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Cerebral Amyloid Angiopathy (CAA) is a condition characterized by the deposition of amyloid-beta protein in the walls of the small to medium-sized blood vessels of the brain. This deposition leads to vascular fragility, increasing the risk of haemorrhagic stroke and other cerebrovascular complications. Suspect if lobar bleeds, age > 70 and no history of hypertension

Introduction

• Cerebral amyloid angiopathy (CAA) is a common cause of ICH in the elderly
• Deposition of beta amyloid in the walls of small and medium-sized blood vessels [Pantoni 2010].
• It should not be confused with the systemic amyloid deposition diseases.
• A more inflammatory variant of CAA which can be steroid responsive has been detected [Moussaddy 2015].

Aetiology

• Deposition of amyloid-ß fibrils in the wall of small/medium-sized blood vessels
• This is mostly arteries of the leptomeninges and cerebral cortex.
• CAA has been found commonly in those with Alzheimer disease.
• Only a minority of those with CAA develop Alzheimer disease.
• There is an increased risk of dementia in those with ICH.

Genetics

• There is a genetic association with apolipoprotein E gene epsilon 2 and 4 alleles.
• Hereditary forms of CAA are generally familial (rare), more severe and earlier in onset. These are
• Dutch type: late middle age. ICH. Amyloid deposition. Some get dementia. Defect in amyloid protein precursor protein (APP) gene on chromosome 21.
• Icelandic type: Presents young adults with ICH. Dementia seen. Involves brainstem and cerebellum too. Mutation of the cysteine protease inhibitor cystatin C.

Pathology

• Cerebral amyloid angiopathy is a major cause of haemorrhagic stroke in older patients. There is localised amyloid deposition which increases vessel wall fragility which leads to increased bleeding risk.
• Suspect amyloid if lobar bleeds are seen in those over age > 70 without evidence of pre-existing hypertension. By lobar we are referring to the cortex and subcortical white matter in distinction to the deep hypertensive bleeds affecting putamen, thalamus and pons.
• CAA bleeds are slightly commoner in temporal and occipital lobes rather than frontal and parietal lobes. The main differentials of a lobar bleed will be the extension from a large putaminal haemorrhage, Haemorrhagic transformation of an infarct, arteriovenous malformation (AVM) or Haemorrhagic tumour .
• Histological examination reveals the deposition of ß-amyloid in the media and adventitia of small and mid-sized arteries (and, less frequently, veins) of the cerebral cortex and the leptomeningeal amyloid

Clinical

• Unprovoked cerebral haemorrhage in those over 70 usually with headache and focal neurology and seizures.
• Coma may be seen at presentation and suggest a poor outcome
• TIA like "amyloid spells" syndromes may occur which have a haemorrhagic basis and can be due to small ICH or SAH from leptomeningeal CAA
• Recurrent macro and microbleeds common
• Mild trauma or IV thrombolysis or antiplatelets can be enough to provoke bleed
• Progressive Cognitive impairment if multiple small bleeds

Rare Genetic forms with ICH and amyloid

• Dutch type: late middle age. ICH. Amyloid deposition. Some get dementia. Defect in amyloid protein precursor protein (APP) gene on chromosome 21.
• Icelandic type: Presents young adults with ICH. Dementia seen. Involves the brainstem and cerebellum too. Mutation of the cysteine protease inhibitor cystatin C.

Investigations and Imaging

• CT Brain: acutely this will show a single or possibly more than one lobar haemorrhage in a superficial location. There may be local extension to the subarachnoid or into the ventricles. As time passes there may be an accumulation of bleeds. Bleeds tend to be more common in the frontal and parietal lobes both cortically and subcortical. Posterior structures including the cerebellum and deep nuclei can be affected but usually, the traditional sites for hypertensive bleeds such as putamen, thalamus and pontine are avoided.
• MRI Brain: using the Gradient echo or T2* sequences is very sensitive at detecting haemosiderin a breakdown product of blood and therefore indicating evidence of old bleeds.
• Brain Microbleeds may suggest subclinical CAA. They are seen in 5-20% of the population depending on the population studied and radiological techniques in their imaging diagnosis [Rosand J et al. 2000]. These have been defined radiologically as homogeneous, round foci, < 10 mm diameter (no minimum size was specified), of low signal intensity on GRE T2*-weighted MRI.
• They need to be differentiated from lesions compatible with an infarct with haemorrhagic transformation [Cordonnier et al. 2009].
• Microbleeds are commoner in those taking anti-thrombotic agents. Those with CAA RI will usually have dramatic T2 changes of oedema which may be out of proportion to clinical signs.
• CTA/MRA/CTV: may be needed when other aetiologies are being considered.
• PET brain imaging: is very much a research tool
• Genetic studies where needed in those with suspected familial disease may show apoE e4/e4 genotype
• Biopsies taken at surgery or post mortem the brain will show amyloid with congo red staining

Differentials

• Hypertensive Lobar bleed
• Lobar extension from a large putaminal haemorrhage
• Haemorrhagic transformation of an infarct
• Arteriovenous malformation (AVM) or Haemorrhagic tumour .
• Bleed due to tumour
• Bleed due to cerebral venous thrombosis

Boston Criteria

CAA

CAA

Possible Complications

• Repeated episodes of bleeding in the brain
• Hydrocephalus , Seizures, Dementia

Management

• Avoid antiplatelets and antithrombotics and thrombolysis
• Standard care for Haemorrhagic stroke including surgery
• Falls prevention is useful
• Good management of hypertension and vascular risks
• Long term dementia and seizure care

References

• Knudsen KA, Rosand J, Karluk D et-al. Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria. Neurology. 2001;56 (4): 537-9.
• Cerebral Amyloid Angiopathy: A Systematic Review. J Clin Neurol 2011;7:1-9
• Amyloid imaging at radiopedia