Motor neurons are dispensable for the assembly of a sensorimotor circuit for gaze stabilization.

Sensorimotor reflex circuits engage distinct neuronal subtypes, defined by precise connectivity, to transform sensation into compensatory behavior. Whether and how motor neuron populations specify the subtype fate and/or sensory connectivity of their pre-motor partners remains controversial. Here, we discovered that motor neurons are dispensable for proper connectivity in the vestibular reflex circuit that stabilizes gaze. We first measured activity following vestibular sensation in pre-motor projection neurons after constitutive loss of their extraocular motor neuron partners. We observed normal responses and topography indicative of unchanged functional connectivity between sensory neurons and projection neurons. Next, we show that projection neurons remain anatomically and molecularly poised to connect appropriately with their downstream partners. Lastly, we show that the transcriptional signatures that typify projection neurons develop independently of motor partners. Our findings comprehensively overturn a long-standing model: that connectivity in the circuit for gaze stabilization is retrogradely determined by motor partner-derived signals. By defining the contribution of motor neurons to specification of an archetypal sensorimotor circuit, our work speaks to comparable processes in the spinal cord and advances our understanding of general principles of neural development.

Choline supplementation in early life improves and low levels of choline can impair outcomes in a mouse model of Alzheimer's disease.

Maternal choline supplementation (MCS) improves cognition in Alzheimer's disease (AD) models. However, effects of MCS on neuronal hyperexcitability in AD are unknown. We investigated effects of MCS in a well-established mouse model of AD with hyperexcitability, the Tg2576 mouse. The most common type of hyperexcitability in Tg2576 mice, and many other mouse models and AD patients, are generalized EEG spikes (interictal spikes; IIS). Hyperexcitability is also reflected by elevated expression of the transcription factor ΔFosB in the granule cells (GCs) of the dentate gyrus (DG), which are the principal cell type. We also studied the hilus of the DG because hilar neurons regulate GC excitability. We found reduced expression of the neuronal marker NeuN within hilar neurons in Tg2576 mice, which other studies have shown is a sign of oxidative stress or other pathology. Tg2576 breeding pairs received a diet with a relatively low, intermediate or high concentration of choline. After weaning, all mice received the intermediate diet. In offspring of mice fed the high choline diet, IIS frequency declined, GC ΔFosB expression was reduced, and NeuN expression was restored. Spatial memory improved using the novel object location task. In contrast, offspring exposed to the relatively low choline diet had several adverse effects, such as increased mortality. They had the weakest hilar NeuN immunoreactivity and greatest GC ΔFosB. However, their IIS frequency was low, which was surprising. The results provide new evidence that a diet high in choline in early life can improve outcomes in a mouse model of AD, and relatively low choline can have mixed effects. This is the first study showing that dietary choline can regulate hyperexcitability, hilar neurons, ΔFosB and spatial memory in an animal model of AD.

A feasibility assessment of a traumatic brain injury predictive modelling tool at Kilimanjaro Christian Medical Center and Duke University Hospital.

Traumatic brain injury (TBI) is the most common cause of death and disability globally. TBI, which disproportionately affects low middle-income countries (LMIC), uses significant amounts of health system resources in costly care and management. Innovative solutions are required to address this high burden of TBI. One possible solution is prognostic models which enhance diagnostic ability of physicians, thereby helping to tailor treatments more effectively. This study aims to evaluate the feasibility of a TBI prognostic model developed in Tanzania for use by Kilimanjaro Christian Medical Center (KCMC) healthcare providers and Duke-affiliated healthcare providers using human centered design methodology. Duke participants were included to gain insight from a different context with more established practices to inform the TBI tool implementation strategy at KCMC. To evaluate the feasibility of integrating the TBI tool into potential workflows, co-design interviews were conducted with emergency physicians and nursing staff at KCMC and Duke. Qualitatively, the TBI tool was assessed using human centered design (HCD) techniques. Our research design methods were created using the Consolidated Framework for Implementation Research which considers overarching characteristics of successful implementation to contribute to theory development and verification of implementation strategies across multiple contexts. Our knowledge translation method was guided using the knowledge-to-action framework. Of the 21 participants interviewed, 12 were associated with Duke Hospital, and 9 from Kilimanjaro Christian Medical Centre. Emerging from the data were 6 themes that impacted the implementation of the TBI tool: access, barriers, facilitators, use of the TBI tool, outer setting, and inner setting. To our knowledge, this is the first study to investigate the pre-implementation of a sub-Saharan Africa (SSA) data- based TBI prediction tool using human centered design methodology. Findings of this study will aid in determining under what conditions a TBI prognostic model intervention will work at KCMC.

