Targeting the Labile Iron Pool with Engineered DFO Nanosheets to Inhibit Ferroptosis for Parkinson's Disease Therapy.

Ferroptosis in neurons is considered one of the key factors that induces Parkinson's disease (PD), which is caused by excessive iron accumulation in the intracellular labile iron pool (LIP). The iron ions released from the LIP lead to the aberrant generation of reactive oxygen species (ROS) to trigger ferroptosis and exacerbate PD progression. Herein, a pioneering design of multifunctional nanoregulator deferoxamine (DFO)-integrated nanosheets (BDPR NSs) is presented that target the LIP to restrict ferroptosis and protect against PD. The BDPR NSs are constructed by incorporating a brain-targeting peptide and DFO into polydopamine-modified black phosphorus nanosheets. These BDPR NSs can sequester free iron ions, thereby ameliorating LIP overload and regulating iron metabolism. Furthermore, the BDPR NSs can decrease lipid peroxidation generation by mitigating ROS accumulation. More importantly, BDPR NSs can specifically accumulate in the mitochondria to suppress ROS generation and decrease mitochondrial iron accumulation. In vivo experiments demonstrated that the BDPR NSs highly efficiently mitigated dopaminergic neuronloss and its associated behavioral disorders by modulating the LIP and inhibiting ferroptosis. Thus, the BDPR-based nanovectors holds promise as a potential avenue for advancing PD therapy.

Prevalence of Parkinson's disease among adults aged 45 years and older in China: a cross-sectional study based on the China health and retirement longitudinal study.

BACKGROUND: In recent decades, China has experienced a rapid increase in the number of elderly individuals and life expectancy, as well as industrialization, which is associated with an increased prevalence of Parkinson's disease (PD). However, inconsistent results have recently been reported. Therefore, this study aimed to investigate the prevalence and distribution characteristics of PD among individuals aged 45 years and older. METHODS: Using data from the China Health and Retirement Longitudinal Study (CHARLS), we attempted to estimate the prevalence of PD and its distribution characteristics among 19,034 individuals aged 45 years and older residing in 446 communities/villages within 27 provinces/autonomous regions/municipalities in mainland China. Cases were established based on a doctor's previous diagnosis. Crude and age-adjusted prevalence rates were calculated and stratified by age, sex, area of residence, education level, marital status, and geographic region. Logistic regression models were used to identify risk factors associated with PD. RESULTS: We identified 178 patients with PD among 19,034 residents aged 45 years and older. The crude prevalence was 0.94%, and the age-adjusted prevalence was 0.82% for individuals aged 45 years and older. The prevalence of PD increased with age (P < 0.001). No significant differences were found in terms of sex, area of residence, or education level. Stratified by geographic region, the prevalence of PD was greater in North and Northwest China and lower in southern China (p < 0.001). Multiple regression analyses showed that age was a significant risk factor for PD. CONCLUSION: The prevalence of PD increased with age in the Chinese population.

Transcranial alternating current stimulation improves quality of life in Parkinson's disease: study protocol for a randomized, double-blind, controlled trial.

BACKGROUND: The neural cells in the brains of patients with Parkinson's disease (PWP) display aberrant synchronized oscillatory activity within the beta frequency range. Additionally, enhanced gamma oscillations may serve as a compensatory mechanism for motor inhibition mediated by beta activity and also reinstate plasticity in the primary motor cortex affected by Parkinson's disease. Transcranial alternating current stimulation (tACS) can synchronize endogenous oscillations with exogenous rhythms, thereby modulating cortical activity. The objective of this study is to investigate whether the addition of tACS to multidisciplinary intensive rehabilitation treatment (MIRT) can improve symptoms of PWP so as to enhance the quality of life in individuals with Parkinson's disease based on the central-peripheral-central theory. METHODS: The present study was a randomized, double-blind trial that enrolled 60 individuals with Parkinson's disease aged between 45 and 70 years, who had Hoehn-Yahr scale scores ranging from 1 to 3. Participants were randomly assigned in a 1:1 ratio to either the tACS + MIRT group or the sham-tACS + MIRT group. The trial consisted of a two-week double-blind treatment period followed by a 24-week follow-up period, resulting in a total duration of twenty-six weeks. The primary outcome measured the change in PDQ-39 scores from baseline (T0) to 4 weeks (T2), 12 weeks (T3), and 24 weeks (T4) after completion of the intervention. The secondary outcome assessed changes in MDS-UPDRS III scores at T0, the end of intervention (T1), T2, T3, and T4. Additional clinical assessments and mechanistic studies were conducted as tertiary outcomes. DISCUSSION: The objective of this study is to demonstrate that tACS can enhance overall functionality and improve quality of life in PWP, based on the framework of MIRT. Additionally, it seeks to establish a potential correlation between these therapeutic effects and neuroplasticity alterations in relevant brain regions. The efficacy of tACS will be assessed during the follow-up period in order to optimize neuroplasticity and enhance its potential impact on rehabilitation efficiency for PWP. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2300071969. Registered on 30 May 2023.

