F]-FP-DTBZ) positron emission tomography (PET) provides reliable information for the diagnosis of Parkinson’s disease (PD). In this study, we proposed a multi-atlas-based [18F]-FP-DTBZ PET image segmentation method for PD quantification assessment.MethodsA total of 99 subjects from Xuanwu Hospital of Capital Medical University were included in this study, and both brain PET and magnetic resonance (MR) scans were conducted. Data from 20 subjects were used to generate atlases, based on which a multi-atlas-based [18F]-FP-DTBZ PET segmentation method was developed especially for striatum and its subregions. The proposed method was compared with the template-based method through striatal subregion parcellation performance and the standard uptake value ratio (SUVR) quantification accuracy. Discriminant analysis between healthy controls (HCs) and PD patients was further performed.ResultsSegmentation results of the multi-atlas-based method showed better consistency than the template-based method with the ground truth, yielding a dice coefficient of 0.81 over 0.73 on the full striatum. The SUVRs calculated by the multi-atlas-based method had an average interclass correlation coefficient (ICC) of 0.953 with the standardized result, whereas the template-based method only reached 0.815. The SUVRs of HCs were generally higher than that of patients with PD and showed significant differences in all of the striatal subregions (all p < 0.001). The median and posterior putamen performed best in discriminating patients with PD from HCs.ConclusionThe proposed multi-atlas-based [18F]-FP-DTBZ PET image segmentation method achieved better performance than the template-based method, indicating great potential in improving accuracy and efficiency for PD diagnosis in clinical routine.

Abstract Background New therapies are urgently needed for Alzheimer’s disease (AD). Sodium oligomannate (GV-971) is a marine-derived oligosaccharide with a novel proposed mechanism of action. The first phase 3 clinical trial of GV-971 has been completed in China. Methods We conducted a phase 3, double-blind, placebo-controlled trial in participants with mild-to-moderate AD to assess GV-971 efficacy and safety. Participants were randomized to placebo or GV-971 (900 mg) for 36 weeks. The primary outcome was the drug-placebo difference in change from baseline on the 12-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog12). Secondary endpoints were drug-placebo differences on the Clinician’s Interview-Based Impression of Change with caregiver input (CIBIC+), Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, and Neuropsychiatric Inventory (NPI). Safety and tolerability were monitored. Results A total of 818 participants were randomized: 408 to GV-971 and 410 to placebo. A significant drug-placebo difference on the ADAS-Cog12 favoring GV-971 was present at each measurement time point, measurable at the week 4 visit and continuing throughout the trial. The difference between the groups in change from baseline was − 2.15 points (95% confidence interval, − 3.07 to − 1.23; p

Abstract Background With the extended life expectancy of the Chinese population and improvements in surgery and anesthesia techniques, the number of aged patients undergoing surgery has been increasing annually. However, safety, effectiveness, and quality of life of aged patients undergoing surgery are facing major challenges. In order to standardize the perioperative assessment and procedures, we have developed a perioperative evaluation and auxiliary decision-making system named “Aged Patient Perioperative Longitudinal Evaluation–Multidisciplinary Trial (APPLE-MDT)”. Methods We will conduct a perioperative risk evaluation and targeted intervention, with follow-ups at 1, 3, and 6 months after surgery. The primary objective of the study is to evaluate the effectiveness of the “Aged Patient Perioperative Longitudinal Evaluation-Multiple Disciplinary Trial Path” (hereinafter referred to as the APPLE-MDT path) in surgical decision-making for aged patients (≥75 years) undergoing elective surgery under non-local anesthesia in the operating room. The secondary objectives of the study are to evaluate the postoperative outcome and health economics of the APPLE-MDT path applied to the surgical decision-making of aged patients (≥75 years) undergoing elective surgery under non-local anesthesia and to optimize intervention strategies for aged patients undergoing surgery to reduce the occurrence of postoperative complications and improve the quality of life after surgery. Discussion It is necessary to formulate a reliable, effective, and concise evaluation tool, which can effectively predict the perioperative complications and mortality of aged patients, support targeted intervention strategies, and allow for a more comprehensive risk and benefit analysis, thereby forming an effective senile perioperative surgery management path. It is expected that the implementation of this protocol can reduce the occurrence of postoperative complications, improve the postoperative quality of life, shorten hospital stay, reduce hospitalization expenses, reduce social burden, and allow the elderly to have a good quality of life after surgery. Trial registration ChiCTR, ChiCTR1800020363 , Registered 15 December 2018.

