Associations of Chinese Herbal Medicine Usage with Risk of Dementia in Patients with Parkinson's Disease: A Population-Based,Nested Case

Abstract

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 efficacy of current treatments in dementia of PD is limited. Previous studies indicated the potential roles of Chinese herbal medicine (CHM) in treating dementia, yet the correlation between CHM usage and risk of dementia in PD patients is unclear.

Methods:

This case–control study was nested within a National Health Insurance database of patients over 50 years with newly diagnosed PD from year 2000 to 2010. Among these PD patients, dementia and nondementia groups were discussed, respectively, in terms of the duration of taking CHM (≥90 vs. <90 days), age (50–64 vs. ≥65 years) and gender.

Results:

The risk of dementia in patients with PD is lower in CHM users compared with non-CHM users, especially in those taking CHM for more than 90 days (adjusted odds ratio [aOR] 0.58; 95% confidence interval [95% CI] 0.39–0.87). The use of CHM was significantly related to the lower risk of dementia in the subgroups of patients with age ≥65 years for CHM usage <90 days (aOR 0.68; 95% CI 0.53–0.88), patients with age ≥65 years for CHM usage ≥90 days (aOR 0.63; 95% CI 0.42–0.94), female patients using CHM for ≥90 days (aOR 0.43; 95% CI 0.22–0.84), and male patients using CHM for <90 days (aOR 0.62; 95% CI 0.43–0.88).

Conclusions:

The authors demonstrated the association of CHM usage with lower risk of dementia in patients with PD, especially in women with the usage of CHM for more than 90 days. Since no arbitrary causal conclusions could be drawn from retrospective cohort studies, the finding in this study could be used to generate a hypothesis for a subsequent design of prospective longitudinal study.

Introduction

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 PD. Besides, there is a tendency that women with PD live longer than men with PD and, therefore, higher chance for 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.³

A previous study indicated that some Chinese herbal medicine (CHM) have specific effects on certain determining factors of dementia, such as acetylcholinesterase (AChE) inhibitors and neuronal injury inhibitors. Moreover, functions such as nootropic, anti-inflammation, antihypertension, antihyperlipidemia, antidiabetes, anticonvulsion, and curing cognition disorders are also noted in Traditional Chinese Medicine.⁶ It is also stated in the analysis that the antidementia CHM formulae were directly associated with ameliorating dementia or having synergy and adjunctive effects.⁶

However, the association of CHM with risk of dementia for patients who have PD was unknown. This study aims to accomplish this goal through a case–control study nested within a longitudinal health insurance database of patients.

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.

Materials and Methods

Data source

The study data were obtained from the Taiwan's NHI Research Database. The NHI is a compulsory program with coverage rate of 99.9% of the 23 million residents in Taiwan. Every participant of NHI received equal medical care resources under NHI system regardless of their social statuses. The NHI-claimed data provide clinical information for population-based epidemiologic research. All diagnoses were coded using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) format. This study was approved by the Institutional Review Board of Chung Shan Medical University Hospital.

Study subjects

The study design was a nested case–control study. Since a previous article had revealed that most Taiwanese patients diagnosed of PD were aging ≥50 years,⁷ the selection of the study subjects was defined as patients aging ≥50 years with newly diagnosed PD (ICD-9-CM = 332) at least twice in outpatient department or one admission from year 2000 to 2010. Patients diagnosed of dementia before the diagnosis of PD were excluded.

The selection of 90 days duration for the washout period was based on the policy of NHI Ministry of Health and Welfare in Taiwan. Patients who need long-term drug use for specific chronic disease control can have “chronic illness refill prescription” issued from doctors, and the validity of refill prescription is 90 days.⁸ Therefore, patients not using CHM 90 days before PD diagnosis were considered as none CHM usage. To confirm that the patients with history of CHM usage would not be misclassified into non-CHM group, patients who used CHM 90 days before the first diagnosis of PD were excluded.

