Association of Postural Instability With Asymptomatic Cerebrovascular Damage and Cognitive Decline
The Japan Shimanami Health Promoting Program Study
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Abstract
Background and Purpose—Asymptomatic cerebral small-vessel disease (cSVD) in elderly individuals are potent risk factors for stroke. In addition to common clinical risk factors, postural instability has been postulated to be associated with cSVD in older frail patients. Here, we conducted a cross-sectional study to understand the possible link between postural instability and asymptomatic cSVD further, namely periventricular hyperintensity, lacunar infarction, and microbleeds, as well as cognitive function, in a middle-aged to elderly general population (n=1387).
Methods—Postural instability was assessed based on one-leg standing time (OLST) and posturography findings. cSVD was evaluated by brain magnetic resonance imaging. Mild cognitive impairment was assessed using a computer-based questionnaire, and carotid intima-media thickness as an index of atherosclerosis was measured via ultrasonography.
Results—Frequency of short OLST, in particular <20 s, increased linearly with severity of cSVD (lacunar infarction lesion: none, 9.7%; 1, 16.0%; >2, 34.5%; microbleeds lesion: none, 10.1%; 1, 15.3%; >2, 30.0%; periventricular hyperintensity grade: 0, 5.7%; 1, 11.5%; >2, 23.7%). The association of short OLST with lacunar infarction and microbleeds but not periventricular hyperintensity remained significant even after adjustment for possible covariates (lacunar infarction, P=0.009; microbleeds, P=0.003; periventricular hyperintensity, P=0.601). In contrast, no significant association was found between posturographic parameters and cSVD, whereas these parameters were linearly associated with OLST. Short OLST was also significantly associated with reduced cognitive function independent of covariates, including cSVD (P=0.002).
Conclusions—Postural instability was found to be associated with early pathological changes in the brain and functional decline, even in apparently healthy subjects.
Introduction
Brain magnetic resonance imaging (MRI) in elderly individuals frequently detects asymptomatic cerebral small-vessel disease (cSVD), such as small infarction in the perforator territory (namely lacunar infarction) and periventricular hyperintensity (PVH).1,2 Frequency of lacunar infarction and PVH has been reported to increase with age, potentially indicating strong risk of future symptomatic stroke.3,4 In addition to these ischemic pathological changes, microbleeds—minor blood leakage through damaged blood vessels detectable via gradient-echo T2*-weighted MRI—are observed relatively frequently in the general population5 and have also been suggested to be a risk factor for stroke6,7 and stroke-related mortality.8 cSVDs arise from age- and hypertension-related small-vessel damage that shares cerebral amyloid angiopathy as a common cause.9
In addition to these clinical risk factors and pathogenesis, postural instability in the elderly has also been postulated to be associated with cSVD, particularly with PVH.10 Reduced physical activity, which includes postural instability as a component, has been suggested to be associated with cSVD in observational analysis11,12 and in longitudinal studies.13,14 Although the study population in these previous studies numbered <700 individuals, a large-scale longitudinal study (the Cardiovascular Health Study) provided further support for the relationship between physical inactivity and subclinical brain MRI abnormalities in community-dwelling adults aged ≥65 years.15,16 However, these studies were based on elderly subjects, with no results available for middle-aged individuals, despite the fact that cSVD can be detected in middle age.1 Furthermore, only 1 study16 has examined the association between lacunar infarction and postural instability, and no data are available on the association between microbleeds and postural instability, despite individuals with lacunar infarction and PVH being frequently complicated with microbleeds.17
Here, we conducted a cross-sectional study to understand the possible link between postural instability and asymptomatic cSVDs further—namely, PVH, lacunar infarction, and microbleeds—in a middle-aged to elderly general population. As we previously showed that individuals with mild cognitive impairment, particularly those with Alzheimer disease, were prone to instability while standing on 1 leg,18 we attempted to gather more evidence in the present study.
