Covert Brain Infarcts in Patients with Philadelphia Chromosome-Negative Myeloproliferative Disorders

Backgrounds and Purpose. Philadelphia chromosome-negative myeloproliferative disorders (Ph-negative MPD) are a rare group of hematological diseases, including three distinct pathologies: essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). They most often manifest with thrombotic complications, including cerebrovascular events. Covert brain infarcts (CBIs) are defin ed as predominantly small ischemic cerebral lesions that are detected using magnetic resonance imaging (MRI) in the absence of clinical stroke events. The relationship between MPD and CBIs remains unclear. Methods. Included in the study were 103 patients with the diagnosis of Ph-MPD (according to WHO 2016 criteria) (median age—47 (35; 54) years; 67% female). In total, 38 patients had ET, 42 had PV, and 23 had PMF. They underwent clinical examination, routine laboratory analyses (complete blood count), brain MRI, ultrasound carotid artery, flow-mediated dilatation (as a measure of endothelial dysfunction—FMD). Results. Overall, 23 patients experienced an ischemic stroke (as per MRI and/or clinical history), of which 16 (15.5%) could be classified as CBIs. The rate of CBIs per MPD subtype was statistically non-significant between groups (p = 0.35): ET–13.2%, PV–21.4%, and PMF–8.7%. The major vascular risk factors, including arterial hypertension, carotid atherosclerosis, and prior venous thrombosis, were not associated with CBIs (p > 0.05). Age was significantly higher in patients with CBIs compared to patients without MRI ischemic lesions: 50 (43; 57) years vs. 36 (29; 48) (p = 0.002). The frequency of headaches was comparable between the two groups. CBIs were associated with endothelial dysfunction (OR - 0.71 (95% CI: 0.49–0.90; p = 0.02)) and higher hemoglobin levels (OR—1.21 (95% CI: 1.06–1.55); p =0.03). Conclusions. CBIs are common in patients with Ph-negative MPD. Arterial hypertension and carotid atherosclerosis were not associated with CBIs in this group of patients. The most significant factors in the development of CBIs were endothelial dysfunction (as measured by FMD) and high hemoglobin levels. Patients with Ph-negative MPD and CBIs were older and had more prevalent endothelial dysfunction.

Association of Serum Neurofilament Light Chain Concentration and MRI Findings in Older Adults: The Cardiovascular Health Study

BACKGROUND AND OBJECTIVES:Neurofilament light chain (NfL) in blood is a sensitive but non-specific marker of brain injury. This study sought to evaluate associations between NfL concentration and MRI findings of vascular brain injury in older adults.METHODS:A longitudinal cohort study included two cranial MRI scans performed about 5 years apart and assessed for white matter hyperintensities (WMH) and infarcts. About one year before their second MRI, 1,362 participants (median age 77 years and 61.4% women) without a history of TIA or stroke had measurement of four biomarkers: NfL, total tau, glial fibrillary acidic protein (GFAP), and ubiquitin carboxyl-terminal hydrolase L1. Most (n = 1,279) also had the first MRI scan, and some (n=633) had quantitative measurements of hippocampal and WMH. In primary analyses, we assessed associations of NfL with a 10-point white matter grade (WMG) and prevalent infarcts on second MRI and with worsening WMG and incident infarct comparing the two scans. A p-value <0.0125 (0.05/4) was considered significant for these analyses. We also assessed associations with hippocampal and WMH volume.RESULTS:In fully adjusted models, log2(NfL) concentration was associated with WMG (β=0.27; p=2.3x10-4) and worsening WMG (RR=1.24; p=0.0022), but less strongly with prevalent brain infarcts (RR=1.18; p=0.013) and not with incident brain infarcts (RR=1.18; p=0.18). Associations were also present with WMH volume (beta=2242.9, p=0.0036). For the other three biomarkers, the associations for log2(GFAP) concentration with WMG and worsening WMG were significant.DISCUSSION:Among older adults without a history of stroke, higher serum NfL concentration was associated with covert MRI findings of vascular brain injury, especially the burden of WMH and its worsening. Whether these results offer opportunities for the use of NfL as a non-invasive biomarker of WMH or to control vascular risk factors remains to be determined.

