Background: Studies on the effects of γ-radiation on nonhuman primate (NHP) brains are limited, despite the critical need to understand the impact of radiation exposure on the brain from various sources like radiotherapy equipment, space travel, and potential nuclear events. Methods: We investigated molecular and neuropathological changes in rhesus macaque brains after a single 5.8 Gy total-body γ-radiation exposure. We analyzed samples dissected from frontal cortex (FCtx), hippocampus (Hippo), and cerebellum (CRB) of irradiated (RAD) vs. unirradiated/control (CTRL) animals. Western blotting and digital PCR (dPCR) analyses were used to measure different phosphorylated-Tau (pTau) forms and neurodegeneration markers (i.e., amyloid protein precursor [APP], neurofilament-light chain [NFL], glial fibrillary acidic protein [GFAP], ionized calcium-binding adapter molecule 1 [IBA1/AIF1], and myelin basic protein [MBP]). Results: We detected lower levels of different forms of soluble pTau species (pTau181, and pTau217, among others) in RAD vs. CTRL animals across all three examined brain regions. While APP and GFAP levels were unchanged in the FCtx, increased IBA1 and NFL levels were detected alongside decreased MBP levels. Moreover, dPCR data identified decreased expression of GFAP and MBP in the FCtx. Importantly, the molecular changes observed were not accompanied by overt signs of neurodegeneration or cellular abnormalities upon neuropathological assessment. Conclusions: These findings in irradiated NHPs’ brains are novel and indicate that a single total-body γ-radiation exposure significantly alters soluble pTau levels after a few weeks from irradiation without causing obvious neurohistological damage. These results open intriguing new possibilities of exploring γ-radiation-based strategies to modulate the progression of tauopathies, including Alzheimer's disease.

Idiopathic Parkinson’s Disease (iPD) involves genetic and environmental factors, including ionizing radiation. While high-dose radiation induces neurodegeneration, the effects of low-dose radiation (LDR) remain unclear. This study examined the impact of a single acute total-body LDR exposure (1.79 Gy) on the substantia nigra (SN) of swine, a large mammal model closely resembling humans. Fourteen male Göttingen minipigs were assigned to radiation (RAD; n = 6) or sham (SH; n = 8) groups. We analyzed iPD-related markers (α-synuclein, phosphorylated α-syn, tyrosine hydroxylase), genetic PD markers (LRRK2, GBA, VPS13C, Cathepsin D), neuroinflammation (GFAP), and mitochondrial proteins (ATP5A, SDHB, NDUF8). No significant molecular, histological, or immunohistochemical differences were observed between RAD and SH animals. LRRK2 was undetectable, and no structural damage or neuroglial changes were found. These findings suggest that single acute LDR exposure does not elicit short-term PD-related alterations in the SN of swine, although long-term or cumulative effects warrant further investigation.

Neurodegenerative diseases activate innate and adaptive immune responses that can either slow or accelerate disease progression. Here, we sought to define beneficial immune pressures that emerge during tauopathy development in mice and humans. Using mice that express mutant human tau in neurons, we observed that microglia slowed tauopathy development by controlling the spread of phosphorylated tau (pTau) in the central nervous system and blood. However, over time microglia converted into distressed antigen-presenting cells, acquired neuronal transcripts and were targeted by resident, clonally expanded CD8+ T cells. These cells did not express traditional effector molecules, such as IFNγ, TNF or granzymes a/b/c, but instead deposited granzyme K (GZMK) onto microglia and were regulated by immune checkpoint proteins (TIGIT, PD-1), as blockade of TIGIT and PD-1 enhanced disease progression. GZMK+CD8+ T cells also targeted microglia in pTau-rich human brain lesions resulting from age, Alzheimer’s disease or chronic traumatic encephalopathy. Deletion of CD8+ T cells in mice promoted the emergence of distressed microglia containing neuronal transcripts, markedly enhanced pTau spread and accelerated neurological decline. These data demonstrate that GZMK+CD8+ T cells are a signature of tauopathy development and could potentially be harnessed to slow disease progression. McGavern and colleagues identified a CD8+ T cell population that expresses GZMK in ʽtau-richʼ brains, where it may play a protective role against neurodegeneration.

