• Cerebral Amyloid Angiopathy (CAA) is 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; this accumulation can lead to vessel weakening, rupture, and cerebral hemorrhages
    • 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”)
    • 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

  • a definitive diagnosis can only be confirmed postmortem
  • however, in elderly patients presenting with two or more lobar hemorrhages and concomitant microangiopathic changes on MRI, the diagnosis of CCA is highly probable
  • typical findings on MRI include:
Superficial siderosis in a patient with CAA
Cerebral amyloid angiopathy (CAA)
Cerebral amyloid angiopathy (CAA)

Cerebral amyloid angiopathy (CAA) on GRE

Cerebral amyloid angiopathy (GRE and FLAIR)
Cerebral amyloid angiopathy (FLAIR and GRE)

Diagnostic Boston criteria 2.0

The Boston criteria 2.0 were proposed in 2022 (Charidimou, 2022)

  • possible CAA
    • patients > 50 years of age, presenting with ICH, TFNE, or cognitive impairment
    • MRI criteria:
      • one strictly lobar hemorrhagic lesion on GRE/SWI  OR at least one white matter feature (severe perivascular spaces or WML)
      • absence of deep hemorrhagic lesions on GRE and other cause of hemorrhage (AVM, vasculitis, trauma, hemorrhagic trnasformation of ischemia, etc.)
      • hemorrhagic lesion in the cerebellum is not counted as either lobar or deep hemorrhagic lesion
  • probable CAA
    • MRI criteria:
      • demonstrates either ≥ 2 of the following strictly lobar hemorrhagic lesions on MRI in any combination
        • intracerebral hemorrhage (ICH), cerebral microbleeds (CMBs), cortical superficial siderosis (CSS) ) or convexity subarachnoid hemorrhage (convexity SAH)
      • OR 1 lobar hemorrhagic lesion + white matter features:
        • enlarged perivascular spaces in the centrum semiovale (>20 visible in one hemisphere)
        • white matter hyperintensities in a multi-spot pattern (>10 subcortical FLAIR dots bilaterally)
      • AND absence of deep hemorrhagic lesions and other causes of hemorrhage
  • probable CAA with supporting pathology
    • clinical data + pathological tissue (from evacuated hematoma or biopsy) demonstrating some degree of CAA in the specimen
  • definite CAA
    • post-mortem examination demonstrating severe CAA on histology + signs of spontaneous lobal ICH and/or cortical cortical siderosis


Anticoagulation in patients with suspected CAA

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Thrombolysis in patients with suspected CAA

  • IVT is a reasonable treatment option for patients with CMBs < 10 (AHA/ASA 2019 IIa/B-NR)
  • for patients 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 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/