Traditional Chinese Medicine Might Reduce Risk of Dementia in Patients with Parkinson’s disease: A Population-based Nested Case-control Study

Background Patients who have Parkinson’s disease (PD) comorbid with dementia is common. With the prolonged life expectancy, dementia is gradually becoming prevalent and affects most patients’ life qualities. However, the ecacy of current treatments in dementia of Parkinson’s disease is limited. Previous studies indicated the potential roles of Traditional Chinese Medicine (TCM) in treating dementia, yet its effects in preventing dementia from Parkinson’s patients are unknown. Methods This case–control study was nested within a national health insurance database of patients over 50 years old with newly diagnosed Parkinson’s disease from year 2000 to 2010. Among these PD patients, dementia and non-dementia groups were discussed respectively in terms of the duration of taking TCM ( ≥ 90 days versus < 90 days), age (50–64 versus ≥ 65) and gender. Results The risk of dementia in patients with Parkinson's disease is decreased by using TCM for < 90 days and ≥ 90 days, especially in the group who took TCM for more than 90 days. The use of TCM signicantly reduces the risk of dementia in the subgroups of age ≥ 65 years, female patients using TCM for both < 90 days and ≥ 90 days, and male patients using TCM for < 90 days. Overall, we can see the protection tendency among all of the target population under TCM use. Conclusions The results showed that there is a signicant reduction of nearly 38% in the risk of dementia for patients with Parkinson’s disease after the usage of Traditional Chinese Medicine. The benecial effects for using TCM ≥ 90 days in women age ≥ 65 years are most prominent. Trial registration The study data were acquired from the Taiwan’s National Health Insurance (NHI) Research Database. The NHI-claimed data provide clinical information for population-based epidemiologic research. This study was approved by the Institutional Review Board of Chung Shan Medical University Hospital. this study showed the protection tendency of TCM usage in preventing for patients previously diagnosed with PD. Statistically signicant association was found between the use of TCM and regression of dementia risk in the subgroups of age ≥ 65 years, female patients using TCM for < 90 days and ≥ 90 days and male patients using TCM for less than 90 days. Protection tendency under TCM was revealed among all of the target population.


Background
Parkinson's disease (PD) and other causes of dementia can occur at the same time. In addition, PD can lead to dementia itself. [1][2] According to the previous studies, the cumulative prevalence of dementia was 75-90% in PD, particularly in patients with PD for more than 10 years. [3] The incidence of dementia in PD patients is around 10% per year. [4] In the long-term, with the progression of the PD, dementia can affect up to 90% of patients with Parkinson's disease. Besides, there is a tendency that women with PD live longer than men with PD, and therefore higher chance of PD women to obtain dementia. [5] Studies suggested that with increasing life expectancy, dementia is almost inevitable in patients with PD, especially in women. Furthermore, current treatments in treating dementia of PD only provide limited effects and new treatments are slow in development. [6] A previous study indicated that some Traditional Chinese Medicine (TCM) have speci c effects on certain determining factors of dementia, such as acetylcholinesterase (AChE) inhibitors and neuronal injury inhibitors. Moreover, functions such as nootropic, anti-in ammation, anti-hypertension, antihyperlipidemia, anti-diabetes, anti-convulsion and curing cognition disorders are also noted in TCM. It is also stated in the analysis that the anti-dementia TCM formulae were directly associated with ameliorating dementia or having synergy and adjunctive effects. [7] However, the effects of TCM in preventing dementia for patients who have Parkinson's disease were unknown. This study aims to accomplish this goal through a case-control study nested within a longitudinal health insurance database of patients.

Data source
The study data were obtained from the Taiwan's National Health Insurance Research Database. The National Health Insurance (NHI) is a compulsory program with coverage rate of 99.9% of the 23 million residents in Taiwan. The NHI-claimed data provide clinical information for population-based epidemiologic research. All diagnoses were coded using the International Classi cation of Diseases, Ninth Revision, Clinical Modi cation (ICD-9-CM) format. This study was approved by the Institutional Review Board of Chung Shan Medical University Hospital.

Study subjects
The study design is a nested case-control study. Eligible subjects ful lled following conditions: (1) ≥ 50 years old (2)

Statistical analyses
Chi-square and t-tests were used to compare the differences between discrete and continuous variables. Conditional logistic regression analysis was used to compare the effects of TCM usage on reducing the risk of dementia among patients with Parkinson's disease in different subgroups. The effects of TCM usage were analyzed to see if there were signi cant differences between the following subgroups: the duration of taking TCM (≥ 90 days versus < 90 days), age (50-64 versus ≥ 65), and gender. Adjustments were made for age, sex, hypertension, hyperlipidemia, chronic liver disease, chronic kidney disease, diabetes, COPD, autoimmune disease, cardiovascular disease, stroke, gout, TCM usage, warfarin usage, statin usage and follow-up periods. The statistical software used was SPSS version 18.0 (SPSS Inc., Chicago, IL, USA).

