Neshika Samarasekera

The association between cerebral amyloid angiopathy and intracerebral haemorrhage: systematic review and meta-analysis

Background The aim of this study was to determine the strength of the association between intracerebral haemorrhage (ICH) and cerebral amyloid angiopathy (CAA) in a systematic review of published neuropathological studies. Methods In April 2011, Ovid Medline (from 1950) and Embase (from 1980) were searched for neuropathological studies that quantified the prevalence of CAA in patients with ICH and in a control group without ICH. Two authors extracted data from each study and meta-analysed their results using a random effects model. Results 10 neuropathological cross sectional or case control studies were identified, involving 481 cases with ICH and 3219 controls. There was no association between CAA and ICH in any location (OR 1.21, 95% CI 0.87 to 1.68; 10 studies, I2 29%), deep ICH (OR 0.81, 95% CI 0.30 to 2.19; five studies, I2 58%) or cerebellar ICH (OR 2.05, 95% CI 0.55 to 7.63; four studies, I2 0%). CAA was significantly associated with lobar ICH, both overall (OR 2.21, 95% CI 1.09 to 4.45; six studies, I2 40%) and in the three studies where average ages for cases and controls were comparable (OR 3.24, 95% CI 1.02 to 10.26). Conclusions There is an association between CAA and lobar ICH, although the association might be stronger if potential confounding factors, distinctive clinical and imaging features of ICH due to CAA and CAA neuropathological severity are taken into account.

Genetics of cerebral amyloid angiopathy: systematic review and meta-analysis

Background and purpose Cerebral amyloid angiopathy (CAA) is common in the ageing brain and is associated with dementia and lobar intracerebral haemorrhage. We systematically reviewed genetic associations with CAA to better understand its pathogenesis. Methods We comprehensively sought and critically appraised published studies of associations between any genetic polymorphism and histopathologically confirmed CAA. We assessed the effects of genotype by calculating study specific and pooled odds ratios (ORs) in meta-analyses, and assessed small study bias. Results 58 studies (6855 participants) investigated apolipoprotein E (APOE) genotype and sporadic CAA. Meta-analysis of 24 (3520 participants) of these showed an association of APOE ɛ4 with CAA (ɛ4 present vs absent, pooled OR 2.7, 95% CI 2.3 to 3.1, p<0.00001), which was dose dependent, robust to potential small study biases and occurred irrespective of dementia status. There was no significant association between APOE ɛ2 and CAA. Among 24 studies (4703 participants) of other genetic polymorphisms, there was preliminary evidence of an association with CAA of polymorphisms in the transforming growth factor β1 gene (two studies, 449 participants), translocase of outer mitochondrial membrane 40 gene (one study, 723 participants) and the complement component receptor 1 gene (one study, 544 participants). There were insufficient data to draw conclusions from 24 studies (∼200 participants) of APOE and hereditary CAA or familial Alzheimers disease. Conclusions There is convincing evidence for a dose dependent association between APOE ɛ4 and sporadic CAA. Further work is needed to better understand the mechanism of this association and to further investigate other genetic associations with CAA.

APOE associations with severe CAA-associated vasculopathic changes: collaborative meta-analysis

Objectives Cerebral amyloid angiopathy (CAA) is associated with lobar intracerebral haemorrhage (ICH). While only the ε4 allele of the apolipoprotein E (APOE) gene is associated with the presence of CAA, both APOE-ε4 and ε2 are associated with lobar ICH. The generally accepted explanation is that APOE-ε4 promotes vascular amyloid deposition, while APOE-ε2 promotes progression to severe CAA with associated vasculopathic changes that cause vessel rupture and ICH. We assessed the evidence for these allele-specific effects. Methods We systematically identified published studies with data on APOE genotype and histopathological assessment of postmortem brains for CAA severity. We obtained unpublished data from these for meta-analyses of the effects of ε4-containing (ε4+) and ε2-containing (ε2+) genotypes on progression to severe CAA. Results Of six eligible studies (543 eligible participants), data were available from 5 (497 participants, 353 with CAA). Meta-analyses showed a possible association of ε4+ genotypes with severe CAA (ε4+ vs ε4−: severe vs mild/moderate CAA, OR 2.5, 95% CI 1.4 to 4.5, p=0.002; severe vs moderate CAA, OR 1.7, 95% CI 0.9 to 3.1, p=0.11). For ε2+ versus ε2− genotypes, there was no significant association, but the very small number of participants with ε2+ genotypes (22) precluded reliable estimates. Conclusions We found a possible association of severe CAA with APOE-ε4 but not APOE-ε2. However, our findings do not exclude a biologically meaningful association between APOE-ε2 and severe CAA. Further work is needed to elucidate fully the allele-specific associations of APOE with CAA and their mechanisms.