Abstract Iron deposition is present in main lesion areas in the brains of patients with Parkinson’s disease (PD) and an abnormal iron content may be associated with dopaminergic neuronal cytotoxicity and degeneration in the substantia nigra of the midbrain. However, the cause of iron deposition and its role in the pathological process of PD are unclear. In the present study, we investigated the effects of the nasal mucosal delivery of synthetic human α-synuclein (α-syn) preformed fibrils (PFFs) on the pathogenesis of PD in Macaca fascicularis. We detected that iron deposition was clearly increased in a time-dependent manner from 1 to 17 months in the substantia nigra and globus pallidus, highly contrasting to other brain regions after treatments with α-syn PFFs. At the cellular level, the iron deposits were specifically localized in microglia but not in dopaminergic neurons, nor in other types of glial cells in the substantia nigra, whereas the expression of transferrin (TF), TF receptor 1 (TFR1), TF receptor 2 (TFR2), and ferroportin (FPn) was increased in dopaminergic neurons. Furthermore, no clear dopaminergic neuron loss was observed in the substantia nigra, but with decreased immunoreactivity of tyrosine hydroxylase (TH) and appearance of axonal swelling in the putamen. The brain region-enriched and cell-type-dependent iron localizations indicate that the intranasal α-syn PFFs treatment-induced iron depositions in microglia in the substantia nigra may appear as an early cellular response that may initiate neuroinflammation in the dopaminergic system before cell death occurs. Our data suggest that the inhibition of iron deposition may be a potential approach for the early prevention and treatment of PD.

ObjectiveTo explore the roles of striatal subdivisions in the pathogenesis of frontotemporal dementia with parkinsonism (FTDP) in a patient resulting from prion protein gene (PRNP) mutation.MethodsThis patient received clinical interviews and underwent neuropsychological assessments, genetic testing, [18F]-fluorodeoxyglucose positron emission tomography ([18F]-FDG PET)/MRI, and [18F]-dihydrotetrabenazine positron emission tomography ([18F]-DTBZ PET)/CT. Region-of-interest analysis was conducted concerning metabolism, and dopamine transport function between this patient and 12 controls, focusing on the striatum subregions according to the Oxford-GSK-Imanova Striatal Connectivity Atlas.ResultsA 64-year-old man initially presented with symptoms of motor dysfunction and subsequently behavioral and personality changes. FTDP was initially suspected. Sequence analysis disclosed a valine to isoleucine at codon 180 in PRNP. Compared to controls, this patient had a severe reduction (> 2SD) of standard uptake value ratio (SUVR) in the limbic and executive subregions but relative retention of metabolism in rostral motor and caudal motor subregions using [18F]-FDG PET/MRI, and the SUVR decreased significantly across the striatal in [18F]-DTBZ PET/CT, especially in the rostral motor and caudal motor subregions.ConclusionThe alteration of frontal striatal loops may be involved in cognitive impairment in FTDP, and the development of parkinsonism in FTDP may be primarily due to the involvement of the presynaptic nigrostriatal loops in PRNP V180I mutation.

