Abstract
Background and Purpose:
Data on the significance of combined white matter hyperintensities (WMH)/lacunar brain infarcts), and their progression over time for the prediction of stroke are scarce. We studied associations between the progression in combined measures of microvascular brain disease and risk of stroke in the Atherosclerosis Risk in Communities (ARIC) Study.
Methods:
Prospective analysis of 907 stroke-free ARIC participants who underwent a brain MRI in 1993-1995, a second brain MRI in 2004-2006, and were subsequently followed for stroke incidence through December 31st, 2017 (median [25%-75%] follow-up 12.6 [8.9-13.4] years). A combined measure of microvascular brain disease was defined at each visit and categorized by progression from 1st to 2nd brain MRI as no progression; mild progression (increase of ≥1 unit in WMH grade or new lacune), and moderate progression (increase of ≥1 unit in WMH grade and new lacune). All definite/probable ischemic or hemorrhagic incident strokes occurring after this 2nd MRI, and through 2017, were included. Associations between microvascular brain disease, progression in the combined measures, and stroke incidence were studied with Cox proportional hazard models, adjusting for age, sex, race, education level, time from 1st to 2nd MRI, BMI, smoking, hypertension, diabetes and CHD.
Results:
At the 2nd brain MRI (mean age 72), the distribution of the combined measure was 37% WMH grade<2 and no lacune; 57% WMH grade≥2 or lacune and 6% WMH grade≥2 and lacune. No progression in the combined measures was observed in 38% of participants, 57% showed mild progression and 5% showed moderate progression. Sixty-four incident strokes occurred during the follow-up period. Compared to no change in the combined measure, moderate progression of microvascular brain disease was significantly associated with higher risk of stroke (adjusted HR 3.00, 95% CI 1.30-6.94).
Conclusion:
Progression of microvascular brain disease, manifesting as both new lacunes and increase in WMHs grade, is related to substantial increase in long-term risk of stroke.
Keywords: Microvascular brain disease, lacunes, white matter hyperintensities, leukoaraiosis, stroke, prospective cohort, progression, Cerebrovascular Disease/Stroke, Epidemiology, Risk Factors, MRI
Introduction
Microvascular brain disease may manifest as asymptomatic ischemic lesions readily identified on CT and MRI scans as white matter hyperintensities (WMH) or as lacunes. Both are likely due, at least in part, to arteriolar disease. WMHs are associated with vascular risk factors, particularly age and hypertension, and have been related to increased risk of stroke in several studies1, 2 including studies in the Atherosclerosis Risk in Communities (ARIC) Study participants3. In elderly populations, WMH has been associated with global or selective cognitive deficits, changes in mood, decreased motor function and urinary disturbances, all contributing to increased disability in the elderly4, 5. In patients with acute ischemic stroke, WMH volume has been reported as an independent predictor of infarct growth6 and associated with poor outcome, including reduced physical functioning, decreased quality of life and low community integration7, stroke recurrence8, and mortality9.
Subclinical infarctions, most characterized as lacunes10, are present in 8%-28% of participants in population-based studies, and up to 50% of patients with acute stroke11. They share risk factors with WMH and have been associated with physical functional decline12, frailty13, impaired cognition and visual field deficits14. In population-based studies, increased risks of stroke2, 15 and dementia16 have been reported for participants with evidence of subclinical infarctions. Post-stroke disabilities for patients with prior subclinical stroke are similar to those of patients with prior overt stroke17. Despite similarities in pathophysiology, risk factors, outcomes, as well as the frequent difficulty in clearly distinguishing between WMH and lacunes11, there are few reports on the clinical profile of the two entities in a single study18, 19. In the ARIC cohort study, associations between retinal microvascular abnormalities and progression of brain microvascular disease20 were assessed using both volumetric measures of progression of WMH and a dichotomous characterization of new lacune as outcome. A study on asymptomatic ARIC participants with no history of clinical stroke suggested that not only brain lesions of typical clinically-defined size thresholds (3-20 mm) are associated with risks of future stroke and mortality, but even very small lesions (<3 mm) and WMHs increase the risk of stroke19; however, associations between the progression of WMHs and lacunes and risk of stroke have not been evaluated. We aimed to study associations between microvascular brain disease (combined brain MRI measures, including both WMHs and lacunes) and its progression over time, and risk of stroke in participants of the prospective ARIC study.
Materials and Methods:
Anonymized data from the ARIC study are available through the National Heart, Lung, and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center. Interested researchers may additionally contact the ARIC study Coordinating Center to access the study data.
