Brain pathology and symptoms linked to concussion history: beyond chronic traumatic encephalopathy.

Repeated head trauma acquired through sports injuries has been associated with the development of long-term disabling symptoms that negatively impact the quality of life. In this retrospective case series, 52 male former professional athletes involved in contact sports and with a history of multiple concussions were evaluated for chronic clinical symptoms and post-mortem neuropathological diagnoses. The clinical symptoms of 19 cases were examined in greater detail for symptom type, severity and duration. Information on neurological, psychiatric and physical symptoms, substance use profiles and concussion histories was obtained from the athletes' next of kin and assessed in relation to post-mortem neuropathological diagnoses. Cases were categorized into three different neuropathological groups: no major neuropathological findings, the presence of only chronic traumatic encephalopathy (CTE) and the diagnosis(es) of other neurodegenerative diseases. Age at death and the presence of DNA damage in the post-mortem brains were analysed for correlation with the clinical symptoms. In this case series, 14/52 (26.9%) cases (mean age 48.2 ± 11.4) had neuropathological evidence of low-stage/low-burden CTE. A total of 11/52 (21.2%) cases (mean age 38.7 ± 12.7) presented a similar profile and severity of behavioural symptoms to those with CTE, despite the lack of significant post-mortem neuropathological findings. A total of 27/52 (51.9%) cases (mean age 75.5 ± 8.7) presented with complex post-mortem neurodegenerative diagnoses, including Alzheimer's disease and other mixed pathologies, and clinical symptoms associated with language, memory and sensory dysfunction. The presence of DNA damage in the brain was found in all neuropathological groups, predominantly in the ependymal lining of ventricles, and phosphorylated histone H2AX staining was correlated with higher age at death (r = 0.59) and symptoms of language dysfunction (r = 0.56). Findings from our case series suggest that post-concussive symptoms are not driven by CTE. Our findings show that proteinopathies alone may not account for the complexity of the clinical manifestations and suggest the possibility of other drivers, such as DNA damage, as potentially useful markers of brain trauma. Broadening the search for biological markers that reflect the effects of brain injury, even when proteinopathy is not observed, and taking a symptom-driven approach are therefore advised.

Association of Structural Forms of 17q21.31 with the Risk of Progressive Supranuclear Palsy and MAPT Sub-haplotypes.

Importance: The chromosome 17q21.31 region, containing a 900 Kb inversion that defines H1 and H2 haplotypes, represents the strongest genetic risk locus in progressive supranuclear palsy (PSP). In addition to H1 and H2, various structural forms of 17q21.31, characterized by the copy number of α, ß, and γ duplications, have been identified. However, the specific effect of each structural form on the risk of PSP has never been evaluated in a large cohort study. Objective: To assess the association of different structural forms of 17q.21.31, defined by the copy numbers of α, ß, and γ duplications, with the risk of PSP and MAPT sub-haplotypes. Design setting and participants: Utilizing whole genome sequencing data of 1,684 (1,386 autopsy confirmed) individuals with PSP and 2,392 control subjects, a case-control study was conducted to investigate the association of copy numbers of α, ß, and γ duplications and structural forms of 17q21.31 with the risk of PSP. All study subjects were selected from the Alzheimer's Disease Sequencing Project (ADSP) Umbrella NG00067.v7. Data were analyzed between March 2022 and November 2023. Main outcomes and measures: The main outcomes were the risk (odds ratios [ORs]) for PSP with 95% CIs. Risks for PSP were evaluated by logistic regression models. Results: The copy numbers of α and ß were associated with the risk of PSP only due to their correlation with H1 and H2, while the copy number of γ was independently associated with the increased risk of PSP. Each additional duplication of γ was associated with 1.10 (95% CI, 1.04-1.17; P = 0.0018) fold of increased risk of PSP when conditioning H1 and H2. For the H1 haplotype, addition γ duplications displayed a higher odds ratio for PSP: the odds ratio increases from 1.21 (95%CI 1.10-1.33, P = 5.47 × 10-5) for H1ß1γ1 to 1.29 (95%CI 1.16-1.43, P = 1.35 × 10-6) for H1ß1γ2, 1.45 (95%CI 1.27-1.65, P = 3.94 × 10-8) for H1ß1γ3, and 1.57 (95%CI 1.10-2.26, P = 1.35 × 10-2) for H1ß1γ4. Moreover, H1ß1γ3 is in linkage disequilibrium with H1c (R2 = 0.31), a widely recognized MAPT sub-haplotype associated with increased risk of PSP. The proportion of MAPT sub-haplotypes associated with increased risk of PSP (i.e., H1c, H1d, H1g, H1o, and H1h) increased from 34% in H1ß1γ1 to 77% in H1ß1γ4. Conclusions and relevance: This study revealed that the copy number of γ was associated with the risk of PSP independently from H1 and H2. The H1 haplotype with more γ duplications showed a higher odds ratio for PSP and were associated with MAPT sub-haplotypes with increased risk of PSP. These findings expand our understanding of how the complex structure at 17q21.31 affect the risk of PSP.

Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy.

Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method: In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results: Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73×10-3) in PSP. Conclusions: Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

BRCA1 heterozygosity promotes DNA damage-induced senescence in a sex-specific manner following repeated mild traumatic brain injury.

Emerging evidence suggests cellular senescence, as a consequence of excess DNA damage and deficient repair, to be a driver of brain dysfunction following repeated mild traumatic brain injury (rmTBI). This study aimed to further investigate the role of deficient DNA repair, specifically BRCA1-related repair, on DNA damage-induced senescence. BRCA1, a repair protein involved in maintaining genomic integrity with multiple roles in the central nervous system, was previously reported to be significantly downregulated in post-mortem brains with a history of rmTBI. Here we examined the effects of impaired BRCA1-related repair on DNA damage-induced senescence and outcomes 1-week post-rmTBI using mice with a heterozygous knockout for BRCA1 in a sex-segregated manner. Altered BRCA1 repair with rmTBI resulted in altered anxiety-related behaviours in males and females using elevated zero maze and contextual fear conditioning. Evaluating molecular markers associated with DNA damage signalling and senescence-related pathways revealed sex-specific differences attributed to BRCA1, where females exhibited elevated DNA damage, impaired DNA damage signalling, and dampened senescence onset compared to males. Overall, the results from this study highlight sex-specific consequences of aberrant DNA repair on outcomes post-injury, and further support a need to develop sex-specific treatments following rmTBI.

The pathological potential of ependymal cells in mild traumatic brain injury.

Mild traumatic brain injury (mTBI) is a common neurological condition affecting millions of individuals worldwide. Although the pathology of mTBI is not fully understood, ependymal cells present a promising approach for studying the pathogenesis of mTBI. Previous studies have revealed that DNA damage in the form of γH2AX accumulates in ependymal cells following mTBI, with evidence of widespread cellular senescence in the brain. Ependymal ciliary dysfunction has also been observed, leading to altered cerebrospinal fluid homeostasis. Even though ependymal cells have not been extensively studied in the context of mTBI, these observations reflect the pathological potential of ependymal cells that may underlie the neuropathological and clinical presentations of mTBI. This mini review explores the molecular and structural alterations that have been reported in ependymal cells following mTBI, as well as the potential pathological mechanisms mediated by ependymal cells that may contribute to overall dysfunction of the brain post-mTBI. Specifically, we address the topics of DNA damage-induced cellular senescence, dysregulation of cerebrospinal fluid homeostasis, and the consequences of impaired ependymal cell barriers. Moreover, we highlight potential ependymal cell-based therapies for the treatment of mTBI, with a focus on neurogenesis, ependymal cell repair, and modulation of senescence signaling pathways. Further insight and research in this field will help to establish the role of ependymal cells in the pathogenesis of mTBI and may lead to improved treatments that leverage ependymal cells to target the origins of mTBI pathology.

Chronic traumatic encephalopathy neuropathologic change is uncommon in men who played amateur American football.

Introduction: We examined postmortem brain tissue from men, over the age of 50, for chronic traumatic encephalopathy neuropathologic change (CTE-NC). We hypothesized that (i) a small percentage would have CTE-NC, (ii) those who played American football during their youth would be more likely to have CTE-NC than those who did not play contact or collision sports, and (iii) there would be no association between CTE-NC and suicide as a manner of death. Methods: Brain tissue from 186 men and accompanying clinical information were obtained from the Lieber Institute for Brain Development. Manner of death was determined by a board-certified forensic pathologist. Information was obtained from next of kin telephone interviews, including medical, social, demographic, family, and psychiatric history. The 2016 and 2021 consensus definitions were used for CTE-NC. Two authors screened all cases, using liberal criteria for identifying "possible" CTE-NC, and five authors examined the 15 selected cases. Results: The median age at the time of death was 65 years (interquartile range = 57-75; range = 50-96). There were 25.8% with a history of playing American football and 36.0% who had suicide as their manner of death. No case was rated as definitively having "features" of CTE-NC by all five authors. Ten cases were rated as having features of CTE-NC by three or more authors (5.4% of the sample), including 8.3% of those with a personal history of playing American football and 3.9% of those who did not play contact or collision sports. Of those with mood disorders during life, 5.5% had features of CTE-NC compared to 6.0% of those who did not have a reported mood disorder. Of those with suicide as a manner of death, 6.0% had features of CTE-NC compared to 5.0% of those who did not have suicide as a manner of death. Discussion: We did not identify a single definitive case of CTE-NC, from the perspective of all raters, and only 5.4% of cases were identified as having possible features of CTE-NC by some raters. CTE-NC was very uncommon in men who played amateur American football, those with mood disorders during life, and those with suicide as a manner of death.

