Grading and Interpretation of White Matter Hyperintensities Using Statistical Maps

Abstract

Background and Purpose-We aimed to generate rigorous graphical and statistical reference data based on volumetric measurements for assessing the relative severity of white matter hyperintensities (WMHs) in patients with stroke. Methods-We prospectively mapped WMHs from 2699 patients with first-ever ischemic stroke (mean age=66.8±13.0 years) enrolled consecutively from 11 nationwide stroke centers, from patient (fluid-attenuated-inversion-recovery) MRIs onto a standard brain template set. Using multivariable analyses, we assessed the impact of major (age/hypertension) and minor risk factors on WMH variability. Results-We have produced a large reference data library showing the location and quantity of WMHs as topographical frequency-volume maps. This easy-to-use graphical reference data set allows the quantitative estimation of the severity of WMH as a percentile rank score. For all patients (median age=69 years), multivariable analysis showed that age, hypertension, atrial fibrillation, and left ventricular hypertrophy were independently associated with increasing WMH (0-9.4%, median=0.6%, of the measured brain volume). For younger (≤69) hypertensives (n=819), age and left ventricular hypertrophy were positively associated with WMH. For older (≥70) hypertensives (n=944), age and cholesterol had positive relationships with WMH, whereas diabetes mellitus, hyperlipidemia, and atrial fibrillation had negative relationships with WMH. For younger nonhypertensives (n=578), age and diabetes mellitus were positively related to WMH. For older nonhypertensives (n=328), only age was positively associated with WMH. Conclusions-We have generated a novel graphical WMH grading (Kim statistical WMH scoring) system, correlated to risk factors and adjusted for age/hypertension. Further studies are required to confirm whether the combined data set allows grading of WMH burden in individual patients and a tailored patient-specific interpretation in ischemic stroke-related clinical practice. Other risk factors such as diabetes mellitus, hyperlipidemia, atrial fibrillation, and smoking were inconsistently reported in the literature and seem less strongly associated with WMHs (Table I in the online-only Data Supplement). 3,[6][7][8][9][10] Despite a rapidly growing body of knowledge from population studies, substantial variability in WMH volume among individuals with similar cerebrovascular risk factors complicates a tailored interpretation of patient-specific implications of WMHs in daily clinical practice. [10][11][12] What is lacking is a comprehensive, quantitative study with substantial numbers, and robust methodology, which correlates WMHs to stroke risk factors so that the associations and interplay between risk factors can be better understood. Clinically, there have been no rigorous graphical and statistical reference data available for the individualized estimation of the relative severity (expressed as percentile ranks) of WMH burden adjusted for major risk factors (age/hypertension).In this study, we have combined (1) a la...

What are White Matter Hyperintensities Made of?

“…A large multicenter study of WMH in 2699 stroke patients in 11 stroke centers in China suggested that raised cholesterol was a more important risk factor for WMH in older hypertensive patients whereas age alone was the major risk factor in older non-hypertensive patients. Diabetes mellitus was an important risk factor in younger non-hypertensives 35. It is unclear as yet if hypertension has most of its effect directly on the brain, or if it results in systemic vascular stiffening, which in turn affects the brain white matter36,37 and cognition 38.…”

“…Some studies differentiate periventricular from deep WMH12,76,77 although imaging studies indicate that periventricular and deep WMH are probably mostly part of a continuous pathology 76,78. A recent very large study in 2699 patients with stroke from 11 stroke centers in China created statistical maps of WMH distribution and provided more evidence to support treating periventricular and deep WMH as a continuous pathology, any apparent difference in distribution in some patients simply reflecting an earlier stage in disease 35. Notwithstanding, the available pathology describes periventricular WMH as having discontinuous ependyma, gliosis, loosening of the white matter fibers, and myelin loss around tortuous venules in perivascular spaces,11,12,79 the gliosis, demyelination, and fiber loss worsening as the periventricular WMH worsened.…”

“…Diabetes mellitus was an important risk factor in younger non-hypertensives. 35 It is unclear as yet if hypertension has most of its effect directly on the brain, or if it results in systemic vascular stiffening, which in turn affects the brain white matter 36,37 and cognition. 38 Accumulating evidence, including associations with left ventricular hypertrophy, tend to point to the former explanation, 35,37 but more longitudinal studies to determine the sequence of development of WMH in relation to risk factors are required.…”

“…35 It is unclear as yet if hypertension has most of its effect directly on the brain, or if it results in systemic vascular stiffening, which in turn affects the brain white matter 36,37 and cognition. 38 Accumulating evidence, including associations with left ventricular hypertrophy, tend to point to the former explanation, 35,37 but more longitudinal studies to determine the sequence of development of WMH in relation to risk factors are required. Additionally, there are as yet mixed results from randomized trials on whether risk factor reduction can prevent WMH progression or cognitive decline in older subjects, [39][40][41] and some evidence that too aggressive blood pressure reduction in old age could actually worsen white matter damage 42 and cognitive decline, perhaps if autoregulation is impaired through vessel stiffening and loss of vasoreactivity.…”

“…Additionally, there are as yet mixed results from randomized trials on whether risk factor reduction can prevent WMH progression or cognitive decline in older subjects, [39][40][41] and some evidence that too aggressive blood pressure reduction in old age could actually worsen white matter damage 42 and cognitive decline, perhaps if autoregulation is impaired through vessel stiffening and loss of vasoreactivity. Further trials of risk factor management are needed and specifically at different ages because different vascular risk factors may have more impact at different ages (eg, hypertension in middle age, cholesterol at older ages 35 ). Physical activity is suggested to protect against WMH in cross-sectional studies, [43][44][45] but whether exercise can prevent progression or development of WMH remains to be tested in randomized clinical trials.…”