Outpatient EMRs with a first-listed diagnosis of PD, whether confirmed or suspected, were identified in the electronic EMR system of GPHCM between July 2018 and June 2023. Only patient encounters (PEs) for the initial medical visits for Parkinsonism were retrieved out of these EMRs, and exported to an Excel sheet, with assistance provided by the Information Technology Department of GPHCM.

Eligibility screening was carried out by Shaohua Lyu, a clinician specializing in PD and neurological conditions. Follow-up PEs with initial encounters outside the research timeframe and initial PEs lacking detailed descriptions of medical history (including symptoms) were excluded. Any uncertainty was resolved through consultation with a senior PD specialist (X Luo or Q Su).

As medical diagnosis may or may not have been definitively established during the initial visit (CAER Inc, 2023), the status of the first-listed PD diagnosis at the initial visit was further classified into three categories: (1) A “confirmed diagnosis,” if the patient had received a formal PD diagnosis before visiting the studied hospital; (2) A “suspected diagnosis,” if the patient's symptoms and complaints were indicative of parkinsonism, but a confirmed PD diagnosis had not been established at the initial visits; (3) An “unclear status of diagnosis,” when there was insufficient information to determine whether a PD diagnosis has been established from the initial PEs (Shah et al., 2019).

General information such as age, disease duration (time from the onset of motor symptoms), onset age, and gender, visited departments, typical motor symptoms, common motor complications, and non-motor symptoms along with details of prescriptions including herb ingredients of prescribed CHM decoctions, names and herb ingredients of patented Chinese herbal medicine products (PCHMPs), acupuncture, and names of antiparkinsonian medications, were extracted by Shaohua Lyu and double-checked by Zhenhui Mao.

Extracted motor symptoms included bradykinesia, rest tremor, rigidity and postural instability (Postuma et al., 2015). Motor complications comprised dyskinesia and motor fluctuations, which encompassed the “on-off” phenomenon and/or “wearing off” (Freitas et al., 2017). These complications may either signify the progressive degeneration of nigrostriatal dopaminergic neurons in nature or result from levodopa-induced side effects (Kim et al., 2020). Non-motor symptoms extracted during this study encompassed constipation, musculoskeletal pain, fatigue, orthostatic hypotension, restless legs, sweating, swallowing dysfunction, salivation, cognitive impairment, urinary problems, hallucinations and delusions, anxiety and/or depression, excessive daytime sleepiness, and sleep disturbance (including RBD) (Chaudhuri et al., 2007; Carroll et al., 2021).

Diverse descriptions of the same PD symptom in the EMRs text were standardized using common medical terms. For instance, rigidity in arms, legs or neck were standardized as rigidity, irrespective of the specific locations mentioned in the text. Herbs being processed in different ways were also standardized. For example, zhi huang qi (fried huang qi) was simplified as huang qi as no distinction was observed in their nature. A similar approach was taken with gan cao and zhi gan cao, as well as zhi qiao and chao zhi qiao. It should be noted that zhi qiao, zhi shi and chen pi are all fruit peels collected at various stages from the same plant (Citrus aurantium L.). However, the former two share a similar function, while chen pi has a distinguishing role in Chinese medicine theory and was separated from the other two herbs during frequency analysis. Scientific names commonly used Latin names and traditional Chinese names of the herbs involved in this study are introduced in Table 1.

IBS SPSS statistics (version 28.0, IBM Corp., Armonk, NY, USA) was employed for the descriptive analyses of patients' characteristics and treatment information. Categorical variables were presented as frequency and percentage, while continuous variables were expressed as mean with standard deviation. Furthermore, IBS SPSS Modeler 18.0 was utilized to generate association rules between herbs and symptoms, employing the Apriori algorithm.

A total of 4,494 outpatient initials PEs with a first-listed diagnosis of PD were identified and exported from the EMR system of GPHCM. During the screening procedure, 152 PEs were excluded for incomplete data, and 1,136 PEs were excluded because they were follow-up PEs rather than initial PEs. Ultimately, 3,206 PEs, each corresponding to an individual patient, were included in the analyses (Figure 1).

