Parekh Center for Interdisciplinary Neurology Main Research Projects | NYU Langone Health

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

Parekh Center for Interdisciplinary Neurology Main Research Projects

Researchers at NYU Langone’s Parekh Center for Interdisciplinary Neurology are focused on four core projects that benefit from cross-discipline collaborations: clinical measures and imaging, high-dimensional immunological profiles, single-cell transcriptomes of peripheral (PBMC) and cerebrospinal fluid (CSF) immune cells, and characterizing the gut microbiome and blood metabolome for each patient.

In addition, understanding the interaction of these systems in relation to the changes that occur within the brain is essential. We will also incorporate cell biology into our portfolio by investigating the role of non-neuronal glial cells, particularly astrocytes, in driving neurodegeneration and pathophysiology across diseases, starting with amyotrophic lateral sclerosis, but expanding to cover other themes of the Parekh Center for Interdisciplinary Neurology in later years.

Through these efforts, we will build a framework for how the gut microbiome, peripheral immune system, and immune and glial cells in the central nervous system interact at different stages from cross-sectional data and longitudinal data in prodromal groups in the future.

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 (MS). This initial neuronal dysfunction that defines prodromal neurodegeneration can be reliably identified by subtle inconsistencies in cognitive processes. Cognitive consistency can be easily measured using simple computer-based psychomotor tasks, capturing intra-individual variability (IIV) across an individual’s repeated reaction times. IIV, compared to the conventional measures of cognitive accuracy or speed, is a highly sensitive marker of future health status at the population level as well as in prodromal neurological disease.

Applied in the context of neurodegenerative disorders, IIV marks the earliest onset of disease and risk of future onset of 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.

Learn more about this project.

Gut Microbiome as a Mechanism of Drug Resistance in Epilepsy

Principal investigator: Claude Steriade, MD

There are an estimated 3.4 million people with active epilepsy in the United States, with an annual cost of about $38 billion. 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.

The gut microbiome is altered in drug-resistant epilepsy. Ketogenic diet studies suggest that the gut microbiome influences seizure control. Gut microbiome manipulation may therefore be an effective epilepsy therapy. Neuroinflammation is a potential mechanism by which seizures may impact gut dysbiosis, and vice versa. Seizures are associated with neuro-inflammation, specifically IL1β and IL6 upregulation. Inflammatory dysregulation, such as IL1β, can in turn lead to dysbiosis in animal models.

This project is improving the understanding of the independent role of seizures on the gut microbiome and explore neuro-inflammation as a potential mediator of the relationship between seizures and gut dysbiosis. These key potential mediators can inform the design of a rational targeted microbiome interventions.

Learn more about this project.

Pathogenetic Mechanisms of Oligodendrocytes in Multiple System Atrophy

Principal investigators: Thong C. Ma, PhD, and Un Jung 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 (nucSeq) 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, as well as in mice to understand how these changes contribute to disease pathogenesis, which is necessary for developing new therapeutic approaches.

These reverse translational studies are overcoming the limitations of current MSA models that force overexpression of α-synuclein in specific cell types, limiting scientific questions to downstream events rather than addressing the fundamental upstream stressors that lead to dysregulation of α-synuclein.

Learn more about this project.

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 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.

Learn more about this project.

Pilot Projects

The Parekh Center for Interdisciplinary Neurology also hosts a request for applications (RFA) for pilot grants to supplement our growing center. These pilot grants are open to all research faculty at NYU Langone Health, with the provision that the research aims are not descriptive of a single disease pathology or etiology. Special consideration will be given to those projects that focus on the Parekh Center for Interdisciplinary Neurology’s goals of cross-disciplinary, cross-disease research.

For more information or to participate in our pilot projects RFA, please email us at parekh.center@nyulangone.org.