Long-Term Outcomes in Patients With Spontaneous Cerebellar Hemorrhage: An International Cohort Study.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) in the cerebellum has a poor short-term prognosis, whereas data on the long-term case fatality and recurrent vascular events are sparse. Herewith, we aimed to assess the long-term case fatality and recurrence rate of vascular events after a first cerebellar ICH. METHODS: In this international cohort study, we included patients from 10 hospitals (the United States and Europe from 1997 to 2017) aged ≥18 years with a first spontaneous cerebellar ICH who were discharged alive. Data on long-term case fatality and recurrence of vascular events (recurrent ICH [supratentoria or infratentorial], ischemic stroke, myocardial infarction, or major vascular surgery) were collected for survival analysis and absolute event rate calculation. RESULTS: We included 405 patients with cerebellar ICH (mean age [SD], 72 [13] years, 49% female). The median survival time was 67 months (interquartile range, 23-100 months), with a cumulative survival rate of 34% at 10-year follow-up (median follow-up time per center ranged: 15-80 months). In the 347 patients with data on vascular events 92 events occurred in 78 patients, after initial cerebellar ICH: 31 (8.9%) patients had a recurrent ICH (absolute event rate, 1.8 per 100 patient-years [95% CI, 1.2-2.6]), 39 (11%) had an ischemic stroke (absolute event rate, 2.3 [95% CI, 1.6-3.2]), 13 (3.7%) had a myocardial infarction (absolute event rate, 0.8 [95% CI, 0.4-1.3]), and 5 (1.4%) underwent major vascular surgery (absolute event rate, 0.3 [95% CI, 0.1-0.7]). The median time to a first vascular event during follow-up was 27 months (interquartile range, 8.7-50 months), with a cumulative hazard of 47% at 10 years. CONCLUSIONS: The long-term prognosis of patients who survive a first spontaneous cerebellar ICH is poor and comparable to that of patients who survive a first supratentorial ICH. Further identification of patients at high risk of vascular events following the initial cerebellar ICH is needed. Including patients with cerebellar ICH in randomized controlled trials on secondary prevention of patients with ICH is warranted.

Perihaematomal oedema evolution over two weeks after spontaneous intracerebral haemorrhage and association with outcome: prospective cohort study.

Introduction We know little about the evolution of perihaematomal oedema (PHO) >24 hours after ICH onset. We aimed to determine the trajectory of PHO after ICH onset and its association with outcome. Methods We did a prospective cohort study using a pre-specified scanning protocol in adults with first-ever spontaneous ICH and measured absolute PHO volumes on CT head scans at ICH diagnosis and 3±2, 7±2 and 14±2 days after ICH onset. We used the largest ICH if ICHs were multiple. The primary outcomes were (a) the trajectory of PHO after ICH onset and (b) the association between PHO (absolute volume at the time when most repeat CT head scans were obtained, and change in PHO volume at this time compared with the first CT head scan) and poor functional outcome (modified Rankin scale 3-6 at 90 days). We pre-specified multivariable logistic regression models of this association adjusting analyses for potential confounders: age, GCS, infratentorial ICH location and intraventricular extension. Results In 106 participants of whom forty nine (46%) were female, with a median ICH volume 7ml (interquartile range [IQR] 2-22ml), the trajectory of median PHO volume was an increase from 14ml (IQR 7-26ml) at diagnosis to 18ml (IQR 8-40ml) at 3±2 days (n=87), 20ml (IQR 8-48ml) at 7±2 days (n=93) and 21ml (IQR 10-54ml) at 14±2 days (n=78) (p=<0.001). PHO volume at each time point was collinear with ICH volume at diagnosis (│r│>0.7) but the change in PHO volume between diagnosis and each time point was not. Given collinearity, we used total lesion (i.e. ICH+PHO) volume instead of PHO volume in a logistic regression model of its association at each time point with outcome. Increasing total lesion (ICH+PHO) volume at day 7±2 was associated with poor functional outcome (adjusted OR per ml 1.02, 95% CI 1.00-1.03; p=0.036) but the increase in PHO volume between diagnosis and day 7±2 was not associated with poor functional outcome (adjusted OR per ml 1.03, 95% CI 0.99-1.07; p=0.132). Conclusion PHO volume increases throughout the first two weeks after onset of mild to moderate ICH. Total lesion (ICH+PHO) volume at day 7±2 was associated with poor functional outcome but the change in PHO volume between diagnosis and day 7±2 was not. Prospective cohort studies with larger sample sizes are needed to investigate these associations and their modifiers.

Association between Computed Tomographic Biomarkers of Cerebral Small Vessel Diseases and Long-Term Outcome after Spontaneous Intracerebral Hemorrhage.

