Each year, the American Academy of Neurology (AAN) hosts a meeting wherein neurologists nationwide convene to present on their latest research findings and to learn from their peers. The following members of Yale Neurology presented abstracts at the 2021 virtual annual meeting:
“N3: Neuroscience in the Clinic: Emerging Neuroscience in Neurologic Complications of COVID-19.” Dr. Farhadian discussed research studies of the cerebrospinal fluid in hospitalized patients with acute COVID-19.
“Machine Learning Evaluation of Multiple Sclerosis Patient During the time of COVID-19.” During the COVID_19 pandemic most routine and non-essential healthcare matters have been switched over to telehealth or placed on hold altogether. Neurologic visits have been billed based on time spent and complexity of care without the necessity of a comprehensive neurologic assessment. The BeCare app, a mobile application, was developed to evaluate the symptomatology and neurologic function of patients becoming a digital equivalent to the EDSS. The primary objective of this clinical trial is to validate the measurements taken during the use of the app compared to clinically-derived functional score. With the use of the BeCare app, both the patient and the provider gain greater control over disease management.
“Stroke Disparities Across Racial and other Minorities: Results from the ‘All of Us’ Research Program.” The All of Us” Research Program is a population-based study aimed at enrolling 1 million Americans to accelerate research in minority populations underrepresented in biomedical research. Using data from this novel research program, we evaluated the burden of stroke across race/ethnicity, as well as other minority populations defined by features such as age, disability, education, income, gender identity and sexual orientation, and access to health insurance. Several minority groups showed higher prevalence of stroke, including persons older than 75 years, those with disability, those without access to health insurance, and those with lower household income.
“Race and Ethnicity Influence Perihematomal Edema Volume in Supratentorial Intracerebral Hemorrhage.” Perihematomal edema (PHE) is a biomarker of secondary injury in patients with intracerebral hemorrhage (ICH) and a strong predictor of outcome in these patients. However, there is limited data on how racial/ethnic differences influence PHE development and growth. We aimed to test whether race/ethnicity influences the volume of baseline PHE in patients with supratentorial ICH. Using data from the ERICH observational study, we evaluated the relationship between race/ethnicity and baseline PHE volume, and we found that both White and Hispanic participants had higher baseline PHE volume compared to Black participants. Further research is needed to validate these results and look into the possible mediating mechanisms.
“Klotho-VS Heterozygosity Is Associated with Lower Risk of Lobar Intracerebral Hemorrhage.” Klotho is a transmembrane protein implicated in reducing aging-associated phenotypes and cognitive decline. KL-VS is a genetic haplotype in the KL gene. Heterozygosity for KL-VS (KL-VS Het+) has shown to increase serum levels of Klotho. We tested whether KL-VS Het+ lowers the risk of intracerebral hemorrhage (ICH) and the excess in risk conferred by the APOE epsilon variants. Using data from three genetic case-control studies of ICH, we evaluated the relationship between KL-VS Het+ and the risk of ICH and found that persons carrying KL-VS Het+ had a lower risk of ICH, particularly of lobar ICH. Exploratory analysis suggested a greater effect among APOE-E2 carriers. Future research should look into possible mediating mechanisms.
“Klotho-VS Heterozygosity Is Associated with Lower Risk of Non-Traumatic Subarachnoid Hemorrhage.” Klotho is a transmembrane protein implicated in reducing aging-associated phenotypes and cognitive decline, as well as some cardiovascular diseases. KL-VS is a genetic haplotype in the KL gene. Heterozygosity for KL-VS (KL-VS Het+) has shown to increase serum levels of Klotho. We tested whether KL-VS Het+ lowers the risk of non-traumatic subarachnoid hemorrhage (SAH). Using data from the UK Biobank, we evaluated the relationship between KL-VS Het+ and the risk of SAH and found that persons carrying KL-VS Het+ had a lower risk of SAH. Exploratory analyses suggested that this effect could be stronger in men, hypertensives and smokers.
“Polygenic Susceptibility to Hypertension is Associated with Uncontrolled and Resistant Hypertension in Stroke Survivors.” Hypertension is one of the main contributors to stroke recurrence, but achieving blood pressure control after a stroke is challenging. As blood pressure is a highly heritable trait, we tested whether polygenic susceptibility to hypertension (PSH) is associated with the risk of uncontrolled and resistant hypertension in stroke survivors. Using data from the UK Biobank, we developed a polygenic risk score comprising 732 genetic variants associated with blood pressure levels, and categorized participants in quintiles according to this polygenic risk score. We found that those in the highest quintile of PSH had a 73% increased risk of uncontrolled hypertension (OR 1.73, 95%CI 1.46-2.04, p<0.001) and almost 4 times the risk of resistant hypertension (OR 3.70, 95%CI 2.32-6.12, p<0.001) when compared to those in the lowest quintile of genetic risk. Follow-up research should evaluate whether precision medicine strategies based on blood pressure-related genetic information could help identify patients that could benefit from aggressive diagnostic or therapeutic interventions.
