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 can 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.

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 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

Infusable 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 6 months, achieves complete B-cell depletion in the blood of 98% 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% of our patients self-identify as African-Americans—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.