Association of Data-Driven White Matter Hyperintensity Spatial Signatures With Distinct Cerebral Small Vessel Disease Etiologies

Abstract

Objectives:Topographical distribution of white matter hyperintensities (WMH) are hypothesized to vary by cerebrovascular risk factors. We used an unbiased pattern discovery approach to identify distinct WMH spatial patterns and investigate their association with different WMH etiologies.Methods:We performed a cross-sectional study on participants of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to identify spatially distinct WMH distribution patterns using voxel-based spectral clustering analysis of aligned WMH probability maps. We included all participants from the ADNI Grand Opportunity/ADNI 2 study with available baseline 2D-FLAIR MRI scans, without prior history of stroke or presence of infarction on imaging. We evaluated the associations of these WMH spatial patterns with vascular risk factors, amyloid-β PET, and imaging biomarkers of cerebral amyloid angiopathy (CAA), characterizing different forms of cerebral small vessel disease (CSVD) using multivariable regression. We also used linear regression models to investigate whether WMH spatial distribution influenced cognitive impairment.Results:We analyzed MRI scans of 1,046 ADNI participants with mixed vascular and amyloid-related risk factors (mean age 72.9, 47.7% female, 31.4% hypertensive, 48.3% with abnormal amyloid PET). We observed unbiased partitioning of WMH into five unique spatial patterns: deep frontal, periventricular, juxtacortical, parietal, and posterior. Juxtacortical WMH were independently associated with probable CAA, deep frontal WMH were associated with risk factors for arteriolosclerosis (hypertension and diabetes), and parietal WMH were associated with brain amyloid accumulation, consistent with an Alzheimer’s disease (AD) phenotype. Juxtacortical, deep frontal, and parietal WMH spatial patterns were associated with cognitive impairment. Periventricular and posterior WMH spatial patterns were unrelated to any disease phenotype or cognitive decline.Discussion:Data-driven WMH spatial patterns reflect discrete underlying etiologies including arteriolosclerosis, CAA, AD, and normal aging. Global measures of WMH volume may miss important spatial distinctions. WMH spatial signatures may serve as etiology-specific imaging markers, helping to resolve WMH heterogeneity, identify the dominant underlying pathological process, and improve prediction of clinical-relevant trajectories that influence cognitive decline.

Spatial Patterns of White Matter Hyperintensities: A Systematic Review

“…[40][41][42][43][44][45][46][47][48][49][50][51]65 In patients with AD and MCI, local WMH burden in the frontal and parietal lobes close to the ventricles was associated with an increased amyloid burden. 42,46,49,65 Increased WMH burden in voxels around the ventricles was found to be associated with age, 40 poor executive function and episodic memory, 41 and with AD. 45 Further, juxtacortical WMH load was found to be associated with CI, male sex, and CAA, and deep frontal WMH burden with hypertension and DM2.…”

Vascular and neural transcriptomics reveal stage-dependent pathways to inflammation and cognitive dysfunction in a rat model of hypertension

“…Elevated expression of Igfbp-5 resulted in motor neuron degeneration and myelination defects due to insufficient trophic support of axons in human diabetic neuropathy as well as in Igfbp-5 overexpressing rodents [115]. One could hypothesize that similar effects occur locally in the white matter of chronic hypertensive individuals, which would link the susceptibility of frontal white matter tracts to chronic hypertension [17,[19][20][21]. Igf-1 signaling also promotes Aβ clearance through the BBB and is thus involved in protecting against AD pathology [124].…”

“…If fed a normal diet, non-transgenic spontaneously hypertensive stroke-prone rats (SHRSP), perfectly mimic this vulnerable hypertensive patient population in its initial and preclinical disease stages by combining arterial hypertension development and a polygenetic susceptibility to CSVD [16]. The frontal predilection of hypertensive pathology has been underlined by cognitive testing, magnetic resonance imaging (MRI) and a human microarray study in which the frontal cortex exhibited the most gene expression alterations [17][18][19][20][21]. Here, we investigated the frontal cortex of initial hypertensive (6-8 weeks) animals, that mimic newly diagnosed hypertension in midlife humans and of two older stroke-free age groups, that represent stages of early (24-25 weeks) and late chronic (32-34 weeks) hypertension.…”

Regional White Matter Hyperintensities and Alzheimer’s Disease Biomarkers Among Older Adults with Normal Cognition and Mild Cognitive Impairment

“…Although WMHs most commonly have a vascular origin [ 4 ], some evidence suggests that there may also be an AD-specific pathway contributing to WMH [ 6 ], particularly to WMH in the parietal lobe [ 7 ]. For example, pre-symptomatic carriers of autosomal dominant AD genetic mutations without appreciable vascular risk have elevated WMH volumes, in addition to abnormal AD biomarkers, several years before expected symptom onset, particularly in parietal and occipital regions [ 8, 9 ].…”