Titin related myopathy with ophthalmoplegia. A novel phenotype.

Titin-related myopathy is an emerging genetic neuromuscular disorder with a wide spectrum of clinical phenotypes. To date, there have not been reports of patients with this disease that presented with extraocular muscle involvement. Here we discuss a 19-year-old male with congenital weakness, complete ophthalmoplegia, thoracolumbar scoliosis, and obstructive sleep apnea. Muscle magnetic resonance imaging revealed severe involvement of the gluteal and anterior compartment muscles, and clear adductor sparing, while muscle biopsy of the right vastus lateralis showed distinctive cap-like structures. Trio Whole Exome Sequencing (WES) showed compound heterozygous likely pathologic variants in the TTN gene. (c.82541_82544dup (p.Arg27515Serfs*2) in exon 327 (NM_001267550.2) and c.31846+1G>A (p.?) in exon 123 (NM_001267550.2). To our knowledge, this is the first report of a TTN-related disorder associated with ophthalmoplegia.

Variants in ACTC1 underlie distal arthrogryposis accompanied by congenital heart defects.

Contraction of the human sarcomere is the result of interactions between myosin cross-bridges and actin filaments. Pathogenic variants in genes such as MYH7, TPM1, and TNNI3 that encode parts of the cardiac sarcomere cause muscle diseases that affect the heart, such as dilated cardiomyopathy and hypertrophic cardiomyopathy. In contrast, pathogenic variants in homologous genes such as MYH2, TPM2, and TNNI2 that encode parts of the skeletal muscle sarcomere cause muscle diseases affecting skeletal muscle, such as distal arthrogryposis (DA) syndromes and skeletal myopathies. To date, there have been few reports of genes (e.g., MYH7) encoding sarcomeric proteins in which the same pathogenic variant affects skeletal and cardiac muscle. Moreover, none of the known genes underlying DA have been found to contain pathogenic variants that also cause cardiac abnormalities. We report five families with DA because of heterozygous missense variants in the gene actin, alpha, cardiac muscle 1 (ACTC1). ACTC1 encodes a highly conserved actin that binds to myosin in cardiac and skeletal muscle. Pathogenic variants in ACTC1 have been found previously to underlie atrial septal defect, dilated cardiomyopathy, hypertrophic cardiomyopathy, and left ventricular noncompaction. Our discovery delineates a new DA condition because of variants in ACTC1 and suggests that some functions of ACTC1 are shared in cardiac and skeletal muscle.

Variants in ACTC1 underlie distal arthrogryposis accompanied by congenital heart defects.

Contraction of the human sarcomere is the result of interactions between myosin cross-bridges and actin filaments. Pathogenic variants in genes such as MYH7 , TPM1 , and TNNI3 that encode parts of the cardiac sarcomere cause muscle diseases that affect the heart, such as dilated cardiomyopathy and hypertrophic cardiomyopathy. In contrast, pathogenic variants in homologous genes MYH2 , TPM2 , and TNNI2 , that encode parts of the skeletal muscle sarcomere, cause muscle diseases affecting skeletal muscle, such as the distal arthrogryposis (DA) syndromes and skeletal myopathies. To date, there have been few reports of genes (e.g., MYH7 ) encoding sarcomeric proteins in which the same pathogenic variant affects both skeletal and cardiac muscle. Moreover, none of the known genes underlying DA have been found to contain mutations that also cause cardiac abnormalities. We report five families with DA due to heterozygous missense variants in the gene actin, alpha, cardiac muscle 1 ( ACTC1 ). ACTC1 encodes a highly conserved actin that binds to myosin in both cardiac and skeletal muscle. Mutations in ACTC1 have previously been found to underlie atrial septal defect, dilated cardiomyopathy, hypertrophic cardiomyopathy, and left ventricular noncompaction. Our discovery delineates a new DA condition due to mutations in ACTC1 and suggests that some functions of actin, alpha, cardiac muscle 1 are shared in cardiac and skeletal muscle.

