Salman, Rustam

Wardlaw, Joanna

Dhaliwal, Kanwaldeep

Rodrigues, Mark Alexander

Wellcome Trust

2020-04-15T13:28:37Z

2020-04-15T13:28:37Z

2020-06-27

In most cases, spontaneous intracerebral haemorrhage (ICH) is thought to result from cerebral small vessel diseases (SVDs). Cerebral amyloid angiopathy (CAA) and arteriolosclerosis (non-CAA SVD) are the two main types of SVD associated with ICH. The risk of recurrent ICH and post-stroke dementia may be higher with CAA-associated ICH compared with non-CAA SVD-associated ICH. It is, therefore, important to identify the type of SVD associated with ICH. Commonly, ICH in the cerebral lobes (lobar ICH) is thought to be associated with CAA, whereas non-lobar ICH is associated with non-CAA SVD. However, this generalisation is not accurate. The aims of my thesis were to (a) histopathologically assess the types and severity of SVDs associated with lobar and non-lobar ICH using brain autopsy tissue, (b) explore whether brain imaging (magnetic resonance imaging (MRI), positron emission tomography (PET) and computed tomography (CT)) biomarkers can be used in living patients to identify the type of SVDs associated with ICH and (c) determine whether CT biomarkers can predict outcome after ICH. Throughout my thesis, I use data from two overlapping studies of ICH. The Lothian Audit of the Treatment of Cerebral Haemorrhage (LATCH) is a prospective community-based audit of all residents in the Lothian Health board region of Scotland who were aged 16 years or above and had an incident ICH between 1st June 2010 and 31st May 2013 inclusive. During LATCH and until 31st May 2016, consecutive adults with SVD-associated ICH were able to consent to have apolipoprotein E genotyping, brain MRI and brain autopsy as part of the prospective Lothian INtraCerebral Haemorrhage Pathology, Imaging and Neurological outcome (LINCHPIN) study. In an autopsy study of 126 LINCHPIN participants with first-ever SVDassociated ICH, I found that 98% of participants with a non-lobar ICH had moderate or severe non-CAA SVD. In contrast, 60% of participants with a lobar ICH had moderate or severe CAA, while many had moderate or severe non-CAA SVD, either with or without CAA. The most common approach used in clinical practice to identify CAAassociated ICH is the MRI-based modified Boston criteria for CAA. However, I found that only about one-third of ICH patients during LATCH were able to undergo MRI. Also, in 16 LINCHPIN participants with research MRI, the modified Boston criteria showed limited accuracy against the histopathological assessment of CAA on subsequent research autopsy. Molecular imaging using tracers designed to detect parenchymal β-amyloid in Alzheimer’s disease, such as flutemetamol, may also identify the perivascular β-amyloid found in CAA. I found that in LINCHPIN brain tissue samples, the amyloid tracer flutemetamol labelled both parenchymal and perivascular β amyloid. Among 20 participants with first-ever ICH, flutemetamol PET scans were 86% sensitive and 77% specific for CAA-associated ICH based on the modified Boston criteria. Brain CT is the test that usually diagnoses ICH. I found in 62 LINCHPIN participants with first-ever lobar ICH that subarachnoid haemorrhage and finger-like projections on CT, and APOE ε4 allele possession were independently associated with CAA-associated lobar ICH defined on subsequent autopsy. I developed diagnostic models and criteria (“Edinburgh criteria”) based on these predictors that could accurately rule in or exclude CAA-associated lobar ICH. I performed a multicentre external validation study of the Edinburgh criteria. In a preliminary analysis, the CT-only diagnostic criteria (subarachnoid haemorrhage and finger-like projections) had high sensitivity (88%) and good specificity (84%) for CAA-associated lobar ICH. The risk of recurrent ICH is a key outcome for ICH survivors. I found that the risk of recurrent ICH was significantly higher in participants with first-ever lobar compared with non-lobar ICH. Among lobar ICH participants, the risk of recurrent ICH was significantly higher in those classified as high risk on the CT-only Edinburgh criteria for CAA-associated lobar ICH compared with those classified as low risk. Predicting death or disability is also important in ICH. I found that the severity of SVD on the diagnostic brain CT was an independent predictor of death or disability at one year after the ICH, after adjusting for known prognostic factors. Brain imaging biomarkers, particularly on brain CT, are potentially useful for identifying the type of SVD associated with ICH. Having developed the CTbased Edinburgh criteria for CAA-associated lobar ICH, I performed preliminary multicentre studies assessing their diagnostic accuracy and prognostic value. In the future, I aim to perform the full analyses of these diagnostic test accuracy and prognostic studies to determine the clinical utility of the Edinburgh criteria. Other research should assess the clinical and economic effect of the Edinburgh criteria on the prognosis of ICH. More work is needed to investigate the prognostic relevance of coexistence of CAA and non-CAA SVDs in lobar ICH, and whether these groups can be differentiated using imaging biomarkers.

https://hdl.handle.net/1842/36976

http://dx.doi.org/10.7488/era/277

en

The University of Edinburgh

Samarasekera N, Rodrigues MA, Toh PS, Al-Shahi R. Imaging features of intracerebral hemorrhage with cerebral amyloid angiopathy: Systematic review and meta-analysis. (2017) PloS one. 12 (7): e0180923

Rodrigues MA, Samarasekera N, Lerpiniere C, Humphreys C, McCarron MO, White PM, Nicoll JAR, Sudlow CLM, Cordonnier C, Wardlaw JM, Smith C, Al-Shahi Salman R. The Edinburgh CT and genetic diagnostic criteria for lobar intracerebral haemorrhage associated with cerebral amyloid angiopathy: model development and diagnostic test accuracy study. (2018) The Lancet. Neurology. 17 (3): 232-240

Perry LA, Rodrigues M, Al-Shahi Salman R, Samarasekera N. Incident Cerebral Microbleeds After Intracerebral Hemorrhage. (2019) Stroke. 50 (8): 2227-2230

Al-Shahi Salman R, Minks DP, Mitra D, Rodrigues MA, Bhatnagar P, du Plessis JC, Joshi Y, Dennis MS, Murray GD, Newby DE, Sandercock PAG, Sprigg N, Stephen J, Sudlow CLM, Werring DJ, Whiteley WN, Wardlaw JM, White PM. Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, openlabel trial. (2019) The Lancet. Neurology. 18 (7): 643-652

Andreas Charidimou, Matthew P Frosch, Rustam Al-Shahi Salman, Jean-Claude Baron, Charlotte Cordonnier, Mar Hernandez-Guillamon, Jennifer Linn, Nicolas Raposo, Mark Rodrigues, Jose Rafael Romero, Julie A Schneider, Stefanie Schreiber, Eric E Smith, Mark A van Bucheman and Viswanathan, Frank A Wollenweber, David J Werring, Steven M Greenberg, for the International CAA Association. Advancing diagnostic criteria for sporadic cerebral amyloid angiopathy: Study protocol for a multicenter MRI-pathology validation of Boston criteria v2.0. (2019) International Journal of Stroke. 14(9): 956-971

stroke

intracerebral haemorrhage

small vessel diseases

SVD

cerebral amyloid angiopath

CAA

ICH

MRI

CT

non-CAA SVD

lobar ICH

diagnostic brain CT

risk factors

Multi-modality imaging assessment of cerebral small vessel disease biomarkers after stroke due to spontaneous intracerebral haemorrhage

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy