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Programs utilizing research-tested evaluation tools can help identify effective educational strategies and document program effectiveness and impact. Using the case of the UF/IFAS Extension Family Nutrition Program (FNP), this article illustrates steps for conducting a rigorous assessment of the measurement properties of evaluation instruments. The Youth Behavior Survey (YBS) was originally developed to measure students’ nutrition and physical activity behaviors before and after an educational intervention. In order to report FNP behavior change data under indicators for the national evaluation framework, the evaluation instrument was revised. The revision included modifying item wording to reflect national indicators and changing response options. The psychometric characteristics of the revised instrument were assessed in comparison to those of the original instrument. The main objective was to examine aspects of content and construct validity for the scores produced by the instruments. The assessment included content validity of the instrument, item discrimination, consistency of relationships in item response patterns, and change between pre-test and post-test scores. We concluded that the scores produced by the revised instrument were modestly more accurate than the original. This research suggests procedures that can be applied widely to evaluating instruments for other educational interventions.

Objective: Understanding the course of individual neuropsychiatric symptoms (NPS) and their relationship with function is important for planning targeted interventions for preventing and delaying functional decline. This study aims to disentangle relative contributions of individual NPS on functional decline., Methods: Longitudinal study of 9,358 well-characterized participants with baseline diagnoses of Mild Cognitive Impairment or AD in the National Alzheimer's Coordinating Center Uniform Data Set. Function was measured using the Functional Assessment Questionnaire (FAQ). Clinician judgment of seven common behavioral symptoms were examined simultaneously: apathy-withdrawal, depressed mood, visual or auditory hallucinations, delusions, disinhibition, irritability, and agitation., Results: Apathy was the most common NPS at baseline (33.7%) and throughout follow-up, endorsed by clinicians in 63.7% of visits. Apathy was the most persistent with 36.7% of participants having clinician-endorsed apathy in ≥50% of their visits. Apathy strongly correlated with faster rate of functional decline. Compared to those who never had apathy, baseline FAQ was worse in those with intermittent or persistent/always apathy (intermittent: estimated coefficient ±SE=1.228±0.210, 95% CI=[0.817, 1.639]; persistent/always: 2.354±0.244 (95% CI=[1.876, 2.832], both p <0.001). Over time, rate of functional decline was faster in those with intermittent and persistent/always apathy (intermittent: 0.454±0.091, 95% CI=[0.276, 0.632]; persistent/always: 0.635±0.102, 95% CI=[0.436, 0.835], both p <0.001). Worse agitation, delusions, and hallucinations also correlated with functional decline, but magnitudes of the estimates were smaller., Conclusion: Individual NPS may be sensitive targets for tracking longitudinal change in function. The study raises awareness of the need for more comprehensive assessment of functional decline in AD patients with noncognitive symptoms., Competing Interests: DISCLOSURES All authors report no disclosures relevant to the manuscript., (Published by Elsevier Inc.)

The long-term effects of exposure to blast overpressure are an important health concern in military personnel. Increase in amyloid beta (Aβ) has been documented after non-blast traumatic brain injury (TBI) and may contribute to neuropathology and an increased risk for Alzheimer's disease. We have shown that Aβ levels decrease following exposure to a low-intensity blast overpressure event. To further explore this observation, we examined the effects of a single 37 kPa (5.4 psi) blast exposure on brain Aβ levels, production, and clearance mechanisms in the acute (24 h) and delayed (28 days) phases post-blast exposure in an experimental rat model. Aβ and, notably, the highly neurotoxic detergent soluble Aβ42 form, was reduced at 24 h but not 28 days after blast exposure. This reduction was not associated with changes in the levels of Aβ oligomers, expression levels of amyloid precursor protein (APP), or increase in enzymes involved in the amyloidogenic cleavage of APP, the β- and ϒ-secretases BACE1 and presenilin-1, respectively. The levels of ADAM17 α-secretase (also known as tumor necrosis factor α-converting enzyme) decreased, concomitant with the reduction in brain Aβ. Additionally, significant increases in brain levels of the endothelial transporter, low-density related protein 1 (LRP1), and enhancement in co-localization of aquaporin-4 (AQP4) to perivascular astrocytic end-feet were observed 24 h after blast exposure. These findings suggest that exposure to low-intensity blast may enhance endothelial clearance of Aβ by LRP1-mediated transcytosis and alter AQP4-aided glymphatic clearance. Collectively, the data demonstrate that low-intensity blast alters enzymatic, transvascular, and perivascular clearance of Aβ.

Many military veterans who experienced blast-related traumatic brain injuries in the conflicts in Iraq and Afghanistan currently suffer from chronic cognitive and mental health problems that include depression and post-traumatic stress disorder (PTSD). Male rats exposed to repetitive low-level blast develop cognitive and PTSD-related behavioral traits that are present for more than 1 year after exposure. We previously reported that a group II metabotropic receptor (mGluR2/3) antagonist reversed blast-induced behavioral traits. In this report, we explored mGluR2/3 expression following blast exposure in male rats. Western blotting revealed that mGluR2 protein (but not mGluR3) was increased in all brain regions studied (anterior cortex, hippocampus, and amygdala) at 43 or 52 weeks after blast exposure but not at 2 weeks or 6 weeks. mGluR2 RNA was elevated at 52 weeks while mGluR3 was not. Immunohistochemical staining revealed no changes in the principally presynaptic localization of mGluR2 by blast exposure. Administering the mGluR2/3 antagonist LY341495 after behavioral traits had emerged rapidly reversed blast-induced effects on novel object recognition and cued fear responses 10 months following blast exposure. These studies support alterations in mGluR2 receptors as a key pathophysiological event following blast exposure and provide further support for group II metabotropic receptors as therapeutic targets in the neurobehavioral effects that follow blast injury.

Background and Objectives: Apathy strongly affects function in Alzheimer's disease and frontotemporal dementia, however its effect on function in Lewy Body Disease (LBD) has not been well-described. This study aims to (1) examine the prevalence and persistence of apathy in a large, national cohort of well-characterized patients with LBD, and (2) estimate the effect of apathy on function over time., Methods: Study included 676 participants with mild cognitive impairment (MCI) or dementia in the National Alzheimer's Coordinating Center Uniform Data Set. Participants were followed for an average of 3.4 ± 1.7 years and consistently had a primary diagnosis of LBD. Apathy was defined by clinician judgment, categorized into four mutually exclusive profiles: (1) never apathetic across all visits, (2) at least one but <50% of visits with apathy ( intermittent apathy ), (3) ≥50% but not all visits with apathy ( persistent apathy ), and (4) always apathy across all visits. Dementia severity was measured by baseline Clinical Dementia Rating score. Parkinsonism was defined by the presence of bradykinesia, resting tremor, rigidity, gait, and postural instability. Functional impairment was assessed using the Functional Assessment Questionnaire (FAQ)., Results: Baseline characteristics of the sample were: average age = 72.9 ± 6.9, years of education = 15.6 ± 3.4, Mini Mental State Exam (MMSE) = 24.4 ± 5.4, Geriatric Depression Scale (GDS) = 3.8 ± 3.2, FAQ = 12.0 ± 9.1. 78.8% were male and 89% were non-Hispanic white. Prevalence of apathy increased from 54.4% at baseline to 65.5% in year 4. 77% of participants had apathy at some point during follow-up. Independent of cognitive status and parkinsonian features, FAQ was significantly higher in participants with intermittent/persistent and always apathetic than never apathetic. Annual rate of decline in FAQ was faster in participants who were always apathetic than never apathy., Discussion: In this large national longitudinal cohort of LBD patients with cognitive impairment, apathy was strongly associated with greater functional impairment at baseline and faster rate of decline over time. The magnitude of these effects were clinically important and were observed beyond the effects on function from participants' cognitive status and parkinsonism, highlighting the importance of specifically assessing for apathy in LBD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhu, Grossman, Elder, Rosen and Sano.)