CNS tumor with BCOR internal tandem duplication.

CNS tumor with BCOR internal tandem duplication is a recently proposed malignant tumor. The patient was an 18-month-old boy with torticollis and vomiting due to cerebellar hemispheric mass with extension to cerebellopontine angle and foramen magnum. Histopathologic examination of the tumor showed a moderately cellular tumor with microcystic formation, myxoid change, and atypical rosettes resembling Homer Wright rosettes. Illumina TruSight RNA Pan-Cancer NGS of the tumor genome revealed BCOR gene exon 15 internal tandem duplications.

Neurons and glial cells acquire a senescent signature after repeated mild traumatic brain injury in a sex-dependent manner.

Mild traumatic brain injury (mTBI) is an important public health issue, as it can lead to long-term neurological symptoms and risk of neurodegenerative disease. The pathophysiological mechanisms driving this remain unclear, and currently there are no effective therapies for mTBI. In this study on repeated mTBI (rmTBI), we have induced three mild closed-skull injuries or sham procedures, separated by 24 h, in C57BL/6 mice. We show that rmTBI mice have prolonged righting reflexes and astrogliosis, with neurological impairment in the Morris water maze (MWM) and the light dark test. Cortical and hippocampal tissue analysis revealed DNA damage in the form of double-strand breaks, oxidative damage, and R-loops, markers of cellular senescence including p16 and p21, and signaling mediated by the cGAS-STING pathway. This study identified novel sex differences after rmTBI in mice. Although these markers were all increased by rmTBI in both sexes, females had higher levels of DNA damage, lower levels of the senescence protein p16, and lower levels of cGAS-STING signaling proteins compared to their male counterparts. Single-cell RNA sequencing of the male rmTBI mouse brain revealed activation of the DNA damage response, evidence of cellular senescence, and pro-inflammatory markers reminiscent of the senescence-associated secretory phenotype (SASP) in neurons and glial cells. Cell-type specific changes were also present with evidence of brain immune activation, neurotransmission alterations in both excitatory and inhibitory neurons, and vascular dysfunction. Treatment of injured mice with the senolytic drug ABT263 significantly reduced markers of senescence only in males, but was not therapeutic in females. The reduction of senescence by ABT263 in male mice was accompanied by significantly improved performance in the MWM. This study provides compelling evidence that senescence contributes to brain dysfunction after rmTBI, but may do so in a sex-dependent manner.

Ependymal cells and neurodegenerative disease: outcomes of compromised ependymal barrier function.

Within the central nervous system, ependymal cells form critical components of the blood-cerebrospinal fluid barrier and the cerebrospinal fluid-brain barrier. These barriers provide biochemical, immunological and physical protection against the entry of molecules and foreign substances into the cerebrospinal fluid while also regulating cerebrospinal fluid dynamics, such as the composition, flow and removal of waste from the cerebrospinal fluid. Previous research has demonstrated that several neurodegenerative diseases, such as Alzheimer's disease and multiple sclerosis, display irregularities in ependymal cell function, morphology, gene expression and metabolism. Despite playing key roles in maintaining overall brain health, ependymal barriers are largely overlooked and understudied in the context of disease, thus limiting the development of novel diagnostic and treatment options. Therefore, this review explores the anatomical properties, functions and structures that define ependymal cells in the healthy brain, as well as the ways in which ependymal cell dysregulation manifests across several neurodegenerative diseases. Specifically, we will address potential mechanisms, causes and consequences of ependymal cell dysfunction and describe how compromising the integrity of ependymal barriers may initiate, contribute to, or drive widespread neurodegeneration in the brain.

Evidence of sex differences in cellular senescence.