United States Special Operations Forces (SOF) experience neurobehavioral symptoms that can adversely affect training and combat operations. Understanding the neurobiological basis for these symptoms may guide prevention and treatment. In 29 male active-duty SOF with mean (SD) 17(4) years of service, we tested whether self-reported symptoms of apathy, disinhibition, and executive dysfunction measured by the Frontal Systems Behavior Scale, were related to functional magnetic resonance imaging and positron emission tomography biomarkers (translocator protein and tau) of the limbic, salience, and executive control networks. Higher disinhibition was associated with lower functional connectivity and higher tau signal within the salience network, though both associations diminished with age. These findings provide the basis for future multimodal studies to elucidate the relationship between neurobehavioral symptoms and neuroimaging biomarkers in the context of repeated blast exposure.

Importance:Chronic traumatic encephalopathy (CTE) is a tauopathy mostly observed following a history of repeated impact-type head injury, usually from contact sports. The overwhelming majority of published, high-stage CTE cases are in older, former high-level contact sport athletes. CTE was infrequent in a large case series of brains donated by military service members, wherein it was most often of minimal severity, while being unanimously present in former contact sport participants. Objective:To describe the neuropathological examination of a brain donated from a US Naval special warfare combatant crewman (SWCC) who had a 12-year career. Design, Setting, and Participants:This case study of a whole brain specimen donated after death from a 44.9-year-old military donor with multiple deployments was conducted at a US biorepository dedicated to studies of brains donated from deceased military personnel. The detailed neuropathological examination included comprehensive molecular genetic testing. Exposure:SWCC are trained to execute high-risk warfare and reconnaissance missions typically operating small, mobile, fast watercraft in numerous maritime environments, including operation in the high seas. In this context, SWCC sustain repetitive physical forces to the body from high-speed boat impacts with waves, which may number in the millions. Main Outcomes and Measures:Postmortem diagnosis for CTE using the National Institute of Neurological Disorders and Stroke-National Institute of Biomedical Imaging and Bioengineering (NINDS-NIBIB) consensus criteria as well as the McKee staging system; molecular genetic assessment for neurodegenerative disease. Results:The case specimen was from a male 44.9-year-old who served a 12.2-year SWCC career from ages 28.9 to 41.1 years. Following his last deployment, he experienced posttraumatic stress disorder, alcohol misuse, migraines, and impaired cognition. He died by suicide. Neuropathological evaluation revealed severe CTE (high CTE according to NINDS-NIBIB consensus criteria; McKee Stage IV of IV), with extensive pathology involving numerous brain regions. Molecular genetic testing for neurodegenerative disease risk was negative. Conclusions and Relevance:In this neuropathological case study of a 44-year-old former SWCC, we found severe CTE. Given the severity of the pathology at a relatively young age, we consider that exposures of a SWCC career, including repetitive physical forces applied to the head from high-speed boat impacts with waves, may be sufficient to promote or otherwise contribute to CTE development.

Emerging research highlights the gut microbiota's critical role in modulating brain activity via the gut-brain axis. This study explores whether targeted gastrointestinal irradiation induces abscopal effects on the brain proteome, revealing microbiota-mediated neurobiological changes. Male Sinclair minipigs were randomized to receive either sham treatment (n = 6) or 8 Gy lower hemibody (gut-targeted) irradiation (n = 5). Over 14 days, rectal swabs were collected to monitor microbiota dynamics, followed by frontal cortex proteomic analysis. Irradiation altered gut microbiota composition, notably reducing Chlamydiae and Firmicutes phyla, while increasing Coriobacteriaceae and Acinetobacter. Proteomic analysis identified 75 differentially abundant proteins in the frontal cortex, including a significant decrease in pannexin-1 (PANX1), suggesting modulation of the NLRP3 inflammasome pathway. Functional enrichment analysis revealed immune and neurotransmission-related changes linked to microbial shifts. These results demonstrate that gut-targeted radiation can remotely affect brain protein expression, emphasizing the microbiota's role in neuroimmune regulation and pointing to novel therapeutic opportunities in gut-brain axis disorders.

