Victoria E. Johnson

Axonal Pathology in Traumatic Brain Injury

Over the past 70years, diffuse axonal injury (DAI) has emerged as one of the most common and important pathological features of traumatic brain injury (TBI). Axons in the white matter appear to be especially vulnerable to injury due to the mechanical loading of the brain during TBI. As such, DAI has been found in all severities of TBI and may represent a key pathologic substrate of mild TBI (concussion). Pathologically, DAI encompasses a spectrum of abnormalities from primary mechanical breaking of the axonal cytoskeleton, to transport interruption, swelling and proteolysis, through secondary physiological changes. Depending on the severity and extent of injury, these changes can manifest acutely as immediate loss of consciousness or confusion and persist as coma and/or cognitive dysfunction. In addition, recent evidence suggests that TBI may induce long-term neurodegenerative processes, such as insidiously progressive axonal pathology. Indeed, axonal degeneration has been found to continue even years after injury in humans, and appears to play a role in the development of Alzheimers disease-like pathological changes. Here we review the current understanding of DAI as a uniquely mechanical injury, its histopathological identification, and its acute and chronic pathogenesis following TBI.

Inflammation and white matter degeneration persist for years after a single traumatic brain injury

A single traumatic brain injury is associated with an increased risk of dementia and, in a proportion of patients surviving a year or more from injury, the development of hallmark Alzheimers disease-like pathologies. However, the pathological processes linking traumatic brain injury and neurodegenerative disease remain poorly understood. Growing evidence supports a role for neuroinflammation in the development of Alzheimers disease. In contrast, little is known about the neuroinflammatory response to brain injury and, in particular, its temporal dynamics and any potential role in neurodegeneration. Cases of traumatic brain injury with survivals ranging from 10 h to 47 years post injury (n = 52) and age-matched, uninjured control subjects (n = 44) were selected from the Glasgow Traumatic Brain Injury archive. From these, sections of the corpus callosum and adjacent parasaggital cortex were examined for microglial density and morphology, and for indices of white matter pathology and integrity. With survival of ≥3 months from injury, cases with traumatic brain injury frequently displayed extensive, densely packed, reactive microglia (CR3/43- and/or CD68-immunoreactive), a pathology not seen in control subjects or acutely injured cases. Of particular note, these reactive microglia were present in 28% of cases with survival of >1 year and up to 18 years post-trauma. In cases displaying this inflammatory pathology, evidence of ongoing white matter degradation could also be observed. Moreover, there was a 25% reduction in the corpus callosum thickness with survival >1 year post-injury. These data present striking evidence of persistent inflammation and ongoing white matter degeneration for many years after just a single traumatic brain injury in humans. Future studies to determine whether inflammation occurs in response to or, conversely, promotes white matter degeneration will be important. These findings may provide parallels for studying neurodegenerative disease, with traumatic brain injury patients serving as a model for longitudinal investigations, in particular with a view to identifying potential therapeutic interventions.

Widespread Tau and Amyloid-Beta Pathology Many Years After a Single Traumatic Brain Injury in Humans

While a history of a single traumatic brain injury (TBI) is associated with the later development of syndromes of cognitive impairment such as Alzheimers disease, the long‐term pathology evolving after single TBI is poorly understood. However, a progressive tauopathy, chronic traumatic encephalopathy, is described in selected cohorts with a history of repetitive concussive/mild head injury. Here, post‐mortem brains from long‐term survivors of just a single TBI (1–47 years survival; n = 39) vs. uninjured, age‐matched controls (n = 47) were examined for neurofibrillary tangles (NFTs) and amyloid‐β (Aβ) plaques using immunohistochemistry and thioflavine‐S staining. Detailed maps of findings permitted classification of pathology using semiquantitative scoring systems. NFTs were exceptionally rare in young, uninjured controls, yet were abundant and widely distributed in approximately one‐third of TBI cases. In addition, Aβ‐plaques were found in a greater density following TBI vs. controls. Moreover, thioflavine‐S staining revealed that while all plaque‐positive control cases displayed predominantly diffuse plaques, 64% of plaque‐positive TBI cases displayed predominantly thioflavine‐S‐positive plaques or a mixed thioflavine‐S‐positive/diffuse pattern. These data demonstrate that widespread NFT and Aβ plaque pathologies are present in up to a third of patients following survival of a year or more from a single TBI. This suggests that a single TBI induces long‐term neuropathological changes akin to those found in neurodegenerative disease.

