Parkinson’s disease (PD) is the second most common degenerative brain disease after dementia, and its incidence increases with age. The prevalence is highest in people in their 70s, but gradually decreases thereafter, suggesting the influence of factors other than age. PD begins with problems with motor skills, and as the disease progresses, it affects cognitive ability. The problem with motor ability is that the dopaminergic neurons in the substantia nigra in the center of the brainstem are destroyed, resulting in insufficient production of dopamine, leading to a decrease in motor ability. However, the cause of the decrease in dopamine neurons is not yet clear, and although there are research results on environmental influences, toxic substances, and genetic predisposition, the pathophysiological mechanism is not yet clear enough to explain many patients.^1-3)

Despite their multifactorial etiologies, PD and cancer share some common biological pathways. Specific gene mutations, such as those in the LRRK2 gene, along with chronic inflammation and oxidative stress, play significant roles in the pathogenesis of both diseases.^4,5) Epidemiologic studies have shown that patients with Parkinson’s disease have a lower morbidity associated with most neoplasms than the general population.^6,7)

Based on the type of cancer, the age at which cancer develops varies. Cancers that mainly occur before the age of 50 include leukemia, thyroid cancer, melanoma, and breast cancer, and after the age of 50, the incidence of lung cancer, colon cancer, bladder cancer, and prostate cancer is high.⁸⁾ A majority of existing studies on the correlation between PD and cancer have examined the development of cancer in PD patients. Still, if we consider the order of onset of cancer and PD, there may be a correlation in the opposite direction. Therefore, we investigated the factors associated with PD development in cancer patients.

Study design and data source

In this population-based nested case-control study, we used customized cohort data with PD from 2010 to 2021 from Korean National Insurance Service system. This database contains individual beneficiary and healthcare service information including diagnosis, procedures, and prescriptions. The 10th revision of the International Classification of Diseases (ICD-10) has been used to code diagnoses. All data were de-identified for research purposes to protect the patients’ private information. Medical claims data are encrypted to protect personal information and are provided with anonymous identification numbers. This study was approved by the Institutional Review Board of Chungbuk National University (CBNU-202204-HR-0068).

Defining case and control groups

We used the date of the first record of cancer diagnosis as the index date and 365 days before the index date as a washout period. Among cancer patients, subjects with missing demographic data, diagnosis data or prescription data were excluded. Patients with one or more inpatient diagnosis or two or more outpatient diagnosis of PD in a year were selected as the case group and patients without the diagnosis of PD were defined as the control group. To consider the time of PD development after cancer diagnosis, we set minimum of 6 months prior to the PD diagnosis. Subjects with missing data were not included in this study. Risk set sampling was used to match each case with one control by age and sex based on a nested case-control study.

Statistical analysis

Baseline characteristics were summarized for the case (PD) and control groups. Results were presented as numbers and percentages for categorical variables, and differences between groups were estimated according to chi-square tests. The comorbidities include all variables from the Charlson comorbidities except for any malignancy and metastatic solid tumor. Covariates with statistical significance in univariate analysis were entered into the multivariable analysis to estimate adjusted odds ratios. Odds ratios for Parkinson’s disease risk were calculated in matched subjects after risk set sampling. We conducted conditional logistic regression to determine significant differences between groups. All statistical analyses were done using the SAS Enterprise Guide version 9.4 (SAS Institute Inc, Cary, NC, USA), and a two-tailed confidence interval of 0.05 was considered to indicate statistical significance.

Of 218,171 patients diagnosed any type of cancer, 95,114 patients met the inclusion criteria and were included in the matching process. Among them, 17,338 patients were diagnosed with PD. After 1:1 matching with age and sex, the case and control groups were selected, 11,347 in each group (Fig. 1). There were more male patients (57.25%) than female patients (42.75%) and the average age of each group was 72 years. All comorbidities included in the analysis were found to be statistically significant (Table 1). The average follow-up duration of PD group was 3.99±3.7 years. The most prevalent types of cancer were colorectal cancer, prostate cancer and gastric cancer (Table 2). After adjusting for age, sex, and comorbidities, dementia followed by cerebrovascular disease were associated with PD development in adjusted odds ratio of 2.06 and 1.64, respectively (95% CI=1.92-2.22, 1.54-1.74, respectively) (Table 3).

