White matter lesions: Spatial heterogeneity, links to risk factors, cognition, genetics, and atrophy

Abstract

Objectives: To investigate spatial heterogeneity of white matter lesions or hyperintensities (WMH).

Methods: MRI scans of 1,836 participants (median age 52.2 ± 13.16 years) encompassing a wide age range (22-84 years) from the cross-sectional Study of Health in Pomerania (Germany) were included as discovery set identifying spatially distinct components of WMH using a structural covariance approach. Scans of 307 participants (median age 73.8 ± 10.2 years, with 747 observations) from the Baltimore Longitudinal Study of Aging (United States) were included to examine differences in longitudinal progression of these components. The associations of these components with vascular risk factors, cortical atrophy, Alzheimer disease (AD) genetics, and cognition were then investigated using linear regression.

Results: WMH were found to occur nonuniformly, with higher frequency within spatially heterogeneous patterns encoded by 4 components, which were consistent with common categorizations of deep and periventricular WMH, while further dividing the latter into posterior, frontal, and dorsal components. Temporal trends of the components differed both cross-sectionally and longitudinally. Frontal periventricular WMH were most distinctive as they appeared in the fifth decade of life, whereas the other components appeared later in life during the sixth decade. Furthermore, frontal WMH were associated with systolic blood pressure and with pronounced atrophy including AD-related regions. AD polygenic risk score was associated with the dorsal periventricular component in the elderly. Cognitive decline was associated with the dorsal component.

Conclusions: These results support the hypothesis that the appearance of WMH follows age and disease-dependent regional distribution patterns, potentially influenced by differential underlying pathophysiologic mechanisms, and possibly with a differential link to vascular and neurodegenerative changes.

Figure 1. Cross-sectional and longitudinal trend lines of WMHCs representing regional covariation

(A) Three-dimensional rendering of the 4 WMHCs calculated from the whole SHIP sample (n = 1,836). The 4 WMHCs are posterior periventricular (WMHC-post., blue), frontal periventricular (WMHC-fron., green), dorsal periventricular (WMHC-dors., yellow), and deep white matter (WMHC-deep, red). (B) Axial sections of the 4 WMHCs. (C.a) Total white matter hyperintensity volume as a function of age in the SHIP sample (n = 1,836). (C.b) Trend lines of the 4 WMHCs as a function of age for SHIP participants. (D) Longitudinal age trajectories of the 4 WMHCs in the Baltimore Longitudinal Study of Aging sample (n = 307 and 747 observations). (E) Cortical thickness reduction associated with the 4 WMHCs in SHIP (n = 1,836) after adjusting for age, age², sex, and SHIP subcohort. Results survived cluster-wise correction for multiple comparisons, p < 0.05. SHIP = Study of Health in Pomerania; WMHC = white matter hyperintensities component.

Figure 2. Heterogeneity and staging of WMH in the 4 WMHCs for (A) SHIP (n = 1,836), (B) BLSA baseline (n = 307), and (C) BLSA last MRI visit samples

Each row of the matrix corresponds to a study participant and each column to 1 of the 4 components. WMHC values were binarized (absence or presence of WMH) using a threshold value calculated as the median of total WMH volume for the baseline sample divided by 4. Absence of WMH is denoted by gray and presence by the indicative color of a component. The data tables show percentage of participants for different combinations of WMH presence in the 4 components. BL = baseline; BLSA = Baltimore Longitudinal Study of Aging; deep = deep white matter; dors. = dorsal periventricular; front. = frontal periventricular; post. = posterior periventricular; SHIP = Study of Health in Pomerania; WMH = white matter hyperintensities; WMHC = white matter hyperintensities component.