Towards the Development of an Integrative, Evidence-based Suite of Indicators for the Prediction of Outcome Following Mild Traumatic Brain Injury

This thesis focuses on identifying factors that could be used to predict recovery following concussion. The first study is a pilot assessment of blood-based biomarkers, neuropsychological tests and MRI outcomes, followed by a protocol paper for a large scale clinical study designed to identify predictive indicators. The thesis features three journal publications, one of which is a seminal review article on a novel neuroimaging analysis technique called Quantitative Susceptibility Mapping

Brain Injury

The present two volume book "Brain Injury" is distinctive in its presentation and includes a wealth of updated information on many aspects in the field of brain injury. The Book is devoted to the pathogenesis of brain injury, concepts in cerebral blood flow and metabolism, investigative approaches and monitoring of brain injured, different protective mechanisms and recovery and management approach to these individuals, functional and endocrine aspects of brain injuries, approaches to rehabilitation of brain injured and preventive aspects of traumatic brain injuries. The collective contribution from experts in brain injury research area would be successfully conveyed to the readers and readers will find this book to be a valuable guide to further develop their understanding about brain injury

Functional neurophysiological biomarkers of early-stage Alzheimer's disease:A perspective of network hyperexcitability in disease progression

Network hyperexcitability (NH) has recently been suggested as a potential neurophysiological biomarker of Alzheimer's disease (AD), as new, more accurate biomarkers of AD are sought. NH has generated interest as a potential biomarker of certain stages in the disease trajectory and even as a disease mechanism by which network dysfunction could be modulated. NH has been demonstrated in several animal models of AD pathology and multiple lines of evidence point to the existence of NH in patients with AD, strongly supporting the physiological and clinical relevance of this indication. Several hypotheses have been put forward to explain the prevalence of NH in animal models through neurophysiological, biochemical, and imaging techniques. However, some of these hypotheses have been built on animal models with limitations and caveats that may have derived NH through other mechanisms or mechanisms without translational validity to sporadic AD patients, potentially leading to an erroneous conclusion of the underlying cause of NH occurring in patients with AD. In this review, we discuss the substantiation for NH in animal models of AD pathology and in human patients, as well as some of the hypotheses considering recently developed animal models that challenge existing hypotheses and mechanisms of NH. In addition, we provide a preclinical perspective on how the development of animal models incorporating AD-specific NH could provide physiologically relevant translational experimental data that may potentially aid the discovery and development of novel therapies for AD

Current and emerging technologies for probing molecular signatures of traumatic brain injury

Traumatic brain injury (TBI) is understood as an interplay between the initial injury, subsequent secondary injuries, and a complex host response all of which are highly heterogeneous. An understanding of the underlying biology suggests a number of windows where mechanistically inspired interventions could be targeted. Unfortunately, biologically plausible therapies have to-date failed to translate into clinical practice. While a number of stereotypical pathways are now understood to be involved, current clinical characterization is too crude for it to be possible to characterize the biological phenotype in a truly mechanistically meaningful way. In this review, we examine current and emerging technologies for fuller biochemical characterization by the simultaneous measurement of multiple, diverse biomarkers. We describe how clinically available tech- niques such as cerebral microdialysis can be leveraged to give mechanistic insights into TBI pathobiology and how multiplex proteomic and metabolomic techniques can give a more complete description of the underlying biology. We also describe spatially resolved label-free multiplex techniques capable of probing structural differences in chemical signatures. Finally, we touch on the bioinformatics challenges that result from the acquisition of such large amounts of chemical data in the search for a more mechanistically complete description of the TBI phenotype.GV received a fellowship by “Associazione Amici del Mario Negri.