OBJECTIVE: A study was undertaken to assess whether cerebral small vessel disease (SVD) computed tomographic (CT) biomarkers are associated with long-term outcome after intracerebral hemorrhage. METHODS: We performed a prospective, community-based cohort study of adults diagnosed with spontaneous intracerebral hemorrhage between June 1, 2010 and May 31, 2013. A neuroradiologist rated the diagnostic brain CT for acute intracerebral hemorrhage features and SVD biomarkers. We used severity of white matter lucencies and cerebral atrophy, and the number of lacunes to calculate the CT SVD score. We assessed the association between CT SVD biomarkers and either death, or death or dependence (modified Rankin Scale scores = 4-6) 1 year after first-ever intracerebral hemorrhage using logistic regression, adjusting for known predictors of outcome. RESULTS: Within 1 year of intracerebral hemorrhage, 224 (56%) of 402 patients died. In separate models, 1-year death was associated with severe atrophy (adjusted odds ratio [aOR] = 2.54, 95% confidence interval [CI] = 1.44-4.49, p = 0.001) but not lacunes or severe white matter lucencies, and CT SVD sum score ≥ 1 (aOR = 2.50, 95% CI = 1.40-4.45, p = 0.002). Two hundred seventy-seven (73%) of 378 patients with modified Rankin Scale data were dead or dependent at 1 year. In separate models, 1-year death or dependence was associated with severe atrophy (aOR = 3.67, 95% CI = 1.71-7.89, p = 0.001) and severe white matter lucencies (aOR = 2.18, 95% CI = 1.06-4.51, p = 0.035) but not lacunes, and CT SVD sum score ≥ 1 (aOR = 2.81, 95% CI = 1.45-5.46, p = 0.002). INTERPRETATION: SVD biomarkers on the diagnostic brain CT are associated with 1-year death and dependence after intracerebral hemorrhage, independent of known predictors of outcome. ANN NEUROL 2021;89:266-279.

Pharmacokinetic modelling for the simultaneous assessment of perfusion and 18F-flutemetamol uptake in cerebral amyloid angiopathy using a reduced PET-MR acquisition time: Proof of concept.

PURPOSE: Cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease associated with perivascular ß-amyloid deposition. CAA is also associated with strokes due to lobar intracerebral haemorrhage (ICH). 18F-flutemetamol amyloid ligand PET may improve the early detection of CAA. We performed pharmacokinetic modelling using both full (0-30, 90-120 min) and reduced (30 min) 18F-flutemetamol PET-MR acquisitions, to investigate regional cerebral perfusion and amyloid deposition in ICH patients. METHODS: Dynamic18F-flutemetamol PET-MR was performed in a pilot cohort of sixteen ICH participants; eight lobar ICH cases with probable CAA and eight deep ICH patients. A model-based input function (mIF) method was developed for compartmental modelling. mIF 1-tissue (1-TC) and 2-tissue (2-TC) compartmental modelling, reference tissue models and standardized uptake value ratios were assessed in the setting of probable CAA detection. RESULTS: The mIF 1-TC model detected perfusion deficits and 18F-flutemetamol uptake in cases with probable CAA versus deep ICH patients, in both full and reduced PET acquisition time (all P < 0.05). In the reduced PET acquisition, mIF 1-TC modelling reached the highest sensitivity and specificity in detecting perfusion deficits (0.87, 0.77) and 18F-flutemetamol uptake (0.83, 0.71) in cases with probable CAA. Overall, 52 and 48 out of the 64 brain areas with 18F-flutemetamol-determined amyloid deposition showed reduced perfusion for 1-TC and 2-TC models, respectively. CONCLUSION: Pharmacokinetic (1-TC) modelling using a 30 min PET-MR time frame detected impaired haemodynamics and increased amyloid load in probable CAA. Perfusion deficits and amyloid burden co-existed within cases with CAA, demonstrating a distinct imaging pattern which may have merit in elucidating the pathophysiological process of CAA.

Cerebral microbleeds: from depiction to interpretation.

Cerebral microbleeds (CMBs) are defined as hypointense foci visible on T2*-weighted and susceptible-weighted MRI sequences. CMBs are increasingly recognised with the widespread use of MRI in healthy individuals as well as in the context of cerebrovascular disease or dementia. They can also be encountered in major critical medical conditions such as in patients requiring extracorporeal mechanical oxygenation. The advent of MRI-guided postmortem neuropathological examinations confirmed that, in the context of cerebrovascular disease, the vast majority of CMBs correspond to recent or old microhaemorrhages. Detection of CMBs is highly influenced by MRI parameters, in particular field strength, postprocessing methods used to enhance T2* contrast and three dimensional sequences. Despite recent progress, harmonising imaging parameters across research studies remains necessary to improve cross-study comparisons. CMBs are helpful markers to identify the nature and the severity of the underlying chronic small vessel disease. In daily clinical practice, presence and numbers of CMBs often trigger uncertainty for clinicians especially when antithrombotic treatments and acute reperfusion therapies are discussed. In the present review, we discuss those clinical dilemmas and address the value of CMBs as diagnostic and prognostic markers for future vascular events.

Diffusion-weighted imaging lesions and risk of recurrent stroke after intracerebral haemorrhage.

OBJECTIVE: To determine whether the presence of diffusion-weighted imaging-positive (DWI+) lesions is associated with recurrent stroke after intracerebral haemorrhage (ICH). METHODS: The REstart or STop Antithrombotics Randomised Trial (RESTART) assessed the effect of restarting versus avoiding antiplatelet therapy after ICH on major vascular events for up to 5 years. We rated DWI sequences of MRI done before randomisation for DWI+ lesion presence, masked to outcome and antiplatelet use. Cox proportional hazards regression models were used to quantify associations. RESULTS: Of 537 participants in RESTART, 247 (median (IQR) age 75.7 (69.6-81.1) years; 170 men (68.8%); 120 started vs 127 avoided antiplatelet therapy) had DWI sequences on brain MRI at a median of 57 days (IQR 19-103) after ICH, of whom 73 (30%) had one or more DWI+ lesion. During a median follow-up of 2 years (1-3), 18 participants had recurrent ICH and 21 had ischaemic stroke. DWI+ lesion presence was associated with all stroke, (adjusted HR 2.2 (95% CI 1.1 to 4.2)) and recurrent ICH (4.8 (95% CI 1.8 to 13.2)), but not ischaemic stroke (0.9 (95% CI 0.3 to 2.5)). DWI+ lesion presence (0.5 (95% CI 0.2 to 1.3)) vs absence (0.6 (95% CI 0.3 to 1.5), pinteraction=0.66) did not modify the effect of antiplatelet therapy on a composite outcome of recurrent stroke. CONCLUSIONS: DWI+ lesion presence in ICH survivors is associated with recurrent ICH, but not with ischaemic stroke. We found no evidence of modification of effects of antiplatelet therapy on recurrent stroke after ICH by DWI+ lesion presence. These findings provide a new perspective on the significance of DWI+ lesions, which may be markers of microvascular mechanisms associated with recurrent ICH. TRIAL REGISTRATION NUMBER: ISRCTN71907627.

Incident Cerebral Microbleeds After Intracerebral Hemorrhage.

Background and Purpose- The frequency and prognostic implications of incident cerebral microbleeds (CMB), defined as development of one or more new CMB, after intracerebral hemorrhage (ICH) is unclear. Therefore, we performed a systematic review and meta-analysis to investigate the frequency and prognostic implications of incident CMB after ICH. Methods- We searched Ovid Medline and Embase in May 2018 for longitudinal studies of adults who underwent brain magnetic resonance imaging at 2 or more times after ICH. We calculated the pooled proportion of adults with incident CMB and sought associations between incident CMB and clinical outcomes (death, recurrent ICH, or new ischemic stroke). We planned subgroup analyses to investigate clinical variables associated with incident CMB. Results- We identified 2354 publications, of which we included 4 cohort studies involving 349 patients. The pooled proportion of adults with at least one new CMB during a mean 27 months follow-up (SD 20 months) was ≈40% (95% CI, 30%-50%). In one study, as the number of incident CMB increased (0 versus 1-3 new CMB versus ≥4 new CMB) the risk of recurrent symptomatic lobar ICH increased (hazard ratio 3.0; 95% CI, 1.2-7.3). No study reported on outcomes of incident ischemic stroke or death. Conclusions- Incident CMB occurs in ≈40% of adults after ICH. The association of incident CMB with recurrent lobar ICH needs confirmation and their association with death and ischemic stroke investigation.

Serum high-density lipoprotein is associated with better cognitive function in a cross-sectional study of aging women.

Purpose/Aim of the study: Poor cardiovascular health, including obesity and altered lipid profiles at mid-life, are linked to increased risk of Alzheimer's disease (AD). The biological mechanisms linking cardiovascular health and cognitive function are unclear though are likely to be multifactorial. This study examined the association between various lipoproteins and cognitive functioning in ageing women. MATERIALS AND METHODS: We investigated the relationship between readily available biomarkers (i.e. serum lipoprotein) and cognitive decline in domains associated with increased risk of AD (e.g. episodic verbal memory performance and subjective memory complaint). We report cross-sectional data investigating the relationship between serum total cholesterol, triglycerides, high-density lipoprotein (HDL-C) and low-density lipoprotein with verbal memory and learning ability in 130 women with and without memory complaints (n = 71 and 59, respectively) drawn from a study investigating cognitively healthy Western Australians (average age 62.5 years old). RESULTS: After statistical modelling that controlled for the effects of age, depression and apolipoprotein E genotype, HDL-C was significantly associated with better verbal learning and memory performance, specifically short and long delay-free recalls (F = 3.062; p < .05 and F = 3.2670; p < .05, respectively). CONCLUSION: Our cross-sectional findings suggest that the positive effect of HDL-C on verbal memory may be present much earlier than previously reported and provide further support for the role of HDL-C in healthy brain ageing. Further exploration of the protective effect of HDL-C on cognitive function in ageing is warranted through follow-up, longitudinal studies.

Observer reliability of CT angiography in the assessment of acute ischaemic stroke: data from the Third International Stroke Trial.