Blast-induced neurotrauma has received much attention over the past decade. Vascular injury occurs early following blast exposure. Indeed, in animal models that approximate human mild traumatic brain injury or subclinical blast exposure, vascular pathology can occur in the presence of a normal neuropil, suggesting that the vasculature is particularly vulnerable. Brain endothelial cells and their supporting glial and neuronal elements constitute a neurovascular unit (NVU). Blast injury disrupts gliovascular and neurovascular connections in addition to damaging endothelial cells, basal laminae, smooth muscle cells, and pericytes as well as causing extracellular matrix reorganization. Perivascular pathology becomes associated with phospho-tau accumulation and chronic perivascular inflammation. Disruption of the NVU should impact activity-dependent regulation of cerebral blood flow, blood-brain barrier permeability, and glymphatic flow. Here, we review work in an animal model of low-level blast injury that we have been studying for over a decade. We review work supporting the NVU as a locus of low-level blast injury. We integrate our findings with those from other laboratories studying similar models that collectively suggest that damage to astrocytes and other perivascular cells as well as chronic immune activation play a role in the persistent neurobehavioral changes that follow blast injury.

Background: Modulation of physical activity represents an important intervention that may delay, slow, or prevent mild cognitive impairment (MCI) or dementia due to Alzheimer's disease (AD). One mechanism proposed to underlie the beneficial effect of physical exercise (PE) involves the apparent stimulation of adult hippocampal neurogenesis (AHN). BCI-838 is a pro-drug whose active metabolite BCI-632 is a negative allosteric modulator at group II metabotropic glutamate receptors (mGluR2/3). We previously demonstrated that administration of BCI-838 to a mouse model of brain accumulation of oligomeric Aβ E22Q ( APP E 693 Q = " Dutch APP ") reduced learning behavior impairment and anxiety, both of which are associated with the phenotype of Dutch APP mice., Methods: 3-month-old mice were administered BCI-838 and/or physical exercise for 1 month and then tested in novel object recognition, neurogenesis, and RNAseq., Results: Here we show that (i) administration of BCI-838 and a combination of BCI-838 and PE enhanced AHN in a 4-month old mouse model of AD amyloid pathology ( APP KM 670/671 NL /PSEN1 Δ exon 9 = APP/PS1), (ii) administration of BCI-838 alone or with PE led to stimulation of AHN and improvement in recognition memory, (iii) the hippocampal dentate gyrus transcriptome of APP/PS1 mice following BCI-838 treatment showed up-regulation of brain-derived neurotrophic factor (BDNF), PIK3C2A of the PI3K-mTOR pathway, and metabotropic glutamate receptors, and down-regulation of EIF5A involved in modulation of mTOR activity by ketamine, and (iv) validation by qPCR of an association between increased BDNF levels and BCI-838 treatment., Conclusion: Our study points to BCI-838 as a safe and orally active compound capable of mimicking the beneficial effect of PE on AHN and recognition memory in a mouse model of AD amyloid pathology., Competing Interests: JB was employed by Generable, Inc. CB was employed by E-Scape Bio. MS has served as a consultant for Bayer Schering Pharma, Bristol-Meyers Squibb, Elan Corporation, Genentech, Medivation, Medpace, Pfizer, Janssen, Takeda Pharmaceutical Company Limited, and United Biosource Corporation. She receives research support from the NIH. FHG was a founder and member of the SAB for BCI, but he no longer serves as a consultant or has stock because BCI no longer exists as a company. He has received funding from NIA, HIH, and NIMH on projects related to adult neurogenesis but not related to this or related compounds. CB is a former employee of BrainCells, Inc. BrainCells, Inc. provided drug and advice. JD has served as a consultant for Janssen and is an equity holder in Thorne HealthTech. BG is a consultant for Anthem AI and a scientific advisor and consultant for Prometheus Biosciences. He has received consulting fees from GLG Research and honoraria from Virtual EP Connect. ME receives research support from the NIH, the XDP Foundation, and the Cure Alzheimer's Fund. SG is a co-founder of Recuerdo Pharmaceuticals. He has served as a consultant in the past for J&J, Diagenic, and Pfizer, and he currently consults for Cognito Therapeutics, GLG Group, SVB Securities, Guidepoint, Third Bridge, Leerink, MEDACORP, Altpep, Vigil Neurosciences, and Eisai. He has received research support from Warner-Lambert, Pfizer, Baxter Healthcare, Amicus, Avid, and ADDF. He served on the DSMB for an amyloid vaccine trial by Elan Pharmaceuticals. He receives research support from the VA, NIH, and the Cure Alzheimer's Fund. SG and ME have received compensation for chart review in the areas of cognitive neurology and pediatric neurology, respectively. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) SG, BG, FHG, MG, and J-VH-M declare that they were editors board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Perez Garcia, Bicak, Buros, Haure-Mirande, Perez, Otero-Pagan, Gama Sosa, De Gasperi, Sano, Gage, Barlow, Dudley, Glicksberg, Wang, Readhead, Ehrlich, Elder and Gandy.)

In the course of military operations in modern war theaters, blast exposures are associated with the development of a variety of mental health disorders associated with a post-traumatic stress disorder-related features, including anxiety, impulsivity, insomnia, suicidality, depression, and cognitive decline. Several lines of evidence indicate that acute and chronic cerebral vascular alterations are involved in the development of these blast-induced neuropsychiatric changes. In the present study, we investigated late occurring neuropathological events associated with cerebrovascular alterations in a rat model of repetitive low-level blast-exposures (3 × 74.5 kPa). The observed events included hippocampal hypoperfusion associated with late-onset inflammation, vascular extracellular matrix degeneration, synaptic structural changes and neuronal loss. We also demonstrate that arteriovenous malformations in exposed animals are a direct consequence of blast-induced tissue tears. Overall, our results further identify the cerebral vasculature as a main target for blast-induced damage and support the urgent need to develop early therapeutic approaches for the prevention of blast-induced late-onset neurovascular degenerative processes., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Many military veterans who experienced blast-related traumatic brain injuries (TBIs) in the conflicts in Iraq and Afghanistan suffer from chronic cognitive and mental health problems, including post-traumatic stress disorder (PTSD). Male rats subjected to repetitive low-level blast exposure develop chronic cognitive and PTSD-related traits that develop in a delayed manner. Ketamine has received attention as a treatment for refractory depression and PTSD. (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] is a ketamine metabolite that exerts rapid antidepressant actions. (2R,6R)-HNK has become of clinical interest because of its favorable side-effect profile, low abuse potential, and oral route of administration. We treated three cohorts of blast-exposed rats with (2R,6R)-HNK, beginning 7-11 months after blast exposure, a time when the behavioral phenotype is established. Each cohort consisted of groups ( n  = 10-13/group) as follows: 1) Sham-exposed treated with saline, 2) blast-exposed treated with saline, and 3) blast-exposed treated with a single dose of 20 mg/kg of (2R,6R)-HNK. (2R,6R)-HNK rescued blast-induced deficits in novel object recognition (NOR) and anxiety-related features in the elevated zero maze (EZM) in all three cohorts. Exaggerated acoustic startle was reversed in cohort 1, but not in cohort 3. (2R,6R)-HNK effects were still present in the EZM 12 days after administration in cohort 1 and 27 days after administration in NOR testing of cohorts 2 and 3. (2R,6R)-HNK may be beneficial for the neurobehavioral syndromes that follow blast exposure in military veterans. Additional studies will be needed to determine whether higher doses or more extended treatment regimens may be more effective., Competing Interests: No competing financial interests exist., (© Georgina Perez Garcia et al., 2023; Published by Mary Ann Liebert, Inc.)

Chronic mental health problems are common among military veterans who sustained blast-related traumatic brain injuries. The reasons for this association remain unexplained. Male rats exposed to repetitive low-level blast overpressure (BOP) exposures exhibit chronic cognitive and post-traumatic stress disorder (PTSD)-related traits that develop in a delayed fashion. We examined blast-induced alterations on the transcriptome in four brain areas (anterior cortex, hippocampus, amygdala, and cerebellum) across the time frame over which the PTSD-related behavioral phenotype develops. When analyzed at 6 weeks or 12 months after blast exposure, relatively few differentially expressed genes (DEGs) were found. However, longitudinal analysis of amygdala, hippocampus, and anterior cortex between 6 weeks and 12 months revealed blast-specific DEG patterns. Six DEGs (hyaluronan and proteoglycan link protein 1 [Hapln1], glutamate metabotropic receptor 2 [Grm2], purinergic receptor P2y12 [P2ry12], C-C chemokine receptor type 5 [Ccr5], phenazine biosynthesis-like protein domain containing 1 [Pbld1], and cadherin related 23 [Cdh23]) were found altered in all three brain regions in blast-exposed animals. Pathway enrichment analysis using all DEGs or those uniquely changed revealed different transcription patterns in blast versus sham. In particular, the amygdala in blast-exposed animals had a unique set of enriched pathways related to stress responses, oxidative phosphorylation, and mitochondrial dysfunction. Upstream analysis implicated tumor necrosis factor (TNF)α signaling in blast-related effects in amygdala and anterior cortex. Eukaryotic initiating factor eIF4E (EIF4e), an upstream regulator of P2ry12 and Ccr5, was predicted to be activated in the amygdala. Quantitative polymerase chain reaction (qPCR) validated longitudinal changes in two TNFα regulated genes (cathepsin B [Ctsb], Hapln1), P2ry12, and Grm2. These studies have implications for understanding how blast injury damages the brain and implicates inflammation as a potential therapeutic target.

