Neurovascular decoupling is associated with severity of cerebral amyloid angiopathy

Abstract

Objectives: We used functional MRI (fMRI), transcranial Doppler ultrasound, and visual evoked potentials (VEPs) to determine the nature of blood flow responses to functional brain activity and carbon dioxide (CO 2 ) inhalation in patients with cerebral amyloid angiopathy (CAA), and their association with markers of CAA severity.Methods: In a cross-sectional prospective cohort study, fMRI, transcranial Doppler ultrasound CO 2 reactivity, and VEP data were compared between 18 patients with probable CAA (by Boston criteria) and 18 healthy controls, matched by sex and age. Functional MRI consisted of a visual task (viewing an alternating checkerboard pattern) and a motor task (tapping the fingers of the dominant hand).Results: Patients with CAA had lower amplitude of the fMRI response in visual cortex compared with controls (p 5 0.01), but not in motor cortex (p 5 0.22). In patients with CAA, lower visual cortex fMRI amplitude correlated with higher white matter lesion volume (r 5 20.66, p 5 0.003) and more microbleeds (r 5 20.78, p , 0.001). VEP P100 amplitudes, however, did not differ between CAA and controls (p 5 0.45). There were trends toward reduced CO 2 reactivity in the middle cerebral artery (p 5 0.10) and posterior cerebral artery (p 5 0.08).Conclusions: Impaired blood flow responses in CAA are more evident using a task to activate the occipital lobe than the frontal lobe, consistent with the gradient of increasing vascular amyloid severity from frontal to occipital lobe seen in pathologic studies. Reduced fMRI responses in CAA are caused, at least partly, by impaired vascular reactivity, and are strongly correlated with other neuroimaging markers of CAA severity. Neurology ® 2013;81:1659-1665 GLOSSARY BOLD 5 blood oxygen level-dependent; CAA 5 cerebral amyloid angiopathy; CO 2 5 carbon dioxide; DEF 5 dynamic end-tidal forcing; DSM-IV 5 Diagnostic and Statistical Manual of Mental Disorders, 4th edition; fMRI 5 functional MRI; ICH 5 intracerebral hemorrhage; PETCO 2 5 partial pressure of end-tidal carbon dioxide; VEP 5 visual evoked potential; WMH 5 white matter hyperintensity.Cerebral amyloid angiopathy (CAA) is best recognized clinically as a cause of frequent recurrent intracerebral hemorrhages (ICHs) and microbleeds, reflecting loss of vascular integrity due to b-amyloid deposition.1 However, accumulating evidence suggests that impaired vascular reactivity is another feature of CAA. In a mouse model of severe CAA, there was decreased vasodilation in response to whisker barrel stimulation and to carbon dioxide (CO 2 ) inhalation, a vasodilatory stimulus.2 In a small study of patients with probable CAA, posterior cerebral artery flow velocity responses were lower than controls when viewing a visual stimulus, but middle cerebral artery flow velocity responses to CO 2 inhalation were relatively preserved.3 It was not clear whether the differential responses observed in the visual and CO 2 experiments were due to the different arteries tested, the different types of vasodilatory stimulus used, or wer...

Pathophysiology of Hypoperfusion of the Precuneus in Early Alzheimer's Disease

“…The elevated production of EDN1 may be an unfortunate side effect of over‐activation of this pathway by excessive Aβ42. In contrast, endothelial production of EDN1, mediated by ECE1 and driven by Aβ40, is more likely to contribute to episodic, free radical‐dependent dysfunction of vascular regulation in AD 48 (Figure 7), including abnormalities of autoregulation and functional hyperaemia demonstrated initially in mouse models of cerebral Aβ accumulation 24, 39 and CAA 49, 54, and more recently in patients with AD 14 and probable CAA 50. It should be noted, in addition, that EDN1 is very unlikely to be the sole nonstructural mediator of hypoperfusion of the precuneus in early AD.…”

Ischemic brain injury in cerebral amyloid angiopathy

“…longer BOLD time to peak in patients were related to greater WMH volume, independent of age, sex, and hypertension, [88][89][90] providing a possible mechanism for subcortical ischemic injury. The authors hypothesize that impaired vasoreactivity in CAA might cause a mismatch between perfusion and metabolic demand, thereby inducing ischemic damage.…”

Cerebral Amyloid Angiopathy Is Associated With Executive Dysfunction and Mild Cognitive Impairment

“…4 The participants were recruited from a stroke prevention clinic or memory clinic. Participants were assessed >90 days after symptomatic ICH to avoid confounding effects of acute ICH.…”

“…WMH volumes were measured using Quantomo (Cybertrials, Inc, Calgary, Canada), a custom-designed software application. 4 WMH volumes were expressed as a fraction of intracranial volume and are presented in cm 3 relative to a typical intracranial volume of 1448.9 cm 3 to account for differences in head size, as in past studies. 19 Good measurement reliability was demonstrated on measurement of 30 CATCH participants by 3 independent raters, with intraclass correlation coefficients 0.98 for inter-rater and 0.98 to 0.99 for intrarater reliability.…”

“…The percent of blood oxygen level-dependent (BOLD) response in the visual cortex was determined using functional MRI (fMRI) during a visual stimulation task, as previously described. 4 MRI data were missing from 2 participants because of claustrophobia, and 1 participant did not have susceptibility-weighted imaging.…”