Lifelong Chronic Sleep Disruption in a Mouse Model of Traumatic Brain Injury.

Chronic sleep/wake disturbances (SWDs) are strongly associated with traumatic brain injury (TBI) in patients and are being increasingly recognized. However, the underlying mechanisms are largely understudied and there is an urgent need for animal models of lifelong SWDs. The objective of this study was to develop a chronic TBI rodent model and investigate the lifelong chronic effect of TBI on sleep/wake behavior. We performed repetitive midline fluid percussion injury (rmFPI) in 4-month-old mice and monitored their sleep/wake behavior using the non-invasive PiezoSleep system. Sleep/wake states were recorded before injury (baseline) and then monthly thereafter. We found that TBI mice displayed a significant decrease in sleep duration in both the light and dark phases, beginning at 3 months post-TBI and continuing throughout the study. Consistent with the sleep phenotype, these TBI mice showed circadian locomotor activity phenotypes and exhibited reduced anxiety-like behavior. TBI mice also gained less weight, and had less lean mass and total body water content, compared to sham controls. Further, TBI mice showed extensive brain tissue loss and increased glial fibrillary acidic protein and ionized calcium-binding adaptor molecule 1 levels in the hypothalamus and vicinity of the injury, indicative of chronic neuropathology. In summary, our study identified a critical time window of TBI pathology and associated circadian and sleep/wake phenotypes. Future studies should leverage this mouse model to investigate the molecular mechanisms underlying the chronic sleep/wake phenotypes post-TBI early in life.

Sleep Disruption in a Mouse Model of Chronic Traumatic Brain Injury.

Chronic sleep/wake disturbances are strongly associated with traumatic brain injury (TBI) in patients and are being increasingly recognized. However, the underlying mechanisms are largely understudied and there is an urgent need for animal models of lifelong sleep/wake disturbances. The objective of this study was to develop a chronic TBI rodent model and investigate the lifelong chronic effect of TBI on sleep/wake behavior. We performed repetitive midline fluid percussion injury (rmFPI) in four months old mice and monitored their sleep/wake behavior using the non-invasive PiezoSleep system. The sleep/wake states were recorded before injury (baseline) and then monthly thereafter. We found that TBI mice displayed a significant decrease in sleep duration in both the light and dark phases, beginning at three months post-TBI and continuing throughout the study. Consistent with the sleep phenotype, these TBI mice showed circadian locomotor activity phenotypes and exhibited reduced anxiety-like behavior. TBI mice also gained less weight, and had less lean mass and total body water content, compared to sham controls. Furthermore, TBI mice showed extensive brain tissue loss and increased GFAP and IBA1 levels in the hypothalamus and the vicinity of the injury, indicative of chronic neuropathology. In summary, our study identified a critical time window of TBI pathology and associated circadian and sleep/wake phenotypes. Future studies should leverage this mouse model to investigate the molecular mechanisms underlying the chronic sleep/wake phenotypes following TBI early in life.

Traumatic Brain Injury in Cameroon: A Prospective Observational Study in a Level I Trauma Centre.

Background and Objective: About 14 million people will likely suffer a traumatic brain injury (TBI) per year by 2050 in sub-Saharan Africa. Studying TBI characteristics and their relation to outcomes can identify initiatives to improve TBI prevention and care. The objective of this study was to define the features and outcomes of TBI patients seen over a 1-year period in a level-I trauma centre in Cameroon. Materials and Methods: Data on demographics, causes, clinical aspects, and discharge status were collected over a period of 12 months. The Glasgow Outcome Scale-Extended (GOSE) and the Quality-of-Life Questionnaire after Brain Injury (QoLIBRI) were used to evaluate outcomes six months after TBI. Comparisons between two categorical variables were done using Pearson's chi-square test. Results: A total of 160 TBI patients participated in the study. The age group 15-45 years was most represented (78%). Males were more affected (90%). A low educational level was seen in 122 (76%) cases. Road traffic incidents (RTI) (85%), assaults (7.5%), and falls (2.5%) were the main causes of TBI, with professional bike riders being frequently involved (27%). Only 15 patients were transported to the hospital by ambulance, and 14 of these were from a referring hospital. CT-imaging was performed in 78% of cases, and intracranial traumatic abnormalities were identified in 64% of cases. Financial constraints (93%) was the main reason for not performing a CT scan. Forty-six (33%) patients were discharged against medical advice (DAMA) due to financial constraints. Mortality was 14% (22/160) and high in patients with severe TBI (46%). DAMA had poor outcomes with QoLIBRI. Only four patients received post-injury physical therapy services. Conclusions: TBI in Cameroon mainly results from RTIs and commonly affects young adult males. Lack of pre-hospital care, financial constraints limiting both CT scanning and medical care, and a lack of acute physiotherapy services likely influenced care and outcomes adversely.