Antiparkinsonian medications are recommended for managing Parkinsonism or assisting in the establishment or differentiation of a PD diagnosis based on patients' responses to medications (Postuma et al., 2015). Additionally, Chinese medicine is also recommended for Parkinsonism following the principle of syndrome differentiation (Yun and Liu, 2022). The regularity of treatment, both conventional and Chinese medicine, was conducted based on the included PEs, regardless of the status of PD diagnosis.

Based on the analysis of 3,206 real-world EMRs, our study not only synthesized first-hand clinical expertise in prescribing CHM for PD, but also identified patient' characteristics and treatment categories. In summary, our study contributes to evidence-based Chinese medicine practice for PD, encompassing dimensions of clinical expertise, patients' preferences and values (Sackett, 1997; Dawes et al., 2005; Yates, 2013).

In the examinations of 348 initial PEs with a suspected PD diagnosis, the duration from the onset of motor symptoms to the first medical consultation was found to be 1.11 years, aligning with the average duration of 15 months reported in a previous survey in China (Wan et al., 2019). However, the majority of patients visited GPHCM after receiving a confirmed PD diagnosis, with an average delay of 4.59 years from the onset of motor symptoms. Within this group, some patients may have been following a routine of conventional antiparkinsonian medications without concurrent Chinese medicine treatment, while others may have previously undergone Chinese medicine treatments elsewhere. At this stage, ~50% of patients may have already developed motor complications (Bhidayasiri and Truong, 2008; Kim et al., 2020). Despite this, the percentage of motor complications based on the included real-world PEs was merely around 2.5%. This discrepancy may be attributed to the limited awareness of motor complications among non-PD specialists from the internal medicine outpatient clinic, which constitutes over 75% of PD-related outpatient visits. There is a need for education targeting non-PD specialists to enhance their understanding of motor complications and promote optimal management of motor complications in the later stages.

Before visiting the studied Chinese medicine hospital, 96.84% of patients adhered to regular conventional antiparkinsonian medications, whereas a mere 3.16% deviated from regular treatments. This smaller percentage comprised individuals either awaiting the initiation of antiparkinsonian treatments or those unable to tolerate the associated side effects. The delayed commencement of antiparkinsonian treatment until disease progression is not uncommon among PD patients (Stocchi et al., 2015). Additionally, intolerable side effects of antiparkinsonian medications were frequently reported (Rascol et al., 2003). Among those consistently on regular treatments, the decision to seek Chinese medicine may be influenced by factors such as a suboptimal response to conventional antiparkinsonian medications, the “wearing off” phenomenon as PD advances to later stages, and insufficient managements for non-motor symptoms.

Early diagnosis and intervention of non-levodopa for PD patients have been recommended (Pan et al., 2015; Tinelli et al., 2016), despite ongoing controversies regarding the timing and strategies for the initial pharmacological therapy for PD (Waller et al., 2021). Factors contributing to the diagnostic delay in PD may include physicians' unfamiliarity with PD symptomology (Wan et al., 2019). Given the substantial involvement of non-PD specialists, it may be imperative to educate clinicians on PD knowledge as a strategy to reduce diagnostic latency. In term of treatment, initiating non-levodopa medications early not only alleviates troublesome PD symptoms but also delays the initiation of levodopa and its subsequent side effects, potentially slowing disease progression (Murman, 2012). CHM has demonstrated potential as an effective treatment in conjunction with conventional antiparkinsonian medications in improving motor symptoms, non-motor symptoms and quality of life (Li et al., 2016; Chen et al., 2020; Liu et al., 2020a; Gu et al., 2023; Jun et al., 2023) (Supplementary File 1). However, the current study indicated that most PD patients initiated their Chinese medicine intervention from GPHCM after 4.59 years from the onset of motor symptoms. To complement early intervention in PD and enhance prognosis, there is a need for community education and promotion regarding the effectiveness of Chinese medicine interventions, alongside efforts to improve the availability and accessibility of CHM.