Six month incidence of major adverse cardiovascular events among adults with HIV in northern Tanzania: a prospective observational study.

OBJECTIVES: We aimed to prospectively describe incident cardiovascular events among people living with HIV (PLWH) in northern Tanzania. Secondary aims of this study were to understand non-communicable disease care-seeking behaviour and patient preferences for cardiovascular care and education. DESIGN: A prospective observational study. SETTING: This study was conducted at the Majengo HIV Care and Treatment Clinic, an outpatient government-funded clinic in Moshi, Tanzania PARTICIPANTS: Adult patients presenting to an HIV clinic for routine care in northern Tanzania were enrolled from 1 September 2020 to 1 March 2021. INTERVENTIONS: At enrolment, participants completed a survey and a resting 12-lead ECG was obtained. At 6 month follow-up, a repeat survey regarding interim health events and repeat ECG was obtained. PRIMARY AND SECONDARY OUTCOME MEASURES: Interim major adverse cardiovascular events (MACE) were defined by: self-reported interim stroke, self-reported hospitalisation for heart failure, self-reported interim myocardial infarction, interim myocardial infarction by ECG criteria (new pathologic Q waves in two contiguous leads) or death due to cardiovascular disease (CVD). RESULTS: Of 500 enrolled participants, 477 (95.4%) completed 6 month follow-up and 3 (0.6%) died. Over the 6 month follow-up period, 11 MACE occurred (3 strokes, 6 myocardial infarctions, 1 heart failure hospitalisation and 1 cardiovascular death), resulting in an incidence rate of 4.58 MACE per 100 person-years. Of participants completing 6 month follow-up, 31 (6.5%) reported a new non-communicable disease diagnosis, including 23 (4.8%) with a new hypertension diagnosis. CONCLUSIONS: The incidence of MACE among PLWH in Tanzania is high. These findings are an important preliminary step in understanding the landscape of CVD among PLWH in Tanzania and highlight the need for interventions to reduce cardiovascular risk in this population.

Six-month incidence of hypertension and diabetes among adults with HIV in Tanzania: A prospective cohort study.

Data describing the incidence of hypertension and diabetes among people with HIV in sub-Saharan Africa remain sparse. In this study, adults with HIV were enrolled from a public clinic in Moshi, Tanzania (September 2020-March 2021). At enrollment, a survey was administered to collect information on comorbidities and medication use. Each participant's blood pressure and point-of-care glucose were measured. Baseline hypertension was defined by blood pressure ≥140/90 mmHg or self-reported hypertension at enrollment. Baseline diabetes was defined by self-reported diabetes or hyperglycemia (fasting glucose ≥126 mg/dl or random glucose ≥200 mg/dl) at enrollment. At 6-month follow-up, participants' blood pressure and point-of-care glucose were again measured. Incident hypertension was defined by self-report of new hypertension diagnosis or blood pressure ≥140/90 mmHg at follow-up in a participant without baseline hypertension. Incident diabetes was defined as self-report of new diabetes diagnosis or measured hyperglycemia at follow-up in a participant without baseline diabetes. During the study period, 477 participants were enrolled, of whom 310 did not have baseline hypertension and 457 did not have baseline diabetes. At six-month follow-up, 51 participants (95% CI: 38, 67) had new-onset hypertension, corresponding to an incidence of 33 new cases of hypertension per 100 person-years. Participants with incident hypertension at 6-month follow-up were more likely to have a history of alcohol use (90.2% vs. 73.7%, OR = 3.18, 95% CI:1.32-9.62, p = 0.008) and were older (mean age = 46.5 vs. 42.3, p = 0.027). At six-month follow-up, 8 participants (95% CI: 3, 16) had new-onset diabetes, corresponding to an incidence of 3 new cases of diabetes per 100 person-years. In conclusion, the incidence of elevated blood pressure and diabetes among Tanzanians with HIV is higher than what has been reported in high-income settings.