Neuroinflammatory Biomarkers for Traumatic Brain Injury Diagnosis and Prognosis: A TRACK-TBI Pilot Study.

The relationship between systemic inflammation and secondary injury in traumatic brain injury (TBI) is complex. We investigated associations between inflammatory markers and clinical confirmation of TBI diagnosis and prognosis. The prospective TRACK-TBI Pilot (Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot) study enrolled TBI patients triaged to head computed tomography (CT) and received blood draw within 24 h of injury. Healthy controls (HCs) and orthopedic controls (OCs) were included. Thirty-one inflammatory markers were analyzed from plasma. Area under the receiver operating characteristic curve (AUC) was used to evaluate discriminatory ability. AUC >0.7 was considered acceptable. Criteria included: TBI diagnosis (vs. OC/HC); moderate/severe vs. mild TBI (Glasgow Coma Scale; GCS); radiographic TBI (CT positive vs. CT negative); 3- and 6-month Glasgow Outcome Scale-Extended (GOSE) dichotomized to death/greater relative disability versus less relative disability (GOSE 1-4/5-8); and incomplete versus full recovery (GOSE <8/ = 8). One-hundred sixty TBI subjects, 28 OCs, and 18 HCs were included. Markers discriminating TBI/OC: HMGB-1 (AUC = 0.835), IL-1b (0.795), IL-16 (0.784), IL-7 (0.742), and TARC (0.731). Markers discriminating GCS 3-12/13-15: IL-6 (AUC = 0.747), CRP (0.726), IL-15 (0.720), and SAA (0.716). Markers discriminating CT positive/CT negative: SAA (AUC = 0.767), IL-6 (0.757), CRP (0.733), and IL-15 (0.724). At 3 months, IL-15 (AUC = 0.738) and IL-2 (0.705) discriminated GOSE 5-8/1-4. At 6 months, IL-15 discriminated GOSE 1-4/5-8 (AUC = 0.704) and GOSE <8/ = 8 (0.711); SAA discriminated GOSE 1-4/5-8 (0.704). We identified a profile of acute circulating inflammatory proteins with potential relevance for TBI diagnosis, severity differentiation, and prognosis. IL-15 and serum amyloid A are priority markers with acceptable discrimination across multiple diagnostic and outcome categories. Validation in larger prospective cohorts is needed. ClinicalTrials.gov Registration: NCT01565551.

Neurobiochemical, Peptidomic, and Bioinformatic Approaches to Characterize Tauopathy Peptidome Biomarker Candidates in Experimental Mouse Model of Traumatic Brain Injury.

Traumatic brain injury (TBI) is a multidimensional damage, and currently, no FDA-approved medicine is available. Multiple pathways in the cell are triggered through a head injury (e.g., calpain and caspase activation), which truncate tau and generate variable fragment sizes (MW 400-45,000 K). In this study, we used an open-head TBI mouse model generated by controlled cortical impact (CCI) and collected ipsilateral (IC) and contralateral (CC) mice htau brain cortices at one (D1) three (D3), and seven (D7) days post-injury. We implemented immunological (antibody-based detection) and peptidomic approaches (nano-reversed-phase liquid chromatography/tandem mass spectrometry) to investigate proteolytic tau peptidome (low molecular weight (LMW) < 10 K)) and pathological phosphorylation sites (high-molecular-weight (HMW); > 10 K) derived from CCI-TBI animal models. Our immunoblotting analysis verified tau hyperphosphorylation, HMW, and HMW breakdown products (HMW-BDP) formation of tau (e.g., pSer202, pThr181, pThr231, pSer396, and pSer404), following CCI-TBI. Peptidomic data revealed unique sequences of injury-dependent proteolytic peptides generated from human tau protein. Among the N-terminal tau peptides, EIPEGTTAEEAGIGDTPSLEDEAAGHVTQA (a.a. 96-125) and AQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARM (a.a. 91-127). Examples of tau C-terminal peptides identified include NVSSTGSIDMVDSPQLATLADEVSASLAKQGL (a.a. 410-441) and QLATLADEVSASLAKQGL (a.a. 424-441). Our peptidomic bioinformatic tools showed the association of proteases, such as CAPN1, CAPN2, and CTSL; CASP1, MMP7, and MMP9; and ELANE, GZMA, and MEP1A, in CCI-TBI tau peptidome. In clinical trials for novel TBI treatments, it might be useful to monitor a subset of tau peptidome as targets for biomarker utility and use them for a "theranostic" approach.

Concomitant Guillain-Barré Syndrome and COVID-19: A Meta-Analysis of Cases.

Background and Objectives: Recent findings demonstrate that the transmigration of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) to the nervous system implicates severe neurotropic pathologies, including the onset of the rare disease called Guillain-Barré syndrome (GBS) which is characterized by immune-mediated polyneuropathy. This study aimed to identify the predisposing factors and the clinical features of coronavirus disease 2019 (COVID-19)-induced GBS. Materials and Methods: We have performed an analysis of 147 cases. A systematic review of the published research work was performed per the PRISMA statement to obtain individual participant data (IPD) for the meta-analysis. The search was conducted through PubMed, using the combined search terms "Guillain-Barré syndrome" and "COVID-19". All case reports and series in the English language with accessed full text were included in the search. Results: A systematic database search led to the retrieval of 112 peer-reviewed articles published between 1 April 2020, and 8 February 2022. The articles comprised 16 case series and 96 case reports containing IPD for 147 patients. Our findings showed that 77.6% of all cases were 40 years or older. Males comprised most of the cases (65.3%; n = 96). The intensive care unit (ICU) admission was 44.9%, and the need for mechanical ventilation (MV) was 38.1%. The patients presented with hyporeflexia or areflexia (84.4%; n = 124), lower limb strength and sensation impairment (93.2%; n = 138), upper limb strength and sensation impairment (85.7; n = 126), and somatic sensation impairment (72.8%; n = 107). The patients presented with increased cerebral spinal fluid (CSF) protein levels (92%; n = 92) and the presence of CSF albuminocytological dissociation (83.5%; n = 71). The most common variant of GBS observed was acute inflammatory demyelinating polyneuropathy (AIDP). We found that predisposing factors concomitant with COVID-19 and GBS were male gender and older age. Among the cases, patient mortality was 10.9%. Conclusions: A gap of knowledge exists regarding the complete spectrum of clinical characteristics of COVID-19-related GBS. Recent findings suggest that SARS-CoV-2 triggers GBS, as it follows a similar para-infectious pattern as the other viral agents contributing to the onset of GBS.

Exploring serum glycome patterns after moderate to severe traumatic brain injury: A prospective pilot study.

