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Background and Purpose: Although most strokes present with mild symptoms, these have been poorly represented in clinical trials. The objective of this study is to describe multidimensional outcomes, identify predictors of worse outcomes, and explore the effect of thrombolysis in this population. Methods: This prospective observational study included patients with ischemic stroke or transient ischemic attack, a baseline National Institutes of Health Stroke Scale (NIHSS) score 0 to 5, presenting within 4.5 hours from symptom onset. The primary outcome was a 90-day modified Rankin Scale score of 0 to 1; secondary outcomes included good outcomes in the Barthel Index, Stroke Impact Scale-16, and European Quality of Life. Multivariable models were created to determine predictors of outcomes and the effect of alteplase. Results: A total of 1765 participants were included from 100 Get With The Guidelines-Stroke participating hospitals (age, 65±14; 42% women; final diagnosis of ischemic stroke, 90%; transient ischemic attack, 10%; 57% received alteplase). At 90 days, 37% were disabled and 25% not independent. Worse outcomes were noted for older individuals, women, non-Hispanic Blacks and Hispanics, Medicaid recipients, smokers, those with diabetes, atrial fibrillation, prior stroke, higher baseline NIHSS, visual field defects, and extremity weakness. Similar outcomes were noted for the alteplase-treated and untreated groups. Alteplase-treated patients were younger (64±13 versus 67±1.4) with higher NIHSS (2.9±1.4 versus 1.7±1.4). After adjusting for age, sex, race/ethnicity, and baseline NIHSS, we did not identify an effect of alteplase on the primary outcome but did find an association with Stroke Impact Scale-16 in the restricted sample of baseline NIHSS score 3–5. Few symptomatic intracerebral hemorrhages were recorded ( Conclusions: A large proportion of stroke patients presenting with low NIHSS have a disabled outcome. Baseline predictors of worse outcomes are described. An effect of alteplase on outcomes was not identified in the overall cohort, but a suggestion of efficacy was noted in the NIHSS 3–5 subgroup. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02072681.

Background and Purpose: Clinical fluctuations in ischemic stroke symptoms are common, but fluctuations before hospital arrival have not been previously characterized. Methods: A standardized qualitative assessment of fluctuations before hospital arrival was obtained in an observational study that enrolled patients with mild ischemic stroke symptoms (National Institutes of Health Stroke Scale [NIHSS] score of 0–5) present on arrival to hospital within 4.5 hours of onset, in a subset of 100 hospitals participating in the Get With The Guidelines–Stroke quality improvement program. The number of fluctuations, direction, and the overall improvement or worsening was recorded based on reports from the patient, family, or paramedics. Baseline NIHSS on arrival and at 72 hours (or discharge if before) and final diagnosis and stroke subtype were collected. Outcomes at 90 days included the modified Rankin Scale, Barthel Index, Stroke Impact Scale 16, and European Quality of Life. Prehospital fluctuations were examined in relation to hospital NIHSS change (admission to 72 hours or discharge) and 90-day outcomes. Results: Among 1588 participants, prehospital fluctuations, consisting of improvement, worsening, or both were observed in 35.5%: 25.1% improved once, 5.3% worsened once, and 5.1% had more than 1 fluctuation. Those who improved were less likely and those who worsened were more likely to receive alteplase. Those who improved before hospital arrival had lower change in the hospital NIHSS than those who did not fluctuate. Better adjusted 90-day outcomes were noted in those with prehospital improvement compared to those without any fluctuations. Conclusions: Fluctuations in neurological symptoms and signs are common in the prehospital setting. Prehospital improvement was associated with better 90-day outcomes, controlling for admission NIHSS and alteplase treatment. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT 02072681.

