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.

Small subclinical hyperintense lesions are frequently encountered on brain diffusion-weighted imaging (DWI) scans of patients with cerebral amyloid angiopathy (CAA). Interpretation of these DWI+ lesions, however, has been limited by absence of histopathological examination. We aimed to determine whether DWI+ lesions represent acute microinfarcts on histopathology in brains with advanced CAA, using a combined in vivo MRI-ex vivo MRI-histopathology approach. We first investigated the histopathology of a punctate cortical DWI+ lesion observed on clinical in vivo MRI 7 days prior to death in a CAA case. Subsequently, we assessed the use of ex vivo DWI to identify similar punctate cortical lesions postmortem. Intact formalin-fixed hemispheres of 12 consecutive cases with CAA and three non-CAA controls were subjected to high-resolution 3 T ex vivo DWI and T2 imaging. Small cortical lesions were classified as either DWI+/T2+ or DWI−/ T2+. A representative subset of lesions from three CAA cases was selected for detailed histopathological examination. The DWI+ lesion observed on in vivo MRI could be matched to an area with evidence of recent ischemia on histopathology. Ex vivo MRI of the intact hemispheres revealed a total of 130 DWI+/T2+ lesions in 10/12 CAA cases, but none in controls (p = 0.022). DWI+/T2+ lesions examined histopathologically proved to be acute microinfarcts (classification accuracy 100%), characterized by presence of eosinophilic neurons on hematoxylin and eosin and absence of reactive astrocytes on glial fibrillary acidic protein-stained sections. In conclusion, we suggest that small DWI+ lesions in CAA represent acute microinfarcts. Furthermore, our findings support the use of ex vivo DWI as a method to detect acute microinfarcts postmortem, which may benefit future histopathological investigations on the etiology of microinfarcts.

Background: Damping of heartbeat-induced pressure pulsations occurs in large arteries such as the aorta and extends to the small arteries and microcirculation. Since recently, 7 T MRI enables investigation of damping in the small cerebral arteries. Purpose: To investigate flow pulsatility damping between the first segment of the middle cerebral artery (M1) and the small perforating arteries using magnetic resonance imaging. Study Type: Retrospective. Subjects: Thirty-eight participants (45% female) aged above 50 without history of heart failure, carotid occlusive disease, or cognitive impairment. Field Strength/Sequence: 3 T gradient echo (GE) T1-weighted images, spin-echo fluid-attenuated inversion recovery images, GE two-dimensional (2D) phase-contrast, and GE cine steady-state free precession images were acquired. At 7 T, T1-weighted images, GE quantitative-flow, and GE 2D phase-contrast images were acquired. Assessment: Velocity pulsatilities of the M1 and perforating arteries in the basal ganglia (BG) and semi-oval center (CSO) were measured. We used the damping index between the M1 and perforating arteries as a damping indicator (velocity pulsatility M1 /velocity pulsatility CSO/BG ). Left ventricular stroke volume (LVSV), mean arterial pressure (MAP), pulse pressure (PP), and aortic pulse wave velocity (PWV) were correlated with velocity pulsatility in the M1 and in perforating arteries, and with the damping index of the CSO and BG. Statistical Tests: Correlations of LVSV, MAP, PP, and PWV with velocity pulsatility in the M1 and small perforating arteries, and correlations with the damping indices were evaluated with linear regression analyses. Results: PP and PWV were significantly positively correlated to M1 velocity pulsatility. PWV was significantly negatively correlated to CSO velocity pulsatility, and PP was unrelated to CSO velocity pulsatility (P = 0.28). PP and PWV were uncorrelated to BG velocity pulsatility (P = 0.25; P = 0.68). PWV and PP were significantly positively correlated with the CSO damping index. Data Conclusion: Our study demonstrated a dynamic damping of velocity pulsatility between the M1 and small cerebral perforating arteries in relation to proximal stress. Level of Evidence: 4 Technical Efficacy: Stage 1