Functional and structural gradients reveal atypical hierarchical organization of Parkinson's disease.

Parkinson's disease (PD) patients exhibit deficits in primary sensorimotor and higher-order executive functions. The gradient reflects the functional spectrum in sensorimotor-associated areas of the brain. We aimed to determine whether the gradient is disrupted in PD patients and how this disruption is associated with treatment outcome. Seventy-six patients (mean age, 59.2 ± 12.4 years [standard deviation], 44 women) and 34 controls participants (mean age, 58.1 ± 10.0 years [standard deviation], 19 women) were evaluated. We explored functional and structural gradients in PD patients and control participants. Patients were followed during 2 weeks of multidisciplinary intensive rehabilitation therapy (MIRT). The Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) was administered to patients before and after treatment. We investigated PD-related alterations in the principal functional and structural gradients. We further used a support vector machine (SVM) and correlation analysis to assess the classification ability and treatment outcomes related to PD gradient alterations, respectively. The gradients showed significant differences between patients and control participants, mainly in somatosensory and visual networks involved in primary function, and higher-level association networks (dorsal attentional network (DAN) and default mode network (DMN)) related to motor control and execution. On the basis of the combined functional and structural gradient features of these networks, the SVM achieved an accuracy of 91.2% in discriminating patients from control participants. Treatment reduced the gradient difference. The altered gradient exhibited a significant correlation with motor improvement and was mainly distributed across the visual network, DAN and DMN. This study revealed damage to gradients in the brain characterized by sensorimotor and executive control deficits in PD patients. The application of gradient features to neurological disorders could lead to the development of potential diagnostic and treatment markers for PD.

Exploring the application and challenges of fNIRS technology in early detection of Parkinson's disease.

Background: Parkinson's disease (PD) is a prevalent neurodegenerative disorder that significantly benefits from early diagnosis for effective disease management and intervention. Despite advancements in medical technology, there remains a critical gap in the early and non-invasive detection of PD. Current diagnostic methods are often invasive, expensive, or late in identifying the disease, leading to missed opportunities for early intervention. Objective: The goal of this study is to explore the efficiency and accuracy of combining fNIRS technology with machine learning algorithms in diagnosing early-stage PD patients and to evaluate the feasibility of this approach in clinical practice. Methods: Using an ETG-4000 type near-infrared brain function imaging instrument, data was collected from 120 PD patients and 60 healthy controls. This cross-sectional study employed a multi-channel mode to monitor cerebral blood oxygen changes. The collected data were processed using a general linear model and ß values were extracted. Subsequently, four types of machine learning models were developed for analysis: Support vector machine (SVM), K-nearest neighbors (K-NN), random forest (RF), and logistic regression (LR). Additionally, SHapley Additive exPlanations (SHAP) technology was applied to enhance model interpretability. Results: The SVM model demonstrated higher accuracy in differentiating between PD patients and control group (accuracy of 85%, f1 score of 0.85, and an area under the ROC curve of 0.95). SHAP analysis identified the four most contributory channels (CH) as CH01, CH04, CH05, and CH08. Conclusion: The model based on the SVM algorithm exhibited good diagnostic performance in the early detection of PD patients. Future early diagnosis of PD should focus on the Frontopolar Cortex (FPC) region.

Human subcortical pathways automatically detect collision trajectory without attention and awareness.