Methods
Study Subjects
The study subjects were 1387 apparently healthy middle-aged to elderly individuals who were consecutive participants in the medical checkup program at Ehime University Hospital Anti-aging Center from February 2006 to June 2013. This medical checkup is provided to general residents of Ehime Prefecture, Japan, and is specifically designed to evaluate aging-related disorders, including atherosclerosis, cardiovascular disease, physical function, and mild cognitive impairment.19,20 A full list of clinical parameters measured in the medical checkup program is presented in Table I in the online-only Data Supplement. Evaluation of diagnostic and prognostic significance of postural instability was an initially planned study theme.18
Recruitment was performed via mass communications, such as internet homepages, periodical newspapers in the local community, and commercial newspapers, and a total of 1816 individuals gave written informed consent to this study. Of the 1691 middle-aged to elderly individuals aged ≥50 years at enrollment, those who were free from symptomatic stroke (n=1619), underwent brain MRI (n=1417), were not taking drugs for dementia or dizziness (n=1398), were not taking insulin therapy (n=1393), and completed all clinical measurements used in this study (n=1387) were ultimately included in this analysis. Brain MRI was provided as an optional examination for who requested to undergo such a procedure. All participants were physically independent and completed all clinical measurements.
The present study was part of a series of the Japan Shimanami Health Promoting Program (the J-SHIPP study), which was approved by the ethics committee of Ehime University Graduate School of Medicine.
Assessment of Postural Instability
One-leg standing time (OLST) with eyes open was used as an index of postural stability, with the leg selected by the subject. Time interval until the raised leg was put down was measured twice, with a maximum time of 60 s allowed. The better of the 2× was used for statistical analysis.
Postural instability was also measured using a posturograph (Gravicorder G-5500; Anima Inc, Tokyo, Japan) consisting of an equilateral triangular footplate with 3 built-in vertical force transducers to determine instantaneous fluctuations in the center of pressure. Signals were processed by a DC amplifier and low-pass filters (cutoff frequency 10 Hz) and stored in a computer after analog-digital conversion at a sampling rate of 20 Hz. Subjects were instructed to maintain a static upright posture on the footplate with their feet together while watching a circular achromatic target placed 200 cm ahead of their eye point. Data were acquired for 1 minute, beginning after the subject’s posture had stabilized. The subject then rested for 1 minute while seated, after which the measurement was repeated with the eyes closed to assess the effects of visual feedback on postural stability. All measurements were performed barefoot with both arms held at the side of the body. Path length and circumferential area of the center of pressure movement were considered parameters for movement of center of gravity and used as indices of postural stability.
MRI and Assessment of Silent Cerebral Damage
The presence of cSVDs, including lacunar infarctions, PVH, and microbleeds, was evaluated based on findings on brain MRI with a 3-tesla scanner (Signa Excite 3.0T; GE Healthcare, Milwaukee, WI). MRI was performed within ≈1 month before the clinical measurements (mean, 19±10 days). The following images parallel to the orbitomeatal line were obtained: T1-weighted axial images (repetition time, 2000.0 ms; echo time, 16.0 ms; thickness, 6.0 mm; gap, 1.0 mm; matrix, 288×224), T2-weighted axial images (repetition time, 4800.0 ms; echo time, 92.0 ms; thickness, 6.0 mm; gap, 1.0 mm; matrix, 512×256), fluid-attenuated inversion recovery images (repetition time, 11000.0 ms; echo time, 140.0 ms; thickness, 6.0 mm; gap, 1.0 mm; matrix, 288×224), and gradient-echo (T2*-weighted) images (repetition time, 600.0 ms; echo time, 7.2 ms; thickness, 6.0 mm; gap, 1.0 mm; matrix, 320×192).