Study setting and population:
The Atherosclerosis Risk in Communities (ARIC) study has been previously described21. Briefly, ARIC is a prospective cohort study including at baseline (1987-1989) 15,792 men and women aged 45-64 selected by probability sampling among residents of four United States communities: Jackson, Mississippi, Washington County, Maryland, suburbs of Minneapolis, Minnesota, and Forsyth County, North Carolina21. At ARIC Visit 3 (1993-1995), participants 55 years old and over from the ARIC study sites in Forsyth County and Jackson were invited to undergo brain magnetic resonance imaging (brain MRI). A subset of participants in the original ARIC cohort who had an initial brain MRI in 1993-1995 (n=1,934) was recruited for a follow-up brain MRI in 2004-2006. Details on criteria for recruitment for follow-up have been previously published 22. In total 1,064 (55%) with no history of stroke underwent a second brain MRI in 2004-2006. We excluded participants with a history of clinical stroke at time of second brain MRI (n=14) and those who were missing data on covariates in the statistical models (n=143). Therefore, the present analysis included 907 white and African-American ARIC participants who underwent two brain MRIs, had no clinical stroke before the second brain MRI, and were either subsequently followed up through December 31, 2017 (median [25%-75%]=12.6 [8.9-13.4] years), or were censored or died before end of follow-up . Nine participants (1%) were lost to follow-up. For participants in this analysis, the time between 1st and 2nd MRI was 8.7-12.7 years (median and mean=10.5 years). Institutional Review Boards at all participating institutions approved study protocols; all participants provided informed consent.
Definition of the combined WMH/lacune measure and progression of microvascular brain disease:
At ARIC Visit 3 (1993-1995), the first MRIs were obtained on 1.5 Tesla GE or Picker scanners. Scans including axial 5-mm contiguous T1, T2, and proton density-weighted images were performed at two of the four ARIC sites (Forsyth County and Jackson), and were interpreted at the ARIC MRI Reading Center at Johns Hopkins Medical Institutions22 using protocols identical to those used in the Cardiovascular Health Study (CHS)23. The second brain MRIs (2004-2006) were performed on GE 1.5 Tesla scanners. The parameters used for scanning were chosen to match as closely as possible the earlier MRI signal-to-noise, resolution, and contrast weighting, despite hardware and software upgrades occurring during the 10-year interval between the scans. Scans performed in 2004-2006 were scored at the University of Washington by trained neuroradiologists using standardized criteria22. On both MRI scans, we categorized WMH according to the CHS rating scale, similarly to previous ARIC papers24, 25. WMH progression was determined with two methods. Periventricular and subcortical WMH were graded from visual comparison with 8 template images for both MRI visits using the CHS 10 points (0-9) rating scale. The change in grade between visits was calculated. WMH continuous measurements were performed on the 2nd MRI scan, as reported in a previous publication26 and briefly explained in the Supplemental Materials (please see https://www.ahajournals.org/journal/str) ; these are only considered in sensitivity analyses. Lacunes were defined as 3-20 mm focal hyperintense lesions19 located in the following regions: basal ganglia, thalamus, brainstem, internal capsule, deep cerebellum, and subcortical white matter. Only non-hemorrhagic lesions hyperintense on proton density and T2-weighted images and hypointense on T1-weighted images were selected. The number of lacunes at the 1st brain MRI was subtracted from the number of lacunes in the 2nd brain MRI, and if this value was one or greater, the individual was considered as having progressed in the lacune score (had one or more new lacunes). The group with no progression in lacune included 8 participants who had lacunes at both visits, as there was no progression between visits. Based on the previous definitions, we categorized the combined WMH/lacune measure into 3 levels of microvascular brain disease: WMH grade<2 and no lacune; WMH grade≥2 or lacune; WMH grade≥2 and lacune. Progression from the first (1993-1995) to the second brain MRI (2004-2006) was categorized as: no progression; mild progression (increase of ≥1 unit in WMH grade or new lacune), and moderate progression (increase of ≥1 unit in WMH grade and new lacune). Sensitivity analyses considered each imaging marker separately, to allow consideration of continuous change of each (number of new lacunes, and change in WMH volume using the methods described in the supplement).
Definition of incident stroke outcome:
Nonfatal and fatal hospitalized clinical strokes were identified based on hospital record reviews for identified hospitalizations and through annual phone interviews. Discharges from all local hospitals with International Classification of Diseases, Ninth Revision (ICD-9), Clinical Modification codes 430- 438 until 1997, and ICD-9 codes 430-436 or ICD-10 codes G45.X, I60.X, I61.X, I62.X, I63.X, I65.X, I66.X, I67.X after 1997 were identified and reviewed as possible stroke-related admissions in ARIC participants. Data on stroke-related death cases were collected through linkage with the National Death Index. All stroke events were adjudicated by expert stroke reviewers as ischemic or hemorrhagic stroke27. For the present study, all definite/probable incident strokes occurring in the participants through December 31st, 2017 were included.
