Introduction
Cerebral amyloid angiopathy (CAA) is a microangiopathy defined by progressive deposition of beta amyloid (Aβ) in the walls of distal cortical and leptomeningeal vessels. The resulting small vessel damage can result in hemorrhage, infarction, and/or chronic hypoperfusion, the sequela of which produce a spectrum of characteristic neuroimaging findings. Although both hereditary and sporadic forms exist, in this chapter, we will focus on sporadic CAA, which is most commonly found in older individuals and is associated with Alzheimer dementia (AD).
Epidemiology, Pathology, and Clinical Presentation
CAA is a frequent neuropathologic finding and fairly common clinical entity in the elderly. Population studies estimate the presence of CAA in approximately 30% of individuals older than 60 years and approximately 55% of patients with dementia. The most severe complication of CAA is hemorrhage. Approximately 20% of spontaneous intracranial hemorrhage in the elderly is attributable to CAA.
CAA results from impaired perivascular lymphatic drainage and failure of elimination of Aβ from the brain with age and AD. Aβ is derived from proteolysis of the amyloid precursor protein, an integral membrane protein found in many tissues but concentrated in the synapses of neurons. Different proteolytic enzymes produce Aβ of varying lengths, solubility, and aggregation capabilities. Under normal conditions, all forms diffuse through the narrow extracellular spaces of the brain parenchyma before entering the bulk flow lymphatic drainage pathways located in the basement membranes of distal cortical and leptomeningeal arterioles and capillaries. These peripheral vessels seem particularly prone to Aβ deposition due to the basic composition of the arterial wall and absence of alternative perivascular lymphatic drainage pathways. Age and certain genetic factors contribute to changes in the basement membrane and hardening of the arterial walls, which disrupts this drainage. In this setting, the longer, insoluble form of Aβ (Aβ42), which tends to aggregate more easily, is more readily deposited in the brain parenchyma, contributing to the formation of senile plaques and AD. The shorter, soluble form (Aβ40), which does not aggregate as easily, can still diffuse through the extracellular matrix but is not easily cleared by the cerebral lymphatics and becomes deposited in the basement membrane, laying the foundation for CAA.
As disease progresses and Aβ accumulates, it disrupts the basement membrane, erodes smooth muscle, and eventually replaces the entire vessel wall, extending into the adventitia ( Fig. 4.1 ). Severe CAA is often accompanied pathologically by obliterative intimal changes, hyaline degeneration, microaneurysmal dilation, and fibrinoid necrosis. The resulting vasculopathy is the basis for CAA pathology, leading to development of acute and chronic hemorrhage, ischemia, and chronic hypoperfusion, any or all of which can be reflected in the computed tomography (CT) and magnetic resonance imaging (MRI).
Clinical and Imaging Features
Overview
Patients with CAA are frequently asymptomatic, particularly in the early stages. As disease progresses, there can be tremendous overlap with other diseases commonly afflicting the elderly, such as transient ischemic attacks (TIAs), other acute neurologic deficits, and dementia. Individual patient presentation and progression is extremely varied, in part due to how different CAA risk factors affect the process of perivascular clearance. For instance, the ApoE4 genotype alters the biochemical composition of the basement membrane, whereas midlife hypertension alters the biochemical forces on the arterial wall. Whether alone or combined, these mechanisms make the vessel wall more susceptible to Aβ deposition. Delineation of individual risk factors to predict potential hemorrhage and progression to ischemia or dementia are the subject of continued research.
Although definitive diagnosis of CAA still relies on brain biopsy, there has been a trend toward more definitive diagnosis with imaging. The Boston criteria were developed in the mid-1990s as a tool to both improve and standardize the diagnosis of CAA and have been refined since then ( Box 4.1 ).
Definite CAA
Full postmortem examination, demonstrating:
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Lobar, cortical, or corticosubcortical hemorrhage
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Severe CAA with vasculopathy
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Absence of other diagnostic lesion
Probable CAA with supporting pathology
Clinical data and pathologic tissues demonstrating:
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Lobar, cortical, or corticosubcortical hemorrhage
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Some degree of CAA in specimen
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Absence of other diagnostic lesion
Probable CAA
Clinical data and MRI or CT demonstrating:
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Multiple hemorrhage restricted to lobar, cortical or corticosubcortical regions
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Age >55 years
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Absence of other cause of hemorrhage
Possible CAA
Clinical data and MRI or CT demonstrating:
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Single lobar, cortical, or corticosubcortical regions
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Age >55 years
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Absence of other cause of hemorrhage
CAA , Cerebral amyloid angiopathy; CT , computed tomography; MRI , magnetic resonance imaging.