Six-month blood pressure and glucose control among HIV-infected adults with elevated blood pressure and hyperglycemia in northern Tanzania: A prospective observational study.

BACKGROUND: People with HIV in sub-Saharan Africa are increasingly developing age-related comorbidities. The purpose of this prospective observational study was to describe 6-month outcomes among Tanzanians with HIV and elevated blood pressure or hyperglycemia under current care pathways. METHODS: Adults presenting for routine HIV care were enrolled and underwent blood pressure and blood glucose measurements. Participants with abnormal blood pressure or glucose were referred for further care, as per current guidelines. Participants' blood pressure and point-of-care glucose were re-evaluated during their 6-month follow-up visit. Elevated blood pressure was defined as systolic ≥140 mmHg or diastolic ≥90 mmHg. Hyperglycemia was defined as fasting glucose ≥126 mg/dl or random glucose ≥200 mg/dl. An electrocardiogram was obtained at enrollment and at follow-up. Interim myocardial infarction and interim myocardial ischemia were defined as new pathologic Q waves and new T-wave inversions, respectively. RESULTS: Of 500 participants, 155 had elevated blood pressure and 17 had hyperglycemia at enrolment. At 6-month follow-up, 7 (4.6%) of 155 participants with elevated blood pressure reported current use of an anti-hypertensive medication, 100 (66.2%) had persistent elevated blood pressure, 12 (7.9%) developed interim myocardial infarction, and 13 (8.6%) developed interim myocardial ischemia. Among 17 participants with hyperglycemia, 9 (56%) had persistent hyperglycemia at 6 months and 2 (12.5%) reported current use of an anti-hyperglycemic medication. CONCLUSIONS: Interventions are needed to improve non-communicable disease care pathways among Tanzanians with HIV.

The epidemiology of pediatric traumatic brain injury presenting at a referral center in Moshi, Tanzania.