Detecting imminent collisions is essential for survival. Here, we used high-resolution fMRI at 7 Tesla to investigate the role of attention and consciousness for detecting collision trajectory in human subcortical pathways. Healthy participants can precisely discriminate collision from near-miss trajectory of an approaching object, with pupil size change reflecting collision sensitivity. Subcortical pathways from the superior colliculus (SC) to the ventromedial pulvinar (vmPul) and ventral tegmental area (VTA) exhibited collision-sensitive responses even when participants were not paying attention to the looming stimuli. For hemianopic patients with unilateral lesions of the geniculostriate pathway, the ipsilesional SC and VTA showed significant activation to collision stimuli in their scotoma. Furthermore, stronger SC responses predicted better behavioral performance in collision detection even in the absence of awareness. Therefore, human tectofugal pathways could automatically detect collision trajectories without the observers' attention to and awareness of looming stimuli, supporting "blindsight" detection of impending visual threats.

Association between autonomic dysfunction with motor and non-motor symptoms in patients with Parkinson's disease.

To investigate the association between autonomic dysfunction (AutD) and motor as well as non-motor symptoms (NMS) in patients with Parkinson's disease (PD). Fifty-three PD patients were divided into two groups based on the number of domains affected by AutD: a multi-domain AutD group (AutD-M) and a single-domain AutD group (AutD-S), as evaluated using the Scale for Outcomes in Parkinson's disease-Autonomic (SCOPA-AUT), which assesses autonomic symptoms, one of the NMS. A comprehensive comparison was conducted between the two groups, including clinical measures such as clinical scales, quantitative evaluations of motor function and exercise capacity. Spearman correlation analysis was employed to investigate the relationship between AutD severity and PD symptoms. Additionally, we performed multiple linear regression model analysis to determine whether associations between SCOPA-AUT scores and clinical assessments remained significant after adjusting for Hoehn and Yahr stage, sex, and age. PD patients in the AutD-M group exhibited significantly more severe NMS and motor symptoms compared to those in the AutD-S group. In correlation analysis, SCOPA-AUT scores showed significant correlations with multiple clinical symptoms, such as most of the NMS, 10-MWT and CPET parameters. Furthermore, regression analysis also revealed that more pronounced fatigue, anxiety, depressive symptoms, worse walking speed and impaired exercise capacity were associated with higher SCOPA-AUT scores. The presence of AutD is correlated with emotional disturbances, decreased exercise endurance, and impaired gait function in patients with PD. Early management of AutD may prove beneficial in alleviating some NMS and motor symptoms in PD.

The Efficacy of Wearable Cueing Devices on Gait and Motor Function in Parkinson Disease: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: To summarize the efficacy of wearable cueing devices for improving gait and motor function of patients with Parkinson disease (PWP). DATA SOURCES: PubMed, Embase, and Cochrane CENTRAL databases were searched for papers published in English, from inception to October 23, 2022. STUDY SELECTION: Randomized controlled trials focusing on the effects of wearable cueing devices on gait and motor function in PWP were included. DATA EXTRACTION: Two reviewers independently selected articles and extracted the data. The Cochrane Bias Risk Assessment Tool was used to assess risk of bias and the Grading of Recommendations Assessment, Development and Evaluation was used to evaluate the quality of evidence. DATA SYNTHESIS: Seven randomized controlled trials with 167 PWP were included in the meta-analysis. Significant effect of wearable cueing devices on walking speed (mean difference [MD]=0.07 m/s, 95% confidence interval [CI]: [0.05, 0.09], P<.00001) was detected; however, after sensitivity analysis, no significant overall effect on walking speed was noted (MD=0.04 m/s, 95% CI: [-0.03, 0.12], P=.25). No significant improvements were found in stride length (MD=0.06 m, 95% CI: [0.00, 0.13], P=.05), the Unified Parkinson's Disease Rating Scale-III score (MD=-0.61, 95% CI: [-4.10, 2.88], P=.73), Freezing of Gait Questionnaire score (MD=-0.83, 95% CI: [-2.98, 1.33], P=.45), or double support time (MD=-0.91, 95% CI: [-3.09, 1.26], P=.41). Evidence was evaluated as low quality. CONCLUSIONS: Wearable cueing devices may result in an immediate improvement on walking speed; however, there is no evidence that their use results in a significant improvement in other gait or motor functions.

Hyperglycemia affects axial signs in patients with Parkinson's disease through mechanisms of insulin resistance or non-insulin resistance.

