Cerebral Microbleeds, Cerebral Amyloid Angiopathy, and Their Relationships to Quantitative Markers of Neurodegeneration

Abstract

Background and objectives: Age-related cognitive impairment is driven by the complex interplay of neurovascular and neurodegenerative disease. There is a strong relationship between cerebral microbleeds (CMBs), cerebral amyloid angiopathy (CAA), and the cognitive decline observed in conditions such as Alzheimer disease. However, in the early, preclinical phase of cognitive impairment, the extent to which CMBs and underlying CAA affect volumetric changes in the brain related to neurodegenerative disease remains unclear.

Methods: We performed cross-sectional analyses from 3 large cohorts: The Northern Manhattan Study (NOMAS), Alzheimer's Disease Neuroimaging Initiative (ADNI), and the Epidemiology of Dementia in Singapore study (EDIS). We conducted a confirmatory analysis of 82 autopsied cases from the Brain Arterial Remodeling Study (BARS). We implemented multivariate regression analyses to study the association between 2 related markers of cerebrovascular disease-MRI-based CMBs and autopsy-based CAA-as independent variables and volumetric markers of neurodegeneration as dependent variables. NOMAS included mostly dementia-free participants age 55 years or older from northern Manhattan. ADNI included participants living in the United States age 55-90 years with a range of cognitive status. EDIS included community-based participants living in Singapore age 60 years and older with a range of cognitive status. BARS included postmortem pathologic samples.

Results: We included 2,657 participants with available MRI data and 82 autopsy cases from BARS. In a meta-analysis of NOMAS, ADNI, and EDIS, superficial CMBs were associated with larger gray matter (β = 4.49 ± 1.13, p = 0.04) and white matter (β = 4.72 ± 2.1, p = 0.03) volumes. The association between superficial CMBs and larger white matter volume was more evident in participants with 1 CMB (β = 5.17 ± 2.47, p = 0.04) than in those with ≥2 CMBs (β = 1.97 ± 3.41, p = 0.56). In BARS, CAA was associated with increased cortical thickness (β = 6.5 ± 2.3, p = 0.016) but not with increased brain weight (β = 1.54 ± 1.29, p = 0.26).

Discussion: Superficial CMBs are associated with larger morphometric brain measures, specifically white matter volume. This association is strongest in brains with fewer CMBs, suggesting that the CMB/CAA contribution to neurodegeneration may not relate to tissue loss, at least in early stages of disease.

Figure 1. Example Vessels With Cerebral Amyloid Angiopathy and Their Anatomic Distribution

(A) Double-barrel appearance of cerebral amyloid angiopathy (CAA) in the frontal cortex showing detachment and delamination of the outer part of the tunica media. Many neuritic plaques observed in surrounding tissue. (B) Copious vessels affected by CAA noted in the leptomeningeal space of the frontal cortex. (C) CAA vessels observed in the caudate nucleus. (D) CAA vessel observed in the globus pallidus.

Figure 2. Mean Prevalence of Cerebral Microbleeds by Age and Anatomical Location for the 3 Cohorts

Age is discretized into 5-year increments. (1) Blue indicates any cerebral microbleed (CMB). (2) Red indicates superficial (or lobar) CMBs (i.e., cortical or adjacent subcortical white matter). (3) Green indicates deep (basal ganglia, brainstem, or cerebellar nuclei) CMBs. The prevalence of CMBs was significantly associated with age in Northern Manhattan Study (NOMAS) (odds ratio [OR] 1.035 [1.008–1.063]), Alzheimer's Disease Neuroimaging Initiative (ADNI) (OR 1.040 [1.021–1.059]), and Epidemiology of Dementia in Singapore (EDIS) (OR 1.036 [1.008–1.064]) cohorts.

Figure 3. Mean Cerebral Amyloid Angiopathy Number of Vessels per 40 μm² in BARS Cohort

The gray matter areas seen in the caudate, internal capsule, globus pallidus, and thalamus were excluded from the cortical and extracortical columns and represented instead under the subcortical column. BARS = Brain Arterial Remodeling Study; CAA = cerebral amyloid angiopathy.