Patients classified in the dementia group were those newly diagnosed of dementia at least twice in outpatient department or one admission after the diagnosis of PD and at least 3 years apart. Nondementia group were patients never diagnosed of dementia after the diagnosis of PD and were matched in a 1:1 ratio for age (±2 years), gender, and diagnosed year of PD with the patients in the dementia group. The index date was set at the date of the second time diagnosis of dementia at outpatient department or the first admission due to diagnosis of dementia and matching was also used to provide the same index date.

Exposure to CHM and covariates

The use of CHM was defined within 3 years before the index date and the prescription days were calculated to perform the cumulative usage effect. Baseline comorbidities included hypertension (ICD-9-CM = 401–405), hyperlipidemia (ICD-9-CM = 272.0–272.4), chronic liver disease (ICD-9-CM = 571), chronic kidney disease (CKD; ICD-9-CM = 585), diabetes (ICD-9-CM = 250), chronic obstructive pulmonary disease (COPD; ICD-9-CM = 491, 492, 496), autoimmune disease (ICD-9-CM = 710.0, 714.0, 720.0), cardiovascular disease (ICD-9-CM = 410–414), stroke (ICD-9-CM = 430–438), and gout (ICD-9-CM = 274). These comorbidities were defined as a disease diagnosed at least twice in outpatient department or one admission within 3 years before the index date. In addition, the use of warfarin and statin were included in this study.

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 CHM usage on reducing the risk of dementia among patients with PD in different subgroups.

Usage of CHM ≥90 days was defined as long-term use. According to the policy of NHI Ministry of Health and Welfare in Taiwan, patients with specific chronic diseases and need long-term drug use for disease stability maintenance can have “chronic illness refill prescription” issued from doctors. The validity of refill prescription is 90 days, and during this period, patients can fill the prescription from pharmacy without doctor visits.⁸ After 90 days, patients have to be re-evaluated by physicians and may receive the refill prescription again if their diseases are under well controlled. Most qualified patients adhere to this policy to save their time, money, and social resources, and regularly follow up every 90 days. Therefore, the authors regarded medicine usage ≥90 days as long-term use.

The effects of CHM usage were analyzed to see if there were significant differences between the following subgroups: the duration of taking CHM (≥90 vs. <90 days), age (50–64 vs. ≥65 years), and gender. Adjustments were made for age, sex, hypertension, hyperlipidemia, chronic liver disease, CKD, diabetes, COPD, autoimmune disease, cardiovascular disease, stroke, gout, CHM usage, warfarin usage, statin usage, and follow-up periods. The statistical software used was SPSS version 18.0 (SPSS, Inc., Chicago, IL).

Results

The study design was a nested case–control study (Fig. 1). The study subjects were over 50 years with newly diagnosed PD (ICD-9-CM = 332) at least twice in outpatient department or one admission from year 2000 to 2010 (N = 7990). Patients diagnosed of dementia (ICD-9-CM = 290.0–290.4, 294.1, 331.0–331.2) before the diagnosis of PD and patients used CHM 90 days before the first diagnosis of PD were excluded. The patients in the dementia group were newly diagnosed of dementia at least twice in outpatient department or one admission after diagnosis of PD and at least 3 years apart (N = 1203). Nondementia group were patients not diagnosed of dementia after the diagnosis of PD and were matched in a 1:1 ratio for age (±2 years), gender, and the diagnosed year of PD with patients in the dementia group (N = 847).

FIG. 1.

Flow diagram of nested case–control study of CHM and dementia in Parkinson's disease. CHM, Chinese herbal medicine.

Demographic characteristics of dementia and nondementia in cohort of PD are shown in Table 1.

Table 1.

Demographic Characteristics of Dementia and Nondementia in Cohort of Parkinson's Disease