BACKGROUND: Over 95% of childhood injury deaths occur in low- and middle-income countries (LMICs). Patients with severe traumatic brain injury (TBI) have twice the likelihood of dying in LMICs than in high-income countries (HICs). In Africa, TBI estimates are projected to increase to upwards of 14 million new cases in 2050; however, these estimates are based on sparse data, which underscores the need for robust injury surveillance systems. We aim to describe the clinical factors associated with morbidity and mortality in pediatric TBI at the Kilimanjaro Christian Medical Centre (KCMC) in Moshi, Tanzania to guide future prevention efforts. METHODS: We conducted a secondary analysis of a TBI registry of all pediatric (0-18 years of age) TBI patients presenting to the KCMC emergency department (ED) between May 2013 and April 2014. The variables included demographics, acute treatment and diagnostics, Glasgow Coma Scores (GCSs, severe 3-8, moderate 9-13, and mild 14-15), morbidity at discharge as measured by the Glasgow Outcome Scale (GOS, worse functional status 1-3, better functional status 4-6), and mortality status at discharge. The analysis included descriptive statistics, bivariable analysis and multivariable logistic regression to report the predictors of mortality and morbidity. The variables used in the multivariable logistic regression were selected according to their clinical validity in predicting outcomes. RESULTS: Of the total 419 pediatric TBI patients, 286 (69.3%) were male with an average age of 10.12 years (SD = 5.7). Road traffic injury (RTI) accounted for most TBIs (269, 64.4%), followed by falls (82, 19.62%). Of the 23 patients (5.58%) who had alcohol-involved injuries, most were male (3.6:1). Severe TBI occurred in 54 (13.0%) patients. In total, 90 (24.9%) patients underwent TBI surgery. Of the 21 (5.8%) patients who died, 11 (55.0%) had severe TBI, 6 (30.0%) had moderate TBI (GCS 9-13) and 3 (15.0%) presented with mild TBI (GCS>13). The variables most strongly associated with worse functional status included having severe TBI (OR = 9.45) and waiting on the surgery floor before being moved to the intensive care unit (ICU) (OR = 14.37). CONCLUSIONS: Most pediatric TBI patients were males who suffered RTIs or falls. Even among children under 18 years of age, alcohol was consumed by at least 5% of patients who suffered injuries, and more commonly among boys. Patients becoming unstable and having to be transferred from the surgery floor to the ICU could reflect poor risk identification in the ED or progression of injury severity. The next steps include designing interventions to reduce RTI, mitigate irresponsible alcohol use, and improve risk identification and stratification in the ED.

Utility of Family Reports in Predicting Emergency Department Patient Alcohol Use in Tanzania.

OBJECTIVE: Myriad reasons, including stigma, may prevent patients from self-reporting harmful use of alcohol in Tanzania. Family members may be more forthright but might not know the extent of the patient's alcohol use or suffer alcohol-related stigma as well. Our study aims to compare the reporting of patient alcohol use by emergency department patients themselves and their family members in Tanzania in order to describe the potential use of family reports as a proxy for patient self-reports. METHOD: We conducted a secondary descriptive analysis of a prospective cohort of adult patients seeking treatment for injury and their family members. We evaluated alcohol use behavior, alcohol-related consequences, and alcohol-related stigma reported by 231 patients and 231 family members (both majority male, ages 25-45 years), measured by the Alcohol Use Disorders Identification Test (AUDIT), Perceived Alcohol Stigma (PAS) scale, and the Drinker Inventory of Consequences (DrInC). Alcohol use behavior concordance/discordance between patients and families was established, and alcohol use and perceived stigma were analyzed. RESULTS: More than 72% of patient-family pairs showed alcohol use (AUDIT) concordance. Receiver operating characteristic curve and regression analysis suggests family reports to be clinically relevant, significant, and potentially accurate markers of patient alcohol use (sensitivity: 95.10%, specificity: 69.77%). Findings support the existence of stigma toward alcohol in this context, with similar stigma levels of patients and family members. CONCLUSIONS: Family-reported patient alcohol use may be an accurate proxy for patient self-reporting. Further research is needed into stigma toward alcohol that is culturally appropriate and adopted.

Enhanced excitability of the hippocampal CA2 region and its contribution to seizure activity in a mouse model of temporal lobe epilepsy.

The hippocampal CA2 region, an area important for social memory, has been suspected to play a role in temporal lobe epilepsy (TLE) because of its resistance to degeneration observed in neighboring CA1 and CA3 regions in both humans and rodent models of TLE. However, little is known about whether alterations in CA2 properties promote seizure generation or propagation. Here, we addressed the role of CA2 using the pilocarpine-induced status epilepticus model of TLE. Ex vivo electrophysiological recordings from acute hippocampal slices revealed a set of coordinated changes that enhance CA2 PC intrinsic excitability, reduce CA2 inhibitory input, and increase CA2 excitatory output to its major CA1 synaptic target. Moreover, selective chemogenetic silencing of CA2 pyramidal cells caused a significant decrease in the frequency of spontaneous seizures measured in vivo. These findings provide the first evidence that CA2 actively contributes to TLE seizure activity and may thus be a promising therapeutic target.

PRACT: a pragmatic randomized adaptive clinical trial protocol to investigate a culturally adapted brief negotiational intervention for alcohol use in the emergency department in Tanzania.

BACKGROUND: Alcohol use in resource-limited settings results in significant morbidity and mortality. These settings lack the necessary specialty-trained personnel and infrastructure. Therefore, implementing evidence-based interventions from high-income settings, like a brief negotiational intervention (BNI) for alcohol, will require rapid production of evidence of effectiveness to guide implementation priorities. Thus, this study describes a clinical trial protocol to rapidly optimize and evaluate the impact of a culturally adapted BNI to reduce alcohol-related harms and alcohol consumption among injury patients. METHODS: Our pragmatic, adaptive, randomized controlled trial (PRACT) is designed to determine the most effective intervention approach to reduce hazardous alcohol use among adult (≥18 years old) in acute (< 24 h) injury patients. Our culturally adapted, nurse-delivered, intervention (PPKAY) has been augmented with evidence-based, culturally appropriate standards and will be evaluated as follows. Stage 1 of the trial will determine if PPKAY, either with a standard short-message-service (SMS) booster or with a personalized SMS booster is more effective than usual care (UC). While optimizing statistical efficiency, Stage 2 drops the UC arm to compare the PPKAY with a standard SMS booster to PPKAY with a personalized SMS booster. Finally, in Stage 3, the more effective arm in Stage 2 is compared to PPKAY without an SMS booster. The study population is acute injury patients who present to Kilimanjaro Christian Medical Centre, Tanzania, who (1) test alcohol positive by breathalyzer upon arrival; (2) have an Alcohol Use Disorder Identification Test of 8 or above; and/or (3) have reported drinking alcohol prior to their injury. Outcome measures will be evaluated for all arms at 3, 6, 9, 12, and 24 months. The primary outcome for the study is the reduction of the number of binge drinking days in the 4 weeks prior to follow-up. Secondary outcomes include alcohol-related consequences, measured by the Drinker Inventory of Consequences. DISCUSSION: The findings from this study will be critically important to identify alcohol harm reduction strategies where alcohol research and interventions are scarce. Our innovative and adaptive trial design can transform behavior change research and identify the most effective nurse-driven intervention to be targeted for integration into standard care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04535011 . Registered on September 1, 2020.

Efference copies: Side-eyeing across species.

Efference copies of movement-inducing neural signals have been proposed to serve a role in gaze stabilization. Prior work has demonstrated a spino-extraocular motor circuit in the tadpole that relays copies of spinal commands to extraocular motor neurons. A recent study demonstrates the presence of this circuitry in mice, suggesting a unique method of gaze stabilization in the locomoting mouse.

An Excitatory and Epileptogenic Effect of Dentate Gyrus Mossy Cells in a Mouse Model of Epilepsy.

The sparse activity of hippocampal dentate gyrus (DG) granule cells (GCs) is thought to be critical for cognition and behavior, whereas excessive DG activity may contribute to disorders such as temporal lobe epilepsy (TLE). Glutamatergic mossy cells (MCs) of the DG are potentially critical to normal and pathological functions of the DG because they can regulate GC activity through innervation of GCs or indirectly through GABAergic neurons. Here, we test the hypothesis that MC excitation of GCs is normally weak, but under pathological conditions, MC excitation of GCs is dramatically strengthened. We show that selectively inhibiting MCs during severe seizures reduced manifestations of those seizures, hippocampal injury, and chronic epilepsy. In contrast, selectively activating MCs was pro-convulsant. Mechanistic in vitro studies using optogenetics further demonstrated the unanticipated ability of MC axons to excite GCs under pathological conditions. These results demonstrate an excitatory and epileptogenic effect of MCs in the DG.

Adult-born hippocampal neurons bidirectionally modulate entorhinal inputs into the dentate gyrus.