Rest tremor is recorded as the most frequently experienced motor symptom by over 60% of patients with either a confirmed or suspected PD diagnosis, given its widely recognized association with PD (Baumann, 2012). In contrast, postural instability is documented by < 20% of PEs, a prevalence consistent with previous report (16%) (Appeadu and Gupta, 2023). Constipation, sleep disturbance, fatigue and musculoskeletal pain are the prominent non-motor symptoms documented in the EMRs, irrespective of the diagnosis status. Their prevalence aligns with previously documented non-motor symptoms (Tanveer et al., 2018; Kwok et al., 2021; Li L. C. et al., 2021). However, other non-motor symptoms such as cognitive impairment, restless legs, and daytime sleepiness in our study were not as prevalent as reported among middle-late-stage PD patients in other studies (Kwok et al., 2021; Li L. C. et al., 2021). Non-motor symptoms like constipation, insomnia, anxiety, and depression have been reported to exert the greatest negative impact on the quality of life among PD patients (Duncan et al., 2014). In the studied Chinese medicine hospital, PCHMPs were tailored to address these commonly reported non-motor symptoms. For instance, Zao ren an shen capsule can be prescribed for patients experiencing sleep disturbance (Birling et al., 2022), and Tong fu xing shen capsule is known for its efficacy in addressing constipation among PD patients (Huang, 2012). Additionally, herb ingredients of CHM decoctions can also be modified to target specific non-motor symptoms. For example, Rehmannia glutinosa (Gaertn.) DC. (da huang) was frequently prescribed for constipation.

In the studied Chinese medicine hospital, integrated Chinese and conventional medicine emerged as the most popular treatment method, followed by the single use of CHM and single use of antiparkinsonian medications. The use of acupuncture for PD was limited, and its utilization regularity was not analyzed due to the insufficient available information. As the predominant treatment for PD, CHM decoctions were analyzed in depth.

Compared to previously published data-mining studies for PD based on Health Insurance Research Database in Taiwan Province of China (Chen et al., 2018; Lin et al., 2021), Gastrodia elata Blume (tian ma) and Rehmannia glutinosa (Gaertn.) DC. (da huang) maintained consistency in popularity among CHM prescriptions. However, the high frequency of tonifying herbs like Astragalus mongholicus Bunge (huang qi), Atractylodes macrocephala Koidz. (bai zhu), Angelica sinensis (Oliv.) Diels (dang gui), Panax ginseng C. A. Mey. (ren shen), etc. was seldom reported in the Taiwan studies (Chen et al., 2018; Lin et al., 2021). This disparity may be attributed to the use of different datasets with geographical differences. Nonetheless, tonifying herbs were frequently used for PD, as indicated by a literature review (Gu and Yuan, 2023).

Eight out of the top 15 most frequently used herbs in our study, including Panax ginseng C. A. Mey. (ren shen), Astragalus mongholicus Bunge (huang qi), Atractylodes macrocephala Koidz. (bai zhu), Citrus aurantium L. (chen pi), Angelica sinensis (Oliv.) Diels (dang gui), Cimicifuga heracleifolia Kom. (sheng ma), Bupleurum chinense DC. (chai hu) and Glycyrrhiza uralensis Fisch. (gan cao), are the herb ingredients of Bu zhong yi qi tang (BZYQT), a classical formula widely employed for neurodegenerative conditions such as Alzheimer's Disease and amyotrophic lateral sclerosis (Lim et al., 2018; Yang, 2023). BZYQT has been recommended by clinical guidelines for PD and PD-associated autonomous neurofunctional disorders (Luo et al., 2021; Zhao and Liu, 2021). Additionally, the logical combination of other herbs, including Paeonia lactiflora Pall. (bai shao), Angelica sinensis (Oliv.) Diels (dang gui), Citrus aurantium L. (chen pi), Panax ginseng C. A. Mey. (ren shen), Atractylodes macrocephala Koidz. (bai zhu), Astragalus mongholicus Bunge (huang qi) and Poria cocos (Schw.) Wolf (fu ling), contributes to the main ingredients of Ren shen yang rong tang (RSYRT). RSYRT was recommended for motor complications of PD (Liu et al., 2020). However, both classical formulas were not mentioned in other Chinese medicine clinical guidelines for PD (Wu et al., 2020; Li W. et al., 2021; Yang et al., 2021; Yun and Liu, 2022).

