3rd Annual Neurology Research Retreat

June 8, 2018

Part I
Child Neurology: Growing
Sylvie Goldman, PhD
“Research in Autism in Child Neurology: Understanding Motor Manifestations through Kinematics and Neuro-Modulation” 

Although not listed among the core diagnostic criteria of autism spectrum disorder (ASD), motor abnormalities are highly prevalent (>85%) in children with ASD.  Research by my team and others suggests that these motor signs may be among the earliest and strongest predictors of later ASD diagnosis in high-risk siblings (children with an older sibling with ASD). Motor behaviors are culture-free, observable early in development, and quantifiable using novel, child-friendly, wearable technology. Moreover, these behaviors provide insight into the brain mechanisms underlying ASD and the developmental trajectory.

In collaboration with a physical therapist and mechanical engineer, we have been developing precise quantifiable measures of two specific motor behaviors, stereotypies and gait. Due to common disrupting behaviors presented by children with ASD, it is often challenging to obtain accurate measures of their motor performance. Thus, building on our previous findings, which showed how features of hand stereotypies can help differentiate Rett Syndrome from ASD, we are working to refine the ASD phenotype for further genotype/phenotype research.

Most recently, we have put together a "Big Idea" research group, comprised of faculty from child neurology, movement disorders, epilepsy, electrical bioengineering, and neurosurgery, to develop translational hypotheses aimed at assessing neuro-modulation and deep brain stimulation as treatments for the life-threatening, self-injurious behaviors in young adults with ASD.

Jennifer Gelinas, MD, PhD
"Development of Interictal Neural Networks: Implications for Epilepsy and Cognition"

Interictal epileptiform discharges (IEDs) are a prominent feature in the neural activity of patients with epilepsy. IEDs are commonly used as indicators of spreading epileptogenesis. They are implicated in the development of cognitive impairment and can induce cortical oscillations in anatomically remote brain regions. How IEDs interact with brain rhythms across distributed neural networks and throughout brain development remains poorly elucidated. We study the effects of IEDs on large-scale cortical networks, from the neonatal period to adulthood. Using intracranial EEG data from patients with epilepsy, we found that IEDs couple with sleep spindles across diverse brain regions, extending the anatomical influence of IEDs beyond the local network. We also perform in vivo neurophysiological recordings from mouse pups (aged postnatal day 5 to 14) exhibiting mutations associated with pediatric epileptic encephalopathies, including KCNT1 and dynamin 1. Our high spatiotemporal resolution neural interface devices allow us to map the epileptic network in these animals. We have identified focal IEDs and distinct electrographic seizure patterns that resemble those observed in children with these genetic abnormalities. Overall, we aim to better understand how the aberrant neurophysiologic activity associated with epilepsy perturbs normal development of cortical networks and leads to deficits in cognition.

Jacqueline Montes, PT, EdD, NCS
"Estimating Muscle Oxygen Consumption During Exercise Using Near Infrared Spectroscopy (NIRS) in Ambulatory Patients with Spinal Muscular Atrophy"

Spinal Muscular Atrophy (SMA) is a progressive, recessive neuromuscular disease characterized by weakness and muscle atrophy due to spinal cord motor neuron loss. Individuals with milder SMA phenotypes can walk independently but their residual weakness causes gait impairments, reduced endurance, and fatigue. Ambulatory patients with SMA have a marked reduction in oxidative capacity and a blunted conditioning response to exercise. In contrast, other neuromuscular conditions derive significant benefit from exercise programs of aerobic conditioning. There has been laboratory evidence to suggest that the molecular mechanisms underlying mitochondrial biogenesis may be vulnerable to SMN deficiency.