Young adult-born granule cells (abGCs) in the dentate gyrus (DG) have a profound impact on cognition and mood. However, it remains unclear how abGCs distinctively contribute to local DG information processing. We found that the actions of abGCs in the DG depend on the origin of incoming afferents. In response to lateral entorhinal cortex (LEC) inputs, abGCs exert monosynaptic inhibition of mature granule cells (mGCs) through group II metabotropic glutamate receptors. By contrast, in response to medial entorhinal cortex (MEC) inputs, abGCs directly excite mGCs through N-methyl-d-aspartate receptors. Thus, a critical function of abGCs may be to regulate the relative synaptic strengths of LEC-driven contextual information versus MEC-driven spatial information to shape distinct neural representations in the DG.

Converging and Differential Brain Phospholipid Dysregulation in the Pathogenesis of Repetitive Mild Traumatic Brain Injury and Alzheimer's Disease.

Repetitive mild traumatic brain injury (rmTBI) is a major epigenetic risk factor for Alzheimer's disease (AD). The precise nature of how rmTBI leads to or precipitates AD pathology is currently unknown. Numerous neurological conditions have shown an important role for dysfunctional phospholipid metabolism as a driving factor for the pathogenesis of neurodegenerative diseases. However, the precise role in rmTBI and AD remains elusive. We hypothesized that a detailed phospholipid characterization would reveal profiles of response to injury in TBI that overlap with age-dependent changes in AD and thus provide insights into the TBI-AD relationship. We employed a lipidomic approach examining brain phospholipid profiles from mouse models of rmTBI and AD. Cortex and hippocampal tissue were collected at 24 h, 3, 6, 9, and 12 months post-rmTBI, and at ages representing 'pre', 'peri' and 'post' onset of amyloid pathology (i.e., 3, 9, 15 months-old). Total levels of phosphatidylcholine (PC), phosphatidylethanolamine (PE), LysoPE, and phosphatidylinositol (PI), including their monounsaturated, polyunsaturated and saturated fatty acid (FA) containing species were significantly increased at acute and/or chronic time points post-injury in both brain regions. However, levels of most phospholipid species in PS1/APP mice were nominal in the hippocampus, while in the cortex, levels were significantly decreased at ages post-onset of amyloid pathology. Sphingomyelin and LysoPC levels showed coincidental trends in our rmTBI and AD models within the hippocampus, an increase at acute and/or chronic time points examined. The ratio of arachidonic acid (omega-6 FA) to docosahexaenoic acid (omega-3 FA)-containing PE species was increased at early time points in the hippocampus of injured versus sham mice, and in PS1/APP mice there was a coincidental increase compared to wild type littermates at all time points. This study demonstrates some overlapping and diverse phospholipid profiles in rmTBI and AD models. Future studies are required to corroborate our findings in human post-mortem tissue. Investigation of secondary mechanisms triggered by aberrant downstream alterations in bioactive metabolites of these phospholipids, and their modulation at the appropriate time-windows of opportunity could help facilitate development of novel therapeutic strategies to ameliorate the neurodegenerative consequences of rmTBI or the potential triggering of AD pathogenesis by rmTBI.

Disruption in Brain Phospholipid Content in a Humanized Tau Transgenic Model Following Repetitive Mild Traumatic Brain Injury.