Cerebrovascular Risk-Factors of Prevalent and Incident Brain Infarcts in the General Population: The AGES-Reykjavik Study

Background and Purpose: Studies on the association of cerebrovascular risk factors to magnetic resonance imaging detected brain infarcts have been inconsistent, partly reflecting limits of assessment to infarcts anywhere in the brain, as opposed to specific brain regions. We hypothesized that risk-factors may differ depending on where the infarct is located in subcortical-, cortical-, and cerebellar regions. Methods: Participants (n=2662, mean age 74.6±4.8) from the longitudinal population-based AGES (Age, Gene/Environment Susceptibility)-Reykjavik Study underwent brain magnetic resonance imaging at baseline and on average 5.2 years later. We assessed the number and location of brain infarcts (prevalent versus incident). We estimated the risk-ratios of prevalent (PRR) and incident (IRR) infarcts by baseline cerebrovascular risk-factors using Poisson regression. Results: Thirty-one percent of the study participants had prevalent brain infarcts and 21% developed new infarcts over 5 years. Prevalent subcortical infarcts were associated with hypertension (PRR, 2.7 [95% CI, 1.1–6.8]), systolic blood pressure (PRR, 1.2 [95% CI, 1.1–1.4]), and diabetes (PRR, 2.8 [95% CI, 1.9–4.1]); incident subcortical infarcts were associated with systolic (IRR, 1.2 [95% CI, 1.0–1.4]) and diastolic (IRR, 1.3 [95% CI, 1.0–1.6]) blood pressure. Prevalent and incident cortical infarcts were associated with carotid plaques (PRR, 1.8 [95% CI, 1.3–2.5] and IRR, 1.9 [95% CI, 1.3–2.9], respectively), and atrial fibrillation was significantly associated with prevalent cortical infarcts (PRR, 1.8 [95% CI, 1.2–2.7]). Risk-factors for prevalent cerebellar infarcts included hypertension (PRR, 2.45 [95% CI, 1.5–4.0]), carotid plaques (PRR, 1.45 [95% CI, 1.2–1.8]), and migraine with aura (PRR, 1.6 [95% CI, 1.1–2.2]). Incident cerebellar infarcts were only associated with any migraine (IRR, 1.4 [95% CI, 1.0–2.0]). Conclusions: The risk for subcortical infarcts tends to increase with small vessel disease risk-factors such as hypertension and diabetes. Risk for cortical infarcts tends to increase with atherosclerotic/coronary processes and risk for cerebellar infarcts with a more mixed profile of factors. Assessment of risk-factors by location of asymptomatic infarcts found on magnetic resonance imaging may improve the ability to target and optimize preventive therapeutic approaches to prevent stroke.

Rivaroxaban versus aspirin for prevention of covert brain infarcts in patients with embolic stroke of undetermined source: NAVIGATE ESUS MRI substudy

Background Covert brain infarcts are associated with important neurological morbidity. Their incidence in patients with embolic stroke of undetermined source (ESUS) is unknown. Aims To assess the incidence of covert brain infarcts and cerebral microbleeds using MRI in a prospective substudy of the NAVIGATE ESUS randomized trial and to evaluate the effects of antithrombotic therapies. Methods At 87 sites in 15 countries, substudy participants were randomly assigned to receive rivaroxaban 15 mg daily or aspirin 100 mg daily and underwent brain MRI near randomization and after study termination. The primary outcome was incident brain infarct (clinical ischemic stroke or covert brain infarct). Brain infarcts and microbleeds were ascertained centrally by readers unaware of treatment. Treatment effects were estimated using logistic regression. Results Among the 718 substudy participants with interpretable, paired MRIs, the mean age was 67 years and 61% were men with a median of 52 days between the qualifying ischemic stroke and randomization and a median of seven days between randomization and baseline MRI. During the median (IQR) 11 (12) month interval between scans, clinical ischemic strokes occurred in 27 (4%) participants, while 60 (9%) of the remaining participants had an incident covert brain infarct detected by MRI. Assignment to rivaroxaban was not associated with reduction in the incidence of brain infarct (OR 0.77, 95% CI 0.49, 1.2) or of covert brain infarct among those without clinical stroke (OR 0.85, 95% CI 0.50, 1.4). New microbleeds were observed in 7% and did not differ among those assigned rivaroxaban vs. aspirin (HR 0.95, 95% CI 0.52–1.7). Conclusions Incident covert brain infarcts occurred in twice as many ESUS patients as a clinical ischemic stroke. Treatment with rivaroxaban compared with aspirin did not significantly reduce the incidence of covert brain infarcts or increase the incidence of microbleeds, but the confidence intervals for treatment effects were wide. Registration: https://www.clinicaltrials.gov . Unique identifier: NCT 02313909