It is noteworthy that motor fluctuations and dyskinesia were likely to be managed using Chinese medicine herbs such as Angelica sinensis (Oliv.) Diels (dang gui), Codonopsis pilosula Nannf. (dang shen)/Panax ginseng C. A. Mey. (ren shen/hong shen), Astragalus mongholicus Bunge (huang qi), according to the association rules. The findings might offer a novel perspective for motor fluctuations and dyskinesia, where there is a lack of efficient treatments (Liu et al., 2020). Although the specific mechanism and effects of these herbs for motor fluctuations and dyskinesia require further examination and exploration, the findings provide a basis for future research. It is also interesting to observe that RBD was associated with prescribing Rheum tanguticum Maxim. ex Balf. (da huang), a herb specific for constipation, while RBD has been reported to be correlated with constipation (Kong et al., 2020; Chen et al., 2023). This finding indicated that PD-induced RBD may be treated via anti-constipation herbs like Rheum tanguticum Maxim. ex Balf. (da huang).

To support the clinical utilization of the above-mentioned herbs and formulas for PD, mechanisms of herb actions for PD were summarized.

BZYQT has been widely reported to address PD-induced constipation and orthostatic hypotension (Bi et al., 2014; Chen and Wang, 2014; Wu et al., 2018). It exhibited effects in preventing reduction of tyrosine hydroxylase and accumulation of alpha-synuclein in the intestine of PD mouse model (Bi and Gao, 2015). In addition, BZYQT also exerted anti-apoptosis, anti-dementia and neuroprotective effects for ACL, Alzheimer's disease and ischemic stroke models (Lim et al., 2018; Li Q. et al., 2022; Yang, 2023).

The adjunct use of RSYRT showed superior effects compared to the single use of antiparkinsonian medications for PD with a Chinese medicine syndrome of Deficiency of qi and Blood in a RCT (Wen, 2013). Clinical trials also found RSYRT to be effective in improving fatigue symptom (Xu et al., 2020), and anti-microinflammation in haemodialysis patients (Hsiao et al., 2015). Moreover, RSYRT demonstrated anti-aging effects via improving insulin resistance in the brain (Zhao, 2023).

Mechanisms of individual herb actions for PD were summarized in Supplementary File 2. These frequently used herbs exerted evident antioxidant, neuroprotective, anti-apoptosis, anti-neuroinflammatory effects, except for Citrus aurantium L. [mainly involved anti-constipation effects (Yan et al., 2020; Gong et al., 2023)] and Poria cocos (Schw.) Wolf [possessing antidepressant and sedative-hypnotic effects (Shah et al., 2014; Huang et al., 2020; Pang et al., 2020; Chen et al., 2021; Kim et al., 2022)].

Glycyrrhiza uralensis Fisch. (gan cao) is the most frequently used herb for PD. A RCT indicated that 6-weeks licorice intake significantly improved PD symptoms without serious adverse events (Petramfar et al., 2020). Water extracts of Glycyrrhiza uralensis Fisch. (gan cao) demonstrated neuroprotective effects via regulating ERK-1/2 pathways and the mTORC1-AMPK1 axis, as well as inhibiting MAO-2 action in in vitro studies (Karthikkeyan et al., 2021, 2022; Ramadan et al., 2022). Its active compounds like Licopyranocoumarin, glycyrurol, and isoliquiritigenin, exerted anti-apoptosis against oxidative stress (Hwang and Chun, 2012; Fujimaki et al., 2014).

Astragaloside IV and Calycosin are bioactive compounds of Astragalus mongholicus Bunge (huang qi), they could protect dopaminergic neuron against neuroinflammation and oxidative stress, prevent dopaminergic neurodegeneration and mitigate PD symptoms, via regulating signaling ways of TLR/NF-κb and MAPK, Nrf2, nfκb/NLRP3, JAK2/STAT3, PI3K/AKT/mtor, and p38 MAPK signaling pathways (Chan et al., 2009; Liu et al., 2017; Yang C. et al., 2019; Yang J. et al., 2019; Tan et al., 2020; Xia et al., 2020; Xu et al., 2021).

Atractylenolide I, atractylenolide III, and atractylodin are the main bioactive compounds of Atractylodes macrocephala Koidz. (bai zhu), they decreased microglial activation, conferred protection to dopaminergic neurons, protected dopaminergic neurons from apoptosis, inflammatory cytokines and oxidant protein, attenuated transcriptional activities of NF-κb and MAPK phosphorylation in PD mouse models or in vitro experiments (More and Choi, 2017a,b; Jeong et al., 2019; Li H. et al., 2022).