OBJECTIVE: To investigate the influence of hyperglycemia on motor symptoms, especially axial signs, and potential mechanisms related to insulin resistance (IR) in patients with Parkinson's disease (PWP). METHODS: According to glycated hemoglobin (HbA1c) level, PWP were divided into the low-HbA1c and the high-HbA1c groups. Demographic information, glucose metabolism-related variables, Hoehn-Yahr stage, and motor function were compared between the two groups. Correlations between levels of HbA1c and the homeostatic model assessment (HOMA)-IR and motor function in PWP were further analyzed. RESULTS: HbA1c level was significantly and positively correlated with the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III score, axial signs subscore, the Timed Get Up and Go test time, the center of pressure displacement of standing with eyes open and closed, and significantly and negatively correlated with the 10-m walk test comfortable gait speed. HOMA-IR level was significantly and negatively correlated with 10-m walk test comfortable gait speed, but not with others. CONCLUSIONS: PWP with high HbA1c showed worse axial symptoms, including dysfunction of automatic walking, dynamic balance, and postural control than those with low HbA1c. In PWP, the effects of hyperglycemia on automatic walking speed may be associated with the IR-related mechanisms, and the effects on dynamic balance and postural control may be related to mechanisms other than IR.

Neurovascular coupling dysfunction of visual network organization in Parkinson's disease.

Parkinson's disease (PD) has been showed perfusion and neural activity alterations in specific regions, such as the motor and visual networks; however, the clinical significance of coupling changes is still unknown. To identify how neurovascular coupling changes during the pathophysiology of PD, patients and healthy controls underwent multiparametric magnetic resonance imaging to measure neural activity organization of segregation and integration using amplitude of low-frequency fluctuation (ALFF) and functional connectivity strength (FCS), and measure vascular responses using cerebral blood flow (CBF). Neurovascular coupling was calculated as the global CBF-ALFF and CBF-FCS coupling and the regional CBF/ALFF and CBF/FCS ratio. Correlations and dynamic causal modeling was then used to evaluate relationships with disease-alterations to clinical variables and information flow. Neurovascular coupling was impaired in PD with decreased global CBF-ALFF and CBF-FCS coupling, as well as decreased CBF/ALFF in the parieto-occipital cortex (dorsal visual stream) and CBF/FCS in the temporo-occipital cortex (ventral visual stream); these decouplings were associated with motor and non-motor impairments. The distinctive patterns of neurovascular coupling alterations within the dorsal and ventral visual streams of the visual system could potentially provide additional understanding into the pathophysiological mechanisms of PD.

Added forearm weights for gait pattern normalization in patients with Parkinson's disease.

Patients with Parkinson's Disease presented gait impairment. Applying additional weights to enhancing sensory input may improve gait impairment. We assumed that gait impairment could be improved when patients walked with additional forearm weights, and the gait improvement was associated with clinical characteristic of Parkinson's Disease. Thirty patients with Parkinson's Disease and 30 age-sex matched controls were recruited. Spatiotemporal and joint kinematics parameters were evaluated by a three-dimensional motion capture system in normal walking and walking with sandbags, respectively. The comparisons of spatiotemporal parameters were analyzed using t-test or nonparametric tests. The comparison of joint kinematic data was analyzed using statistical parametric mapping. The correlation between motor symptom and gait parameters changes was analyzed using Pearson's correlation analysis. During normal walking, patients showed deteriorated gait compared with controls. After applying weights to forearms patients increased cadence (p = 0.004), speed (p < 0.001) and step length (p = 0.048), and decreased stride time (p = 0.003). The hip angles significantly increased during 5%-23% and 87%-100% of gait cycle, while knee angles during 9%-25% and 88%-98% of the gait cycle, and ankle angles in 92%-100% of gait cycle. The gait parameters of patients with forearm-loading showed no significant difference compared with healthy subjects walking normally. The change of gait parameters correlated positively with the axial and tremor severity while correlated negatively with the rigidity sub-score. Patients with tremor dominant subtype also showed greater improvement of speed and step time compared with patients with postural instability/gait difficulty subtype. Applying added weights bilaterally to the forearms of patients can normalize gait patterns. Notably, patients with higher scores on axial and tremor and lower rigidity scores gained more benefits.

Intermittent theta-burst stimulation combined with physical therapy as an optimal rehabilitation in Parkinson's disease: study protocol for a randomised, double-blind, controlled trial.

BACKGROUND: First-line rehabilitative strategies to improve motor deficits are based on functional training (physical or occupational therapy), which has been demonstrated to facilitate neural reorganisation. Accumulating evidence suggests that non-invasive brain stimulation techniques, such as repetitive TMS (rTMS), may enhance neuroplasticity, thereby facilitating neural reorganisation and recovery from Parkinson's disease. Evidence also shows that intermittent theta-burst stimulation (iTBS) can improve motor function and quality of life in patients by promoting the excitability and neural remodelling of cerebral cortex. We aimed to combine iTBS stimulation with physiotherapy to improve the rehabilitation effect compared to physiotherapy alone in patients with Parkinson's disease. METHODS: This randomised, double-blind clinical trial will enrol 50 Parkinson's disease patients aged 45-70 years with Hoehn and Yahr scale scores of 1-3. Patients are randomly assigned to either the iTBS + physiotherapy or sham-iTBS + physiotherapy group. The trial consists of a 2-week double-blind treatment period and a 24-week follow-up period. iTBS and sham-iTBS will be administered twice daily for 10 days based on physiotherapy. The primary outcome will be the third part of Movement Disorders-Unified Parkinson's Disease Rating Scale (MDS-UPDRS III) from the baseline to the first 2 days following completion hospitalised intervention. The secondary outcome will be 39-item Parkinson's Disease Questionnaire (PDQ-39) at 4 weeks, 12 weeks and 24 weeks after intervention. Tertiary outcomes are clinical evaluations and mechanism study outcomes such as NMSS, 6MWD, 10MT, TUG, BBS, MRI, and EEG, the length of time between the drug needs to be adjusted when symptoms fluctuate. DISCUSSION: The aim of this study is to demonstrate that iTBS can promote overall function and quality of life in Parkinson's disease patients using physiotherapy and that this efficacy may be associated with altered neuroplasticity in exercise-related brain regions. The iTBS combined with physiotherapy training model will be evaluated during a 6-month follow-up period. With significant improvement in quality of life and motor function, iTBS combined with physiotherapy can be considered as a first-line rehabilitation option for Parkinson's disease. The potential of iTBS to enhance neuroplasticity in the brain should have a more positive impact in increasing the generality and efficiency of physiotherapy, improving the quality of life and overall functional status of patients with Parkinson's disease. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200056581. Registered on 8 February 2022.

Effects of three kinds of anti-amyloid-ß drugs on clinical, biomarker, neuroimaging outcomes and safety indexes: A systematic review and meta-analysis of phase II/III clinical trials in Alzheimer's disease.

OBJECTIVE: To investigate the effects of the three kinds of anti-amyloid-ß (Aß) drugs on cognitive and other functions, fluid and neuroimaging biomarkers, and safety on patients with Alzheimer's disease (AD), and rank the three kinds of anti-Aß drugs. METHODS: We searched Medline, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and AlzForum from inception to January 21, 2023 to include randomized controlled clinical trials. Random effects meta-analyses were performed. RESULTS: Forty-one clinical trials (20929 participants, 9167 male) were included. Anti-Aß drugs had significant but relatively low efficacy in preventing cognitive decline (ADAS-Cog SMD -0.07, 95% CI: -0.10 to -0.03, p < 0.001; CDR-SOB -0.05, -0.09 to -0.01, p = 0.017). Instrumental variable meta-analysis and trial sequential analysis confirmed the reliability of the pooled estimation. Beneficial effects were also observed by assessing other cognitive and activity of daily living scales and biomarkers, with acceptable safety of anti-Aß drugs. Meta-regression demonstrated significant association between higher baseline mini-mental statement examination scores (MMSE) and better cognitive protective effects on cognitive function (ADAS-Cog ß: -0.02, -0.05 to 0.00, p = 0.017) and clearance of pathological productions of anti-Aß drugs. Network meta-analysis ranked the passive immunotherapy drugs to have the best cognitive efficacy, followed by active immunotherapy and small molecule drugs. CONCLUSION: Anti-Aß drugs have relatively low efficacy in preventing cognitive decline, and they reduce pathological productions with acceptable safety. Patients with higher baseline MMSE scores benefit more from anti-Aß drugs. Passive immunotherapy anti-Aß drugs show relatively better efficacy than active immunotherapy and small molecule anti-Aß drugs.

Longitudinal cognitive changes in patients with early Parkinson's disease and neuropsychiatric symptoms.