Fig. 1. Patient selection flowchart

Table 1 Baseline characteristics of subjects

	Control group N=11347 (%)	Parkinson’s disease group N=11347 (%)	p-value
Sex			1.000
Male	6496 (57.25)	6496 (57.25)
Female	4851 (42.75)	4851 (42.75)
Age, years (mean±SD)	72.3±6.9	72.3±6.9	1.000
Charlson Comorbidity Index	5.93±3.4	6.96±3.7	<0.001
0-2	2787 (24.56)	1929 (17.00)
3-5	4339 (38.24)	3678 (32.41)
6≤	4221 (37.20)	5740 (50.59)
Comorbidities
Myocardial infarction	387 (3.41)	559 (4.93)	<0.001
Congestive heart failure	1719 (15.15)	2429 (21.41)	<0.001
Peripheral vascular disease	3747 (33.02)	4758 (41.93)	<0.001
Cerebrovascular disease	2690 (23.71)	4590 (40.45)	<0.001
Dementia	1503 (13.25)	3268 (28.20)	<0.001
Chronic pulmonary disease	6858 (60.44)	7437 (65.54)	<0.001
Rheumatic disease	1132 (9.98)	1531 (13.49)	<0.001
Peptic ulcer disease	6363 (56.08)	7013 (61.08)	<0.001
Mild liver disease	5766 (50.82)	6469 (57.01)	<0.001
Diabetic without chronic complications	5430 (47.85)	6420 (56.58)	<0.001
Mild renal disease	1075 (9.47)	1446 (12.74)	<0.001
Diabetic with chronic complications	2005 (17.67)	2777 (24.47)	<0.001
Hemiplegia or paraplegia	298 (2.63)	639 (5.63)	<0.001
Severe liver disease	135 (1.19)	182 (1.60)	0.0079
Severe renal disease	344 (3.03)	496 (4.37)	<0.001

Table 2 Cancer types in each group after risk set sampling

Cancer type	ICD-10 code	Control group N=10272	Parkinson’s disease group N=10943
Oral cavity and pharyngeal cancer	C00, C01-14	120	119
Laryngeal cancer	C32	73	58
Oesophageal cancer	C15	80	66
Gastric cancer	C16	1620	1504
Colorectal cancer	C18-21	1729	1596
Liver cancer	C22	585	689
Pancreatic cancer	C25	248	374
Biliary cancer	C23, C24	174	164
Lung cancer	C33, C34	655	748
Renal cancer	C64	216	235
Bladder cancer	C67	372	405
Thyroid cancer	C73	737	811
Leukaemia	C91-95	48	42
Lymphoma	C81-86	130	119
Multiple myeloma	C90	32	55
Skin cancer	C43	40	35
Breast cancer (women)	C50	527	480
Uterine cervical cancer (women)	C53	124	136
Uterine corpus cancer (women)	C54, C55	64	64
Ovarian cancer (women)	C56	78	93
Prostate cancer (men)	C61	1620	1987
Testicular cancer (men)	C62	7	9

ICD: International Classification of Diseases

Table 3 Crude and adjusted odds ratio for Parkinson’s disease

	Crude odds ratio (95%CI)	Adjusted odds ratio* (95%CI)
Myocardial infarction	1.467 (1.286-1.675)	1.059 (0.920-1.218)
Congestive heart failure	1.526 (1.425-1.633)	1.179 (1.094-1.271)
Peripheral vascular disease	1.465 (1.388-1.546)	1.116 (1.052-1.185)
Cerebrovascular disease	2.064 (2.064-2.315)	1.637 (1.536-1.744)
Dementia	2.649 (2.475-2.835)	2.061 (1.917-2.216)
Chronic pulmonary disease	1.245 (1.179-1.314)	0.968 (0.912-1.028)
Rheumatic disease	1.407 (1.297-1.527)	1.140 (1.045-1.243)
Peptic ulcer disease	1.267 (1.202-1.336)	1.025 (0.967-1.086)
Mild liver disease	1.283 (1.218-1.352)	0.985 (0.928-1.045)
Diabetic without chronic complications	1.420 (1.348-1.496)	1.085 (1.021-1.153)
Mild renal disease	1.396 (1.284-1.517)	1.082 (0.986-1.186)
Diabetic with chronic complications	1.510 (1.416-1.610)	1.130 (1.050-1.216)
Hemiplegia or paraplegia	2.212 (1.923-2.545)	1.307 (1.127-1.515)
Severe liver disease	1.354 (1.082-1.694)	1.017 (0.804-1.286)
Severe renal disease	1.462 (1.271-1.682)	1.068 (0.919-1.242)