Background: Glycans play essential functional roles in the nervous system and their pathobiological relevance has become increasingly recognized in numerous brain disorders, but not fully explored in traumatic brain injury (TBI). We investigated longitudinal glycome patterns in patients with moderate to severe TBI (Glasgow Coma Scale [GCS] score ≤12) to characterize glyco-biomarker signatures and their relation to clinical features and long-term outcome. Methods: This prospective single-center observational study included 51 adult patients with TBI (GCS ≤12) admitted to the neurosurgical unit of the University Hospital of Pecs, Pecs, Hungary, between June 2018 and April 2019. We used a high-throughput liquid chromatography-tandem mass spectrometry platform to assess serum levels of N-glycans up to 3 days after injury. Outcome was assessed using the Glasgow Outcome Scale-Extended (GOS-E) at 12 months post-injury. Multivariate statistical techniques, including principal component analysis and orthogonal partial least squares discriminant analysis, were used to analyze glycomics data and define highly influential structures driving class distinction. Receiver operating characteristic analyses were used to determine prognostic accuracy. Findings: We identified 94 N-glycans encompassing all typical structural types, including oligomannose, hybrid, and complex-type entities. Levels of high mannose, hybrid and sialylated structures were temporally altered (p<0·05). Four influential glycans were identified. Two brain-specific structures, HexNAc5Hex3DeoxyHex0NeuAc0 and HexNAc5Hex4DeoxyHex0NeuAc1, were substantially increased early after injury in patients with unfavorable outcome (GOS-E≤4) (area under the curve [AUC]=0·75 [95%CI 0·59-0·90] and AUC=0·71 [0·52-0·89], respectively). Serum levels of HexNAc7Hex7DeoxyHex1NeuAc2 and HexNAc8Hex6DeoxyHex0NeuAc0 were persistently increased in patients with favorable outcome, but undetectable in those with unfavorable outcome. Levels of HexNAc5Hex4DeoxyHex0NeuAc1 were acutely elevated in patients with mass lesions and in those requiring decompressive craniectomy. Interpretation: In spite of the exploratory nature of the study and the relatively small number of patients, our results provide to the best of our knowledge initial evidence supporting the utility of glycomics approaches for biomarker discovery and patient phenotyping in TBI. Further larger multicenter studies will be required to validate our findings and to determine their pathobiological value and potential applications in practice. Funding: This work was funded by the Italian Ministry of Health (grant number GR-2013-02354960), and also partially supported by a NIH grant (1R01GM112490-08).

Western and ketogenic diets in neurological disorders: can you tell the difference?

The prevalence of obesity tripled worldwide between 1975 and 2016, and it is projected that half of the US population will be overweight by 2030. The obesity pandemic is attributed, in part, to the increasing consumption of the high-fat, high-carbohydrate Western diet, which predisposes to the development of the metabolic syndrome and correlates with decreased cognitive performance. In contrast, the high-fat, low-carbohydrate ketogenic diet has potential therapeutic roles and has been used to manage intractable seizures since the early 1920s. The brain accounts for 25% of total body glucose metabolism and, as a result, is especially susceptible to changes in the types of nutrients consumed. Here, we discuss the principles of brain metabolism with a focus on the distinct effects of the Western and ketogenic diets on the progression of neurological diseases such as epilepsy, Parkinson's disease, Alzheimer's disease, and traumatic brain injury, highlighting the need to further explore the potential therapeutic effects of the ketogenic diet and the importance of standardizing dietary formulations to assure the reproducibility of clinical trials.

Delayed-Onset Neuropathological Complications From a Foramen Magnum and Occipital Crest-Focused Traumatic Brain Injury of the Vietnam War and Other Conflicts: Part II, Research Analysis.

INTRODUCTION: Much of the research impacting diagnosis, outcome, and treatment of traumatic brain injuries (TBIs) has favored time of consciousness criteria indicative of hemispheric blast focus alone. However, recent animal-based research has widely expanded the diagnostic knowledge base and potential treatment options. METHODS: Recent animal-based research findings of foramen magnum and occipital crest-focused blast injuries in laboratory rats were reviewed and compared to the Part I human case report. RESULTS: Comparing the human case report (Part I) to that of animal research studies found very similar neuropathological outcomes, many deep and delayed, and supports why non-cerebral-focused TBIs have gone unrecognized. The overpressure wave is funneled through skull openings of the foramen magnum, with the possibility of a rebound secondary contrecoup injury impacting the orbits, oral-nasal cavity, and ears resulting in additional occult axonal and white matter injury. CONCLUSIONS: Research analysis prompted by a human case report (Part I) has helped identify mechanisms that assist in recognizing and defining non-cerebral hemispheric-focused TBI injuries. Position of the head in relationship to the blast wave, the setting in which the blast occurs, and close diagnostic follow-up are critical to the recognition, diagnosis, and treatment of injuries that have otherwise gone unrecognized and unstudied in humans since the Vietnam War.

Delayed-Onset Neuropathological Complications From a Foramen Magnum and Occipital Crest Focused Traumatic Brain Injury of the Vietnam War and Other Conflicts: Part I, Case Report.