Brain banking for neurological disorders

Brain banks are used to gather, store, and provide human brain tissue for research and have been fundamental to improving our knowledge of the brain in health and disease. To maintain this role, the legal and ethical issues relevant to the operations of brain banks need to be more widely understood. In recent years, researchers have reported that shortages of high-quality brain tissue samples from both healthy and diseased people have impaired their efforts. Closer collaborations between brain banks and improved strategies for brain donation programmes will be essential to overcome these problems as the demand for brain tissue increases and new research techniques become more widespread, with the potential for substantial scientific advances in increasingly common neurological disorders.

Deposition of amyloid β in the walls of human leptomeningeal arteries in relation to perivascular drainage pathways in cerebral amyloid angiopathy

Deposition of amyloid β (Aβ) in the walls of cerebral arteries as cerebral amyloid angiopathy (CAA) suggests an age-related failure of perivascular drainage of soluble Aβ from the brain. As CAA is associated with Alzheimers disease and with intracerebral haemorrhage, the present study determines the unique sequence of changes that occur as Aβ accumulates in artery walls. Paraffin sections of post-mortem human occipital cortex were immunostained for collagen IV, fibronectin, nidogen 2, Aβ and smooth muscle actin and the immunostaining was analysed using Image J and confocal microscopy. Results showed that nidogen 2 (entactin) increases with age and decreases in CAA. Confocal microscopy revealed stages in the progression of CAA: Aβ initially deposits in basement membranes in the tunica media, replaces first the smooth muscle cells and then the connective tissue elements to leave artery walls completely or focally replaced by Aβ. The pattern of development of CAA in the human brain suggests expansion of Aβ from the basement membranes to progressively replace all tissue elements in the artery wall. Establishing this full picture of the development of CAA is pivotal in understanding the clinical presentation of CAA and for developing therapies to prevent accumulation of Aβ in artery walls. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.

Variation in Restarting Antithrombotic Drugs at Hospital Discharge After Intracerebral Hemorrhage

Background and Purpose— Whether intracerebral hemorrhage (ICH) survivors should restart antithrombotic drugs is unknown. We analyzed the frequency of restarting antithrombotic drugs in ICH survivors who had taken prophylactic antithrombotic drugs in atrial fibrillation or after thromboembolic disease in 5 cohorts and explored factors associated with doing so. Methods— We compared the characteristics and proportions of patients taking antithrombotic drugs at ICH onset and discharge in 4 hospital-based cohorts (Lille, France, n=542; Utrecht, The Netherlands, n=389; multicenter Clinical Relevance of Microbleeds in Stroke-2 (CROMIS-2) ICH, United Kingdom, n=667; and Amsterdam, The Netherlands, n=403) and 1 community-based study (Lothian, Scotland, n=137), using bivariate analyses. We sought characteristics associated with restarting using bivariate and multivariable logistic regression analyses. Results— A total of 942 (44%) patients with ICH took antithrombotic drugs at hospital admission (no difference between cohorts). Antithrombotic drugs were restarted in 96 (20%) of the 469 survivors who had taken antithrombotic drugs for secondary prevention or atrial fibrillation, but this proportion differed when stratified by the cohort of origin (Lille, 18%; Utrecht, 45%; Lothian, 15%; CROMIS-2 ICH, 11%; Amsterdam, 20%; P<0.001) and by type of antithrombotic drug pre-ICH (14% in patients with previous antiplatelet drugs versus 26% in patients with previous vitamin K antagonists and 41% in patients with both drugs; P<0.001). We did not find other consistent, independent associations with restarting antithrombotic drugs. Conclusions— The variation in clinical practice and lack of consistent associations with restarting antithrombotic drugs after ICH reflect current knowledge and support the need for randomized controlled trials to resolve this dilemma.

