The contribution of amyloid angiopathy to intracerebral haemorrhage: a clinico-radio-pathological case-control study
Lead Research Organisation:
University of Edinburgh
Department Name: Sch of Molecular. Genetics & Pop Health
Abstract
About one in six strokes are due to bleeding into the brain. Around 10,000 adults in the UK suffer such a bleed annually and the effects can be devastating. 50% of patients die within the first month, and those that survive are significantly functionally impaired; their quality of life is badly affected. I seek to understand more about a condition that may commonly cause such bleeding. It is called cerebral amyloid angiopathy (CAA). It occurs because the body deposits an abnormal protein called amyloid in the blood vessels of the brain. CAA is thought to cause bleeds which occur near the surface of the brain, whereas other conditions (such as high blood pressure) are assumed to cause bleeding deep within the brain. This project seeks to test these assumptions and see if brain imaging can help detect CAA. In the future, this might help to detect and treat CAA before a bleed occurs. I will compare imaging and brain tissue samples of people who have died from such bleeds with people who have died from other causes. I hope this work will help doctors to develop a more rational and effective approach to managing this devastating condition.
Technical Summary
Background: Spontaneous intracerebral haemorrhage (ICH) affects ~10,000 adults in the UK per year, ~50% of whom die within one month. However, understanding of the causes of ICH is limited: ICH occurring deep in the brain is commonly attributed to hypertension and lobar ICH is often assumed to be due to cerebral amyloid angiopathy (CAA). My meta-analysis of existing controlled neuropathological studies revealed only a non-significant trend towards an association of CAA with ICH. Furthermore, brain microbleeds (BMBs) on magnetic resonance imaging (MRI) are thought to diagnose CAA, although there are no radiological-pathological studies of their diagnostic utility.
Aims and objectives:
(1) Create an ICH brain bank, to establish whether pathologically-proven CAA is more prevalent in lobar ICH than controls with deep ICH or age-matched controls without cerebrovascular disease.
(2) To study the presence and distribution of brain microbleeds, to determine their diagnostic utility for identifying pathologically-proven CAA, and comparison with MRI of ischaemic stroke thought to be due to small vessel diseases
Design: I will set up a two-year, community-based, prospective study of patients with ICH who are admitted to hospital or who die suddenly in the community. By obtaining MRI and autopsy tissue from subsets of this ICH cohort, and using existing imaging studies and brain tissue from participants in ischaemic stroke studies in Edinburgh, I will perform clinico-radio-pathological matched case control studies to address my aims.
Methodology: I will ascertain incident diagnoses of ICH by hot pursuit through collaboration within the local Stroke Research Network, facilitated by my participation in the local stroke service. Swift assessment will maximise the number who consent to autopsy (especially in those who die early) and consent to brain MRI at two months after onset. Brain MRIs on controls with ischaemic stroke are available from the established Edinburgh Stroke Study. Autopsy tissue on controls without cerebrovascular disease exists in the MRC Sudden Death Brain bank in Edinburgh, and tissue from patients with ischaemic stroke will be sought from participants in the Edinburgh Stroke Study.
Opportunities: The training environment, local expertise, and existing imaging and brain tissue resources make this an ideal environment for this project. Understanding the strength of the association between CAA and ICH will affect assumptions that are made about ICH cause in clinical practice. If BMBs are a sensitive and specific marker of CAA, ante mortem diagnosis would facilitate trials of treatments that slow amyloid deposition.
Aims and objectives:
(1) Create an ICH brain bank, to establish whether pathologically-proven CAA is more prevalent in lobar ICH than controls with deep ICH or age-matched controls without cerebrovascular disease.
(2) To study the presence and distribution of brain microbleeds, to determine their diagnostic utility for identifying pathologically-proven CAA, and comparison with MRI of ischaemic stroke thought to be due to small vessel diseases
Design: I will set up a two-year, community-based, prospective study of patients with ICH who are admitted to hospital or who die suddenly in the community. By obtaining MRI and autopsy tissue from subsets of this ICH cohort, and using existing imaging studies and brain tissue from participants in ischaemic stroke studies in Edinburgh, I will perform clinico-radio-pathological matched case control studies to address my aims.
Methodology: I will ascertain incident diagnoses of ICH by hot pursuit through collaboration within the local Stroke Research Network, facilitated by my participation in the local stroke service. Swift assessment will maximise the number who consent to autopsy (especially in those who die early) and consent to brain MRI at two months after onset. Brain MRIs on controls with ischaemic stroke are available from the established Edinburgh Stroke Study. Autopsy tissue on controls without cerebrovascular disease exists in the MRC Sudden Death Brain bank in Edinburgh, and tissue from patients with ischaemic stroke will be sought from participants in the Edinburgh Stroke Study.
Opportunities: The training environment, local expertise, and existing imaging and brain tissue resources make this an ideal environment for this project. Understanding the strength of the association between CAA and ICH will affect assumptions that are made about ICH cause in clinical practice. If BMBs are a sensitive and specific marker of CAA, ante mortem diagnosis would facilitate trials of treatments that slow amyloid deposition.
