Pathways to cures for multiple sclerosis: A research roadmap.

BACKGROUND: Multiple Sclerosis (MS) is a growing global health challenge affecting nearly 3 million people. Progress has been made in the understanding and treatment of MS over the last several decades, but cures remain elusive. The National MS Society is focused on achieving cures for MS. OBJECTIVES: Cures for MS will be hastened by having a roadmap that describes knowledge gaps, milestones, and research priorities. In this report, we share the Pathways to Cures Research Roadmap and recommendations for strategies to accelerate the development of MS cures. METHODS: The Roadmap was developed through engagement of scientific thought leaders and people affected by MS from North America and the United Kingdom. It also included the perspectives of over 300 people living with MS and was endorsed by many leading MS organizations. RESULTS: The Roadmap consist of three distinct but overlapping cure pathways: (1) stopping the MS disease process, (2) restoring lost function by reversing damage and symptoms, and (3) ending MS through prevention. Better alignment and focus of global resources on high priority research questions are also recommended. CONCLUSIONS: We hope the Roadmap will inspire greater collaboration and alignment of global resources that accelerate scientific breakthroughs leading to cures for MS.

Spinal cord injury chronically depresses glucose uptake in the rodent model.

The pathophysiology following spinal cord injury (SCI) progresses from its lesion epicenter resulting in cellular and systemic changes acutely, sub-acutely and chronically. The symptoms of the SCI depend upon the severity of the injury and its location in the spinal cord. However, there is lack of studies that have longitudinally assessed acute through chronic in vivo changes following SCI. In this combinatorial study we fill this gap by evaluating acute to chronic effects of moderate SCI in rats. We have used fluorodeoxyglucose (FDG) imaging with positron emission tomography (PET) as a marker to assess glucose metabolism, motor function, and immunohistochemistry to examine changes following moderate SCI. Our results demonstrate decreased FDG uptake at the injury site chronically at days 28 and 90 post injury compared to baseline. This alteration in glucose uptake was not restricted to the lesion site, showing depressed FDG uptake in non-injured areas (cervical spinal cord and cerebellum). The alteration in glucose uptake was correlated with reductions in neuronal cell viability and increases in glial cell activation at 90 days at the lesion site, as well as chronic impairments in motor function. These data demonstrate the chronic effects of SCI on glucose metabolism both within the lesion and distally within the spinal cord and brain.

Role of Insulin in Neurotrauma and Neurodegeneration: A Review.

Insulin is a hormone typically associated with pancreatic release and blood sugar regulation. The brain was long thought to be "insulin-independent," but research has shown that insulin receptors (IR) are expressed on neurons, microglia and astrocytes, among other cells. The effects of insulin on cells within the central nervous system are varied, and can include both metabolic and non-metabolic functions. Emerging data suggests that insulin can improve neuronal survival or recovery after trauma or during neurodegenerative diseases. Further, data suggests a strong anti-inflammatory component of insulin, which may also play a role in both neurotrauma and neurodegeneration. As a result, administration of exogenous insulin, either via systemic or intranasal routes, is an increasing area of focus in research in neurotrauma and neurodegenerative disorders. This review will explore the literature to date on the role of insulin in neurotrauma and neurodegeneration, with a focus on traumatic brain injury (TBI), spinal cord injury (SCI), Alzheimer's disease (AD) and Parkinson's disease (PD).

RNA-seq data of soleus muscle tissue after spinal cord injury under conditions of inactivity and applied exercise.

Reduced muscle mass and increased fatiguability are major complications after spinal cord injury (SCI), and often hinder the rehabilitation efforts of patients. Such detriments to the musculoskeletal system, and the concomitant reduction in level of activity, contribute to secondary complications such as cardiovascular disease, diabetes, bladder dysfunction and liver damage. As a result of decreased weight-bearing capacity after SCI, muscles undergo morphological, metabolic, and contractile changes. Recent studies have shown that exercise after SCI decreases muscle wasting and reduces the burden of secondary complications. Here, we describe RNA sequencing data for detecting chronic transcriptomic changes in the rat soleus after SCI at two levels of injury severity, under conditions of restricted in-cage activity and two methods of applied exercise, swimming or shallow water walking. We demonstrate that the sequenced data are of good quality and show a high alignment rate to the Rattus norvegicus reference assembly (Rn6). The raw data, along with UCSC Genome Browser tracks created to facilitate exploration of gene expression, are available in the NCBI Gene Expression Omnibus (GEO; GSE129694).

