Association among Parkinsonism-related motor complaints, cerebral small vessel disease, and cerebrovascular risk factors in a community-dwelling population

Background Parkinsonism-related motor complaints are commonly seen in the elderly. Our study aimed to investigate the association among Parkinsonism-related motor complaints, cerebral small vessel disease and cerebrovascular risk factors in a community-dwelling population in a Chinese rural area. Methods Individuals who were 50 years old or older, were independently living, were well-functioning, and had no history of ischemic or hemorrhagic stroke, were included. Brain magnetic resonance imaging (MRI), quantified motor function assessment, and questionnaire screening for Parkinsonism-related motor complaints were performed. Clinical data including cerebrovascular risk factors were collected. In univariate analysis, Chi-square test and student t-test were used to compare dichotomous variables and continuous variables, respectively, between individuals with or without motor complaints. In multivariate analysis, binary Logistic regression models were generated to determine risk factors for Parkinsonism-related motor complaints. General linear models were used to compare motor parameters between individuals with or without motor complaints. Results In the final analysis, 854 people were included. Individuals with motor complaints had a longer time for finger taping (6.2s v.s. 5.6s, p = 0.006), and a longer time for 3m-walking(4.0s v.s. 3.6s, p = 0.034) than did those without motor complaints. Hypertension was associated with motor complaints (odds ratio, 1.82; 95% confidence interval [CI], [1.21, 2.73]; p = 0.004). Age was not associated with motor complaints; none of the neuroimaging markers of cerebral small vessel disease was associated with motor complaints. The questionnaire that used

disease in a community-dwelling population.

Background
Signs of Parkinsonism have been found to be increased with age and are often considered as benign concomitants of aging. Recent studies have shown that in a community-dwelling population, mild Parkinsonian syndrome [1][2][3] and gait impairment [4][5][6][7] are related to neuroimaging markers of cerebral small vessel disease (CSVD) such as white matter hyperintensity (WMH), lacunes, cerebral microbleeds (CMB), and brain atrophy. In addition, Parkinsonian signs are associated with mortality [8]. A cross-sectional study showed that motor deficits of upper and lower extremities are associated with CSVD, especially with WMH and brain atrophy [9]. Moreover, hypertension, as a cerebrovascular risk factor, is associated with decreased gait speed in the elderly population [10].
These studies were all conducted by neurologists or medical staff trained to assess motor deficits, which were time-and resource-consuming. Because of the very high rate of undiagnosed Parkinsonism, a screening method based on a questionnaire for patients' motor complaints was built and was proven to be effective in enhancing recognition of incipient Parkinsonism [11][12][13]. Considering that both neuroimaging changes of CSVD and motor deficits are highly prevalent in the general aging population, we hypothesize that the questionnaire for Parkinsonism-related motor complaints might also be useful in screening for CSVD in the general population. Therefore, we investigated the association among Parkinsonism-related motor complaints quantified using a questionnaire, neuroimaging markers of CSVD, and cerebrovascular risk factors in a population-based study.

Inclusion and exclusion criteria
Our study was based on the the Shunyi Study, a population-based prospective cohort study designed to investigate the risk factors and consequences of brain changes in community-dwelling adults in the Chinese population. Between June 2013 and April 2016, inhabitants from 5 villages of Shunyi, a suburb district of Beijing, who were 35 years or older and independently living, were invited to participate. Standard baseline assessments including structured questionnaires, physical examination, and laboratory tests were accomplished. We included participants accomplished MRI study and Tanner's standard questionnaire. Participants were excluded if they had a history of ischemic/hemorrhagic stroke or muscle strength less than 4 of any limb. Participants younger than 50 years old were also excluded since motor complaints were rarely seen in this group.
Imaging parameters MRI acquisition was performed from July 2014 to April 2016 using a single 3-Tesla Siemens Skyra scanner (Siemens, Erlangen, Germany). Three-dimensional T1-weighted images were acquired using magnetization-prepared rapid gradient-echo sequences in the sagittal