Human brain bank is the foundation for neurology and neuroscience, which provides research materials for medical scientists to explore what happen in human brains. Through voluntary postmortem brain tissue donation, brain bank collects, classifies, stores and distributes brain tissue samples for researchers with appropriate research proposals, so as to facilitate researchers to conduct human brain research. History showed that the act of brain only autopsy distinguished neurology as a distinct discipline. The emerges of brain banking accompanied with the advances of neurology and neuroscience. It facilitates the development of neurology from neuropathological examination feedback about the clinical presentations of the brain donor, plays an important role in the definition of novel neurological diseases, and also makes an extraordinary contribution to the disease mechanisms and novel therapeutic discoveries. This manuscript elaborated the history, current situation, and the impacts of human brain banking on current neurology. Furthermore, we discussed about the opportunities and challenges of brain banking in China. DOI:10.3969/j.issn.1672⁃6731.2020.10.012

Abstract Background We aimed to investigate the correlation of factors involved in the change of Mini-Mental State Examination (MMSE) and type 2 diabetes in the elderly. Methods This study was a secondary analysis of a prospective cohort study. Type 2 diabetes patients aged > 55 years were recruited and assigned into three groups based on their glycated hemoglobin (HbA1c) levels: HbA1c

Abstract Background Early morning off (EMO) is a common feature of Parkinson’s disease (PD). This study aimed to characterize its clinical features and develop a convenient and pragmatic self-assessment instrument in a Chinese nationwide population. Methods This study was conducted on 942 PD patients admitted to 55 clinic centers for movement disorders between June 2018 and May 2019 in China. Stepwise logistic regression analyses were performed to determine potential risk factors and the most predictive symptoms of EMO, as well as whether EMO was an independent risk factor of functional dependency in daily life. Based on this, a 7-question scale was derived for EMO screening. Diagnostic accuracy of this scale was assessed from the area under the receiver operative characteristic curve (AUROC) and its 95% confidence intervals (CIs). We further calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the optimal cutoff point. Results EMO occurred in 49.2% of PD patients across all disease stages. We identified 7 symptoms most predictive of EMO, including bradykinesia or rigidity, excessive sweating or salivation, difficulty in turning on or getting out of bed, muscle cramp, fatigue or sleepiness, frozen state or freezing gait, and tremor. The resulting 7-item scale was confirmed to be of good discrimination with a relatively large AUROC of 0.83, a relatively high sensitivity of 75.7%, specificity of 77.5%, PPV of 76.5%, and NPV of 76.7%. Nonideal nighttime sleep, long PD duration, advanced H&Y stages, posture instability gait difficulty-dominant or mixed subtypes, and high levodopa dose were independently associated with increased risk of EMO. EMO patients were at 87% higher (OR = 1.87, 95%CI: 1.07–3.32) risk of experiencing functional dependency in daily living compared with their counterparts. Conclusions We demonstrated that EMO is a common feature for PD patients across all disease stages and put forward an EMO-specific screening card of sufficient accuracy and brevity. Meanwhile we have thrown some light upon potential determinants and negative health effects of EMO. Our findings may exert great impact on improving the awareness, recognition and management of EMO in PD patients.

Arterial degeneration, closely associated with cardiovascular diseases, is driven by aging-related vascular cell-specific transcriptomics changes. This study provides a single-cell transcriptomic atlas for senile aortic and coronary arteries and underscores FOXO3A-based the transcriptional network in vasoprotection during aging.

Semantic fluency is the ability to name items from a given category within a limited time, which relies on semantic memory, working memory, and executive function. Semantic disfluency is a common problem in Parkinson’s disease (PD) and Alzheimer’s disease (AD). We demonstrated a graph theoretical analysis of semantic fluency in patients with PD (N=86), patients with AD (N=40), and healthy controls (HC, N=88). All participants completed a standard animal fluency test. Their verbal responses were recorded, transcripted, and transformed into directed speech graphs. Patients with PD generated fewer correct words than HC and more correct words than patients with AD. Patients with PD showed higher density, shorter diameter, and shorter average shortest path length than HC, but lower density, longer diameter, and longer average shortest path length than patients with AD. It suggests that patients with PD produced relatively smaller and denser speech graphs. Moreover, in PD, the densities of speech graphs correlated with the severity of non-motor symptoms, but not the severity of motor symptoms. The graph theoretical analysis revealed new features of semantic disfluency in patients with PD.

