One-hundred years (and counting) of blast-associated traumatic brain injury

Blast-associated traumatic brain injury (TBI) has become one of the signature issues of modern warfare and is increasingly a concern in the civilian population due to a rise in terrorist attacks. Despite being a recognised feature of combat since the introduction of high explosives in conventional warfare over a century ago, only recently has there been interest in understanding the biology and pathology of blast TBI and the potential long-term consequences. Progress made has been slow and there remain remarkably few robust human neuropathology studies in this field. This article provides a broad overview of the history of blast TBI and reviews the pathology described in the limitedscientific studies found in the literature

Sex-dependent influence of endogenous estrogen in pulmonary hypertension

Rationale: The incidence of pulmonary arterial hypertension (PAH) is greater in women suggesting estrogens may play a role in the disease pathogenesis. Experimentally, in males exogenously administered estrogen can protect against PH; however in models that display female susceptibility estrogens may play a causative role. Objectives: To clarify the influence of endogenous estrogen and gender in PH and assess the therapeutic potential of a clinically available aromatase inhibitor. Methods: We interrogated the effect of reduced endogenous estrogen in males and females using the aromatase inhibitor, anastrozole, in two models of PH; the hypoxic mouse and Sugen 5416/hypoxic rat. We also determined the effects of gender on pulmonary expression of aromatase in these models and in lungs from PAH patients. Results: Anastrozole attenuated PH in both models studied, but only in females. To verify this effect was due to reduced estrogenic activity we confirmed that in hypoxic mice inhibition of estrogen receptor alpha also has a therapeutic effect specifically in females. Female rodent lung displays increased aromatase and decreased BMPR2 and Id1 expression compared to male. Anastrozole treatment reversed the impaired BMPR2 pathway in females. Increased aromatase expression was also detected in female human pulmonary artery smooth muscle cells compared to male. Conclusions: The unique phenotype of female pulmonary arteries facilitates the therapeutic effects of anastrozole in experimental PH confirming a role for endogenous estrogen in the disease pathogenesis in females and suggests aromatase inhibitors may have therapeutic potential

Presence of cerebral microbleeds is associated with worse executive function in pediatric brain tumor survivors.

BackgroundA specific form of small-vessel vasculopathy-cerebral microbleeds (CMBs)-has been linked to various types of dementia in adults. We assessed the incidence of CMBs and their association with neurocognitive function in pediatric brain tumor survivors.MethodsIn a multi-institutional cohort of 149 pediatric brain tumor patients who received cranial radiation therapy (CRT) between 1987 and 2014 at age <21 years and 16 patients who did not receive CRT, we determined the presence of CMBs on brain MRIs. Neurocognitive function was assessed using a computerized testing program (CogState). We used survival analysis to determine cumulative incidence of CMBs and Poisson regression to examine risk factors for CMBs. Linear regression models were used to assess effect of CMBs on neurocognitive function.ResultsThe cumulative incidence of CMBs was 48.8% (95% CI: 38.3-60.5) at 5 years. Children who had whole brain irradiation developed CMBs at a rate 4 times greater than those treated with focal irradiation (P < .001). In multivariable analysis, children with CMBs performed worse on the Groton Maze Learning test (GML) compared with those without CMBs (Z-score -1.9; 95% CI: -2.7, -1.1; P < .001), indicating worse executive function when CMBs are present. CMBs in the frontal lobe were associated with worse performance on the GML (Z-score -2.4; 95% CI: -2.9, -1.8; P < .001). Presence of CMBs in the temporal lobes affected verbal memory (Z-score -2.0; 95% CI: -3.3, -0.7; P = .005).ConclusionCMBs are common and associated with neurocognitive dysfunction in pediatric brain tumor survivors treated with radiation

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Examining cholinergic fuction in the ventral tegmental area and dorsal hippocampus

