PLENARY SESSION: Derek Denny-Brown Young Neurological Scholar Symposium*

Hemorrhage-prone cerebral small vessel diseases (Hp-CSVD), such as arteriolosclerosis and cerebral amyloid angiopathy, and ischemic vascular diseases necessitating antithrombotic treatments are age-related conditions that are expected to increase in prevalence with our aging population. Whether patients with comorbid Hp-CSVD and ischemic vascular diseases should be treated with antithrombotic agents is a challenging dilemma that requires balancing the benefit of reducing thrombo-embolic events against the potential increase in incident or recurrent intracerebral hemorrhage risk. This lecture will provide an overview of the latest evidence on optimal vascular protection in these vulnerable patients, the potential of novel treatments that can mitigate thrombosis without compromising hemostasis, such as factor XI(a)
inhibitors and colchicine, and ongoing trials aiming to answer major lingering questions in this field.

Disruption of blood-neural barriers occurs during numerous central and peripheral neurological disorders; yet, it is unresolved whether this breakdown is sufficient, in and of itself, to trigger neurodegeneration. Furthermore, there are few therapeutic strategies to mitigate barrier hyperpermeability. We and others previously showed that dominant missense mutations of the cell-surface expressed cation channel TRPV4 (transient receptor potential vanilloid 4) cause Charcot Marie Tooth disease 2C and distal SMA. To gain insights into the cellular mechanisms of these disorders, we generated knock-in mouse models of TRPV4 channelopathy by introducing two human disease-causing mutations (R269C, R232C) into the endogenous mouse Trpv4 gene. TRPV4 mutant mice developed weakness particularly of the neck and forelimb muscles, lethality by 3 weeks of life, and regional proximal axon and motor somata loss in the cervical spinal cord. Genetic deletion of the mutant Trpv4 allele from endothelial cells (but not neurons, glia, or muscle) completely prevented these phenotypes. Weakness and degeneration in mutant mice was associated with focal disruptions of blood neural barriers. Expression of the mutant TRPV4 in neural vascular endothelial cells (NVEC) was associated with a gain of channel function, increased intracellular calcium levels, and alterations of NVEC tight junction structure. To determine whether disease features could be reversed, we repurposed an exisiting small molecule TRPV4 antagonist, which has already demonstrated safety in human trials for other disease indications. Systemic administration of this antagonist daily to symptomatic mutant TRPV4 mice abrogated channel-mediated blood-neural barrier breakdown and provided a marked rescue of motor behavior and survival. Together, these studies demonstrate that mutant TRPV4 channels can drive motor axon degeneration in a non-cell autonomous manner by triggering focal breakdown of blood neural barriers. In addition, these data highlight the reversibility of TRPV4-mediated blood-neural barrier impairments, and identify a potential therapeutic strategy for patients with TRPV4 mutations.

Many neurologic diseases can be caused by mutations in single genes. Dominant mutations that cause disease through toxic gain of function mechanisms are ideal targets for CRISPR gene therapies. We are developing CRISPR gene therapies for neurodegenerative diseases including dementias and amyotrophic lateral sclerosis (ALS) starting with C9orf72, the leading genetic cause of frontotemporal dementia (FTD) and ALS. We demonstrate allele-specific and bi-allelic CRISPR editing approaches to C9orf72 that can reverse pathologic hallmarks of C9-FTD/ALS in patient iPSC-derived neurons, including RNA abnormalities, dipeptide repeats and TDP-43 pathology. Utilizing isogenic iPSC-derived patient neurons, we show that removing the normal C9-allele, leaving the diseased allele intact, can increase pathology from the C9-repeat expansion mutation, providing potential insight into the futility of the first-generation of C9-ASOs in clinical trials. We develop the reagents and pipelines to screen guide RNAs, and to measure and minimize the potential in vivo genotoxic effects of genome editors through delivery vehicle design and preclinical off-target analysis. Despite great success in human model system, delivery of CRISPR reagents to the brain and spinal cord remains the major barrier to advancing this technology to clinic. The CNS is arguably the most challenging target given its innate exclusion of large molecules and its defenses against bacterial invasion (from which CRISPR originates). We have developed screening platforms in patient iPSCs, mice and human tissue to identify and optimize CNS delivery reagents to enable delivery of next-generation biologics to the CNS.

Migraine, a common disabling neurological disease and headache disorder, is more prevalent in African Americans (Black people living in the United States) than diabetes, asthma or depression.1-4 Yet, Black people living in the United States are underrepresented as providers, researchers, and academic leadership in neurology and headache medicine; suffer disproportionate morbidity in headache medicine; receive low value headache care; and are underrepresented in headache research.5-19 Race is a social construct, yet racism and social determinants including those resulting from discriminatory practices may drive racial health inequities in neurology and headache medicine.20 It has been suggested that providers who care for patients with neurological disease cannot fulfill their professional and ethical responsibility to care for Black patients without understanding how racism, not biological race drives neurological health disparities.20 This lecture will briefly explore race, racism, race-based headache disparities focusing on Black people living in the United States and discuss why neurologists have an ethical and professional obligation to progress beyond awareness of neurological disparities and toward amelioration of race-based disparities and inequities in headache medicine. Finally, this lecture will suggest strategies to better understand and mitigate race-based disparities and inequities in headache medicine.

The Paredes Lab studies the genetic and molecular basis of perinatal human brain development with the overarching goal of understanding the cellular and anatomical architecture that underlie the unique functions of the human brain. We seek to advance ways to both directly investigate the human brain and to better model its development, using gyrencephalic brain model systems such as the piglet cortex. Our studies also focus on a poorly understood yet clinically important time in brain development, the perinatal period. This developmental window is of high interest in understanding the early formation and function of higher associative cortical areas, such as regions within the frontal and temporal cortices. These studies will provide new insight into how the complex gyrated brain forms and reveal the neurodevelopmental processes that are most vulnerable to perinatal injury, resulting in neurodevelopmental disorders such as Epilepsy.