Transcriptome of dorsal root ganglia caudal to a spinal cord injury with modulated behavioral activity.

Spinal cord injury (SCI) is a devastating clinical condition resulting in significant disabilities. Apart from local injury within the spinal cord, SCI patients develop a myriad of complications including multi-organ dysfunction. Some of the dysfunctions may be directly or indirectly related to the sensory neurons of the dorsal root ganglia (DRG), which signal to both the spinal cord and the peripheral organs. After SCI, some classes of DRG neurons exhibit sensitization and undergo axonal sprouting both peripherally and centrally. Such physiological and anatomical re-organization after SCI contributes to both adaptive and maladaptive plasticity processes, which may be modulated by activity and exercise. In this study, we collected comprehensive gene expression data in whole DRG below the levels of the injury to compare the effects of SCI with and without two different forms of exercise in rats.

Activity/exercise-induced changes in the liver transcriptome after chronic spinal cord injury.

Multi-organ dysfunction is a major complication after spinal cord injury (SCI). In addition to local injury within the spinal cord, SCI causes major disruption to the peripheral organ innervation and regulation. The liver contains sympathetic, parasympathetic, and small sensory axons. The bi-directional signaling of sensory dorsal root ganglion (DRG) neurons that provide both efferent and afferent information is of key importance as it allows sensory neurons and peripheral organs to affect each other. SCI-induced liver inflammation precedes and may exacerbate intraspinal inflammation and pathology after SCI, which may be modulated by activity and exercise. In this study, we collected comprehensive gene expression data through RNA sequencing of liver tissue from rats with chronic SCI to determine the effects of activity and exercise on those expression patterns. The sequenced data are of high quality and show a high alignment rate to the Rn6 genome. Gene expression is demonstrated for genes associated with known liver pathologies. UCSC Genome Browser expression tracks are provided with the data to facilitate exploration of the samples.

The effects of insulin on the inflammatory activity of BV2 microglia.

Microglia are the macrophages of the central nervous system (CNS), which function to monitor and maintain homeostasis. Microglial activation occurs after CNS injury, infection or disease. Prolonged microglial activation is detrimental to the CNS as they produce nitric oxide (NO), reactive oxygen species (ROS) and pro-inflammatory cytokines, resulting in neuronal cell dysfunction and death. Microglial activation is implicated in the neurological deficits following traumatic brain injury (TBI) and Alzheimer's disease. Intranasal insulin administration is a promising treatment of Alzheimer's disease and TBI. However, the exact effect of insulin on microglia is currently unclear. The goal of this study was therefore to examine the effect of insulin administration on activated microglia. The microglial cell line BV2 were exposed to a pro-inflammatory stimulus, lipopolysaccharide (LPS), followed by insulin administration. Outcome measures were conducted at 24 hours after treatment. In vitro assays quantified NO and ROS production. Western blot, immunocytochemistry and phagocytosis assay further examined the effect of insulin on microglial activity. Insulin treatment significantly reduced NO, ROS and TNFα production and increased phagocytic activity. Insulin treatment also significantly reduced iNOS expression, but had no significant effect on any other M1 or M2 macrophage polarization marker examined. These data suggest that insulin has very specific effects to reduce pro-inflammatory or chemoattractant properties of microglia, and this may be one mechanism by which insulin has beneficial effects in CNS injury or neurodegenerative conditions.

Intranasal insulin treatment of an experimental model of moderate traumatic brain injury.