Covariate definitions:
Models for the study of associations between the combined WMH/lacune measures and risk of stroke included covariates as measured at 2nd brain MRI. Body mass index (BMI) was calculated as kilogram/meter2 (kg/m2). Hypertension was defined as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or use of antihypertensive medication during the past 2 weeks. Diabetes was defined by history or treatment for diabetes, a fasting blood glucose level of ≥126 mg/dL or a non-fasting blood glucose level of ≥200 mg/dL. Coronary heart disease (CHD) was adjudicated based on medical records or self-report of previous myocardial infarction, coronary artery bypass graft or angioplasty, or myocardial infarction determined by ECG. Smoking was categorized as never, former, or current. Education was categorized as high school diploma or less versus high school, GED, or vocational school versus college, graduate, or professional school.
Statistical analysis:
Participants’ characteristics were studied by level of the combined microvascular brain disease. Distribution of demographic variables and risk factors at time of the 2nd brain MRI were presented. Associations of level of microvascular brain disease at time of the 2nd brain MRI, as well as progression of microvascular disease during the time interval from the first (1993-1995) to the second brain MRI (2004-2006) with incident stroke risk, were studied with Cox proportional hazard models. Time of follow-up in the Cox models started at time of 2nd brain MRI and models were adjusted for demographics and cardiovascular disease risk factors chosen a-priori. Models included age, sex, race, education level, time from 1st to 2nd MRI, BMI, smoking, hypertension, diabetes and CHD. Although the focus of the paper was a composite variable for progression, considering both WMH and lacunes, we conducted a sensitivity analysis considering continuous counts of lacunes and continuous WMH volumes, in separate models. Analyses were performed with Stata version 13 (StataCorp LP, College Station, TX) and a two-sided p-value <0.05 was considered significant.
Results
Participant characteristics
At the 2nd brain MRI (2004-2006, baseline for stroke incidence follow-up), 335 (37%) individuals had WMH grade<2 and no lacune, 521 (57%) had WMH grade≥2 or lacune and 51 (6%) had both WMH grade≥2 and lacune in MRI. Characteristics of participants at time of the 2nd brain MRI, by level of microvascular brain disease are shown in Table 1. Compared with participants without microvascular disease, those with microvascular disease were ~3 years older on average and showed different distributions of education level, current smoking, hypertension and diabetes. The proportion of participants with no lacune or WMH was 69.4% at 1st Brain MRI and 36.9% at 2nd Brain MRI. Evidence of lacune or WMH was found in 29.4% at 1st Brain MRI and 57.5% at 2nd Brain MRI, whereas lacune and WMH were reported in 1.2% at 1st Brain MRI and 5.6% at 2nd Brain MRI. Cross-tabulation of brain MRI classification at 1st Brain MRI (1993-1995) vs. 2nd Brain MRI (2004-2006) is shown in Table 2.
Table 1:
Characteristics of participants by level of microvascular brain disease at the 2nd brain MRI, ARIC 2004-2006.
| Overall N=907 | No lacune, WMH grade<2 n=335, 36.9% | Lacune or WMH grade≥2 n=521, 57.5% | Lacune and WMH grade≥2 n=51, 5.6% | |
|---|---|---|---|---|
| Age, mean (SD), years | 72.3 (4.4) | 70.4 (3.9) | 73.4 (4.3) | 73.8 (4.2) |
| Women, % | 62.0 | 60.6 | 63.2 | 58.8 |
| African-Americans, % | 49.4 | 47.5 | 51.3 | 43.1 |
| Education, % | ||||
| Less than high school diploma | 21.3 | 17.0 | 23.8 | 23.5 |
| High school diploma | 35.1 | 35.2 | 35.1 | 33.3 |
| More than high school diploma | 43.7 | 47.8 | 41.1 | 43.1 |
| BMI, mean (SD), kg/m2 | 28.5 (5.2) | 28.0 (5.0) | 28.9 (5.2) | 28.5 (5.8) |
| Smoking, % | ||||
| Never | 7.5 | 7.5 | 7.1 | 11.8 |
| Former | 36.3 | 33.4 | 36.9 | 49.0 |
| Current | 56.2 | 59.1 | 56.1 | 39.2 |
| Hypertension, % | 71.4 | 60.6 | 77.2 | 84.3 |
| Diabetes, % | 18.1 | 13.1 | 20.7 | 23.5 |
| CHD, % | 4.3 | 4.5 | 3.5 | 11.8 |
Grade of WMH categorized according to the Cardiovascular Health Study (CHS) rating scale.