Physical trauma, psychosocial stress, and oxidative stress increase the neuronal transcription ratio of genes encoding the sodium-potassium chloride cotransporter (Nkcc1, Slc12a2) and the potassium chloride cotransporter (Kcc2, Slc12a5), which leads to neuronal depolarization and excitability. We hypothesized that increases in the Nkcc1:Kcc2 ratio of gene transcription in these injuries would be countered with downregulation of the gene encoding the cardiac and neuronal isoform of the chloride/bicarbonate exchanger (Ae3, Slc4a3). We found a reflex decrease in cardiac and neuronal Ae3 transcription that was associated with diminished traumatic brain injury (TBI)-induced increases in systolic blood pressure and decrements in heart rate and posttraumatic stress disorder (PTSD)-induced anxiety. We also observed pronounced sex differences in Nkcc1:Kcc2 expression, with female control and Ae3 knockout mice exhibiting significantly higher brain Nkcc1:Kcc2 ratios compared with males. Administration of testosterone after injury reduced the excessive cardiovascular reactivity induced by TBI. We suggest that pharmacologic antagonism of the cardiac/neuronal isoform of Ae3, perhaps with testosterone supplementation, may prove salutary in reducing the adverse cardiovascular and behavioral sequelae of TBI or psychological stress.NEW & NOTEWORTHY Our findings may lead to a new way to effectively treat the chronic stress, anxiety, and excessive cardiovascular reactivity that frequently follow head injuries, such as sports concussion.

INTRODUCTION:High-speed boat operations expose personnel to slamming-induced impacts, which can lead to musculoskeletal injuries and cognitive impairments. Despite existing safety measures, regulations and protocols, the risk of injuries remains significant. The MultiAgency, prospective, exploratory, non-intervention, cohort Study on Human Impact Exposure oNboard high-speed boats study aims to investigate the nature and magnitude of these impacts, their acute and long-term health effects, and potential injury prevention strategies to improve operational safety and performance. METHODS AND ANALYSIS:This is an ongoing multicentre, prospective, non-intervention, observational cohort study. The first participant was enrolled on 23 August 2024. High-speed boat operators log self-reported pain data via a smartphone app, using a Visual Analogue Scale and pain drawings. Triaxial accelerometers are installed on boat hulls and worn by participants to measure impact exposure. Data analysis assesses correlations between exposure and reported pain, enabling the identification of risk factors and the development of safety guidelines for high-speed boat operations. ETHICS AND DISSEMINATION:The study has received ethical approval from the relevant ethics committees, including the Swedish Ethics Review Authority (no. 2022-04931-01). All participants will provide informed consent before enrolment. The findings will be disseminated through technical reports, articles in peer-reviewed journals, conference presentations and direct engagement with military and maritime stakeholders to enhance training protocols and safety measures. TRIAL REGISTRATION NUMBER:NCT05299736.

Traumatic brain injury (TBI) after high-energy, behind helmet blunt trauma (BHBT) is an important but poorly understood clinical entity often associated with apnea and death in humans. In this study, we use a swine model of high-energy BHBT to characterize key neuropathologies and their association with acute respiratory decompensation. Animals with either stable or critical vital signs were euthanized within 4 h after injury for neuropathological assessment, with emphasis on axonal and vascular pathologies in the brainstem. The majority of cases were characterized by fractures of the cranium at or about the impact site, extensive subarachnoid hemorrhages, coup and contrecoup contusions, and primarily diffuse axonal and vascular lesions throughout the cerebrum, particularly in the brainstem. Absence of spontaneous respiration that was encountered frequently was associated with both severity of impact and the severity of brainstem axonal and vascular lesions. A focused regional examination of brainstem pathology indicated a link between adverse outcomes and diffuse axonal lesions within the medial medulla or vascular lesions within the anteroventral brainstem, a pattern suggesting that injury to brainstem respiratory centers may play a role in apnea following BHBT. In addition, while the overall burden of diffuse axonal and vascular pathologies correlated with each other, we found minimal overlap in their regional distribution. Our findings indicate that high-energy, blunt-force impact TBI causes diffuse lesions in axons and blood vessels associated with poor outcomes. They also suggest that axons and vessels may have distinct responses to tissue deformation and that commonly used markers of vascular pathology, for example, in diagnostic radiology, cannot be used as direct surrogates of diffuse axonal injury. In concert, our study underscores the role of regional axonal and vascular injuries in the brainstem in acute respiratory decompensation after high-rate blunt TBI, even in the presence of head protection; it also emphasizes the importance of detailed clinicopathological work in complex brains in the field of TBI.