Background: Insulin-like growth factor 1 (IGF-1), reduces progression of atherosclerosis and in cross-sectional studies low circulating IGF-1 is associated with increased carotid intima-media thickness. Yet, prospective data linking IGF-1 levels to development of stroke remain sparse and inconsistent. We related circulating IGF-1 levels to risk of incident stroke in a community-dwelling sample. Methods: Serum IGF-1 levels were assayed in 757 stroke-free participants (age 79+5 years, 62% women) from the Framingham original cohort (1990-1994), and related to prospectively ascertained, incident all-stroke and ischemic stroke using Cox models. Results: During a mean follow-up of 10.2 years in 757 participants, 119 developed stroke including 99 with ischemic stroke. After adjustment for age and sex, higher log-IGF1 levels were associated with a lower risk of incident ischemic stroke [hazard ratio (HR): 0.79, 95% confidence interval (CI): 0.63- 0.99, p=0.043]. There was a threshold effect with subjects in the lowest quintile of IGF-1 levels having 2.56-fold higher risk of incident ischemic stroke (95% CI: 1.20, 5.45, p=0.015) compared to all others. We observed significant interaction between diabetes and IGF1 in their relation to ischemic stroke (p=0.016). In pre-specified subgroup analyses the effect was restricted to persons with diabetes and central obesity (waist-to-hip ratio in top quartile) in whom each SD increase in IGF-1 was associated with a 61% (HR: 0.39, 95%CI: 0.20-0.78, p=0.007), and 41% (HR: 0.59, 95%CI: 0.37- 0.95, p=0.031) lower risk of incident ischemic stroke, respectively. Results were similar for all-stroke. Conclusions: IGF-1 may have a protective role in the pathogenesis of ischemic stroke among persons with insulin resistance as manifested by diabetes and/or obesity.

Background: Leptin is a major adipokine that regulates weight balance and energy homeostasis. There is some inconsistent evidence linking circulating leptin levels to risk of stroke. We tested the hypothesis that leptin levels are associated with risk of first ever stroke in an elderly community-based population. Methods: Serum leptin levels were assayed in 757 stroke-free individuals (mean age 79 [SD, 5 years], 62% women) from the Framingham Original cohort at the 22nd examination cycle (1990-1994). Incidence of all-stroke and ischemic stroke were prospectively ascertained. Results: During a mean follow-up of 10 years, 119 individuals developed stroke, 99 of whom had ischemic stroke. In multivariable Cox regression models, log-leptin levels were not associated with incidence of all-stroke or ischemic stroke (hazard ratios [HR] per SD increment in log-leptin 0.9 [0.73-1.09] and 0.89 [0.72-1.11], respectively). The results were highly suggestive for effect modification by WHR for the association between leptin and ischemic stroke. Analysis in sub-groups stratified by waist-to-hip ratio (WHR) and adjusting for age, sex and established stroke risk factors revealed a lower incidence of first-ever all-stroke and ischemic stroke associated with higher leptin levels among subjects in the top WHR quartile but not in others (HR, 0.64 [0.43, 0.95] versus 0.98 [0.77, 1.25] for incident all-stroke and 0.61 [0.39, 0.95] versus 0.96 [0.74, 1.26] for ischemic stroke). Conclusions: Our data suggests that leptin may exert protective effects against first ever stroke in obese individuals. Further investigations are required to confirm these findings and explore possible mechanisms for this protective effect.

Objectives: To determine and compare the accuracy of the Boston criteria for the diagnosis of cerebral amyloid angiopathy (CAA) applied to: 1) a large hospital-based cohort; 2) a cohort of community-dwelling individuals. Methods: Among patients seen at a single academic medical center and participants enrolled in the Framingham Heart Study (FHS) we identified all individuals having had brain MRI (including hemosiderin-specific sequences) and pathological assessment of CAA at age ≥55. CAA was defined as Vonsattel degree ≥2, except in non-autopsy studies, where any vascular amloyid deposition was considered diagnostic of CAA. We excluded cases with: 1) non-lobar ICH; 2) alternative clinical diagnosis for the lobar hemorrhage/es; 3) CAA-negative studies based on small brain biopsy samples (greater diameter 1 strictly lobar hemorrhage) in both cohorts. Results: The study included 143 cases: 96 from the hospital cohort (mean age at time of MRI 74.1±8.2 years, 47.9% women, 47.9% autopsy studies, 54.2% cases with any lobar microbleed, 44.8% with any lobar ICH) and 47 from FHS (mean age at time of MRI 83.4±10.9 years, 48.9% women, 100% autopsy studies, 17% cases with any lobar microbleed, no lobar ICH cases). Hospital cohort: CAA prevalence was 72.6%. Specificity/sensitivity of “possible CAA” and “probable CAA” were 78.2%/33.3% and 92%/57.7%. Community cohort: CAA prevalence was 47%. Specificity/sensitivity of “probable CAA” were 88%/3%. Discussion: Specificity of detection of multiple lobar hemorrhages on MRI (“probable CAA”) for moderate-severe CAA is similarly high in both hospital and community cohorts. This increases the opportunity to identify individuals with CAA for observational studies and emerging anti-amyloid therapeutic trials. In view of its poor sensitivity, “probable CAA” diagnosis represents an inadequate screening tool for exclusion of CAA in both populations.