Table 2:
Cross-tabulation of brain MRI classification at 1st Brain MRI (1993-1995) vs. 2nd Brain MRI (2004-2006).
| 1st Brain MRI | |||||
|---|---|---|---|---|---|
| No lacune or WMH | Lacune or WMH | Lacune and WMH | Total (%) | ||
| 2nd Brain MRI | No lacune or WMH | 303 | 32 | 0 | 335 (36.9) |
| Lacune or WMH | 309 | 205 | 7 | 521 (57.5) | |
| Lacune and WMH | 17 | 30 | 4 | 51 (5.6) | |
| Total (%) | 629 (69.4) | 267 (29.4) | 11 (1.2) | 907 (100) | |
Incidence of stroke by level of microvascular disease at the 2nd brain MRI (2004-2006)
In total, there were 64 incident strokes occurring after the 2nd brain MRI visit until the end of the study period (median [25%-75%] follow-up of 12.6 [8.9-13.4] years). Increasing risk of stroke was observed in individuals with higher levels of microvascular disease at the 2nd brain MRI. Associations between microvascular disease at the 2nd brain MRI and stroke occurring over follow-up after that time point were significant after controlling for risk factors: HR (95% CI) 2.16 (1.10-4.24)] for lacune or WMH grade≥2, and 4.36 (1.73-11.00)] for lacune and WMH grade≥2 compared to the WMH grade<2 and no lacune group (Table 3).
Table 3:
Hazard ratios (95% CIs) for incidence of stroke associated with level of the combined measure of microvascular brain disease at the 2nd brain MRI, ARIC 2004-2006.
| HR | 95% CI | p | |
|---|---|---|---|
| Microvascular brain disease | |||
| No lacune, WMH grade<2 | 1 (Ref.) | - | - |
| Lacune or WMH grade≥2 | 2.16 | 1.10-4.24 | 0.025 |
| Lacune and WMH grade≥2 | 4.36 | 1.73-11.00 | 0.002 |
| Age, per year | 1.05 | 0.99-1.12 | 0.12 |
| Female sex | 1.09 | 0.63-1.89 | 0.76 |
| African-American race | 1.31 | 0.75-2.30 | 0.35 |
| Education | |||
| Less than high school diploma | 1 (Ref.) | - | - |
| High school diploma | 0.93 | 0.48-1.80 | 0.82 |
| More than high school diploma | 0.75 | 0.39-1.44 | 0.39 |
| BMI, per 1 kg/m2 | 1.02 | 0.97-1.07 | 0.44 |
| Smoking | |||
| Never | 1 (Ref.) | - | - |
| Former | 1.39 | 0.80-2.41 | 0.25 |
| Current | 3.16 | 1.40-7.12 | 0.006 |
| Hypertension | 1.79 | 0.88-3.62 | 0.11 |
| Diabetes | 0.73 | 0.37-1.46 | 0.38 |
| CHD | 1.79 | 0.64-4.99 | 0.27 |
Grade of WMH categorized according to the Cardiovascular Health Study (CHS) rating scale.
Incidence of stroke by progression in microvascular disease from 1st brain MRI (1993-1995) to 2nd brain MRI (2004-2006)
About two-thirds of participants had evidence of progression in the combined WMH/lacune measure from 1993-1995 to 2004-2006; among them, 518 (57%) showed evidence of mild progression (increase of ≥1 unit in WMH grade or new lacune), and 45 (5%) had moderate progression (increase of ≥1 unit in WMH grade and new lacune) (Table 4). HRs (95% CIs) for incident stroke were 1.10 (0.62-1.94) for individuals with mild progression and 3.00 (1.30-6.94) for those with moderate progression (no progression was the reference group). Age and smoking at baseline were also significantly associated with stroke incidence in the multivariable model (Table 5). Separate analyses of the difference between 1st to 2nd MRI in WMH volume and number of lacunes as continuous measures were not statistically significant (Tables I and II, in the Supplemental Materials [please see https://www.ahajournals.org/journal/str]).
Table 4:
Hazard ratios (95% CIs) for incidence of stroke associated with progression in WMH, lacune and the combined microvascular brain disease measure from 1st brain MRI (1993-1995) to 2nd brain MRI (2004-2006).