*Adjusted for age, sex, myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, rheumatic disease, peptic ulcer disease, mild liver disease, diabetic without chronic complications, mild renal disease, diabetic with chronic complications, hemiplegia or paraplegia, severe liver disease, severe renal disease

As the colorectal cancer had the highest frequency in our cohort reflecting the high incidence in Korean population,^9,10) subgroup analysis was performed. Male subjects comprised of 53.35% and the mean age was 72 years in each group. Charlson comorbidity index was higher in PD group when compared to the control group (4.8 and 3.8, respectively). Among the comorbidities, all variables except for mild renal disease showed statistical significance (Table 4). In multivariable regression analysis, severe liver disease, cerebrovascular disease and dementia showed relatively high incidence of PD (Table 5).

Table 4 Baseline characteristics of colorectal cancer subjects

Sub analysis (Colorectal)	Control group N=2641 (%)	Parkinson’s disease group N=2641 (%)	p-value
Sex			1.00
Male	1409 (53.35)	1409 (53.35)
Female	1232 (46.65)	1232 (46.65)
Age, years (mean±SD)	71.69±8.65	71.62±8.89	0.78
Charlson Comorbidity Index (mean±SD)	3.84±2.67	4.79±3.07	<0.001
Comorbidities
Myocardial infarction	113 (4.28)	145 (5.49)	0.041
Congestive heart failure	498 (18.86)	572 (21.66)	0.011
Peripheral vascular disease	901 (34.12)	1080 (40.89)	<0.001
Cerebrovascular disease	605 (22.91)	1014 (38.39)	<0.001
Dementia	419 (15.87)	750 (28.40)	<0.001
Chronic pulmonary disease	1519 (57.52)	1726 (65.35)	<0.001
Rheumatic disease	288 (10.90)	354 (13.40)	0.0054
Peptic ulcer disease	1410 (53.39)	1607 (60.85)	<0.001
Mild liver disease	1458 (55.21)	1533 (58.05)	0.037
Diabetic without chronic complications	1387 (52.52)	1549 (58.65)	<0.001
Mild renal disease	237 (8.97)	277 (10.49)	0.063
Diabetic with chronic complications	466 (17.64)	631 (23.89)	<0.001
Hemiplegia or paraplegia	67 (2.54)	155 (5.87)	<0.001
Severe liver disease	20 (0.76)	49 (1.86)	0.0004
Severe renal disease	95 (3.60)	166 (4.39)	0.140

Table 5 Crude and adjusted odds ratio for Parkinson’s disease in colorectal cancer subjects

	Crude odds ratio (95%CI)	Adjusted odds ratio* (95%CI)
Myocardial infarction	1.30 (1.01-1.67)	1.06 (0.81-1.39)
Congestive heart failure	1.18 (1.04-1.36	0.93 (0.80-1.08)
Peripheral vascular disease	1.33 (1.19-1.49)	1.06 (0.94-1.20)
Cerebrovascular disease	2.09 (1.86-2.36)	1.67 (1.46-1.91)
Dementia	2.10 (1.83-2.40)	1.65 (1.42-1.90)
Chronic pulmonary disease	1.39 (1.24-1.55)	1.16 (1.03-1.31)
Rheumatic disease	1.26 (1.07-1.49)	1.08 (0.90-1.29)
Peptic ulcer disease	1.35 (1.21-1.51)	1.13 (1.005-1.27)
Mild liver disease	1.12 (1.007-1.250	0.89 (0.79-1.01)
Diabetic without chronic complications	1.28 (1.15-1.43)	1.04 (0.92-1.17)
Mild renal disease	1.88 (0.99-1.42)	1.00 (0.81-1.22)
Diabetic with chronic complications	1.46 (1.28-1.67)	1.16 (1.003-1.35)
Hemiplegia or paraplegia	2.39 (1.78-3.20)	1.52 (1.12-2.06)
Severe liver disease	2.47 (1.46-4.17)	1.89 (1.10-3.23)
Severe renal disease	1.23 (0.93-1.62)	0.91 (0.67-1.23)

*Adjusted for age, sex, myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, rheumatic disease, peptic ulcer disease, mild liver disease, diabetic without chronic complications, mild renal disease, diabetic with chronic complications, hemiplegia or paraplegia, severe liver disease, and severe renal disease.

