Emerging concepts in sporadic cerebral amyloid angiopathy

Abstract

Sporadic cerebral amyloid angiopathy is a common, well-defined small vessel disease and a largely untreatable cause of intracerebral haemorrhage and contributor to age-related cognitive decline. The term 'cerebral amyloid angiopathy' now encompasses not only a specific cerebrovascular pathological finding, but also different clinical syndromes (both acute and progressive), brain parenchymal lesions seen on neuroimaging and a set of diagnostic criteria-the Boston criteria, which have resulted in increasingly detected disease during life. Over the past few years, it has become clear that, at the pathophysiological level, cerebral amyloid angiopathy appears to be in part a protein elimination failure angiopathy and that this dysfunction is a feed-forward process, which potentially leads to worsening vascular amyloid-β accumulation, activation of vascular injury pathways and impaired vascular physiology. From a clinical standpoint, cerebral amyloid angiopathy is characterized by individual focal lesions (microbleeds, cortical superficial siderosis, microinfarcts) and large-scale alterations (white matter hyperintensities, structural connectivity, cortical thickness), both cortical and subcortical. This review provides an interdisciplinary critical outlook on various emerging and changing concepts in the field, illustrating mechanisms associated with amyloid cerebrovascular pathology and neurological dysfunction.

Keywords: Alzheimer’s disease; cerebral amyloid angiopathy; intracerebral haemorrhage; perivascular drainage; small vessel disease.

Figure 1

Schematic representation of the spectrum of haemorrhagic and ischaemic manifestations of sporadic CAA, visible on structural MRI, including three key common neuropathological lesions seen in CAA brains. (A) A lobar cerebral microbleed identified on post-mortem 7 T MRI in the brain tissue of an 81-year-old male with dementia and severe CAA on pathology. On haematoxylin and eosin stain, brown and yellow deposits representing haemosiderin, and haematoidin, are seen, indicating that this haemorrhage is not chronic but subacute. (B) Prussian blue stain from an area corresponding to cortical superficial siderosis on in vivo MRI of a patient with advanced CAA. Blue deposits corresponding to haemosiderin are seen in the subarachnoid space (SAS) surrounding a leptomeningeal arteriole (which shows a vessel-within-vessel appearance) and in the superficial layers of the cortex. (C) A cortical microinfarct identified on histopathological examination. Note the severe vascular amyloid deposition (dark brown: immunostained for amyloid-β) in both the overlying leptomeningeal small vessels of different diameters and two cortical arterioles in the vicinity of the microinfarct. Bottom: Imaging CAA in clinical practice. 1.5 T brain MRI sequences. (D) Seventy-five-year-old male; initial evaluation of stereotyped episodes of right sided of tingling in the past year, axial section of SWI demonstrating a focus of cortical superficial siderosis on both banks of the left central sulcus, and multiple strictly lobar microbleeds (arrowheads in magnification). (E) Eighty-eight-year-old female with history of cognitive complaints, 6 months after initial imaging demonstrating multiple lobar microbleeds. Persistent headache and recent episode of left hand numbness and weakness; axial section of FLAIR sequence showing a linear hyperintensity in the right central sulcus, corresponding to acute subarachnoid blood. (F) Seventy-seven-year-old male otherwise meeting Boston criteria for CAA; coronal section (top) of T₁-weighted, and axial section of T₂-weighted sequences showing multiple dilated perivascular spaces (magnification) in the centrum semiovale, following the path of small calibre arteries. Diffuse widening of cerebral sulci due to marked cortical atrophy can also be appreciated. (G) Sixty-five-year-old male with acute onset of right hemiplegia and impaired consciousness at hospital arrival. Large right lobar (mostly parietal) ICH ruptured into the convexities and subarachnoid space. Contralateral multiple strictly lobar microbleeds are seen. EPVS = enlarged perivascular space; CMBs = cerebral microbleeds; sSAH = spinal subarachnoid haemorrhage; WMH = white matter hyperintensity.

Figure 2

Schematic overview of potential mechanisms of CAA pathophysiology as a self-reinforcing process. See text for details. Aβ = amyloid-β; BBB = blood–brain barrier; NVU = neurovascular unit.

Figure 3

Cortical thickness and functional MRI measures in cerebral amyloid angiopathy. (A) Regional differences in cortical thickness between patients with sporadic CAA and their age-matched controls (Fotiadis et al., 2016, reproduced with permission). Topographic surface maps were generated based on a general linear model (adjusting for age and sex) using a threshold of P < 0.01 (with false discovery rate correction for multiple comparisons) (Fotiadis et al., 2016). The resulting maps show the statistically significant regional differences in cortical thickness between the two groups. (B) Functional MRI visually activated region of interest of a representative probable CAA subject. The colour scale denotes the Z-statistic for activation using the canonical haemodynamic response function. (C) Functional MRI measurements in response to visual stimulation in an elderly probable CAA patient (red error space) versus an age-matched control subject (blue error space). For the CAA patient, functional MRI was done at baseline (red error space) and again with the same scanner and protocol after one clinically asymptomatic year (yellow error space). The solid lines represent the change from baseline BOLD signal averaged over 16 cycles of visual stimulation (on 20 s, shaded region, then off 28 s), with standard deviations of the responses shown in blue, red and yellow spaces and the trapezoidal model fits, as previously described (Dumas et al., 2012a). In the CAA patient, the amplitude of the modelled peak response decreased from 0.80% at baseline to 0.65% at 1 year.

