Cerebral amyloid angiopathy

From Ganfyd

Introduction

Cerebral amyloid angiopathy (CAA, congophilic angiography) is characterised by cerebrovascular amyloid deposition in the walls of arteries, arterioles, and, less often, capillaries and veins of the central nervous system.^[1] It is associated with:

• Intracerebral haemorrhage
• Ischaemic lesions
• Dementia
• Transient ischaemic attacks
• Epilepsy
• Subarachnoid haemorrhage

Prevalence

Very common (36% of all over 60)^[2], with increase with age (60% of all over 90 in a small Japanese series^[3]). Ten percent of primary intracerebral haemorrhage (PICT) is due to it.

Aetiologies

The proteins that have mutations to date described as causing it are:

• Amyloid beta protein (Aβ) - certain kinds of familial Alzheimers
• BRI2 gene-related - ABri and ADan mutations
• Cystatin C - Hereditary cerebral hemorrhage with amyloidosis of Icelandic type
• Gelsolin (AGel) - Familial amyloidosis of Finnish type
• Presenilin-1 - certain kinds of familial Alzheimers
• Prion protein - Prion protein cerebral amyloid angiopathy (PrP-CAA)
• Transthyretins (ATTR) - hereditary leptomeningeal amyloidosis ...if you ever get a case doxycycline works in mice.

Also there are gene polymorphisms associated with sporadic CAA or CAA-related hemorrhage:

• Alpha-1-antichymotrypsin (ACT)
• Apolipoprotein E (APOE)
  • ε4 allele - CAA
  • ε2 allele - CAA-related hemorrhage
• Neprilysin (NEP) - shorter GT repeats in the enhancer/promoter region alleles increases CAA severity. This is a Aβ degrading enzyme^[4]
• Presenilin 1 (PS1)
• Transforming growth factor-β1 (TGF-β1) - T/C polymorphism at codon 10 in exon 1 increases CAA severity. This is a cytokine implicated in Aβ deposition. ^[4]

Associations

• Genetics as above
• Hypertension
• Japanese and black race
• Lobar PICT (accounts for 74%)
• Apolipoprotein ε2 as above

Diagnosis

Presently only post mortem but there are strong clinical correlates, especially as CAA is the commonest cause of small chronic haemorragic lesions in the cerebral hemispheres which are well shown on gradient-echo (susceptibility-weighed) MRI. Criteria for the diagnosis of CAA associated intracerebral haemorrhage have been published^[5]

Importance

Disruption of amyloid disposition may prevent the condition. It is also a theoretical contra-indication if actually diagnosed to long term anticoagulation in atrial fibrillation or after ischaemic stroke (which can occur in CAA). The development of potential serum markers such as circulating Aβ peptide may allow high risk patients for cerebral haemorrhage on warfarin to be screened out. It presently seems that over half of all intracerebral haemorrhage on anticoagulation may be due to CAA^[6]. Alzheimer's disease is closely related to cerebral amyloid angiopathy (CAA) being present in over 80% of patients at post mortem. The degree of dementia can be correlated with CAA-related lobar microhemorrhage burden^[7].

References