Definition of cerebrovascular risk factors
Hypertension was defined as blood pressure ≥ 140/90 mmHg; diabetes mellitus was defined as a fasting plasma glucose level ≥ 7.0 mmol/L or 2-h plasma glucose level ≥ 11.1 mmol/L during an oral glucose tolerance test; hyperlipidemia was defined as total cholesterol > 5.2 mmol/L or low-density lipoprotein > 2.58 mmol/L; and smoking was defined as an individual smoking at least 1 cigarette per day for more than 6 months before enrollment. was degree 2 or more. Automated segmentation of 3D-T1 images was used to obtain the probability maps of gray matter (GM), white matter [10], and cerebral spinal fluid (CSF). Total brain volume was than calculated as the sum of the volumes of GM, WM, and CSF. The brain parenchymal fraction (BPF) was defined as the ratio of total brain volume to intracranial volume. WMH, lacunes, CMBs, and PVS were independently rated by well-trained researchers who were blinded to the clinical data. Intra-rater agreement was assessed in a random sample

Assessment of motor function
Participants in the Shunyi cohort were all invited to a motor function assessment of upper and lower extremities[9]. Times for 3-m walking, 5-repeat chair-stand, 10-repeat pronation-supination, and 10-repeat finger-tapping were used in our study.

Statistical analysis
Continuous variables were expressed as mean and standardized deviation, and categorical variables were expressed as frequencies and proportions. All statistical analyses were performed using IBM-SPSS version 22.0.
Individuals were assigned into the motor complaint group if they had a score 1 or more on the questionnaire. Otherwise they were assigned to the no motor complaint group. Clinical characteristics and neuroimaging markers were compared between groups using student ttest for continuous variables and Chi-square test for dichotomous variables. General linear models were generated to compare each motor function parameters between groups.
Model 1 adjusted for age and sex. Model 2 adjusted for age, sex and cerebrovascular risk factors.
To investigate whether age and sex were risk factors of motor complaints, we generated a binary logistic regression model including age and sex as predictor variables and motor complaints as dependent variable. To determine the association between motor complaints and cerebrovascular risk factors, binary logistic regression models were built.
Model 1 adjusted for age and sex. Model 2 included age, sex, hypertension, diabetes, hyperlipidemia and smoking.
To determine whether neuroimaging markers of CSVD were risk factors of motor complaints, we generated two kinds of binary logistic regression models. years old were excluded since motor complaints were rarely seen in this age group. A total of 854 participants (male, 38.6%) were finally analyzed. The average age was 60.7 years old. Demographic, clinical and imaging markers are shown in Table 1. Based on our questionnaire, 133 (15.6%) individuals had at least one motor complaint. The most reported complaint on the questionnaire was having difficulty fastening buttons (6.1%). Table 2. Shows motor function parameters between the two groups. After adjusting for age and sex, finger-tapping time was positively associated with motor complaints Association between motor complaints and cerebrovascular risk factors are shown in Table   3. Hypertension was associated with motor complaints (odds ratio, The relationship between motor complaints and CSVD markers are shown in Table 4. No association was found between CSVD markers and motor complaints in both univariate analysis, multivariate analysis adjusting for age and sex, or multivariate analysis adjusting for age, sex, MMSE and cerebrovascular risk factors.