Tauopathies are a heterogeneous group of neurodegenerative disorders that are clinically and pathologically distinct from Alzheimer's disease (AD) having tau inclusions in neurons and/or glia as their most prominent neuropathological feature. BCI-838 (MGS00210) is a group II metabotropic glutamate receptor (mGluR2/3) antagonist pro-drug. Previously, we reported that orally administered BCI-838 improved learning behavior and reduced anxiety in Dutch (APP E693Q ) transgenic mice, a model of the pathological accumulation of Aβ oligomers found in AD. Herein, we investigated effects of BCI-838 on PS19 male mice that express the tauopathy mutation MAPT P301S associated with human frontotemporal lobar degeneration (FTLD). These mice develop an aging-related tauopathy without amyloid accumulation. Mice were divided into three experimental groups: (1) non-transgenic wild type mice treated with vehicle, (2) PS19 mice treated with vehicle and (3) PS19 mice treated with 5 mg/kg BCI-838. Groups of 10-13 mice were utilized. Vehicle or BCI-838 was administered by oral gavage for 4 weeks. Behavioral testing consisting of a novel object recognition task was conducted after drug administration. Two studies were performed beginning treatment of mice at 3 or 7 months of age. One month of BCI-838 treatment rescued deficits in recognition memory in PS19 mice whether treatment was begun at 3 or 7 months of age. These studies extend the potential utility of BCI-838 to neurodegenerative conditions that have tauopathy as their underlying basis. They also suggest an mGluR2/3 dependent mechanism as a basis for the behavioral deficits in PS19 mice., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Introduction: Understanding of the natural history of apathy and its impact on patient function is limited. This study examines, in a large, national sample of Alzheimer's disease (AD) patients with long follow-ups: (1) prevalence, incidence, and persistence of apathy, and (2) impact of apathy on function across dementia severity., Methods: A longitudinal study of 9823 well-characterized AD patients in the National Alzheimer's Coordinating Center Uniform Data Set., Results: Apathy was highly prevalent across disease severity with cumulative prevalence of 48%, 74%, and 82% in Clinical Dementia Rating (CDR) 0.5, 1.0, and 2.0, respectively. Persistence of apathy from clinician judgment varied from visit to visit at earlier disease stages but remained high at moderate dementia. Independent of cognition, persistent apathy was strongly associated with accelerated rate of functional decline., Discussion: Findings point to important targets for the treatment and management of apathy, include functional outcomes, and study designs that account for variable persistence of the apathy syndrome., Competing Interests: The authors have no conflicts of interest to declare. The sponsor played no role in the design, methods, participant recruitment, data collections, analysis, and preparation of the article., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Many military veterans who experienced blast-related traumatic brain injuries (TBIs) in the conflicts in Iraq and Afghanistan suffer from chronic cognitive and mental health problems, including post-traumatic stress disorder (PTSD). Transcranial laser therapy (TLT) uses low-power lasers emitting light in the far- to near-infrared ranges. Beneficial effects of TLT have been reported in neurological and mental-health-related disorders in humans and animal models, including TBI. Rats exposed to repetitive low-level blast develop chronic cognitive and PTSD-related behavioral traits. We tested whether TLT treatment could reverse these traits. Rats received a 74.5-kPa blast or sham exposures delivered one per day for 3 consecutive days. Beginning at 34 weeks after blast exposure, the following groups of rats were treated with active or sham TLT: 1) Sham-exposed rats ( n  = 12) were treated with sham TLT; 2) blast-exposed rats ( n  = 13) were treated with sham TLT; and 3) blast-exposed rats ( n  = 14) were treated with active TLT. Rats received 5 min of TLT five times per week for 6 weeks (wavelength, 808 nm; power of irradiance, 240 mW). At the end of treatment, rats were tested in tasks found previously to be most informative (novel object recognition, novel object localization, contextual/cued fear conditioning, elevated zero maze, and light/dark emergence). TLT did not improve blast-related effects in any of these tests, and blast-exposed rats were worse after TLT in some anxiety-related measures. Based on these findings, TLT does not appear to be a promising treatment for the chronic cognitive and mental health problems that follow blast injury., Competing Interests: No competing financial interests exist., (© Georgina Perez Garcia et al., 2021; Published by Mary Ann Liebert, Inc.)

Public awareness of traumatic brain injury (TBI) in the military increased recently because of the conflicts in Iraq and Afghanistan where blast injury was the most common mechanism of injury. Besides overt injuries, concerns also exist over the potential adverse consequences of subclinical blast exposures, which are common for many service members. A TBI is a risk factor for the later development of neurodegenerative diseases, including Alzheimer disease (AD)-like disorders. Studies of acute TBI in humans and animals have suggested that increased processing of the amyloid precursor protein (APP) toward the amyloid beta protein (Aβ) may explain the epidemiological associations with AD. In a previous study, however, we found in both rat and mouse models of blast overpressure exposure that rather than increasing, rodent brain Aβ42 levels were decreased after acute blast exposure. Here we subjected APP/presenilin 1 transgenic mice (APP/PS1 Tg) to an extended sequence of repetitive low-level blast exposures (34.5 kPa) administered three times per week over eight weeks. If initiated at 20 weeks of age, these repetitive exposures, which were designed to mimic human subclinical blast exposures, reduced anxiety and improved cognition as well as social interactions in APP/PS1 Tg mice, returning many behavioral parameters in APP/PS1 Tg mice to levels of non-transgenic wild type mice. Repetitive low-level blast exposure was less effective at improving behavioral deficits in APP/PS1 Tg mice when begun at 36 weeks of age. While amyloid plaque loads were unchanged, Aβ 42 levels and Aβ oligomers were reduced in the brain of mice exposed to repetitive low-level blast exposures initiated at 20 weeks of age, although levels did not directly correlate with behavioral parameters in individual animals. These results have implications for understanding the nature of blast effects on the brain and their relationship to human neurodegenerative diseases.

Cerebral vascular injury as a consequence of blast-induced traumatic brain injury is primarily the result of blast wave-induced mechanical disruptions within the neurovascular unit. In rodent models of blast-induced traumatic brain injury, chronic vascular degenerative processes are associated with the development of an age-dependent post-traumatic stress disorder-like phenotype. To investigate the evolution of blast-induced chronic vascular degenerative changes, Long-Evans rats were blast-exposed (3 × 74.5 kPa) and their brains analyzed at different times post-exposure by X-ray microcomputed tomography, immunohistochemistry and electron microscopy. On microcomputed tomography scans, regional cerebral vascular attenuation or occlusion was observed as early as 48 h post-blast, and cerebral vascular disorganization was visible at 6 weeks and more accentuated at 13 months post-blast. Progression of the late-onset pathology was characterized by detachment of the endothelial and smooth muscle cellular elements from the neuropil due to degeneration and loss of arteriolar perivascular astrocytes. Development of this pathology was associated with vascular remodeling and neuroinflammation as increased levels of matrix metalloproteinases (MMP-2 and MMP-9), collagen type IV loss, and microglial activation were observed in the affected vasculature. Blast-induced chronic alterations within the neurovascular unit should affect cerebral blood circulation, glymphatic flow and intramural periarterial drainage, all of which may contribute to development of the blast-induced behavioral phenotype. Our results also identify astrocytic degeneration as a potential target for the development of therapies to treat blast-induced brain injury., (© 2021. The Author(s).)

