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Background: Tremor-dominant (TD) and nontremor-dominant (NTD) Parkinson's disease (PD) showed different responses to rehabilitation. However, the neural mechanism behind this remains unclear., Methods: This cohort study explores changes in motor function, brain activation, and functional connectivity following 2 weeks of rehabilitation in TD-PD and NTD-PD patients, respectively. A total of 11 TD-PD patients, 24 NTD-PD patients, and 21 age-matched healthy controls (HCs) were included. At baseline, all participants underwent functional magnetic resonance imaging (fMRI) while performing the foot tapping task. Motor symptoms, gait, balance, and task-based fMRI were then evaluated in patients before and after rehabilitation., Results: Compared to HCs, TD-PD patients showed increased activity in the left inferior frontal gyrus and the right insula, and NTD-PD patients showed increased activations in the left postcentral gyrus and decreased within-cerebellar connectivity at baseline. Rehabilitation improved motor function in PD patients regardless of motor subtype. TD-PD patients showed increased recruitments of the sensorimotor cortex and the bilateral thalamus after rehabilitation, and NTD-PD patients showed increased cerebellar activation and within-cerebellar connectivity that was associated with better motor performance., Conclusions: This study demonstrated that rehabilitation-induced brain functional reorganization varied by motor subtypes in PD, which may have important implications for making individualized rehabilitation programs., Trial Registration: ClinicalTrials.gov identifier: ChiCTR1900020771., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

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., (© 2024 Wiley‐VCH GmbH.)

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., (© 2024. The Author(s).)

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., (© 2023. Fondazione Società Italiana di Neurologia.)

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., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

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., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

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&#95;circ&#95;0001535 and hsa&#95;circ&#95;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&#95;circ&#95;0001535 may be related to the aggregation of a-syn, while hsa&#95;circ&#95;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., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2022. Fondazione Società Italiana di Neurologia.)

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., (Copyright © 2023 the authors.)

