Association of Long-Term Blood Pressure Variability with Cerebral Amyloid Angiopathy-related Brain Injury and Cognitive Decline

Abstract

Introduction: Long-term systolic blood pressure variability (BPV) has been proposed as a novel risk factor for dementia, but the underlying mechanisms are largely unknown. We aimed to investigate the association between long-term blood pressure variability (BPV), brain injury, and cognitive decline in patients with mild cognitive symptoms and cerebral amyloid angiopathy (CAA), a well-characterized small-vessel disease that causes cognitive decline in older adults.

Methods: Using a prospective memory clinic cohort, we enrolled 102 participants, of whom 52 with probable CAA. All underwent a 3-tesla research MRI at baseline and annual neuropsychological evaluation over 2 years, for which standardized z-scores for four cognitive domains were calculated. BPV was assessed using a coefficient of variation derived from serial outpatient BP measurements (median 12) over five years. We measured the peak width of skeletonized mean diffusivity (PSMD) as a marker of white matter integrity, and other neuroimaging markers of CAA, including lacunes and cortical cerebral microinfarcts. Using regression models, we evaluated the association of BPV with microstructural brain injury and whether CAA modified this association. We also examined the association of BPV with subsequent cognitive decline.

Results: Systolic BPV was dose-dependently associated with PSMD (estimate=0.22, 95% CI: 0.06, 0.39, p=0.010), independent of age, sex, mean BP, common vascular risk factors, brain atrophy, and CAA severity. The presence of probable CAA strengthened the association between BPV and PSMD (estimate=9.33, 95% CI: 1.32, 17.34, p for interaction = 0.023). Higher BPV correlated with greater ischemic injury (lobar lacunes and cortical cerebral microinfarcts) and a decline in global cognition and processing speed (estimate=-0.30, 95% CI: -0.55, -0.04, p=0.022).

Discussion: Long-term BPV has a dose-dependent association with alterations in white matter integrity, lobar lacunes, and cortical cerebral microinfarcts, and predicts cognitive decline. Controlling BPV is a potential strategic approach to prevent cognitive decline, especially in early-stage CAA.

Keywords: Alzheimer’s Disease; Blood pressure variability; Cerebral amyloid angiopathy; Cerebrovascular disease/Stroke; MCI (mild cognitive impairment); Vascular Dementia.

Figure 1.. Methods of white matter integrity assessment with peak width of skeletonized mean diffusivity and emerging non hemorrhagic markers in cerebral amyloid angiopathy

(A) Probable cerebral amyloid angiopathy (CAA) subject with high burden of white matter hyperintensity (Fazekas 3) and increased mean diffusivity of main white matter tracts. (B) CAA subject with low white matter hyperintensity burden (Fazekas 1) and preserved mean diffusivity of white main white matter tracts. (C) Histogram analysis allows calculating the peak width of skeletonized mean diffusivity (PSMD). As the PSMD value increases, the integrity of the white matter decreases. Emerging non-hemorrhagic imaging markers of cerebral amyloid angiopathy are (D) cortical cerebral microinfarcts identified on a sagittal T1-weighted images, and (E) lobar lacunes, identified on axial FLAIR images.

Figure 2.. Participant selection flowchart

Abbreviations: BP, blood pressure; CAA, cerebral amyloid angiopathy; CMB, cerebral microbleeds; MGH, Massachusetts General Hospital; MRI, magnetic resonance imaging. Possible CAA was defined as a single CMB in lobar regions or a single cortical superficial siderosis. Mixed CMB pattern was defined by the concomitant presence of lobar and deep microbleeds.

Figure 3.. Associations between 5-year blood pressure (BP) variability and white matter microstructural integrity in participants with and without probable CAA

Legend: (A) Interaction plot showing the interaction of probable CAA and non-CAA participants on the association between systolic BP variability and PSMD controlling for age (PSMD = 0.383 + 0.042*Age + 9.329*[SBP_CV*Probable_CAA]). Probable CAA increased the effect size of the association between systolic BP variability and PSMD (p for interaction = 0.023). Linear regression models for (B) systolic and (C) diastolic BP variability and PSMD, adjusted for age. Shaded areas represent 95% confidence intervals. Abbreviations: BP, blood pressure; CAA, cerebral amyloid angiopathy; PSMD, peak width of skeletonized mean diffusivity.

Figure 4.. Associations between 5-year BP variability and annualized cognitive decline in non-demented participants with and without probable CAA

Legend: Linear regression models between systolic BP variability and domain-specific cognitive decline in (A) global cognition measured by MMSE, (B) processing speed, (C) executive function, and (D) memory. Cognitive decline is represented in annualized cognitive composite z-scores adjusted for age, sex, and education. Global cognition and processing speed scores were missing in one participant. Associations are presented in standardized β coefficients with shaded areas representing 95% confidence intervals. Abbreviations: BP, blood pressure; CAA, cerebral amyloid angiopathy; MMSE, mini-mental state examination.