Chronic Dysregulation of the Cerebrovasculature in a Mouse Model of Repetitive Mild Traumatic Brain Injury

There are over 2 million reports of Traumatic Brain Injury (TBI) every year in the United States alone, the majority of which are classified as a mild head injury. Incidences of mild TBI (mTBI), the kind of which are sustained most routinely by contact sports athletes, active military personnel, are now well accepted as being a risk factor for development of chronic neurodegenerative disorders such as Chronic Traumatic Encephalopathy (CTE). To date, the diagnosis of CTE has been based on post-mortem neuropathological assessment of brain tissue, precluding the possibility of prophylactic or interventional therapy in human patients presenting with symptomatology too ambiguous for antemortem diagnosis, and ergo, appropriate clinical trial stratification. Recently, it has been reported that military personnel and players of contact sports experiencing repetitive m-TBI (r-mTBI), as well as individuals suffering from chronic TBI-related illness, demonstrate a deficit in Cerebral Vascular Reactivity (CVR). This physiological impairment is non-invasively detected following repeat mTBI, and seen to be sustained at chronic time-points post-injury in both r-mTBI and moderate to severe TBI patients alike, implicating CVR detriment as an endophenotypic biomarker and possible in vivo diagnostic of TBI-related neuropathogenesis, and Traumatic Cerebral Vascular Injury (TCVI). In this thesis, I developed and validated a preclinical in vivo imaging setup to examine CVR in our CTE-like neuropathology exhibiting mouse model of r-mTBI, with an aim to characterizing the evolving pathobiology of TCVI and concurrent euro behavioral impairment, and their correlation to perturbed CVR. I demonstrated recapitulation of the CVR deficit seen in the human population in our animal model, alongside sustained memory and learning impairment, and signs of an underlying response of the cerebral vasculature to injury. These finding implicate measurement of CVR as a valid preclinical diagnostic, and the treatment of TCVI as a compelling parallel pathological target in r-mTBI

Lifecycle management of a commercial platform monoclonal antibody process: The promise of ICHQ12

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Chronic repetitive mild traumatic brain injury results in reduced cerebral blood flow, axonal injury, gliosis, and increased T-Tau and Tau oligomers

Exposure to repetitive mild traumatic brain injury (mTBI) is a risk factor for chronic traumatic encephalopathy, which is characterized by patchy deposition of hyperphosphorylated tau aggregates in neurons and astrocytes at the depths of cortical sulci. We developed an mTBI paradigm to explore effects of repetitive concussive-type injury over several months in mice with a human tau genetic background (hTau). Two injuries were induced in the hTau mice weekly over a period of 3 or 4 months and the effects were compared with those in noninjured sham animals. Behavioral and in vivo measures and detailed neuropathological assessments were conducted 6 months after the first injury. Our data confirm impairment in cerebral blood flow and white matter damage. This was accompanied by a 2-fold increase in total tau levels and mild increases in tau oligomers/conformers and pTau (Thr231) species in brain gray matter. There was no evidence of neurofibrillary/astroglial tangles, neuropil threads, or perivascular foci of tau immunoreactivity. There were neurobehavioral deficits (ie, disinhibition and impaired cognitive performance) in the mTBI animals. These data support the relevance of this new mTBI injury model for studying the consequences of chronic repetitive mTBI in humans, and the role of tau in TBI

Negative impact of female sex on outcomes from repetitive mild traumatic brain injury in hTau mice is age dependent: a Chronic Effects of Neurotrauma Consortium study

Traumatic brain injury (TBI) is a serious public health concern which strikes someone every 15 s on average in the US. Even mild TBI, which comprise as many as 75% of all TBI cases, carries long term consequences. The effects of age and sex on long term outcome from TBI is not fully understood, but due to the increased risk for neurodegenerative diseases after TBI it is important to understand how these factors influence the outcome from TBI. This study examined the neurobehavioral and neuropathological effects of age and sex on the outcome 15 days following repetitive mild traumatic brain injury (r-mTBI) in mice transgenic for human tau (hTau). These mice express the six human isoforms of tau but do not express endogenous murine tau and they develop tau pathology and memory impairment in an age-dependent manner. After 5 mild impacts, aged female mice showed motor impairments that were absent in aged male mice, as well as younger animals. Conversely, aged female sham mice outperformed all other groups of aged mice in a Barnes maze spatial memory test. Pathologically, increases in IBA-1 and GFAP staining typically seen in this model of r-mTBI showed the expected increases with both injury and age, but phosphorylated tau stained with CP13 in the hippocampus (reduced in female sham mice compared to males) and PHF1 in the cortex (reduced in female TBI mice compared to male TBI mice) showed the only histological signs of sex-dependent differences in these mice