Background: Fatigue is a common symptom in patients with Multiple system atrophy (MSA), but effective treatments remain elusive. The present study aims to investigate whether high-frequency repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) could relieve fatigue in patients with MSA.Methods: This is a single-center, randomized and double-blind trial. Twenty-two patients with MSA and fatigue were randomly allocated to receive 10 sessions of either active (N = 11) or sham (N = 11) 10 Hz rTMS over the left DLPFC. The participants were assessed at baseline (T0), after the last session of treatment (T1), and at 2-week (T2), and 4-week (T3) follow-up timepoints. The primary outcomes were Fatigue Severity Scale-9 (FSS-9) scores, with Unified Multiple System Atrophy Rating Scale (UMSARS), 17-item Hamilton Depression Scale (HAMD-17), and Hamilton Anxiety Scale (HAMA) as secondary outcomes.Results: Two-way repeated ANOVAs revealed significant group × time interactions for FSS-9 scores (p < 0.001), HAMD-17 scores (p = 0.01), HAMA scores (p = 0.01), and UMRSA part II (p = 0.05). Post-hoc analyses showed that compared to T0, the active group exhibited remarkable improvements in FSS-9 and UMRSA part II scores at T1 and T2, but not at T3, and also in HAMD-17 and HAMA scores at T1, T2, and T3. No significant improvement was found in the sham group.Conclusion: High-frequency rTMS over the left DLPFC could provide short-term improvements for alleviating fatigue in patients with MSA, but the beneficial effects last no more than 4 weeks.

BackgroundMusculoskeletal pain is commonly experienced in patients with Parkinson's disease (PD). Few studies have investigated the clinical characteristics and risk factors associated with musculoskeletal pain.ObjectivesTo investigate the distribution, clinical characteristics, and factors associated with musculoskeletal pain in a large sample of patients with PD.MethodsWe enrolled 452 patients from two clinics and used a standardized questionnaire to collect demographic and clinical information. Musculoskeletal pain was diagnosed based on the Ford Classification System, and pain severity was assessed with the numeric rating scale (NRS). Multivariate regression models explored the association between clinical features of PD and quality of life and pain.ResultsTwo hundred and six patients (45.58%) reported musculoskeletal pain, typically in their lower limbs and backs. Levodopa resulted in a ≥30% reduction in pain intensity scores in 170 subjects. Female sex (odds ratio [OR], 1.57; 95% CI, 1.07–2.29) and Levodopa-equivalent daily doses (LEDDs; OR, 3.35; 95% CI, 1.63–6.59) were associated with an increased risk for musculoskeletal pain. Pain duration (p = 0.017), motor symptoms (p < 0.001), and depression (p < 0.001) were significantly associated with quality of life.ConclusionsThe lower limbs and back are common sites of musculoskeletal pain in patients with PD, and up to 82.52% of patients were responsive to Levodopa. Female sex and LEDDs are associated with musculoskeletal pain, suggesting that dopamine deficiencies, and not the motor and non-motor impairment, might be the most critical baseline risk factor of musculoskeletal pain.

Introduction: Fatigue is one of the most common and disabling symptoms of Parkinson’s Disease (PD). The occurrence and clinical features of fatigue in patients with prodromal PD remain largely elusive. This study aimed to investigate the prevalence and clinical characteristics of fatigue in patients with idiopathic/isolated REM sleep behavior disorders (iRBD). Methods: A total of 97 polysomnography-confirmed iRBD patients were enrolled in this study. A comprehensive neurological assessment (including motor and non-motor assessment) was performed. Fatigue was assessed using the Fatigue Severity Scale (FSS). Motor and non-motor characteristics were compared between iRBD patients with and without fatigue. Logistic regression was used to identify the factors associated with fatigue. Results: The prevalence of fatigue was 35.05%. Compared to the non-fatigue patients, patients with fatigue had higher non-motor symptom scale (NMSS) score (p = 0.009), higher Hamilton Depression Rating Scale (HAMD) score (p = 0.002), and a higher prevalence of orthostatic hypotension (p = 0.021). Multivariate regression analysis showed that depression (OR 4.17, 95% CI 1.13–15.49, p = 0.033) and orthostatic hypotension (OR 2.80, 95% CI 1.09–7.18, p = 0.032) were significantly associated with fatigue in iRBD patients. Additionally, both NMSS (rs = 0.310, p = 0.002) and HAMD (rs = 0.385, p < 0.001) scores were mildly correlated with fatigue severity. Conclusion: Our study showed that fatigue is common in patients with iRBD. In addition, depression and orthostatic hypotension were independently associated with fatigue in iRBD patients.