In Greater Depth
The Boston criteria rely heavily on the hemorrhagic manifestations of CAA, which are most characteristic of the disease, and include lobar hemorrhages, cerebral microbleeds (also called petechial microhemorrhages), and cortical superficial siderosis (cSS). However, nonhemorrhagic manifestations of the disease may predominate in individual patients, underscoring the radiologist’s role in arriving at the diagnosis. These include white matter changes, cortical microinfarcts, MRI visible perivascular spaces, and CAA-related inflammation ( Fig. 4.2 ).
Hemorrhagic Manifestations of Cerebral Amyloid Angiopathy
The most clinically devastating manifestation of CAA is spontaneous lobar intracerebral hemorrhage (ICH). The lobar predominance is due the underlying Aβ deposition pattern that favors cortical vessels over those in the deep gray or white matter or the brainstems. CAA-related ICHs tend to cluster in the posterior cortical regions and also affect the cerebellar hemispheres. Because of their superficial location, CAA-related ICHs more readily dissect into the subarachnoid spaces and less so into the ventricles.
Cerebral microbleeds (CMs) are very common in CAA and therefore one of the diagnostic markers of the Boston criteria. Their imaging signature on MRI arises from perivascular hemosiderin deposition in CAA-affected vessels, which gets concentrated in macrophages. The paramagnetic properties of this deposited hemosiderin result in local inhomogeneities in the magnetic field, resulting in loss of signal on T2* gradient echo and susceptibility-weighted imaging. Although most papers define CMs as having a size of approximately 5 mm (range 2–10 mm), it cannot be overemphasized that size and number detected vary dramatically with imaging technique. CAA-related CMs are, like CAA-related ICHs, lobar in distribution, with a predilection for the posterior brain regions, thereby distinguishing themselves from the more central CMs of hypertension. When strictly lobar, they strongly predict CAA pathology in a hospital setting. However, in the general population, this correlation does not appear as strong. CAA-related CMs appear to be spatially correlated with areas of amyloid deposition in positron emission tomography (PET) using the amyloid radioligand Pittsburgh Compound B (PiB PET). Overall, they represent a relatively easily assessable biomarker for disease severity and possibly progression.
cSS is another key hemorrhagic feature of CAA. It describes a specific imaging pattern of linear signal loss along the gyral surface of the cerebral convexities. cSS is a common finding in patients with symptomatic probable or definite CAA, found in 40% to 60% of cases. Although the exact pathophysiologic mechanism is not known, observational data indicate that the cSS most likely represents the hemosiderin residues from acute convexity subarachnoid hemorrhage resulting from rupture of CAA-laden cortical or leptomeningeal vessels. CAA-related cSS is a predictor of future spontaneous ICH, with potential implications for antithrombotic therapies.
Nonhemorrhagic Manifestations of Cerebral Amyloid Angiopathy
CAA is closely associated with the presence and severity of white matter hyperintensities (WMHs) of presumed vascular origin. These lesions are hyperintense on T2 or fluid-attenuated inversion recovery (FLAIR) sequences and located in the periventricular and subcortical white matter. In CAA patients, these WMHs are more severe than those in healthy older adults or patients with AD. CAA-related WMHs appear to predominate in the posterior (parietooccipital) brain regions and are shown to correlate with higher concentrations of Aβ deposition on PiB PET. Based on Aβ’s observed effects on vessel wall structure and function, WMHs in CAA most likely arise from some mix of acute ischemic and chronic hypoperfusion.
Cerebral microinfarcts are tiny infarcts, in the millimeter to submillimeter range, which are frequently only visible on microscopic tissue examination. Diffusion-weighted imaging lesions are detected in approximately 15% of patients with CAA and ICH, and chronic cortical infarcts are seen in up to 100% of CAA patients on ultra-high-field MRI. Although commonly associated with other hemorrhagic and nonhemorrhagic manifestations of CAA, there is evidence of that the cortical microinfarcts independently contribute to cognitive impairment and brain atrophy, making them a promising target of research.
Perivascular spaces in the centrum semiovale identified on MRI were recently shown to be associated with PiB PET cerebrovascular Aβ burden. Their appearance is thought to reflect obstructed perivascular lymphatic drainage channels resulting from progressive Aβ deposition, and their presence is a proposed marker for CAA ( Fig. 4.3 ).