Impact of age on acute post-TBI neuropathology in mice expressing humanized tau: a Chronic Effects of Neurotrauma Consortium Study

Objectives: We hypothesized that polypathology is more severe in older than younger mice during the acute phase following repetitive mild traumatic brain injury (r-mTBI). Methods: Young and aged male and female mice transgenic for human tau (hTau) were exposed to r-mTBI or a sham procedure. Twenty-four hours post-last injury, mouse brain tissue was immunostained for alterations in astrogliosis, microgliosis, tau pathology, and axonal injury. Results: Quantitative analysis revealed a greater percent distribution of glial fibrillary acid protein and Iba-1 reactivity in the brains of all mice exposed to r-mTBI compared to sham controls. However, no noticeable difference was observed between the young and aged groups as initially hypothesized. With respect to axonal injury, the number of amyloid precursor protein-positive profiles was increased in young vs aged mice post r-mTBI. An increase in tau immunoreactivity was found in young and aged injured male hTau mice. Conclusions: We report the first evidence in our model that r-mTBI precipitates a complex sequelae of events in aged vs young hTau mice at an acute time point, typified by an increase in phosphorylated tau and astroglisosis, and a diminished microgliosis response and axonal injury. These findings suggest differential age-dependent effects in TBI pathobiology

Mural cell dysfunction leads to altered cerebrovascular tau uptake following repetitive head trauma

A pathological characteristic of repetitive traumatic brain injury (TBI) is the deposition of hyperphosphorylated and aggregated tau species in the brain and increased levels of extracellular monomeric tau are believed to play a role in the pathogenesis of neurodegenerative tauopathies. The pathways by which extracellular tau is eliminated from the brain, however, remains elusive. The purpose of this study was to examine tau uptake by cerebrovascular cells and the effect of TBI on these processes. We found monomeric tau interacts with brain vascular mural cells (pericytes and smooth muscle cells) to a greater extent than other cerebrovascular cells, indicating mural cells may contribute to the elimination of extracellular tau, as previously described for other solutes such as beta-amyloid. Consistent with other neurodegenerative disorders, we observed a progressive decline in cerebrovascular mural cell markers up to 12 months post-injury in a mouse model of repetitive mild TBI (r-mTBI) and human TBI brain specimens, when compared to control. These changes appear to reflect mural cell degeneration and not cellular loss as no difference in the mural cell population was observed between r-mTBI and r-sham animals as determined through flow cytometry. Moreover, freshly isolated r-mTBI cerebrovessels showed reduced tau uptake at 6 and 12 months post-injury compared to r-sham animals, which may be the result of diminished cerebrovascular endocytosis, as caveolin-1 levels were significantly decreased in mouse r-mTBI and human TBI cerebrovessels compared to their respective controls. Further emphasizing the interaction between mural cells and tau, similar reductions in mural cell markers, tau uptake, and caveolin-1 were observed in cerebrovessels from transgenic mural cell-depleted animals. In conclusion, our studies indicate repeated injuries to the brain causes chronic mural cell degeneration, reducing the caveolar-mediated uptake of tau by these cells. Alterations in tau uptake by vascular mural cells may contribute to tau deposition in the brain following head trauma and could represent a novel therapeutic target for TBI or other neurodegenerative disorders. [Abstract copyright: Published by Elsevier Inc.

