Cerebral amyloid angiopathy: emerging concepts

Abstract

Cerebral amyloid angiopathy (CAA) involves cerebrovascular amyloid deposition and is classified into several types according to the amyloid protein involved. Of these, sporadic amyloid β-protein (Aβ)-type CAA is most commonly found in older individuals and in patients with Alzheimer's disease (AD). Cerebrovascular Aβ deposits accompany functional and pathological changes in cerebral blood vessels (CAA-associated vasculopathies). CAA-associated vasculopathies lead to development of hemorrhagic lesions [lobar intracerebral macrohemorrhage, cortical microhemorrhage, and cortical superficial siderosis (cSS)/focal convexity subarachnoid hemorrhage (SAH)], ischemic lesions (cortical infarction and ischemic changes of the white matter), and encephalopathies that include subacute leukoencephalopathy caused by CAA-associated inflammation/angiitis. Thus, CAA is related to dementia, stroke, and encephalopathies. Recent advances in diagnostic procedures, particularly neuroimaging, have enabled us to establish a clinical diagnosis of CAA without brain biopsies. Sensitive magnetic resonance imaging (MRI) methods, such as gradient-echo T2(*) imaging and susceptibility-weighted imaging, are useful for detecting cortical microhemorrhages and cSS. Amyloid imaging with amyloid-binding positron emission tomography (PET) ligands, such as Pittsburgh Compound B, can detect CAA, although they cannot discriminate vascular from parenchymal amyloid deposits. In addition, cerebrospinal fluid markers may be useful, including levels of Aβ40 for CAA and anti-Aβ antibody for CAA-related inflammation. Moreover, cSS is closely associated with transient focal neurological episodes (TFNE). CAA-related inflammation/angiitis shares pathophysiology with amyloid-related imaging abnormalities (ARIA) induced by Aβ immunotherapies in AD patients. This article reviews CAA and CAA-related disorders with respect to their epidemiology, pathology, pathophysiology, clinical features, biomarkers, diagnosis, treatment, risk factors, and future perspectives.

Keywords: Amyloid β-protein; Cerebral amyloid angiopathy; Cerebrospinal fluid; Cerebrovascular disorders; MRI; PET.

Figure 1

CAA and CAA-associated vasculopathies. Massive amyloid deposition of amyloid fibrils with degeneration of smooth muscle cells in the media (A). Microaneurysmal dilatation (arrow) with fibrinoid necrosis (^*) (B). Thickening of the intima (arrow) and double barreling of vascular walls (arrowheads) (C). (A, electron micrograph, bar=1 µm; B, Congo red, original magnification 110×; C, Congo red, original magnification 170×).

Figure 2

Immunohistochemistry of adjacent brain sections with antibodies to Aβ40 (A) and Aβ42 (B). Positive immunoreactivity to Aβ40 is mainly observed in vessel walls (CAA) (A), whereas Aβ42 immunoreactivity is mainly observed in the brain parenchyma (senile plaques) (B).

Figure 3

Pathophysiology of cerebral amyloid angiopathy (CAA)-related disorders. Aβ shows parenchymal (senile plaques) or vascular deposition (CAA) depending on dominance of Aβ42 or Aβ40, respectively. CAA is related to stroke and dementia. Hx, hemorrhagic events; Ix, ischemic events; IR, immune reaction against Aβ.

Figure 4

Imaging findings of CAA-related hemorrhages and white matter lesions. Fresh (arrow) and old (arrowhead) lobar macrohemorrhages in the frontal lobes on CT (A). Cortical microhemorrhages with lobar distribution (B) and focal subarachnoid hemorrhages (superficial siderosis) (C) on gradient echo T2^*-weighted MRI. Posterior distribution of white matter hyperintensities (arrows on T2-weighted MRI) (D).

Figure 5

Amyloid positron emission tomography (PET) using 11C-Pittsburgh Compound B (PiB) (A) with gradient echo T2^*-weighted MRI (B) in a non-demented patient with multiple CAA-related intracerebral hemorrhages and disseminated cortical superficial siderosis. The left parietal region with an old intracerebral hemorrhage shows a relative scarcity of PiB uptake.