P.083 Early and 30-day clinical and neuropsychological effects of iatrogenic brain infarcts in the ENACT randomized-controlled trial

Background: Small brain infarcts are often seen on diffusion-weighted MRI(DWI) following surgical/endovascular procedures. Little is known about their clinical effects. We examined the association of iatrogenic infarcts with outcomes in the ENACT(Evaluating Neuroprotection in Aneurysm Coiling Therapy) trial of nerinetide in endovascular aneurysm repair. Methods: In this post-hoc analysis, we used multi-variable models to evaluate the association of presence/number of DWI iatrogenic infarcts with NIHSS(National Institutes of Health Stroke Scale), mRS(modified Rankin Scale), and cognitive/neuropsychological scores(30-minute battery) at 1-4 and 30-days post-procedure. We also related infarct number to a Z-score-derived composite outcome score(quantile regression). Results: Among 185 patients(median age:56,IQR:50-64), 124(67.0%) had iatrogenic infarcts(median:4,IQR:2-10.5). Nerinetide resulted in fewer infarcts. Patients with infarcts had lower Mini-Mental State Exam(MMSE) scores at 2-4 days(median:28 vs 29, adjusted-coefficient[acoef] per additional infarct:-1.11,95%CI:-1.88 to -0.34,p=0.005). Infarct number was associated with worse day-1 NIHSS(aOR for NIHSS≥1:1.07,1.02-1.12,p=0.009), day 2-4 mRS(adjusted common odds-ratio[aOR]:1.05,1.01-1.09,p=0.005) and MMSE(acoef:-0.07,-0.13 to -0.003,p=0.040), 30-day mRS(aOR:1.04,1.01-1.07,p=0.016) and Hopkins Verbal Learning Test scores(acoef:-0.21,-0.39 to -0.03,p=0.020), as well as worse composite scores at 1-4 and 30-days(acoef:-0.09,-0.15 to -0.03,p=0.006). Conclusions: Iatrogenic infarcts were associated with subtle differences in post-procedural(1-4 days) and 30-day outcomes in this middle-aged cohort. Future studies should use batteries of similar/greater granularity to validate optimal measures for short- versus long-term manifestations.

Frequency and Patterns of Brain Infarction in Patients With Embolic Stroke of Undetermined Source: NAVIGATE ESUS Trial

Background and Purpose: The spectrum of brain infarction in patients with embolic stroke of undetermined source (ESUS) has not been well characterized. Our objective was to define the frequency and pattern of brain infarcts detected by magnetic resonance imaging (MRI) among patients with recent ESUS participating in a clinical trial. Methods: In the NAVIGATE ESUS trial (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source), an MRI substudy was carried out at 87 sites in 15 countries. Participants underwent an MRI using a specified protocol near randomization. Images were interpreted centrally by those unaware of clinical characteristics. Results: Among the 918 substudy cohort participants, the mean age was 67 years and 60% were men with a median (interquartile range) of 64 (26–115) days between the qualifying ischemic stroke and MRI. On MRI, 855 (93%) had recent or chronic brain infarcts that were multiple in 646 (70%) and involved multiple arterial territories in 62% (401/646). Multiple brain infarcts were present in 68% (510/755) of those without a history of stroke or transient ischemic attack before the qualifying ESUS. Prior stroke/transient ischemic attack ( P <0.001), modified Rankin Scale score >0 ( P <0.001), and current tobacco use ( P =0.01) were associated with multiple infarcts. Topographically, large and/or cortical infarcts were present in 89% (757/855) of patients with infarcts, while in 11% (98/855) infarcts were exclusively small and subcortical. Among those with multiple large and/or cortical infarcts, 57% (251/437) had one or more involving a different vascular territory from the qualifying ESUS. Conclusions: Most patients with ESUS, including those without prior clinical stroke or transient ischemic attack, had multiple large and/or cortical brain infarcts detected by MRI, reflecting a substantial burden of clinical stroke and covert brain infarction. Infarcts most frequently involved multiple vascular territories. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02313909.