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., (© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Early Parkinson's disease (PD) may cause respiratory dysfunction; however the findings vary among studies. The aim of the preliminary prospective observational study was to explore the deterioration of pulmonary function at various stages in patients with early PD. A total of 237 patients with PD were screened. Fifty-six patients were included (modified Hoehn and Yahr stage ≤ 2.5). In addition, 56 age-matched healthy controls were also included in the study. Significant differences between the PD and control groups were found in all the investigated lung-function parameters. The maximal voluntary ventilation (MVV) percent predicted was the only parameter that distinguished PD stages (101.1 ± 14.9% vs. 82.8 ± 19.2% vs. 71.4 ± 12.9%, Hoehn and Yahr stages 1.5 vs. 2 vs. 2.5, respectively; p < 0.005). MVV could be the most sensitive parameter for distinguishing the severity of early-stage PD., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Rehabilitation has been reported to improve the quality of life (QoL) of patients with Parkinson's disease (PD). Nevertheless, not all patients are satisfied with rehabilitation outcomes and could achieve a significant improvement in QoL., Objective: To detect possible predictors of QoL improvement in patients with PD after rehabilitation., Methods: A total of 86 PD patients were included and followed up for 3 months with a 39-item Parkinson's Disease Questionnaire summary index (PDQ-39 SI) as the primary endpoint. All patients received 2 weeks of multidisciplinary intensive rehabilitation treatment (MIRT). Changes in patients' QoL were assessed using the PDQ-39 at baseline and at the 3-month follow-up. The reliable change index (RCI) was adapted to determine the individual QoL outcome. The predictors of QoL outcome were detected using logistic regression analysis., Results: After a 3-month follow-up, PDQ-39 SI decreased significantly from 22.95 ± 9.75 to 18.73 ± 10.32 (P < 0.001). Scores for QoL improved (RCI>10.9) after rehabilitation for 18.6% of the patients, and 74.4% of patients reported an unchanged QoL (-10.9≤RCI≤10.9), while 7.0% of patients reported a worsening of QoL (RCI<-10.9). Among the baseline parameters, the PDQ-39 SI was a baseline predictor for changes in QoL in the logistic regression model (OR: 1.15, CI: 1.07-1.24, P < 0.001)., Conclusions: MIRT could improve QoL for some patients with PD, and PDQ-39 score at baseline is the most important predictor for QoL improvements after rehabilitation for this patients., (© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: To improve understanding of gender differences on quality of life (QoL) in patients with Parkinson's disease (PWP) of a different race, the differences of clinical features and health-related quality of life (HRQoL) between male and female PWP were studied in a small cohort early to middle stage of Chinese PWP., Methods: A cross-sectional study was carried out. PWP were consecutively included from April 2020 to July 2021 in Beijing Rehabilitation Hospital. HRQoL, motor symptoms, and nonmotor symptoms in each patient were evaluated. The differences of demographic, motor symptoms assessments, nonmotor symptoms assessments, and QoL between two gender groups were tested using t-test statistics, Mann-Whitney-Wilcoxon test, or χ 2 depending on the data type. To eliminate the possible factors contributing to the QoL, linear regression models were constructed to sort out the effect of gender., Results: One hundred and sixty-two Parkinson's disease (PD) patients were included. Demographic, clinical characteristics, and symptom scale assessments had no statistical differences except for levodopa equivalent daily dose, Hamilton Anxiety Rating Score, REM sleep behavior disorder sleep questionnaire, and Hyposmia Rating Scale score. After baseline imbalance corrections, a significantly higher score of PD Questionnaire-39 (PDQ-39) in female than in male patients(p<.05) was found. In the questionnaire, summary Index and bodily discomfort, stigma, and emotional well-being subscores were the main contribution differences., Conclusions: Gender differences are associated with the QoL in the early to middle stage PWP in China. Female patients have poorer QoL than male patients, especially bodily discomfort, stigma, and emotional well-being., (© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: Walking adaptability is an obvious manifestation of Parkinson's disease (PD). Augmented reality technologies such as interactive walkways may improve walking adaptability in patients with Parkinson's Disease (PWP)., Research Question: How effective is C-Mill gait adaptability training in the early and middle stages of PD for improving walking adaptability in motor subtypes of the disease?, Methods: Fifty-two patients with early- or middle-stage PD were divided into two groups according to motor subtype (postural instability/gait disorder [PIGD] and non-PIGD) and received 7 days of training (0.5 h every day, 2 h after medication) on an augmented reality treadmill with built-in visual targets and obstacles. Functional assessments were performed before and after intervention, including posture control and walking, C-gait assessment, and participant experience. The Parkinson Disease Quality of Life questionnaire was administered at 3-month follow-up., Results: Both the PIGD (n = 29) and non-PIGD (n = 23) groups showed improved tandem walking, obstacle avoidance, and overall score in C-gait assessment and Timed Up and Go test after C-Mill training. However, there were no differences between the two groups. The PIGD group showed improvement in visually guided stepping and Speed adaptations, whereas the non-PIGD group did not improve. The non-PIGD group reported they could complete the training with less exertion after the intervention and at the 3-month follow-up, these patients reported improvement in quality of life., Significance: C-Mill gait adaptation training in the early and middle stages of PD improves walking adaptability in both motor subtypes. Cue strategies are the probable mechanism and may decrease fall risk after training. There was no difference between the groups in the improvements of perceived exertion and quality of life at follow-up. Although PIGD patients showed statistic improvements in visually guided stepping compared with non-PIGD patients, but the difference was not likely to be clinically meaningful. Specific effects of C-mill training for different types of PD were not observed in our study., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Parkinson's disease (PD) can be considered as the dysfunction in segregation and integration of large-scale structural networks in the late stage of disease progression. However, the altered patterns in the early stage have not been extensively investigated, especially the altered structural rich-club patterns, which is proved powerful to detect the altered patterns of structural networks in Alzheimer's disease and schizophrenia. To this end, we investigated the rich-club organization of the structural networks derived from diffusion tensor imaging (DTI) data in the early stage of PD, and further investigated the relationship between rich-club organization and clinicopathological measures, including motor and non-motor scales and cerebrospinal fluid (CSF) biomarkers. Two datasets were included for validation in this study. The first one included 41 healthy controls (HC) and 64 PD patients from Parkinson's Disease Progression Marker Initiative (PPMI) dataset, and the second one included 24 HC and 26 PD patients. Results revealed that PD patients in early stage had disrupted rich-club organization, with abnormal connectivity strength between peripheral regions (two-sample t-test between PD and HC: p < 0.001), whereas connectivity strength between rich-club regions remained relatively stable (two-sample t-test between PD and HC: p = 0.108). The classification accuracies on three types of connections were 59.93%, 73.96% and 77.44% for rich-club, feeder and local connections. Furthermore, abnormal local and feeder connections showed significant correlation with poor clinical scales and CSF biomarkers. In summary, a selective disruption of non-rich-club connections here could be regarded as a potential marker in the early diagnosis of PD., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Constipation is a common nonmotor symptom of Parkinson disease (PD). Constipation can also impact patient's quality of life. Chinese herbal medicines have been used for the treatment of constipation in PD. This trial will evaluate the efficacy and safety of a Chinese herbal formula Bushen Yisui and Ziyin Jiangzhuo (BYZJ) for the treatment of constipation in PD., Methods and Analysis: This randomized, double-blind, placebo-controlled, multicenter clinical trial will involve 4 hospitals in Beijing, China. The study will aim to recruit 90 PD patients with constipation between 30 and 80 years-of age with a score of 1 - 4 on the Hoehn and Yahr scale. Once recruited, Patients will be randomized into a BYZJ group or a placebo group in a 2:1 ratio. The trial will include a 1-week run-in period, a 4-week double-blind treatment period, a 4-week and a 12-week follow-up period. All patients will be educated about PD-related constipation during the run-in period. BYZJ granules and simulated granules will be administered twice daily for 4 weeks to the BYZJ group and the placebo group respectively. Assessments will be performed during run-in period, before the start of treatment (baseline, week 0), and at 4, 8, and 16 weeks. The primary outcome will be measured with the Constipation Severity Instrument, and secondary outcomes will be evaluated with the Patient Assessment of Constipation Quality of Life questionnaire, Bristol Stool Form Scale, Movement Disorders-Unified Parkinson Disease Rating Scale, Nonmotor Symptoms Scale, PD Sleep Scale, Parkinson Fatigue Scale-16. Laxative use (dose and frequency) will also be recorded. Intention-to-treat and per-protocol set analyses will be used to compare symptom improvement between the 2 groups. Any adverse events will be recorded., Discussion: If found effective and safe, BYZJ formula will be one of Chinese herb to treat constipation and even other nonmotor or motor symptoms in PD patients. The results will sustain the broader use of BYZJ formula in PD.