Traumatic brain injury and amyloid-β pathology: a link to Alzheimer's disease?

Traumatic brain injury (TBI) has devastating acute effects and in many cases seems to initiate long-term neurodegeneration. Indeed, an epidemiological association between TBI and the development of Alzheimers disease (AD) later in life has been demonstrated, and it has been shown that amyloid-β (Aβ) plaques — one of the hallmarks of AD — may be found in patients within hours following TBI. Here, we explore the mechanistic underpinnings of the link between TBI and AD, focusing on the hypothesis that rapid Aβ plaque formation may result from the accumulation of amyloid precursor protein in damaged axons and a disturbed balance between Aβ genesis and catabolism following TBI.

Multiple proteins implicated in neurodegenerative diseases accumulate in axons after brain trauma in humans

Studies in animal models have shown that traumatic brain injury (TBI) induces the rapid accumulation of many of the same key proteins that form pathologic aggregates in neurodegenerative diseases. Here, we examined whether this rapid process also occurs in humans after TBI. Brain tissue from 18 cases who died after TBI and from 6 control cases was examined using immunohistochemistry. Following TBI, widespread axonal injury was persistently identified by the accumulation of neurofilament protein and amyloid precursor protein (APP) in axonal bulbs and varicosities. Axonal APP was found to co-accumulate with its cleavage enzymes, beta-site APP cleaving enzyme (BACE), presenilin-1 (PS1) and their product, amyloid-beta (Abeta). In addition, extensive accumulation of alpha-synuclein (alpha-syn) was found in swollen axons and tau protein was found to accumulate in both axons and neuronal cell bodies. These data show rapid axonal accumulation of proteins implicated in neurodegenerative diseases including Alzheimers disease and the synucleinopathies. The cause of axonal pathology can be attributed to disruption of axons due to trauma, or as a secondary effect of raised intracranial pressure or hypoxia. Such axonal pathology in humans may provide a unique environment whereby co-accumulation of APP, BACE, and PS1 leads to intra-axonal production of Abeta as well as accumulation of alpha-syn and tau. This process may have important implications for survivors of TBI who have been shown to be at greater risk of developing neurodegenerative diseases.

A Lack of Amyloid β Plaques Despite Persistent Accumulation of Amyloid β in Axons of Long-Term Survivors of Traumatic Brain Injury

Traumatic brain injury (TBI) is a risk factor for developing Alzheimers disease (AD). Additionally, TBI induces AD‐like amyloid β (Aβ) plaque pathology within days of injury potentially resulting from massive accumulation of amyloid precursor protein (APP) in damaged axons. Here, progression of Aβ accumulation was examined using brain tissue from 23 cases with post‐TBI survival of up to 3 years. Even years after injury, widespread axonal pathology was consistently observed and was accompanied by intra‐axonal co‐accumulations of APP with its cleavage enzymes, beta‐site APP cleaving enzyme and presenilin‐1 and their product, Aβ. However, in marked contrast to the plaque pathology noted in short‐term cases post TBI, virtually no Aβ plaques were found in long‐term survivors. A potential mechanism for Aβ plaque regression was suggested by the post‐injury accumulation of an Aβ degrading enzyme, neprilysin. These findings fail to support the premise that progressive plaque pathology after TBI ultimately results in AD.

Blood-Brain Barrier Disruption Is an Early Event That May Persist for Many Years After Traumatic Brain Injury in Humans.