Repetitive mild traumatic brain injury (mTBI) is a risk factor for the development of neurodegenerative diseases such as chronic traumatic encephalopathy typified by immunoreactive tau aggregates in the depths of the sulci. However, the underlying neurobiological mechanisms involved have not been largely explored. Phospholipids are important molecules which form membrane lipid bilayers; they are ubiquitous to every cell in the brain, and carry out a host of different functions. Imbalance in phospholipid metabolism, signaling and transport has been documented in some neurological conditions. However, not much is currently known about their roles in repetitive mTBI and how this may confer risk for the development of age-related neurodegenerative diseases. To address this question, we designed a longitudinal study (24 h, 3, 6, 9, and 12 months post-injury) to comprehensively investigate mTBI dependent brain phospholipid profiles compared to sham counterparts. We use our established mouse model of repetitive mTBI that has been extensively characterized up to 1-year post-injury in humanized tau (hTau) mice, which expresses all six human tau isoforms, on a null murine background. Our data indicates a significant increase in sphingomyelin, phosphatidylethanolamine (PE), phosphatidylcholine (PC), and derivative lysoPE and lysoPC at acute and/or sub-acute time points post-injury within the cortex and hippocampus. There was also a parallel increase at early time points in monounsaturated, polyunsaturated and saturated fatty acids. Omega-6 (arachidonic acid) to omega-3 (docosahexaenoic acid) fatty acid ratio for PE and PC species was increased also at 24 h and 3 months post-injury in both hippocampus and cortex. The long-term consequences of these early changes in phospholipids on neuronal and non-neuronal cell function is unclear, and warrants further study. Understanding phospholipid metabolism, signaling and transport following TBI could be valuable; they may offer novel targets for therapeutic intervention not only in TBI but other neurodegenerative diseases.

Subchronic Pathobiological Response Following Chronic Repetitive Mild Traumatic Brain Injury in an Aged Preclinical Model of Amyloid Pathogenesis.

Repetitive mild traumatic brain injury (r-mTBI) is a risk factor for Alzheimer disease (AD). The precise nature of how r-mTBI leads to, or precipitates, AD pathogenesis remains unclear. In this study, we explore subchronic effects of chronic r-mTBI (12-impacts) administered over 1-month in aged-PS1/APP mice and littermate controls. We investigate specific mechanisms that may elucidate the molecular link between AD and r-mTBI, focusing primarily on amyloid and tau pathology, amyloid processing, glial activation states, and associated clearance mechanisms. Herein, we demonstrate r-mTBI in aged PS1/APP mice does not augment, glial activation, amyloid burden, or tau pathology (with exception of pS202-positive Tau) 1 month after exposure to the last-injury. However, we observed a decrease in brain soluble Aß42 levels without any appreciable change in peripheral soluble Aß42 levels. This was accompanied by an increase in brain insoluble to soluble Aß42 ratio in injured PS1/APP mice compared with sham injury. A parallel reduction in phagocytic receptor, triggering receptor expressed on myeloid cells 2, was also observed. This study demonstrates very subtle subchronic effects of r-mTBI on a preexisting amyloid pathology background, which may be on a continuum toward a slow and worsening neurodegenerative outcome compared with sham injury, and therefore, have many implications, especially in the elderly population exposed to TBI.

Unbiased Proteomic Approach Identifies Unique and Coincidental Plasma Biomarkers in Repetitive mTBI and AD Pathogenesis.