Traumatic brain injury (TBI) results in learning and memory dysfunction. Cognitive deficits result from cellular and metabolic dysfunction after injury, including decreased cerebral glucose uptake and inflammation. This study assessed the ability of intranasal insulin to increase cerebral glucose uptake after injury, reduce lesion volume, improve memory and learning function and reduce inflammation. Adult male rats received a controlled cortical impact (CCI) injury followed by intranasal insulin or saline treatment daily for 14 days. PET imaging of [18F]-FDG uptake was performed at baseline and at 48 h and 10 days post-injury and MRI on days three and nine post injury. Motor function was tested with the beam walking test. Memory function was assessed with Morris water maze. Intranasal insulin after CCI significantly improved several outcomes compared to saline. Insulin-treated animals performed better on beam walk and demonstrated significantly improved memory. A significant increase in [18F]-FDG uptake was observed in the hippocampus. Intranasal insulin also resulted in a significant decrease in hippocampus lesion volume and significantly less microglial immunolabeling in the hippocampus. These data show that intranasal insulin improves memory, increases cerebral glucose uptake and decreases neuroinflammation and hippocampal lesion volume, and may therefore be a viable therapy for TBI.

[18F]FDG-PET Combined with MRI Elucidates the Pathophysiology of Traumatic Brain Injury in Rats.

Non-invasive measurements of brain metabolism using 18F-fluorodeoxyglucose (FDG) with positron emission tomography (PET) may provide important information about injury severity following traumatic brain injury (TBI). There is growing interest in the potential of combining functional PET imaging with anatomical and functional magnetic resonance imaging (MRI). This study aimed to investigate the effectiveness of combining clinically available FDG-PET with T2 and diffusion MR imaging, with a particular focus on inflammation and the influence of glial alterations after injury. Adult male Sprague Dawley rats underwent a moderate controlled cortical impact (CCI) injury followed by FDG-PET, MRI, and histological evaluation. FDG uptake showed significant alterations in the corpus callosum, hippocampus, and amygdala after TBI, demonstrating that a relatively "focal" CCI injury can result in global alterations. Analysis of MRI T2 intensity and apparent diffusion coefficient (ADC) also showed significant alterations in these regions to include cytotoxic and vasogenic edema. Histology showed increased glial activation in the corpus callosum and hippocampus that was associated with increased FDG uptake at sub-acute time-points. Glial activation was not detected in the amygdala but neuronal damage was evident, as the amygdala was the only region to show a reduction in both FDG uptake and ADC at sub-acute time-points. Overall, FDG-PET detected glial activation but was confounded by the presence of cell damage, whereas MRI consistently detected cell damage but was confounded by glial activation. These results demonstrate that FDG-PET and MRI can be used together to improve our understanding of the complex alterations in the brain after TBI.

FDG-PET imaging in mild traumatic brain injury: a critical review.

Traumatic brain injury (TBI) affects an estimated 1.7 million people in the United States and is a contributing factor to one third of all injury related deaths annually. According to the CDC, approximately 75% of all reported TBIs are concussions or considered mild in form, although the number of unreported mild TBIs (mTBI) and patients not seeking medical attention is unknown. Currently, classification of mTBI or concussion is a clinical assessment since diagnostic imaging is typically inconclusive due to subtle, obscure, or absent changes in anatomical or physiological parameters measured using standard magnetic resonance (MR) or computed tomography (CT) imaging protocols. Molecular imaging techniques that examine functional processes within the brain, such as measurement of glucose uptake and metabolism using [(18)F]fluorodeoxyglucose and positron emission tomography (FDG-PET), have the ability to detect changes after mTBI. Recent technological improvements in the resolution of PET systems, the integration of PET with magnetic resonance imaging (MRI), and the availability of normal healthy human databases and commercial image analysis software contribute to the growing use of molecular imaging in basic science research and advances in clinical imaging. This review will discuss the technological considerations and limitations of FDG-PET, including differentiation between glucose uptake and glucose metabolism and the significance of these measurements. In addition, the current state of FDG-PET imaging in assessing mTBI in clinical and preclinical research will be considered. Finally, this review will provide insight into potential critical data elements and recommended standardization to improve the application of FDG-PET to mTBI research and clinical practice.