INTRODUCTION: CT angiography (CTA) is often used for assessing patients with acute ischaemic stroke. Only limited observer reliability data exist. We tested inter- and intra-observer reliability for the assessment of CTA in acute ischaemic stroke. METHODS: We selected 15 cases from the Third International Stroke Trial (IST-3, ISRCTN25765518) with various degrees of arterial obstruction in different intracranial locations on CTA. To assess inter-observer reliability, seven members of the IST-3 expert image reading panel (>5 years experience reading CTA) and seven radiology trainees (<2 years experience) rated all 15 scans independently and blind to clinical data for: presence (versus absence) of any intracranial arterial abnormality (stenosis or occlusion), severity of arterial abnormality using relevant scales (IST-3 angiography score, Thrombolysis in Cerebral Infarction (TICI) score, Clot Burden Score), collateral supply and visibility of a perfusion defect on CTA source images (CTA-SI). Intra-observer reliability was assessed using independently repeated expert panel scan ratings. We assessed observer agreement with Krippendorff's-alpha (K-alpha). RESULTS: Among experienced observers, inter-observer agreement was substantial for the identification of any angiographic abnormality (K-alpha = 0.70) and with an angiography assessment scale (K-alpha = 0.60-0.66). There was less agreement for grades of collateral supply (K-alpha = 0.56) or for identification of a perfusion defect on CTA-SI (K-alpha = 0.32). Radiology trainees performed as well as expert readers when additional training was undertaken (neuroradiology specialist trainees). Intra-observer agreement among experts provided similar results (K-alpha = 0.33-0.72). CONCLUSION: For most imaging characteristics assessed, CTA has moderate to substantial observer agreement in acute ischaemic stroke. Experienced readers and those with specialist training perform best.

Association of Antithrombotic Drug Use With Incident Intracerebral Hemorrhage Location.

BACKGROUND AND OBJECTIVES: Few population-based studies have assessed associations between the use of antithrombotic (platelet antiaggregant or anticoagulant) drugs and location-specific risks of spontaneous intracerebral hemorrhage (s-ICH). In this study, we estimated associations between antithrombotic drug use and the risk of lobar vs nonlobar incident s-ICH. METHODS: Using Danish nationwide registries, we identified cases in the Southern Denmark Region of first-ever s-ICH in patients aged 50 years or older between 2009 and 2018. Each verified case was classified as lobar or nonlobar s-ICH and matched to controls in the general population by age, sex, and calendar year. Prior antithrombotic use was ascertained from a nationwide prescription registry. We calculated odds ratios (aORs) for associations between the use of clopidogrel, aspirin, direct oral anticoagulants (DOACs) or vitamin K antagonists (VKA), and lobar and nonlobar ICH in conditional logistic regression analyses that were adjusted for potential confounders. RESULTS: A total of 1,040 cases of lobar (47.9% men, mean age [SD] 75.2 [10.7] years) and 1,263 cases of nonlobar s-ICH (54.2% men, mean age 73.6 [11.4] years) were matched to 41,651 and 50,574 controls, respectively. A stronger association with lobar s-ICH was found for clopidogrel (cases: 7.6%, controls: 3.5%; aOR 3.46 [95% CI 2.45-4.89]) vs aspirin (cases: 22.9%, controls: 20.4%; aOR 2.14 [1.74-2.63; p = 0.019). Corresponding estimates for nonlobar s-ICH were not different between clopidogrel (cases: 5.4%, controls: 3.4%; aOR 2.44 [1.71-3.49]) and aspirin (cases: 20.7%, controls: 19.2%; aOR 1.77 [1.47-2.15]; p = 0.12). VKA use was associated with higher odds of both lobar (cases: 14.3%, controls: 6.1%; aOR 3.66 [2.78-4.80]) and nonlobar (cases: 15.4%, controls: 5.5%; aOR 4.62 [3.67-5.82]) s-ICH. The association of DOAC use with lobar s-ICH (cases: 3.5%, controls: 2.7%; aOR 1.66 [1.02-2.70]) was weaker than that of VKA use (p = 0.006). Corresponding estimates for nonlobar s-ICH were not different between DOACs (cases: 5.1%, controls: 2.4%; aOR 3.44 [2.33-5.08]) and VKAs (p = 0.20). DISCUSSION: Antithrombotics were associated with higher risks of s-ICH, but the strength of the associations varied by s-ICH location and drug, which may reflect differences in the cerebral microangiopathies associated with lobar vs nonlobar hemorrhages and the mechanisms of drug action.