This project incorporates near-infrared spectroscopy to estimate muscle oxygen consumption during a ramped cardiopulmonary exercise tolerance test in SMA patients, as well as age matched disease and healthy controls. Other clinical measures of function and strength, as well as Dual Energy X-ray Absorptiometry, to measure lean body mass are also included. A reduction in muscle oxygen consumption disproportionate to lean mass would further support evidence of mitochondrial depletion in SMA. Targeted therapeutic treatments, in combination with exercise, may be needed to address the apparent disturbance in mitochondrial biogenesis and permit optimal aerobic conditioning effects.

The More You Know
James Noble, MD, MS
"Old SCHOOL (Seniors Can Have Optimal Aging and Ongoing Longevity) Hip Hop”

Alzheimer’s disease and related dementias are common among elderly individuals, become more prevalent with age, are medically refractory, reduce life expectancy, and diminish quality of life for patients and their caregivers. Cultural barriers to AD diagnosis exist and are potentially modifiable. Interventions that target younger generations may shift cultural perceptions and improve acceptance of AD and reduce barriers to early diagnosis. Emerging evidence suggests that early cognitive impairment may have modifiable or preventable components and a combination of medical and lifestyle interventions may delay or reduce cognitive decline, particularly when delivered early in the course of disease. Health literacy, including perceptions of cognitive aging and awareness of possible modifiable determinants, could be unrealized barriers to diminishing the health disparity of AD. Youth education programs focused on AD could increase community AD awareness, improve AD literacy of parents and grandparents of AD-literate children, shift cultural perceptions of AD to improve its acceptance, and reduce barriers to early diagnosis. Such an approach could uniquely engage minority populations who are least engaged and at greatest risk for AD.

“Old SCHOOL (Seniors Can Have Optimal aging and Ongoing Longevity) Hip Hop” is a validated model using a brief, multimedia, culturally tailored intervention designed to teach minority children key AD signs and symptoms, and actions taken when AD is recognized, which is early clinical evaluation by a physician. Twenty schools (with 3000 total students) will be randomly assigned to either the OSHH intervention arm or attentional control. This program will test the hypotheses that the program will lead to significant improvement of dementia knowledge in parents, and that gains are influenced by child knowledge, the degree of child-parent communication about the topic, and socioeconomic status. The program is additionally designed to create a novel, brief “dementia action test” to fulfill a critical missing tool for efficiently assessing AD recognition and behavioral response.

The Peripheral Nervous System: Front and Center
Hasan Orhan Akman, PhD
"Can Inhibition of Glycogen Synthesis be a Treatment for Glycogen Storage Diseases?"

Adult Polyglucosan Body Disease (APBD) is a late-onset disease caused by the intracellular accumulation of polyglucosan bodies, formed due to glycogen branching enzyme (GBE) deficiency. To find a treatment for APBD, we screened 1700 FDA-approved compounds in fibroblasts derived from an APBD modeling Gbe1-knock-in mice. Capitalizing on fluorescent periodic-acid Schiff reagent which interacts with polyglucosans in the cell, this screen discovered that the flavoring agent Guaiacol can lower polyglucosans, a result also confirmed in APBD patient fibroblasts. Biochemical assays using purified muscle glycogen synthase (GYS1) proved that guaiacol decreases basal and glucose-6-phosphate stimulated GYS1 activity. In cell lysates, Guaiacol also increased inactivating GYS1 phosphorylation and phosphorylation of the master activator of catabolism, the AMP-dependent protein kinase. Guaiacol treatment in the APBD mouse model rescued grip strength and a shorter lifespan. These treatments had no adverse effects except making the mice slightly hyperglycemic, possibly due to the reduced liver glycogen levels. Also, guaiacol corrected penile prolapse in aged Gbe1-knockin mice. Interestingly, despite its curative effect, Guaiacol reduced polyglucosan in the liver and heart only which apparently are not pertinent to neurological damage in APBD. Our results form the basis to use Guaiacol as a treatment and prepare for the clinical trials in APBD.