Biological sex is a factor in many conditions, including aging, neurodegenerative disease, cancer, and more. For each of these, men and women display distinct differences in disease development and progression. To date, studies on the molecular basis of such differences have largely focused on sex hormones, typically highlighting their neuroprotective benefits. However, new research suggests that cellular senescence may underlie sex differences in both neurological and non-neurological pathologies. Cellular senescence-stable proliferative arrest with a unique pro-inflammatory phenotype-occurs in response to persistent DNA damage signaling, safeguarding against tissue-level consequences of DNA damage (e.g., tumorigenesis). Though critical for maintaining tissue health, senescence has also been implicated in disease. Indeed, senescent cell accumulation occurs in multiple disease contexts, and the elimination of such cells (via senolytic therapies) alleviates associated disease hallmarks. If cell senescence is a driver of pathophysiology, sex differences in cellular senescence may underlie sex-specific disease outcomes. This review summarizes evidence of sex differences in cellular senescence-highlighting findings from both human and animal studies-and briefly discusses the potential relevance of sex chromosome epigenetics and mosaicism. Current studies show that female sex is associated with greater susceptibility to DNA damage and greater likelihood of senescence onset, despite additional evidence that estrogen protects against genotoxic insult and inhibits senescence regulatory proteins. Further studies on sex differences in cellular senescence are needed, both to verify whether findings from animal studies hold true in human contexts and to validate whether senescence manifests differently between men and women following comparable senescence-inducing stimuli.

Investigating the use of plasma pTau181 in retired contact sports athletes.

BACKGROUND: Considering the wide range of outcomes following sport-related concussions, biomarkers are needed to detect underlying pathological changes. The objective was to analyze the use of plasma phosphorylated tau 181 (pTau181) as a non-invasive measure of underlying brain changes in a cohort of retired contact sports athletes at risk of neurodegeneration. METHODS: Fifty-four retired contact sport athletes and 27 healthy controls whose blood plasma was analyzed for pTau181 were included. A portion (N = 21) of retired athletes had a 2-years follow-up visit. All participants had completed a neuropsychological battery and MRI imaging. RESULTS: Plasma pTau181 was significantly higher in retired athletes compared to healthy controls (8.94 ± 5.08 pg/mL vs. 6.00 ± 2.53 pg/mL, respectively; 95% BCa CI 1.38-4.62; p = 0.02); and was significantly associated with fornix fractional anisotropy values only in the athletes group (ß = - 0.002; 95% BCa CI - 0.003 to - 0.001; p = 0.002). When the retired athletes cohort was divided into high vs. normal pTau181 groups, the corpus callosum (CC) volume and white-matter integrity was significantly lower in high pTau181 compared to older healthy controls (CC volume: 1.57 ± 0.19 vs. 2.02 ± 0.32, p = 0.002; CC medial diffusivity: 0.96 ± 0.04 × 10-3 mm2/s vs. 0.90 ± 0.03 × 10-3 mm2/s, p = 0.003; CC axial diffusivity: 1.49 ± 0.04 × 10-3 mm2/s vs. 1.41 ± 0.02 × 10-3 mm2/s, p < 0.001, respectively). CONCLUSIONS: Although high plasma pTau181 levels were associated with abnormalities in CC and fornix, baseline pTau181 did not predict longitudinal changes in regional brain volumes or white-matter integrity in the athletes. pTau181 may be useful for identifying those with brain abnormalities related to repeated concussion but not for predicting progression.

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.

Temporal patterns of microglial activation in white matter following experimental mild traumatic brain injury: a systematic literature review.

Mild traumatic brain injuries (mTBIs) are a prevalent form of injury that can result in persistent neurological impairments. Microglial activation has become increasingly recognized as a key process regulating the pathology of white matter in a wide range of brain injury and disease contexts. As white matter damage is known to be a major contributor to the impairments that follow mTBI, microglia have rightfully become a common target of investigation for the development of mTBI therapies and biomarkers. Recent work has demonstrated that the efficacy of microglial manipulation as a therapeutic intervention following injury or disease is highly time-sensitive, emphasizing the importance of advancing our understanding of the dynamics of post-mTBI microglial activation from onset to resolution. Current reporting of microglial activation in experimental studies of mTBI is non-standardized, which has limited our ability to identify concrete patterns of post-mTBI microglial activation over time. In this review, we examine preclinical studies of mTBI that report on microglial activation in white matter regions to summarize our current understanding of these patterns. Specifically, we summarize timecourses of post-mTBI microglial activation in white matter regions of the brain, identify factors that influence this activation, examine the temporal relationship between microglial activation and other post-mTBI assessments, and compare the relative sensitivities of various methods for detecting microglial activation. While the lack of replicated experimental conditions has limited the extent of conclusions that can confidently be drawn, we find that microglia are activated over a wide range of timecourses following mTBI and that microglial activation is a long-lasting outcome of mTBI that may resolve after most typical post-mTBI assessments, with the exception of those measuring oligodendrocyte lineage cell integrity. We identify several understudied parameters of post-mTBI microglial activation in white matter, such as the inclusion of female subjects. This review summarizes our current understanding of the progression of microglial activation in white matter structures following experimental mTBI and offers suggestions for important future research directions.