The Boston criteria version 2.0 for cerebral amyloid angiopathy: a multicentre, retrospective, MRI-neuropathology diagnostic accuracy study.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is an age-related small vessel disease, characterised pathologically by progressive deposition of amyloid ß in the cerebrovascular wall. The Boston criteria are used worldwide for the in-vivo diagnosis of CAA but have not been updated since 2010, before the emergence of additional MRI markers. We report an international collaborative study aiming to update and externally validate the Boston diagnostic criteria across the full spectrum of clinical CAA presentations. METHODS: In this multicentre, hospital-based, retrospective, MRI and neuropathology diagnostic accuracy study, we did a retrospective analysis of clinical, radiological, and histopathological data available to sites participating in the International CAA Association to formulate updated Boston criteria and establish their diagnostic accuracy across different populations and clinical presentations. Ten North American and European academic medical centres identified patients aged 50 years and older with potential CAA-related clinical presentations (ie, spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes), available brain MRI, and histopathological assessment for CAA diagnosis. MRI scans were centrally rated at Massachusetts General Hospital (Boston, MA, USA) for haemorrhagic and non-haemorrhagic CAA markers, and brain tissue samples were rated by neuropathologists at the contributing sites. We derived the Boston criteria version 2.0 (v2.0) by selecting MRI features to optimise diagnostic specificity and sensitivity in a prespecified derivation cohort (Boston cases 1994-2012, n=159), then externally validated the criteria in a prespecified temporal validation cohort (Boston cases 2012-18, n=59) and a geographical validation cohort (non-Boston cases 2004-18; n=123), comparing accuracy of the new criteria to the currently used modified Boston criteria with histopathological assessment of CAA as the diagnostic standard. We also assessed performance of the v2.0 criteria in patients across all cohorts who had the diagnostic gold standard of brain autopsy. FINDINGS: The study protocol was finalised on Jan 15, 2017, patient identification was completed on Dec 31, 2018, and imaging analyses were completed on Sept 30, 2019. Of 401 potentially eligible patients presenting to Massachusetts General Hospital, 218 were eligible to be included in the analysis; of 160 patient datasets from other centres, 123 were included. Using the derivation cohort, we derived provisional criteria for probable CAA requiring the presence of at least two strictly lobar haemorrhagic lesions (ie, intracerebral haemorrhages, cerebral microbleeds, or foci of cortical superficial siderosis) or at least one strictly lobar haemorrhagic lesion and at least one white matter characteristic (ie, severe visible perivascular spaces in centrum semiovale or white matter hyperintensities in a multispot pattern). The sensitivity and specificity of these criteria were 74·8% (95% CI 65·4-82·7) and 84·6% (71·9-93·1) in the derivation cohort, 92·5% (79·6-98·4) and 89·5% (66·9-98·7) in the temporal validation cohort, 80·2% (70·8-87·6) and 81·5% (61·9-93·7) in the geographical validation cohort, and 74·5% (65·4-82·4) and 95·0% (83·1-99·4) in all patients who had autopsy as the diagnostic standard. The area under the receiver operating characteristic curve (AUC) was 0·797 (0·732-0·861) in the derivation cohort, 0·910 (0·828-0·992) in the temporal validation cohort, 0·808 (0·724-0·893) in the geographical validation cohort, and 0·848 (0·794-0·901) in patients who had autopsy as the diagnostic standard. The v2.0 Boston criteria for probable CAA had superior accuracy to the current Boston criteria (sensitivity 64·5% [54·9-73·4]; specificity 95·0% [83·1-99·4]; AUC 0·798 [0·741-0854]; p=0·0005 for comparison of AUC) across all individuals who had autopsy as the diagnostic standard. INTERPRETATION: The Boston criteria v2.0 incorporate emerging MRI markers of CAA to enhance sensitivity without compromising their specificity in our cohorts of patients aged 50 years and older presenting with spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes. Future studies will be needed to determine generalisability of the v.2.0 criteria across the full range of patients and clinical presentations. FUNDING: US National Institutes of Health (R01 AG26484).

Association of baseline hematoma and edema volumes with one-year outcome and long-term survival after spontaneous intracerebral hemorrhage: A community-based inception cohort study.

BACKGROUND: Hospital-based studies have reported variable associations between outcome after spontaneous intracerebral hemorrhage and peri-hematomal edema volume. AIMS: In a community-based study, we aimed to investigate the existence, strength, direction, and independence of associations between intracerebral hemorrhage and peri-hematomal edema volumes on diagnostic brain CT and one-year functional outcome and long-term survival. METHODS: We identified all adults, resident in Lothian, diagnosed with first-ever, symptomatic spontaneous intracerebral hemorrhage between June 2010 and May 2013 in a community-based, prospective inception cohort study. We defined regions of interest manually and used a semi-automated approach to measure intracerebral hemorrhage volume, peri-hematomal edema volume, and the sum of these measurements (total lesion volume) on first diagnostic brain CT performed at ≤3 days after symptom onset. The primary outcome was death or dependence (scores 3-6 on the modified Rankin Scale) at one-year after intracerebral hemorrhage. RESULTS: Two hundred ninety-two (85%) of 342 patients (median age 77.5 y, IQR 68-83, 186 (54%) female, median time from onset to CT 6.5 h (IQR 2.9-21.7)) were dead or dependent one year after intracerebral hemorrhage. Peri-hematomal edema and intracerebral hemorrhage volumes were colinear (R2 = 0.77). In models using both intracerebral hemorrhage and peri-hematomal edema, 10 mL increments in intracerebral hemorrhage (adjusted odds ratio (aOR) 1.72 (95% CI 1.08-2.87); p = 0.029) but not peri-hematomal edema volume (aOR 0.92 (0.63-1.45); p = 0.69) were independently associated with one-year death or dependence. 10 mL increments in total lesion volume were independently associated with one-year death or dependence (aOR 1.24 (1.11-1.42); p = 0.0004). CONCLUSION: Total volume of intracerebral hemorrhage and peri-hematomal edema, and intracerebral hemorrhage volume alone on diagnostic brain CT, undertaken at three days or sooner, are independently associated with death or dependence one-year after intracerebral hemorrhage, but peri-hematomal edema volume is not. DATA ACCESS STATEMENT: Anonymized summary data may be requested from the corresponding author.