AIMS: In this study, we aimed to investigate the effect of neuropsychiatric symptoms (NPS) on the rate of cognitive decline for both global cognition and specific cognitive domains in a cohort of patients from the Parkinson's Progression Markers Initiative (PPMI). METHOD: Prospectively longitudinal data were obtained from the PPMI cohort. NPS, including depression, anxiety, apathy, psychosis, impulse control disorders (ICDs), and cognition ability, were evaluated by a series of questionnaires. Linear mixed-effects models were used to investigate the relationship between NPS and the rate of cognitive decline. Generalized estimating equations (GEEs) were used to investigate the relationship between NPS and the occurrence of mild cognitive impairment (MCI). RESULTS: In total, 423 patients with Parkinson's disease (PD) were recruited at baseline and 395, 378, 366, 346, and 315 participants were followed up at 1, 2, 3, 4, and 5 years, respectively. Depression, anxiety, apathy, and psychosis were associated with global cognitive decline. Except for those with ICDs, patients with psychosis, depression, anxiety, and apathy were more likely to meet the criteria for MCI. Patients with depression and anxiety showed a progressive decline in four major cognitive domains. Apathy and ICDs were separately associated with a progressive decline in processing speed-attention and memory, respectively. CONCLUSIONS: Neuropsychiatric symptoms, including psychosis, depression, anxiety, and apathy, could be used to predict future cognitive decline in patients with PD.

Circular RNAs in Parkinson's Disease: Reliable Biological Markers and Targets for Rehabilitation.

In clinical practice, the underlying pathogenesis of Parkinson's disease (PD) remains unknown. Circular RNAs (circRNAs) have good biological properties and can be used as biological marker. Rehabilitation as a third treatment alongside drug and surgery has been shown to be clinically effective, but biomarkers of rehabilitation efficiency at genetic level is still lacking. In this study, we identified differentially expressed circRNAs in peripheral blood exosomes between PD patients and health controls (HCs) and determined whether these circRNAs changed after rehabilitation, to explore the competing RNA networks and epigenetic mechanisms affected. We found that there were 558 upregulated and 609 downregulated circRNAs in PD patients compared to HCs, 3398 upregulated and 479 downregulated circRNAs in PD patients after rehabilitation compared to them before rehabilitation, along with 3721 upregulated and 635 downregulated circRNAs in PD patients after rehabilitation compared to HCs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that differentially expressed circRNAs may affect the stability of the cellular actin backbone and synaptic structure by influencing the aggregation of α-synuclein (a-syn). We selected two circRNAs overexpressed in PD patients for validation (hsa_circ_0001535 and hsa_circ_0000437); the results revealed that their expression levels were all reduced to varying degrees (p < 0.05) after rehabilitation. After network analysis, we believe that hsa_circ_0001535 may be related to the aggregation of a-syn, while hsa_circ_0000437 may act on hsa-let-7b-5p or hsa-let-7c-5p through sponge effect to cause inflammatory response. Our findings suggest that rehabilitation can mitigate the pathological process of PD by epigenetic means.

Altered Neurovascular Coupling for Multidisciplinary Intensive Rehabilitation in Parkinson's Disease.

Effective rehabilitation in Parkinson's disease (PD) is related to brain reorganization with restoration of cortico-subcortical networks and compensation of frontoparietal networks; however, further neural rehabilitation evidence from a multidimensional perspective is needed. To investigate how multidisciplinary intensive rehabilitation treatment affects neurovascular coupling, 31 PD patients (20 female) before and after treatment and 30 healthy controls (17 female) underwent blood oxygenation level-dependent functional magnetic resonance imaging and arterial spin labeling scans. Cerebral blood flow (CBF) was used to measure perfusion, and fractional amplitude of low-frequency fluctuation (fALFF) was used to measure neural activity. The global CBF-fALFF correlation and regional CBF/fALFF ratio were calculated as neurovascular coupling. Dynamic causal modeling (DCM) was used to evaluate treatment-related alterations in the strength and directionality of information flow. Treatment reduced CBF-fALFF correlations. The altered CBF/fALFF exhibited increases in the left angular gyrus and the right inferior parietal gyrus and decreases in the bilateral thalamus and the right superior frontal gyrus. The CBF/fALFF alteration in right superior frontal gyrus showed correlations with motor improvement. Further, DCM indicated increases in connectivity from the superior frontal gyrus and decreases from the thalamus to the inferior parietal gyrus. The benefits of rehabilitation were reflected in the dual mechanism, with restoration of executive control occurring in the initial phase of motor learning and compensation of information integration occurring in the latter phase. These findings may yield multimodal insights into the role of rehabilitation in disease modification and identify the dorsolateral superior frontal gyrus as a potential target for noninvasive neuromodulation in PD.SIGNIFICANCE STATEMENT Although rehabilitation has been proposed as a promising supplemental treatment for PD as it results in brain reorganization, restoring cortico-subcortical networks and eliciting compensatory activation of frontoparietal networks, further multimodal evidence of the neural mechanisms underlying rehabilitation is needed. We measured the ratio of perfusion and neural activity derived from arterial spin labeling and blood oxygenation level-dependent fMRI data and found that benefits of rehabilitation seem to be related to the dual mechanism, restoring executive control in the initial phase of motor learning and compensating for information integration in the latter phase. We also identified the dorsolateral superior frontal gyrus as a potential target for noninvasive neuromodulation in PD patients.