Natalia Szejko, MD, PhD, BA, MA, ScD:
“Polygenic susceptibility to hypertension is associated with worse cognitive function.” While observational studies indicate that hypertension is associated with higher risk of cognitive decline and dementia, clinical trials have failed to demonstrate that aggressive blood pressure control reduces this risk. We conducted a nested genetic study within the UK Biobank, a large population study that enrolled Britons aged 38-72 years. The systolic BP PRS was significantly associated with the worse performance in the verbal numeric reasoning test (β = -0.002, p= 0.05), while the diastolic BP PRS was significantly associated with worse performance in reaction time test (β = 0.40, p= 0.02). The diastolic BP PRS was associated with worsened reaction time (β =-1.49, SE=0.62, p=0.02). These findings provide evidence for a causal link between SBP and DBP and worse cognitive functioning in selected measures.
2021 Michael S. Pessin Stroke Leadership Prize – In this invited talk, Dr. Falcone reviewed several important discoveries in the field of cerebrovascular disease genomics, emphasizing the biological overlap with diseases and traits related to aging (cognition, dementia and functional status). He also reviewed important ongoing projects focused on the utilization of genomic medicine tools in the care is stroke patients.
"Ischemic Stroke, Inflammation, and Endotheliopathy in COVID-19 Patients." We provide evidence of endotheliopathy and systemic inflammation in ischemic stroke patients with vascular risk factors due to COVID-19 compared to contemporaneous controls. These results provide insight on potential pathways to investigate in prospective studies in order to optimize therapies for COVID-19 related stroke prevention and treatment.
"Intrathecal SARS-CoV-2 and anti-neural antibodies in COVID-19 patients with neuropsychiatric symptoms." We used single cell RNA-seq and cytokine analyses of CSF and blood from COVID-19 patients with neurological symptoms. We found compartmentalized, CNS-specific T-cell activation and B-cell responses. All COVID-19 cases had CSF anti-SARS-CoV-2 antibodies whose target epitopes diverged from serum antibodies. We produced CSF-derived monoclonal antibodies from a COVID-19 patient and found that these mAbs target both anti-viral and anti-neural antigens, including one mAb that reacted to both spike protein and neural tissue. Overall, CSF IgG from 5/7 patients contains anti-neural reactivity. This immune survey reveals evidence of a compartmentalized immune response in the CNS of COVID-19 patients and suggests a role for autoimmunity in neurologic sequelae of COVID-19.
“Race/ethnicity and insurance status impact acute ischemic stroke treatment within three large U.S. states.” Racial disparities in thrombolysis and EVT rates were different across California, Florida, and New York in the Healthcare Cost and Utilization Project State Inpatient Databases. Distance from a thrombectomy-capable center did not affect EVT rates in New York or Florida; California did not have patient zip code data. Low insurance status patients are less likely to receive interventions, irrespective of race.
Dave Hwang, MD, FAAN(Neurology), FCCM, FNCS:
“A two-center, parallel-arm randomized-controlled feasibility trial of a goals-of-care decision aid for surrogates of severe acute brain injury patients.” We have collaborated with researchers from the University of Massachusetts Medical School to create a decision aid booklet that guides families of incapacitated Neuro-ICU patients with severe ischemic stroke, intracerebral hemorrhage, or traumatic brain injury through the process of goals-of-care decision making. The decision aid contains information and a worksheet for families regarding prognosis, the implications of inserting long-term breathing and/or feeding tubes in a loved one, and the options of comfort care. We conducted a two-center, parallel-arm, randomized pilot trial to see whether it would be feasible to implement the decision aid in a real-world setting with families faced with making such decisions. Among our 66 family members who participated, we found that it was indeed feasible to implement the aid and conduct a randomized trial, and that 96% of families in our intervention arm reported that the decision aid was useful. In examining several secondary outcomes, though, we found that families of surviving patients reported higher levels of anxiety and depression at 3 months than those of patients who had died, suggesting that decision makers who select continued aggressive care and who become informal caregivers may need additional psychosocial support beyond the Neuro-ICU admission.
“Tomorrow, and Tomorrow, and Tomorrow: Understanding Neurologic Syndromes Post-Acute COVID-19.” This talk provided an overview of the clinical neurologic and psychiatric syndromes observed in patients after the acute phase of COVID-19 and an update on the state of knowledge regarding the pathogenesis of these disorders. Finally, Dr. Spudich outlined ideas for future research to investigate these disorders in order to characterize and treat the many patients now presenting with neurologic symptoms after recovery from acute COVID-19.