Risks of recurrent stroke and all serious vascular events after spontaneous intracerebral haemorrhage: pooled analyses of two population-based studies.

BACKGROUND: Patients with stroke due to spontaneous (non-traumatic) intracerebral haemorrhage (ICH) are at risk of recurrent ICH, ischaemic stroke, and other serious vascular events. We aimed to analyse these risks in population-based studies and compare them with the risks in RESTART, which assessed antiplatelet therapy after ICH. METHODS: We pooled individual patient data from two prospective, population-based inception cohort studies of all patients with an incident firs-in-a-lifetime ICH in Oxfordshire, England (Oxford Vascular Study; April 1, 2002, to Sept 28, 2018) and Lothian, Scotland, UK (Lothian Audit of the Treatment of Cerebral Haemorrhage; June 1, 2010, to May 31, 2013). We quantified the absolute and relative risks of recurrent ICH, ischaemic stroke, or any serious vascular event (non-fatal stroke, non-fatal myocardial infarction, or vascular death), stratified by ICH location (lobar vs non-lobar) and comorbid atrial fibrillation (AF). We compared pooled event rates with those after allocation to avoid antiplatelet therapy in RESTART. FINDINGS: Among 674 patients (mean age 74·7 years [SD 12·6], 320 [47%] men) with 1553 person-years of follow-up, 46 recurrent ICHs (event rate 3·2 per 100 patient-years, 95% CI 2·0-5·1) and 25 ischaemic strokes (1·7 per 100 patient-years, 0·8-3·3) were reported. Patients with lobar ICH (n=317) had higher risk of recurrent ICH (5·1 per 100 patient-years, 95% CI 3·6-7·2) than patients with non-lobar ICH (n=355; 1·8 per 100 patient-years, 1·0-3·3; hazard ratio [HR] 3·2, 95% CI 1·6-6·3; p=0·0010), but there was no evidence of a difference in the risk of ischaemic stroke (1·8 per 100 patient-years, 1·0-3·2, vs 1·6 per 100 patient-years, 0·6-4·4; HR 1·1, 95% CI 0·5-2·8). Conversely, there was no evidence of a difference in recurrent ICH rate in patients with AF (n=147; 3·3 per 100 patient-years, 95% CI 1·0-10·7) compared with those without (n=526; 3·2 per 100 patient-years, 2·2-4·7; HR 0·9, 95% CI 0·4-2·1), but the risk of ischaemic stroke was higher with AF (6·3 per 100 patient-years, 3·7-10·9, vs 0·7 per 100 patient-years, 0·1-5·6; HR 8·2, 3·3-20·3; p<0·0001), resulting in patients with AF having a higher risk of all serious vascular events than patients without AF (15·5 per 100 patient-years, 10·0-24·1, vs 6·8 per 100 patient-years, 3·6-12·5; HR 1·78, 95% CI 1·16-2·74; p=0·0090). Only for patients with lobar ICH without comorbid AF was the risk of recurrent ICH greater than the risk of ischaemic stroke (5·2 per 100 patient-years, 95% CI 3·6-7·5, vs 0·9 per 100 patient-years, 0·2-4·8; p=0·00034). Comparing data from the pooled population-based studies with that from patients allocated to not receive antiplatelet therapy in RESTART, there was no evidence of a difference in the rate of recurrent ICH (3·5 per 100 patient-years, 95% CI 1·9-6·0, vs 4·4 per 100 patient-years, 2·6-6·1) or ischaemic stroke (3·4 per 100 patient-years, 1·9-5·9, vs 5·3 per 100 patient-years, 3·3-7·2). INTERPRETATION: The risks of recurrent ICH, ischaemic stroke, and all serious vascular events after ICH differ by ICH location and comorbid AF. These data enable risk stratification of patients in clinical practice and ongoing randomised trials. FUNDING: UK Medical Research Council, Stroke Association, British Heart Foundation, Wellcome Trust, and the National Institute for Health Research Oxford Biomedical Research Centre.

Rare Missense Functional Variants at COL4A1 and COL4A2 in Sporadic Intracerebral Hemorrhage.

ObjectiveTo test the genetic contribution of rare missense variants in COL4A1 and COL4A2 in which common variants are genetically associated with sporadic intracerebral hemorrhage (ICH), we performed rare variant analysis in multiple sequencing data for the risk for sporadic ICH.MethodsWe performed sequencing across 559Kbp at 13q34 including COL4A1 and COL4A2 among 2,133 individuals (1,055 ICH cases; 1,078 controls) in US-based and 1,492 individuals (192 ICH cases; 1,189 controls) from Scotland-based cohorts, followed by sequence annotation, functional impact prediction, genetic association testing, and in silico thermodynamic modeling.ResultsWe identified 107 rare nonsynonymous variants in sporadic ICH, of which two missense variants, rs138269346 (COL4A1I110T) and rs201716258 (COL4A2H203L), were predicted to be highly functional and occurred in multiple ICH cases but not in controls from the US-based cohort. The minor allele of rs201716258 was also present in Scottish ICH patients, and rs138269346 was observed in two ICH-free controls with a history of hypertension and myocardial infarction. Rs138269346 was nominally associated with non-lobar ICH risk (P=0.05), but not with lobar ICH (P=0.08), while associations between rs201716258 and ICH subtypes were non-significant (P>0.12). Both variants were considered pathogenic based on minor allele frequency (<0.00035 in EUR), predicted functional impact (deleterious or probably damaging), and in silico modeling studies (substantially altered physical length and thermal stability of collagen).ConclusionsWe identified rare missense variants in COL4A1/A2 in association with sporadic ICH. Our annotation and simulation studies suggest that these variants are highly functional and may represent targets for translational follow-up.

