Supported Projects

2024 Tissue cAccess Projects

NOX2/NLRP3/IL-1b inflammatory axis: a novel target for microglial dysfunction and neurodegeneration in chronic TBI

Trinity College Dublin/The Roskamp Institute

Investigators: David Loane/Joseph Ojo

Abstract: TBI is the leading cause of death and morbidity in the under-45 age group, and strong risk-factor for neurodegenerative disease. There are no disease modifying therapies for TBI of any severity. This is because the chronic biological consequences to TBI, which constitute the brain’s secondary response to injury are still mostly unknown. These complex molecular mechanisms may persist for months and even years after the event, and naturally are significant contributors to the patient’s overall outcome.

To address this problem, we developed and characterized mouse models of TBI which recapitulate many features of human TBI pathology, and the heterogeneity of TBI in humans. In our models, we reveal a vital role of an inflammatory cell type ‘microglia’ which remain chronically activated in the brain many months after injury and promote inflammation and cognitive deficits. Importantly, we have confirmed a critical molecule and novel target (NOX2) that appears to regulate the maladaptive transformation of these cells in the chronic stages of TBI from a neurorestorative to a dysfunctional pathogenic phenotype. In this study, we plan to confirm this molecular signature in autopsy TBI brain tissue to demonstrate translational relevance prior to validation of our target using genetic and pharmacological tools.

Multimodal Investigation of the Vascular Consequences of TBI

Icahn School of Medicine at Mount Sinai

Investigator: Enna Selmanovic

Abstract: Traumatic cerebral vascular injury (TCVI) and its subsequent pathophysiology remains an understudied although universal consequence following various etiologies of traumatic brain injury (TBI). This project seeks to investigate the chronic physiologic and molecular components of TCVI with the overall goal of addressing the relationship between vascular health and post-traumatic neurodegeneration. This study will provide a multi-modal in vivo and ex vivo evaluation of both chronic vascular and neurodegenerative effects as well as varying outcomes following singular TBI or repetitive head trauma, in a well-characterized post-mortem cohort.

Cerebral amyloid angiopathy following traumatic brain injury

University of Glasgow

Investigator: Shannon Gilchrist

Abstract: Traumatic brain injury (TBI) is the leading cause of death worldwide. Following TBI, there are many after-effects that may lead to long-term health complications. These after-effects include build-up of materials within the brain that have been linked to dementias, including Chronic Traumatic Encephalopathy (CTE), also known as “punch drunk” syndrome. Understanding how changes can result in dementia is essential for improved patient recovery and treatment. This project investigates how one protein, called β-amyloid, can build up in blood vessels in the brain during life. We aim to understand how this process is altered following either a single severe TBI or multiple mild TBIs, such as what would be experienced by contact sports players. Work that has been conducted so far, suggests that both groups of individuals (single TBI and sports players) have an accelerated build-up of β-amyloid in blood vessels. However, we must confirm whether the effects observed in our group of former sports players is unique compared to what is seen in dementias without TBI. Therefore, we need to study various brain regions from people who have died with Alzheimer’s disease, to compare the build-up of β-amyloid in these individuals with the groups that have previously been investigated.

Axonal sodium channel changes after blast-related traumatic brain injury

University of Pennsylvania

Investigator: Hailong Song

Abstract: Blast injuries to the brain can cause lasting problems, with symptoms that are often complicated. There's growing evidence that damage to the thin fibers, called axons, which connect brain cells, might be a major cause of these symptoms. Axons rely on sodium channels to keep their "electrical" activity normal, but we don't yet know if or how these sodium channels are affected by blast exposure.

In this study, we'll examine changes in the sodium channels of axons in people who have been exposed to blasts. We'll then compare these findings to those from people with no history of blast exposure. By understanding how sodium channels in axons change after a blast-related brain injury, we hope to gain insight into a possible new type of axon damage in this complex condition.

The effect of TBI on synaptic function

University of Pennsylvania

Investigator: Hailong Song

Disruption of the blood-brain barrier following traumatic brain injury (DISRUPT-TBI)

University of Glasgow

Investigator: Shannon Gilchrist

Abstract: Traumatic brain injury (TBI) is the leading cause of death worldwide. After a TBI, there are many lasting effects that can lead to serious health issues, including brain disorders like dementia. It is important to understand how changes in the brain after an injury can lead to long-term problems, allowing us to improve patient diagnosis and treatment.