Figure 4

White matter injury in CAA detected with diffusion tensor imaging. (A) Whole brain fibre tract reconstruction from fractional anisotropy map reflecting the degree of anisotropic diffusion of water molecules. (B) Left hemisphere: visualization of a DTI-based brain network from a patient with severe CAA. Brain regions are depicted by nodes and fibre tracts between regions are depicted by edges. Right hemisphere: local differences in connectivity strength between patients with CAA compared to age-matched controls, as previously described (Reijmer et al., 2015). Results show that tracts projecting to occipital, parietal, and temporal regions are most affected, whereas tracts projecting to frontal and subcortical regions are relatively spared (darker nodes show greater differences from controls). (C) Regions marked in red were selected for histopathological evaluation of an autopsied CAA subject who underwent DTI scanning during life. The white matter near a region of reduced nodal strength showed considerable myelin loss on Luxol^® Fast Blue stained sections relative to a region of relatively reserved nodal strength.

Figure 5

Suggested heuristic schematic of the possible different phenotypes of CAA and directions in the expression of the disease. The two main trees (from right to left) depict Alzheimer’s disease (AD) neurodegeneration, in which CAA is commonly found, and sporadic CAA. The third tree, in the background, represents sporadic non-amyloid microangioapathies. All three pathologies often co-exist in different combinations and severity in the ageing brain. Initially, different but overlapping pathophysiological pathways (roots of each tree in the grey box) can result in progressive vascular amyloid accumulation and pathophysiological alterations, which might culminate in structural vascular damage and brain injury. In extreme forms these might result in different neuroimaging and clinical phenotypes of the disease (different branches in each tree). At the one end we have the primarily haemorrhagic types of CAA, predominantly characterized by either multiple lobar cerebral microbleeds (CMB) (i.e. ‘microbleeders’) or cortical superficial siderosis (cSS) (‘superficial bleeders’), and/or symptomatic ICH (i.e. ‘macrobleeders’); at the other end we have the less haemorrhagic phenotypes of CAA, clinically expressed with more cognitive impairment and probably more strongly associated with cortical microinfarcts (CMI), with or without Alzheimer’s disease. Many patients can have intermediate phenotypes of the disease. The APOE ɛ genotype and vascular risk factors likely influence all the critical steps and different directions taken during the course of the disease in the ageing brain. Aβ = amyloid-β; TFNEs = transient focal neurological episodes; WMH = white matter hyperintensity.

Figure 6

Brain anatomical patterns, evolution and neuropathological phenotypes of cerebrovascular amyloid-β deposition in advanced CAA. (A) Schematic representation of the superficial cortical small vessel disease system in the brain, typically affected by CAA. Leptomeningeal arterioles give off short (S) penetrating arterioles (‘cortical’) reaching three different depths in the cortex (i.e. cortical layer III, V and the grey–white matter junction, S1–3, respectively), while long penetrators (‘medullary’, not usually affected by CAA) continue into the subcortical white matter. In advanced disease, often decreasing severity of CAA is seen between leptomeningeal, superficial and deeper layers in the cortex. (B) Regional severity of CAA with more heavy involvement of occipital and temporal lobes. Severe CAA probably progresses in a posterior-to-anterior fashion in the brain. (C) Neuropathological patterns spectrum of severe amyloid-β deposition. C(a)–C(d). Amyloid co-localization with basement membranes, to replacement of smooth muscle cells with some preservation of basement membrane elements, to complete replacement of the artery wall. C(e) More pronounced CAA-related vessel wall damage resulting in vasculopathic changes. C(f) Very focal amyloid deposition, but with complete replacement of smooth muscle and basement membrane layers at the point of vessel wall cracking, potentially providing a site of weakness and haemorrhage. C(g) Amyloid-β deposition in the tunica adventitia surrounding the perimeter of the vessel (instead of the tunica media). C(h) Capillary CAA, which might range from mild to severe, with dysfunction of pericytes and endothelial cells to complete capillary occlusion. A–C could potentially influence the spectrum of clinical imaging phenotypes of CAA, as neuropathological patterns of amyloid deposition can differentially affect leptomeningeal and cortical parenchymal vessels, with distinct anatomical patterns of deposition, degrees of accumulation, progression and pathophysiological consequences during the disease course. [C was redesigned and modified based on data and figures from (Keable et al., 2016), doi: 10.1007/s00401-016-1555-z, under Creative Commons Attribution License (CC BY)].