Lacunar Infarcts Rather than White Matter Hyperintensity as a Predictor of Future Higher Level Functional Decline: The Ohasama Study

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Lacunar Infarcts Rather than White Matter Hyperintensity as a Predictor of Future Higher Level Functional Decline: The Ohasama Study Megumi Tsubota-Utsugi, MPH, PhD,* Michihiro Satoh, PhD,† Naoki Tomita, MD, MPH, PhD,‡ Azusa Hara, PhD,§ Takeo Kondo, PhD,‖ Miki Hosaka, PhD,¶ Sho Saito, PhD,# Kei Asayama, MD, PhD,** Ryusuke Inoue, MD, PhD,†† Mikio Hirano, PhD,‡‡ Aya Hosokawa, PhD,§§ Keiko Murakami, MPH, DMsc,** Takahisa Murakami, DDS, PhD,† Hirohito Metoki, MD, PhD,† Masahiro Kikuya, MD, PhD,‖‖ Shin-Ichi Izumi, MD, PhD,‖ Yutaka Imai, MD, PhD,¶ and Takayoshi Ohkubo, MD, PhD,**

Objective: We aimed to determine the associations between silent cerebrovascular lesions, characterized by lacunar infarcts and white matter hyperintensity, and future decline in higher level functional capacity in older community-dwelling adults. Materials and Methods: For this observational study, we selected individuals from the general population of Ohasama, a rural Japanese community. Three hundred thirty-one participants who were free of functional decline at baseline and who were at least 60 years old underwent brain magnetic resonance imaging and answered a questionnaire on higher level functional capacity derived from the Tokyo Metropolitan Institute of Gerontology Index of Competence. We

From the *Department of Hygiene and Preventive Medicine, Iwate Medical University School of Medicine, Iwate, Japan; †Division of Public Health, Hygiene and Epidemiology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan; ‡Institute of Development, Aging and Cancer, Department of Geriatrics and Gerontology, Tohoku University, Sendai, Japan; §Department of Social Pharmacy and Public Health, Showa Pharmaceutical University, Tokyo, Japan; ‖Physical Medicine and Rehabilitation, Tohoku University Hospital, Sendai, Japan; ¶Department of Planning for Drug Development and Clinical Evaluation, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan; #Division of Aging and Geriatric Dentistry, Tohoku University Graduate School of Dentistry, Sendai, Japan; **Department of Hygiene and Public Health, Teikyo University School of Medicine, Tokyo, Japan; ††Department of Medical Informatics, Tohoku University Graduate School of Medicine, Sendai, Japan; ‡‡Department of Community Medical Support, Tohoku University, Sendai, Japan; §§Center for Gerontology and Social Science, National Center for Geriatrics and Gerontology, Aichi, Japan; ‖‖Tohoku Medical Megabank organization, Tohoku University, Sendai, Japan. Received July 25, 2016; revision received September 16, 2016; accepted September 22, 2016. Funding sources and related paper presentations: This study was supported by Grants for Scientific Research (JP23249036, JP23390171, JP24390084, JP24591060, JP24790654, JP25253059, JP25461083, JP25461205, JP25860156, JP26282200, JP26860093, JP16H05243, JP16K09472, JP16K11850, and JP16K15359) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan; a Grant-in-Aid from the Japan Society for the Promotion of Science (JSPS) fellows (25*7756, 25*9328, 26*857, and 27*656); the Japan Arteriosclerosis Prevention Fund; an Intramural Research Fund (22-4-5) for Cardiovascular Diseases of National Cerebral and Cardiovascular Center; and a Health Labor Sciences Research Grant (H26-Junkankitou [Seisaku]-Ippan-001) from the Ministry of Health, Labour and Welfare. Address correspondence to Megumi Tsubota-Utsugi, PhD, MPH, Department of Hygiene and Preventive Medicine, Iwate Medical University School of Medicine, 2-1-1 Nishitokuda, Yahaba-cho, Shiwa-gun, Iwate 028-3694, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.09.036

Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (), 2016: pp ■■–■■

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assessed the relationship between silent cerebrovascular lesions with a decline in higher level functional capacity at 7 years using multiple logistic regression analysis adjusted for possible confounding factors. Results: During the follow-up, 22.1% reported declines in higher level functional capacity. After adjustment for putative confounding factors, the presence of silent cerebrovascular lesions (odds ratio [95% confidence interval], 2.10 [1.05-4.21]) and both lacunar infarcts (2.04 [1.053.95]) and white matter hyperintensity (2.02 [1.02-3.95]) was significantly associated with the risk of functional decline at 7-year follow-up. In subscale analysis, specifically lacunar infarcts were strongly associated with the future risk of decline in intellectual activity (3.16 [1.27-7.84]). Conclusion: Silent cerebrovascular lesions are associated with future risk of decline in higher level functional capacity. Appropriate management of health risk factors to prevent silent cerebrovascular lesions may prevent higher level functional decline in the elderly population. Key Words: Functional capacity in early stage—elderly—Japanese—silent cerebrovascular lesions—lacunar infarcts—white matter hyperintensity. © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Introduction The Japanese population is rapidly aging; the percentage of individuals aged ≥65 years increased from 10.3% in 1985 to 20.1% in 2005.1 Concomitantly, there has been a noticeable increase in elderly people living with functional decline, which has an enormous effect on morbidity and mortality.2 A hierarchical model of functional and behavioral competence has been defined and systematized into seven stages by Lawton: life maintenance, functional health, perception and cognition, physical self-maintenance, instrumental self-maintenance (corresponding to instrumental activities of daily living [IADL]), intellectual activity (effectance), and social role performance.3,4 Impairment at any sublevel is more likely to impair the higher sublevels. Higher level functional capacity encompasses the complex abilities in the final three stages, that is, IADL, intellectual activity, and social role, which are crucial for maintaining socially independent living in later life; thus, it is imperative to identify the risks for and preventive factors associated with higher level functional decline in the elderly population. Silent cerebrovascular lesions, characterized by baseline lacunar infarcts and white matter hyperintensity (WMH), are frequently observed on magnetic resonance imaging (MRI) in the elderly. These lesions increase the risk of progression to clinically symptomatic stroke,5,6 kidney dysfunction,7 disability,8,9 motor and gait disturbance,10-13 cognitive impairment and dementia,14-20 and late-onset depression.21,22 Although functional decline can be due to multiple causes, it is unclear whether age-related silent cerebrovascular lesions without overt disease are related to future risk of early functional decline. Identifying the etiological factors related to loss of higher level functional capacity is important, both to corroborate causality between these lesions and functional decline and to highlight targets for preventing future deteriorations in activities of daily living (ADL).23,24 We aimed to clarify the relationship between baseline silent cerebrovascular lesions and declines in higher level

functional capacity in elderly community-dwelling Japanese adults after 7 years.

Materials and Methods The present study was a part of the Ohasama Study, a longitudinal community-based observational study in Ohasama, Iwate Prefecture, Japan. The details of the geographic and demographic characteristics of the study participants have been described previously.25,26 This study was approved by the Institutional Review Board of Tohoku University School of Medicine and by the Department of Health of the Ohasama Town Government. Written informed consent was provided prior to participation.

Participants We selected participants from the total population of Ohasama in 1998 (the study baseline). Initially, those aged 60 years or older were asked to complete queries of functional capacity, and the respondents who provided informed consent underwent MRI examinations from October 1, 1997 through March 23, 2001. Participants were excluded from the follow-up measurement for the following reasons: incomplete answers to the questionnaire at baseline; history of previous stroke or transient ischemic attack; nonindependent on baseline ADL evaluation (<1 point for the six-item physical function measurement of the Medical Outcomes Study Short Form General Health Survey)27,28; or low level of higher level functional capacity (<10 points for the 13-item Tokyo Metropolitan Institute of Gerontology Index of Competence [TMIG]).29 A follow-up study was conducted in 2005, between April 8 and May 20.

