Dumitrascu, Oana M.

Introduction: Prior data suggest that migraine increases the risk of stroke. However, there is a lack of understanding whether specific migraine features like white matter hyperintensities (WMH) commonly found on brain magnetic resonance (MR) imaging in migraine patients and migraine medications might contribute to Major Adverse Cardiovascular Event (MACE) outcomes including ischemic and hemorrhagic stroke. We assess MACE risk estimation model stratified by event types using Mayo Clinic Electronic Health Record (EHR) data. Methods: Case and control sets, based on MACE occurrence among migraine patients at Mayo Clinic Neurology Department, were propensity matched on age, sex, and MACE risk-factors (atrial fibrillation, diabetes, hyperlipidemia, hypertension, tobacco use) to capture migraine-specific predictors ( Figure 1) . Migraine medications were categorized into 9 classes; Triptans, Ditans, Gepants, Ergots, calcitonin gen-related peptide targeting medications (CGRPs), Beta-blockers, Topiramate, Tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRIs). Demographics (age and sex), migraine characteristics (chronic migraine, migraine with aura), and presence of WMH on MR imaging were curated. To model non-linear relationship between predictors, two comparative Random Forest (RF) models were evaluated for MACE prediction; i) Model-1: using demographics, migraine characteristics and WMH, ii) Model-2: medications, demographics, migraine characteristics and WMH ( Table 1) . Results: Model-2 outperformed Model-1 indicating combined interaction between medications, WMH, and migraine characteristics for estimating MACE risk. Model-2 achieved AUC of 0.68 for overall MACE, but showed higher performance for ischemic stroke (AUC 0.76). We visualized the effects of input features on ischemic stroke risk for four individual patients using SHAP force plots ( Figure 2 ). The model often considered use of betablockers, chronic migraine, and presence of WMH as factors for increasing ischemic stroke risk. Discussion: Our experiments show that medications, migraine features, WMH and demographics are more effective estimators for ischemic risk stroke risk compared to overall MACE risk, indicating stronger predictive correlation between ischemic stroke and migraine related clinical features. Interestingly, the model inferred the clinical practice pattern of not prescribing Triptans (TRIPTAN=0) to the patients with high risk of stroke from the data itself.

Introduction: We assess the risk of stroke in individuals with and without a migraine diagnosis, adjusting for demographic variables and stroke risk factors using participant information from the All of Us database. Method: Diagnoses of migraine, stroke and comorbidities were identified using ICD9 and ICD10 codes. A multivariable logistic regression analysis was performed to assess the association between migraine and risk of stroke adjusting for comorbidities including hypertension, atrial fibrillation, hyperlipidemia, diabetes, tobacco use, depression and demographics (age, sex at birth, race and ethnicity). To compare the prevalence of stroke between individuals with and without migraine, odds ratios using a 95% confidence interval (CI) were calculated. Results: Within the All of Us database, 31,444 individuals received a migraine diagnosis (female=25,374/81%, male=5,391/17%, other=679/2%; mean (std) age=54.9 (15.6)) and 379,283 did not have a migraine diagnosis (female=222,104/59%, male=149,182/39%, other=7,997/2%; mean (SD) age=55.9 (17.2)), see Figure 1 for detailed demographics. The migraine cohort had a greater proportion of women (81% vs 59%, p<0.001), a higher proportion of white individuals (61% vs. 55%, p<0.001) fewer African American individuals (15% vs. 19%, p<0.001) and a lower proportion of individuals who were 61 or older (39% vs 45%, p<0.001) compared to the non-migraine cohort. Compared to the non-migraine cohort, individuals with migraine had significantly higher rates of comorbidities, including depression (13% vs. 4%, p<0.001), diabetes (16% vs. 7%), tobacco use (23% vs. 9%, p<0.001), hyperlipidemia (48% vs. 22%, p<0.001), hypertension (57% vs. 27%, p<0.001), and atrial fibrillation (7% vs. 4%, p<0.001). A multivariate regression model adjusted for differences between cohort demographics and comorbidities found that individuals with migraine had 2.14 higher odds of overall stroke compared to the non-migraine cohort (OR 2.14, 95% CI [ 2.04, 2.24]. Discussion: After adjusting for cohort imbalances in demographics and comorbidities, individuals with migraine had a 2.14 times higher risk of stroke compared to those without a migraine diagnosis. Our analysis, using data from the All of Us database, confirms previous findings and suggests that while comorbidities are more prevalent in those with migraine, they do not fully account for the increased stroke risk.