| Level | n (%) | Number of incident strokes by end of follow-up | HR (95% CI) for incident stroke |
|---|---|---|---|
| Progression in WMH grade | |||
| 0 | 357 (39.4) | 20 | 1 (Ref.) |
| 1 | 339 (37.4) | 25 | 1.23 (0.67-2.27) |
| 2 | 152 (16.8) | 12 | 1.30 (0.63-2.72) |
| 3 | 45 (5.0) | 5 | 1.86 (0.68-5.09) |
| 4 | 10 (1.1) | 1 | 2.39 (0.29-19.34) |
| 5 | 4 (0.4) | 1 | 16.36 (1.93-138.53) |
| Progression in lacunes (additional new lacunes) | |||
| 0 | 849 (93.6) | 56 | 1 (Ref.) |
| 1 | 35 (3.9) | 5 | 2.16 (0.85-5.49) |
| 2 | 15 (1.7) | 2 | 2.26 (0.54-9.44) |
| 3 | 4 (0.4) | 1 | 4.70 (0.59-37.38) |
| 4 | 1 (0.1) | 0 | -- |
| 5 | 3 (0.3) | 0 | -- |
| Progression in the combined WMH/lacune measure | |||
| None | 344 (37.9) | 20 | 1 (Ref.) |
| Mild | 518 (57.1) | 36 | 1.10 (0.62-1.94) |
| Moderate | 45 (5.0) | 8 | 3.00 (1.30-6.94) |
Progression in WMH defined as the increase in CHS rating scale grade from 1st brain MRI (1993-1995) to 2nd brain MRI (2004-2006).
Progression in lacune defined as new lacunes in the 2nd brain MRI. The group with no progression includes 8 participants with lacunes in both visits.
Progression in the combined WMH/lacune measure categories: no progression; mild progression (increase of ≥1 unit in WMH grade or new lacune), and moderate progression (increase of ≥1 unit in WMH grade and new lacune).
Participants were followed up from 2nd brain MRI to December 31, 2017 (median [25%-75%]=12.6 [8.9-13.4] years). HR (95% CI) for incident stroke adjusted for age, sex, race, education level, time from 1st to 2nd MRI, BMI, smoking, hypertension, diabetes and CHD.
Table 5:
Hazard ratios (95% CIs) for incidence of stroke associated with progression of the combined microvascular brain disease measure from the 1st Brain MRI (1993-1995) to the 2nd brain MRI (2004-2006).
| HR | 95% CI | p | |
|---|---|---|---|
| Progression in the combined measure | |||
| No progression | 1 (Ref.) | - | - |
| Mild progression | 1.12 | 0.63-1.97 | 0.71 |
| Moderate progression | 3.03 | 1.31-7.00 | 0.01 |
| Age, per year | 1.08 | 1.02-1.15 | 0.01 |
| Female sex | 1.10 | 0.63-1.90 | 0.75 |
| African-American race | 1.46 | 0.81-2.63 | 0.21 |
| Education | |||
| Less than high school diploma | 1 (Ref.) | - | - |
| High school diploma | 0.94 | 0.49-1.83 | 0.87 |
| More than high school diploma | 0.76 | 0.39-1.46 | 0.40 |
| Time from 1st to 2nd MRI, per year | 0.88 | 0.65-1.21 | 0.44 |
| BMI, per 1 kg/m2 | 1.02 | 0.97-1.07 | 0.41 |
| Smoking | |||
| Never | 1 (Ref.) | - | - |
| Former | 1.47 | 0.85-2.56 | 0.17 |
| Current | 3.24 | 1.43-7.34 | 0.005 |
| Hypertension | 1.93 | 0.95-3.91 | 0.07 |
| Diabetes | 0.73 | 0.36-1.46 | 0.38 |
| CHD | 1.77 | 0.64-4.91 | 0.27 |
Progression in the combined WMH/lacune measure categories: no progression; mild progression (increase of ≥1 unit in WMH grade or new lacune), and moderate progression (increase of ≥1 unit in WMH grade and new lacune).
Grade of WMH categorized according to the Cardiovascular Health Study (CHS).
In order to explore whether the association between disease progression and stroke risk varied according to the initial disease status, we assessed potential differences in the observed association in participants with no evidence of microvascular disease (n=629) and those with microvascular disease (WMH or/and lacune, n=278) at 1st MRI. No interaction between microvascular disease status at 1st MRI and progression of microvascular disease from 1st to 2nd MRI was found in Cox models for incident stroke (p for interaction=0.56). Results of this analysis are shown in Table III, in the Supplemental Materials (please see https://www.ahajournals.org/journal/str).
Discussion
In the community-based ARIC study cohort, we found that both the combined WMHs and lacunes measure of microvascular brain disease and the progression in these MRI measures over time were associated with increased risk of stroke. Individuals who had both progression in WMH grade and developed new lacunes had a significant increase in long-term risk of stroke, after adjusting for demographic and clinical risk factors. However, the group with moderate progression, in whom stroke risk was elevated, was relatively small, representing only 5% of the sample, with lesser degrees of progression (which were not associated with elevated risk of stroke) occurring in about 60% of the cohort.