Brain MRI Brain MRI was performed using a 0.5 Tesla superconducting magnet. The brain was imaged on the axial

ARTICLE IN PRESS LACUNAR INFARCTS AND FUNCTIONAL CAPACITY IN ELDERLY

plane in 10-mm thick slices, and T1-weighted and T2weighted MR images were collected. A lacunar infarct was defined as an area of low signal intensity measuring ≤15 mm and ≥3 mm on T1-weighted images that was visible as a hyperintense lesion on T2-weighted images in a patient with no history of stroke or transient ischemic attack (TIA). Hyperintense punctuate lesions, evident only on the T2weighted images, were not considered lacunar infarcts. We defined WMH as hyperintensities on only T2-weighted images and graded them according to the method described by Fazekas et al, as follows30: absent (grade 0), punctate (grade 1), early confluent (grade 2), and confluent (grade 3). Small caps (<5 × 10 mm) on the horns of the lateral ventricles and pencil-thin linings around the ventricles were considered normal. Larger caps (≥5 × 10 mm) were considered grade 2. A neurosurgeon and four trained observers, directed by the neurosurgeon, independently evaluated the MRI findings. In the case of disagreement, a consensus reading was held. Both intra- and inter-reader studies (n = 111) showed good agreement; kappa statistics were between .68 and .86 for lacunar infarcts and between .72 and .86 for WMH. We defined silent cerebrovascular lesions as a WMH of grade 1 or more or the presence of lacunar infarcts.

Higher Level Functional Capacity Higher level functional capacity was measured using the TMIG index.5,24,29,31,32 The TMIG index comprises the following dimensions: IADL (five items: using public transportation, shopping, preparing meals, paying bills, and managing deposits), intellectual activity (four items: filling out forms, reading newspapers, reading books or magazines, and being interested in stories or programs addressing health), and social role (four items: visiting the homes of friends, being called on for advice, visiting sick friends, and initiating conversations with young people). The total score was the sum of the scores for the 13 items, with higher scores indicating higher levels of competence. The TMIG questionnaire is valid and reliable,31 and its high predictive validity was previously confirmed using 1-year mortality as a criterion variable.5,31 In the present study, we calculated changes in higher level functional capacity over a 7-year period by subtracting TMIG scores in 1998 from those in 2005. Then, we classified the participants into two groups: a “decline” group (TMIG deterioration, less than −1) and a “no decline” group (stable or improved, −1 or greater). This cutoff was based on a previous report, which observed that a variation of 1 point for the total TMIG index, and subscales of intellectual activity and social role scores, were within the range of possible measurement error.24 The three competence subscales were also divided into two groups: decline (less than −1) and no decline (−1 or greater) groups for intellectual activity and social role, and decline (less than 0) and no decline (0 or greater) for IADL.24

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Other Putative Confounding Variables Other putative confounding factors related to silent cerebrovascular lesions and functional capacity were taken into account for the following: demographic characteristics (age, sex, current marital status, living alone or with others, educational attainment, and current job), lifestyle habits (smoking and alcohol ingestion status, frequency of mild or vigorous physical activity, and sleep duration), dietary habits (taking supplements, having breakfast, eating regularly, having late-night snacks, and eating out), perception of health (self-rated health), and physical health (body mass index, use of medication for hypertension, hypercholesterolemia, and diabetes mellitus, and any history of cardiovascular disease). Because functional disability and cognitive impairment both increase with age,33,34 we also performed Mini-Mental State Examination (MMSE). Blood samples were collected with participants in a sitting position after a rest interval of approximately 30 minutes, between 09:00 and 11:00 or between 13:00 and 15:00; most participants had not fasted. Diabetes mellitus was defined as a random blood glucose ≥11.11 mmol/L (≥200 mg/dL), a glycosylated hemoglobin (HbA1c) ≥6.5% (based on the Japan Diabetes Society guidelines), use of medication for diabetes, or a history of diabetes mellitus. Hypercholesterolemia was defined as a total cholesterol ≥5.68 mmol/L (≥220 mg/dL), use of medication for hypercholesterolemia, or a history of hypercholesterolemia. Home blood pressure (home BP) was measured using the cuff-oscillometric method with an HEM701C monitor (Omron Healthcare Co. Ltd., Kyoto, Japan), which generated a digital display of both systolic blood pressure and diastolic blood pressure. The device has been validated35 and satisfies the criteria of the Association for the Advancement of Medical Instrumentation. Home BP was defined as the mean of all first measurements recorded during the 4-week period. Hypertension was defined as the use of antihypertensive medication or home BP values of ≥130/85 mmHg.

