Precision Medicine for Recovery and Rehabilitation in the Setting of Neurologic Injury

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Background

Rehabilomics® (Professor Amy Wagner, University of Pittsburgh, 2010) leverages omics approaches to inform recovery and rehabilitation-relevant mechanisms and outcomes following acute injury or onset of disease. In this special edition, the focus is on acute injuries to the central nervous system (CNS), namely stroke, traumatic brain injury (TBI) and spinal cord injury (SCI), as these are among the most common causes of premature death and disability worldwide. On onset, each triggers a complex cascade of primary and secondary pathogenic and regenerative processes to the CNS that can have multifaceted effects and impact an individual across all domains as defined by International Classification of Functioning, Disability and Health (ICF). These include, for Body Structure/Function: motor, sensory, autonomic, pain, language/cognition, behaviour, mood/emotion); for Activity: walking capacity, transfers and activities of daily living (ADLs); and for Participation: employment, quality of life and other Patient Reported Outcome Measures.

Longitudinal observation of these populations has persistently revealed significant heterogeneity in people’s recovery and rehabilitation outcomes – from complete recovery to chronic debilitating and/or degenerative sequelae and premature death. This is despite similar injury mechanisms, anatomical lesion, severity, other clinical and demographic risk factors and management. Actionable understanding of the pathophysiology underlying recovery and rehabilitation outcome and the spectrum of factors contributing to their variability, however, is insufficient, as highlighted by the limited treatment guidelines.

Individuals’ personal biology or “omic” make-up has long been posited to play a role in recovery and rehabilitation outcome. Understanding the genetic pathomechanisms in play following acute CNS injury will aid in characterizing this heterogeneity and is a precursor to potential precision medicine approaches in this field. The identification of objective and reliable fluid biomarkers will aid in confirming diagnosis, defining severity, tracking natural history, predicting sequelae, informing prognosis, evaluating treatment effectiveness, and selecting optimum treatments.

In the past five years, Rehabilomics research has advanced for stroke, TBI and SCI recovery and rehabilitation outcomes, made possible by the collaborative efforts of consortia and the availability of combined datasets of comprehensive, multi-domain longitudinal phenotyping and biobanked samples. For stroke, three genome-wide association studies (GWAS) of long-term functional outcome or neurologic course, as measured by the modified Rankin scale and National Institutes of Health Stroke Scale (NIHSS), respectively, have been completed. These reported significant findings that suggest an underlying genetic architecture contrary to that described for stroke risk. One epigenome-wide association study (EWAS) offers a novel picture of the landscape of genome-wide DNA methylation in stroke outcome. For TBI, the candidate gene approach has led to the identification and validation of a handful of clinically promising CNS-specific injury serum biomarkers that aid in characterizing severity and predicting longer-term functional outcome, particularly when considered together or incorporated into existing prognostic models. On a hypothesis-free genome-wide scale, the first TBI GWAS and transcriptome-wide association study (TWAS) of functional outcome, as measured by the global outcome scale – extended (GOS-E), has been published, providing the first representation of the genetic architecture underlying TBI outcome. Similarly, a comprehensive metabolomics study of TBI severity, using the Glasgow Coma Scale, has identified differences in the metabolomes of mild, moderate and severe injuries and has demonstrated the additive value of metabolites in prognostic modeling. In SCI, comparable Rehabilomics studies in humans appear to be less common. Instead, multi-omic and integrative biology studies in animal models of acute SCI have enhanced our understanding of the pathophysiologic processes that occur after injury to the spinal cord and subsequently identified candidate genes and pathways for study in humans.

This recent progress in Rehabilomics, however, only marks the beginning for unraveling the complex processes and molecular mechanisms underlying recovery and rehabilitation outcome following acute CNS injury. Mirroring the recommendations made for advance complex disease risk genetics, these results also need to be replicated in larger, more diverse samples with meaningful targets that can be functionally validated. Ideally, attention needs to also focus on more diverse phenotypes with consideration of environmental or psychosocial interactions to authentically capture the distinct differences in recovery and rehabilitation outcome as experienced by survivors of these neurological events. This would include addressing post-injury motor or sensory impairment, fatigue, depression, anxiety, and pain while seeking to include the acute through chronic timepoints in recovery trajectories. Future research using these biomarkers would enable the stratification of individuals for comparative effectiveness trials and ultimately treatment for the realization of precision approaches in recovery and rehabilitation for people with stroke, TBI or SCI.

This Specialty Topic invites the submission of all articles related, but not limited to, the following Rehabilomics-related research in stroke, TBI and SCI:

1. Original research reporting results from multi-omics studies focused on recovery and ICF domain-based rehabilitation outcomes (eg. language/cognitive, physical, functional, psychosocial, behavioral) in acute central neurologic injury
2. Systematic reviews and/or meta-analyses of biological mechanisms identified through Rehabilomics research.
3. Development of novel statistical approaches or application of advanced biostatistics methods to quantitatively describe or analyze the relationship between “omic” factor(s) and recovery or rehabilitation outcome. These methods could include Polygenic Risk Score Analysis, integrative biology and pathway/network analyses, Mendelian Randomization, PheWAS, multi-trait or longitudinal data methods, gene-environment interaction and/or epistatic analyses.
4. Development, validation and/or application of multi-trait phenotyping approaches (eg, model- or machine-learning-based approaches, extreme value analysis) that leverage the heterogeneity of these recovery and rehabilitation traits to increase the statistical power for omics-based studies of recovery and rehabilitation outcome.
5. Integration of omics discoveries in rehabilitation-relevant prognostic modeling, prediction algorithms and clinical decision pathways.
6. Rehabilitation outcome research that addresses inequality in genetic research with a focus on minority underrepresented groups.
7. Narrative/Commentary on Strategic Directions from consortia groups and large data initiatives and how they might advance the field of Rehabilomics.

Keywords: neurological injury, Rehabilomics, nervous system, traumatic brain injury, spinal cord injury

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