Joriene de Nooij, PhD
“Sensory Control of Movement”

Proprioceptive sensory feedback is an integral element of motor control. By providing the CNS with a representation of limb and body position, muscle feedback is critical in the planning and adjustment of motor output. Consequently, the absence of this somatic sense, as in large caliber sensory neuropathy (Friedreich’s Ataxia, CIPN, MS, DM), severely impacts overall quality of life. Effective treatment options are limited, due in part to our poor understanding of the molecular basis of the development and maintenance of proprioceptive sensory neurons, and a lack of adequate model systems to evaluate neuroprotective molecules.

We previously identified two molecular markers that uniquely distinguish MS and GTO afferent proprioceptors from other classes of spinal sensory neurons (de Nooij et al, 2013). This enabled us to develop new intersectional genetic approaches to label and purify these neurons for transcriptome analysis. Bulk and single cell RNAseq analysis reveals that proprioceptors undergo extensive molecular changes during their development, and that their subtype maturation may in part depend on extrinsic target-derived signals – a new concept in the field. In addition, our studies begin to identity the molecules that distinguish between MS and GTO afferent subclasses, thus providing genetic access to study their circuitry and role in motor control under normal and pathological conditions. Complementing our in vivo mouse models, we developed new in vitro approaches to differentiate human proprioceptors from embryonic and pluripotent stem cells to model large caliber sensory neuropathy, and to advance new therapeutic strategies using high-throughput drug screening approaches.

Jinsy Andrews, MD, MSc
"Skeletal Muscle Activators as a Potential Treatment for Amyotrophic Lateral Sclerosis (ALS)"
Reldesemtiv, is a selective small molecule fast skeletal muscle troponin activator (FSTA) that sensitizes the sarcomere to calcium by increasing the affinity of troponin for calcium. Reldesemtiv has been shown to increase the force generated by the tibialis anterior muscle versus placebo in response to nerve stimulation in a dose-, plasma concentration-, and frequency-dependent manner in healthy volunteers and has potential in the treatment of amyotrophic lateral sclerosis (ALS). In phase 1 studies in healthy volunteers, reldesemtiv showed a greater pharmacodynamic effect at lower plasma concentrations and a more favorable tolerability profile relative to tirasemtiv, a FSTA of an unrelated chemical structural class. This is a potential novel approach to treating ALS.  An international phase 2 clinical trial is underway in patients with ALS. 
Seize the Brain
Melodie Winawer, MD, MS

Somatic variants cause epilepsy-associated focal malformations of cortical development (MCD). We hypothesized that somatic variants underlie a wider range of focal epilepsy, including non-lesional focal epilepsy (NLFE). Through genetic analysis of resected brain, we assessed somatic variation in focal epilepsy with and without MCD.

We identified somatic variants through high-depth exome and ultra-high-depth candidate gene sequencing of DNA from epilepsy surgery specimens and leukocytes from 18 individuals with NLFE and 38 with focal MCD.

We observed somatic variants in five cases in SLC35A2, a gene associated with glycosylation defects and rare X-linked epileptic encephalopathies. Nonsynonymous variants in SLC35A2 were detected in brain, not leukocytes, in 3/18 individuals (17%) with NLFE, with variant allele frequencies (VAFs) in brain DNA of 2-14%. Pathology revealed focal cortical dysplasia type Ia (FCD1a) in 2/3. In MCD, brain nonsynonymous variants in SCL35A2 were detected from two individuals with intractable epilepsy, developmental delay, and MRI suggesting FCD, with VAFs of 19-53%. However, FCD1a was not found on MCD pathology.

