Cerebral amyloid angiopathy

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 haemorrhage. It is, along with Alzheimer disease, a common cerebral amyloid deposition disease.

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

Sporadic CAA

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 4.

Autopsy 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 CAA

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 haemorrhage with amyloidosis (Dutch, Italian, Flemish, Iowa, Piedmont, Arctic types)
  • ACys peptide with ​precursor protein cystatin C (chromosome 20): hereditary cerebral haemorrhage 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

Cortical vessel involvement results in intracerebral haemorrhage, either as lobar haemorrhages or rarely cerebellar haemorrhages 19, which present as stroke, or smaller lobar cerebral microhaemorrhages, which are often only detected radiologically 15. Vessel damage in corticosubcortical regions can also result in ischaemic leukoencephalopathy 7. It is thought that lobar cerebral microhaemorrhages and ischaemic leukoencephalopathy play a role in the development of cognitive impairment that is independent of Alzheimer disease 15, although recurrent lobar haemorrhages can also cause a step-wise decline in cognitive function.

Leptomeningeal vessel involvement results in convex subarachnoid haemorrhage, which can present with transient focal neurological symptoms (TFNS) or "amyloid spells", especially when localised to the central sulcus 16, which is in close proximity to the primary motor and sensory cortices. These TFNS are classically described as recurrent, stereotyped, spreading paraesthesias lasting several minutes but there is a wide spectrum of presentations encompassing both positive (spreading paraesthesia or visual symptoms) and negative (paresis, aphasia or dysphagia) phenomenology 17. It is important to differentiate TFNS from sensory transient ischaemic attacks and migraine with aura.

Uncommonly an inflammatory reaction may be incited and patients can present in a more subacute fashion with declining cognitive performance, seizures, headache and stroke-like episodes (without haemorrhage) 1,11. This known as cerebral amyloid angiopathy-related inflammation and is discussed separately. 

Occasionally mass like lesions, known as cerebral amyloidoma, have been reported 3,14. This is not to be confused with cerebral amyloidosis seen in patients with systemic amyloidosis. 

The Boston criteria 7 and newer Modified Boston criteria  9 are a combination of clinical, radiographic and pathological criteria which are used to assess the probability of cerebral amyloid angiopathy.

Cerebral amyloid angiopathy is characterised 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, 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 extra-cellular space. It and stains with Congo red yielding classic apple green birefringence when viewed with polarised light 3,20. When staining with thioflavin T and illuminated with ultraviolet light, the deposits emit bright green fluorescence 20.

Associations

Findings reflect the various manifestations of the disease:

  • cerebral haemorrhage
    • usually superficial (lobar
    • appearance will vary according to age of bleed (see blood on MRI)
  • microhaemorrhages
    • not seen on CT
    • small focal regions of signal drop out best seen on T2* sequences (gradient echo, echo-planar, SWI) as regions of blooming 12
    • may be difficult to see on conventional T1 and T2 sequences 4
    • tend to be corticosubcortical (grey-white matter junction) in distribution, but can also be in the cerebellum
    • tend to spare the basal ganglia and pons (c.f. hypertensive microhaemorrhages) 4, 14
  • convexal subarachnoid haemorrhage
    • appearance will vary according to age of bleed (see blood on MRI), but is best acutely seen on CT and T2 FLAIR 18
  • cortical superficial siderosis
    • not seen on CT
    • curvilinear regions of signal drop out localised to one of more sulci best seen on  T2* sequences (gradient echo, echo-planar, SWI) 9
    • thought to be a chronic sequela of covexal subarachnoid haemorrhage 9
    • may be seen in up to 60% of patients 9
    • not present infratenorially (c.f. superficial siderosis of the CNS)
  • ischaemic leukoencephalopathy 

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

  • hypertensive microangiopathy
    • haemorrhages, including microhaemorrhages, are typically located in basal ganglia, pons and cerebellum
    • not associated with subarachnoid haemorrhage or superficial siderosis
  • multiple cavernoma syndrome
    • lesions have a random distribution
    • random size, although Zabramski classification Type IV cavernous malformations are indistinguishable from cerebral microhaemorrhages related to CAA
    • often characteristic cavernous malformations can be identified
  • haemorrhagic metastases (e.g. melanoma)
    • lesions have a variable size and can often be larger than microhaemorrhages
    • 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
  • neurocysticercosis
    • nodular calcified stage visible on CT or phase-filtered SWI
    • random distribution 
  • fat embolism syndrome
    • 'starfield' pattern of distribution
    • lesions also show restricted diffusion on DWI and are likely visible on other sequences
  • radiation induced vasculopathy
    • microhaemorrhages have a very similar appearance (similar pathophysiology)
    • distribution related to treatment field
Neurodegenerative diseases

Neurodegenerative diseases are legion and their classification just as protean. A useful approach is to divide them according to underlying pathological process, although even using this schema, there is much overlap and thus resulting confusion.

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Article information

rID: 6691
Section: Pathology
Synonyms or Alternate Spellings:
  • Cerebral amyloid angiopathy (CAA)
  • Cerebral amyloid microangiopathy
  • CAA
  • Sporadic cerebral amyloid angiopathy
  • Familial cerebral amyloid angiopathy

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Cases and figures

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    Figure 1: histology with Congo red stain
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    Case 1
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    Immunohistochemis...
    Figure 2: histology with immunohistochemistry
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    Vase 2: with PRES
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    Case 3: with lobar haemorrhage
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    Case 4
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    Case 5
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    Case 7: with multiple lobar haemorrhages
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    Case 8: with lobar haemorrhage
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    Case 9
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    Case 10
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    Case 11
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    Superficial sider...
    Case 12: with inflammation
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    Case 13: with lobar haemorrhage
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    Case 14: with lobar haemorrhage
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    Case 15
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    Case 16: with lobar haemorrhage
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    Case 17: familial British dementia
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