Cerebrovascular function in pre-symptomatic and symptomatic individuals with hereditary cerebral amyloid angiopathy: a case-control study

Summary

Background

Previous work suggests that impairments of cerebrovascular flow or reactivity might be early markers of cerebral amyloid angiopathy (CAA). Hereditary cerebral hemorrhage with amyloidosis–Dutch type (HCHWA-D) is a genetic form of CAA that can diagnosed early by DNA testing, allowing study of CAA before onset of clinical symptoms. The aim of the present study was to investigate whether hemodynamic measures are decreased in HCHWA-D mutation carriers compared to healthy controls.

Methods

In this case-control study, we included pre-symptomatic and symptomatic HCHWA-D mutation carriers diagnosed through genetic testing and recruited through the HCHWA-D patient association (Katwijk, Netherlands) and the outpatient clinic of the Department of Neurology of the Leiden University Medical Center (Leiden, Netherlands), and healthy controls. Regional cerebral blood flow (rCBF) was measured using pseudo-continuous arterial spin labeling. Quantitative flow was determined by phase-contrast MR angiography of the cerebropetal vessels. Vascular reactivity was determined by measuring changes in the blood oxygen level-dependent (BOLD) signal after visual stimulation. Data from pre-symptomatic and symptomatic individuals were compared with healthy controls using mixed-model regression analysis.

Results

In the study done between May 15, 2012 and December 22, 2015, we investigated imaging data from 27 HCHWA-D mutation carriers (12 pre-symptomatic and 15 symptomatic) and 33 healthy controls. Compared with controls, symptomatic HCHWA-D carriers had significantly decreased cortical gray matter rCBF in the occipital lobe (mean difference −11.1 ml/100g/min, CI −2.8 to −19.3, p=0.010) and decreased flux in the basilar artery (mean difference −0.9ml/s, CI −1.5 to −0.2, p=0.019). However, no changes were observed in the rCBF and flux in pre-symptomatic carriers compared with controls. Vascular reactivity was significantly decreased in the occipital lobe in both pre-symptomatic (BOLD amplitude 1.1±0.5% change, mean difference −0.4% change, CI −0.7 to −0.2, p=0.001; time to baseline 10.1±7.6 s, mean difference 4.6 s, CI 0.4 to 8.8, p=0.032) and symptomatic carriers (BOLD amplitude 0.4±0.1% change, mean difference −0.9% change, CI −1.1 to −0.6, p<0.0001; TTP 14.8±8.6 s, mean difference 12.2 s, CI 8.6 to 15.9,p<0.0001; TTB 20.3±8.4 s, mean difference 13.1s, CI 9.4 to 16.9, p<0.0001) compared with controls.

Interpretation

Vascular reactivity in the occipital lobe was decreased in both symptomatic and pre-symptomatic individuals with HCHWA-D. This indicates that determination of vascular reactivity might be a useful biomarker for early detection of vascular amyloid pathology in sporadic CAA, and a biomarker of efficacy in future intervention trials.

Funding

National Institutes of Health.