Somatic variants in SLC35A2 explain a significant fraction of NLFE, largely unexplained previously, as well as focal MCD, previously linked to somatic mutation only in PI3K-AKT-mTOR pathway genes. This suggests and important role for glycosylation defects in intractable epilepsies

Part II
Neuroinflammation: Brains on Fire
Wassim Elyaman, PhD
"Influence of MS Genetic Risks on Adaptive Immunity"

Multiple sclerosis (MS) is a T cell-mediated CNS autoimmunity. It is suggested that MS is caused by the interaction of genetic and environmental factors. While genome-wide association studies (GWAS) have identified over 110 MS susceptibility loci, the molecular events leading to the onset of MS remain largely unknown and are untargeted therapeutically. Here, we have characterized the rs6908428 single nucleotide polymorphism (SNP) that is robustly associated with MS susceptibility (p=1.8 x 10-20), and located near the transcription start site (TSS) of the Abelson helper Integration site 1 (AHI1). We characterized the chromatin state of T cells in the MS-associated AHI1 linkage disequilibrium (LD) block. The expression and the role of the AHI1 variant were examined in T cells from genotyped healthy subjects who were recruited from the PhenoGenetic Project, and the function of AHI1 was explored using T cells from Ahi1 knockout mice. We found that Chromatin state analysis reveals that the LD block containing rs4896153, which is robustly associated with MS susceptibility (odds ratio 1.15, p = 1.65 × 10-13), overlaps with strong enhancer regions that are present in human naive and memory CD4+ T cells. Relative to the rs4896153A protective allele, the rs4896153T susceptibility allele is associated with decreased AHI1 mRNA expression, specifically in naive CD4+ T cells (p = 1.73 × 10-74, n = 213), and we replicate this effect in an independent set of subjects (p = 2.5 × 10-9, n = 32). Functional studies then showed that the rs4896153T risk variant and the subsequent decreased AHI1 expression were associated with reduced CD4+ T cell proliferation and a specific differentiation into interferon gamma (IFNγ)-positive T cells when compared with the protective rs4896153A allele. This T cell phenotype was also observed in murine CD4+ T cells with genetic deletion of Ahi1. Our findings suggest that the effect of the AHI1 genetic risk for MS is mediated, in part, by enhancing the development of proinflammatory IFNγ+ T cells that have previously been implicated in MS and its mouse models.

Dritan Agalliu, PhD
"Elucidating the Mechanisms of CNS Entry and the Role of Th17 Cells in Post-Infectious Autoimmune Basal Ganglia Encephalitis"

Group A Streptococcus (GAS) infections in children cause autoimmune basal ganglia encephalitis (BGE) that manifests with either motor [Sydenham’s chorea] or psychiatric [Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS)] symptoms. Autoantibodies that recognize neuronal targets are found in sera from SC/PANDAS children. These autoantibodies elicit behavioral abnormalities when infused into rodent brains or administered intravenously (i.v.) to rodents. We have shown that an intranasal (i.n.) route of GAS infection leads to production of Th17 cells in nasal-associated lymphoid tissue. Th17 cells migrate from the nose into the brain and their presence correlates with BBB breakdown, extravasation and brain deposition of antibodies, microglia activation and synaptic dysfunction.  Here, we examine the mechanisms by which GAS-specific Th17 cells enter the CNS in mice and determine the role that Th17 cells and autoantibodies play in BBB damage, neuroinflammation and circuit dysfunction.

We find that two chemokines are expressed in the olfactory epithelium and bulb when Th17 cells enter the CNS. We are currently testing the role that these chemokines play in this process using genetic studies in mice. We find that genetic ablation of two chemokine receptors that bind to chemokines upregulated in the CNS leads to a significant reduction in T cell entry into the CNS. Using mice that lack Th17 cells and undergo GAS infections, we find that, although the number of T cells is reduced, Th1 cells enter the CNS and produce neurovascular and synaptic damage.  In conclusion, Th17 and Th1 cells are both important for disease pathogenesis in post-infectious BGEs.

