Comprehensive multimodal analysis of patients with neuroimmunological diseases

National Institute Of Allergy And Infectious Diseases

Investigators

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Abstract

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. The data collected under this project identified following reasons for this declining efficacy of immunomodulatory treatments with MS progression: 1. Progressive compartmentalization of intrathecal inflammation to CNS tissue during MS evolution: Contradicting wide-held belief that inflammation decreases with MS progression, we showed that subjects with primary- (PPMS) and secondary-progressive (SPMS) MS have identical levels of cerebrospinal fluid (CSF) biomarkers released by activated T and B cells as RRMS patients, indicating that the levels of intrathecal inflammation remain stable during MS evolution. In contrast, we showed that while intrathecal inflammation in RRMS is dynamic, with lymphocytes migrating between blood and CNS (Hannikainen et al: Extensive healthy donor age/gender adjustments and propensity score matching reveal pathophysiology on multiple sclerosis through immunophenotyping; PMID: 33329307), in progressive MS (PMS), the inflammation is relatively static, compartmentalized to CNS tissue and largely inaccessible to peripherally administered drugs. 2. Terminal differentiation of cells of adaptive immunity: The second process that limits efficacy of current immunomodulatory drugs is progressive differentiation of T- and B-lymphocytes towards non-proliferating, terminally differentiated cells. This limits efficacy of small molecules that may have better CNS penetrance than monoclonal antibodies, but that act on proliferating cells. 3. Broadening of intrathecal inflammation to innate immunity reflected by microglial dysfunction and activation of complement/clotting cascade. 4. Mal-adaptive response of CNS tissue to chronic inflammation, reflected by toxic astrogliosis and restructuring of extracellular matrix into fibrosis. 5. Recovery of neurological functions in young patients in early stages of MS is, to a large extent, mediated by functional, rather than structural recovery: by making new synaptic circuits by remaining neurons. Like capacity to remyelinate, this mode of recovery exhausts itself with progressive CNS tissue damage, leading to accelerated rates of accumulation of clinical disability in PMS. Most importantly, the above-stated mechanisms correlate with MS severity, measured as speed of accumulation of disability. This suggests that these processes, evolving with MS duration may play causal role in CNS tissue destruction. Finally, we also observed considerable inter-individual heterogeneity in the above-stated mechanisms, indicating need for personalized medicine. Without understanding patient-specific driver(s) of the disease, clinicians may prescribe therapies for which a patient lacks target(s), incurring not only unacceptable societal costs, but also exposing patients to side-effects of applied therapies without their potential for benefit. Analogously, if a patient's expression of a disease encompasses more than one pathophysiological mechanism, such patient requires combination treatments that target all contributing processes. Even though these potentially pathogenic mechanisms were described in MS, we observed their presence in other neuroinflammatory diseases, including infectious. This suggests that irrespective of disease onset, there may be limited number of pathogenic mechanisms and reparative processes that mediate interaction of chronic inflammation with CNS tissue. Identification, quantification, and mechanistic understanding of these processes will likely benefit all CNS disease with immune-mediated pathogenesis. Thus, we view establishment of molecular nosology of neuroimmunological diseases and development of molecular tests that can distinguish and quantify different pathogenic processes that lead to destruction of the CNS tissue as essential for therapeutic advances in neuroimmunology. Achieving this goal requires not only multi-omics characterization of the molecular and cellular aspects of neuroimmunological diseases, but also significant improvement of sensitivity and specificity of the clinical measurements of disability progression and CNS tissue destruction. This became especially urgent during COVID19 pandemic, where most neurology patients had to transition to telemedicine, leaving clinicians and researchers without ability to effectively monitor neurological progression. Development and validation of better clinical and neuroimaging scales has been part of our research program for the past decade. Five years ago, we started development of smartphone-based Neurological Function Test Suite (NeuFun-TS), with the goal to reproduce most relevant aspects of neurological examination performed by skilled neurologist in patient-autonomous manner. This would aid identification of neurological deficit and management of chronic neurological disease in an environment with relative paucity of neurologist, previously only in the developing countries but now spread world-wide, including many areas of USA. COVID19 pandemic provided special urgency for this project. Previous 3 years we demonstrated that machine-learning (ML) optimized NeuFun-TS outcomes can reliably measure motoric and cerebellar dysfunction in all 4 limbs. This year we showed that NeuFun-TS simple cognitive test explains 75% of the CNS tissue damage measured by advanced imaging techniques, in the independent validation cohort of MS patients (Lin at al: Smartphone-based symbol-digit modalities test reliably captures brain damage in multiple sclerosis; PMID 33627777). We also completed development of 5 other NeuFun-TS tests designed to measure different sensory dysfunctions and to measure broader cognitive functions. The ML optimization of the outcomes from these test and validation of their clinical value is ongoing. These tools are already deployed to measure neurological functions in different research settings. Our long-term plan is to develop NeuFun-TS to FDA approval, as a tool that will revolutionize care for neurological patients not only by neurologist, but especially by non-neurological practitioners, such as infectious disease specialists or primary care providers.