WMHs have been associated with poor functional outcome 1-month after ischemic stroke28, and associations between severity of white matter lesions and risk of recurrent stroke have been reported in patients with transient symptoms with infarction.29 A meta-analysis including 9 prospective longitudinal studies reported increased risk of stroke associated with WMHs (all measured by MRI) (hazard ratio [95% CI] 3.3 [2.6-4.4])30; however, across the included studies, WMHs were measured with different scales and using either quantitative or visual semiquantitative volume measures30.
The risk of stroke associated with combined measures of WMHs and subclinical brain lesions in ARIC participants was assessed by Windham et al 19. The authors reported increased risks of stroke associated with very small (typically ignored) cerebrovascular lesions (i.e. <3 mm) and higher risk associated with increasing number of lesions, either WMHs or subclinical brain lesions. However, the study did not assess the impact of progression in microvascular brain disease on stroke incidence. 19
There are very few publications on progression in measures of microvascular brain disease and risk of stroke. A longitudinal study on 89 Japanese patients with a mean follow-up of 4.3 years, reported increased risk of stroke from arteriolosclerosis in patients with progression of WMHs compared with those with no progression.31 However, the study was conducted in a selective sample including patients with symptomatic lacunar stroke and stroke-free patients with headache or dizziness; therefore, the generalizability of the study findings is limited. A study in China reported significant associations between WMH progression and incident lacunar stroke32, but this report was based on retrospective data collected in a single medical center. The present study is the first to report associations between progression in microvascular brain disease and incident stroke in a prospective unselected biracial cohort with prolonged follow-up in the United States.
Brain MRI is becoming more frequently used as a diagnostic test for different health conditions. Technological improvements make it possible to identify diffuse white matter lesions and to track their change over time. Previous research has shown the importance of prevalent microvascular brain disease as a risk factor for stroke incidence. The findings of our present study suggest that changes in measures of microvascular brain disease are related to increased risk of stroke, therefore, progression in these lesions should not be considered just a minor finding with no clinical significance for the prevention of stroke. At the very least, these are a marker of more aggressive and ongoing microvascular disease, which could emphasize the value of evaluating control of risk factors for microvascular disease. The study of potential effects of the rate of microvascular disease progression on the association between microvascular disease and risk of stroke is an interesting area for future research.
Our study has many important strengths: the study population was derived from the ARIC community-based prospective cohort including a large population of unselected middle-aged whites and African-Americans, residents of four geographically diverse communities, with long follow up for stroke incidence. MRI lesions were measured using standardized methods and all incident strokes occurring in ARIC participants were centrally adjudicated by physicians. However, our study has some limitations. First, the risk of stroke associated with brain microvascular disease might differ by stroke etiology. The small number of stroke events in our cohort did not allow for evaluation of risk by stroke type (ischemic vs. hemorrhagic stroke) or subtype of ischemic stroke. Second, data on cerebral microbleeds were not available on both MRIs, therefore we did not include cerebral microbleeds in the evaluation of brain microvascular disease. Our classification of lacunes and WMH was done in a standardized way at a central reading center, but we acknowledge that measurement error is a possibility, and image resolution or slice location might limit the ability to identify a lacune on one scan when seen on a previous scan. Furthermore, we acknowledge that the category of “mild progression”, defined by either an incident lacune or WMH progression, is quite common in this cohort, yet is not associated with an elevated risk of stroke. This either indicates that this state is truly more benign than is a condition when both forms of small vessel disease progress, or that it is a reflection of the previously mentioned possibility of measurement error and misclassification into the mild progression group. Last, although we were able to control for important demographic and clinical variables collected at the 2nd brain MRI, residual confounding is a possibility in our study as a result of its observational design.
In conclusion, considerable progression in a combined measure of microvascular brain disease defined as new lacunes and increase in WMHs grade is related to a substantial increase in long-term risk of stroke. Future studies should evaluate whether serial brain MRI can help to identify individuals at high risk of stroke, and furthermore, whether reducing progression of microvascular brain disease actually reduces risk of stroke.
Supplementary Material
Acknowledgment:
The authors thank the staff and participants of the ARIC study for their important contributions.
Financial Support: The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I).
Neurocognitive data is collected by U01 2U01HL096812, 2U01HL096814, 2U01HL096899, 2U01HL096902, 2U01HL096917 from the NIH (NHLBI, NINDS, NIA AND NIDCD), and with previous brain MRI examinations funded by R01-HL70825 from the NHLBI.