Different Strokes
Amelia Boehme, PhD, MSPH

Infection, particularly severe infection, has been identified as a potential risk factor or trigger for stroke. Our recent analyses of administrative datasets has identified sepsis as a risk factor for stroke. However, while there is a low absolute risk of stroke post sepsis, those who are at risk remain at risk up to a year after their sepsis event. We found that younger people have a higher risk of stroke after surviving their sepsis event. Additionally, racial disparities in sepsis and stroke have been identified, with Black patients twice as likely to develop sepsis or stroke as white patients. Prior research has found that even while adjusting for poverty or medically underserved areas, Black patients remain at higher risk of both sepsis and stroke, indicating a link between racial and geographic disparities with sepsis and stroke. Additional novel risk factors such as inflammation and more common infections, including influenza like illness (ILI), or environmental exposures, such as air pollution, are known to be risk factors for stroke. Moreover, ambient air pollution increases the risk of ILI, suggesting the potential for air pollution triggering an ILI event, which then subsequently triggers a stroke event. Racial disparities are highly prevalent in not only the levels of air pollution, but also in the health effects of air pollution, as well as having a major role in the risk of ILI, stroke. Racial and ethnic minorities are at higher risk to be exposed to high levels of air pollution, and are at higher risk for infections, and stroke. We are investigating these relationships in a number of administrative datasets to determine the direct and indirect effects of each of these exposures on the risk of stroke.

Marta Olah, MSc
Poster Platform: "A Single Cell-Based Atlas of Human Microglial States Reveals Associations with Neurological Disorders and Histopathological Features of the Aging Brain"

Recent studies of bulk microglia have provided insights into the role of this immune cell type in central nervous system development, homeostasis and dysfunction. Nonetheless, our understanding of the diversity of human microglial cell states remains limited; microglia are highly plastic and have multiple different roles, making the extent of phenotypic heterogeneity a central question, especially in light of the development of therapies targeting this cell type. Here, we investigated the population structure of human microglia by single-cell RNA-sequencing. Using surgical- and autopsy-derived cortical brain samples, we identified 14 human microglial subpopulations and noted substantial intra- and inter-individual heterogeneity. These putative subpopulations display divergent associations with Alzheimer’s disease, multiple sclerosis, and other diseases. Several states show enrichment for genes found in disease-associated mouse microglial states, suggesting additional diversity among human microglia. Overall, human microglia appear to exist in different functional states with varying levels of involvement in different brain pathologies.

Jose Gutierrez, MD, MPH
Poster Platform: "Genetic Contribution to Brain Arterial Dilatation and its Role in Cognition and Dementia"

There is ample evidence that relates vascular disease to Alzheimer disease, and the vascular contributions to cognitive decline and dementia are a national research priority. The field has long focused on atherosclerosis and stenosis as the sole contributors to cerebrovascular health, however. We believe that brain arterial dilatation may also be deleterious to brain health. Consequently, in our research proposal we propose a change in the paradigm of brain large artery disease that goes beyond atherosclerosis and/or stenosis, and incorporates brain arterial dilatation as a distinct pathological phenotype. In Aim 1, we will define genetic loci that relate to brain arterial dilatation in >5,000 participants of four well-characterized, population-based studies with longitudinal follow-up who also have neuroimaging and cognitive assessments. In Aim 2, we will establish the hemodynamic consequences of brain arterial dilatation by relating it to cerebral blood flow velocities and autoregulation. In Aim 3, we will first confirm the relationship between brain arterial dilatation with cognitive performance and risk of dementia. We will then perform a modification analysis using genetic loci related to brain arterial dilatation and measures of autoregulation as presumed effect modifiers. At the conclusion of these studies, we will definitively establish a role for brain arterial dilatation in cognition and dementia.