N-Butylidenephthalide is a bioactive compound extracted from Angelica sinensis (Oliv.) Diels (dang gui), it can improve PD recovery efficiency in a PD mouse model (Chi et al., 2018), and block egl-1 expression to inhibit apoptosis pathways as well as raise rpn-6 expression to enhance activity of proteasomes (Fu et al., 2014).

The compound of catalpol is extracted from Rehmannia glutinosa (Gaertn.) DC. (di huang), and it demonstrated antioxidant, anti-inflammatory and neuroprotective effects in vitro (Tian et al., 2006; Bi et al., 2008a,b). Formulas consisting of Rehmannia glutinosa (Gaertn.) DC. (di huang) as a main ingredient exerted antiparkinsonian therapeutic effects via modulating apoptosis through MAPK and TLR4/NF-κb signaling ways (Tseng et al., 2014; Wang et al., 2021; He et al., 2023).

Paeoniflorin is one of the active compounds of Paeonia lactiflora Pall. (bai shao), it exerted neuroprotective, anti-ferroptosis, anti-neuroinflammatory, antioxidant and anti-apoptosis effects in PD mouse models and in vitro research, via regulating the α-synuclein/PKC-δ, Bcl-2/Bax/caspase-3, Akt/Nrf2/Gpx4, ROS/pkcδ/NF-κb, and Bcl-2/Bax signaling pathways (Sun et al., 2012; Dong et al., 2015; Zheng et al., 2016; Guo et al., 2021; Wang et al., 2022).

Panax ginseng C. A. Mey. (ren shen) extracts and compounds have been widely investigated for PD. Ginsenoside Rg1 exerted neuroprotective, anti-cytotoxicity and immunomodulatory effects in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse models. More specifically, it regulated prefrontal cortical gabaergic transmission (Liu et al., 2019), moderated the Wnt/β-catenin signaling pathway (Zhou et al., 2016), restored motor functions to physiological level, and attenuated loss of dopaminergic neurons in the substantia nigra and striatum (Jiang et al., 2015), reduced aberrant α-synuclein-mediated neuroinflammation (Heng et al., 2016). Ginsenoside Rg3 regulated glutathione cysteine ligase modulatory subunit and glutathione cysteine ligase regulatory subunit expression in rotenone-induced PD mice (Han et al., 2021) and downregulated apoptosis mediators, egl-1 and ced-3, and upregulation of sod-3 and cat-2 in vitro (Chalorak et al., 2021). Ginsenosides Rd and Re acted anti-apoptosis, anti-inflammatory and antioxidant effects, and maintained blood-brain barrier integrity in MPTP-induced PD mice (Choi et al., 2018a), lowered oxidative stress and neuroinflammation, induced Nrf2/heme oxygenase-1 expression and activated the dual PI3K/AKT and ERK pathways in vitro (Zhang et al., 2016; Qiao et al., 2022). Extract of Panax ginseng C. A. Mey. (ren shen) can also protect against dopaminergic neuronal death (Van Kampen et al., 2014; Jun et al., 2015; Ryu et al., 2018; Liu et al., 2020b), cell stress (Van Kampen et al., 2014) and mitochondrial dysfunction (Liu et al., 2020b), reduce indices of inflammation (Van Kampen et al., 2014; Ryu et al., 2018; Jeon et al., 2020), prevent apoptosis (Hu et al., 2011; Van Kampen et al., 2014), accumulation of α-synuclein aggregates (Van Kampen et al., 2014; Jeon et al., 2020) and MPTP-induced leaky gut barrier (Jeon et al., 2020), stimulate endogenous antioxidant release (Wang J. Y. et al., 2013), regulate neuronal formation and energy metabolism for survival (Kim et al., 2018). Signaling ways involved in these activities include the Bcl-2 family, the nuclear factor erythroid 2-related factor 2 pathways, NF-κB signaling pathways (Choi et al., 2018b; Jeon et al., 2021).

Extracts of Bupleurum chinense DC. (chai hu) exerted anti-inflammatory and neuroprotective effects as they can alleviate mitochondria damage in MPTP-induced PD mouse models (Jeong et al., 2018), regulate nuclear receptor-related 1 protein (Sim et al., 2017), and suppress NF-κb-mediated inflammatory pathways (Park et al., 2015).