Non-standard Abbreviations and Acronyms
- ARIC
Atherosclerosis Risk in Communities
- WMH
White Matter Hyperintensities
- CHS
Cardiovascular Health Study
- GED
General Educational Development
Footnotes
Conflict of Interests: None
References
- 1.Kuller LH, Longstreth WT Jr., Arnold AM, Bernick C, Bryan RN, Beauchamp NJ Jr. White matter hyperintensity on cranial magnetic resonance imaging: A predictor of stroke. Stroke. 2004;35:1821–1825 [DOI] [PubMed] [Google Scholar]
- 2.Vermeer SE, Hollander M, van Dijk EJ, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and white matter lesions increase stroke risk in the general population: The Rotterdam Scan Study. Stroke. 2003;34:1126–1129 [DOI] [PubMed] [Google Scholar]
- 3.Wong TY, Klein R, Sharrett AR, Couper DJ, Klein BE, Liao DP, Hubbard LD, Mosley TH Jr, ARIC Investigators. Cerebral white matter lesions, retinopathy, and incident clinical stroke. JAMA. 2002;288:67–74 [DOI] [PubMed] [Google Scholar]
- 4.Pantoni L, Basile AM, Pracucci G, Asplund K, Bogousslavsky J, Chabriat H, Erkinjuntti T, Fazekas F, Ferro JM, Hennerici M, et al. Impact of age-related cerebral white matter changes on the transition to disability -- the LADIS Study: Rationale, design and methodology. Neuroepidemiology. 2005;24:51–62 [DOI] [PubMed] [Google Scholar]
- 5.Sachdev PS, Wen W, Christensen H, Jorm AF. White matter hyperintensities are related to physical disability and poor motor function. Journal of neurology, neurosurgery, and psychiatry. 2005;76:362–367 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Ay H, Arsava EM, Rosand J, Furie KL, Singhal AB, Schaefer PW, Wu O, Gonzalez RG, Koroshetz WJ, Sorensen AG. Severity of leukoaraiosis and susceptibility to infarct growth in acute stroke. Stroke. 2008;39:1409–1413 [DOI] [PubMed] [Google Scholar]
- 7.Koton S, Schwammenthal Y, Merzeliak O, Philips T, Tsabari R, Orion D, Dichtiar R, Tanne D Cerebral leukoaraiosis in patients with stroke or TIA: Clinical correlates and 1-year outcome. European journal of neurology. 2009;16:218–225 [DOI] [PubMed] [Google Scholar]
- 8.Henon H, Vroylandt P, Durieu I, Pasquier F, Leys D. Leukoaraiosis more than dementia is a predictor of stroke recurrence. Stroke. 2003;34:2935–2940 [DOI] [PubMed] [Google Scholar]
- 9.Henon H, Godefroy O, Leys D, Mounier-Vehier F, Lucas C, Rondepierre P, Duhamel A, Pruvo JP. Early predictors of death and disability after acute cerebral ischemic event. Stroke. 1995;26:392–398 [DOI] [PubMed] [Google Scholar]
- 10.Sacco RL, Kasner SE, Broderick JP, Caplan LR, Connors JJ, Culebras A, Elkind MSV, George MG, Hamdan AD, Higashida RT, et al. An updated definition of stroke for the 21st century: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44:2064–2089 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Vermeer SE, Longstreth WT Jr., Koudstaal PJ. Silent brain infarcts: A systematic review. The Lancet. Neurology. 2007;6:611–619 [DOI] [PubMed] [Google Scholar]
- 12.Rosano C, Kuller LH, Chung H, Arnold AM, Longstreth WT Jr., Newman AB. Subclinical brain magnetic resonance imaging abnormalities predict physical functional decline in high-functioning older adults. Journal of the American Geriatrics Society. 2005;53:649–654 [DOI] [PubMed] [Google Scholar]
- 13.Newman AB, Gottdiener JS, McBurnie MA, Hirsch CH, Kop WJ, Tracy R, Walston JD, Fried LP, Cardiovascular Health Study Research Group. Associations of subclinical cardiovascular disease with frailty. The journals of gerontology. Series A, Biological sciences and medical sciences. 2001;56:M158–166 [DOI] [PubMed] [Google Scholar]
- 14.Price TR, Manolio TA, Kronmal RA, Kittner SJ, Yue NC, Robbins J, Anton-Culver H, O’Leary DH, for the CHS Collaborative Research Group. Silent brain infarction on magnetic resonance imaging and neurological abnormalities in community-dwelling older adults. The Cardiovascular Health Study. CHS collaborative research group. Stroke. 1997;28:1158–1164 [DOI] [PubMed] [Google Scholar]
- 15.Bernick C, Kuller L, Dulberg C, Longstreth WT Jr., Manolio T, Beauchamp N, Price T Cardiovascular Health Study Collaborative Reseach Group. Silent MRI infarcts and the risk of future stroke: The Cardiovascular Health Study. Neurology. 2001;57:1222–1229 [DOI] [PubMed] [Google Scholar]
- 16.Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and the risk of dementia and cognitive decline. The New England journal of medicine. 2003;348:1215–1222 [DOI] [PubMed] [Google Scholar]
