Parekh Center for Interdisciplinary Neurology Research Projects | NYU Langone Health

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Parekh Center for Interdisciplinary Neurology Parekh Center for Interdisciplinary Neurology Research Projects

Parekh Center for Interdisciplinary Neurology Research Projects

Researchers at NYU Langone’s Parekh Center for Interdisciplinary Neurology are focused on four main projects that capitalize on cross-disciplinary collaboration. Each project focuses on commonalities between multiple neurological disorders and strives to build a framework for how the gut microbiome, peripheral immune system, and immune and glial cells in the central nervous system interact at every stage of neurological disorder.

Intra-Individual Variability Measurements as an Earlier Diagnostic for Patients with Multiple Sclerosis

Principal investigators: Leigh E. Charvet, PhD and Lauren B. Krupp, MD

There remains an unmet need to identify patients before the onset of decline and disability in people who have neurodegenerative diseases, such as multiple sclerosis. The initial, undetectable neuronal dysfunction that defines prodromal neurodegeneration can be reliably identified by subtle inconsistencies in cognitive processes, which can in turn be easily measured using simple, computer-based psychomotor tasks. Measuring an individual’s repeated reaction times in these psychomotor tasks captures a measure of cognitive consistency called intra-individual variability (IIV). IIV, compared to conventional measures of cognitive accuracy or speed, is a highly sensitive marker for the earliest onset of disease and risk of future neurologic disability across many conditions, including mild cognitive impairment and early dementia, Parkinson’s disease, epilepsy, and schizophrenia.

This work is developing a clinical measure of IIV as a behavioral measure of prodromal neurodegeneration that can guide early detection and, ultimately, prevention of disability.

Gut Microbiome as a Mechanism of Drug Resistance in Epilepsy

Principal investigators: Claude Steriade, MD, and Deepak Saxena, MS, PhD

There are an estimated 3.4 million people with active epilepsy in the United States. Despite an exponential increase in approved medications to treat epilepsy, one third of patients remain refractory to medications, and mechanisms of drug resistance are not completely understood.

Drug-resistant epilepsy presents with alterations in the gut microbiome, and ketogenic diet studies have suggested that the gut microbiome influences seizure control. Therefore, manipulation of the gut microbiome may be an effective epilepsy therapy. Seizures are also associated with neuro-inflammation, specifically upregulation of IL1β and IL6, and inflammatory dysregulation itself, such as altered levels of IL1β, can in turn lead to dysbiosis in animal models. Thus, neuroinflammation is a potential mechanism by which seizures may impact gut dysbiosis, and vice versa.

This project is improving our understanding of the independent role of seizures in the gut microbiome and explores neuro-inflammation as a potential mediator of the relationship between seizures and gut dysbiosis. In doing so, it will inform the design of rational and targeted microbiome interventions in the treatment of epilepsy.

Pathogenetic Mechanisms of Oligodendrocytes in Multiple System Atrophy

Principal investigators: Thong C. Ma, PhD, and Un J. Kang, MD

Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by parkinsonism and/or cerebellar abnormalities, and autonomic dysfunction. The pathological hallmark of MSA is the accumulation of misfolded α-synuclein protein, primarily in oligodendrocytes. How α-synuclein aggregates form in oligodendrocytes and their contribution to disease pathogenesis remain elusive.

We have begun to obtain gene expression profiles for thousands of individual cells encompassing nearly all cell types using single-nucleus RNA sequencing of postmortem human brain tissue. From these studies, key identified genes of interest and transcriptional pathways will be manipulated in human induced pluripotent stem cell (iPSC)–derived neurons and oligodendrocytes and later, mouse models.

By characterizing genetic contributions to MSA pathogenesis, these reverse translational studies are overcoming the limitations of current MSA models. Historically, MSA models required the overexpression of α-synuclein in specific cell types and thus limited scientific questions to downstream events rather than addressing fundamental upstream stressors that lead to dysregulation of α-synuclein. In discovering fundamental events leading to α-synuclein aggregation, this work will yield new therapeutic insights.

The Role of Astrocyte-Derived Toxic Lipids in Neurodegenerative Disease

Principal investigator: Shane A. Liddelow, PhD

Astrocytes, a major glial cell type in the central nervous system, are required for normal development and functioning of neurons. In response to injury and disease, they change from their normal physiological role to one of many “reactive” states. We recently identified a reactive astrocyte subtype that forms after acute injuries and in chronic neurodegeneration in both rodents and humans.

We show these astrocytes to be potently neurotoxic and that saturated lipids, in particular long-chain free fatty acids, drive this neurotoxicity. We have produced a conditional knockout model in which astrocytes are unable to produce neurotoxic lipids. We are investigating how a lack of neurotoxic lipids can preserve neuron health in models of chronic neurodegeneration.

Our long-term goal is to define pathways in neurotoxic reactive astrocytes and susceptible neuron populations that will provide a blueprint to develop novel therapeutic strategies for a range of neurodegenerative diseases like amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Alzheimer’s disease, glaucoma, and many others.

Mechanistic Basis for Impaired B-cell Depletion After Anti-CD20 Treatment of African Americans with Neuro-Inflammatory Disorders

Principal investigators: Ilya Kister, MD, and Gregg Silverman, MD

Infusible anti-CD20 therapies such as rituximab or ocrelizumab have emerged as mainstays in the treatment of multiple sclerosis and related disorders. Standard dosing, which occurs every six months, achieves complete B-cell depletion in the blood of 98 percent of patients. However, some patients present with early B-cell repletion. We postulate that early B-cell repletion results from genetic polymorphisms influencing antibody-dependent cell cytotoxicity, complement-dependent pathways, body weight, and other factors. Intriguingly, our recent study showed that early B-cell repletion was more common in patients of African descent, who have been underrepresented in multiple sclerosis clinical trials in the past despite being among the fastest growing and highest incidence racial and ethnic groups with multiple sclerosis.