Traumatic brain injury (TBI) is a risk factor for the later development of neurodegenerative diseases that may have various underlying pathologies. Chronic traumatic encephalopathy (CTE) in particular is associated with repetitive mild TBI (mTBI) and is characterized pathologically by aggregation of hyperphosphorylated tau into neurofibrillary tangles (NFTs). CTE may be suspected when behavior, cognition, and/or memory deteriorate following repetitive mTBI. Exposure to blast overpressure from improvised explosive devices (IEDs) has been implicated as a potential antecedent for CTE amongst Iraq and Afghanistan Warfighters. In this study, we identified biomarker signatures in rats exposed to repetitive low-level blast that develop chronic anxiety-related traits and in human veterans exposed to IED blasts in theater with behavioral, cognitive, and/or memory complaints. Rats exposed to repetitive low-level blasts accumulated abnormal hyperphosphorylated tau in neuronal perikarya and perivascular astroglial processes. Using positron emission tomography (PET) and the [ 18 F]AV1451 (flortaucipir) tau ligand, we found that five of 10 veterans exhibited excessive retention of [ 18 F]AV1451 at the white/gray matter junction in frontal, parietal, and temporal brain regions, a typical localization of CTE tauopathy. We also observed elevated levels of neurofilament light (NfL) chain protein in the plasma of veterans displaying excess [ 18 F]AV1451 retention. These findings suggest an association linking blast injury, tauopathy, and neuronal injury. Further study is required to determine whether clinical, neuroimaging, and/or fluid biomarker signatures can improve the diagnosis of long-term neuropsychiatric sequelae of mTBI., (© 2020. The Author(s).)

Traumatic brain injury (TBI) is one of the main causes of death worldwide. It is a complex injury that influences cellular physiology, causes neuronal cell death, and affects molecular pathways in the brain. This in turn can result in sensory, motor, and behavioral alterations that deeply impact the quality of life. Repetitive mild TBI can progress into chronic traumatic encephalopathy (CTE), a neurodegenerative condition linked to severe behavioral changes. While current animal models of TBI and CTE such as rodents, are useful to explore affected pathways, clinical findings therein have rarely translated into clinical applications, possibly because of the many morphofunctional differences between the model animals and humans. It is therefore important to complement these studies with alternative animal models that may better replicate the individuality of human TBI. Comparative studies in animals with naturally evolved brain protection such as bighorn sheep, woodpeckers, and whales, may provide preventive applications in humans. The advantages of an in-depth study of these unconventional animals are threefold. First, to increase knowledge of the often-understudied species in question; second, to improve common animal models based on the study of their extreme counterparts; and finally, to tap into a source of biological inspiration for comparative studies and translational applications in humans., (© 2021 The Authors. Journal of Neuroscience Research published by Wiley Periodicals LLC.)

Many military veterans who experienced blast-related traumatic brain injuries (TBI) in the conflicts in Iraq and Afghanistan currently have chronic cognitive and mental health problems including post-traumatic stress disorder (PTSD). Besides static symptoms, new symptoms may emerge or existing symptoms may worsen. TBI is also a risk factor for later development of neurodegenerative diseases. In rats exposed to repetitive low-level blast overpressure (BOP), robust and enduring cognitive and PTSD-related behavioral traits develop that are present for at least one year after blast exposure. Here we determined the time-course of the appearance of these traits by testing rats in the immediate post-blast period. Three cohorts of rats examined within the first eight weeks exhibited no behavioral phenotype or, in one cohort, features of anxiety. None showed the altered cued fear responses or impaired novel object recognition characteristic of the fully developed phenotype. Two cohorts retested 36 to 42 weeks after blast exposure exhibited the expanded behavioral phenotype including anxiety as well as altered cued fear learning and impaired novel object recognition. Combined with previous work, the chronic behavioral phenotype has been observed in six cohorts of blast-exposed rats studied at 3-4 months or longer after blast injury, and the three cohorts studied here document the progressive nature of the cognitive/behavioral phenotype. These studies suggest the existence of a latent, delayed emerging and progressive blast-induced cognitive and behavioral phenotype. The delayed onset has implications for the evolution of post-blast neurobehavioral syndromes in military veterans and its modeling in experimental animals.

Military veterans who experience blast-related traumatic brain injuries often suffer from chronic cognitive and neurobehavioral syndromes. Reports of abnormal tau processing following blast injury have raised concerns that some cases may have a neurodegenerative basis. Rats exposed to repetitive low-level blast exhibit chronic neurobehavioral traits and accumulate tau phosphorylated at threonine 181 (Thr181). Using data previously reported in separate studies we tested the hypothesis that region-specific patterns of Thr181 phosphorylation correlate with behavioral measures also previously determined and reported in the same animals. Elevated p-tau Thr181 in anterior neocortical regions and right hippocampus correlated with anxiety as well as fear learning and novel object localization. There were no correlations with levels in amygdala or posterior neocortical regions. Particularly striking were asymmetrical effects on the right and left hippocampus. No systematic variation in head orientation toward the blast wave seems to explain the laterality. Levels did not correlate with behavioral measures of hyperarousal. Results were specific to Thr181 in that no correlations were observed for three other phospho-acceptor sites (threonine 231, serine 396, and serine 404). No consistent correlations were linked with total tau. These correlations are significant in suggesting that p-tau accumulation in anterior neocortical regions and the hippocampus may lead to disinhibited amygdala function without p-tau elevation in the amygdala itself. They also suggest an association linking blast injury with tauopathy, which has implications for understanding the relationship of chronic blast-related neurobehavioral syndromes in humans to neurodegenerative diseases.

Vascular structures in the developing brain are thought to form via angiogenesis from preformed blood vessels in the cephalic mesenchyme. Immunohistochemical studies of developing mouse brain from E10.5 to E13.5 revealed the presence of avascular blood islands of primitive erythroid cells expressing hemangioblast markers (Flk1, Tal1/Scl1, platelet endothelial cell adhesion molecule 1, vascular endothelial-cadherin, and CD34) and an endothelial marker recognized by Griffonia simplicifolia isolectin B4 (IB4) in the cephalic mesenchyme. These cells formed a perineural vascular plexus from which angiogenic sprouts originated and penetrated the neuroepithelium. In addition, avascular isolated cells expressing primitive erythroid, hemangioblast and endothelial makers were visible in the neuroepithelium where they generated vasculogenic and hemogenic foci. From E10.5 to E13.5, these vasculogenic foci were a source of new blood vessel formation in the developing brain. In vitro, cultured E13.5 brain endothelial cells contained hemogenic endothelial cells capable of generating erythroid cells. Similar cells were present in primary cultures of dissociated cells from E10.5 embryonic head. Our results provide new evidence that the brain vasculature, like that of the yolk sac and the eye choriocapillaris and hyaloid vascular systems, develops at least in part via hemovasculogenesis, a process in which vasculogenesis and hematopoiesis occur simultaneously., (© 2020 Wiley Periodicals, Inc.)

The short and long-term neurological and psychological consequences of traumatic brain injury (TBI), and especially mild TBI (mTBI) are of immense interest to the Veteran community. mTBI is a common and detrimental result of combat exposure and results in various deleterious outcomes, including mood and anxiety disorders, cognitive deficits, and post-traumatic stress disorder (PTSD). In the current study, we aimed to further define the behavioral and molecular effects of blast-related mTBI using a well-established (3 × 75 kPa, one per day on three consecutive days) repeated blast overpressure (rBOP) model in rats. We exposed adult male rats to the rBOP procedure and conducted behavioral tests for anxiety and fear conditioning at 1-1.5 months (sub-acute) or 12-13 months (chronic) following blast exposure. We also used next-generation sequencing to measure transcriptome-wide gene expression in the amygdala of sham and blast-exposed animals at the sub-acute and chronic time points. Results showed that blast-exposed animals exhibited an anxiety-like phenotype at the sub-acute timepoint but this phenotype was diminished by the chronic time point. Conversely, gene expression analysis at both sub-acute and chronic timepoints demonstrated a large treatment by timepoint interaction such that the most differentially expressed genes were present in the blast-exposed animals at the chronic time point, which also corresponded to a Bdnf -centric gene network. Overall, the current study identified changes in the amygdalar transcriptome and anxiety-related phenotypic outcomes dependent on both blast exposure and aging, which may play a role in the long-term pathological consequences of mTBI., (Copyright © 2020 Blaze, Choi, Wang, Umali, Mendelev, Tschiffely, Ahlers, Elder, Ge and Haghighi.)