Management of Inoperable Supra-Sellar Low-Grade Glioma With BRAF Mutation in Young Children.

Pediatric low-grade gliomas (PLGGs) are the most common central nervous system (CNS) tumors in children. The current standard of care for surgically unresectable and/or progressive cases of PLGGs includes combination chemotherapy. PLGGs are molecularly characterized by alterations in the RAS/RAF/MAPK/ERK pathway in a majority of tumors. PLGGs harboring the BRAF-V600E mutation respond poorly to current chemotherapy strategies. We present a case of a two-year-old female with biopsy-proven low-grade glioma (LGG, pilocytic astrocytoma) involving the hypothalamic/optic chiasm region. At presentation, she had obstructive hydrocephalus, bitemporal hemianopia, central hypothyroidism, and right-sided hemiparesis due to the location/mass effect of the tumor. She was initially treated with chemotherapy (vincristine/carboplatin), but her tumor progressed at six weeks of treatment. She was subsequently started on dabrafenib as her tumor was positive for BRAF-V600E mutation. Dabrafenib monotherapy resulted in dramatic improvement in her clinical symptoms and near-complete resolution of tumor. Our experience and review of the literature suggest that LGGs with BRAF-V600E mutations may benefit from upfront targeted therapy in children. There is an urgent need for prospective clinical trials comparing the efficacy of upfront BRAF inhibitors versus standard chemotherapy in PLGGs with BRAF mutations.

Cellular Senescence in Traumatic Brain Injury: Evidence and Perspectives.

Mild traumatic brain injury (mTBI) can lead to long-term neurological dysfunction and increase one's risk of neurodegenerative disease. Several repercussions of mTBI have been identified and well-studied, including neuroinflammation, gliosis, microgliosis, excitotoxicity, and proteinopathy - however the pathophysiological mechanisms activating these pathways after mTBI remains controversial and unclear. Emerging research suggests DNA damage-induced cellular senescence as a possible driver of mTBI-related sequalae. Cellular senescence is a state of chronic cell-cycle arrest and inflammation associated with physiological aging, mood disorders, dementia, and various neurodegenerative pathologies. This narrative review evaluates the existing studies which identify DNA damage or cellular senescence after TBI (including mild, moderate, and severe TBI) in both experimental animal models and human studies, and outlines how cellular senescence may functionally explain both the molecular and clinical manifestations of TBI. Studies on this subject clearly show accumulation of various forms of DNA damage (including oxidative damage, single-strand breaks, and double-strand breaks) and senescent cells after TBI, and indicate that cellular senescence may be an early event after TBI. Further studies are required to understand the role of sex, cell-type specific mechanisms, and temporal patterns, as senescence may be a pathway of interest to target for therapeutic purposes including prognosis and treatment.

Paediatric atypical choroid plexus papilloma: is adjuvant therapy necessary?

INTRODUCTION: Choroid Plexus Tumours (CPTs) account for 1-4% of all brain tumours in children. Atypical choroid plexus papillomas (aCPPs) are a subset of these tumours, defined over a decade ago, yet no consensus exists on the optimal approach to their management. METHODS: We conducted a retrospective analysis of all patients treated for CPTs at the Hospital for Sick Children between January 1, 2000, and December 31, 2018, and focused on patients with aCPP. Data extracted from the patient records for analysis included: demographic and clinical features, radiological imaging, surgical and adjuvant therapies, key pathological features, immunohistochemical staining for TP53 and tumour karyotype. Six of seven aCPP samples were profiled using Illumina HumanMethylationEPIC arrays and the top 10,000 most variably methylated probes were visualized using tSNE. Copy number inferencing was also performed. RESULTS: Twenty-nine patients were diagnosed with CPT, seven of whom had a diagnosis of aCPP as confirmed by histological review. Methylation profiling demonstrated that aCPPs clustered with both choroid plexus papillomas (CPPs) and choroid plexus carcinomas (CPCs). Complete resection of the tumour was pursued in all cases of aCPP and no patient received adjuvant therapy. All aCPP patients were alive at last follow up. CONCLUSIONS: This limited case series suggests that paediatric aCPP can be successfully managed with surgical resection alone, followed by a 'watch and wait' approach thus avoiding adjuvant therapies. A deeper understanding of the biology of aCPP is required to identify objective markers which can help provide robust risk stratification and inform treatment strategies.