Statistical Analyses To examine the relationships of patient characteristics between participants and nonparticipants in the followup study and between the higher level functional decline and no decline groups, we used the chi-square or Fisher exact test for categorical data and the Student t-test for continuous data. A multiple logistic regression model was employed to clarify whether silent cerebrovascular lesions were associated with future declines in higher level functional capacity in older participants, with adjustment for other putative confounding variables. To improve the multivariate models, all variables with a univariate test P ≤ .10 were considered for inclusion as putative confounding variables. We performed subgroup analyses by sex and age group (<65/≥65 years) to explore associations related to these factors.

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Interaction was tested by introducing a multiplicative term into the main models. Moreover, two sensitivity analyses were performed to examine the influence of death and preclinical cases during follow-up, including death in the decline group and excluding those who reported being not fully independent at follow-up.36,37 For all analyses, statistical significance was set at an alpha level of <.05 for two-sided tests. All statistical analyses were performed using SAS software, version 9.3 (SAS Institute Inc, Cary, NC).

Results Participants and Descriptive Data Figure 1 presents a flow diagram of the present study. The total population of Ohasama was 7202 in 1998 (the study baseline); 2614 were 60 years or older. Of the 2348 who answered the questionnaire (response rate, 89.8%),35,38 532 participants gave informed consent and underwent MRI examinations in the period from October 1, 1997 through March 23, 2001. Overall, 201 participants were excluded from the follow-up measurement for the following reasons: incomplete questionnaire answers at baseline (n = 59); history of previous stroke or transient ischemic attack (n = 46); nonindependent according to baseline ADL (n = 29); low levels of higher level functional capacity (n = 27); death (n = 17); relocation (n = 1); and choosing not to participate in the follow-up study (n = 22). Finally, data from 331 individuals (mean age of 66.1 years; 28.4% men) were analyzed.

Changes in Higher Level Functional Capacity During the 7-year follow-up, declines in higher level functional capacity were reported at the following rates: total TMIG score, 22.1% (n = 60); IADL, 16.9% (n = 48); intellectual activity, 8.5% (n = 26); and social role, 6.4%

1998

(n = 20). There were no differences in any type of higher level functional decline between men and women. Table 1 shows the baseline characteristics of the participants and nonparticipants in the present study, and the groups with and without a decline in higher functioning in the follow-up study. The participants were younger, and had higher IADL scores and a lower prevalence of hypertension and silent cerebrovascular lesions (lacunar infarcts and WMH). However, those who developed a decline in higher functioning during followup were older, slept longer, had poorer self-rated health, and a higher prevalence of hypertension, cardiovascular disease, and silent cerebrovascular lesions (lacunar infarcts and WMH).