AbstractBackgroundWomen with suspected coronary microvascular dysfunction (CMD) may be at higher risk of experiencing cognitive decline due to cerebral small vessel disease, a known contributor to Alzheimer’s disease and related dementias (ADRD). A potential underlying mechanism that could accelerate this cognitive decline is the accumulation of brain tissue iron, which has been previously linked to changes in brain function potentially caused by oxidative stress and cell death. Therefore, we aim to elucidate whether a similar mechanism could affect women with suspected CMD by investigating the potential role of iron deposition on the brain’s functional organization and its effect on cognition using advanced magnetic resonance imaging (MRI).Material and MethodsTwenty‐seven women with suspected CMD [Age; median (range) = 54 (29‐76)], drawn from ongoing cohorts (3R01HL146158‐04S1,3U54AG065141‐04S1), underwent a 3T MRI protocol, including submillimeter T2* 3‐dimensional echo‐planar‐imaging for assessing iron deposition with high‐resolution quantitative susceptibility mapping (QSM) and resting‐state fMRI (rs‐fMRI). Iron content was quantified by total‐generalized‐variation based QSM analysis. Functional integrity was determined via graph theoretical approach (i.e., nodal degree). Cognitive assessment was also performed using the NIH Toolbox. Mediation analysis was conducted using Python Statsmodels.ResultsMost of the women with suspected CMD showed lower performance in processing speed, working memory, executive function, and attention (Figure 1A). We found a significant association between elevated iron levels in paracentral gyrus and lower functional connectivity in left hippocampus (p=0.005, adjusted‐r2=0.19) (Figure 1B). Elevated iron level in the paracentral gyrus showed an impact on cognitive performance in the domains of executive function and attention (p<0.0001, coefficient=531.09) as well as language functions and crystalized abilities (p=0.036, coefficient=362.45), mediated by functional connectivity in the left hippocampus (indirect effect on executive function / language: p = 0.034 / 0.038, coefficient = ‐254.54 /‐ 213.06) (Figure 1C).ConclusionsOur results suggest that changes in hippocampal functional organization are associated with cortical iron deposition and mediate its impact on cognitive performances. These changes may increase the risk of cognitive decline/ADRD or in women with suspected CMD. Future research in a larger cohort with a longitudinal design is necessary to validate and expand upon these findings.

AbstractBackgroundScanning laser ophthalmoscopy (SLO) visualizes two important markers of cognitive dysfunction in the retina: vascular changes and amyloid plaque (AP) deposition. The relationship between retinal arteriolar versus venular changes and perivascular amyloid deposition across the continuum of neurodegeneration is imperfectly understood. We investigate the retinal perivascular AP distribution in relationship to cognitive and neuroimaging measures in a cohort of cognitively normal and impaired individuals.Method34 subjects with normal or impaired cognition underwent retinal SLO, brain magnetic resonance imaging and standard neuropsychometric testing. Retinal peri‐arteriolar and peri‐venular curcumin positive AP were quantified in the supero‐temporal retinal quadrant, in the first, second and third‐order retinal vascular branches. The peri‐venular and peri‐arteriolar AP count were compared between patients with normal and impaired cognition, and their correlation with brain volumes, white matter hyperintensities and cognitive Z‐scores was determined.ResultWe analyzed retinal para‐venous and para‐arteriolar amyloid count in 28 subjects, mean (SD) age 65 (7.3), 50% female, 19 (52.6%) with impaired cognition. Para‐arteriolar plaque count was higher than peri‐venular plaque in the entire cohort (p<0.0001). Secondary branch peri‐venular amyloid plaque count was higher in patients with MOCA ≤26. Tertiary branch perivascular AP count significantly and negatively correlated with hippocampal volume and positively correlated white matter hyperintensity lesion count.ConclusionRetinal AP deposit peri‐arteriolarly overall and peri‐venularly in the secondary branches in cognitively impaired. Perivascular amyloid burden in small retinal branches correlates with hippocampal volume and white matter hyperintensities.