Results
The study design was a nested case-control study (Fig. 1). The study subjects were over 50 years old with Demographic characteristics of dementia and non-dementia in cohort of Parkinson's disease were shown in Table 1. In the univariate analysis, case and control patients were similar with regard to age, sex, hypertension, chronic liver disease, diabetes, autoimmune disease, cardiovascular disease, gout, warfarin usage and follow-up periods. A history of chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), and stroke were more associated with dementia group. A history of TCM usage, statin usage and hyperlipidemia were more associated with non-dementia group (Table 1).
Certain kinds of diseases and medication usage were signi cantly associated with the risk of dementia in cohort of Parkinson's disease after the adjustment for confounding variables ( Table 2). The association decreased signi cantly between dementia and the usage of TCM (adjusted odds ratio = 0.67, P < 0.001) and statin (adjusted odds ratio = 0.57, P < 0.001). However, there was a markedly increasing association between dementia and CKD (adjusted odds ratio = 1.96, P = 0.001), COPD (adjusted odds ratio = 1.76, P < 0.001) and stroke (adjusted odds ratio = 1.90, P < 0.001) ( Table 2).   Among female patients, the risk of dementia was markedly decreased with the usage of TCM for < 90 days (adjusted odds ratio, 0.64; 95% CI, 0.46-0.9) and ≥ 90 days (adjusted odds ratio, 0.50; 95% CI, 0.29-0.86). Among male patients, TCM usage for less than 90 days was bene cial for reducing the risk of dementia (adjusted odds ratio, 0.71; 95% CI, 0.51-0.99), but TCM usage for more than 90 days demonstrated no statistical signi cance; nonetheless, the protection tendency in this group was also revealed (adjusted odds ratio, 0.70). (Table 4)

Discussion
This study provided support for the bene ts from the use of TCM in reducing the risk of dementia in cohort of Parkinson's disease. The risk of dementia in patients with Parkinson's disease decreased markedly by using TCM < 90 days and ≥ 90 days, especially in women who took TCM for more than 90 days, which indicates the use of TCM for longer time may present more bene ts.
Overall, this study showed the protection tendency of TCM usage in preventing dementia for patients previously diagnosed with PD. Statistically signi cant association was found between the use of TCM and regression of dementia risk in the subgroups of age ≥ 65 years, female patients using TCM for < 90 days and ≥ 90 days and male patients using TCM for less than 90 days. Protection tendency under TCM treatment was revealed among all of the target population.
There are many common causes of dementia, and we categorized them into two types: First, neurodegenerative related, such as Alzheimer disease (AD), dementia with Lewy bodies, frontotemporal dementia, and Parkinson's disease dementia (PDD), which are nearly irreversible and ceasing the deterioration would be the treatment target. Second, non-neurodegenerative related, such as vascular dementia, which may be reversible. Aggressive treatment in golden period and slowing down the progression are the treatment goal for the latter group. [1][2] Parkinson's disease would lead to dementia itself, and it can also be accompanied with other causes of dementia. [8][9] Decreased number of cholinergic neurons and decreased cortical acetylcholinesterase (AChE) activity in brain were signi cantly noted in PDD and AD patients, which suggest cholinesterase inhibitors can improve cognitive function in dementia. [10][11][12] Besides, there are many metabolic and cardiovascular risk factors that would lead to dementia. Thus, prevention of the above risk factors could prevent dementia development. Previous studies demonstrated that natural compounds, which act as antioxidative, have positive effects on neuroprotection. [13] Some TCM contain contributing factors as mentioned above on preventing dementia, such as AChE inhibitors and neuronal injury inhibitors. Part of the TCM also exhibit anti-in ammation, anti-hypertension, anti-hyperlipidemia, anti-diabetes, and anticonvulsion characteristics. [7,14] Since the severity of PD is a risk factor of dementia development, meliorating or slowing down the progression of PD can prevent the development of dementia. [15] It was shown that Chinese herbal medicine act as antioxidant, anti-in ammatory, and anti-apoptosis agents. [16] Previous studies showed that Chinese herb formulas improve symptoms of PD, and reduce the use of dopaminergic drugs and prevent the occurrence of dyskinesia. [17] The evidence from the studies above suggests that Chinese herb medicine is a potential treatment for neuroprotection in Parkinson's disease. [18] Therefore, TCM could relieve the symptoms of PD and further decrease the risk of dementia in PD.
TCM is a very popular and historic treatment of PD, particularly in Asian countries. [19] Nowadays, it is increasingly used worldwide, even in the West. [20] An important advantage of TCM for patients with PD is good compliance for long-term use because of its few side effects. [21] According to this study and previous researches, using TCM as a synergy and adjunctive treatment is highly recommended.

Limitation
This study presents some limitations. Focusing on Taiwan National Health Insurance Research Database may limit the generalizability of this study; therefore, researches on different ethnic groups are necessary to strengthen such correlation between TCM and dementia in PD patients. There are a variety of regimen in TCM. Further studies are required to specify the effective TCM regimen for reducing the risk of dementia in patients with Parkinson's disease. However, identifying the effective intergradient of TCM compounds is rather challenging and the comprehensive mechanisms for TCM in reducing the risk of dementia in PD are yet unknown.

Conclusions
The results of this study show that after the use of TCM for more than 90 days, there is a signi cant reduction of nearly 38% in the risk of dementia for patients with Parkinson's disease, and bene cial effects in female patients age ≥ 65 years are more signi cant. This study analyzes the effect of TCM in different subgroups, such as the duration of medication, age and gender, which can provide evidence for future researches in designing relevant clinical trials and can serve as a reference for TCM prescription in patients with PD in the future.  Figure 1 Flow diagram of nested case-control study of TCM and Dementia in