Oncogenic transformation is associated with profound changes in cellular metabolism, but whether tracking these can improve disease stratification or influence therapy decision-making is largely unknown. Using the iKnife to sample the aerosol of cauterized specimens, we demonstrate a new mode of real-time diagnosis, coupling metabolic phenotype to mutant PIK3CA genotype. Oncogenic PIK3CA results in an increase in arachidonic acid and a concomitant overproduction of eicosanoids, acting to promote cell proliferation beyond a cell-autonomous manner. Mechanistically, mutant PIK3CA drives a multimodal signaling network involving mTORC2-PKCζ-mediated activation of the calcium-dependent phospholipase A2 (cPLA2). Notably, inhibiting cPLA2 synergizes with fatty acid-free diet to restore immunogenicity and selectively reduce mutant PIK3CA-induced tumorigenicity. Besides highlighting the potential for metabolic phenotyping in stratified medicine, this study reveals an important role for activated PI3K signaling in regulating arachidonic acid metabolism, uncovering a targetable metabolic vulnerability that largely depends on dietary fat restriction. VIDEO ABSTRACT., Competing Interests: Declaration of Interests N.K. and G.P. are inventors on a patent application covering new methods and compositions useful in the treatment of cancers with PIK3CA mutation (application number GB 2005874.9)., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Traumatic brain injury (TBI) is an unfortunately common event in military life. The conflicts in Iraq and Afghanistan have increased public awareness of TBI in the military. Certain injury mechanisms are relatively unique to the military, the most prominent being blast exposure. Blast-related mild TBI (mTBI) has been of particular concern in the most recent veterans although controversy remains concerning separation of the postconcussion syndrome associated with mTBI from post-traumatic stress disorder. TBI is also a risk factor for the development of neurodegenerative diseases including chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD). AD, TBI, and CTE are all associated with chronic inflammation. Genome wide association studies (GWAS) have identified multiple genetic loci associated with AD that implicate inflammation and - in particular microglia - as key modulators of the AD- and TBI-related degenerative processes. At the molecular level, recent studies have identified TREM2 and TYROBP/DAP12 as components of a key molecular hub linking inflammation and microglia to the pathophysiology of AD and possibly TBI. Evidence concerning the relationship of TBI to chronic mental health problems and dementia is reviewed in the context of its relevance to military veterans., (Published by Elsevier B.V.)

A striking observation among veterans returning from the recent conflicts in Iraq and Afghanistan has been the co-occurrence of blast-related mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD). PTSD and mTBI might coexist due to additive effects of independent psychological and physical traumas experienced in a war zone. Alternatively blast injury might induce PTSD-related traits or damage brain structures that mediate responses to psychological stressors, increasing the likelihood that PTSD will develop following a subsequent psychological stressor. Rats exposed to repetitive low-level blasts consisting of three 74.5 kPa exposures delivered once daily for three consecutive days develop a variety of anxiety and PTSD-related behavioral traits that are present for at least 9 months after blast exposure. A single predator scent challenge delivered 8 months after the last blast exposure induces additional anxiety-related changes that are still present 45 days later. Because the blast injuries occur under general anesthesia, it appears that blast exposure in the absence of a psychological stressor can induce chronic PTSD-related traits. The reaction to a predator scent challenge delivered many months after blast exposure suggests that blast exposure in addition sensitizes the brain to react abnormally to subsequent psychological stressors. The development of PTSD-related behavioral traits in the absence of a psychological stressor suggests the existence of blast-induced "PTSD". Findings that PTSD-related behavioral traits can be reversed by BCI-838, a group II metabotropic glutamate receptor antagonist offers insight into pathogenesis and possible treatment options for blast-related brain injury. This article is part of the Special Issue entitled "Novel Treatments for Traumatic Brain Injury"., (Published by Elsevier Ltd.)

Much concern exists over the role of blast-induced traumatic brain injury (TBI) in the chronic cognitive and mental health problems that develop in veterans and active duty military personnel. The brain vasculature is particularly sensitive to blast injury. The aim of this study was to characterize the evolving molecular and histologic alterations in the neurovascular unit induced by three repetitive low-energy blast exposures (3 × 74.5 kPa) in a rat model mimicking human mild TBI or subclinical blast exposure. High-resolution two-dimensional differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry of purified brain vascular fractions from blast-exposed animals 6 weeks post-exposure showed decreased levels of vascular-associated glial fibrillary acidic protein (GFAP) and several neuronal intermediate filament proteins (α-internexin and the low, middle, and high molecular weight neurofilament subunits). Loss of these proteins suggested that blast exposure disrupts gliovascular and neurovascular interactions. Electron microscopy confirmed blast-induced effects on perivascular astrocytes including swelling and degeneration of astrocytic endfeet in the brain cortical vasculature. Because the astrocyte is a major sensor of neuronal activity and regulator of cerebral blood flow, structural disruption of gliovascular integrity within the neurovascular unit should impair cerebral autoregulation. Disrupted neurovascular connections to pial and parenchymal blood vessels might also affect brain circulation. Blast exposures also induced structural and functional alterations in the arterial smooth muscle layer. Interestingly, by 8 months after blast exposure, GFAP and neuronal intermediate filament expression had recovered to control levels in isolated brain vascular fractions. However, despite this recovery, a widespread vascular pathology was still apparent at 10 months after blast exposure histologically and on micro-computed tomography scanning. Thus, low-level blast exposure disrupts gliovascular and neurovascular connections while inducing a chronic vascular pathology.

Polycythemia vera (PV) is a risk factor for systemic thromboses and ischemic stroke. This has been attributed to blood hyperviscosity, the result of increased blood cell production. Intravenous immunoglobulin, which is indicated for the treatment of numerous hematologic and neurological conditions also causes increased serum viscosity and has been associated with ischemic strokes in the setting of PV. Here we report a case of a 70-year-old man with prior stroke and PV who developed Guillain-Barré syndrome, an acute inflammatory demyelinating disorder of peripheral nerves causing ascending paresis, numbness, and paresthesia, who was treated safely with therapeutic plasma exchange. Plasma exchange may be preferable to administration of intravenous immunoglobulin for treatment of various medical conditions in patients with comorbid PV.

The postconcussion syndrome following mild traumatic brain injuries (mTBI) has been regarded as a mostly benign syndrome that typically resolves in the immediate months following injury. However, in some individuals, symptoms become chronic and persistent. This has been a striking feature of the mostly blast-related mTBIs that have been seen in veterans returning from the recent conflicts in Iraq and Afghanistan. In these veterans a chronic syndrome with features of both the postconcussion syndrome and post-traumatic stress disorder has been prominent. Animal modeling of blast-related TBI has developed rapidly over the last decade leading to advances in the understanding of blast pathophysiology. However, most studies have focused on acute to subacute effects of blast on the nervous system and have typically studied higher intensity blast exposures with energies more comparable to that involved in human moderate to severe TBI. Fewer animal studies have addressed the chronic effects of lower level blast exposures that are more comparable to those involved in human mTBI or subclinical blast. Here we describe a rat model of repetitive low-level blast exposure that induces a variety of anxiety and PTSD-related behavioral traits including exaggerated fear responses that were present when animals were tested between 28 and 35 weeks after the last blast exposure. These animals provide a model to study the chronic and persistent behavioral effects of blast including the relationship of PTSD to mTBI in dual diagnosis veterans., (Published by Elsevier B.V.)

Battlefield blast exposure related to improvised explosive devices (IEDs) has become the most common cause of traumatic brain injury (TBI) in the recent conflicts in Iraq and Afghanistan. Mental health problems are common after TBI. A striking feature in the most recent veterans has been the frequency with which mild TBI (mTBI) and posttraumatic stress disorder (PTSD) have appeared together, in contrast to the classical situations in which the presence of mTBI has excluded the diagnosis of PTSD. However, treatment of PTSD-related symptoms that follow blast injury has become a significant problem. BCI-838 (MGS0210) is a Group II metabotropic glutamate receptor (mGluR2/3) antagonist prodrug, and its active metabolite BCI-632 (MGS0039) has proneurogenic, procognitive, and antidepressant activities in animal models. In humans, BCI-838 is currently in clinical trials for refractory depression and suicidality. The aim of the current study was to determine whether BCI-838 could modify the anxiety response and reverse PTSD-related behaviors in rats exposed to a series of low-level blast exposures designed to mimic a human mTBI or subclinical blast exposure. BCI-838 treatment reversed PTSD-related behavioral traits improving anxiety and fear-related behaviors as well as long-term recognition memory. Treatment with BCI-838 also increased neurogenesis in the dentate gyrus (DG) of blast-exposed rats. The safety profile of BCI-838 together with the therapeutic activities reported here, make BCI-838 a promising drug for the treatment of former battlefield Warfighters suffering from PTSD-related symptoms following blast-induced mTBI.

