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

Abstract

Background: Previous work suggests that impairments of cerebrovascular flow or reactivity might be early markers of cerebral amyloid angiopathy (CAA). Hereditary cerebral haemorrhage with amyloidosis-Dutch type (HCHWA-D) is a genetic form of CAA that can be diagnosed before the onset of clinical symptoms by DNA testing. We aimed to investigate whether haemodynamic measures are decreased in presymptomatic and symptomatic HCHWA-D mutation carriers compared with healthy controls.

Methods: In this case-control study, we included presymptomatic 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. We measured regional cerebral blood flow (rCBF) using pseudo-continuous arterial spin labelling. Quantitative flow was measured by phase-contrast magnetic resonance angiography of the cerebropetal vessels. Vascular reactivity was established by measuring changes in blood-oxygen-level-dependent (BOLD) signal after visual stimulation. Data from presymptomatic and symptomatic individuals were compared with healthy controls using mixed-model regression analysis.

Findings: Between May 15, 2012, and December 22, 2015, we investigated cross-sectional imaging data from 27 HCHWA-D mutation carriers (12 presymptomatic and 15 symptomatic) and 33 healthy controls. Compared with controls, symptomatic HCHWA-D carriers had significantly decreased cortical grey matter rCBF in the occipital lobe (mean difference -11·1 mL/100 g per min, 95% CI -2·8 to -19·3; uncorrected p=0·010) and decreased flux in the basilar artery (mean difference -0·9 mL/s, 95% CI -1·5 to -0·2; uncorrected p=0·019). However, we noted no changes in rCBF and flux in presymptomatic carriers compared with controls. Vascular reactivity was significantly decreased in the occipital lobe in both presymptomatic (mean BOLD change 1·1% [SD 0·5], mean difference -0·4% change, 95% CI -0·7 to -0·2; p=0·001; mean time to baseline 10·1 s [SD 7·6], mean difference 4·6 s, 95% CI 0·4 to 8·8; p=0·032) and symptomatic carriers (mean BOLD change 0·4% [SD 0·1], mean difference -0·9%, 95% CI -1·1 to -0·6; p<0·0001; mean time to baseline 20·3 s [SD 8·4], mean difference 13·1 s, 95% CI 9·4 to 16·9; p<0·0001) compared with controls; however, the difference in mean time to peak was only significant for symptomatic carriers (mean difference 12·2 s, 95% CI 8·6 to 15·9; p<0·0001).

Interpretation: Our findings suggest 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. Our data indicate that vascular reactivity measurements might be useful for differential diagnosis in dementia to determine the vascular component.

Funding: USA National Institutes of Health.

Figure 1. Cerebral blood flow measurements by age

Blue triangles, : control subjects, red squares, : pre-symptomatic mutation carriers, black circles, ; symptomatic mutation carriers. (A) Total flux measured in ml/sec. (B) Flux in the basilar artery measured in cm/sec. (C) Mean total supra-tentorial cortical gray matter perfusion and (D) mean occipital cortical grey matter perfusion both measured in mL/100 g/min.

Figure 2. Blood oxygen level-dependent (BOLD) response within the occipital lobe

(Top panel) Average group block responses relative to baseline (set at 0%) for all HCHWA-D mutation carriers and all controls; and (middle panel) for symptomatic and (bottom panel) pre-symptomatic mutation carriers and age-matched control subjects. BOLD amplitude measured in percentage BOLD change. Grey boxes indicate the time of activation of the visual stimulus.

Figure 2. Blood oxygen level-dependent (BOLD) response within the occipital lobe

(Top panel) Average group block responses relative to baseline (set at 0%) for all HCHWA-D mutation carriers and all controls; and (middle panel) for symptomatic and (bottom panel) pre-symptomatic mutation carriers and age-matched control subjects. BOLD amplitude measured in percentage BOLD change. Grey boxes indicate the time of activation of the visual stimulus.

Figure 2. Blood oxygen level-dependent (BOLD) response within the occipital lobe

(Top panel) Average group block responses relative to baseline (set at 0%) for all HCHWA-D mutation carriers and all controls; and (middle panel) for symptomatic and (bottom panel) pre-symptomatic mutation carriers and age-matched control subjects. BOLD amplitude measured in percentage BOLD change. Grey boxes indicate the time of activation of the visual stimulus.

Figure 3. Blood oxygen level-dependent (BOLD) fMRI measurements by age

Blue triangles, : control subjects, red squares, : pre-symptomatic mutation carriers, black circles, ; symptomatic mutation carriers.(A) BOLD amplitude measured in percentage BOLD change, (B) time to peak, and (C) time to baseline in seconds.