Ischemic brain injury in cerebral amyloid angiopathy

Abstract

Cerebral amyloid angiopathy (CAA) is a common form of cerebral small vessel disease and an important risk factor for intracerebral hemorrhage and cognitive impairment. While the majority of research has focused on the hemorrhagic manifestation of CAA, its ischemic manifestations appear to have substantial clinical relevance as well. Findings from imaging and pathologic studies indicate that ischemic lesions are common in CAA, including white-matter hyperintensities, microinfarcts, and microstructural tissue abnormalities as detected with diffusion tensor imaging. Furthermore, imaging markers of ischemic disease show a robust association with cognition, independent of age, hemorrhagic lesions, and traditional vascular risk factors. Widespread ischemic tissue injury may affect cognition by disrupting white-matter connectivity, thereby hampering communication between brain regions. Challenges are to identify imaging markers that are able to capture widespread microvascular lesion burden in vivo and to further unravel the etiology of ischemic tissue injury by linking structural magnetic resonance imaging (MRI) abnormalities to their underlying pathophysiology and histopathology. A better understanding of the underlying mechanisms of ischemic brain injury in CAA will be a key step toward new interventions to improve long-term cognitive outcomes for patients with CAA.

Progression of Brain Network Alterations in Cerebral Amyloid Angiopathy

“…The accumulated injury of multiple microinfarcts forms one of the possible mechanisms for white matter network damage in CAA. 26 …”

White matter hyperintensity microstructure in amyloid dysmetabolism

“…These findings support our hypothesis of b-amyloid as a putative contributor to WMHs. A recent review concludes with ischemic brain injury as a common finding in CAA, 46 and it is possible to construe that WMHs may in pertinent cases reflect vascular b-amyloid deposition. This is supported by the predilection of WMHs in AD 5 and CAA 47 for posterior brain regions, and an increase in WMH volume over time in patients diagnosed with possible or probable CAA, 48 e.g.…”

MRI-visible perivascular space location is associated with Alzheimer's disease independently of amyloid burden

“…Arteriolosclerosis is associated with hypertension, diabetes and increasing age, and "vascular" dementia (the most common form of which is subcortical vascular cognitive impairment, SVCI), whereas CAA is the result of amyloid-beta (Aβ) deposition in the walls of small to medium vessels in the cortex and leptomeninges, and found in over 90% of those with AD (Charidimou et al, 2012). As well as being a risk factor for spontaneous intracerebral haemorrhage (Samarasekera et al, 2012), CAA can result in cognitive deficits independently of AD (Arvanitakis et al, 2011;Boyle et al, 2015;Reijmer et al, 2015), although the exact interaction between these two processes remains unclear. Traditionally AD and SVCI have been described as having distinct neuroimaging profiles (Wardlaw et al, 2013b;Greenberg et al, 2014), but clinically differentiating between the two remains difficult, as both the cognitive symptoms and the imaging findings frequently overlap (Lee et al, 2011;Wardlaw et al, 2013a;Wardlaw et al, 2013b;Greenberg et al, 2014;Lee et al, 2014).…”

“…PVS in the centrum semiovale (CSO-PVS) are associated with CAA-related intracerebral haemorrhage (ICH) (Charidimou et al, 2013b;Charidimou et al, 2014b) and its "haemorrhagic" markers, namely lobar microbleeds (Martinez- Ramirez et al, 2013;Yakushiji et al, 2014) and cortical superficial siderosis (Charidimou et al, 2014a). Indeed, a recent study using post-mortem 7-Tesla MR in CAA-related ICH found an association between juxta-cortical PVS enlargement and the histopathological grade of CAA in the overlying cortex (van Veluw et al, 2015). In addition, a small study of patients with CAA-related ICH and healthy controls found an association between amyloid-PET burden (as measured using 11-Carbon based Pittsburgh compound B, PiB) and CSO-PVS (Charidimou et al, 2015).…”