Evaluation of Disease Severity Using CSF Biomarkers in Patients With Probable Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) is currently diagnosed using MRI-based Boston criteria. However, imaging markers represent downstream consequences of vascular injury and may not fully reflect disease severity. CSF biomarkers, particularly β-amyloid 1-42 (Aβ42) and β-amyloid 1-40 (Aβ40), may provide a more direct measure of vascular amyloid burden. We investigated the association between CSF biomarkers and hemorrhagic and nonhemorrhagic MRI markers of disease severity in probable CAA.

We conducted a retrospective multicenter cohort study including consecutive patients diagnosed with probable CAA according to Boston criteria v2.0 at 2 tertiary centers (2014-2023) who underwent lumbar puncture (LP) as part of clinical evaluation. CSF Aβ42, Aβ40, total tau, and phosphorylated-tau 181 (p-tau181) were measured using standardized immunoassays. MRI markers included lobar cerebral microbleeds (CMBs), cortical superficial siderosis (cSS), white matter hyperintensity burden, Fazekas score, and enlarged perivascular spaces in the centrum semiovale. Multivariable linear regression models were adjusted for age, sex, MRI sequence type, and delay between onset and LP. False discovery rate correction was applied for multiple testing. We also used principal component analysis to explore associations between MRI and CSF biomarkers.

A total of 102 patients were included (mean age at LP 72.0 ± 7.5 years; 65% male). Initial presentations were cognitive impairment in 53%, intracerebral hemorrhage in 34%, and transient focal neurologic episodes in 13%. Lower CSF Aβ40 and Aβ42 levels were significantly associated with greater cSS burden (standardized β -0.49 [95% CI -0.8 to -0.17], p = 0.002 and -0.42 [-0.73 to -0.11], p = 0.007, respectively) and higher Fazekas score (β -0.18 [-0.33 to -0.03], p = 0.02 and -0.23 [-0.38 to -0.08], p = 0.002) but not with CMB count. No significant association was found between tau species and MRI markers. Associations remained significant after stratification by CSF Aβ42/Aβ40-defined Alzheimer-like profile.

In probable CAA, lower CSF Aβ40 and Aβ42 levels are associated with established MRI markers of disease severity, independently of clinical presentation and concomitant Alzheimer-like profile. These findings suggest that CSF Aβ levels may reflect vascular amyloid burden rather than downstream neurodegeneration. Prospective longitudinal studies are needed to determine their prognostic value.