APOE genotype, hypertension severity and outcomes after intracerebral haemorrhage.

Intracerebral haemorrhage in the elderly is a severe manifestation of common forms of cerebral small vessel disease. Nearly 60% of intracerebral haemorrhage survivors will develop clinical manifestations of small vessel disease progression including recurrent haemorrhage, ischaemic stroke, dementia, late-life depression and gait impairment within 5 years. Blood pressure measurements following intracerebral haemorrhage are strongly associated with this risk. However, aggressive blood pressure lowering in the elderly carries substantial risks. In order to determine whether there might be an opportunity to select individuals at the highest risk for small vessel disease progression for aggressive blood pressure reduction, we investigated whether APOE gene variants ɛ2/ɛ4 modify the association between blood pressure and small vessel disease clinical progression after intracerebral haemorrhage. We conducted a single-centre longitudinal study at a tertiary care referral centre (Massachusetts General Hospital in Boston, MA, USA), analysing 716 consecutive survivors of acute intracerebral haemorrhage, enrolled from January 2006 to December 2016. We conducted research interviews at the time of enrolment and obtained APOE genotypes from peripheral venous blood samples. We followed patients longitudinally by means of validated phone-based research encounters, aimed at gathering measurements of systolic and diastolic blood pressure, as well as information on small vessel disease clinical outcomes (including recurrent haemorrhage, incident ischaemic stroke, incident dementia, incident depression and incident gait impairment). APOE ε4 and systolic blood pressure were associated with the risk of recurrent haemorrhage, ischaemic stroke and post-haemorrhage dementia, depression and gait impairment (all P < 0.05). APOE ε4 and systolic blood pressure interacted to increase the risk of recurrent haemorrhage, ischaemic stroke, dementia and gait impairment (all interaction P < 0.05). Among patients with elevated blood pressure following intracerebral haemorrhage (average systolic blood pressure 120-129 mmHg and diastolic blood pressure <80 mmHg) only those with one or more APOE ε4 copies were at increased risk for one or more small vessel disease outcomes (hazard ratio = 1.97, 95% confidence interval 1.17-3.31). Among haemorrhage survivors with hypertension (stage 1 and beyond) APOE genotype also stratified risk for all small vessel disease outcomes. In conclusion, APOE genotype modifies the already strong association of hypertension with multiple small vessel disease clinical outcomes among intracerebral haemorrhage survivors. These data raise the possibility that genetic screening could inform blood pressure treatment goals in this patient population.

Cardioembolic Stroke Risk and Recovery After Anticoagulation-Related Intracerebral Hemorrhage.

Background and Purpose- Whether to resume oral anticoagulation treatment after intracerebral hemorrhage (ICH) remains an unresolved question. Previous studies focused primarily on recurrent stroke after ICH. We sought to investigate the association between cardioembolic stroke risk, oral anticoagulation therapy resumption, and functional recovery among ICH survivors in the absence of recurrent stroke. Methods- We conducted a joint analysis of 3 observational studies: (1) the multicenter RETRACE study (German-Wide Multicenter Analysis of Oral Anticoagulation Associated Intracerebral Hemorrhage); (2) the Massachusetts General Hospital ICH study (n=166); and (3) the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage; n=131). We included 941 survivors of ICH in the setting of active oral anticoagulation therapy for prevention of cardioembolic stroke because of nonvalvular atrial fibrillation and without evidence of ischemic stroke and recurrent ICH at 1 year from the index event. We created univariable and multivariable models to explore associations between cardioembolic stroke risk (based on CHA2DS2-VASc scores) and functional recovery after ICH, defined as achieving modified Rankin Scale score of ≤3 at 1 year for participants with modified Rankin Scale score of >3 at discharge. Results- In multivariable analyses, the CHA2DS2-VASc score was associated with a decreased likelihood of functional recovery (odds ratio, 0.83 per 1 point increase; 95% CI, 0.79-0.86) at 1 year. Anticoagulation resumption was independently associated with a higher likelihood of recovery, regardless of CHA2DS2-VASc score (odds ratio, 1.89; 95% CI, 1.32-2.70). We found an interaction between CHA2DS2-VASc score and anticoagulation resumption in terms of association with increased likelihood of functional recovery (interaction P=0.011). Conclusions- Increasing cardioembolic stroke risk is associated with a decreased likelihood of functional recovery at 1 year after ICH, but this association was weaker among participants resuming oral anticoagulation therapy. These findings support, including recovery metrics, in future studies of anticoagulation resumption after ICH.

Reflecting on explanatory ability: A mechanism for detecting gaps in causal knowledge.

People frequently overestimate their understanding-with a particularly large blind-spot for gaps in their causal knowledge. We introduce a metacognitive approach to reducing overestimation, termed reflecting on explanatory ability (REA), which is briefly thinking about how well one could explain something in a mechanistic, step-by-step, causally connected manner. Nine experiments demonstrated that engaging in REA just before estimating one's understanding substantially reduced overestimation. Moreover, REA reduced overestimation with nearly the same potency as generating full explanations, but did so 20 times faster (although only for high complexity objects). REA substantially reduced overestimation by inducing participants to quickly evaluate an object's inherent causal complexity (Experiments 4-7). REA reduced overestimation by also fostering step-by-step, causally connected processing (Experiments 2 and 3). Alternative explanations for REA's effects were ruled out including a general conservatism account (Experiments 4 and 5) and a covert explanation account (Experiment 8). REA's overestimation-reduction effect generalized beyond objects (Experiments 1-8) to sociopolitical policies (Experiment 9). REA efficiently detects gaps in our causal knowledge with implications for improving self-directed learning, enhancing self-insight into vocational and academic abilities, and even reducing extremist attitudes.