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Background: We 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., Methods: Data 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., Results: SDMT 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., Conclusion: SDMT is a preferable cognitive assessment tool for PD and genetic factors synergistically contribute to the cognitive dysfunction in PD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Cao, Kong, Chan, Zhang, Morris and Huang.)

Introduction: Accurately 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., Methods: We 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., Results: A 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., Conclusion: The 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wu, Ma, Wei, Shan, Chan, Wang and Zhao.)

Introduction: Orthostatic 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., Methods: This 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)., Results: The 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)., Discussion: PD 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xue, Huang, Zeng, Song, Xing, Chan, Xu and Zhou.)

Background and Purpose: The 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., Methods: This 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 <26, and Mini-Mental State Examination 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., Results: After 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., Conclusions: Although 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ji, Sun, Jin, Chen, Zhou, Zhao, Liang, Shen, Zhang and Chan.)

Background: Musculoskeletal 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., Objectives: To investigate the distribution, clinical characteristics, and factors associated with musculoskeletal pain in a large sample of patients with PD., Methods: We 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., Results: Two 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., Conclusions: The 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Zhu, Gu, Zhang, Mei, Ji, Liu, Han, Chen and Chan.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pan, Mi, Ma, Sun and Chan.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mi, Zhang, Li, Liu, Ren and Chan.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dan, Hu, Sun, Gao, Zhou, Ma, Doyon, Wu and Chan.)

Objectives: To investigate the relationship between probable rapid eye movement (REM) sleep behavior disorder (pRBD) and cognitive/motor impairments in a community-dwelling population and explore the moderating effects of education. Methods: In this cross-sectional study of the Beijing Longitudinal Study of Aging II (BLSA II), 4,477 subjects (≥55 years) fulfilled the inclusion criteria. pRBD was determined by the RBD Questionnaire-Hong Kong (RBDQ-HK). Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were used to test the global cognitive performance. Walking speed was used to measure motor function. Logistic regression was performed to assess the relationship between pRBD and cognitive/motor impairments and the moderating effects of education. Results: There were 147 participants (3.3%) with pRBD. Participants with pRBD showed increased risks for cognitive impairment [odds ratio (OR) = 1.88, 95% CI 1.24-2.85, p = 0.003], decreased gait speed (OR = 1.43, 95% CI 1.02-2.01, p = 0.03), but not for mild cognitive impairment (MCI) (measured by MoCA: OR = 1.01, 95% CI 0.68-1.50, p = 0.95; measured by MMSE: OR = 0.90, 95% CI 0.59-1.37, p = 0.62). Education modified the effect of pRBD on MCI (measured by MoCA: p < 0.001; measured by MMSE: p = 0.061) and gait speed ( p = 0.008). Conclusions: Our findings suggest that pRBD increases the risk of cognitive/motor impairments for a community-dwelling older population, and education could alleviate the negative effects. These findings implicate that education may have beneficial effects on delaying the onset of cognitive/motor decline in pRBD subjects., (Copyright © 2020 Chen, Chen, Xu, Qiao, Wang, Ji, Gu, Chhetri and Chan.)

Background: Early prediction of disease progression in patients with amnestic mild cognitive impairment (aMCI) is important for early diagnosis and intervention of Alzheimer's disease (AD). Previous brain network studies have suggested topological disruptions of the brain connectome in aMCI patients. However, whether brain connectome markers at baseline can predict longitudinal conversion from aMCI to AD remains largely unknown. Methods: In this study, 52 patients with aMCI and 26 demographically matched healthy controls from a longitudinal cohort were evaluated. During 2 years of follow-up, 26 patients with aMCI were retrospectively classified as aMCI converters and 26 patients remained stable as aMCI non-converters based on whether they were subsequently diagnosed with AD. For each participant, diffusion tensor imaging at baseline and deterministic tractography were used to map the whole-brain white matter structural connectome. Graph theoretical analysis was applied to investigate the convergent and divergent connectivity patterns of structural connectome between aMCI converters and non-converters. Results: Disrupted topological organization of the brain structural connectome were identified in both aMCI converters and non-converters. More severe disruptions of structural connectivity in aMCI converters compared with non-converters were found, especially in the default-mode network regions and connections. Finally, a support vector machine-based classification demonstrated the good discriminative ability of structural connectivity in differentiating aMCI patients from controls with an accuracy of 98%, and in discriminating converters from non-converters with an accuracy of 81%. Conclusion: Our study provides potential structural connectome/connectivity-based biomarkers for predicting disease progression in aMCI, which is important for the early diagnosis of AD.

Objective: Increasing evidence suggests a cerebellar contribution to modulate cognitive aspects of motor behavior and executive functions. Supporting findings come from studies on patients with neurodegenerative diseases, in which however, given the extent of the disease, the specific role of the cerebellum, could not be clearly isolated. Anti-saccades are considered a sensitive tool to test executive functions. The anti-saccade underlying neural network, consisting of different cortical areas and their downstream connections including the lateral cerebellum, has been largely clarified. To separate the role of the cerebellum with respect to other cortical structures in executive control, we compared the anti-saccade performances in two distinct cohorts of patients with cerebellar disorders (with and without cerebral cortical involvement)., Methods: Eye movements during the execution of anti-saccades were recorded in 12 patients with spinocerebellar ataxia type 2 (a cortical-subcortical neurodegenerative disease), 10 patients with late onset cerebellar ataxia (an isolated cerebellar atrophy), and 34 matched controls., Results: In the anti-saccade task, besides dynamic changes already demonstrated in the pro-saccades of these patients, we found in both groups of cerebellar patients prolonged latency with larger variability than normal and increased directional error rate. Errors, however, were corrected by cerebellar patients as frequently as normal. No significant differences were found in patients with and without cortical involvement., Conclusion: Our results indicate, in a large cohort of cerebellar patients, that the cerebellum plays a critical role in the regulation of executive motor control not only, as well known, by controlling the end of a movement, but also modulating its initiation and reducing reflexive responses that would perturb voluntary actions.