DIFFUSE TRAUMATIC AXONAL INJURY WITHIN THE VISUAL SYSTEM: IMPLICATIONS FOR VISUAL PATHWAY REORGANIZATION

Traumatic brain injury is a major health problem with much of its morbidity associated with traumatic axonal injury (TAI). To date, significant insight has been gained into the initiating pathogenesis of TAI. However, the specific anterograde and retrograde sequelae of TAI are poorly understood because the diffuse nature of TAI complicates data analysis. To overcome this limitation, we subjected transgenic mice expressing yellow fluorescent protein (YFP) within the visual system to central fluid percussion injury, and consistently generated diffuse TAI within the optic nerve that could easily be followed in the organized YFP positive fibers. We demonstrated progressive axonal swelling, disconnection and proximal and distal axonal dieback, with regression and reorganization of the proximal swellings, and the persistence of the distal disconnected and degenerating swellings. Antibodies targeting the C-terminus of amyloid precursor protein, a marker of TAI, mapped to the proximal axonal segments without distal targeting. Antibodies targeting microglia/macrophages, revealed activated microglia/ macrophages closely encompassing the distal disconnected, degenerating axonal segments at 7 - 28 days post injury, suggesting their role in the delayed axonal degeneration. In contrast, in the proximal reorganizing axonal segments, microglia/macrophages appeared less reactive with their processes paralleling preserved axonal profiles. Concomitant with these events, YFP fluorescence quenching also occurred, complicating data analysis. This quenching mapped to Texas-Red-conjugated-IgG immunoreactive loci, suggesting that blood–brain barrier disruption and its attendant edema participated in fluorescence quenching. This was confirmed through antibodies targeting endogenous YFP, which identified the retention of intact axons despite YFP fluorescent loss. Paralleling these events, TAI was not accompanied by retrograde retinal ganglion cell (RGC) death. Specifically, no TUNEL+ or cleaved caspase-3 immunoreactive RGCs were observed from 2 days to 3 months post-TBI. Further, Brn3a immunoreactive RGC quantification revealed no significant RGC loss. This RGC preservation was accompanied by the persistent phospho-c-Jun expression for up to 3 months post-TBI, a finding linked to neuronal survival and potential axonal repair. Parallel ultrastructural study again failed to identify RGC death. Collectively, this study provides unprecedented insight into the evolving pathobiology associated with TAI, and offers advantages for future studies focusing on its therapeutic management and neuronal reorganization

Biomarkers in Neurodegenerative Diseases

This book focuses on the recent advancements in both fundamental and clinical research, focusing on identifying, developing, and applying new and improved biological markers for specific neurologic disorders in the future. The original research work and review articles published here highlight some unique mechanisms underlying the most prevalent pathophysiological conditions affecting human health. Other areas covered in the book include emerging treatment options and correct diagnoses using different biochemical and imaging techniques

Advances in Clinical Neurophysiology

Including some of the newest advances in the field of neurophysiology, this book can be considered as one of the treasures that interested scientists would like to collect. It discusses many disciplines of clinical neurophysiology that are, currently, crucial in the practice as they explain methods and findings of techniques that help to improve diagnosis and to ensure better treatment. While trying to rely on evidence-based facts, this book presents some new ideas to be applied and tested in the clinical practice. Advances in Clinical Neurophysiology is important not only for the neurophysiologists but also for clinicians interested or working in wide range of specialties such as neurology, neurosurgery, intensive care units, pediatrics and so on. Generally, this book is written and designed to all those involved in, interpreting or requesting neurophysiologic tests

Activation of the pro-resolving receptor Fpr2 attenuates inflammatory microglial activation

Poster number: P-T099 Theme: Neurodegenerative disorders & ageing Activation of the pro-resolving receptor Fpr2 reverses inflammatory microglial activation Authors: Edward S Wickstead - Life Science & Technology University of Westminster/Queen Mary University of London Inflammation is a major contributor to many neurodegenerative disease (Heneka et al. 2015). Microglia, as the resident immune cells of the brain and spinal cord, provide the first line of immunological defence, but can become deleterious when chronically activated, triggering extensive neuronal damage (Cunningham, 2013). Dampening or even reversing this activation may provide neuronal protection against chronic inflammatory damage. The aim of this study was to determine whether lipopolysaccharide (LPS)-induced inflammation could be abrogated through activation of the receptor Fpr2, known to play an important role in peripheral inflammatory resolution. Immortalised murine microglia (BV2 cell line) were stimulated with LPS (50ng/ml) for 1 hour prior to the treatment with one of two Fpr2 ligands, either Cpd43 or Quin-C1 (both 100nM), and production of nitric oxide (NO), tumour necrosis factor alpha (TNFα) and interleukin-10 (IL-10) were monitored after 24h and 48h. Treatment with either Fpr2 ligand significantly suppressed LPS-induced production of NO or TNFα after both 24h and 48h exposure, moreover Fpr2 ligand treatment significantly enhanced production of IL-10 48h post-LPS treatment. As we have previously shown Fpr2 to be coupled to a number of intracellular signaling pathways (Cooray et al. 2013), we investigated potential signaling responses. Western blot analysis revealed no activation of ERK1/2, but identified a rapid and potent activation of p38 MAP kinase in BV2 microglia following stimulation with Fpr2 ligands. Together, these data indicate the possibility of exploiting immunomodulatory strategies for the treatment of neurological diseases, and highlight in particular the important potential of resolution mechanisms as novel therapeutic targets in neuroinflammation. References Cooray SN et al. (2013). Proc Natl Acad Sci U S A 110: 18232-7. Cunningham C (2013). Glia 61: 71-90. Heneka MT et al. (2015). Lancet Neurol 14: 388-40