Cerebral amyloid angiopathy

Last revised by Rohit Sharma on 23 Feb 2024

Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder caused by the accumulation of cerebral amyloid-β (Aβ) in the tunica media and adventitia of leptomeningeal and cortical vessels of the brain. The resultant vascular fragility tends to manifest in normotensive elderly patients as lobar intracerebral hemorrhage. It is, along with Alzheimer disease, a common cerebral amyloid deposition disease.

Cerebral amyloid angiopathy can be divided into sporadic (spontaneous), familial, and iatrogenic forms. 

Cerebral amyloid angiopathy is a frequent incidental finding, found on screening gradient-recalled echo imaging in up to 16% of asymptomatic elderly patients 4. Autopsy studies have found a prevalence of approximately 5-9% in patients between 60 and 69 years, and 43-58% in patients over the age of 90 years 4.

Autopsies of patients who have evidence of Alzheimer disease have found cerebral amyloid angiopathy in the vast majority of cases (90%). This rate is still high (20-40%) in non-demented elderly individuals 14.  

Importantly, it is usually not associated with systemic amyloidoses.

Familial cerebral amyloid angiopathy describes a group of very rare disorders that are usually encountered as autosomal dominant conditions 14,21. Many of these disorders are only isolated to only a few families and they mainly differ from spontaneous CAA in an earlier age of onset, typically in middle to late middle age 14,21. Furthermore, they may also be part of multi-system or other central nervous system genetic disorders 14,21.

Examples of familial CAA include 21:

  • Aß peptide with precursor protein APP (chromosome 21):

    • CAA related to familial Alzheimer disease

    • CAA in Down syndrome

    • hereditary cerebral hemorrhage with amyloidosis (Dutch, Italian, Flemish, Iowa, Piedmont, Arctic types)

  • ACys peptide with ​precursor protein cystatin C (chromosome 20): hereditary cerebral hemorrhage with amyloidosis Icelandic type

  • ATTR peptide with precursor protein transthyretin (chromosome 18): meningovascular amyloidosis (see cerebral transthyretin-associated amyloidoses)

  • AGel peptide with precursor protein gelsolin (chromosome 9): familial amyloidosis - Finnish type

  • PrPSc peptide with precursor prion protein (chromosome 20): Gerstmann-Straussler-Scheinker disease

  • ABri peptide with precursor protein ABri precursor protein (chromosome 13): familial British dementia (see case 17)

  • ADan peptide with precursor protein ADan precursor protein (chromosome 13): familial Danish dementia

Iatrogenic cerebral amyloid angiopathy is an extremely rare but increasingly recognized form, considering the disease to be a prionopathy attributed to transmission of Aβ seeds through surgical procedures, such as exposure to cadaveric dura (e.g. Lyodura dural patches) or growth hormone 30 . It is thought to clinically manifest approximately three decades after transmission has occurred 30.

  • Alzheimer disease

    • pathological cerebral amyloid angiopathy changes are seen in ~80% of those with Alzheimer disease (Aß-42) 5-13 

    • ~40% of those with cerebral amyloid angiopathy have Alzheimer dementia type symptoms

  • Down syndrome 25

  • chronic traumatic encephalopathy

  • other familial syndromes (as discussed above)

Manifestations of cortical vessel involvement:

The primary manifestation of leptomeningeal vessel involvement is due to convexity subarachnoid hemorrhage, which can present with transient focal neurological episodes or symptoms (TFNE or TFNS) or "amyloid spells" 25. These transient focal neurological episodes are classically described as recurrent, stereotyped, spreading paresthesias lasting several minutes but there is a wide spectrum of presentations encompassing both positive (spreading paresthesia or visual symptoms) and negative (paresis, aphasia or dysphagia) phenomenology 17,25. These symptoms are most prominent with the convexity subarachnoid hemorrhage is localized to the central sulcus 16, which is in close proximity to the primary motor and sensory cortices 25.

Other manifestations of CAA, which are discussed separately, include:

  • inflammatory cerebral amyloid angiopathy: an umbrella description for inflammatory reactions that present with rapidly-progressive cognitive decline, seizures, headache and stroke-like episodes (without hemorrhage) 1,11 

  • cerebral amyloidoma: mass-like lesions that have a varied presentation depending on the location of the amyloidoma

Cerebral amyloid angiopathy is characterized by the deposition of amyloid in the tunica media and/or tunica adventitia of small and medium-sized arteries of the cerebral cortex and leptomeninges 4,20. This is associated with fibrinoid degeneration with separation of the tunica media and tunica intima ('double barreling'), and microaneurysm formation 1.

There are a number of different proteins that can lead to intravascular amyloid deposition, however, the most common, as is the case in sporadic CAA, is Aß which is a short 42 amino acid peptide cleaved from amyloid precursor protein (APP) which is encoded on chromosome 21 20

Aß is an eosinophilic, insoluble protein, located in the extracellular space. It stains with Congo red yielding classic apple-green birefringence when viewed with polarized light 3,20. When staining with thioflavin T and illuminated with ultraviolet light, the Aß deposits emit bright green fluorescence 20.

