• a heterogeneous group of sporadic or familial disorders characterized by deposition of amyloid beta-peptide (Aβ) in the walls of small to medium-sized cerebral and leptomeningeal vessels in the absence of systemic amyloidosis
    • sporadic form – affects mainly the elderly population
    • rare familial forms (Icelandic, Arctic, or Dutch type) – occur at younger ages
  • CAA is responsible for ~2-10% of primary intracranial hemorrhages (30-70% of lobar hematomas in elderly patients)  [Chao, 2006]
  • CAA may also present with transient neurologic symptoms or encephalopathy

The APP (Amyloid Precursor Protein) gene

  • a transmembrane protein whose exact function is still under exploration; it is thought to be involved in neuronal development, synapse formation, and repair mechanisms within the nervous system
  • mutations can lead to an altered production or structure of amyloid-beta, which may result in familial forms of Alzheimer’s Disease or CAA (e.g., the Dutch, Italian, Arctic, Iowa, Flemish, and Piedmont types)
  • these mutations often result in increased production or altered clearance of Aβ peptides, which can accumulate in cerebral vessels

CST3 gene

  • the CST3 gene encodes the protein cystatin C, a potent inhibitor of lysosomal proteases known as cathepsins
  • cystatin C is critical for preventing the excessive breakdown of proteins by cathepsins in the body’s cells
  • mutations in the CST3 gene are associated with Hereditary Cystatin C Amyloid Angiopathy (HCCAA), a type of familial CAA prevalent in Iceland 
  • genetic testing can help identify individuals at risk for HCCAA
  • the CST3 gene and cystatin C have been studied for associations with other conditions such as Alzheimer’s disease, kidney disease, and cardiovascular risk

ITM2B gene

  • the ITM2B gene encodes the Integral Membrane Protein 2B (aka BRI2)
    • BRI2 is believed to play a role in protein processing and trafficking
  • mutations are associated with familial forms of CAA, specifically the British and Danish types
  • these mutations lead to abnormal processing of the BRI2 protein, resulting in the accumulation of amyloidogenic peptides in cerebral vessels


  • amyloid deposition in small to medium-sized cerebral arteries without systemic amyloidosis
    • type 1 CAA-  amyloid deposits in cortical capillaries, leptomeningeal and cortical arteries, and arterioles
    • type 2 CAA – deposits are present in leptomeningeal and cortical arteries but not in capillaries
  • there is some association with typical Alzheimer’s changes, such as neuritic plaques and neurofibrillary tangles
  • the reason for the increased deposition of Aβ in sporadic CAA is still unclear (a combination of increased production of the peptide with abnormal clearance has been proposed)
  • increased production is the dominant cause in familial forms
  • apolipoprotein E (APOE) ε2 and ε4 are associated with an increased risk of CAA
Cerebral amyloid angiopathy (CAA)

Clinical presentation

  • Transient Focal Neurological Episodes (TFNE), also called “amyloid spells
  • recurrent lobar intracerebral hemorrhage (ICH)
  • convexal nontraumatic subarachnoid hemorrhage
  • hemocephalus
  • arteriolopathy with leukoaraiosis and encephalopathy
  • development of vascular dementia in advanced stages of the disease
  • Transient focal neurological episodes (TFNE), also called “amyloid spells”)
    • positive symptoms – “aura-like” spreading paresis, visual phenomena (monocular blurred vision, flashes, teichopsia), limb twitching
    • negative symptoms – transient focal symptoms – paresis, speech, and visual disturbances
  • positive symptoms predominate
  • typically, multiple stereotyped episodes occur, each lasting 10-30 minutes
  • approx. 14% of CAA patients exhibit such symptoms [Charidimou, 2012]
  • often caused by convexal SAH
    • FLAIR, DWI/ADC, and GRE/SWI are optimal for diagnostic workup
    • frequently, convexial SAH is seen along with microbleeds or parenchymal hematoma, but also with recent lesions on DWI –  etiology is heterogeneous
  • spells may be confused with TIA (antithrombotic drugs further increase the risk of ICH) or stroke (high risk of ICH during thrombolysis)
  • TFNE often precede subsequent ICH (37.5%/2 months)!! [Charidimou, 2012]

Diagnostic evaluation

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Anticoagulation in patients with suspected CAA

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Thrombolysis in patients with suspected CAA

  • IVT is a reasonable treatment option in patients with CMBs < 10 (AHA/ASA 2019 IIa/B-NR)
  • with CMBs >10, IVT is associated with a higher risk of ICH; the expected benefit of treatment must outweigh the risk (AHA/ASA 2019 IIb/B-NR)
    • consider IVT in a patient with a severe deficit, taking into account premorbid health status and the presence of other risk factors

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Cerebral amyloid angiopathy (CAA)
link: https://www.stroke-manual.com/cerebral-amyloid-angiopathy-caa/