Predictive Value of Exercise Blood Pressure Changes for Orthostatic Hypotension in Patients With Parkinson's Disease.

BACKGROUND AND PURPOSE: Orthostatic hypotension (OH) is common in patients with Parkinson's disease (PD). Early recognition OH is required with sensitive assessments. The purpose of this study was to determine whether blood pressure (BP) changes during exercise can predict the occurrence of OH in PD. METHODS: This prospective cohort study included 80 consecutive patients with PD. All patients agreed to participate in a baseline evaluation and cardiopulmonary exercise test (CPET). According to the initial active standing test (AST), those without OH (PD-nonOH) at baseline had their AST results followed up for 6 months. The main outcome was defined as whether patients without OH at baseline would develop OH after 6 months. Logistic regression analysis was applied to identify the relevant variables. A nomogram was constructed based on clinical features and identified variables. The concordance index (C-index) and area under the receiver operating characteristic curve (AUC) were used to evaluate the accuracy and predictive ability of the nomogram, respectively. RESULTS: CPET results indicated that peak load, peak heart rate, heart rate recovery at 1 min, and systolic BP change (ΔSBP) were lower in those with OH than in the PD-nonOH group (p<0.05) at baseline. Logistic regression analysis indicated that peak load and ΔSBP during CPET had significant effects on OH (p<0.05). Age, sex, peak load, and ΔSBP were used to construct the nomogram model (C-index=0.761). The prediction model had an AUC of 0.782 (95% confidence interval=0.649-0.889) and a specificity and sensitivity of 70.0% and 81.8%, respectively. CONCLUSIONS: This study has identified predictive factors for OH development in patients with PD. CPET could be used as a complementary examination to identify patients at a high risk of OH.

The impact of cerebral small vessel disease burden and its imaging markers on gait, postural control, and cognition in Parkinson's disease.

OBJECTIVE: This study aimed to investigate how cerebral small vessel disease (CSVD) burden and its imaging markers are related to alterations in different gait parameters in Parkinson's disease (PD) and whether they affect attention, information processing speed, and executive function when global mental status is relatively intact. METHODS: Sixty-five PD patients were divided into the low CSVD burden group (n = 43) and the high CSVD burden group (n = 22). All patients underwent brain magnetic resonance imaging scans, clinical scale evaluations, and neuropsychological tests, as well as quantitative evaluation of gait and postural control. Multivariable linear regression models were conducted to investigate associations between CSVD burden and PD symptoms. RESULTS: Between-group analysis showed that the high CSVD group had worse attention, executive dysfunction, information processing speed, gait, balance, and postural control than the low CSVD group. Regression analysis revealed that greater CSVD burden was associated with poor attention, impaired executive function, and slow gait speed; white matter hyperintensity was associated with slow gait speed, decreased cadence, increased stride time, and increased stance phase time; the presence of lacune was associated only with poor attention and impaired executive function; enlarged perivascular space in the basal ganglia was associated with gait speed. CONCLUSIONS: CSVD burden may worsen gait, postural control, attention, and executive function in patients with PD, and different imaging markers play different roles. Early management of vascular risks and treatment of vascular diseases provide an alternate way to mitigate some motor and cognitive dysfunction in PD.

Lacunes may worsen cognition but not motor function in Parkinson's disease.