AbstractBackgroundWomen with suspected coronary microvascular dysfunction (CMD) may be at higher risk of experiencing cognitive decline due to cerebral small vessel disease, a known contributor to Alzheimer’s disease and related dementias (ADRD). A potential underlying mechanism that could accelerate this cognitive decline is the accumulation of brain tissue iron, which has been previously linked to changes in brain function potentially caused by oxidative stress and cell death. Therefore, we aim to elucidate whether a similar mechanism could affect women with suspected CMD by investigating the potential role of iron deposition on the brain’s functional organization and its effect on cognition using advanced magnetic resonance imaging (MRI).Material and MethodsTwenty‐seven women with suspected CMD [Age; median (range) = 54 (29‐76)], drawn from ongoing cohorts (3R01HL146158‐04S1,3U54AG065141‐04S1), underwent a 3T MRI protocol, including submillimeter T2* 3‐dimensional echo‐planar‐imaging for assessing iron deposition with high‐resolution quantitative susceptibility mapping (QSM) and resting‐state fMRI (rs‐fMRI). Iron content was quantified by total‐generalized‐variation based QSM analysis. Functional integrity was determined via graph theoretical approach (i.e., nodal degree). Cognitive assessment was also performed using the NIH Toolbox. Mediation analysis was conducted using Python Statsmodels.ResultsMost of the women with suspected CMD showed lower performance in processing speed, working memory, executive function, and attention (Figure‐1A). We found a significant association between elevated iron levels in paracentral gyrus and lower functional connectivity in left hippocampus (p = 0.005, adjusted‐r2 = 0.19) (Figure‐1B). Elevated iron level in the paracentral gyrus showed an impact on cognitive performance in the domains of executive function and attention (p<0.0001, coefficient = 531.09) as well as language functions and crystalized abilities (p = 0.036, coefficient = 362.45), mediated by functional connectivity in the left hippocampus (indirect effect on executive function / language: p = 0.034 / 0.038, coefficient = ‐254.54 /‐ 213.06) (Figure‐1C).ConclusionsOur results suggest that changes in hippocampal functional organization are associated with cortical iron deposition and mediate its impact on cognitive performances. These changes may increase the risk of cognitive decline/ADRD or in women with suspected CMD. Future research in a larger cohort with a longitudinal design is necessary to validate and expand upon these findings.

Background: Although no tests are currently available to predict post-stroke depression (PSD), a risk factor for diminished quality of life and stroke-related death, emerging evidence suggests that ischemic stroke (IS) may induce behavioral changes by damaging connections throughout the brain rather than via localized injury. Hypothesis: We sought to determine if active (surveys) and passive (accelerometer, GPS, and other sensors) smartphone data could quantify exploratory behavioral proxies of PSD. Methods: Thirty-four adults with a recent IS (n = 12) or transient ischemic attack (TIA) (n = 22) diagnosis were followed for 3 months. Participants used the Beiwe app to complete a weekly Patient Health Questionnaire-8 (PHQ-8) survey and were evaluated every 30 days with the Montgomery-Asberg Depression Rating Scale (MADRS). Results: Preliminary analysis of app survey compliance was adequate (86%), and the quantity of data collected was greater for Android than iOS phones. PHQ-8 indicated depression (moderate or severe) in 20% of participants. MADRS highly correlated with the most recent PHQ-8 ( r = 0.92, 95% CI (0.19, 0.99), P = 0.028). Several exploratory passive physical activity and social measures showed statistically significant change over time and/or associations with PHQ-8 and MADRS. Conclusion: Low-burden smartphone data holds promise for developing novel IS and TIA outcome measures as well as identifying patients most at risk of PSD.

Telemedicine for stroke (Telestroke) has been a key component to efficient, widespread acute stroke care for many years. The expansion of reimbursement through the Furthering Access to Stroke Telemedicine Act and rapid deployment of telemedicine resources during the COVID-19 public health emergency have further expanded remote care, with practitioners of varying educational backgrounds, and experience providing acute stroke care via telemedicine (Telestroke). Some Telestroke practitioners have not had fellowship-level vascular neurology training and many are without training specific to virtual modalities. While many vascular neurology fellowship programs incorporate Telestroke training into the curriculum, components of this curriculum are not consistent, extent of involvement is variable, and not all fellows receive hands-on training in remote care. Furthermore, the extent of training and evaluation of Telestroke in American Board of Psychiatry and Neurology training requirements and Accreditation Council for Graduate Medical Education assessments for vascular neurology fellowship are not standardized. We suggest that Telestroke be formally incorporated into vascular neurology fellowship curricula and provide considerations for key components of this training and metrics for evaluation.