Adam M. Brickman, PhD
"White Matter Hyperintensities and Alzheimer’s Disease: In Media Res" 

Recently-published diagnosed criteria for Alzheimer’s disease (AD) require biomarker evidence of amyloid and tau pathology without consideration of clinical symptomatology. These criteria have been criticized for many reasons, one of which the lack of consideration of other pathological factors that may contribute to disease pathogenesis and clinical presentation. Small vessel cerebrovascular disease, best visualized as white matter hyperintensities (WMH) on MRI scans, commonly co-occurs with AD pathology and has been hypothesized to be a core feature of the disease. Over the past several years, we have been studying the role of WMH in AD. Our work has shown that individuals with prevalent AD and who are at risk for AD have elevated WMH volumes, particularly in posterior brain regions. Longitudinal analyses showed that increasing posterior WMH volumes predict clinical conversion from non-dementia status to AD dementia and recent work in individuals with autosomal dominant, fully-penetrant genetic mutations for AD have elevated WMH volumes in posterior brain regions up to 20 years prior to the estimated time of symptom onset. These WMH increases interact with amyloid pathology, such that those with biomarker evidence of amyloid are much more likely to manifest symptoms if they also have elevated WMH. Our work over the past several years establishes WMH as a core feature of AD. We are currently engaged in a number of projects that seek to understand whether WMH plays an additive role in the expression of AD or whether it is more causally or mechanistically related to AD per se. Our initial findings suggest that WMH potentiate tau-related neurodegenerative changes independently of amyloid. We have used a murine transient hypoperfusion model of WMH, which, on initial analysis, parallels our human observations: hypoperfusion induces tau hyperphosphorylation in APP and wild type mice. In fact, APP mice do not appear to manifest tau pathology without hypoperfusion perturbation. Our work will continue to establish the role of small vessel cerebrovascular disease in AD using translational neuroscientific approaches.

Badri Vardarajan, PhD, MS

ADSP-FUS (PI- Pericak-Vance [Miami], Vardarajan and Mayeux)

The Alzheimer’s Disease Sequencing Project (ADSP) is a national sequencing initiative focused on identifying genetic risk and protective variants for late onset Alzheimer disease (LOAD) in an effort to identify new pathways for prevention and new targets for drug development. The ADSP’s discovery phase included whole exome sequencing (WES) of 10,914 unrelated cases (N=5,778) and controls (N=5,136) (10,571 were Non-Hispanic White (NHW) and only 343 were Hispanic (HI)), and whole genome sequencing (WGS) of 1,019 familial samples (NHW (N=551) and HI (N=468)). The ADSP Replication Working Group met and a ‘Follow-Up Study’ (FUS) Phase was outlined and focused on confirming candidate variants from the discovery phase, and identification of novel variants through combined analysis of diverse datasets. The working group recommended that the highest priority for inclusion in the FUS WGS phase be given to new cohorts with unrelated LOAD cases that‘encompass the richest possible ethnic diversity’. To fulfill the goals of this RFA, we have identified several existing cohorts of African-American (AA) and pan-HI ancestry that specifically addresses this FUS Phase mandate. The cohorts include 2,322 AA LOAD cases and 1,843 AA controls and 2,928 HI LOAD cases and 2,875 HI controls from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study, the Northern Manhattan Study (NOMAS), the Research in African-American Alzheimer’s Disease Initiative (REAAADI), the Mexican Health and Aging Study (MHAS), the Puerto Rican 1066 Study, the Puerto Rican Alzheimer’s Disease Initiative (PRADI), and the Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) study. We will also incorporate existing WGS from the Multi-Ethnic Study of Atherosclerosis (MESA) (~171 AA cases and ~171 AA controls; ~155 HI cases and ~155 HI controls). In total we have 10,430 samples identified for the FUS. Combining these cohorts with existing sequencing from the Washington Heights-Hamilton Heights-Inwood Community Aging Project (WHICAP), the Alzheimer’s Disease Genetics Consortium (ADGC) and the ADSP will provide large ethnically diverse datasets for both validation and generalization of ADSP discovery phase findings and discovery of novel risk and protective variants/genes for LOAD. Additionally, these datasets will become an invaluable resource for the AD research community at-large.

