Neurotrauma: 2021 update

Despite the interruptions and restrictions to the progress of science that the COVID-19 pandemic has introduced, 2020 was marked by a number of important advances in the field of neurotrauma. Here, I will highlight what I believe are among the most important contributions. This year there were notable advances towards providing clinically useful information on neurotrauma outcome through the use of fluid biomarkers. I also introduce fascinating approaches to studying the role of microglia in nervous system repair and neuroinflammatory mechanisms leading to dysfunction through the use of colony-stimulating factor 1 receptor inhibitors, especially Plexxikon 5622 (PLX5622). Oral administration of this compound is able to deplete microglial elements and then, following withdrawal from the drug, a new population of microglia then repopulates the brain. Use of this approach in traumatic brain injury experimental models has produced important insights into the pathogenetic role of microglia in responding to this process. Important new data on the nature and distribution of tau involvement of neurons and astrocytes in cases of chronic traumatic encephalopathy (CTE) also appeared suggesting differences and similarities to Alzheimer’s disease. Additionally, the use of tau-specific PET scan ligands in at-risk populations has suggested that this approach may be able to identify cases with CTE. Lastly, we note the death in the past year of a major contributor to the field of neurotrauma neuropathology, Professor J. Hume Adams

Top ten discoveries of the year: Neurotrauma

Neurotrauma represents a major public health problem and is one of the leading causes of death and disability worldwide. Despite its high prevalence, there are major gaps in our understanding of the underlying patho-physiology leading to the substantial morbidity and mortality associated with this problem. Here, ten studies published in 2019 are reviewed that addressed issues related to the acute and long-term effects of neurotrau-ma. These studies can be broken down into three separate categories, namely, the importance of neurotrau-ma-based damage to the cerebrovascular unit, white matter damage following neurotrauma, and research related to the long-term neurodegenerative consequences of repeated head trauma, especially chronic trau-matic encephalopathy. The advances highlighted here indicate that progress has been made. However, major gaps in knowledge remain which will require additional neuropathologic studies of clinical specimens, as well as the development and investigation of a wide range of relevant pre-clinical models. Further efforts in this field are clearly needed if there are to emerge better clinical outcomes for the numerous patients that suffer neuro-trauma each year as well as those currently suffering from its long-term effects

Neurotrauma: 2022 update

The year 2021 was highlighted by many notable advancements in the field of neurotrauma and associated neuropathology. After a thorough review of the new literature, we call attention to what we feel are among the most impactful studies and publications. In brief, 2021 was marked by published consensus papers related to the diagnosis of chronic traumatic encephalopathy (CTE) and its clinical counterpart, traumatic encephalopathy syndrome. There was also progress toward our understanding of the impact of traumatic brain injury (TBI) on the general population, and how strongly CTE pathology may, or may not, commonly underlie long term clinical sequelae following TBI. Next, a critical new study has identified that acetylated tau protein, which has been found to be increased in the brains of Alzheimer’s disease and CTE patients, can be induced by TBI, is neurotoxic, and that its reduction via already-existent therapeutics is neuroprotective. There are also several important updates that pertain to military and blast TBI, particularly as they pertain to establishing causality of interface astroglial scarring. In addition, and for the first time, a specific signature for diffuse axonal injury has been identified in ex vivo tissues using multidimensional magnetic resonance imaging, providing promise for the clinical diagnosis of this lesion. Finally, several important radiologic studies from 2021 have highlighted long-standing structural reductions in a number of brain regions following both mild and severe TBI, emphasizing the need for neuropathologic correlation. We end by highlighting an editorial piece discussing how TBI is portrayed in entertainment media and how this impacts public perception of TBI and its consequences