Findings reflect the various manifestations of the disease:

  • hemorrhage

    • intracerebral hemorrhage

      • usually cortico-subcortical, in a so-called lobar location 22, but can also be seen in the 'superficial' cerebellum (especially in the cerebellar cortex or vermis) 24,34, may have finger-like projections 26

      • CT: initially hyperdense with hypodense perihaematomal edema, often exerts positive mass-effect 25

      • MRI: appearance will vary according to age of bleed (see blood on MRI25

    • cerebral microhemorrhage

      • defined as 2-10 millimeter, round or ovoid areas of hemorrhage, and tend to be corticosubcortical (grey-white matter junction) in distribution 25, but can also be in the superficial cerebellum 29

      • CT: not appreciated 25

      • MRI: only seen on T2* sequences (GRE, echo-planar, SWI) as regions of low-signal blooming artifact 12,25, not seen on conventional T1 and T2/FLAIR sequences 4

    • convexity subarachnoid hemorrhage

    • cortical superficial siderosis

      • thought to be a chronic sequela of convexity subarachnoid hemorrhage, including of hemorrhage that is asymptomatic 25

      • CT: not appreciated 25

      • MRI: curvilinear regions of signal drop-out localized to one or more sulci best seen on T2* sequences (GRE, echo-planar, SWI) 9,25

    • cerebellar superficial siderosis 28

      • similar to cortical superficial siderosis but involving the folia of the cerebellum, less prevalent than cortical superficial siderosis 28

      • CT: not appreciated

      • MRI: curvilinear regions of signal drop-out localized to one or more folia best seen on T2* sequences (GRE, echo-planar, SWI) 28

    • atraumatic subdural hemorrhage 35

      • often seen in conjunction with intracerebral hemorrhage, but can occur independently (however, a causal link has not been definitely established) 35

      • CT: initially hyperdense, but appearance varies with clot age and organization

      • MRI: appearance will vary according to age of bleed (see blood on MRI)

  • ischemia

    • ischemic leukoencephalopathy 

    • microinfarcts and lobar lacunes

      • acute cortico-subcortical lesions; lobar lacunes are 3-15 millimeters in size while microinfarcts are smaller 25

      • CT: not appreciated 25

      • MRI: same signal changes as in acute ischemic stroke, most pronounced on DWI 25

  • others

    • dilated perivascular spaces of the centrum semiovale

      • dilation of normal perivascular spaces in the centrum semiovale 25

        • tend to spare the basal ganglia and pons (cf. hypertensive dilated perivascular spaces) 25

      • CT: not appreciated 25

      • MRI: best appreciated on T2 images as CSF-signal structures with a varied appearance depending on the orientation of their draining vessel 25

    • cortical atrophy

      • CT: not appreciated 25

      • MRI: not readily appreciated on conventional sequences, requires cortical surface reconstructions 25

    • cortical calcifications

      • very rare in sporadic CAA but can be seen more commonly in certain hereditary forms (e.g. Dutch type) 32

        • tend to be seen in the occipital region 32

      • CT: readily appreciable as calcium-density areas of hyperattenuation

      • MRI: seen on T2* sequences (GRE, echo-planar, SWI) as regions of low-signal blooming artifact

Radiographic features of inflammatory cerebral amyloid angiopathy and cerebral amyloidoma are discussed separately.

The Boston criteria 2.0 31, which supersedes the original Boston criteria 7 and the modified Boston criteria 9, are a combination of clinical, radiographic and pathological criteria which are used to assess the probability of a diagnosis of cerebral amyloid angiopathy. These criteria require patients to have either biopsy specimens and/or brain MRI data available 7,9. Additionally, the Edinburgh criteria for lobar intracerebral hemorrhage associated with cerebral amyloid angiopathy can be utilized, especially for patients with a lobar intracerebral hemorrhage demonstrable on CT without an MRI having been performed 26.

There is currently no disease-modifying treatment available 27. Additionally, there are no guidelines regarding use of antiplatelet, anticoagulant, or thrombolytic drugs in patients with CAA, all medications which have been shown to possibly increase the risk of disabling hemorrhage in this patient group 27

Radiological differential diagnosis, particularly of cerebral microhemorrhages, includes 25,33:

  • hypertensive microangiopathy

    • hemorrhages, including microhemorrhages, are typically located in basal ganglia, pons and cerebellum

    • not associated with subarachnoid hemorrhage or superficial siderosis

  • multiple cavernoma syndrome

    • lesions have a random distribution

    • random size, although Zabramski classification type IV cavernous malformations are indistinguishable from cerebral microhemorrhages related to CAA

    • often characteristic cavernous malformations can be identified

  • hemorrhagic metastases (e.g. melanoma)

    • lesions have a variable size and can often be larger than microhemorrhages

    • enhancing

  • diffuse axonal injury

    • lesions are typically located at the grey-white matter junction, in the corpus callosum and in more severe cases, in the brainstem

  • fat embolism syndrome

    • 'starfield' pattern of distribution

    • lesions also show restricted diffusion on DWI and are likely visible on other sequences

  • radiation-induced vasculopathy

    • microhemorrhages have a very similar appearance (similar pathophysiology)

    • distribution related to the treatment field

  • post-cardiac surgery

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Cases and figures

  • Figure 1: histology with Congo red stain
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  • Figure 2: histology with immunohistochemistry
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  • Figure 3: radiological manifestations
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  • Case 1
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  • Case 2: with PRES
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  • Case 3: with lobar hemorrhage
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  • Case 4
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  • Case 5
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  • Case 6: with lobar hemorrhage
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  • Case 7: with multiple lobar hemorrhages
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  • Case 8: with lobar hemorrhage
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  • Case 9
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  • Case 10
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  • Case 11
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  • Case 12: with inflammation
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  • Case 13: with lobar hemorrhage
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  • Case 14: with lobar hemorrhage
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  • Case 15
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  • Case 16: with lobar hemorrhage
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  • Case 17: familial British dementia
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  • Case 18
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  • Case 19
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