There is a growing interest in low dose radiation (LDR) to counteract neurodegeneration. However, LDR effects on normal brain have not been completely explored yet. Recent analyses showed that LDR exposure to normal brain tissue causes expression level changes of different proteins including neurodegeneration-associated proteins. We assessed the proteomic changes occurring in radiated vs. sham normal swine brains. Due to its involvement in various neurodegenerative processes, including those associated with cognitive changes after high dose radiation exposure, we focused on the hippocampus first. We observed significant proteomic changes in the hippocampus of radiated vs. sham swine after LDR (1.79Gy). Mass spectrometry results showed 190 up-regulated and 120 down-regulated proteins after LDR. Western blotting analyses confirmed increased levels of TPM1, TPM4, PCP4 and NPY (all proteins decreased in various neurodegenerative processes, with NPY and PCP4 known to be neuroprotective) in radiated vs. sham swine. These data support the use of LDR as a potential beneficial tool to interfere with neurodegenerative processes and perhaps other brain-related disorders, including behavioral disorders.

There are currently no noninvasive imaging methods available for astrogliosis mapping in the brain despite its essential role in the response to many disease states. In an ex vivo human brain study we used diffusion-relaxation MRI to derive a signature of astrogliosis and disentangle it from normative brain at the individual level using machine learning. We developed a within-subject anomaly detection procedure that generates MRI-based astrogliosis maps ex vivo, which were significantly and strongly correlated with co-registered histology. Our findings demonstrated spatial sensitivity and specificity in detecting reactive astrocytes, and could significantly impact the studying of injury, disease, and aging.

Introduction: Among gene mutations and variants linked to an increased risk of PD, mutations of leucine-rich repeat kinase 2 gene (LRRK2) are among the most frequently associated with early- and late-onset PD. Clinical and neuropathological characteristics of idiopathic-PD (iPD) and LRRK2-PD are similar, and these similarities suggest that the pathomechanisms between these two conditions are shared. LRRK2 mutations determine a gain-of-function and yield higher levels of lrrk2 across body tissues, including brain. On another side, recent animal studies supported the potential use of low dose radiation (LDR) to modify the pathomechanisms of diseases such as Alzheimer's disease (AD). Methods: We assessed if a single total-body LDR (sLDR) exposure in normal swine could alter expression levels of the following PD-associated molecules: alpha-synuclein (alpha-syn), phosphorylated-alpha-synuclein (p alpha-syn), parkin, tyrosine hydroxylase (th), lrrk2, phosphorylated-lrrk2 (pS935-lrrk2), and some LRRK2 substrates (Rab8a, Rab12) across different brain regions. These proteins were measured in frontal cortex, hippocampus, striatum, thalamus/ hypothalamus, and cerebellum of 9 radiated (RAD) vs. 6 sham (SH) swine after 28 days from a sLDR of 1.79Gy exposure. Results: Western Blot analyses showed lowered lrrk2 levels in the striatum of RAD vs. SH swine (p < 0.05), with no differences across the remaining brain regions. None of the other protein levels differed between RAD and SH swine in any examined brain regions. No lrrk2 and p-lrrk2 (S935) levels differed in the lungs of RAD vs. SH swine. Conclusions: These findings show a specific striatal lrrk2 lowering effect due to LDR and support the potential use of LDR to interfere with the pathomechanisms of PD.