The main finding of this study is that cerebrovascular disease and dementia were associated with the development of PD in cancer patients. Similar results were shown in a subgroup of patients with colorectal cancer, showing cerebrovascular disease, dementia and severe liver disease were significantly associated with higher incidence of PD.

PD is associated with several risk factors, including age, male gender, exposure to pesticides, head injury, and occupation in agriculture.^11,12) There is, however, some inconsistency in the studies on disease factors. Previous studies have reported conflicting findings regarding the link between cerebrovascular risk factors and subsequent PD. For example, Miyake et al found that hypertension was associated with a reduced risk of PD, while Qiu et al reported the opposite, and Simon et al found no association between the two.^13-15) Similarly, Driver et al, Xu et al, and Hu et al reported that diabetes mellitus was associated with an increased risk of PD,^16-18) whereas another study reported the opposite, and no significant PD risk with diabetes was reported by Simon et al.^13,15) These discrepancies may stem from variations in study populations, time frames, analytical methods, and statistical power across different studies. Additionally, previous studies on this topic demonstrated variability in the magnitude of risks, especially those that focused on individual diseases.^{13,16,17,19,20)} In this context, our study offers new insights, showing that a wide range of cerebrovascular risk factors are associated with PD.

Dementia and Parkinson’s disease is closely related. Dementia is a frequent complication of Parkinson’s disease and significant proportion of patients with PD has some form of cognitive impairment at the time of PD diagnosis.²¹⁾ It is rather odd to point out that dementia is an associated factor with PD as dementia is usually followed by PD, not in the opposite direction. PD and dementia can develop concurrently as their pathological changes occur simultaneously.²²⁾ The accumulation of alpha-synuclein, as well as amyloid-beta, and tau have a synergistic relationship between these proteins.²³⁾ However, it is challenging to detect these processes in patients living with the disease. Disease duration (time since diagnosis), which can be useful as a measure of disease progression in other degenerative diseases such as Alzheimer’s disease, is particularly ineffective in Parkinson’s dementia.²⁴⁾ Duration is often negatively related to disease progression as patients with an older age at diagnosis frequently progress more rapidly to dementia while having a shorter duration of disease.²⁵⁾ Therefore, rather than understanding dementia and PD as separate diseases with a chronological precedence, it is better to consider them as comorbid conditions.

There are a few limitations on this study. First, the operational definition was set relatively broadly in order to include a large number of subjects. Secondly, due to the characteristics of the database used, the analysis relied on disease codes, which may result in insufficient reflection of actual clinical situations. Lastly, a subgroup analsis could not be performed in various types of cancer due to the limited number of patients.

As cancer survival rates improve, interest in the development of neurodegenerative diseases is increasing. Cancer and PD share some pathogenetic factors such as acculation and aggregation of alpha-synuclein, PINK1 mutation, loss of function in PARKIN gene, mitochondrial dysfunction and oxidative stress.^26-28) Expanding knowledge on the associated factors of PD and cancer will allow the development of novel diagnostic methods that may have clinical applications. Understanding the possible mechanisms underlying these pathologies and the interdependencies between them could lead to the development of effective targeted therapies that would improve the course of both diseases and their prognosis.

Fig. 2. Factors associated with all-cancer and Parkinson’s disease

Fig. 3. Factors associated with colorectal cancer and Parkinson’s disease

Risk factors such as dementia and cerebrovascular disease may play a significant role in patients with cancer for the development of PD.

This research was supported by “Regional Innovation Strategy (RIS)” through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (MOE) (2021RIS-001).

The authors declare that they have no conflict of interest.

Institutional Review Board Statement: This study was approved by the Institutional Review Board of Chungbuk National University (CBNU-202204-HR-0068).

Informed consent statement: Patient consent was waived due to the retrospective nature of the study and the analysis used anonymous data.

Jin Yeon Gil : Graduate student

Young Sook Ku : Graduate student

Kyung Hyun Min : Graduate student

Jun Hyeob Kim : Graduate student

Jun Hyuk Park : Graduate student

Ji Min Han : Professor

Kyung Eun Lee : Professor