Year of award is 2017.Midbrain dopamine (DA) neurons project from the ventral tegmental area (VTA) to the prefrontal cortex (PFC) and ventral striatum (NAc and OT) forming a key part of the well-defined mesocorticolimbic system, as well as the hippocampal-VTA loop. The mesocorticolimbic system, at least partly, mediates the rewarding effects of drugs of abuse, such as nicotine. The VTA receives cholinergic projections from the pedunculopontine tegmental and laterodorsal tegmental nuclei (PPTg, LDTg). Previous studies have shown that selective bilateral cholinergic lesions of the posterior PPTg or LDTg can be achieved by directly infusing diphtheria-urotensin II toxin (Dtx-UII) into either region. This thesis aimed to selectively destroy the cholinergic input from both mesopontine nuclei to the posterior VTA (pVTA) by injection of Dtx-UII here. Unilateral or bilateral infusion of Dtx-UII into the pVTA did not destroy cholinergic terminals at any of the time points analysed. There was no evidence of neurodegeneration (as measured by Fluoro-jade C) present in the pVTA, PPTg or LDTg. A non-lesion approach was also adopted to better understand the actions of cholinergics in the pVTA. The effects of nicotine self-administered into the VTA or (as a point of contrast in the circuitry of the VTA) the dorsal hippocampus (dHPC) were assessed by measuring lever pressing and quantifying the expression of immediate early gene (IEG) c-fos as a marker of neural activation. Fos expression was quantified in the VTA and in structures on which VTA activity has effect - the shell and core of the NAc, the dorsal striatum and the dHPC. Fos was measured under two conditions: at the end of the very first exposure to nicotine and (in other groups) after repeated exposure. These results demonstrated that rats will lever press to directly administer nicotine into the VTA or dHPC, but that nicotine-induced Fos expression is not correlated with lever pressing. In addition, intra-VTA, but not intra-dHPC nicotine, activated all regions of interest. This demonstrates that intra-VTA nicotine mediates its effects through regions of the mesocorticolimbic system, but that intra-dHPC nicotine must mediate its effects through other brain regions and systems. These results raise questions about the nature of reward processing in the brain.Midbrain dopamine (DA) neurons project from the ventral tegmental area (VTA) to the prefrontal cortex (PFC) and ventral striatum (NAc and OT) forming a key part of the well-defined mesocorticolimbic system, as well as the hippocampal-VTA loop. The mesocorticolimbic system, at least partly, mediates the rewarding effects of drugs of abuse, such as nicotine. The VTA receives cholinergic projections from the pedunculopontine tegmental and laterodorsal tegmental nuclei (PPTg, LDTg). Previous studies have shown that selective bilateral cholinergic lesions of the posterior PPTg or LDTg can be achieved by directly infusing diphtheria-urotensin II toxin (Dtx-UII) into either region. This thesis aimed to selectively destroy the cholinergic input from both mesopontine nuclei to the posterior VTA (pVTA) by injection of Dtx-UII here. Unilateral or bilateral infusion of Dtx-UII into the pVTA did not destroy cholinergic terminals at any of the time points analysed. There was no evidence of neurodegeneration (as measured by Fluoro-jade C) present in the pVTA, PPTg or LDTg. A non-lesion approach was also adopted to better understand the actions of cholinergics in the pVTA. The effects of nicotine self-administered into the VTA or (as a point of contrast in the circuitry of the VTA) the dorsal hippocampus (dHPC) were assessed by measuring lever pressing and quantifying the expression of immediate early gene (IEG) c-fos as a marker of neural activation. Fos expression was quantified in the VTA and in structures on which VTA activity has effect - the shell and core of the NAc, the dorsal striatum and the dHPC. Fos was measured under two conditions: at the end of the very first exposure to nicotine and (in other groups) after repeated exposure. These results demonstrated that rats will lever press to directly administer nicotine into the VTA or dHPC, but that nicotine-induced Fos expression is not correlated with lever pressing. In addition, intra-VTA, but not intra-dHPC nicotine, activated all regions of interest. This demonstrates that intra-VTA nicotine mediates its effects through regions of the mesocorticolimbic system, but that intra-dHPC nicotine must mediate its effects through other brain regions and systems. These results raise questions about the nature of reward processing in the brain

Systematic review: association between circulating microRNA expression & stroke

This systematic review aimed to establish the range and quality of clinical and preclinical evidence supporting the association of individual microRNAs, and the use of microRNA expression in the diagnosis and prognosis of ischaemic or haemorrhagic stroke. Electronic databases were searched from 1993 to October 2021, using key words relevant to concepts of stroke and microRNA. Studies that met specific inclusion and exclusion criteria were selected for data extraction. To minimise erroneous associations, findings were restricted to microRNAs reported to change in more than two independent studies. Of the papers assessed, 155 papers reported a change in microRNA expression observed in more than two independent studies. In ischaemic studies, two microRNAs were consistently differentially expressed in clinical samples (miR-29b & miR-146a) and four were altered in preclinical samples (miR-137, miR-146a, miR-181b & miR-223-3p). Across clinical and preclinical haemorrhagic studies, four microRNAs were downregulated consistently (miR-26a, miR-126, miR-146a & miR-155). Across included studies, miR-126 and miR-146a were the only two microRNAs to be differentially expressed in clinical and preclinical cohorts following ischaemic or haemorrhagic stroke. Further studies, employing larger populations with consistent methodologies, are required to validate the true clinical value of circulating microRNAs as biomarkers of ischaemic and haemorrhagic stroke

Large Vessel Arteriopathy After Cranial Radiation Therapy in Pediatric Brain Tumor Survivors.

Among childhood cancer survivors, increased stroke risk after cranial radiation therapy may be caused by radiation-induced arteriopathy, but limited data exist to support this hypothesis. Herein, we assess the timing and presence of cerebral arteriopathy identified by magnetic resonance angiography (MRA) after cranial radiation therapy in childhood brain tumor survivors. In a cohort of 115 pediatric brain tumor survivors, we performed chart abstraction and prospective annual follow-up to assess the presence of large vessel cerebral arteriopathy by MRA. We identified 10 patients with cerebral arteriopathy. The cumulative incidence of arteriopathy 5 years post-cranial radiation therapy was 5.4% (CI 0.6%-10%) and 10 years was 16% (CI 4.6%-26%). One patient had an arterial ischemic stroke 2.4 years post-cranial radiation therapy in the distribution of a radiation-induced stenotic artery. We conclude that large vessel arteriopathies can occur within a few years of cranial radiation therapy and can become apparent on MRA in under a year