INTRODUCTION: The diagnosis of traumatic brain injuries is typically based on hemispheric blasts resulting in degrees of unconsciousness and associated cerebral injuries. This case report describes a Vietnam War era setting in which a traumatic blast wave struck the posterior cranium in the region of the foramen magnum, occipital crest, and other skull openings (orbit, oronasal, and ear) and the unique secondary clinical signs and symptoms experienced over time. MATERIALS AND METHODS: This case report describes secondary delayed-onset clinical signs and symptoms consistent with progressive decades-long physical and functional complications. The traumatic blast resulted in brief unconsciousness, decreased vision in left eye, confusion, right sided hemotympanum, deafness, severe tinnitus, severe nasopharynx pain and difficulty swallowing, pain in right posterior and occipital area of the head, and loss of dental amalgams. Subsequent exams revealed progressive hyperacusis, sea sickness, dysdiadochokinesis, diagnosis of 9th and 10th cranial nerve traumatic schwannomas, hyperdense changes to the frontal lobe white matter, progressive tinnitus, chronic vertigo, right-sided high-frequency hearing loss, progressive oculo-gyric crisis of Tumarkin-like seizures, left-sided chronic vitreous hemorrhage, and diminished right hemisphere performance of the brain based on neurophysiological assessment. No post-traumatic stress, depression, or other emotional or psychiatric difficulties were claimed. CONCLUSION: This case report, unique to the English language scientific literature, discusses in detail the secondary signs and symptoms of a foramen magnum and occipital crest focused-associated blast injury.

Delayed-Onset Neuropathological Complications From a Foramen Magnum and Occipital Crest Focused TBI of the Vietnam War and Other Conflicts: Part III, Critique of Existing TBI Criteria and Their Operational Controversies.

INTRODUCTION: In this report, we discuss the controversy of the diverse traumatic brain injury (TBI) categorization and taxonomy and the need to develop a new multidimensional and multidisciplinary categorization system that can be an aid in improved diagnostic and prognostic outcomes. Of interest, the heterogeneity of TBI marks the major obstacle to develop effective therapeutic interventions. Currently, the Glasgow Coma Scale has been utilized to guide in the prognosis and clinical management of TBI; it does not encompass the pathophysiological mechanisms leading to neurological deficits that can impede therapeutic interventions and consequently the failure of clinical trials. An unfortunate gap exists between advances in TBI research and existing U.S. Department of Defense (DoD) definitions, categorization, and management. Part I illustrates a unique posterior-focused TBI case report that does not fit any existing TBI definitions. Part II summarizes new animal-based TBI research that supports the case report as a legitimate TBI category. Part III critiques existing TBI criteria and their controversies. METHODS: Current DoD definitions and decision-making protocols based on concussion time alone are reviewed and compared to the myriad of additional TBI definitions that further illustrate the marked differences in definitions, especially in mild TBIs. RESULTS: The DoD definitions are not consistent with what academic research and science bring to the debate. With increasing world conflicts and wars, evaluators are not prepared to accept, evaluate, and properly manage those TBIs that are not associated with immediate levels of unconsciousness alone as the prime determinant of diagnosis and long-term severity. Despite comprehensive research, current understanding among decision-makers of progressive pathology of non-hemispheric TBIs remains limited, inconsistent, and confusing. CONCLUSIONS: This dilemma requires a multidisciplinary, science/medicine-led panel to actively reassess TBI criteria that take into consideration the latest research including non-cerebral hemispheric injuries. We recommend that DoD/Veterans Affairs establish a commission to regularly review the academic-related scientific evidence and incorporate these findings in a timely fashion into their operational definitions. This would guarantee that recognition, diagnosis, and follow-up of all TBIs are properly understood, managed, and documented.

Elevation of Pro-inflammatory and Anti-inflammatory Cytokines in Rat Serum after Acute Methamphetamine Treatment and Traumatic Brain Injury.