The brain is protected by a barrier, called the blood-brain barrier, which controls what can move between the brain and the rest of the body. After a TBI, this barrier often gets damaged, similar to what happens in dementia. This project looks at how the cells in this barrier change after a TBI and how these changes are connected to inflammation and brain tissue damage. Our goal is to understand these changes from the moment of injury through the years that follow. By studying the damage to both the brain tissue and the barrier, we hope to identify what increases the risk of developing long-term brain conditions like dementia after a TBI.

2023 Tissue Access Projects

Using AAV-expressed biologics to target inflammation and treat TBI

University of Cambridge

Investigators: Adrian Liston/Oliver Burton

Abstract: Traumatic brain injury is one of the leading neurological causes of disability in the world, with many patients developing long-lasting cognitive and mental deficits. The involvement of the immune system in the pathology of traumatic brain injury has clearly been established. Traumatic brain injury can be divided into two distinct stages: the initial trauma itself (e.g. blunt force trauma, blast injuries) and a secondary inflammation that develops afterwards. The initial trauma causes cell death in the brain at the impact site, releasing signals that drive an inflammatory response. This inflammation is similar to the bruising that occurs when an ankle or knee is twisted, with the difference being the swelling of the brain within the skull is much more toxic to the tissue, due to the pressure created. This inflammation following a traumatic brain injury causes a secondary wave of damage generation to the brain tissue, which can kill as many brain cells as the primary injury itself. This secondary wave can continue for months or even years, increasing the duration and severity of the brain damage. This proposal seeks to prevent and repair the inflammation-mediated damage caused during this second wave of traumatic brain injury.

Validating Novel Preclincial models of TBI Related Neurodegeneration

University of Pennsylvania

Investigator: Victoria Johnson

Abstract: Traumatic brain injury (TBI) is a substantial health problem that has been linked with the later onset of dementia-related pathologies in the brains of some individuals. However, the changes in the brain that occur in the months and years after injury that drive these pathologies are unknown. One way to better understand how and why some people develop these pathologies is by developing animal models of TBI and examining them over time. During the process of developing these models, it is essential that we directly compare the pathologies observed in the models with that observed following TBI in humans. This allows us to ensure that that the model is accurate and relevant. As such we request access to post-mortem human tissue samples from the CONNECT TBI archive to be examined for pathologies and allowing us to directly compare with TBI models in development. Generating these models will be critical for advancing our understanding of how TBI might contribute to the development of dementia and potentially help develop new therapies to prevent it.

Molecular predictors of susceptibility and resilience in brain injury

University of Michigan

Investigators: Steve Broglio/Sami Barmada

Abstract: Brain injury (BI) affects nearly 1.5 million Americans each year. Only a small fraction of these events (~50,000) result in death, but long-term disability is twice as common, affecting almost 100,000 people with each passing year. Even mild BI has pronounced effects that are only just beginning to become apparent. Despite how common BI is, and its extraordinary short- and long-term consequences, we understand little of what makes the cells of the brain susceptible to injury. Conversely, how some cells remain resilient to injury remains mysterious. In an effort to uncover the molecular signatures of vulnerability as well as resistance to BI, we propose to examine hundreds of different RNA transcripts simultaneously in brains from individuals with mild BI and cognitive symptoms related to BI. These initial studies are intended to highlight biomarkers that may be useful not just for tracking the health of brain cells upon injury, but also those that illustrate mechanisms responsible for susceptibility or resilience in the face of trauma.

Oligodendrocyte and cerebrovascular pathology in TBI and sport concussion: Impact of the neuroinflammatory response

Lund University

Investigator: Niklas Marklund

Abstract: Traumatic brain injury (TBI) is an established risk factor for Alzheimer's disease (AD). TBI may accelerate AD onset, and the risk increase is not only observed in severe TBI but also in milder forms of TBI such as those that may occur in sports (sports concussion). Although the mechanisms linking TBI to dementias have not been established, injury to the small vessels of the brain, a persistent inflammation and injury to the white matter of the brain may all contribute. Injury to the white matter is an important cause of poor recovery and persistent symptoms including impaired memory, fatigue, personality disorders and a poor quality of life. The ongoing worsening of the white matter injury after TBI may be linked to pathology of the cells producing myelin, the insulation responsible for improving communication between brain cells. If they die after the injury, the long processes of the brain cells (axons) will also be injured and this leads to accumulation of factors causing dementias. In this project, we study oligodendrocytes and inflammation with a focus on the link to dementia proteins. If we had more information of these injury processes, improved treatments could be developed.