Due to their interactions with the neurovasculature, microglia are implicated in maladaptive responses to hypobaric hypoxia at high altitude (HA). To explore these interactions at HA, pharmacological depletion of microglia with the colony-stimulating factor-1 receptor inhibitor, PLX5622, was employed in male C57BL/6J mice maintained at HA or sea level (SL) for 3-weeks, followed by assessment of ex-vivo hippocampal long-term potentiation (LTP), fear memory recall and microglial dynamics/physiology. Our findings revealed that microglia depletion decreased LTP and reduced glucose levels by 25% at SL but did not affect fear memory recall. At HA, the absence of microglia did not significantly alter HA associated deficits in fear memory or HA mediated decreases in peripheral glucose levels. In regard to microglial dynamics in the cortex, HA enhanced microglial surveillance activity, ablation of microglia resulted in increased chemotactic responses and decreased microglia tip proliferation during ball formation. In contrast, vessel ablation increased cortical microglia tip path tortuosity. In the hippocampus, changes in microglial dynamics were only observed in response to vessel ablation following HA. As the hippocampus is critical for learning and memory, poor hippocampal microglial context-dependent adaptation may be responsible for some of the enduring neurological deficits associated with HA.

Mild traumatic brain injury (mTBI) has emerged as a potential risk factor for the development of neurodegenerative conditions such as Alzheimer's disease and chronic traumatic encephalopathy. Blast mTBI, caused by exposure to a pressure wave from an explosion, is predominantly experienced by military personnel and has increased in prevalence and severity in recent decades. Yet the underlying pathology of blast mTBI is largely unknown.We examined the expression and localization of AQP4 in human post-mortem frontal cortex and observed distinct laminar differences in AQP4 expression following blast exposure. We also observed similar laminar changes in AQP4 expression and localization and delayed impairment of glymphatic function that emerged 28 days following blast injury in a mouse model of repetitive blast mTBI. In a cohort of veterans with blast mTBI, we observed that blast exposure was associated with an increased burden of frontal cortical MRI-visible perivascular spaces, a putative neuroimaging marker of glymphatic perivascular dysfunction.These findings suggest that changes in AQP4 and delayed glymphatic impairment following blast injury may render the post-traumatic brain vulnerable to post-concussive symptoms and chronic neurodegeneration. Blast traumatic brain injury is associated with an increased risk of long-term neurological and psychiatric sequelae, but the underlying mechanisms are unclear. Using clinical and preclinical data, Braun et al. show that blast injury may impair the function of the glymphatic system, responsible for the removal of waste from the brain.

Traumatic brain injury (TBI) is a complex condition that can resolve over time but all too often leads to persistent symptoms, and the risk of poor patient outcomes increases with aging. TBI damages neurons and long axons within white matter tracts that are critical for communication between brain regions; this causes slowed information processing and neuronal circuit dysfunction. This review focuses on white matter injury after TBI and the multifactorial processes that underlie white matter damage, potential for recovery, and progression of degeneration. A multiscale perspective across clinical and preclinical advances is presented to encourage interdisciplinary insights from whole-brain neuroimaging of white matter tracts down to cellular and molecular responses of axons, myelin, and glial cells within white matter tissue.

2023 was an important year for research in traumatic brain injury (TBI), particularly as it concerned interests in neuropathology. After reviewing the literature, we present the advancements that we felt were of particular importance to the neuropathology community. Highlighted are articles that report upon: (1) the first large-cohort assessment for the neuropathology of intimate partner violence, (2) the assessment of chronic traumatic encephalopathy (CTE) in young athletes, (3) the observation of cortical sulcal depth vascular changes in CTE, (4) a proposal for a tau immunohistochemical panel to evaluate complex cases of CTE in the context of multiple tauopathies, (5) the relationship of TBI and/or CTE with TDP-43 pathology, (6) repetitive TBI inducing pathology in C9orf72-transgenic mice, (7) radiologic patterns of head and neck injury following vehicular underbody blast exposure, (8) chronic alterations in brain metal content following repetitive impact TBI, (9) neurovascular unit injury following low-level blast exposure, and finally (10) an assessment of Muhammad Ali’s clinical history leading to the conclusion that he suffered from young-onset, idiopathic Parkinson Disease. We close our writing with in memoriam to Dr. Byron A. Kakulas, a renowned figure in the neuropathology of spinal cord injury who we lost in 2023.