Lacunar infarction was defined as areas of low signal intensity (3- to 15-mm diameter) on T1-weighted images and of high intensity on T2-weighted and fluid-attenuated inversion recovery images. Microbleeds were defined as small (2- to 5-mm diameter) hypointense lesions on T2*-weighted images. Such lesions within the subarachnoid space and areas of symmetrical hypointensity in the globus pallidus on T2*-weighted images were considered likely to represent adjacent pial blood vessels and calcifications, respectively, and were therefore ignored. PVH were defined as white matter hyperintensities depicted on T2-weighted and fluid-attenuated inversion recovery images in contact with the ventricular wall. PVH was further classified into 5 grades according to a scale developed by Shinohara et al21 and later modified and published as a guideline by the Japan Brain Dock Society, as follows: grade 0, absent or only a rim; grade 1, limited lesion-like caps; grade 2, irregular halo; grade 3, irregular margins and extension into the deep white matter; and grade 4, extension into the deep white matter and subcortical portion. PVH grade ≥2 was considered a pathological condition according to the guideline, as well as based on our previous findings indicating a greater frequency of left ventricular hypertrophy22 and microbleeds23 in subjects showing PVH grade ≥2 than in those with lower scores. Imaging analysis was performed by neurologists without clinical information on the subject. Images were analyzed using OsiriX software (http://www.osirix-viewer.com).24
Assessment of Mild Cognitive Impairment
mild cognitive impairment was assessed using a Touch Panel-type Dementia Assessment Scale (TDAS), which was specifically designed to rate cognitive dysfunction quickly and without the need for a special rater.25 This test battery consists of the following 4 tasks, which were performed in a fixed order: a 3-word memory test for assessing immediate memory, temporal orientation test, 3-dimensional visual-spatial perception test, and delayed recall test for assessing short-term memory. The TDAS provides for a maximum score of 15 points, and a score of 13 was suggested as a cutoff point in discriminating cognitive impairment in a previous study.25 Details of this rating system have been described elsewhere.25
Arterial Parameters
We measured carotid intima-media thickness (IMT) as an index of arteriosclerosis. To measure IMT, ultrasonography of the common carotid artery was performed using an SSD-3500SV or α10 ultrasonograph (Aloka Co, Ltd, Tokyo, Japan) with a 7.5-MHz probe. After 5- minute resting in the supine position, optical visualization of the bilateral carotid arteries was obtained with the subject’s head tilted slightly upward in the midline position. IMT of the far wall was measured from B-mode images using onboard computerized software, which simultaneously measured IMT at 3 points at 1-cm intervals. Nine IMTs of the far wall were measured at 1-cm intervals proximal to the bulb from the anterior, lateral, and posterior approaches. Mean IMT calculated from the 9 readings was used in the analysis. No measurements were taken at the discrete plaque level.
Basic Clinical Parameters
Basic clinical parameters used in this study were measured through the medical checkup program. Brachial blood pressure was measured after 5-minute resting in the sitting position (HEM-9000AI; Omron Healthcare, Kyoto, Japan). Hypertension was defined as either or both systolic blood pressure ≥140 mm Hg or diastolic BP ≥90 mm Hg, or taking antihypertensive drugs. Type 2 diabetes mellitus was defined as any or all of the following: plasma glucose ≥126 mg/dL, glycohemoblobin A1c ≥6.5%, or taking antihyperglycemic drugs.
Statistical Analysis
Differences in numeric variables were assessed by ANOVA, whereas frequency difference was assessed by a χ2 test. Covariate adjusted analysis was performed by linear regression analysis. Factors independently associated with number or grade of cSVDs were assessed by a Poisson regression analysis, whereas a Tobit model with Weibull distribution was used in the multivariate analysis for OLST. Statistical analyses were conducted using commercially available statistical software (JMP version 9.0.2; SAS Institute Inc, Cary, NC) or the free R software (R version 3.0.2. http://www.r-project.org), with P<0.05 considered statistically significant.
Results
Clinical characteristics of the study subjects are shown in Table 1. Differences in the clinical parameters by the presence of cSVD are summarized in Table 2. Subjects with any cSVD tended to be older, more frequently hypertensive, and had higher carotid IMT than those without.
Clinical Characteristics of Study Subjects (n=1387)
Differences in Clinical Parameters Based on the Presence of cSVD
Frequency of short OLST, particularly OLST <20 s, increased linearly with number of lacunar infarctions (P<0.001), number of microbleeds (P=0.023), and PVH grade (P<0.001; Figure 1). Therefore, we used OLST 20 s as a cutoff point. Although several clinical parameters differ based on the presence of cSVD (Table 2), the associations of short OLST with lacunar infarction and microbleeds but not PVH remain significant even after adjustment for the covariates (Table 3). These associations were also found in a subanalysis with elderly subjects (≥65 years; lacunar infarction, P=0.007; microbleeds, P=0.021; PVH, P=0.653). However, conversely, existence of cSVD was not identified as an independent determinant for OLST (lacunar infarction, P=0.717; microbleeds, P=0.737; PVH, P=0.347) on Tobit regression analysis adjusted for age, sex, body mass index, current smoking, neuropsychiatric medication, hypertension, type 2 diabetes mellitus, and carotid IMT. Age and body mass index were identified as major determinants for OLST (P<0.001).