Brain hemorrhage recurrence, small vessel disease type, and cerebral microbleeds: A meta-analysis

Objective: We evaluated recurrent intracerebral hemorrhage (ICH) risk in ICH survivors, stratified by the presence, distribution, and number of cerebral microbleeds (CMBs) on MRI (i.e., the presumed causal underlying small vessel disease and its severity). Methods: This was a meta-analysis of prospective cohorts following ICH, with blood-sensitive brain MRI soon after ICH. We estimated annualized recurrent symptomatic ICH rates for each study and compared pooled odds ratios (ORs) of recurrent ICH by CMB presence/absence and presumed etiology based on CMB distribution (strictly lobar CMBs related to probable or possible cerebral amyloid angiopathy [CAA] vs non-CAA) and burden (1, 2–4, 5–10, and >10 CMBs), using random effects models. Results: We pooled data from 10 studies including 1,306 patients: 325 with CAA-related and 981 CAA-unrelated ICH. The annual recurrent ICH risk was higher in CAA-related ICH vs CAA-unrelated ICH (7.4%, 95% confidence interval [CI] 3.2–12.6 vs 1.1%, 95% CI 0.5–1.7 per year, respectively; p = 0.01). In CAA-related ICH, multiple baseline CMBs (versus none) were associated with ICH recurrence during follow-up (range 1–3 years): OR 3.1 (95% CI 1.4–6.8; p = 0.006), 4.3 (95% CI 1.8–10.3; p = 0.001), and 3.4 (95% CI 1.4–8.3; p = 0.007) for 2–4, 5–10, and >10 CMBs, respectively. In CAA-unrelated ICH, only >10 CMBs (versus none) were associated with recurrent ICH (OR 5.6, 95% CI 2.1–15; p = 0.001). The presence of 1 CMB (versus none) was not associated with recurrent ICH in CAA-related or CAA-unrelated cohorts. Conclusions: CMB burden and distribution on MRI identify subgroups of ICH survivors with higher ICH recurrence risk, which may help to predict ICH prognosis with relevance for clinical practice and treatment trials.

Eligibility for Randomized Trials of Treatments Specifically for Intracerebral Hemorrhage Community-Based Study

Background and Purpose— Acute treatments specifically for intracerebral hemorrhage (ICH) are being sought in randomized controlled trials. The treatment effect sizes in ongoing and future trials are likely to be small, necessitating large sample sizes. Methods— We searched online trial registries for randomized controlled trials investigating an acute treatment for ICH. For the trials whose eligibility criteria could be assessed in a prospective, community-based ICH cohort study (2010–2011), we quantified the proportions of patients who were eligible and investigated influences on these proportions. Results— We applied the eligibility criteria of 17 trials to 166 adults with ICH, of whom between 0.6% (95% confidence interval, 0.1–3.3) to 40% (95% confidence interval, 33–48) were eligible for each trial. Fewer patients were eligible for trials restricted to patients randomized within 12 hours of ICH onset (versus trials with a longer time window; P=0.03) and trials restricting eligibility according to premorbid disability (versus trials without this restriction; P=0.046). Each additional eligibility criterion reduced the portion of eligible patients by 1.3% (95% confidence interval, 0.4–2.2; adjusted R2=0.47; P=0.004). Conclusions— Less than half of patients with ICH were eligible for current randomized controlled trials. Future trials could maximize enrollment by minimizing the number of eligibility criteria, maximizing the time window for recruiting patients after ICH onset, permitting premorbid disability, and using a simulator to assess the impact of other eligibility critiera (www.dcn.ed.ac.uk/ICHsimulator/).

Genetic Variants in CETP Increase Risk of Intracerebral Hemorrhage

In observational epidemiologic studies, higher plasma high‐density lipoprotein cholesterol (HDL‐C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL‐C; as such, medicines that inhibit CETP and raise HDL‐C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL‐C also increase risk for ICH.

The Persisting Burden of Intracerebral Haemorrhage: Can Effective Treatments Be Found?

Colin Josephson, Rustam Al-Shahi Salman, and colleagues discuss the effectiveness of treatments for intracerebral haemorrhage.