Chronic traumatic encephalopathy (CTE) is defined by perivascular neuronal phosphorylated-tau accumulation at cortical sulcal depths. CTE has been mainly described in the context of repetitive, impact-type traumatic brain injury (rTBI), principally from contact sports. Rarely, CTE has been associated with single TBIs, including in relationship to healed leucotomy sites in brains from formerly institutionalized psychiatric patients without documented rTBI. Given that leucotomy principally involves severing of white matter, this could suggest involvement of axonal injury in CTE pathophysiology. We present three cases wherein isolated CTE pathology was identified adjacent to distinct white matter lesions. Case 1 is a 41-year-old man with history of hereditary hemorrhagic telangiectasia and resection of a cerebral arteriovenous malformation (AVM). Case 2 is a 46-year-old man with glioblastoma. Case 3 is a 52-year-old man with a remote cerebral infarct. Isolated CTE lesions were found adjacent to the aforementioned pathologies in each case. Additional CTE lesions were not identified despite extensive sampling. Multiple age-related tau astrogliopathy (ARTAG)-like lesions were also identified at other sulcal depths near the AVM resection site in Case 1. These cases may provide insights regarding the pathophysiology of the CTE pathognomonic lesion and the development of ARTAG-like pathology adjacent to long-standing mass lesions.

Introduction: We demonstrated traumatic brain injury (TBI)-dependent increases in cardiovascular reactivity are associated with increased transcription ratio of the genes controlling intraneuronal chloride concentrations, the sodium chloride cotransporter-1 (Nkcc1) and the potassium chloride cotransporter-2 (Kcc2). We also found that in an effort to maintain constant intraneuronal chloride concentrations, greater Nkcc1:Kcc2 ratios are inversely correlated with the expression of the neuronal chloride/bicarbonate exchanger (Ae3). Hypothesis: Enhancement of Nkcc1:Kcc2 represents a generalized response to hazards confronting the milieu interior, and other challenges such as post-traumatic stress (PTS) would similarly increase Nkcc1:Kcc2 and correspondingly diminish Ae3 expression. Conversely, reductions in the expression of neuronal Ae3 could raise the Nkcc1:Kcc2 ratio and alter cardiovascular reactivity after TBI. Methods: PTS was induced in C57Bl/6 mice with intermittent, unpredictable foot shocks and noise exposure, and mRNA from brain tissue was extracted and quantified for Nkcc1, Kcc2, and Ae3 with RT-PCR. In a separate cohort of FVB/N mice, blood pressure (SBP) and heart rates (HR) were assessed noninvasively in awake, control mice and those with targeted disruption of Ae3 after TBI was induced with mild cortical impact; transcription levels of Nkcc1 and Kcc2 were measured similarly. Results: Compared to control mice, PTS increased the Nkcc1:Kcc2 ratio from (values in percent ± SEM), 1.70 ± 0.14 vs. 4.79 ± 0.53, p < 0.0001, n ≥ 10, and decreased the expression of Ae3 (values expressed as 2^[-Ct] ± SEM) from 5.78 x 10−8 2.21 x 10−8, p < 0.0001. However, the Nkcc1:Kcc2 ratio correlated significantly with Ae3 expression only in the mice without PTS, r = -0.41, p = 0.026. In our cohort of mice with targeted disruption of Ae3, Nkcc1:Kcc2 ratios were unchanged between our inbred FVB/N control mice and knockout animals on an FVB/N background (0.51 ± 0.02 vs. 0.63 ± 0.02, p = n.s.) before surgery, but these values were much lower than the ratios from commercially obtained FVB/N inbred mice (1.03 ± 0.07, p < 0.0001). After TBI, mice with targeted disruption of the Ae3 did not have different HR or blood pressure when compared to our inbred FVB/N mice. TBI increased HR only in the commercially obtained FVB/N mice compared to the knockout mice, but this is likely due to lower resting HR of the commercially obtained FVB/N mice. Conclusions: Similarly to what is found after the stress of TBI, mice with PTS had an increased Nkcc1:Kcc2 ratio, but the relationship between the Nkcc1:Kcc2 ratio and the chloride/bicarbonate exchanger is lost. When compared to commercially inbred FVB/N mice, loss of Ae3 increases HR after TBI, however, whether this relationship will be confirmed with truly inbred FVB/N mice remains to be determined. Henry M. Jackson Foundation for the Advancement of Military Medicine. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.