Poisson Regression Analysis for Cerebral Small-Vessel Disease
A–C, Association between cerebral small-vessel diseases and one-leg standing time (OLST). Number of each subgroup is shown in parentheses.
A significant linear correlation was noted between OLST and posturographic parameters for center of gravity movement (Table 4). However, although the posturographic parameters differed significantly based on the presence of cSVD in crude analysis, these associations disappeared in the covariates-adjusted analysis (Table 4).
Associations Between cSVD and Posturographic Parameters
Association between OLST and cognitive function is illustrated in Figure 2. Short OLST was significantly associated with lower TDAS score (Figure 2) and vice versa (ie, individuals with TDAS score <13 points had significantly shorter mean OLST than subjects with higher scores; 44.9±20.9 versus 52.4±15.9 s; P<0.001 [Tobit regression analysis]). Although subjects with cSVD had significantly lower TDAS scores overall (lacunar infarction, 14.0±1.5 versus 14.2±1.0; P=0.007; microbleeds, 14.0±1.4 versus 14.2±1.1; P=0.038; and PVH, 13.9±1.4 versus 14.3±1.0; P<0.001), the association of short OLST with TDAS score was independent of possible covariates, including cSVD (Figure 2). We included lacunar infarction, micobleeds, and PVH in a same regression model. However, no severe collinearity was detected among these factors (variation inflation factor: lacunar infarction; 1.16; microbleeds, 1.14; and PVH, 1.30).
Association of short one-leg standing time (OLST) and cognitive function. Multiple linear regression analysis for Touch Panel-type Dementia Assessment Scale (TDAS) score was performed with adjustment for age, sex, body mass index, hypertension, type 2 diabetes mellitus, neuropsychiatric medication, carotid intima-media thickness, number of lacunar infarctions, periventricular hyperintensity grade, and number of microbleeds.
Discussion
In the present study, we showed that short OLST (<20 s) but not posturographic parameters for center of gravity movement was significantly associated with cSVDs in an apparently healthy general population of middle-aged to elderly individuals. To our knowledge, this is the first study reporting the independent association of OLST with lacunar infarction and microbleeds, with the previously reported possible association of OLST with PVH not observed in our data set. Short OLST was also independently associated with impaired cognitive function.
The relationship between postural instability and PVH has been investigated in several studies,10–16 with results consistently supporting the positive relationship between the 2 parameters; however, few studies have been concluded on lacunar infarction, and even fewer on microbleeds. One strength of our present study was, therefore, the concomitant evaluation of cSVDs and findings of a positive association of postural instability with lacunar infarction and microbleeds. We also evaluated cognitive function and found a cSVD-independent association of postural instability with cognitive decline. Elucidation of postural instability as a factor for not only brain histological change but also functional decline was another strength of our study.
No significant association was found between postural instability and PVH, even in the subanalysis in elderly subjects although several previous studies have reported greater severity of PVH in subjects with short OLST or low physical function.11–14 Although reasons for the discrepancy are unclear, our results suggest that postural instability might not always be associated with PVH. Subtypes of first-ever stroke observed in both hospital-based or community-based longitudinal studies are known to differ significantly between Japanese population and whites in Western countries, with the Japanese proving more prone to hemorrhage stroke.26 Furthermore, the proportion of lacunar stroke to total ischemic stroke in Japan was higher than that reported in Western countries.27 Given these previous epidemiological data, some ethnic differences might be involved in the differences in relationships of physiological instability and PVH between our study population and whites. However, given the lack of supportive data, additional investigation will be required to clarify this issue.
Short OLST was independently associated with cSVDs and not vice versa. Because age and body mass index were only identified as a major significant determinant for OLST by Tobit regression analysis, OLST might be a strong function of age and anthropometric parameters and, therefore, cSVD might not be independently associated with OLST.