Selective depletion of dopaminergic neurotransmission in the caudal sensorimotor striatum, a subdivision implicated in habitual control, is a major pathological feature in Parkinson’s disease (PD). Here, we evaluated the effects of PD on the formation of goal-directed and habitual control during learning, and for the first time investigated the conflict between these two strategies in the expression of acquired learning. Twenty PD patients and 20 healthy individuals participated in a set of tasks designed to assess relative goal-directed versus habitual behavioral control. In the instrumental training phase, participants first learned by trial and error to respond to different pictured stimuli in order to gain rewarding outcomes. Three associations were trained, with standard and congruent associations mediated predominantly by goal-directed action, and incongruent association regulated predominantly by habitual control. In a subsequent “slips-of-action” test, participants were assessed to determine whether they can flexibly adjust their behavior to changes in the desirability of the outcomes. A baseline test was then administered to rule out the possibility of general inhibitory deficit, and a questionnaire was finally adopted to test the explicit knowledge of the relationships between stimuli, responses, and outcomes. Our results showed that during the instrumental training phase, PD patients had impaired learning not only of the standard and congruent associations (mediated by goal-directed system), but also the incongruent association (mediated by habitual control system). In the slips-of-action test, PD patients responded less for valuable outcomes and more often to stimuli that were associated with devalued outcomes, with poor performance predicted by symptom severity. No significant difference was found between PD and healthy subjects for the baseline test and questionnaire performance. These results collectively demonstrate that the formation of both goal-directed and habitual control are impaired in PD patients. Furthermore, PD patients are more prone to slips of action, suggesting PD patients exhibit an impairment in engaging the goal-directed system with a relatively excessive reliance on habitual control in the expression of acquired learning.

Multiple studies have identified segregated functional territories in the basal ganglia for the control of goal-directed and habitual actions. It has been suggested that in PD, preferential loss of dopamine in the posterior putamen may cause a major deficit in habitual control (mediated by the sensorimotor cortical-striatal loop), and the patients may therefore be forced into a progressive reliance on the goal-directed behavior (regulated by the associative cortical-striatal loop). Functional evidence supporting this point is scarce at present. This study aims to verify the functional connectivity changes within the sensorimotor, associative, and limbic cortical-striatal loops in PD. Resting-state fMRI of 70 PD patients and 30 controls were collected. Bilateral tripartite functional territories of basal ganglia and their associated cortical structures were chosen as regions of interest, including ventral striatum and ventromedial prefrontal cortex for limbic loop; dorsomedial striatum and dorsolateral prefrontal cortex for associative loop; dorsolateral striatum and sensorimotor cortex for sensorimotor loop. Pearson's correlation coefficients for each seed pair were calculated to obtain the functional connectivity. The relationships between functional connectivity and disease severity were further investigated. Functional connectivity between dorsolateral striatum and sensorimotor cortex is decreased in PD patients, and negatively correlated with disease duration; whereas functional connectivity between dorsomedial striatum and dorsolateral prefrontal cortex is also decreased but postitively correlated with disease duration. The functional connectivity within the sensorimotor loop is pathologically decreased in PD, while the altered connectivity within the associative loop may indicate a failed attempt to compensate for the loss of connectivity within the sensorimotor loop.