Neurotrauma: 2023 Update

2022 was a productive year for research in traumatic brain injury (TBI) and resultant neuropathology. After an extensive review, we present related studies and publications which we felt were of particular importance to the neuropathology community. First, 2022 was highlighted by important advancements in the diagnosis and, moreover, our understanding of chronic traumatic encephalopathy (CTE). Important publications include a pair concluding that CTE primarily concerns neuronal accumulation of phosphorylated tau (ptau), but that glial ptau accumulation often helps to facilitate diagnosis. In addition, a new large community study from Australia continues the indication that CTE is relatively uncommon in the community, and the first large-cohort study on brains of military personnel similarly demonstrates that CTE appears to be uncommon among service members and does not appear to explain high rates of neuropsychiatric sequelae suffered by the warfighter. The causation of CTE by impact-type TBI was supported by the application of the Bradford Hill criteria, within the brains of headbutting bovids, and interestingly within an artificial head model exposed to linear impact. Finally, a large-scale analysis of APOE genotypes contends that gene status may influence CTE pathology and outcomes. In experimental animal work, a study using mouse models provided important evidence that TDP-43 facilitates neurodegenerative pathology and is implicated in cognitive dysfunction following TBI, and another study using a swine model for concussion demonstrated that evidence that axonal sodium channel disruption may be a driver of neurologic dysfunction after concussion. Finally, we end with memoriam to Dr. John Q. Trojanowski, a giant of neurodegenerative research and an important contributor to the neurotrauma literature, who we lost in 2022

A novel approach to non-biased systematic random sampling : a stereologic estimate of Purkinje cells in the human cerebellum

Non-biased systematic sampling using the principles of stereology provides accurate quantitative estimates of objects within neuroanatomic structures. However, the basic principles of stereology are not optimally suited for counting objects that selectively exist within a limited but complex and convoluted portion of the sample, such as occurs when counting cerebellar Purkinje cells. In an effort to quantify Purkinje cells in association with certain neurodegenerative disorders, we developed a new method for stereologic sampling of the cerebellar cortex, involving calculating the volume of the cerebellar tissues, identifying and isolating the Purkinje cell layer and using this information to extrapolate non-biased systematic sampling data to estimate the total number of Purkinje cells in the tissues. Using this approach, we counted Purkinje cells in the right cerebella of four human male control specimens, aged 41, 67, 70 and 84 years, and estimated the total Purkinje cell number for the four entire cerebella to be 27.03, 19.74, 20.44 and 22.03 million cells, respectively. The precision of the method is seen when comparing the density of the cells within the tissue: 266,274, 173,166, 167,603 and 183,575 cells/cm3, respectively. Prior literature documents Purkinje cell counts ranging from 14.8 to 30.5 million cells. These data demonstrate the accuracy of our approach. Our novel approach, which offers an improvement over previous methodologies, is of value for quantitative work of this nature. This approach could be applied to morphometric studies of other similarly complex tissues as well

Diagnosis of Neoplasia in Barrett’s Esophagus using Vital-dye Enhanced Fluorescence Imaging

The ability to differentiate benign metaplasia in Barrett’s Esophagus (BE) from neoplasia in vivo remains difficult as both tissue types can be flat and indistinguishable with white light imaging alone. As a result, a modality that highlights glandular architecture would be useful to discriminate neoplasia from benign epithelium in the distal esophagus. VFI is a novel technique that uses an exogenous topical fluorescent contrast agent to delineate high grade dysplasia and cancer from benign epithelium. Specifically, the fluorescent images provide spatial resolution of 50 to 100 μm and a field of view up to 2.5 cm, allowing endoscopists to visualize glandular morphology. Upon excitation, classic Barrett’s metaplasia appears as continuous, evenly-spaced glands and an overall homogenous morphology; in contrast, neoplastic tissue appears crowded with complete obliteration of the glandular framework. Here we provide an overview of the instrumentation and enumerate the protocol of this new technique. While VFI affords a gastroenterologist with the glandular architecture of suspicious tissue, cellular dysplasia cannot be resolved with this modality. As such, one cannot morphologically distinguish Barrett’s metaplasia from BE with Low-Grade Dysplasia via this imaging modality. By trading off a decrease in resolution with a greater field of view, this imaging system can be used at the very least as a red-flag imaging device to target and biopsy suspicious lesions; yet, if the accuracy measures are promising, VFI may become the standard imaging technique for the diagnosis of neoplasia (defined as either high grade dysplasia or cancer) in the distal esophagus