Blast-related traumatic brain injury (TBI) has been a common cause of injury in the recent conflicts in Iraq and Afghanistan. Blast waves can damage blood vessels, neurons, and glial cells within the brain. Acutely, depending on the blast energy, blast wave duration, and number of exposures, blast waves disrupt the blood-brain barrier, triggering microglial activation and neuroinflammation. Recently, there has been much interest in the role that ongoing neuroinflammation may play in the chronic effects of TBI. Here, we investigated whether chronic neuroinflammation is present in a rat model of repetitive low-energy blast exposure. Six weeks after three 74.5-kPa blast exposures, and in the absence of hemorrhage, no significant alteration in the level of microglia activation was found. At 6 weeks after blast exposure, plasma levels of fractalkine, interleukin-1β, lipopolysaccharide-inducible CXC chemokine, macrophage inflammatory protein 1α, and vascular endothelial growth factor were decreased. However, no differences in cytokine levels were detected between blast-exposed and control rats at 40 weeks. In brain, isolated changes were seen in levels of selected cytokines at 6 weeks following blast exposure, but none of these changes was found in both hemispheres or at 40 weeks after blast exposure. Notably, one animal with a focal hemorrhagic tear showed chronic microglial activation around the lesion 16 weeks post-blast exposure. These findings suggest that focal hemorrhage can trigger chronic focal neuroinflammation following blast-induced TBI, but that in the absence of hemorrhage, chronic neuroinflammation is not a general feature of low-level blast injury.

The long-term effects of blast exposure are a major health concern for combat veterans returning from the recent conflicts in Iraq and Afghanistan. We used an optimized diffusion tensor imaging tractography algorithm to assess white matter (WM) fractional anisotropy (FA) in blast-exposed Iraq and Afghanistan veterans ( n  = 40) scanned on average 3.7 years after deployment/trauma exposure. Veterans diagnosed with a blast-related mild traumatic brain injury (mTBI) were compared to combat veterans with blast exposure but no TBI diagnosis. Blast exposure was associated with decreased FA in several WM tracts. However, total blast exposure did not correlate well with neuropsychological testing performance and there were no differences in FA based on mTBI diagnosis. Yet, veterans with mTBI performed worse on every neurocognitive test administered. Multiple linear regression across all blast-exposed veterans using a six-factor prediction model indicated that the amount of blast exposure accounted for 11-15% of the variability in composite FA scores such that as blast exposure increased, FA decreased. Education accounted for 10% of the variability in composite FA scores and 25-32% of FA variability in the right cingulum, such that as level of education increased, FA increased. Total blast exposure, age, and education were significant predictors of FA in the left cingulum. We did not find any effect of post-traumatic stress disorder on cognition or composite FA. In summary, our findings suggest that greater total blast exposure is a contributing factor to poor WM integrity. While FA was not associated with neurocognitive performance, we hypothesize that FA changes in the cingulum in veterans with multiple combat exposures and no head trauma prior to deployment may represent a marker of vulnerability for future deficits. Future work needs to examine this longitudinally.

As a follow-up to the 2008 state-of-the-art (SOTA) conference on traumatic brain injuries (TBIs), the 2015 event organized by the United States Department of Veterans Affairs (VA) Office of Research and Development (ORD) analysed the knowledge gained over the last 7 years as it relates to basic scientific methods, experimental findings, diagnosis, therapy, and rehabilitation of TBIs and blast-induced neurotraumas (BINTs). The current article summarizes the discussions and recommendations of the scientific panel attending the Preclinical Modeling and Therapeutic Development Workshop of the conference, with special emphasis on factors slowing research progress and recommendations for ways of addressing the most significant pitfalls.

Blast-related mild traumatic brain injury (mTBI) has been unfortunately common in veterans who served in the recent conflicts in Iraq and Afghanistan. The postconcussion syndrome associated with these mTBIs has frequently appeared in combination with post-traumatic stress disorder (PTSD). The presence of PTSD has complicated diagnosis, since clinically, PTSD and the postconcussion syndrome of mTBI have many overlapping symptoms. In particular, establishing how much of the symptom complex can be attributed to the psychological trauma associated with PTSD in contrast to the physical injury of traumatic brain injury has proven difficult. Indeed, some have suggested that much of what is now being called blast-related postconcussion syndrome is better explained by PTSD. The relationship between the postconcussion syndrome of mTBI and PTSD is complex. Association of the two disorders might be viewed as additive effects of independent psychological and physical traumas suffered in a war zone. However, we previously found that rats exposed to repetitive low-level blast exposure in the absence of a psychological stressor developed a variety of anxiety and PTSD-related behavioral traits that were present months following the last blast exposure. Here, we show that a single predator scent challenge delivered 8 months after the last blast exposure induces chronic anxiety related changes in blast-exposed rats that are still present 45 days later. These observations suggest that in addition to independently inducing PTSD-related traits, blast exposure sensitizes the brain to react abnormally to a subsequent psychological stressor. These studies have implications for conceptualizing the relationship between blast-related mTBI and PTSD and suggest that blast-related mTBI in humans may predispose to the later development of PTSD in reaction to subsequent psychological stressors.

The objective of this study was to develop an in silico screening model for characterization of potential novel ligands from commercial drug libraries able to functionally activate certain olfactory receptors (ORs), which are members of the class A rhodopsin-like family of G protein couple receptors (GPCRs), in the brain of murine models of concussion. We previously found that concussions may significantly influence expression of certain ORs, for example, OR4M1 in subjects with a history of concussion/traumatic brain injury (TBI). In this study, we built a 3-D OR4M1 model and used it in in silico screening of potential novel ligands from commercial drug libraries. We report that in vitro activation of OR4M1 with the commercially available ZINC library compound 10915775 led to a significant attenuation of abnormal tau phosphorylation in embryonic cortico-hippocampal neuronal cultures derived from NSE-OR4M1 transgenic mice, possibly through modulation of the JNK signaling pathway. The attenuation of abnormal tau phosphorylation was rather selective since ZINC10915775 significantly decreased tau phosphorylation on tau Ser202/T205 (AT8 epitope) and tau Thr212/Ser214 (AT100 epitope), but not on tau Ser396/404 (PHF-1 epitope). Moreover, no response of ZINC10915775 was found in control hippocampal neuronal cultures derived from wild type littermates. Our in silico model provides novel means to pharmacologically modulate select ubiquitously expressed ORs in the brain through high affinity ligand activation to prevent and eventually to treat concussion induced down regulation of ORs and subsequent cascade of tau pathology. J. Cell. Biochem. 117: 2241-2248, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Presenilin 1 (Psen1) is important for vascular brain development and is known to influence cellular stress responses. To understand the role of Psen1 in endothelial stress responses, we investigated the effects of serum withdrawal on wild type (wt) and Psen1-/- embryonic brain endothelial cells. Serum starvation induced apoptosis in Psen1-/- cells but did not affect wt cells. PI3K/AKT signaling was reduced in serum-starved Psen1-/- cells, and this was associated with elevated levels of phospho-p38 consistent with decreased pro-survival AKT signaling in the absence of Psen1. Fibroblast growth factor (FGF1 and FGF2), but not vascular endothelial growth factor (VEGF) rescued Psen1-/- cells from serum starvation induced apoptosis. Inhibition of FGF signaling induced apoptosis in wt cells under serum withdrawal, while blocking γ-secretase activity had no effect. In the absence of serum, FGF2 immunoreactivity was distributed diffusely in cytoplasmic and nuclear vesicles of wt and Psen1-/- cells, as levels of FGF2 in nuclear and cytosolic fractions were not significantly different. Thus, sensitivity of Psen1-/- cells to serum starvation is not due to lack of FGF synthesis but likely to effects of Psen1 on FGF release onto the cell surface and impaired activation of the PI3K/AKT survival pathway.