Silent Cerebrovascular Lesions and Risk of Higher Level Functional Decline Table 2 shows the association between silent cerebrovascular lesions and the future risk of higher level functional decline. The following were identified and included as putative confounding factors: sex (male or female), age (5-year age bands), current marital status (presence of a spouse: yes or no), educational attainment (<10 or ≥10 years), sleep duration (<7, 7-9, or >9 hours/day), self-rated health (excellent, good to fair, or poor), hypertension (yes or no), history of cardiovascular disease (yes or no), and cognitive impairment (<24 or ≥24 on the MMSE).39,40 Multiple logistic regression analysis revealed that silent cerebrovascular lesions (odds ratio [95% confidence interval], 2.10 [1.05-4.21]) and both lacunar infarcts (2.04 [1.05-3.95]) and WMH (2.02 [1.04-3.94]) were independently associated with future higher level functional decline, based on the total TMIG score. Silent cerebrovascular lesions and WMH were not significantly associated with decline in each of the TMIG subscales, whereas lacunar

2,614 eligible subjects, aged >60 yrs, invited to participate in the Ohasama study

2,348 answered the questionnaire (response rate 89.8%)

532 subjects who underwent the MRI in 1998

2005

371 eligible to participate in the follow-up study

331 participated in the follow-up study

161 excluded 102 ineligible: 46 history of previous stroke or transient ischemic attack 29 not fully independent in basal ADL 27 TMIG < 10 59 incomplete answers

40 excluded 17 died 1 moved 22 unwilling to participate in the follow-up study

Figure 1. Flowchart of study participants included in the present analysis of the Ohasama Study, Japan, 1998-2005. Abbreviations: ADL, activities of daily living; TMIG, Tokyo Metropolitan Institute of Gerontology Index of Competence; WMH, white matter hyperintensity.

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Table 1. Baseline characteristics of participants in higher level functional decline and no decline groups in total TMIG score; Ohasama Study, Japan, 1998 Follow-up study (n = 371)

No. of participants Age, y Male, % Married, % Living alone, % Educational attainment <10 years, % Current job, % Current smokers, % Current users of alcohol, % Vigorous leisure-time physical activity such as tennis or jogging, <1 h/wk, % Mild leisure-time physical activity such as walking, <1 h/day, % Sleep duration, % Short time, <7 h/day Long time, ≥9 h/day Self-rated health, poor, % Dietary habits, % Supplements use Breakfast Late-night snack, ≥1 time (s)/wk Eating regularly Eating out, ≥1 time (s)/wk Hypertension, % Hypercholesterolemia, % Diabetes, % Past history of cardiovascular disease, % Body mass index in kg/m2, % Underweight, <18.5 Overweight, ≥25.0 Total TMIG score IADL Intellectual activity Social role MMSE Presence of silent brain infarction, % Silent cerebrovascular lesion Lacunar infarcts White matter hyperintensity

Total TMIG score (n = 331) P value*

No decline

Decline†

P value‡

40 68.9 (5.5) 16 (40.0) 36 (90.0) 4 (10.0) 36 (90.0)

<.001 .129 .586 .483 .341

271 65.6 (4.5) 74 (7.3) 254 (93.7) 19 (7.0) 220 (81.2)

60 68.2 (5.3) 20 (33.3) 52 (86.7) 4 (6.7) 59 (98.3)

<.001 .349 .061 .924 .001

284 (85.8) 32 (9.7) 98 (29.6) 256 (77.3)

33 (82.5) 9 (22.5) 14 (35.0) 27 (67.5)

.576 .046 .752 .383

236 (87.1) 25 (9.2) 81 (29.9) 204 (75.3)

48 (80.0) 7 (11.7) 17 (28.3) 52 (86.7)

.155 .820 .959 .106

60 (18.1)

8 (20.0)

.233

46 (17.0)

14 (23.3)

.286

57 (17.2) 58 (17.5) 91 (27.5)

5 (12.5) 12 (30.0) 15 (37.5)

.186

47 (17.3) 36 (13.3) 66 (24.4)

10 (16.7) 22 (36.7) 25 (41.7)

.007

96 (29.0) 324 (97.9) 25 (7.6)

16 (40.0) 39 (97.5) 1 (2.5)