Discussion
Our study found that in a group of well-functioning, independently living, elderly adults in a Chinese rural area, individuals with Parkinsonism-related motor complaints had slower gait speed and slower finger-tapping. Parkinsonism-related motor complaints were associated with hypertension. No association was found between Parkinsonism-related motor complaints and CSVD markers or cerebrovascular risk factors (hypertension, diabetes, hyperlipidemia, and smoking).
When screening for incidence of Parkinsonism in a community population, questionnaires had higher sensitivity and lower specificity, and trained medical staff had lower sensitivity and higher specificity[12]. Tanner's standard questionnaire is the most widely tested and used questionnaire in screening Parkinsonism, with a very high sensitivity [12,13]. In our community sample, symptoms associated with bradykinesia and rigidity was found to be two of the most common motor complaints. When measured objectively, slower fingertapping, and slower 3m-walking speed, signs of bradykinesia, were found in the motor complaint group. These findings suggest that individuals with subjective motor complaints tend to have worse objectively measured motor performance.
Among all cerebrovascular risk factors, hypertension was found to be associated with motor complaints. In previous studies, Pinter et al. found that age, gender and hypertension were the major predicting factors of gait velocity [5], and Rosano et al. found that hypertension speeds up the gait velocity decline in well-functioning elderly populations[10]. These findings were in agreement with our results. This result could not be explained by structural CSVD brain changes since no association was found between CSVD markers and motor complaints. Subclinical damages of the peripheral vessels, nerves, bones, and muscles due to hypertension might be the cause of motor complaints[10, 17]. Although age was proven to be associated with signs of Parkinsonism[8] and showed a tendency of association with Parkinsonism-related motor complaints when only adjusting for sex, no statistically significant association was found after additional adjustment of cerebrovascular risk factors. The reason might be that elderly people often attribute the decline of their motor performance to aging rather than report them as motor complaints.
No association was found between CSVD markers and motor complaints in univariate analysis and multivariate analysis adjusting only for age and sex or adjusting for age, sex, MMSE and cerebrovascular risk factors (hypertension, diabetes, hyperlipidemia, and smoking). Hence, the questionnaire, which aimed for Parkinsonism, is not suitable to screen CSVD in community-dwelling population.
A few studies have focused on the CSVD markers and motor disorders. In the LADIS study, WMH was associated with worse gait and balance cross-sectionally[18], and a more severe baseline WMH was associated with worse gait and balance in the follow up [19]. In the RUN-DMC study, WMH, lacunes, and CMBs were all found to be independently associated with gait disorders [4,10]. WMH and lacunes were found to be associated with mild parkinsonism syndrome [3]. In a study conducted by Reiz et al., large WMH and lacunes were related with increased risk of resting tremor, and brain atrophy was related with increased risk of rigidity and bradykinesia [1]. In another study conducted by Hatate et al., people with at least one cerebrovascular risk factors were included and WMH, lacunes, CMB, and total CSVD burden scores were all associated with higher incidence of mild Parkinsonism syndrome [2]. However, unlike in the studies above [1,2,20,21], since we partly included people without any cerebrovascular risk factors and excluded people who with a history of ischemic or hemorrhagic stroke, the prevalence of CSVD and cerebrovascular risk factors were lower in our study population. As observed among the elderly population, subjective motor complaints do not increase proportionately with objectively worsened motor performance. Thus, the association between CSVD markers and motor complaints may be weakened.
Motor disorders, especially declining gait speed, were proven to impair the ability for independently living and increase the risk of institutionalization and mortality [22][23][24].
Although motor complaints may not coincide with objectively measured motor deficits, they directly limit daily activities, generate sedentary lifestyles, and promote cerebrovascular risk factors. Therefore, the association between motor complaints and cerebrovascular risk factors reinforces itself in a vicious circle. Screening for those who are at risk and controlling the risk factors would prevent them from falling into that vicious circle, improve their quality of living and reduce the cost of health care.
The strength of our study is the inclusion of a large sample of community-dwelling population. In addition, it is the first study focusing on association of Parkinsonismrelated motor complaints with cerebrovascular risk factors and CSVD.
There are three limitations to be considered. First, the questionnaire we used was designed to screen Parkinsonism-related motor disorders. It could not evaluate motor deficits that generates from non-CNS diseases such as arthritis, myopathy, or peripheral neuropathy. Second, we excluded individuals who had a history of ischemic or hemorrhagic stroke. Considering the high prevalence of cerebrovascular disease among the elderly, our study may underestimate the prevalence and severity of both CSVD and motor complaints, which kept us from generalizing our results to the total elderly population. Third, we did not look further into the time course, degree, and control of hypertension. We hope that future studies would explore this further.

Conclusion
We found that in a group of well-functioning, independently living elderly population from a Chinese rural area, Parkinsonism-related motor complaints were associated with hypertension. No association was found between motor complaint and age or CSVD markers. Tanner's standard questionnaire for parkinsonism is not suitable for screening of CSVD in a community-dwelling population.

Ethics approval and consent to participate
The Shunyi study was approved by the Ethical Committee at Peking Union Medical College Hospital (reference number: B-160).

Consent for publication
Written informed consent were obtained from all participants during inclusion process.

Availability of data and materials
The datasets used and analyzed during the current study are available from corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.   Figure 1 Study profile.