BACKGROUND: As one of the imaging markers of cerebral small vessel disease, lacunes has received little attention. The objective of this study was to investigate the associations of lacunes, cognition and motor function in patients with Parkinson's disease (PD) and whether these associations are independent of other imaging markers. METHODS: Patients were consecutively included from April 2019 to July 2022 in Beijing Rehabilitation Hospital. All patients underwent brain magnetic resonance imaging scans, clinical scale evaluations, and neuropsychological tests, as well as quantitative evaluation of postural control. To eliminate the possible factors contributing to cognition and motor dysfunction in patients with PD, in particular white matter hyperintensities and enlarged perivascular space in the basal ganglia, multivariate linear regression models were constructed to sort out the effect of lacunes. RESULTS: Ninety-four patients were included in this study, 56 without lacunes and 38 with lacunes. Patients with lacunes showed shorter disease duration, slower gait speed and spent more time on Trail-Making Test part A (TMT-A) than those without lacunes. The number of lacunes were positively correlated with the time to complete the TMT-A and negatively related to gait speed. Multivariate linear regression models showed that the presence of lacunes was associated with longer TMT-A time after adjusting for potential confounders. CONCLUSIONS: Lacunes were independently associated with worse visual scanning, attention, and processing speed in patients with PD. In addition, lacunes may accelerate the course of PD. Early treatment of vascular disease provides an alternate way to mitigate some motor and cognitive dysfunction in patients with PD.

Lacunes were independently associated with worse visual scanning, attention, and processing speed in patients with Parkinson's disease (PD). Lacunes may accelerate the course of PD. Early treatment of vascular disease provides an alternate way to mitigate some motor and cognitive dysfunction in patients with PD.

Clinical Manifestation, Auxiliary Examination Features, and Prognosis of GFAP Autoimmunity: A Chinese Cohort Study.

OBJECTIVE: This paper reports the clinical manifestation and auxiliary examination features of 15 Chinese patients with glial fibrillary acidic protein (GFAP) autoimmunity. METHODS: From June 2016 to December 2019, patients suspected to have neurological autoimmune disease after having their serum and cerebrospinal fluid (CSF) tested for conventional neural antibodies were scanned for additional autoantibodies by immunohistochemistry. Samples that showed a characteristic immunoreactive pattern reminiscent of the GFAP of astrocytes were selected and confirmed by cell-based assay using cells-expressing human GFAPα. RESULTS: A total of 15 patients (eight male and seven female) with a median age at onset of 53 years (range 28-72) were identified as GFAP-IgG-positive. Fourteen cases had GFAP-IgG detected in the CSF, while serum GFAP-IgG was detected in 11 cases. Eleven of the fifteen patients (73.3%) presented with an acute monophasic course, of which 10 (90.9%) had antecedent flu-like symptoms. The predominant phenotype was meningoencephalitis (46.7%), followed by meningoencephalomyelitis in 40% of the cases. The most common clinical features included long tract signs, brainstem symptoms, tremors, headaches, and psychiatric symptoms. Magnetic resonance imaging (MRI) revealed the enhancement of the meninges, the surface of the brainstem, the cerebellum, and the spinal cord as predominant. Inflammatory CSF showed mild lymphocyte-predominant pleocytosis with a median of 51/µL and elevated protein with a median of 87.5 mg/dL. Five patients had coexisting antibodies, including NMDAR-IgG in three patients and Yo and MOG-IgG in one patient each. One patient underwent a stereotactic brain biopsy, and the neuropathology diagnosis was diffuse large B-cell lymphoma. One patient had ovarian teratoma. Eleven of the fifteen (73.3%) patients received both intravenous immunoglobulin and steroids. Among them, three patients also received immunosuppressive agents later. During a two-year follow-up, 9 of the 15 (60%) patients achieved complete clinical remission. CONCLUSIONS: The clinical presentation of GFAP astrocytopathy is heterogeneous. It can be characterized by an acute monophasic course and a chronic relapsing course. Tremors are a prominent clinical manifestation in patients with an acute monophasic course with GFAP-IgG antibodies only. Most patients responded well to immunotherapy. In patients with GFAP autoimmunity, presenting with a chronic relapsing course, one should actively search for immunogenic factors and the culprit antibodies. In the case of primary central nervous system lymphoma, GFAP autoimmunity does not always equate to autoimmune GFAP astrocytopathy.