	Dementia (N = 847)		Nondementia (N = 847)		p
	n	%	n	%	p
Age					0.362
50–64	31	3.7	30	3.5
65–79	447	52.8	476	56.2
≥80	369	43.6	341	40.3
Mean ± SD	78.5 ± 7.2		78 ± 7.1		0.133
Gender					1
Female	441	52.1	441	52.1
Male	406	47.9	406	47.9
Hypertension	621	73.3	583	68.8	0.042
Hyperlipidemia	200	23.6	241	28.5	0.023
Chronic liver disease	92	10.9	87	10.3	0.693
Chronic kidney disease	72	8.5	41	4.8	0.003
Diabetes	276	32.6	260	30.7	0.403
COPD	220	26.0	150	17.7	<0.001
Autoimmune disease	19	2.2	14	1.7	0.379
Cardiovascular disease	244	28.8	251	29.6	0.708
Stroke	426	50.3	299	35.3	<0.001
Gout	92	10.9	99	11.7	0.591
Medication usage
CHM	236	27.9	307	36.2	<0.001
Warfarin	31	3.7	23	2.7	0.269
Statin	185	21.8	251	29.6	<0.001
Follow-up period, years	5.2 ± 2.2		5.2 ± 2.2		0.984

CHM, Chinese herbal medicine; COPD, chronic obstructive pulmonary disease; SD, standard deviation.

In the univariate analysis, case and control patients were similar with regard to age, sex, chronic liver disease, diabetes, autoimmune disease, cardiovascular disease, gout, warfarin usage, and follow-up periods. A history of hypertension, CKD, COPD, and stroke were more associated with dementia group. A history of CHM usage, statin usage, and hyperlipidemia were more associated with nondementia group (Table 1).

Certain kinds of diseases and medication usage were significantly associated with the risk of dementia in cohort of PD after the adjustment for confounding variables (Table 2). The data demonstrated negative correlation between risk of dementia and some medication usage, including the usage of CHM (adjusted odds ratio [aOR] = 0.64, p < 0.001) and statin (aOR = 0.58, p < 0.001). However, there was a positive correlation between risk of dementia and some underlying diseases, including CKD (aOR = 1.89, p = 0.004), COPD (aOR = 1.66, p < 0.001), and stroke (aOR = 1.89, p < 0.001) (Table 2).

Table 2.

Conditional Logistic Regression of Risk of Dementia

	Crude OR	95% CI	p	Adjusted OR^a	95% CI	p
CHM	0.67	0.54–0.83	<0.001	0.64	0.51–0.8	<0.001
Hypertension	1.25	1.01–1.54	0.041	1.15	0.91–1.46	0.249
Hyperlipidemia	0.76	0.6–0.95	0.018	0.93	0.7–1.24	0.629
Chronic liver disease	1.06	0.78–1.43	0.701	1.18	0.85–1.63	0.325
Chronic kidney disease	1.82	1.22–2.7	0.003	1.89	1.23–2.91	0.004
Diabetes	1.09	0.89–1.34	0.403	1.10	0.87–1.38	0.435
COPD	1.75	1.36–2.26	<0.001	1.66	1.27–2.17	<0.001
Autoimmune disease	1.36	0.68–2.71	0.386	1.19	0.57–2.47	0.650
Cardiovascular disease	0.96	0.77–1.19	0.701	0.94	0.74–1.19	0.620
Stroke	1.85	1.52–2.26	<0.001	1.89	1.53–2.34	<0.001
Gout	0.92	0.68–1.24	0.593	0.88	0.63–1.22	0.436
Warfarin	1.40	0.79–2.49	0.250	1.30	0.7–2.4	0.402
Statin	0.64	0.51–0.81	<0.001	0.58	0.44–0.78	<0.001

Adjusted for CHM, hypertension, hyperlipidemia, chronic liver disease, chronic kidney disease, diabetes, COPD, autoimmune disease, cardiovascular disease, stroke, gout, warfarin, and statin.

CI, confidence interval; CHM, Chinese herbal medicine; COPD, chronic obstructive pulmonary disease; OR, odds ratio.

The risk of dementia in cohort of PD was also associated with the duration of CHM usage (Table 3). The risk of dementia was significantly lower in groups of both CHM usage <90 days (aOR 0.66; 95% confidence interval [95% CI] 0.51–0.84), and ≥90 days (aOR 0.58; 95% CI 0.39–0.87), especially in the group who used CHM for more than 90 days.

Table 3.