.152 .874 .237

83 (30.6) 266 (98.2) 21 (7.8)

13 (21.7) 58 (96.7) 4 (6.7)

.166 .468 .774

260 (78.6) 55 (16.6) 177 (53.5) 124 (37.5) 49 (14.8) 27 (8.2)

34 (85.0) 6 (15.0) 29 (72.5) 11 (27.5) 5 (12.5) 3 (7.5)

.342 .795 .022 .216 .696 .886

214 (79.0) 48 (17.7) 137 (50.6) 103 (38.0) 40 (17.8) 16 (5.9)

46 (76.7) 7 (11.7) 40 (66.7) 21 (35.0) 9 (15.0) 11 (18.3)

.695 .255 .024 .663 .962 .002

20 (6.0) 102 (30.8) 12.4 (.1) 5.0 (.2) 3.6 (.7) 3.8 (.5) 26.6 (3.8)

6 (15.0) 8 (20.0) 12.3 (.2) 4.9 (.3) 3.6 (.8) 3.8 (.6) 26.2 (3.3)

.462 .018 .740 .967 .569

16 (5.9) 81 (30.0) 12.4 (1.0) 5.0 (.0) 3.6 (.0) 3.8 (.0) 26.8 (3.3)

4 (6.7) 21 (35.0) 12.5 (.9) 5.0 (.0) 3.6 (.1) 3.9 (.1) 25.5 (5.6)

.604 .747 .849 .177 .014

159 (48.0) 87 (26.3) 136 (41.1)

28 (70.0) 19 (47.5) 26 (65.0)

.009 .005 .004

117 (43.2) 59 (21.8) 100 (36.9)

42 (70.0) 28 (46.7) 36 (60.0)

<.001 <.001 .001

Participants

Nonparticipants

331 66.1 (4.7) 94 (28.4) 306 (92.5) 23 (6.9) 279 (84.3)

<.001

.153

.064

.694

Abbreviations: IADL, instrumental activity of daily living; MMSE, Mini-Mental State Examination; SD, standard deviation; TMIG, Tokyo Metropolitan Institute of Gerontology Index of Competence. Results are expressed as mean (SD). *Obtained by t-test for continuous variables and chi-square or Fisher exact test for categorical variables, comparing participants and nonparticipants. †Changes in higher level functional capacity during the 7-year period were calculated by subtracting the sum of the TMIG score in 1998 from that in 2005. Participants were classified into two groups: decline (TMIG change less than −1) and no decline (stable or improved) (TMIG change –1 or greater). ‡Obtained by t-test for continuous variables and chi-square or Fisher exact test for categorical variables, comparing decline and no decline groups.

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Table 2. Adjusted odds ratios for the association between the presence of silent cerebrovascular lesions, lacunar infarct, and WMH and future risk for higher level functional decline† in the Ohasama Study, Japan, 1998-2005 Silent cerebrovascular lesions (versus absent) Decline/No decline

OR (95% CI)*

P value

WMH (versus grade 0)

OR (95% CI)

P value

OR (95% CI)

P value

.036

2.04 (1.05-3.95)

.034

2.02 (1.04-3.94)

.038

.349 .120 .503

1.40 (.69-2.87) 3.16 (1.27-7.84) 1.65 (.59-4.58)

.356 .013 .340

1.46 (.72-2.99) 1.46 (.57-3.72) 1.96 (.69-5.60)

.296 .432 .207

.063

2.06 (1.12-3.77)

.020

1.71 (.93-3.14)

.085

.426 .203 .579

1.51 (.80-2.84) 2.92 (1.39-6.14) 1.88 (.86-4.11)

.203 .005 .116

1.31 (.69-2.46) 1.18 (.55-2.53) 1.40 (.63-3.10)

.410 .670 .410

.013

2.90 (1.37-6.12)

.005

2.66 (1.22-5.80)

.014

.831 .053 .265

1.69 (.74-3.88) 3.86 (1.37-10.85) 3.22 (.83-12.52)

.215 .010 .091

1.19 (.51-2.78) 2.14 (.73-6.30) 3.95 (.89-17.58)

.693 .167 .071 M. TSUBOTA-UTSUGI ET AL.