Fifteen Years of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study: Progress and Observations from 2,359 Older Adults Spanning the Spectrum from Cognitive Normality to Alzheimer's Disease.

BACKGROUND: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Study commenced in 2006 as a prospective study of 1,112 individuals (768 cognitively normal (CN), 133 with mild cognitive impairment (MCI), and 211 with Alzheimer's disease dementia (AD)) as an 'Inception cohort' who underwent detailed ssessments every 18 months. Over the past decade, an additional 1247 subjects have been added as an 'Enrichment cohort' (as of 10 April 2019). OBJECTIVE: Here we provide an overview of these Inception and Enrichment cohorts of more than 8,500 person-years of investigation. METHODS: Participants underwent reassessment every 18 months including comprehensive cognitive testing, neuroimaging (magnetic resonance imaging, MRI; positron emission tomography, PET), biofluid biomarkers and lifestyle evaluations. RESULTS: AIBL has made major contributions to the understanding of the natural history of AD, with cognitive and biological definitions of its three major stages: preclinical, prodromal and clinical. Early deployment of Aß-amyloid and tau molecular PET imaging and the development of more sensitive and specific blood tests have facilitated the assessment of genetic and environmental factors which affect age at onset and rates of progression. CONCLUSION: This fifteen-year study provides a large database of highly characterized individuals with longitudinal cognitive, imaging and lifestyle data and biofluid collections, to aid in the development of interventions to delay onset, prevent or treat AD. Harmonization with similar large longitudinal cohort studies is underway to further these aims.

The relationship between memory complaints, perceived quality of life and mental health in apolipoprotein Eepsilon4 carriers and non-carriers.

Apolipoprotein E epsilon4 (APOE-epsilon4) is a major genetic risk factor for Alzheimer's disease. In this study, we addressed the question of whether possession of the APOE-epsilon4 allele results in adverse effects on perceived health-related quality of life (HRQL) and on symptoms of depression and anxiety in people with subjective memory complaints (SMC). 138 healthy, community-dwelling elderly volunteers, aged 52 to 85, were assessed for HRQL, depression, and anxiety. The participants were classified as i) APOE-epsilon4 carriers or ii) non-carriers with a) SMC or b) without memory complaints. The possible interactions of APOE genotype, gender, and SMC on HRQL, depression, and anxiety were investigated statistically. SMC was significantly associated with poorer outcomes on measures of depression, trait anxiety, and mental health. APOE-epsilon4 carriers did not significantly differ from non-carriers on HRQL, depression, and anxiety. However, significant interaction was found between APOE-epsilon4 genotype and SMC on depression. These findings are important from a health perspective and suggest that memory complaints are associated with markers of mental health and quality of life that are independent of possession of the APOE-epsilon4 allele, despite the importance of this polymorphism in the risk of AD and other health problems.

Olfactory dysfunction is associated with subjective memory complaints in community-dwelling elderly individuals.

Olfactory dysfunction has been reported in clinical and preclinical phases of Alzheimer's disease. Subjective memory complaints have been proposed as a potential early indicator for increased risk of Alzheimer's disease, but have also been associated with depression, personality characteristics, and health problems. In this study, we aimed to determine which of these putative markers can predict memory complaints in community-dwelling elderly individuals, focusing on olfactory symptoms. A cohort of 144 elderly volunteers (42 males and 102 females), aged 50 to 86, was recruited from an ongoing longitudinal study. Participants were assessed for olfactory capacities (threshold, discrimination, and identification), subjective memory complaints, depression, and cognitive functions. Subjective memory complaints were significantly associated with olfactory discrimination and identification but not with threshold. Olfactory functions and depressive symptoms were both significantly associated with subjective memory complaints. In addition, memory complainers were significantly worse than non-complainers with respect to olfactory discrimination, identification, and overall olfactory functioning. The findings suggest that olfactory capacity may be a potentially significant biomarker for identifying community-dwelling elderly with memory complaints who are at increased risk for age-related cognitive decline and Alzheimer's disease.

Advancing diagnostic criteria for sporadic cerebral amyloid angiopathy: Study protocol for a multicenter MRI-pathology validation of Boston criteria v2.0.

