Small vessel disease lesion type and brain atrophy: The role of co-occurring amyloid

Abstract

Introduction: It is unknown whether different types of small vessel disease (SVD), differentially relate to brain atrophy and if co-occurring Alzheimer's disease pathology affects this relation.

Methods: In 725 memory clinic patients with SVD (mean age 67 ± 8 years, 48% female) we compared brain volumes of those with moderate/severe white matter hyperintensities (WMHs; n = 326), lacunes (n = 132) and cerebral microbleeds (n = 321) to a reference group with mild WMHs (n = 197), also considering cerebrospinal fluid (CSF) amyloid status in a subset of patients (n = 488).

Results: WMHs and lacunes, but not cerebral microbleeds, were associated with smaller gray matter (GM) volumes. In analyses stratified by CSF amyloid status, WMHs and lacunes were associated with smaller total brain and GM volumes only in amyloid-negative patients. SVD-related atrophy was most evident in frontal (cortical) GM, again predominantly in amyloid-negative patients.

Discussion: Amyloid status modifies the differential relation between SVD lesion type and brain atrophy in memory clinic patients.

Keywords: Alzheimer's disease; brain atrophy; cerebral microbleeds; cerebral small vessel disease; lacunes; magnetic resonance imaging; vascular cognitive impairment; white matter hyperintensities.

FIGURE 1

Occurrence of lesion types. Venn diagram showing the occurrence of lesion types in the entire study population (n = 725) as well as in the cerebrospinal fluid (CSF) amyloid‐positive (n = 261) and amyloid‐negative (n = 227) patients in the CSF subgroup. In 719 patients (99%), information regarding presence/absence of cerebral microbleeds (CMBs) was present. The number of patients with a certain lesion type (alone or in combination with another lesion type) is shown. The colors represent the percentage of the respective patient group, illustrating which (combination of) lesion types were observed. The majority of patients only had mild white matter hyperintensities (WMHs; Fazekas score of 1) or moderate/severe WMHs (Fazekas score 2 or 3) but no other lesions. Multiple lesion types occurred in 321 patients (44%) of the entire study population. Of 382 patients (53%) with either cerebral microbleeds/lacunes, 242 (63%) had multiple cerebral microbleeds/lacunes; 71 patients (10%) had multiple lacunes (max: 30). 171 patients (24%) had multiple cerebral microbleeds (CMBs; max: ∼500). Of the patients with CMBs, 37 patients (12%) had only deep CMBs, 212 patients (66%) had only lobar CMBs, and 70 patients (22%) both had deep and lobar CMBs. In two patients, no information regarding CMB location was available

FIGURE 2

Bayesian networks. Bayesian networks for total brain volume (TBV, panel A), gray matter volume (GMV, panel B), and white matter volume (WMV, panel C). Variables that are directly connected to one of the cognitive domains are identified as direct determinants. Variables that are connected indirectly to the cognitive domains (via other variables) are conditionally independent. As such, this method separates determinants with a direct deterministic influence on the outcome variable from other determinants that, although showing a univariate correlation with the outcome variable, have only an indirect influence when taking the direct determinants into account. Percentages indicate the confidence level of the arcs toward brain volumes determined by 100 bootstrap replications. These analyses showed white matter hyperintensities (WMHs) directly determined gray matter volume, independent of lacunes and cerebral microbleeds. CMB, presence of cerebral microbleed(s); WMH, moderate/severe WMHs (Fazekas score 2 or 3)

FIGURE 3

Regional brain volume analysis. Effect size map showing the relation between log white matter hyperintensity (WMH) volume and regional gray matter (GM) volume using standardized beta coefficients (red: GM volume smaller in patients with higher log WMH volume; blue: GM volume smaller in patients with lower log WMH volume) in all patients (n = 725). Across all patients higher log WMH volume was associated with smaller GM volume in several (predominantly frontotemporal) brain regions. * Bonferroni‐corrected P < .05

FIGURE 4

Regional brain volume analysis in cerebrospinal fluid (CSF) subgroup. Effect size map showing the relation between log white matter hyperintensity (WMH) volume and regional gray matter (GM) volume using standardized beta coefficients (Red: GM volume smaller in patients with higher log WMH volume; blue: GM volume smaller in patients with lower log WMH volume). A, CSF amyloid‐negative patients (n = 261); (B) CSF amyloid‐positive patients (n = 227). The stratified analyses show that the effect is highly dependent on CSF amyloid status. While amyloid‐positive patients have a lower GM volume than amyloid‐negative patients, the association between higher log WMH volume and more GM atrophy was more pronounced in several brain regions for amyloid‐negative patients only. * Bonferroni‐corrected P < .05