Objective: This study aimed to assess the status of intrinsic capacity (IC)—a novel function-centered construct proposed by the WHO and examine whether impairment in IC predicts subsequent 1-year activities of daily living (ADL) disability better than a disease-based approach, i. e., multimorbidity status.Methods: This study included data of community-dwelling older adults from the Beijing Longitudinal Study on Aging II aged 65 years or older who were followed up at 1 year. Multivariate logistic regressions were performed to estimate the odds of ADL disability at baseline and 1-year follow-up.Results: A total of 7,298 older participants aged 65 years or older were included in the current study. About 4,742 older adults were followed up at 1 year. At baseline, subjects with a higher impairment in IC domains showed higher odds of ADL disability [adj. odds ratio (OR) = 9.51 for impairment in ≥3 domains, area under the curve (AUC) = 0.751] compared to much lower odds of ADL disability in subjects with a higher number (≥3) of chronic diseases (adj. OR 3.92, AUC = 0.712). At 1-year follow-up, the overall incidence of ADL disability increased with the impairment in IC domains higher than the increase in multimorbidity status. A higher impairment in IC domains showed higher odds of incidence ADL disability for impairment in 2 or ≥3 IC domains (adj. OR 2.32 for impairment in ≥3 domains, adj. OR 1.43 for impairment in two domains, AUC = 0.685). Only subjects who had ≥3 chronic diseases had higher odds of 1-year incident ADL disability (adj. OR 1.73, AUC = 0.681) that was statistically significant.Conclusion: Our results imply that a function-centered construct could have higher predictability of disability compared to the multimorbidity status in community older people. Our results need to be confirmed by studies with longer follow-up.

Ganoderma lucidum, one of the most valued medicinal mushrooms, has been used for health supplements and medicine in China. Our previous studies have proved that Ganoderma lucidum extract (GLE) could inhibit activation of microglia and protect dopaminergic neurons in vitro. In the present study, we investigated the anti-neuroinflammatory potential of GLE in vivo on Parkinsonian-like pathological dysfunction. Male C57BL/6J mice were subjected to acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion, and a treatment group was administered intragastrically with GLE at a dose of 400 mg/kg. Immunohistochemistry staining showed that GLE efficiently repressed MPTP-induced microglia activation in nigrostriatal region. Accordingly, Bio-plex multiple cytokine assay indicated that GLE treatment modulates abnormal cytokine expression levels. In microglia BV-2 cells incubated with LPS, increased expression of iNOS and NLRP3 were effectively inhibited by 800 μg/mL GLE. Furthermore, GLE treatment decreased the expression of LC3II/I, and further enhanced the expression of P62. These results indicated that the neuroprotection of GLE in an experimental model of PD was partially related to inhibition of microglia activation in vivo and vitro, possibly through downregulating the iNOS/NLRP3 pathway, inhibiting abnormal microglial autophagy and lysosomal degradation, which provides new evidence for Ganoderma lucidum in PD treatment.

Background: Cognitive impairment is one of the most prominent non-motor symptoms in Parkinson's disease (PD), due in part to known cerebellar dysfunctions. Furthermore, previous studies have reported altered cerebellar functional connectivity (FC) in PD patients. Yet whether these changes are also due to the cognitive deficits in PD remain unclear.Methods: A total of 122 non-dementia participants, including 64 patients with early PD and 58 age- and gender-matched elderly controls were stratified into four groups based on their cognitive status (normal cognition vs. cognitive impairment). Cerebellar volumetry and FC were investigated by analyzing, respectively, structural and resting-state functional MRI data among groups using quality control and quantitative measures. Correlation analysis between MRI metrics and clinical features (motor and cognitive scores) were performed.Results: Compared to healthy control subjects with no cognitive deficits, altered cerebellar FC were observed in early PD participants with both motor and cognitive deficits, but not in PD patients with normal cognition, nor elderly subjects showing signs of a cognitive impairment. Moreover, connectivity between the “motor” cerebellum and SMA was positively correlated with motor scores, while intracerebellar connectivity was positively correlated with cognitive scores in PD patients with cognitive impairment. No cerebellar volumetric difference was observed between groups.Conclusions: These findings show that altered cerebellar FC during resting state in early PD patients may be driven not solely by the motor deficits, but by cognitive deficits as well, hence highlighting the interplay between motor and cognitive functioning, and possibly reflecting compensatory mechanisms, in the early PD.