The multi-ethnic composition of NYU Langone’s Multiple Sclerosis Comprehensive Care Center—30 percent of our patients self-identify as African American—allows us to conduct detailed analyses of B-cell repletion kinetics on anti-CD20 therapies in this underrepresented population. To unravel the mechanistic basis for early B-cell repletion, we will perform in-depth microfluorometric analyses of blood samples, measure levels of B-cell activating factor (BAFF) cytokines, and analyze genetic polymorphisms relevant to B-cell biology. Identifying mechanisms responsible for accelerated repletion, which may reflect suboptimal treatment, may enhance our understanding of how B-cell repletion is achieved through anti-CD20 therapies and lead to personalized treatment regimens.

Genetic and Cellular Interactions in Familial Dysautonomia and Hirschsprung Disease

Principal investigator: Sumantra Chatterjee, PhD, and Horacio Kaufmann, MD
Collaborator: Maria Alejandra Gonzalez-Duarte Briseno, MD

Familial dysautonomia (FD) is a congenital, sensory, and autonomic nervous system disorder. Familial dysautonomia’s key clinical features include cardiovascular instability, gastrointestinal (GI) tract dysfunction, and autonomic crises. Familial dysautonomia patient autopsy and pathology studies reveal a reduction in enteric neurons in the GI tract, which is also a classic hallmark of Hirschsprung disease (HSCR), a congenital disorder of the enteric nervous system. The primary cause of familial dysautonomia is a single mutation in the gene ELP1, but isolated cases of Hirschsprung disease arise from multiple coding and regulatory variants in genes within a RET gene regulatory network which control enteric nervous system development.

We hypothesize that in patients with FD+HSCR or other GI dysfunction, there are additional mutations in RET and other genes of the gene regulatory network, along with ELP1. These combined mutations lead to disruption of the genetic program that impacts the existing gene regulatory network, leading to GI phenotypes. To detect cellular changes leading to GI phenotypes, we will perform single cell RNA-sequencing in the developing GI tract of mouse models of familial dysautonomia and Hirschsprung disease. In addition, we will perform targeted sequencing of 24 genes of the RET gene regulatory network in human patients to discover new modifier genes which, in the background of an ELP1 mutation, may lead to GI phenotypes observed in familial dysautonomia patients.

Converging Lines of Evidence between Alzheimer’s Disease and Epilepsy

Principal Investigator: Jayeeta Basu, PhD, and Orrin Devinsky, MD

Converging lines of evidence support that Alzheimer’s disease (AD) and epilepsy share underlying mechanisms: AD patients have an increased risk of seizures, and developing epilepsy while temporal lobe epilepsy (TLE) patients suffer from memory loss and cognitive impairments that mirror AD symptoms. The hippocampus (HC) and entorhinal cortex (EC) are common seizure foci in TLE and are affected early in AD. While these brain regions are extensively studied in rodents, the cellular and circuit organization of human EC-HC network is not well defined. What are the underlying changes at the level of cell types, molecular and synaptic physiological, that disrupt circuit dynamics causing hyperexcitability in TLE and AD?

A critical gap remains in understanding the consequences of seizure activity on HC neurons and circuit dynamics that limits our ability to effectively treat seizures and prevent or reverse cognitive and behavioral comorbidities. In an unprecedented, multidisciplinary collaboration, our study will decipher the synaptic, cellular, and circuit-level mechanisms for neuronal hyperexcitability in human epilepsy patients, and in rodent models of AD prone to epilepsy. By identifying common brain regions and cell-types of vulnerability in TLE and AD, we seek to better understand the mechanisms of epileptogenesis, neurodegeneration, and memory and cognitive dysfunctions, and to identify novel therapeutic targets for early intervention, to prevent or reverse cognitive deficits.

Inhibition of the CAMKK2-AMPK Dyad to Prevent Sleep-Deficit Alzheimer’s Disease Pathogenesis

Principal Investigators: Timothy Cardozo, MD, PhD, Ricardo Osorio, MD, and Thomas Wisniewski, MD

Individuals with sleep problems appear to have nearly double the risk for developing cognitive impairment (CI) or Alzheimer’s Disease (AD) and up to 15% of AD prevalence may be directly attributable to sleep dysfunction. Poor sleep quality and daytime sleepiness have been associated with β-amyloid (Aβ) and tau accumulation in cerebrospinal fluid (CSF). Conversely, Aβ, the pathological hallmark of AD, appears to directly impair sleep and its benefits, which is observable in rodent models of AD.

The CAMKK2-AMPK kinase pathway is over-activated by Aβ42 oligomers (Aβ42o) and triggers activation of several downstream effectors, leading to early loss of excitatory synapses (synaptotoxic effects) in neurons before plaque formation and without compromising neuronal viability. This strongly suggests that synaptotoxicity is an early event in AD progression, triggered by Aβ42o.

Sleep disturbance enhances AMPK phosphorylation and CAMKK2 levels in the brain. Thus, CAMKK2-AMPK, sleep, and AD are linked, suggesting that both Aβ42o and sleep disturbance impose a stress on brain tissues that is responded to deleteriously by the CAMKK2-AMPK pathway. AMPK is ubiquitously expressed by all cells in the body, but CAMKK2 expression is largely restricted to AD relevant regions of the brain, and thus constitutes an ideal drug target. The Cardozo lab developed a small molecule CAMKK2 inhibitor, which has properties suggesting it could be delivered orally and penetrate the brain to have its effects. Thus, this research team is in a unique position to establish a highly innovative, long-term research program into the key signaling pathway controlling the intersection of sleep disturbance and AD.