2022 Tissue Access Projects

Axonal sodium channel changes after traumatic brain injury

University of Pennsylvania

Investigator: Hailong Song

Traumatic brain injury (TBI) is a major health concern and leads to persisting and often complex symptoms. Emerging evidence suggests that damage to the fine fibers forming connections between brain cells, known as axons, might be a key contributor to clinical symptoms of TBI. Sodium channels are known to be an essential component of axons for maintaining their normal activity. However, it remains unknown if and how sodium channels might be involved in TBI.

In this study, we will examine changes in the sodium channels of axons in patients with a history of TBI. We will then compare these to control patients with no history of TBI. Understanding how axonal sodium channels change with TBI would provide a newfound form of axon damage after injury and might help our understanding of the pathology of this complex disease.

Sodium channel changes after concussion and TBI

University of Pennsylvania

PI: Hailong Song, PhD

Abstract: Although TBI is a major health concern, little is known about pathophysiological changes that cause post-traumatic cognitive dysfunction. Nonetheless, emerging evidence suggests that selective damage to white matter axons, or diffuse axonal injury (DAI), disrupts brain network connectivity and function. While voltage-gated sodium channels (NaChs) and their anchoring proteins at the nodes of Ranvier (NOR) on axons are key elements of the brain’s network signaling machinery, changes in their integrity have not been studied in context with DAI.

To address this, we propose to examine the changes in NaChs, Nav1.6 in particular, and associated NOR morphologies in material from patients with known history of single moderate or severe TBI. We will then compare our findings to material from age matched, non-injured controls with no known history of neurological disease. We will further employ immunofluorescent staining approach to examine the relevance of NaCh changes to DAI.

Outcome: Dr. Song successfully used this human tissue request from the CONNECT-TBI network to confirm sodium channel and Node of Ranvier changes found in an experimental concussion model of TBI.

Effects of SARS-CoV-2 on human brain

University of Pennsylvania

PI: Hailong Song, PhD

Abstract: Increasing evidence supports that the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with neurological manifestations, such as impaired consciousness, headache, and neuropsychiatric disorder. A few neuropathological examinations have observed a spectrum of neuroinflammatory and hypoxic damage in post-mortem brains of COVID-19 patients. However, less is known about whether SARS-CoV-2 infection is associated with blood-brain barrier (BBB) disruption.

To address this, we will first determine the presence of SARS-CoV-2 in patients with COVID-19 using RNA fluorescence in-situ hybridization. In parallel, we will use immunohistochemical staining of fibrinogen to examine any BBB disruption. This will be done in conjunction with control patients without a history of COVID-19 and no degenerative brain diseases. This study, upon completion, will help to understand if SARS-CoV-2 infection leads to BBB disruption.

Investigating the role of neuronal pentraxins in TBI-related neurodegeneration

University of Glasgow

Investigator: Samuel Jones

Head injury in athletes often leads to toxic protein build up in the brain. This usually gets worse later in life. Similarly, Alzheimer Disease (AD) and Parkinson's Disease (PD) involve protein accumulation in the brain. A newly discovered protein that builds up in AD and PD is NPTX2. This protein is usually involved in making memories, but in AD and PD, it accumulates with other toxic proteins and cannot carry out its normal job. This study looks to see if athletes that died with head injuries accumulate NPTX2 like in other brain diseases.