Traumatic brain injury (TBI) is a common cause of morbidity and mortality in military life. Interest in military TBI has increased recently due to the conflicts in Iraq and Afghanistan. Certain types of TBI are relatively unique to the military, the most prominent being blast-related TBI. Blast-related mild TBI has been of particular concern in veterans from the most recent conflicts although controversy remains concerning its separation from post-traumatic stress disorder. TBI is also a risk factor for the later development of neurodegenerative diseases in which cognitive impairment is prominent putting veterans at risk for disorders including Alzheimer's disease and chronic traumatic encephalopathy. Recent evidence associating TBI with chronic cognitive impairment is reviewed in the context of its relevance to military veterans.

The apolipoprotein E4 (ApoE4) allele is the strongest genetic risk factor for developing sporadic Alzheimer's disease (AD). However, the mechanisms underlying the pathogenic nature of ApoE4 are not well understood. In this study, we have found that ApoE proteins are critical determinants of brain phospholipid homeostasis and that the ApoE4 isoform is dysfunctional in this process. We have found that the levels of phosphoinositol biphosphate (PIP2) are reduced in postmortem human brain tissues of ApoE4 carriers, in the brains of ApoE4 knock-in (KI) mice, and in primary neurons expressing ApoE4 alleles compared with those levels in ApoE3 counterparts. These changes are secondary to increased expression of a PIP2-degrading enzyme, the phosphoinositol phosphatase synaptojanin 1 (synj1), in ApoE4 carriers. Genetic reduction of synj1 in ApoE4 KI mouse models restores PIP2 levels and, more important, rescues AD-related cognitive deficits in these mice. Further studies indicate that ApoE4 behaves similar to ApoE null conditions, which fails to degrade synj1 mRNA efficiently, unlike ApoE3 does. These data suggest a loss of function of ApoE4 genotype. Together, our data uncover a previously unidentified mechanism that links ApoE4-induced phospholipid changes to the pathogenic nature of ApoE4 in AD.

Long-term molecular changes in the brain resulting from blast exposure may be mediated by epigenetic changes, such as deoxyribonucleic acid (DNA) methylation, that regulate gene expression. Aberrant regulation of gene expression is associated with behavioral abnormalities, where DNA methylation bridges environmental signals to sustained changes in gene expression. We assessed DNA methylation changes in the brains of rats exposed to three 74.5 kPa blast overpressure events, conditions that have been associated with long-term anxiogenic manifestations weeks or months following the initial exposures. Rat frontal cortex eight months post-exposure was used for cell sorting of whole brain tissue into neurons and glia. We interrogated DNA methylation profiles in these cells using Expanded Reduced Representation Bisulfite Sequencing. We obtained data for millions of cytosines, showing distinct methylation profiles for neurons and glia and an increase in global methylation in neuronal versus glial cells (p<10(-7)). We detected DNA methylation perturbations in blast overpressure-exposed animals, compared with sham blast controls, within 458 and 379 genes in neurons and glia, respectively. Differentially methylated neuronal genes showed enrichment in cell death and survival and nervous system development and function, including genes involved in transforming growth factor β and nitric oxide signaling. Functional validation via gene expression analysis of 30 differentially methylated neuronal and glial genes showed a 1.2 fold change in gene expression of the serotonin N-acetyltransferase gene (Aanat) in blast animals (p<0.05). These data provide the first genome-based evidence for changes in DNA methylation induced in response to multiple blast overpressure exposures. In particular, increased methylation and decreased gene expression were observed in the Aanat gene, which is involved in converting serotonin to the circadian hormone melatonin and is implicated in sleep disturbance and depression associated with traumatic brain injury.

Blast-related traumatic brain injury (TBI) has received much recent attention because of its frequency in the conflicts in Iraq and Afghanistan. This renewed interest has led to a rapid expansion of clinical and animal studies related to blast. In humans, high-level blast exposure is associated with a prominent hemorrhagic component. In animal models, blast exerts a variety of effects on the nervous system including vascular and inflammatory effects that can be seen with even low-level blast exposures which produce minimal or no neuronal pathology. Acutely, blast exposure in animals causes prominent vasospasm and decreased cerebral blood flow along with blood-brain barrier breakdown and increased vascular permeability. Besides direct effects on the central nervous system, evidence supports a role for a thoracically mediated effect of blast; whereby, pressure waves transmitted through the systemic circulation damage the brain. Chronically, a vascular pathology has been observed that is associated with alterations of the vascular extracellular matrix. Sustained microglial and astroglial reactions occur after blast exposure. Markers of a central and peripheral inflammatory response are found for sustained periods after blast injury and include elevation of inflammatory cytokines and other inflammatory mediators. At low levels of blast exposure, a microvascular pathology has been observed in the presence of an otherwise normal brain parenchyma, suggesting that the vasculature may be selectively vulnerable to blast injury. Chronic immune activation in brain following vascular injury may lead to neurobehavioral changes in the absence of direct neuronal pathology. Strategies aimed at preventing or reversing vascular damage or modulating the immune response may improve the chronic neuropsychiatric symptoms associated with blast-related TBI.

High-pressure blast waves can cause extensive CNS injury in human beings. However, in combat settings, such as Iraq and Afghanistan, lower level exposures associated with mild traumatic brain injury (mTBI) or subclinical exposure have been much more common. Yet controversy exists concerning what traits can be attributed to low-level blast, in large part due to the difficulty of distinguishing blast-related mTBI from post-traumatic stress disorder (PTSD). We describe how TBI is defined in human beings and the problems posed in using current definitions to recognize blast-related mTBI. We next consider the problem of applying definitions of human mTBI to animal models, in particular that TBI severity in human beings is defined in relation to alteration of consciousness at the time of injury, which typically cannot be assessed in animals. However, based on outcome assessments, a condition of "low-level" blast exposure can be defined in animals that likely approximates human mTBI or subclinical exposure. We review blast injury modeling in animals noting that inconsistencies in experimental approach have contributed to uncertainty over the effects of low-level blast. Yet, animal studies show that low-level blast pressure waves are transmitted to the brain. In brain, low-level blast exposures cause behavioral, biochemical, pathological, and physiological effects on the nervous system including the induction of PTSD-related behavioral traits in the absence of a psychological stressor. We review the relationship of blast exposure to chronic neurodegenerative diseases noting the paradoxical lowering of Abeta by blast, which along with other observations suggest that blast-related TBI is pathophysiologically distinct from non-blast TBI. Human neuroimaging studies show that blast-related mTBI is associated with a variety of chronic effects that are unlikely to be explained by co-morbid PTSD. We conclude that abundant evidence supports low-level blast as having long-term effects on the nervous system.

Single, severe traumatic brain injury (TBI) which elevates CNS amyloid, increases the risk of Alzheimer's disease (AD); while repetitive concussive and subconcussive events as observed in athletes and military personnel, may increase the risk of chronic traumatic encephalopathy (CTE). We describe two clinical cases, one with a history of multiple concussions during a career in the National Football League (NFL) and the second with frontotemporal dementia and a single, severe TBI. Both patients presented with cognitive decline and underwent [(18)F]-Florbetapir positron emission tomography (PET) imaging for amyloid plaques; the retired NFL player also underwent [(18)F]-T807 PET imaging, a new ligand binding to tau, the main constituent of neurofibrillary tangles (NFT). Case 1, the former NFL player, was 71 years old when he presented with memory impairment and a clinical profile highly similar to AD. [(18)F]-Florbetapir PET imaging was negative, essentially excluding AD as a diagnosis. CTE was suspected clinically, and [(18)F]-T807 PET imaging revealed striatal and nigral [(18)F]-T807 retention consistent with the presence of tauopathy. Case 2 was a 56-year-old man with personality changes and cognitive decline who had sustained a fall complicated by a subdural hematoma. At 1 year post injury, [(18)F]-Florbetapir PET imaging was negative for an AD pattern of amyloid accumulation in this subject. Focal [(18)F]-Florbetapir retention was noted at the site of impact. In case 1, amyloid imaging provided improved diagnostic accuracy where standard clinical and laboratory criteria were inadequate. In that same case, tau imaging with [(18)F]-T807 revealed a subcortical tauopathy that we interpret as a novel form of CTE with a distribution of tauopathy that mimics, to some extent, that of progressive supranuclear palsy (PSP), despite a clinical presentation of amnesia without any movement disorder complaints or signs. A key distinguishing feature is that our patient presented with hippocampal involvement, which is more frequently seen in CTE than in PSP. In case 2, focal [(18)F]-Florbetapir retention at the site of injury in an otherwise negative scan suggests focal amyloid aggregation. In each of these complex cases, a combination of [(18)F]-fluorodeoxyglucose, [(18)F]-Florbetapir and/or [(18)F]-T807 PET molecular imaging improved the accuracy of diagnosis and prevented inappropriate interventions.