Abbreviations: CI, confidence interval; IADL, instrumental activities of daily living; OR, odds ratio; TMIG, Tokyo Metropolitan Institute of Gerontology Index of Competence; WMH, white matter hyperintensity. *Adjusted for sex (male/female), age (every 5 years), educational attainment (<10/≥10 years), current marital status (presence of a spouse: yes or no), sleep duration (<7, 7-9, or >9 hours/day), self-rated health (excellent, good to fair, or poor), hypertension, history of cardiovascular disease, and Mini-Mental State Examination score (<24/≥24). †Changes in higher level functional capacity during the 7-year period were calculated by subtracting the sum of the TMIG score in 1998 from that in 2005. Participants were classified into two groups: decline (TMIG change less than −1) and no decline (stable or improved) (TMIG change −1 or greater).

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Main model (n = 331) Total TMIG score 60/271 2.10 (1.05-4.21) Subscale of TMIG score IADL 48/283 1.43 (.68-3.00) Intellectual activity 26/305 2.22 (.81-6.07) Social role 20/311 1.45 (.49-4.26) Including death in the decline group (n = 348) Total TMIG score 77/271 1.82 (.97-3.43) Subscale of TMIG score IADL 65/283 1.31 (.68-2.54) Intellectual activity 43/305 1.69 (.75-3.79) Social role 37/311 1.27 (.55-2.95) Excluding individuals who reported not fully independent in basic ADL at follow-up (n = 303) Total TMIG score 43/260 2.81 (1.25-6.31) Subscale of TMIG score IADL 32/271 1.10 (.46-2.61) Intellectual activity 20/283 3.20 (.99-10.37) Social role 11/292 2.37 (.52-10.79)

Lacunar infarcts (versus none)

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infarcts were strongly related to decline in intellectual activity (3.16 [1.27-7.84]). The risk trends in the subgroup analyses indicated that, with silent cerebrovascular lesions, the risk of future higher level functional decline was only significant among women (2.51 [1.08-5.80]) and younger participants (<65 years) (5.93 [1.34-26.30]), with significant interactions observed in the age group for silent cerebrovascular lesions (P = .027). After excluding individuals who scored <24 on the MMSE (n = 33), only lacunar infarcts were significantly associated with a decline in intellectual activity (2.93 [1.16-7.42]), but no interaction was observed (P = .971). Additional sensitivity analyses, which included death in the decline group and excluded individuals who were not fully independent at follow-up, strengthened and altered the significant results. Only lacunar infarcts were significantly associated with a decline in the total TMIG score for the analyses including death in the decline group (2.06 [1.12-3.77]). However, all MRI measurements were associated with future higher level functional decline, based on the total TMIG score in the analyses excluding individuals who were not fully independent at follow-up (silent cerebrovascular lesions: 2.81 [1.25-6.31]; lacunar infarcts: 2.90 [1.37-6.12]; and WMH: 2.66 [1.22-5.80]). When we adjusted for the baseline total TMIG score, the results were comparable. No participants died in the first 2 years of follow-up.

Discussion The current study found that silent cerebrovascular lesions, both lacunar infarcts and WMH, were associated with a risk of future higher level functional decline. For each subscale analysis, only lacunar infarcts predicted future decline in intellectual activity. These results are consistent with previous studies demonstrating a positive association between lacunar infarcts and white matter changes on MRI and risk of disability.8-11 However, these studies measured disability by assessing basic activities of daily living, such as feeding, bathing, dressing, toileting, transferring, continence, gait impairment, or cognitive function, rather than functional capacity at the early stage of disability. To the best of our knowledge, this is the first study to clarify whether silent cerebrovascular lesions predict higher level functional decline above basic activities of daily living. Within the subscales of silent cerebrovascular lesions, only lacunar infarcts were associated with a decline in future intellectual activity at 7-year follow up. This result seems consistent with previous studies indicating lacunar infarcts predict a decline of cognitive function, through decreasing information processing speed, executive function, and primary memory,14,16-19 because a previous study reported that the intellectual activity was most likely to be impaired in the mild cognitive decline among subscales of the TMIG.41 Unlike other subscales of TMIG (IADL