The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neurodegeneration characterized by the abnormal accumulation of hyperphosphorylated tau protein within the brain. Like many other neurodegenerative conditions, at present, CTE can only be definitively diagnosed by post-mortem examination of brain tissue. As the first part of a series of consensus panels funded by the NINDS/NIBIB to define the neuropathological criteria for CTE, preliminary neuropathological criteria were used by 7 neuropathologists to blindly evaluate 25 cases of various tauopathies, including CTE, Alzheimer's disease, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, primary age-related tauopathy, and parkinsonism dementia complex of Guam. The results demonstrated that there was good agreement among the neuropathologists who reviewed the cases (Cohen's kappa, 0.67) and even better agreement between reviewers and the diagnosis of CTE (Cohen's kappa, 0.78). Based on these results, the panel defined the pathognomonic lesion of CTE as an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern. The group also defined supportive but non-specific p-tau-immunoreactive features of CTE as: pretangles and NFTs affecting superficial layers (layers II-III) of cerebral cortex; pretangles, NFTs or extracellular tangles in CA2 and pretangles and proximal dendritic swellings in CA4 of the hippocampus; neuronal and astrocytic aggregates in subcortical nuclei; thorn-shaped astrocytes at the glial limitans of the subpial and periventricular regions; and large grain-like and dot-like structures. Supportive non-p-tau pathologies include TDP-43 immunoreactive neuronal cytoplasmic inclusions and dot-like structures in the hippocampus, anteromedial temporal cortex and amygdala. The panel also recommended a minimum blocking and staining scheme for pathological evaluation and made recommendations for future study. This study provides the first step towards the development of validated neuropathological criteria for CTE and will pave the way towards future clinical and mechanistic studies

Detection of astrocytic tau pathology facilitates recognition of chronic traumatic encephalopathy neuropathologic change

Traumatic brain injury (TBI) is associated with the development of a range of neurodegenerative pathologies, including chronic traumatic encephalopathy (CTE). Current consensus diagnostic criteria define the pathognomonic cortical lesion of CTE neuropathologic change (CTE-NC) as a patchy deposition of hyperphosphorylated tau in neurons, with or without glial tau in thorn-shaped astrocytes, typically towards the depths of sulci and clustered around small blood vessels. Nevertheless, although incorporated into consensus diagnostic criteria, the contribution of the individual cellular components to identification of CTE-NC has not been formally evaluated. To address this, from the Glasgow TBI Archive, cortical tissue blocks were selected from consecutive brain donations from contact sports athletes in which there was known to be either CTE-NC (n = 12) or Alzheimer’s disease neuropathologic change (n = 4). From these tissue blocks, adjacent tissue sections were stained for tau antibodies selected to reveal either solely neuronal pathology (3R tau; GT-38) or mixed neuronal and astroglial pathologies (4R tau; PHF-1). These stained sections were then randomised and independently assessed by a panel of expert neuropathologists, blind to patient clinical history and primary antibody applied to each section, who were asked to record whether CTE-NC was present. Results demonstrate that, in sections stained for either 4R tau or PHF-1, consensus recognition of CTE-NC was high. In contrast, recognition of CTE-NC in sections stained for 3R tau or GT-38 was poor; in the former no better than chance. Our observations demonstrate that the presence of both neuronal and astroglial tau pathologies facilitates detection of CTE-NC, with its detection less consistent when neuronal tau pathology alone is visible. The combination of both glial and neuronal pathologies, therefore, may be required for detection of CTE-NC