Conditional Logistic Regression of Risk of Dementia

	N	No. of dementia	Crude OR	95% CI	p	Adjusted OR^a	95% CI	p
CHM, days
None	1151	611	1			1
<90	416	183	0.68	0.54–0.86	0.001	0.66	0.51–0.84	0.001
≥90	127	53	0.64	0.44–0.92	0.017	0.58	0.39–0.87	0.008

Adjusted for CHM, hypertension, hyperlipidemia, chronic liver disease, chronic kidney disease, diabetes, COPD, autoimmune disease, cardiovascular disease, stroke, gout, warfarin, and statin.

CI, confidence interval; CHM, Chinese herbal medicine; COPD, chronic obstructive pulmonary disease; OR, odds ratio.

The population size of PD between the ages of 50 and 64 years was small. Therefore, instead of dividing this group into usage of CHM for <90 days and ≥90 days, they were divided into usage of CHM and none usage of CHM. Although no statistically significant interaction was found among the risk of dementia in cohort of PD and CHM usage between age of 50 and 64 years, the tendency of lower risk was revealed (aOR 0.26). Among the patients older than 65 years, the risk of dementia was significantly lower in both groups of CHM usage for <90 days (aOR 0.68; 95% CI 0.53–0.88) and CHM usage for ≥90 days (aOR 0.63; 95% CI 0.42–0.94) compared with none CHM usage group (Table 4).

Table 4.

Subgroup Analysis of Conditional Logistic Regression of Risk of Dementia

	N	No. of dementia	Crude OR	95% CI	p	Adjusted OR	95% CI	p
Age = 50–64
CHM^a
None	42	25	1			1
Yes	14	5	0.50	0.13–2	0.327	0.26	0.03–2.57	0.249
Age ≥65
CHM, days^b
None	1109	586	1			1
<90	402	178	0.70	0.55–0.89	0.004	0.68	0.53–0.88	0.003
≥90	122	52	0.68	0.46–0.99	0.044	0.63	0.42–0.94	0.025
Female
CHM, days^b
None	603	321	1			1
<90	222	98	0.66	0.47–0.92	0.015	0.70	0.48–1.01	0.058
≥90	57	22	0.52	0.29–0.94	0.029	0.43	0.22–0.84	0.013
Male
CHM, days^b
None	548	290	1			1
<90	194	85	0.70	0.5–0.97	0.034	0.62	0.43–0.88	0.007
≥90	70	31	0.73	0.45–1.19	0.209	0.66	0.39–1.1	0.112

Adjusted for CHM, hypertension, hyperlipidemia, chronic liver disease, diabetes, stroke, gout and statin.

Adjusted for CHM, hypertension, hyperlipidemia, chronic liver disease, chronic kidney disease, diabetes, COPD, autoimmune disease, cardiovascular disease, stroke, gout, warfarin, and statin.

CI, confidence interval; CHM, Chinese herbal medicine; COPD, chronic obstructive pulmonary disease; OR, odds ratio.

Among female patients with age ≥65 years, the risk of dementia was markedly lower in the group of CHM usage for ≥90 days (aOR 0.43; 95% CI 0.22–0.84), and despite no statistical significance was discovered for CHM <90 days, the data demonstrated the tendency of lower risk (aOR 0.70). Among male patients with age ≥65 years, risk of dementia (aOR 0.62; 95% CI 0.43–0.88) was lower for CHM usage <90 days compared with none CHM usage. And CHM usage for more than 90 days demonstrated no statistical significance; nonetheless, the tendency of lower risk in this group was also revealed (aOR 0.66) (Table 4).

Discussion

This study provided the evidence of the strong association of the CHM usage with the lower risk of dementia in patients with PD. The lower risk of dementia in patients with PD is markedly related to the group with CHM usage for more than 90 days.

Overall, statistically significant correlation was found between the use of CHM and the lower risk of dementia in the subgroups of patients with age ≥65 years, female patients using CHM for ≥90 days and male patients using CHM for <90 days. The phenomena of the correlation between lower risk of dementia and CHM treatment was revealed in all of the target population.