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and social role), the intellectual activity domain assesses cognitively stimulating activities, such as filling out pension forms, reading newspapers, books, or magazines, and being interested in stories or programs dealing with health, which relate to interest in basic human needs and surroundings and motivation to create and explore.3,4,42 Lacunar infarcts might better reflect a decline in motivation, interest, and reaction to the environment than WMH. Although the exact role of the location of lacunar infarcts in early-stage functional decline and the complex interaction of brain networks involved in maintaining functional capacity with silent cerebrovascular lesions’ tract remain unclear, lacunar infarcts in the thalamus would therefore cause the deterioration of both speed and motor control but not memory performance.19 In the present study, both lacunar infarcts and WMH were associated with deteriorating future higher level functional capacity that can lead to deteriorations in ADL.23,24 Significant associations were particularly observed in women and in younger participants. Previous studies have commented that women showed more marked progression of subcortical lacunar infarcts and WMH than did men.43,44 On the other hand, any association with sex disappeared after adjusting for age in the WMH group. The significant interactions between age and silent cerebrovascular lesions suggest that the impact of silent cerebrovascular lesions and the risk to higher level functional capacity were greater in the younger population. Early prevention for intellectual activity is also important to prevent future stroke incidence,45 as well as future disability and cognitive decline.46-48 It is possible to improve ADL function, even among those with low baseline ADL levels,36 and those improvements were greatest among younger participants.49 High-level functional capacity might not decline linearly, and may in fact improve with age. Therefore, appropriate management of health risk factors related to silent cerebrovascular lesions and a decline in intellectual activity, such as smoking cessation, maintaining a low blood pressure, and increasing fish intake,50-53 might contribute to preventing not only future higher level functional decline but also stroke and dementia. Our study had several limitations. We did not evaluate lifestyle modifications and changes in cognitive and brain lesions during the 7-year follow-up period. However, given the difficulties with lifestyle-related behavioral changes among the elderly, positive changes were unlikely. The functional capacity of some participants who were excluded deteriorated due to other illnesses. On the other hand, we did not obtain information about these lesions and cognitive changes during the follow-up period. Therefore, we consider that our study included highrisk individuals with lesions at baseline and those with lesions that deteriorated during follow-up. We also did not include those who developed new lesions and new cognitive impairment during follow-up. Further followup is required to clarify the relationship between the

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trajectories of developing lesions and cognitive decline with declining functional capacity. Second, there might have been a selection bias because participants had to be sufficiently independent to participate. Therefore, participants who underwent MRI scans were also somewhat healthier than those who did not. The lower prevalence in older people could be explained by the exclusion of people with cardiovascular disease and by the low response rate for MRI. The limited sample size also led to low statistical power with a wider range of confidential intervals. Lastly, because information about the numbers and sites of infarction and grade of WMH was unavailable, further follow-up is needed to elucidate the association between the location of lacunar infarcts and the grade of WMH as well as functional capacity during the early stage. Marked differences exist in the epidemiology of higher level functional decline between Japan and Western countries. Thus, further research is needed with a large sample that includes other ethnic and cultural populations. This should confirm the generalizability of our findings and the associated functional capacity by age and sex.

Conclusions Silent cerebrovascular lesions, characterized by lacunar infarcts and WMH, were associated with a future risk of decline in higher level functional capacity. Appropriate management of health risk factors known to prevent silent cerebrovascular lesions might be useful in preventing future deteriorations of functional capacity.

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