PR AD Initiative (PRADI) (PI- Pericak-Vance/Beecham [Miami], CU Site-PI, Vardarajan)

With over 5 million individuals, the Puerto Rican (PR) population makes up over 1.5% of the US population, and is the 2nd largest Hispanic/Latino population in the continental US. The prevalence of AD in the Caribbean Hispanic population of the island of PR is estimated in 65,000.  Yet genetic studies have been limited to a few rare families with PSEN mutations. The PR population is highly admixed, with average ancestry values of 64% European, 21% African, and 15% Native American, but individual ancestries are highly variable. The unique genetic make-up of the PR AD population will be critical in new discovery, as well as in replication of findings from the ADSP Caribbean Hispanic data and the Alzheimer’s Disease Genetics Consortium (ADGC) AA data.  Our hypothesis is that AD risk in the PR population is due both to race/ethnic-specific genetic factors, as well as genetic risk factors across multiple populations. Thus, discovery of genetic contributions to AD risk and protective variants in PR HI would have a substantial influence on our understanding of AD, and our goal of identifying new treatment targets.  Through this proposal in response to PAR-15-356 we will address this important issue by conducting genomic studies of AD in PR.  Specifically we propose a family-based study in PR that parallels the family-based efforts in the ADSP Discovery phase and that will enhance and extend both current ADSP and ADGC efforts to a broader AD community.

Christiane Reitz, MD, PhD
"Genetics of Early-Onset Alzheimer’s Disease and Alzheimer’s Disease in African Americans"

Mutations in APP, PSEN1 and PSEN2 explain less than 10% of early-onset Alzheimer’s Disease (EOAD) cases and few studies have been performed using subjects and families with EOAD without clear Mendelian inheritance patterns. The few studies that have assessed this EOAD subtype have suggested that the genetic architectures overlap with the late-onset form, but only partially. Thus, studying EOAD in subjects without APP, PSEN1 and PSEN2 mutations (i.e. unexplained EOAD) is a critical gap that provides a unique opportunity for discovery of novel targets and pathways. To begin addressing this issue, in collaboration with Dr. Gary Beecham from the University of Miami, we are assembling the Resource for Early-onset Alzheimer’s Disease Research (READR), an initiative that ascertains and whole-genome sequences multiplex families with unexplained EOAD from various ethnic groups.

A second focus of research that I am pursuing is the identification of genetic risk factors underlying Alzheimer’s Disease in African Americans. African Americans have a higher prevalence of dementia than non-Hispanic Whites but are significantly underrepresented in research studies. Through the REAAADI initiative, a project performed in collaboration with the Universities of Miami and North Carolina A&T, we are collecting multiplex African American families with Alzheimer’s disease, who are then thoroughly phenotyped and whole-genome sequenced for variant discovery.

Shaking it Up
Un Kang, MD

The focus of my research is understanding basal ganglia plasticity in Parkinson’s disease (PD), to explore neurorestorative therapy. We focus on a component of L-DOPA’s anti-parkinsonian response, known as the long-duration response (LDR), that occurs in the scales of days to weeks. We are testing the hypothesis that gradual motor impairment during LDR decay is task specific and results from aberrant long-term potentiation (LTP) in specific ensembles of indirect pathway medium spiny neurons, which are normally suppressed but become pathologically active during task exposure if dopamine (DA) is depleted. Another aspect of motor fluctuation is excessive abnormal involuntary movements that develop over several years of treatment. We utilize chemogenetic and optogenetic modulation of the striatal cholinergic neurons and circuitry involving substantia nigra pars reticulata to study their functional effects. We also employ transcriptomic analysis to find potential mechanisms of altered activity and therapeutic targets. Understanding the changes in specific cell types and connectivity between the basal ganglia structures will help us to design new approaches that overcome the limitation of current pharmacological therapy that targets the whole brain, and the current deep brain stimulation (DBS) that targets anatomical structures and passing fibers without discriminating circuit and cell type specificity.