The initial application of Chinese medicine in managing PD has been a subject of controversy. Nonetheless, Chinese medicine therapies, particularly CHM, emerges as a promising non-levodopa intervention. These therapies can be prescribed either in conjunction with antiparkinsonian medications or as standalone treatments for PD patients (Cho et al., 2018). Notably, the integration of Chinese and conventional medicine is believed to contribute significantly to improve PD symptoms (Li and Le, 2021). Our study indicated PD patients undergoing regular conventional medicine would still seek Chinese medicine to enhance their current treatments, when PD condition progressed with “wearing-off” phenomenon, or reluctance and/or intolerance to conventional treatment were observed. PD patients can also initiate their antiparkinsonian treatment with CHM, as an alternative to conventional medicine. When deciding on treatment methods, various factors should be taken into consideration, including the patients' age, individual preferences, treatment responses, tolerance of medications, the severity of PD in terms of both non-motor and motor disability, impairment in quality of life, and presence of comorbidities (Marsili et al., 2017; de Bie et al., 2020; Waller et al., 2021).

As previously discussed, each herb ingredient in BZYQT exerts one or several actions, including antioxidant, neuroprotective, anti-apoptosis, anti-neuroinflammatory, anti-constipation, antidepressant, and sedative-hypnotic effects. Furthermore, BZYQT itself exhibits potential anti-dementia and neuroprotective effects (Lim et al., 2018; Li Q. et al., 2022; Yang, 2023). We advocate for the prescription of BZYQT in the management of PD. Tailored modifications to the formula can be implemented to address specific individual non-motor symptoms, such as incorporating Rheum tanguticum Maxim. ex Balf. (da huang) for constipation. Additionally, PCHMPs can be prescribed to deal with comorbidities or accompanying symptoms. For instance, Suan zao ren capsule may be considered for sleep disturbances.

Moreover, many of the frequent herbs, including Glycyrrhiza uralensis Fisch. (gan cao), Astragalus mongholicus Bunge (huang qi), Panax ginseng C. A. Mey. (ren shen), etc., are categorized as dietary and herbal supplements (Coates et al., 2010; China National Health and Family Planning Commission, 2018; China National Health Commission, 2020). These can be provided as part of “food therapy” or “medicinal diet therapy” (Wu and Liang, 2018), serving as beneficial supplements in daily self-management of individuals with PD.

Patients with PD often seek complementary therapies to improve both motor and non-motor symptoms (Ferry et al., 2002; Tan et al., 2006; Kim et al., 2009; Pecci et al., 2010; Wang Y. et al., 2013). RCT evidence has demonstrated the efficacy of CHM for PD in controlled settings with supportive findings from laboratory experiments. However, the generalizability of this evidence remains limited in nature. Real-world effects of CHM for PD remain uncertain and warrant further exploration. In addition, existing evidence focused on short-to-intermediate term effects of CHM for PD. Given the chronic and progressive nature of PD, investigating the prolonged effects and safety of long-term CHM for PD holds significant clinical value and merits thorough exploration. Furthermore, PD patients, especially those in advanced ages, often exhibit comorbidities such as Alzheimer's disease, hypertension, and others. Investigating the multi-targeted effects of CHM for these co-existing conditions is an avenue awaiting exploration.

In the present study, an association was identified between motor complications and the use of herbs such as Angelica sinensis (Oliv.) Diels (dang gui), Astragalus mongholicus Bunge (huang qi), and Codonopsis pilosula Nannf. (dang shen)/Panax ginseng C. A. Mey. (ren shen/hong shen). This herb combination may be utilized for motor complications in future research, and its clinical effects deserve future examination. Similarly, the exploration of treating RBD with anti-constipation herb like Rheum tanguticum Maxim. ex Balf. (da huang) is also recommended.

Inevitable limitations should be acknowledged in this study. Firstly, the research relied on EMRs from a single hospital and failed to retrieve previous treatments outside the studied hospital, limiting the generalizability and reliability of the findings, despite the hospital's tertiary status and the analysis being based on data from over 3,000 patients. Secondly, the absence of recorded treatment response in the initial PEs include in the study diminishes confidence in the practical effectiveness of the concluded CHM prescriptions for PD. Prospective longitudinal studies with quantitative measurements are needed to better ascertain the regularity of “effective” CHM prescriptions for PD. Thirdly, the timing and real-world effectiveness of Chinese medicine intervention for PD remain unresolved issues that warrant further exploration.