Diagnostics of Brain Rehabilitation

Traumatic brain injury (TBI) is a leading cause of long-term morbidity among the young resulting in significant societal impacts. Yet advances in TBI therapeutic care have been largely limited by the complexity of the pathobiology, heterogeneity among patients, and imprecise endpoint assessments with which to evaluate efficacy. Thus, there remains a significant need for improved diagnostics, particularly for guiding novel therapeutic use and outcomes. So-called theragnostic assays are of particular interest in the new area of TBI rehabilitation, which ideally would target a window of heightened brain plasticity during which circuit remodeling would support recapitulation of lost function. The biochemical processes associated with brain plasticity following TBI produce metabolized components that are small enough in size to passively diffuse into peripheral fluid and by natural means are excreted into urine. We employ high performance mass spectrometry to quantify these byproducts, comprising a “TBI urinary signature” of some 2,500 TBI selective molecules. In this study we hypothesized that the urinary signature would evolve with the advent of a plasticity window during the course of inpatient rehabilitation. Urine samples from eight TBI patients were collected at admission and discharge from the VCU Health Science Center Brain Injury Rehabilitation Unit. Application of non-supervised dimensional reduction analysis demonstrates that the TBI urinary signature is highly effective at classifying TBI patients from non-traumatized age / sex matched individuals. Further, our data demonstrate that the TBI urinary signature evolves distinctively between admission to rehabilitation (mean of 22 days post-TBI) and discharge from the unit (mean of 32 days post-TBI), clearly differentiating the point in recovery. Results further suggest individualized features grouping subjects into recovery classes that are being evaluated for functional correlates. Future research with these results will further evaluate the prognostic capacity of the TBI urinary signature as subjects are followed out one year from their injury.https://scholarscompass.vcu.edu/uresposters/1076/thumbnail.jp

BETA-OXIDATION OF ADIPOSE-DERIVED FATTY ACIDS FUEL PTH-INDUCED BONE FORMATION

The energetic costs of bone formation require osteoblasts to coordinate their activities with tissues able to supply fuel molecules. In the case of intermittent parathyroid hormone (iPTH) treatment, a therapeutic strategy used clinically to reduce fracture risk, the increase in bone formation is preceded by a change in lipid homeostasis. The sequence of these events led us to hypothesize that fatty acid beta-oxidation is required for the anabolic actions of this therapy. In vitro, osteoblasts treated with PTH exhibited increases in oxidation of oleate, genes involved in fatty acid beta-oxidation (RNA sequencing) and in the rate of oxygen consumption. Etomoxir, an irreversible inhibitor of the rate limiting enzyme in beta-oxidation, attenuated the effect of PTH on oxygen consumption, indicating that fatty acid catabolism is key to this response. In vivo, iPTH-induced (100 μg/kg/d for six weeks) increases in trabecular bone volume were reduced by approximately 50% in mice lacking Cpt2, an obligate enzyme in beta-oxidation, in osteoblasts (Cpt2flox/flox; Ocn-Cre) when compared to control littermates. We speculated that the fatty acids necessary to fuel iPTH-induced bone formation are released from adipose tissue since acute PTH administration increased serum free fatty acids, induced the phosphorylation of hormone sensitive lipase in white adipose depots, and stimulated a rapid decrease in the respiratory exchange ratio, indicative of an increase in fatty acid oxidation. To test this hypothesis, mice lacking the PTH receptor in adipocytes (Pth1rflox/flox; AdipoQ-Cre), or mice with impaired lipolysis due to the ablation of Atgl in adipocytes (Atglflox/flox; AdipoQ-Cre) were treated with iPTH for six weeks. When compared to control littermates, iPTH-induced acquisition of bone volume was severely blunted in each mutant mouse line. Dynamic histomorphometric analysis of Pth1rflox/flox; AdipoQ-Cre and Atglflox/flox; AdipoQ-Cre mice revealed an impaired ability of iPTH to enhance the mineral apposition rate and the bone formation rate. Collectively, these data suggest that PTH’s anabolic effect requires signaling in bone as well as in fat, wherein a lipolytic response in adipose tissue liberates fatty acids that are oxidized by osteoblasts to fuel bone formation

Effects of nandrolone on recovery after neurotization of chronically denervated muscle in a rat model.

OBJECT: Suboptimal recovery following repair of major peripheral nerves has been partially attributed to denervation atrophy. Administration of anabolic steroids in conjunction with neurotization may improve functional recovery of chronically denervated muscle. The purpose of this study was to evaluate the effect of the administration of nandrolone on muscle recovery following prolonged denervation in a rat model. METHODS: Eight groups of female Sprague-Dawley rats (15 rats per group, 120 in all) were divided into 3- or 6-month denervated hind limb and sham surgery groups and, then, nandrolone treatment groups and sham treatment groups. Evaluation of treatment effects included nerve conduction, force of contraction, comparative morphology, histology (of muscle fibers), protein electrophoresis (for muscle fiber grouping), and immunohistochemical evaluation. RESULTS: Although a positive trend was noted, neither reinnervated nor normal muscle showed a statistically significant increase in peak muscle force following nandrolone treatment. Indirect measures, including muscle mass (weight and diameter), muscle cell size, muscle fiber type, and satellite cell counts, all failed to support significant anabolic effect. CONCLUSIONS: There does not seem to be a functional benefit from nandrolone treatment following reinnervation of either mild or moderately atrophic muscle (related to prolonged denervation) in a rodent model