There are many common causes of dementia, and the authors 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 PD would lead to dementia itself, and it can also be accompanied with other causes of dementia.^9,10

Decreased number of cholinergic neurons and decreased cortical AChE activity in brain were significantly noted in PDD and AD patients, which suggests cholinesterase inhibitors can improve cognitive function in dementia.^11
–13 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.¹⁴ Some CHM contain contributing factors as mentioned earlier on preventing dementia, such as AChE inhibitors and neuronal injury inhibitors.

Besides, there are many metabolic and cardiovascular risk factors that would lead to dementia. Thus, prevention of the aforementioned risk factors could prevent dementia development, and some CHM exhibit anti-inflammation, antihypertension, antihyperlipidemia, antidiabetes, and anticonvulsion characteristics.^6,15 Previous studies demonstrated that natural compounds, which act as antioxidative, have positive effects on neuroprotection.¹⁶ And it was proved that some CHM act as antioxidant, anti-inflammatory, and antiapoptosis agents.¹⁷ Furthermore, a recent study showed that Chinese herb formulas improve symptoms of PD, and reduce the use of dopaminergic drugs and prevent the occurrence of dyskinesia.¹⁸

The evidence from the aforementioned studies suggests that Chinese herb medicine is a potential treatment for neuroprotection in PD.¹⁹ Therefore, CHM could relieve the symptoms of PD and is related to the reducing risk of dementia in PD.

CHM is a very popular and historic treatment of PD, particularly in Asian countries.²⁰ Nowadays, it is increasingly used worldwide, even in the West.²¹ An important advantage of CHM for patients with PD is good compliance for long-term use because of its few side effects.²² According to this study and previous researches, using CHM is prominently associated with lower risk of dementia in PD patients. Further prospective study may be designed to confirm the cause-and-effect relationship based on the finding from this study.

Limitation

This study presents some limitations. Focusing on Taiwan NHI Research Database may limit the generalizability of this study; therefore, future researches on different ethnic groups are necessary to strengthen such correlation between CHM and dementia in PD patients. There are a variety of regimen in CHM. Further studies are required to specify the effective CHM regimen for reducing the risk of dementia in patients with PD. However, identifying the effective ingredient of CHM compounds is rather challenging and the mechanisms of CHM in reducing the risk of dementia in PD are yet unknown. Furthermore, there may be some residual confounding factors not being considered. Some personal information, such as education level and social status, were not included in this study. On one hand, although social status may be one of the concerns, every participant of NHI acquired equal medical resources under NHI system regardless of their socioeconomic status. On the other hand, education may be a potential variable. Due to the fact that NHI database did not provide the information of education levels of participants, this is one of the limitations of this study. Misclassification of PD and dementia may also occur in this study. In addition, since no arbitrary causal conclusions could be drawn from retrospective cohort studies, further prospective study may be constructed to confirm the causal relationship between CHM usage and risk of dementia in patients with PD based on this study.

Conclusions

Usage of CHM is associated with lower risk of dementia in patients with PD, especially in female patients aging ≥65 years. This study can provide evidence for future researches in designing relevant clinical trials.

Footnotes

Acknowledgments

The authors thank all the researchers who participated in this study.

Authors' Contributions

Y.-T.L., C.-Y.L., H.-H.C., Y.-H.W., and J.C.-C.W. conceived and designed this article. Y.-H.W. contributed to acquisition of data. Y.-T.L., C.-Y.L., and Y.-H.W. analyzed and interpreted the data of this study. Y.-T.L., C.-Y.L., and Y.-H.W. wrote the original draft. Y.-T.L., C.-Y.L., H.-H.C., Y.-H.W., and J.C.-C.W. reviewed and edited the article. All authors contributed to drafting and/or revising the article, and approved the final version to be published.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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Associations of Chinese Herbal Medicine Usage with Risk of Dementia in Patients with Parkinson's Disease: A Population-Based,Nested Case–Control Study

Abstract

Background:

Methods:

Results:

Conclusions:

Introduction

Trial registration

Materials and Methods

Data source

Study subjects

Exposure to CHM and covariates

Statistical analyses

Results

Discussion

Limitation

Conclusions

Footnotes

Acknowledgments

Authors' Contributions

Author Disclosure Statement

Funding Information

References