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Principal Investigator: Bibiana Bielekova
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2024
Award: $1,388,137
Funding agency: National Institute of Allergy and Infectious Diseases
Neuroimmunological diseases of the central nervous system (CNS) represent a growing spectrum of diagnoses, most of which are considered rare disorders. The pathophysiology of these diseases is poorly understood, and effective therapies are sporadic. The most common immune-mediated CNS disease is multiple sclerosis (MS). The initial stage of MS, relapsing-remitting MS (RRMS) can be effectively treated by immunomodulatory treatments, if these are initiated at young age, before the substantial CNS damage occurred. Although there are currently more than 20 Food and Drug Administration (FDA)-approved treatments of MS, their efficacy on disability progression strongly declines with advancing age of patients, so that after age of 54 years, no efficacy on disability progression is seen on a group level. This protocol is advancing knowledge about disease mechanisms that are not targeted by current FDA-approved treatments and is also developing and validating tools of clinical utility.
This review period (September 2023-August 2024) we have generated following results:
Neuroimmunological diseases of the central nervous system (CNS) represent a growing spectrum of diagnoses, most of which are considered rare disorders. The pathophysiology of these diseases is poorly understood, and effective therapies are sporadic. The most common immune-mediated CNS disease is multiple sclerosis (MS). The initial stage of MS, relapsing-remitting MS (RRMS) can be effectively treated by immunomodulatory treatments, if these are initiated at young age, before the substantial CNS damage occurred. Although there are currently more than 20 Food and Drug Administration (FDA)-approved treatments of MS, their efficacy on disability progression strongly declines with advancing age of patients, so that after age of 54 years, no efficacy on disability progression is seen on a group level. This protocol is advancing knowledge about disease mechanisms that are not targeted by current FDA-approved treatments and is also developing and validating tools of clinical utility.
This review period (September 2023-August 2024) we have generated following results:
1. For patients with neuroimmunological disorders, including infections of the central nervous system (CNS), autoimmune and auto-inflammatory CNS diseases, optimal treatment depends on timely access to neurology specialists. However, accelerated demand due to an aging US population far outpaces neurologists supply. The COVID-19 pandemic has highlighted the power of telemedicine to expand healthcare, but it has also revealed limited ability of telemedicine to identify and quantify neurological deficit, especially at the beginning of immune-mediated disease processes, when instituting early treatments is critical for preventing irreparable CNS injury. Therefore, we continue working on an ambitious project to recreate most aspects of neurological examination in patient-autonomous (i.e., self-administered) smartphone tool called Neurological Functions Test Suite (NeuFun-TS). NeuFun-TS currently consists of 12 simple tests of neurological functions. We have already fully analyzed and optimized 5 of these tests and showed that they provide digital biomarkers that correlate highly with the neurological dysfunction measured by expert neurological examination and by brain/spinal cord MRI imaging. This review period we fully analyzed 2 additional NeuFun-TS tests, this time measuring lower extremities functions: a digitalized walk tests and toe tapping test. A digital walking test offers the opportunity to extract biomarkers from triaxial accelerometers and gyroscope data built into smartphones. We integrated accelerometer data with knowledge of the human gait cycle. By connecting digital biomarkers to well-characterized muscle movements, we identified features with high psychometric properties. Specifically, the total number of taps per each foot, as well as number of gait-cycle derived digital biomarkers had strong test-retest reliability (i.e., Intraclass correlation coefficient >0.75), demonstrated moderate or strong correlation with relevant clinical scales (Rho 0.83-0.59; all p<0.01 after adjusting for multiple comparisons) and imaging outcomes, such as cervical spinal cord lesion load and atrophy. Using machine learning (ML), these digital biomarkers of lower extremities function could be aggregated to novel digital disability scales. These ML-derived/optimized digital biomarkers predicted relevant physician-derived disability scales in the independent validation cohort of people with neuroimmunological diseases with high accuracy (R2 = 0.78-0.68; p<0.0001). Through analyses of collected data we also learned how to further optimize NeuFun-TS tests of lower extremities functions to enhance accuracy of the results and convenience of the tester. We are currently implemented these modifications. We have been also actively analyzing 2 other NeuFun-TS tests this review period: the pronator drift and postural sway. We are currently writing paper describing these results and we will report them next year.
2. For the past several years under this project we performed extensive studies aimed to elucidate the role of Epstein Barr Virus (EBV) in MS initiation and progression. To this end we generated B cell receptor (BCR) and T cell receptor (TCR) mRNA libraries from 791 cerebrospinal fluid (CSF) immune cells samples before unblinding diagnostic categories. We observed that MS patients have significantly higher BCR clonality and BCR CDR3 length compared to control subjects that included other inflammatory (OIND) and non-inflammatory neurological (NIND) disorders that mimic MS. From specific IGHV categories MS patients had significant expansion of IGHV4.31 and especially IGHV4.39 clonotypes. Likewise, we observed that MS patients have significantly higher TCR clonality compared to controls and that TCR and BCR clonality correlated (p<2.2e-16). We then used TCR CDR3 similarity algorithm to ask if any of the sequenced CSF TCRs recognize viral epitopes based on the published TCR repertoire databases. We observed that the highest proportion of CSF TCRs were predicted to recognized CMV epitopes, with no differences between MS and controls (p=0.86). Likewise, although MS patients have slightly lower proportion of TCRs recognizing influenza epitopes, the difference was not statistically significant (p=0.09). However, MS patients had significantly higher TCRs predicted to bind EBV epitopes (p=0.003). Among these, MS CSF T cells recognized non-significantly more latent EBV proteins (p=0.32). The biggest difference was in TCRs predicted to recognize epitopes from EBV lytic proteins, which were almost 2-fold enriched in MS CSF as compared to control subjects (p=0.0005). We then asked which CSF cells (flow cytometry) and RNA transcripts were enriched in the CSF of subjects with high TCR similarity to EBV lytic proteins. We identified unique transcriptomic signature of CSF T cells that also correlated with clinical and radiological outcomes of MS activity. We are currently performing mechanistic studies to understand relationship between these MS-specific, EBV-targeting intrathecal immune responses contribute to CNS injury in MS.
3. Our Research also contributed to following research led by other investigators: 1. a variant (p93S) in Annexin A11 (ANXA11) - an amyotrophic lateral sclerosis/frontotemporal dementia-associated gene was identified in family with a corticobasal degeneration syndrome. Mechanistic studies showed that this variant decreased lysosome colocalization and cryptic exon expression in TDP-43. These changes resulted in neuronal degeneration characterized by axonal damage and microglial activation of type I interferon signaling; 2. We have participated in multicentric validation of a fully automated digital immunoassay for neurofilament l
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pandemic><smart phone><smartphone><social role><spinal fluid><thymus derived lymphocyte><tissue repair><tool><transcriptomics><validations><virus protein>