The use of methamphetamine (METH) is a growing worldwide epidemic that bears grave societal implications. METH is known to exert its neurotoxic effects on the dopaminergic and serotonergic systems of the brain. In addition to this classical studied mechanism of damage, findings from our laboratory and others have shown that acute METH treatment and mechanical injury, i.e. traumatic brain injury (TBI), share common cell injury mechanism(s). Since neuro-inflammation is a signature event in TBI, we hypothesize that certain cytokine levels might also be altered in rat brain exposed to an acute METH insult. In this study, using a cytokine antibody array chip, we evaluated the serum levels of 19 cytokines in rats 24 h after exposure to a 40 mg/kg acute regimen of METH. Data were compared to rats subjected to experimental TBI using the controlled cortical impact (CCI) injury model and saline controls. Sandwich ELISA method was used to further validate some of the findings obtained from the antibody cytokine array. We confirmed that three major inflammatory-linked cytokines (IL-1ß, IL-6, and IL-10) were elevated in the METH and TBI groups compared to the saline group. Such finding suggests the involvement of an inflammatory process in these brain insults, indicating that METH use is, in fact, a stressor to the immune system where systemic involvement of an altered cytokine profile may play a major role in mediating chemical brain injury after METH use.

Modulation of Neuro-Inflammatory Signals in Microglia by Plasma Prekallikrein and Neuronal Cell Debris.

Microglia, the resident phagocytes of the central nervous system and one of the key modulators of the innate immune system, have been shown to play a major role in brain insults. Upon activation in response to neuroinflammation, microglia promote the release of inflammatory mediators as well as promote phagocytosis. Plasma prekallikrein (PKall) has been recently implicated as a mediator of neuroinflammation; nevertheless, its role in mediating microglial activation has not been investigated yet. In the current study, we evaluate the mechanisms through which PKall contributes to microglial activation and release of inflammatory cytokines assessing PKall-related receptors and their dynamics. Murine N9-microglial cells were exposed to PKall (2.5 ng/ml), lipopolysaccharide (100 ng/ml), bradykinin (BK, 0.1 µM), and neuronal cell debris (16.5 µg protein/ml). Gene expression of bradykinin 2 receptor (B2KR), protease-activated receptor 2 (PAR-2), along with cytokines and fibrotic mediators were studied. Bioinformatic analysis was conducted to correlate altered protein changes with microglial activation. To assess receptor dynamics, HOE-140 (1 µM) and GB-83 (2 µM) were used to antagonize the B2KR and PAR-2 receptors, respectively. Also, the role of autophagy in modulating microglial response was evaluated. Data from our work indicate that PKall, LPS, BK, and neuronal cell debris resulted in the activation of microglia and enhanced expression/secretion of inflammatory mediators. Elevated increase in inflammatory mediators was attenuated in the presence of HOE-140 and GB-83, implicating the engagement of these receptors in the activation process coupled with an increase in the expression of B2KR and PAR-2. Finally, the inhibition of autophagy significantly enhanced the release of the cytokine IL-6 which were validated via bioinformatics analysis demonstrating the role of PKall in systematic and brain inflammatory processes. Taken together, we demonstrated that PKall can modulate microglial activation via the engagement of PAR-2 and B2KR where PKall acts as a neuromodulator of inflammatory processes.

Searching for Novel Candidate Biomarkers of RLS in Blood by Proteomic Analysis.

PURPOSE: We performed comparative proteomic analyses of blood of patients with RLS and healthy individuals aiming to identify potential biomarker and therapeutic target candidate for RLS. PATIENTS AND METHODS: Blood serum samples from 12 patients with a clinical diagnosis of RLS (8 females and 4 males, with a mean age of 68.52 years) and 10 healthy controls (5 females and 5 males, with a mean age of 67.61 years) underwent proteomic profiling by liquid chromatography coupled with tandem mass spectrometry. Pathway analysis incorporating protein-protein interaction networks was carried out to identify pathological processes linked to the differentially expressed proteins. RESULTS: We quantified 272 proteins in patients with RLS and healthy controls, of which 243 were shared. Five proteins - apolipoprotein C-II, leucine-rich alpha-2-glycoprotein 1, FLJ92374, extracellular matrix protein 1, and FLJ93143 - were substantially increased in RLS patients, whereas nine proteins - vitamin D-binding protein, FLJ78071, alpha-1-antitrypsin, CD5 antigen-like, haptoglobin, fibrinogen alpha chain, complement factor H-related protein 1, platelet factor 4, and plasma protease C1 inhibitor - were decreased. Bioinformatics analyses revealed that these proteins were linked to 1) inflammatory and immune response, and complement activation, 2) brain-related development, cell aging, and memory disorders, 3) pregnancy and associated complications, 4) myocardial infarction, and 5) reactive oxygen species generation and subsequent diabetes mellitus. CONCLUSION: Our findings shed light on the multifactorial nature of RLS and identified a set of circulating proteins that may have clinical importance as biomarkers and therapeutic targets.

