Cerebral amyloid angiopathy (CAA) is a form of angiopathy in which specific proteins deposit in the walls of small to medium-sized blood vessels of the central nervous system and meninges. The term congophilic is sometimes used because the presence of the abnormal aggregations of amyloid can be demonstrated by microscopic examination of brain tissue after staining with Congo red. The amyloid material is only found in the brain and as such the disease is not related to other forms of amyloidosis.

Types Several familial variants exist. The condition is usually associated with amyloid beta (Aβ). However, there are types involving other amyloid peptides: The "Icelandic type" is associated with cystatin C amyloid (ACys). The "British type" and "Danish type" are associated with British amyloid (ABri) and Danish amyloid (ADan), respectively. Both peptides are linked to mutations in ITM2B. Familial amyloidosis-Finnish type is associated with gelsolin amyloid (AGel). Some prion diseases exhibit CAA caused by deposition of the prion protein.

Signs and symptoms CAA is associated with brain hemorrhages, particularly microhemorrhages. The accumulation of Aβ peptide deposits in the blood vessel walls results in damage to the blood vessels and hindrance of normal blood flow, making blood vessels more prone to bleeding. Since CAA can be caused by the same amyloidogenic protein that is associated with Alzheimer's disease, brain bleeds are more common in people who have a diagnosis of Alzheimer's disease. However, they can also occur in those who have no history of dementia. The bleeding within the brain is usually confined to a particular lobe and this is slightly different compared to brain bleeds which occur as a consequence of high blood pressure (hypertension) – a more common cause of a hemorrhagic stroke (or bleeding in the brain). The location of the cerebral microbleed determines whether it is more likely to have been caused by hypertension or CAA. Tsai et al. conducted amyloid PET imaging in an Asian population with cerebral amyloid angiopathy–intracerebral hemorrhage and noticed that superficial cerebellar microbleeds are related to CAA, whereas deep or mixed-location cerebellar microbleeds are more likely related to hypertension.

Causes

CAA has been identified as occurring either sporadically (generally in elderly populations) or in familial forms such as Flemish, Iowa, and Dutch types. In these cases, it is defined by the deposition of amyloid beta (Aβ) in the leptomeningeal and cerebral vessel walls. CAA occurring in the Flemish type has been observed to be linked to large dense-core plaques observed in this pedigree. Very rare cases of iatrogenic CAA have occurred in people who had been exposed to biologic therapeutics that had been contaminated with prion-like seeds of Aβ. The biologic materials, which are no longer in use, included growth hormone and dura mater patches that had been sourced from human cadavers.

The reason for the deposition of Aβ in sporadic CAA is still unclear, with both increased production of the peptide and abnormal clearance having been proposed as potential causes. Under normal physiology Aβ is cleared from the brain by four pathways: (1) endocytosis by astrocytes and microglial cells, (2) enzymatic degradation by neprilysin or insulysin (3) clearance by way of the blood–brain barrier or (4) drainage along periarterial spaces. Abnormalities in each of these clearance pathways have been linked to CAA.

In familial forms of CAA, Aβ buildup is likely due to increased production rather than poor clearance. Mutations in the amyloid precursor protein (APP), Presenilin (PS) 1 and PS2 genes can result in increased rates of cleavage of the APP into Aβ. An immune mechanism has also been proposed. Apolipoprotein E (APOE) subtypes ε2 and ε4 are associated with an increased probability of getting cerebral amyloid angiopathy. The use of antiplatelet and anticoagulant therapy increases the risk of intracerebral haemorrhage in people with CAA.

Pathophysiology The vascular amyloid pathology characteristic of CAA can be classified as either Type 1 or Type 2, the latter type being more common. Type 1 CAA entails detectable amyloid deposits within cortical capillaries as well as within leptomeningeal and cortical arteries, arterioles, veins, and venules. In type 2 CAA pathology, amyloid deposits are present in leptomeningeal and cortical arteries and arterioles but not in capillaries. Deposits in veins or venules are possible in either type but are far less prevalent.

Diagnosis

Diagnosis of CAA in living patients is improving, but definitive diagnosis requires examination of the brain at autopsy. In rare cases, biopsy can play a role in diagnosing probable cases. When no tissue is available for microscopic examination, the Boston criteria are used to determine probable CAA cases from MRI or CT scan data. The Boston Criteria for diagnosis are based largely on specific findings on MRI, including lobar hemorrhage and/or cortical microbleeds, cortical superficial siderosis, and often a characteristic non-bleed sign such as spotty white matter hyperintensities. Susceptibility weighted imaging has been proposed as a tool for identifying CAA-related microhemorrhages.

Imaging Cerebral amyloid angiopathy can present with lobar intracerebral hemorrhage or microbleeds in the brain. The bleeding usually occurs on the surfaces of the brain in contrast with intracranial haemorrhage due to high blood pressure, which occurs in deep locations of the brain such as basal ganglia and pons. In a lobar intracerebral bleed, computed tomography (CT) scan would show a hyperdense haemorrhage area and hypodense oedema around the haemorrhagic site.MRI sequences of gradient echo and susceptibility weighted imaging (SWI) are useful in detecting microbleeds and deposition of iron on the brain cortex (cortical superficial siderosis). Other MRI indicators of CAA include white matter hyperintensities and cortical thinning.

Management The aim in cerebral amyloid angiopathy is to treat the symptoms, as there is no current cure. Physical, occupational, and/or speech therapy may be helpful in the management of this condition.

History Gustav Oppenheim was the first to report amyloid deposits in the vasculature of the central nervous system in 1909. The first paper focusing solely on what would come to be known as CAA was published in 1938 by WZ Scholz. In 1979, H. Okazaki published a paper implicating CAA in certain cases of lobar intracerebral hemorrhage. The Boston Criteria for CAA originated in a 1995 paper from Harvard Medical School.

In animals

Cerebral Aβ-amyloid angiopathy develops with age in several nonhuman species, including primates, dogs, cats, and other vertebrates. Among primates, CAA has been documented in prosimians, New World monkeys, Old World monkeys and great apes. In older squirrel monkeys, CAA can be abundant, particularly in capillaries, although larger vessels also are involved.

In one aged squirrel monkey, CAA has been associated with amyloid-related imaging abnormalities (ARIA). Mice and rats don't naturally manifest CAA, but several genetically modified rodent models have been generated that develop CAA as they age.

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