RATIONALE: The Boston criteria are used worldwide for the in vivo diagnosis of cerebral amyloid angiopathy and are the basis for clinical decision-making and research in the field. Given substantial advances in cerebral amyloid angiopathy's clinical aspects and MRI biomarkers, we designed a multicenter study within the International cerebral amyloid angiopathy Association aimed at further validating the diagnostic accuracy of the Boston and potentially improving and updating them. AIM: We aim to derive and validate an updated "version 2.0" of the Boston criteria across the spectrum of cerebral amyloid angiopathy-related presentations and MRI biomarkers. SAMPLE SIZE ESTIMATES: Participating centers with suitable available data (see Methods) were identified from existing collaborations and an open invitation to the International Cerebral Amyloid Angiopathy Association emailing list. Our study sample will include: (1) a derivation cohort - Massachusetts General Hospital (MGH), Boston cases from inception to 2012 (∼150 patients); (2) temporal external validation cohort - MGH, Boston cases from 2012 to 2018 (∼100 patients); and (3) geographical external validation cohort - non-Boston cases (∼85 patients). METHODS AND DESIGN: Multicenter collaborative study. We will collect and analyze data from patients' age ≥ 50 with any potential sporadic cerebral amyloid angiopathy-related clinical presentations (spontaneous intracerebral hemorrhage, transient focal neurological episodes and cognitive impairment), available brain MRI ("index test"), and histopathologic assessment for cerebral amyloid angiopathy ("reference standard" for diagnosis). Trained raters will assess MRI for all prespecified hemorrhagic and non-hemorrhagic small vessel disease markers of interest, according to validated criteria and a prespecified protocol, masked to clinical and histopathologic features. Brain tissue samples will be rated for cerebral amyloid angiopathy, defined as Vonsattel grade ≥2 for whole brain autopsies and ≥1 for cortical biopsies or hematoma evacuation. Based on our estimated available sample size, we will undertake pre-specified cohort splitting as above. We will: (a) pre-specify variables and statistical cut-offs; (b) examine univariable and multivariable associations; and (c) then assess classification measures (sensitivity, specificity etc.) for each MRI biomarker individually, in relation to the cerebral amyloid angiopathy diagnosis reference standard on neuropathology in a derivation cohort. The MRI biomarkers strongly associated with cerebral amyloid angiopathy diagnosis will be selected for inclusion in provisional (probable and possible cerebral amyloid angiopathy) Boston criteria v2.0 and validated using appropriate metrics and models. STUDY OUTCOMES: Boston criteria v2.0 for clinical cerebral amyloid angiopathy diagnosis. DISCUSSION: This work aims to potentially update and improve the diagnostic test accuracy of the Boston criteria for cerebral amyloid angiopathy and to provide wider validation of the criteria in a large sample. We envision that this work will meet the needs of clinicians and investigators and help accelerate progress towards better treatment of cerebral amyloid angiopathy.

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, open-label trial.

BACKGROUND: Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy. METHODS: RESTART was a prospective, randomised, open-label, blinded-endpoint, parallel-group trial at 122 hospitals in the UK that assessed whether starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. For this prespecified subgroup analysis, consultant neuroradiologists masked to treatment allocation reviewed brain CT or MRI scans performed before randomisation to confirm participant eligibility and rate features of the intracerebral haemorrhage and surrounding brain. We followed participants for primary (recurrent symptomatic intracerebral haemorrhage) and secondary (ischaemic stroke) outcomes for up to 5 years (reported elsewhere). For this report, we analysed eligible participants with intracerebral haemorrhage according to their treatment allocation in primary subgroup analyses of cerebral microbleeds on MRI and in exploratory subgroup analyses of other features on CT or MRI. The trial is registered with the ISRCTN registry, number ISRCTN71907627. FINDINGS: Between May 22, 2013, and May 31, 2018, 537 participants were enrolled, of whom 525 (98%) had intracerebral haemorrhage: 507 (97%) were diagnosed on CT (252 assigned to start antiplatelet therapy and 255 assigned to avoid antiplatelet therapy, of whom one withdrew and was not analysed) and 254 (48%) underwent the required brain MRI protocol (122 in the start antiplatelet therapy group and 132 in the avoid antiplatelet therapy group). There were no clinically or statistically significant hazards of antiplatelet therapy on recurrent intracerebral haemorrhage in primary subgroup analyses of cerebral microbleed presence (2 or more) versus absence (0 or 1) (adjusted hazard ratio [HR] 0·30 [95% CI 0·08-1·13] vs 0·77 [0·13-4·61]; pinteraction=0·41), cerebral microbleed number 0-1 versus 2-4 versus 5 or more (HR 0·77 [0·13-4·62] vs 0·32 [0·03-3·66] vs 0·33 [0·07-1·60]; pinteraction=0·75), or cerebral microbleed strictly lobar versus other location (HR 0·52 [0·004-6·79] vs 0·37 [0·09-1·28]; pinteraction=0·85). There was no evidence of heterogeneity in the effects of antiplatelet therapy in any exploratory subgroup analyses (all pinteraction>0·05). INTERPRETATION: Our findings exclude all but a very modest harmful effect of antiplatelet therapy on recurrent intracerebral haemorrhage in the presence of cerebral microbleeds. Further randomised trials are needed to replicate these findings and investigate them with greater precision. FUNDING: British Heart Foundation.