- 17.Koton S, Tsabari R, Molshazki N, Kushnir M, Shaien R, Eilam A, Tanne, D. NASIS Investigators. Burden and outcome of prevalent ischemic brain disease in a national acute stroke registry. Stroke. 2013;44:3293–3297 [DOI] [PubMed] [Google Scholar]
- 18.Leistner S, Koennecke HC, Dreier JP, Strempel AK, Kathke M, Nikolova A, Heuschman P, Malzahn U, Audebert HJ, Mackert BM. Clinical characterization of symptomatic microangiopathic brain lesions. Frontiers in neurology. 2011;2:61. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Windham BG, Deere B, Griswold ME, Wang W, Bezerra DC, Shibata D, Butler K, Knopman D, Gottesman RF, Heiss G, et al. Small brain lesions and incident stroke and mortality: A cohort study. Annals of internal medicine. 2015;163:22–31 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Hanff TC, Sharrett AR, Mosley TH Jr, Shibata D, Knopman DS, Klein R, Klein BE, Gottesman RF. Retinal microvascular abnormalities predict progression of brain microvascular disease: An Atherosclerosis Risk in Communities magnetic resonance imaging study. Stroke. 2014;45:1012–1017 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.The Atherosclerosis Risk in Communities (ARIC) study: Design and objectives. The ARIC investigators. American journal of epidemiology. 1989;129:687–702 [PubMed] [Google Scholar]
- 22.Knopman DS, Penman AD, Catellier DJ, Coker LH, Shibata DK, Sharrett AR, Mosley TH Jr. Vascular risk factors and longitudinal changes on brain MRI: The ARIC study. Neurology. 2011;76:1879–1885 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Bryan RN, Manolio TA, Schertz LD, Jungreis C, Poirier VC, Elster AD, et al. A method for using MR to evaluate the effects of cardiovascular disease on the brain: The Cardiovascular Health Study. AJNR. American journal of neuroradiology. 1994;15:1625–1633 [PMC free article] [PubMed] [Google Scholar]
- 24.Bryan RN, Cai J, Burke G, Hutchinson RG, Liao D, Toole JF, Dagher AP, Cooper L. Prevalence and anatomic characteristics of infarct-like lesions on MR images of middle-aged adults: The Atherosclerosis Risk in Communities study. AJNR. American journal of neuroradiology. 1999;20:1273–1280 [PMC free article] [PubMed] [Google Scholar]
- 25.Liao D, Cooper L, Cai J, Toole J, Bryan N, Burke G, Shahar E, Nieto J, Mosley TH Jr, Heiss G. The prevalence and severity of white matter lesions, their relationship with age, ethnicity, gender, and cardiovascular disease risk factors: The ARIC study. Neuroepidemiology. 1997;16:149–162 [DOI] [PubMed] [Google Scholar]
- 26.Gottesman RF, Coresh J, Catellier DJ, Sharrett AR, Rose KM, Coker LH, Shibata DK, Knopman DS, Jack CR, Mosley TH Jr. Blood pressure and white-matter disease progression in a biethnic cohort: Atherosclerosis Risk in Communities (ARIC) study. Stroke. 2010;41:3–8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Koton S, Schneider AL, Rosamond WD, Shahar E, Sang Y, Gottesman RF, Coresh J. Stroke incidence and mortality trends in US communities, 1987 to 2011. JAMA. 2014;312:259–268 [DOI] [PubMed] [Google Scholar]
- 28.Liou LM, Chen CF, Guo YC, Cheng HL, Lee HL, Hsu JS, Lin RT, Lin HF. Cerebral white matter hyperintensities predict functional stroke outcome. Cerebrovascular diseases. 2010;29:22–27 [DOI] [PubMed] [Google Scholar]
- 29.Fang H, Zhao L, Pei L, Song B, Gao Y, Liu K, Xu Y, Li Y, Wu J, Xu Y. Severity of white matter lesions correlates with subcortical diffusion-weighted imaging abnormalities and predicts stroke risk. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2017;26:2964–2970 [DOI] [PubMed] [Google Scholar]
- 30.Debette S, Markus HS. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: Systematic review and meta-analysis. BMJ. 2010;341:c3666. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Yamauchi H, Fukuda H, Oyanagi C. Significance of white matter high intensity lesions as a predictor of stroke from arteriolosclerosis. Journal of neurology, neurosurgery, and psychiatry. 2002;72:576–582 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Xu X, Gao Y, Liu R, Qian L, Chen Y, Wang X, Xu Y. Progression of white matter hyperintensities contributes to lacunar infarction. Aging and disease. 2018;9:444–452 [DOI] [PMC free article] [PubMed] [Google Scholar]
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