Marked cognitive decline was observed in subjects with short OLST. Although cSVDs was naturally associated with a relatively low TDAS score, the association between short OLST and cognitive decline was independent of the existence of cSVD. Previous studies have suggested that, in addition to the well-known risk factors, dementia increases risk of falls28–30 and fall-related bone fractures31 in elderly subjects, likely by impairing judgment, motor function, visual-spatial perception, and the ability to recognize and avoid hazards. Given the present findings, postural instability might also be a factor involved in the elevated incidence of falls in subjects with dementia.
OLST was strongly and inversely associated with age; as same in a previous study,32 marked shortening of OLST occurred in subjects aged ≥60 years; it was also strongly and age-independently associated with increasing center of gravity movement; however, no significant correlation was observed between posturographic parameters and cSVD. As posturographic measurements were performed with subjects in a static upright posture, greater difficulty of postural control in one-leg standing than in an upright position with feet together might be a reason for the relevance of short OLST, but not high posturographic parameters, to cSVD. Previous studies reported that gait dysfunction was a physical marker that was associated with brain white matter lesions14,33 and small infarction.34 Because gait consists of 3 primary components (balance, locomotion, and adaptation to the environment),35 the relevance of gait dysfunction to brain abnormalities further supports the importance of balance-function as a physical factor for cSVD.
Several limitations to the present study warrant mention. First, we measured postural instability using a posturograph for 60 s. Previous studies have suggested that 3 trials of 120-s measurements are needed to obtain reliable results36; as such, our findings for OLST may lead to underestimation. Second, we measure neither physical functions, such as gait speed or gait abnormality, nor history or incident of falls. These data would help further clarify the relationship between physical function and brain abnormalities, including impaired cognitive function. Third, the present study is a cross-sectional design. Additional longitudinal studies are, therefore, required to clarify the prognostic significance of postural instability.
Summary
Our data from community-dwelling residents identifies postural instability as a factor in early pathological changes in the brain and functional decline, even in apparently healthy subjects. In older individuals, comprehensive geriatric assessment of frailty has been reported useful in increasing hospitalized patient’s survival duration.37 Furthermore, complex intervention was reported to be useful in helping community-dwelling elderly people to live independently.38 Comprehensive geriatric assessment is usually defined as a multidimensional diagnostic process focused on determining medical, psychological, and functional capability of a frail older patient.39 Our findings incorporates postural instability as an important measure of comprehensive geriatric assessment, and individuals showing postural instability should subsequently receive increased attention because this instability may signal potential brain abnormalities and cognitive decline.
Acknowledgments
We thank Yoko Ochi and Hideka Fuyuki for their help in collecting clinical data.
Sources of Funding
This study was supported by Grants-in-Aid for Scientific Research from The Ministry of Education, Culture, Sports, Science and Technology of Japan; The Ministry of Health, Labour and Welfare of Japan; The Japan Arteriosclerosis Prevention Fund; and a Research Promotion Award from Ehime University.
Disclosures
None.
Footnotes
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.114.006704/-/DC1.
- Received July 8, 2014.
- Revision received October 6, 2014.
- Accepted October 24, 2014.
- © 2014 American Heart Association, Inc.
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- Association of Postural Instability With Asymptomatic Cerebrovascular Damage and Cognitive DeclineYasuharu Tabara, Yoko Okada, Maya Ohara, Eri Uetani, Tomoko Kido, Namiko Ochi, Tokihisa Nagai, Michiya Igase, Tetsuro Miki, Fumihiko Matsuda and Katsuhiko KoharaStroke. 2015;46:16-22, originally published December 18, 2014https://doi.org/10.1161/STROKEAHA.114.006704
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- Association of Postural Instability With Asymptomatic Cerebrovascular Damage and Cognitive DeclineYasuharu Tabara, Yoko Okada, Maya Ohara, Eri Uetani, Tomoko Kido, Namiko Ochi, Tokihisa Nagai, Michiya Igase, Tetsuro Miki, Fumihiko Matsuda and Katsuhiko KoharaStroke. 2015;46:16-22, originally published December 18, 2014https://doi.org/10.1161/STROKEAHA.114.006704