Introduction: The vascular contribution to Alzheimer’s disease (AD) and AD-related dementias is increasingly recognized. Scanning laser ophthalmoscopy (SLO) visualizes two important markers of cognitive dysfunction in the retina, vascular changes and amyloid plaque deposition. The relationship between retinal vascular changes and peri-vascular amyloid deposition in the continuum of neurodegeneration is imperfectly understood. In this exploratory topographic analysis of a cohort of subjects with normal and impaired cognition that underwent SLO, we investigated the retinal vascular-adjacent (para-vascular) amyloid plaque distribution and its correlation with cognitive measures. Methods: 34 subjects with cognitive decline underwent retinal SLO, brain magnetic resonance imaging and standard neuropsychometric testing. Retinal para-arteriolar and para-venular curcumin positive amyloid plaques were quantified in the supero-temporal retinal quadrant, in the first-, second- and third-order retinal vascular branches. The para-venous and para-arteriolar amyloid count were compared between patients with normal and impaired cognition, and their correlation with brain volumes and white matter hyperintensities was determined. Results: We analyzed retinal para-venous and para-arteriolar amyloid and vascular-structural parameters derived from 29 subjects, mean (SD) age 65(7), 48% female. Para-arteriolar plaque was higher than para-venular plaque in the entire cohort (p<0.0001). Secondary branch para-venular amyloid plaque count was higher in patients with impaired cognition, CDR ≥1 and MOCA ≤26. The para-arterial plaque count in the secondary branches significantly correlated with hippocampal volume and white matter hyperintensities scores. Conclusion: Our topographic analysis of the amyloid plaque distribution in retinal para-vascular regions shows higher amyloid accumulation in the para-arteriolar regions overall, and specifically in the secondary para-venular branches in patients with impaired cognition. Larger longitudinal studies are needed to study the temporal and spatial relationship between vascular dysfunction and para-vascular amyloid deposition in AD.

Objective: To assess whether diffusion restriction (DR) of the retina and optic nerve (ON) can be accurately and reliably identified on standard stroke protocol brain magnetic resonance diffusion-weighted imaging (DWI-MRI) in patients presenting with acute non-arteritic central retinal artery occlusion (CRAO). Background: Retinal DR (RDR) and ONDR in patients with acute non-arteritic CRAO have been described with various diagnostic accuracies and often identified by experienced neuroradiologists with fair inter-rater agreement. Methods: This retrospective case-control study included patients that presented to our academic center from 2013-2021 with acute non-arteritic CRAO or acute cerebral ischemia (controls, age and gender-matched) and had brain MRI performed within 14 days from symptom onset. Two neuroradiologists, blinded to the site of CRAO and diagnosis, independently reviewed MRI of CRAO cases and controls to assess for the presence of RDR and ONDR. Their inter-rater agreement was calculated (prevalence and bias- adjusted kappa coefficient) and their final consensus was used to perform sensitivity and specificity analyses. Results: We included 128 patients with CRAO (mean age 69 years; 50% males; median time from CRAO to MRI 2 days (IQR 1-5)) and 128 matched controls with acute cerebral ischemia (mean age 68 years; 51% males). After neuroradiologists’ consensus, DR was correctly identified in the retina or ON in 51/128 (39.8%), retina alone 35/128 (27.3%), ON alone 31/128 (24.2%), both retina and ON 15/128 (11.7%), with excellent inter-rater agreement for retina (K=0.91) and ON (K=0.83). There were no cases of RDR or ONDR in the control group. After neuroradiologists’ consensus, sensitivity, specificity, PPV and NPV were 28.1%, 100%, 100%, and 58.2% for RDR and 27.3%, 100%, 100%, and 57.9% for ONDR. Conclusion: Though RDR and ONDR can be identified with excellent interrater reliability, they are infrequent findings and their role in diagnosing acute CRAO is unclear. Observational prospective studies with large cohort of patients, optimization of dedicated and standardized orbit DWI-MRI protocols, and education of neurology and neuroradiology providers are needed to facilitate more accurate identification of RDR and ONDR in hyperacute CRAO.