Identification of clinically relevant biomarkers of epileptogenesis - a strategic roadmap.

Onset of many forms of epilepsy occurs after an initial epileptogenic insult or as a result of an identified genetic defect. Given that the precipitating insult is known, these epilepsies are, in principle, amenable to secondary prevention. However, development of preventive treatments is difficult because only a subset of individuals will develop epilepsy and we cannot currently predict which individuals are at the highest risk. Biomarkers that enable identification of these individuals would facilitate clinical trials of potential anti-epileptogenic treatments, but no such prognostic biomarkers currently exist. Several putative molecular, imaging, electroencephalographic and behavioural biomarkers of epileptogenesis have been identified, but clinical translation has been hampered by fragmented and poorly coordinated efforts, issues with inter-model reproducibility, study design and statistical approaches, and difficulties with validation in patients. These challenges demand a strategic roadmap to facilitate the identification, characterization and clinical validation of biomarkers for epileptogenesis. In this Review, we summarize the state of the art with respect to biomarker research in epileptogenesis and propose a five-phase roadmap, adapted from those developed for cancer and Alzheimer disease, that provides a conceptual structure for biomarker research.

Thorough overview of ubiquitin C-terminal hydrolase-L1 and glial fibrillary acidic protein as tandem biomarkers recently cleared by US Food and Drug Administration for the evaluation of intracranial injuries among patients with traumatic brain injury.

Traumatic brain injury (TBI) is a major cause of mortality and morbidity affecting all ages. It remains to be a diagnostic and therapeutic challenge, in which, to date, there is no Food and Drug Administration-approved drug for treating patients suffering from TBI. The heterogeneity of the disease and the associated complex pathophysiology make it difficult to assess the level of the trauma and to predict the clinical outcome. Current injury severity assessment relies primarily on the Glasgow Coma Scale score or through neuroimaging, including magnetic resonance imaging and computed tomography scans. Nevertheless, such approaches have certain limitations when it comes to accuracy and cost efficiency, as well as exposing patients to unnecessary radiation. Consequently, extensive research work has been carried out to improve the diagnostic accuracy of TBI, especially in mild injuries, because they are often difficult to diagnose. The need for accurate and objective diagnostic measures led to the discovery of biomarkers significantly associated with TBI. Among the most well-characterized biomarkers are ubiquitin C-terminal hydrolase-L1 and glial fibrillary acidic protein. The current review presents an overview regarding the structure and function of these distinctive protein biomarkers, along with their clinical significance that led to their approval by the US Food and Drug Administration to evaluate mild TBI in patients.

Western diet aggravates neuronal insult in post-traumatic brain injury: Proposed pathways for interplay.

Traumatic brain injury (TBI) is a global health burden and a major cause of disability and mortality. An early cascade of physical and structural damaging events starts immediately post-TBI. This primary injury event initiates a series of neuropathological molecular and biochemical secondary injury sequelae, that last much longer and involve disruption of cerebral metabolism, mitochondrial dysfunction, oxidative stress, neuroinflammation, and can lead to neuronal damage and death. Coupled to these events, recent studies have shown that lifestyle factors, including diet, constitute additional risk affecting TBI consequences and neuropathophysiological outcomes. There exists molecular cross-talk among the pathways involved in neuronal survival, neuroinflammation, and behavioral outcomes, that are shared among western diet (WD) intake and TBI pathophysiology. As such, poor dietary intake would be expected to exacerbate the secondary damage in TBI. Hence, the aim of this review is to discuss the pathophysiological consequences of WD that can lead to the exacerbation of TBI outcomes. We dissect the role of mitochondrial dysfunction, oxidative stress, neuroinflammation, and neuronal injury in this context. We show that currently available data conclude that intake of a diet saturated in fats, pre- or post-TBI, aggravates TBI, precludes recovery from brain trauma, and reduces the response to treatment.

Correction to: Qualitative vs. Quantitative Methods in Psychiatric Research: Updated.

Chapter 2 was published with incorrect family name of the chapter author as Kobiessy.