Abstract Traumatic brain injury (TBI) is a risk factor for dementia. Mixed neurodegenerative pathologies have been described in late survivors of TBI, but the mechanisms driving post-TBI neurodegeneration remain elusive. Increasingly, blood-brain barrier (BBB) disruption has been recognized in a range of neurologic disorders including dementias, but little is known of the consequences of TBI on the BBB. Autopsy cases of single moderate or severe TBI from the Glasgow TBI Archive (n = 70) were selected to include a range from acute (10 hours–13 days) to long-term (1–47 years) survival, together with age-matched uninjured controls (n = 21). Multiple brain regions were examined using immunohistochemistry for the BBB integrity markers fibrinogen and immunoglobulin G. After TBI, 40% of patients dying in the acute phase and 47% of those surviving a year or more from injury showed multifocal, abnormal, perivascular, and parenchymal fibrinogen and immunoglobulin G immunostaining localized to the gray matter, with preferential distribution toward the crests of gyri and deep neocortical layers. In contrast, when present, controls showed only limited localized immunostaining. These preliminary data demonstrate evidence of widespread BBB disruption in a proportion of TBI patients emerging in the acute phase and, intriguingly, persisting in a high proportion of late survivors.

Animal models of traumatic brain injury.

Traumatic brain injury (TBI) is a major health issue comprising a heterogeneous and complex array of pathologies. Over the last several decades, numerous animal models have been developed to address the diverse nature of human TBI. The clinical relevance of these models has been a major point of reflection given the poor translation of pharmacologic TBI interventions to the clinic. While previously characterized broadly as either focal or diffuse, this classification is falling out of favor with increased awareness of the overlap in pathologic outcomes between models and an emerging consensus that no one model is sufficient. Moreover, an appreciation of injury biomechanics is essential in recapitulating and interpreting the spectrum of TBI neuropathology observed in various established models of dynamic closed-head TBI. While these models have replicated many specific features of human TBI, an enhanced context with clinical relevancy will facilitate the further elucidation of the mechanisms and treatment of injury.

Chronic Traumatic Encephalopathy: The Neuropathological Legacy of Traumatic Brain Injury

Almost a century ago, the first clinical account of the punch-drunk syndrome emerged, describing chronic neurological and neuropsychiatric sequelae occurring in former boxers. Thereafter, throughout the twentieth century, further reports added to our understanding of the neuropathological consequences of a career in boxing, leading to descriptions of a distinct neurodegenerative pathology, termed dementia pugilistica. During the past decade, growing recognition of this pathology in autopsy studies of nonboxers who were exposed to repetitive, mild traumatic brain injury, or to a single, moderate or severe traumatic brain injury, has led to an awareness that it is exposure to traumatic brain injury that carries with it a risk of this neurodegenerative disease, not the sport or the circumstance in which the injury is sustained. Furthermore, the neuropathology of the neurodegeneration that occurs after traumatic brain injury, now termed chronic traumatic encephalopathy, is acknowledged as being a complex, mixed, but distinctive pathology, the detail of which is reviewed in this article.

The effects of managed care on physician and clinical integration in hospitals.

OBJECTIVE To empirically estimate the effects that managed care has had on physician and clinical integration in urban hospitals. DATA SOURCES The 1993 Hospital-Physician Relationship Survey conducted for the Prospective Payment Assessment Commission, augmented with data from a variety of secondary sources. The entire 1,495 responding hospitals were used to construct measures of integration; 591 responding hospitals in urban areas were used for the managed care analysis. STUDY DESIGN Factor analysis was used to reduce 23 integration variables into 5 physician and 3 clinical integration factors. Two-stage least-squares regression techniques were used to estimate the effects of endogenous managed care. Models were estimated for all urban hospitals and for hospital subsets based upon ownership, multi-hospital system status, and teaching. PRINCIPAL FINDINGS Other things equal, physician involvement in hospital management and governance increased with managed care involvement; to a lesser degree, the use of physician organization arrangements and other joint ventures also increased. Practice management and support services were lower in hospitals with high managed care activity. Larger hospitals, investor owned, system, and non-teaching hospitals had larger managed care revenues. Managed care revenues were lower in more concentrated hospital markets. CONCLUSIONS The relationship between managed care and physician and clinical integration is relatively modest. Much of the realignment under managed care has been limited to certain types of efforts. Those efforts can best be described as foundation-building rather than comprehensive or fundamental.