International, expert-based, consensus statement regarding the management of acute diverticulitis

IMPORTANCE This Delphi study provides consensus related to many aspects of acute diverticulitis and identifies other areas in need of research. OBJECTIVE To generate an international, expert-based, consensus statement to address controversies in the management of acute diverticulitis. DESIGN, SETTING, AND PARTICIPANTS This study was conducted using the Delphi technique from April 3 through October 21, 2014. A survey website was used and a panel of acute diverticulitis experts was formed via the snowball method. The top 5 acute diverticulitis experts in 5 international geographic regions were identified based on their number of publications related to acute diverticulitis. INTERVENTIONS The Delphi study used 3 rounds of questions, after which the consensus statement was collated. MAIN OUTCOMES AND MEASURES A consensus statement related to the management of acute diverticulitis. RESULTS Twenty items were selected for inclusion in the consensus statement following 3 rounds of questioning. A clear definition of uncomplicated and complicated diverticulitis is provided. In uncomplicated diverticulitis, consensus was reached regarding appropriate laboratory and radiological evaluation of patients as well as nonsurgical, surgical, and follow-up strategies. A number of important topics, including antibiotic treatment, failed to reach consensus. In addition, consensus was reached regarding many nonsurgical and surgical treatment strategies in complicated diverticulitis. CONCLUSIONS AND RELEVANCE Controversy continues internationally regarding the management of acute diverticulitis. This study demonstrates that there is more nonconsensus among experts than consensus regarding most issues, even in the same region. It also provides insight into the status quo regarding the treatment of acute diverticulitis and provides important direction for future research

International, expert-based, consensus statement regarding the management of acute diverticulitis

IMPORTANCE This Delphi study provides consensus related to many aspects of acute diverticulitis and identifies other areas in need of research. OBJECTIVE To generate an international, expert-based, consensus statement to address controversies in the management of acute diverticulitis. DESIGN, SETTING, AND PARTICIPANTS This study was conducted using the Delphi technique from April 3 through October 21, 2014. A survey website was used and a panel of acute diverticulitis experts was formed via the snowball method. The top 5 acute diverticulitis experts in 5 international geographic regions were identified based on their number of publications related to acute diverticulitis. INTERVENTIONS The Delphi study used 3 rounds of questions, after which the consensus statement was collated. MAIN OUTCOMES AND MEASURES A consensus statement related to the management of acute diverticulitis. RESULTS Twenty items were selected for inclusion in the consensus statement following 3 rounds of questioning. A clear definition of uncomplicated and complicated diverticulitis is provided. In uncomplicated diverticulitis, consensus was reached regarding appropriate laboratory and radiological evaluation of patients as well as nonsurgical, surgical, and follow-up strategies. A number of important topics, including antibiotic treatment, failed to reach consensus. In addition, consensus was reached regarding many nonsurgical and surgical treatment strategies in complicated diverticulitis. CONCLUSIONS AND RELEVANCE Controversy continues internationally regarding the management of acute diverticulitis. This study demonstrates that there is more nonconsensus among experts than consensus regarding most issues, even in the same region. It also provides insight into the status quo regarding the treatment of acute diverticulitis and provides important direction for future research

Impairment of cerebrovascular reactivity in response to hypercapnic challenge in a mouse model of repetitive mild traumatic brain injury

Incidences of repetitive mild TBI (r-mTBI), like those sustained by contact sports athletes and military personnel, are thought to be a risk factor for development of neurodegenerative disorders. Those suffering from chronic TBI-related illness demonstrate deficits in cerebrovascular reactivity (CVR), the ability of the cerebral vasculature to respond to a vasoactive stimulus. CVR is thus an important measure of traumatic cerebral vascular injury (TCVI), and a possible in vivo endophenotype of TBI-related neuropathogenesis. We combined laser speckle imaging of CVR in response to hypercapnic challenge with neurobehavioral assessment of learning and memory, to investigate if decreased cerebrovascular responsiveness underlies impaired cognitive function in our mouse model of chronic r-mTBI. We demonstrate a profile of blunted hypercapnia-evoked CVR in the cortices of r-mTBI mice like that of human TBI, alongside sustained memory and learning impairment, without biochemical or immunohistopathological signs of cerebral vessel laminar or endothelium constituent loss. Transient decreased expression of alpha smooth muscle actin and platelet-derived growth factor receptor β, indicative of TCVI, is obvious only at the time of the most pronounced CVR deficit. These findings implicate CVR as a valid preclinical measure of TCVI, perhaps useful for developing therapies targeting TCVI after recurrent mild head trauma