Background Stroke thrombolysis with alteplase is currently recommended 0-4•5 h after stroke onset. We aimed to determine whether perfusion imaging can identify patients with salvageable brain tissue with symptoms 4•5 h or more from stroke onset or with symptoms on waking who might benefit from thrombolysis.Methods In this systematic review and meta-analysis of individual patient data, we searched PubMed for randomised trials published in English between Jan 1, 2006, and March 1, 2019. We also reviewed the reference list of a previous systematic review of thrombolysis and searched ClinicalTrials.gov for interventional studies of ischaemic stroke. Studies of alteplase versus placebo in patients (aged ≥18 years) with ischaemic stroke treated more than 4•5 h after onset, or with wake-up stroke, who were imaged with perfusion-diffusion MRI or CT perfusion were eligible for inclusion. The primary outcome was excellent functional outcome (modified Rankin Scale [mRS] score 0-1) at 3 months, adjusted for baseline age and clinical severity. Safety outcomes were death and symptomatic intracerebral haemorrhage. We calculated odds ratios, adjusted for baseline age and National Institutes of Health Stroke Scale score, using mixed-effects logistic regression models. This study is registered with PROSPERO, number CRD42019128036. FindingsWe identified three trials that met eligibility criteria: EXTEND, ECASS4-EXTEND, and EPITHET. Of the 414 patients included in the three trials, 213 (51%) were assigned to receive alteplase and 201 (49%) were assigned to receive placebo. Overall, 211 patients in the alteplase group and 199 patients in the placebo group had mRS assessment data at 3 months and thus were included in the analysis of the primary outcome. 76 (36%) of 211 patients in the alteplase group and 58 (29%) of 199 patients in the placebo group had achieved excellent functional outcome at 3 months (adjusted odds ratio [OR] 1•86, 95% CI 1•15-2•99, p=0•011). Symptomatic intracerebral haemorrhage was more common in the alteplase group than the placebo group (ten [5%] of 213 patients vs one [<1%] of 201 patients in the placebo group; adjusted OR 9•7, 95% CI 1•23-76•55, p=0•031). 29 (14%) of 213 patients in the alteplase group and 18 (9%) of 201 patients in the placebo group died (adjusted OR 1•55, 0•81-2•96, p=0•66).Interpretation Patients with ischaemic stroke 4•5-9 h from stroke onset or wake-up stroke with salvageable brain tissue who were treated with alteplase achieved better functional outcomes than did patients given placebo. The rate of symptomatic intracerebral haemorrhage was higher with alteplase, but this increase did not negate the overall net benefit of thrombolysis.

This is the first study indicating that midlife sleep length, sleep quality, and use of hypnotics are associated with late life cognitive function. Further confirmation is needed, but sleep-related characteristics may emerge as new risk factors for cognitive impairment.

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Cardiovascular risk factors increase the risk of dementia in later life. The aims of the current study were to assess the effect of multiple midlife cardiovascular risk factors on the risk of cognitive impairment in later life, and to assess the validity of the previously suggested CAIDE Study risk score predicting dementia risk 20 years later. A total of 2,165 Finnish twins were followed and at the end of the follow-up their cognitive status was assessed with a validated telephone interview. The assessment of the risk factors at baseline was based on a self-report questionnaire. Relative risk ratios (RR) were calculated and receiver operating characteristic analyses performed. Midlife obesity (RR 2.42, 95 % CI 1.47-3.98), hypertension (RR 1.38, 95 % CI 1.01-1.88) and low leisure time physical activity (RR 2.52, 95 % CI 1.10-5.76) increased the risk of cognitive impairment after a mean follow-up of 22.6 ± 2.3 years. Hypercholesterolemia did not significantly increase the risk (RR 1.52, 95 % CI 0.92-2.51). Overweight individuals who gained more than 10 % weight between 1981 and 1990 had an increased risk of cognitive impairment (RR 4.27, 95 % CI 1.62-11.2). The CAIDE Study risk score combining various individual risk factors had an area-under-curve of 0.74 (95 % CI 0.69-0.79, n = 591), and there was a strong association between an increasing risk score and the risk of cognitive impairment. The results indicate that multiple midlife cardiovascular risk factors increase the risk of cognitive impairment in later life. Also, a risk score including easily measurable midlife factors predicts an individual's cognitive impairment risk well.