2021 Tissue Access Projects

Pilot study of the role of spleen tyrosine kinase in pathobiology of repetitive mild TBI

Roskamp Institute

Investigators: Fiona Crawford and Benoit Mouzon

We have identified a novel molecular target (Spleen Tyrosine Kinase, Syk) for Alzheimer’s disease, inhibition of which, by the compound Nilvadipine, results in mitigation of amyloid, tau and neuroinflammatory pathology in mouse models of Alzheimer’s disease. Nilvadipine was demonstrated to reduce Alzheimer’s cognitive decline in early-stage Alzheimer’s patients in a Phase III trial. We have tested Nilvadipine in our mouse models of repetitive mild TBI and shown reduction in neuroinflammation and tau pathology, as well as improvement in cognitive outcomes. We therefore wish to determine the relevance of our findings to the human TBI patient population by determining if Syk or related Syk signalling molecules can be detected in the brains of TBI patients versus controls.

TDP-43 proteinopathy in traumatic brain injury related neurodegeneration (TReND)

University of Pennsylvania

Investigator: Hailong Song

Traumatic brain injury (TBI) is a risk factor for dementia and related degenerative brain diseases. Pathology studies of the brains of people with a history of TBI show a range of abnormalities. Among these, abnormal deposition of a protein known as TDP-43 has been described. However, this abnormal TDP-43 protein can also be found in many other degenerative brain diseases. To date it remains uncertain whether the TDP-43 abnormalities in patients with TBI are unique or are simply a reflection of other, coincident pathologies.

In this study, we will investigate the pattern and distribution of TDP-43 protein deposition in patients with a history of TBI. We will then compare our findings in patients with TBI to the deposition of TDP-43 in normal aging and other degenerative brain diseases. This will give us a picture of the effect of TBI on TDP-43 deposition which might help our understanding of the link between brain injury and dementia.

Single Nucleus Transcriptomics in Chronic TBI

University of Pennsylvania

Investigator: Victoria Johnson

Moderate or severe traumatic brain inJury (TBI) is a substantial health problem that in addition to oftendevastating acute effects, can trigger complex chronic pathologies. In a subset of individuals, progressive loss of both the grey and white matter in the brain has been observed following moderate or severe TBI, in some cases persisting many months and years after injury. However, the processes occurring that drive this chronic degeneration are unknown. By examining post-mortem brain tissue from individuals both with and without progressive degeneration after TBI, we aim to perform a detailed examination of the function of cells in the brain. We will achieve this using single cell RNA sequencing - a technique that permits us to identify the genes that each individual cell is expressing. This will allow us to identify the specific ways in which cells in the brain degenerate over time. Understanding these processes may help elucidate potential pathways that can be targeted to prevent progressive degeneration following TBI.

Defining Hypo N-Glycosylation following TBI

University of Kentucky

Investigator: Douglas A. Andres

N-linked protein glycosylation is a complex process that decorates a large number of proteins that are: (1) found at the cell surface, (2) are secreted, or (3) circulate within the human body. Synthesis of N-linked glycans involves over 700 different enzymes acting in a highly regulated fashion to determine the unique glycan profile of each cell. N-glycosylated proteins modulate a myriad of molecular processes in the brain from electrical gradients to glial activation and neurotransmission. Aberrant N-linked glycosylation is a direct activator of the integrated stress response pathway and can drive neurological disorders. For example, glycoprotein aggregates play key roles in Alzheimer’s and Parkinson’s disease. In a mouse model of cortical contusion injury (CCI) we performed a spatial analysis of global changes in N-linked glycans using cutting edge technology (matrix-assisted laser desorption/ionization mass spectroscopy imaging MALDI-MSI). These data demonstrate that CCI results in a region-specific and chronic (>1 month) reductions in N-glycosylation within the injured mouse brain. These data suggest that N-linked glycosylation dysregulation could be one of the underpinnings of TBI pathophysiology. We wish to determine whether similar N-glycosylation alterations occur within the injured human brain following traumatic brain injury.

2020 Tissue Access Projects

Effects of SARS-CoV-2 on human brain

University of Pennsylvania

Investigator: Hailong Song

Emerging data support that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or COVID-19 infection leads to abnormal brain functions, such as impaired consciousness, headache, and changes in behavior and emotion. A few brain examinations have seen some evidence of inflammation and ischemic damage to brain cells. However, less is known if COVID-19 further cause brain vessel leakage.

Here, we will first examine if COVID-19 virus enters and presents in brain of patients. We will further test if brain vessels are changed because of COVID-19 infection. Together, this study will provide information whether COVID-19 leads to brain vessel leakage and be useful to guide future research to understand its effect on brain.