The relationship between repetitive mild traumatic brain injury (r-mTBI) and Alzheimer's disease (AD) is well-recognized. However, the precise nature of how r-mTBI leads to or precipitates AD pathogenesis is currently not understood. Plasma biomarkers potentially provide non-invasive tools for detecting neurological changes in the brain, and can reveal overlaps between long-term consequences of r-mTBI and AD. In this study we address this by generating time-dependent molecular profiles of response to r-mTBI and AD pathogenesis in mouse models using unbiased proteomic analyses. To model AD, we used the well-validated hTau and PSAPP(APP/PS1) mouse models that develop age-related tau and amyloid pathological features, respectively, and our well-established model of r-mTBI in C57BL/6 mice. Plasma were collected at different ages (3, 9, and 15 months-old for hTau and PSAPP mice), encompassing pre-, peri- and post-"onset" of the cognitive and neuropathological phenotypes, or at different timepoints after r-mTBI (24 h, 3, 6, 9, and 12 months post-injury). Liquid chromatography/mass spectrometry (LC-MS) approaches coupled with Tandem Mass Tag labeling technology were applied to develop molecular profiles of protein species that were significantly differentially expressed as a consequence of mTBI or AD. Mixed model ANOVA after Benjamini-Hochberg correction, and a stringent cut-off identified 31 proteins significantly changing in r-mTBI groups over time and, when compared with changes over time in sham mice, 13 of these were unique to the injured mice. The canonical pathways predicted to be modulated by these changes were LXR/RXR activation, production of nitric oxide and reactive oxygen species and complement systems. We identified 18 proteins significantly changing in PSAPP mice and 19 proteins in hTau mice compared to their wild-type littermates with aging. Six proteins were found to be significantly regulated in all three models, i.e., r-mTBI, hTau, and PSAPP mice compared to their controls. The top canonical pathways coincidently changing in all three models were LXR/RXR activation, and production of nitric oxide and reactive oxygen species. This work suggests potential biomarkers for TBI and AD pathogenesis and for the overlap between these two, and warrant targeted investigation in human populations. Data are available via ProteomeXchange with identifier PXD010664.

Chronic cerebrovascular abnormalities in a mouse model of repetitive mild traumatic brain injury.

PRIMARY OBJECTIVE: To investigate the status of the cerebrovasculature following repetitive mild traumatic brain injury (r-mTBI). RESEARCH DESIGN: TBI is a risk factor for development of various neurodegenerative disorders. A common feature of neurodegenerative disease is cerebrovascular dysfunction which includes alterations in cerebral blood flow (CBF). TBI can result in transient reductions in CBF, with severe injuries often accompanied by varying degrees of vascular pathology post-mortem. However, at this stage, few studies have investigated the cerebrovasculature at chronic time points following repetitive mild brain trauma. METHODS AND PROCEDURES: r-mTBI was delivered to wild-type mice (12 months old) twice per week for 3 months and tested for spatial memory deficits (Barnes Maze task) at 1 and 6 months post-injury. At 7 months post-injury CBF was assessed via Laser Doppler Imaging and, following euthanasia, the brain was probed for markers of cerebrovascular dysfunction and inflammation. MAIN OUTCOMES AND RESULTS: Memory impairment was identified at 1 month post-injury and persisted as late as 6 months post-injury. Furthermore, significant immunopathological insult, reductions in global CBF and down-regulation of cerebrovascular-associated markers were observed. CONCLUSIONS: These results demonstrate impaired cognitive behaviour alongside chronic cerebrovascular dysfunction in a mouse model of repetitive mild brain trauma.

Chronic Repetitive Mild Traumatic Brain Injury Results in Reduced Cerebral Blood Flow, Axonal Injury, Gliosis, and Increased T-Tau and Tau Oligomers.

Exposure to repetitive mild traumatic brain injury (mTBI) is a risk factor for chronic traumatic encephalopathy, which is characterized by patchy deposition of hyperphosphorylated tau aggregates in neurons and astrocytes at the depths of cortical sulci. We developed an mTBI paradigm to explore effects of repetitive concussive-type injury over several months in mice with a human tau genetic background (hTau). Two injuries were induced in the hTau mice weekly over a period of 3 or 4 months and the effects were compared with those in noninjured sham animals. Behavioral and in vivo measures and detailed neuropathological assessments were conducted 6 months after the first injury. Our data confirm impairment in cerebral blood flow and white matter damage. This was accompanied by a 2-fold increase in total tau levels and mild increases in tau oligomers/conformers and pTau (Thr231) species in brain gray matter. There was no evidence of neurofibrillary/astroglial tangles, neuropil threads, or perivascular foci of tau immunoreactivity. There were neurobehavioral deficits (ie, disinhibition and impaired cognitive performance) in the mTBI animals. These data support the relevance of this new mTBI injury model for studying the consequences of chronic repetitive mTBI in humans, and the role of tau in TBI.