Central arginine vasopressin receptor 1A (AVPR1A) modulates a wide range of behaviors, including stress management and territorial aggression, as well as social bonding and recognition. Inter- and intra-species variations in the expression pattern of AVPR1A in the brain and downstream differential behavioral phenotypes have been attributed to differences in the non-coding regions of the AVPR1A gene, including polymorphic elements within upstream regulatory areas. Gene association studies have suggested a link between AVPR1A polymorphisms and autism, and AVPR1A has emerged as a potential pharmacological target for treatment of social cognitive impairments and mood and anxiety disorders. To further investigate the genetic mechanism giving rise to species differences in AVPR1A expression patterns and associated social behaviors, and to create a preclinical mouse model useful for screening drugs targeting AVPR1A, we engineered and extensively characterized bacterial artificial chromosome (BAC) transgenic mice harboring the entire human AVPR1A locus with the surrounding regulatory elements. Compared with wild-type animals, the humanized mice displayed a more widely distributed ligand-AVPR1A binding pattern, which overlapped with that of primates. Furthermore, humanized AVPR1A mice displayed increased reciprocal social interactions compared with wild-type animals, but no differences in social approach and preference for social novelty were observed. Aspects of learning and memory, specifically novel object recognition and spatial relocation recognition, were unaffected. The biological alterations in humanized AVPR1A mice resulted in the rescue of the prepulse inhibition impairments that were observed in knockout mice, indicating conserved functionality. Although further behavioral paradigms and additional cohorts need to be examined in humanized AVPR1A mice, the results demonstrate that species-specific variations in the genomic content of regulatory regions surrounding the AVPR1A locus are responsible for differential receptor protein expression patterns across species and that they are likely to contribute to species-specific behavioral variation. The humanized AVPR1A mouse is a potential preclinical model for further understanding the regulation of receptor gene expression and the impact of variation in receptor expression on behaviors, and should be useful for screening drugs targeting human AVPR1A, taking advantage of the expression of human AVPR1A in human-relevant brain regions., (© 2014. Published by The Company of Biologists Ltd.)

Background: Blast-related traumatic brain injury (TBI) is a common cause of injury in the military operations in Iraq and Afghanistan. How the primary blast wave affects the brain is not well understood. The aim of the present study was to examine whether blast exposure affects the cerebral vasculature in a rodent model. We analyzed the brains of rats exposed to single or multiple (three) 74.5 kPa blast exposures, conditions that mimic a mild TBI. Rats were sacrificed 24 hours or between 6 and 10 months after exposure. Blast-induced cerebral vascular pathology was examined by a combination of light microscopy, immunohistochemistry, and electron microscopy., Results: We describe a selective vascular pathology that is present acutely at 24 hours after injury. The vascular pathology is found at the margins of focal shear-related injuries that, as we previously showed, typically follow the patterns of penetrating cortical vessels. However, changes in the microvasculature extend beyond the margins of such lesions. Electron microscopy revealed that microvascular pathology is found in regions of the brain with an otherwise normal neuropil. This initial injury leads to chronic changes in the microvasculature that are still evident many months after the initial blast exposure., Conclusions: These studies suggest that vascular pathology may be a central mechanism in the induction of chronic blast-related injury.

Haploinsufficiency of SHANK3, caused by chromosomal abnormalities or mutations that disrupt one copy of the gene, leads to a neurodevelopmental syndrome called Phelan-McDermid syndrome, symptoms of which can include absent or delayed speech, intellectual disability, neurological changes and autism spectrum disorders. The SHANK3 protein forms a key structural part of the post-synaptic density. We previously generated and characterized mice with a targeted disruption of Shank3 in which exons coding for the ankyrin-repeat domain were deleted and expression of full-length Shank3 was disrupted. We documented specific deficits in synaptic function and plasticity, along with reduced reciprocal social interactions, in Shank3 heterozygous mice. Changes in phenotype owing to a mutation at a single locus are quite frequently modulated by other loci, most dramatically when the entire genetic background is changed. In mice, each strain of laboratory mouse represents a distinct genetic background and alterations in phenotype owing to gene knockout or transgenesis are frequently different across strains, which can lead to the identification of important modifier loci. We have investigated the effect of genetic background on phenotypes of Shank3 heterozygous, knockout and wild-type mice, using C57BL/6, 129SVE and FVB/Ntac strain backgrounds. We focused on observable behaviors with the goal of carrying out subsequent analyses to identify modifier loci. Surprisingly, there were very modest strain effects over a large battery of analyses. These results indicate that behavioral phenotypes associated with Shank3 haploinsufficiency are largely strain-independent., (© 2014. Published by The Company of Biologists Ltd.)

Background: Blast-related traumatic brain injury (TBI) has been a significant cause of injury in the military operations of Iraq and Afghanistan, affecting as many as 10-20% of returning veterans. However, how blast waves affect the brain is poorly understood. To understand their effects, we analyzed the brains of rats exposed to single or multiple (three) 74.5 kPa blast exposures, conditions that mimic a mild TBI., Results: Rats were sacrificed 24 hours or between 4 and 10 months after exposure. Intraventricular hemorrhages were commonly observed after 24 hrs. A screen for neuropathology did not reveal any generalized histopathology. However, focal lesions resembling rips or tears in the tissue were found in many brains. These lesions disrupted cortical organization resulting in some cases in unusual tissue realignments. The lesions frequently appeared to follow the lines of penetrating cortical vessels and microhemorrhages were found within some but not most acute lesions., Conclusions: These lesions likely represent a type of shear injury that is unique to blast trauma. The observation that lesions often appeared to follow penetrating cortical vessels suggests a vascular mechanism of injury and that blood vessels may represent the fault lines along which the most damaging effect of the blast pressure is transmitted.

Blast-induced traumatic brain injury (TBI) has been a major cause of morbidity and mortality in the conflicts in Iraq and Afghanistan. How the primary blast wave affects the brain is not well understood. In particular, it is unclear whether blast injures the brain through mechanisms similar to those found in non-blast closed impact injuries (nbTBI). The β-amyloid (Aβ) peptide associated with the development of Alzheimer's disease is elevated acutely following TBI in humans as well as in experimental animal models of nbTBI. We examined levels of brain Aβ following experimental blast injury using enzyme-linked immunosorbent assays for Aβ 40 and 42. In both rat and mouse models of blast injury, rather than being increased, endogenous rodent brain Aβ levels were decreased acutely following injury. Levels of the amyloid precursor protein (APP) were increased following blast exposure although there was no evidence of axonal pathology based on APP immunohistochemical staining. Unlike the findings in nbTBI animal models, levels of the β-secretase, β-site APP cleaving enzyme 1, and the γ-secretase component presenilin-1 were unchanged following blast exposure. These studies have implications for understanding the nature of blast injury to the brain. They also suggest that strategies aimed at lowering Aβ production may not be effective for treating acute blast injury to the brain.

Background: Presenilin-1 (PS1) is a transmembrane protein first discovered because of its association with familial Alzheimer's disease. Mice with null mutations in PS1 die shortly after birth exhibiting multiple CNS and non-CNS abnormalities. One of the most prominent features in the brains of PS1-/- embryos is a vascular dysgenesis that leads to multiple intracerebral hemorrhages. The molecular and cellular basis for the vascular dysgenesis in PS1-/- mice remains incompletely understood. Because the extracellular matrix plays key roles in vascular development we hypothesized that an abnormal extracellular matrix might be present in endothelial cells lacking PS1 and examined whether the lack of PS1 affects expression of fibronectin a component of the extracellular matrix known to be essential for vascular development., Results: We report that primary as well as continuously passaged PS1-/- endothelial cells contain more fibronectin than wild type cells and that the excess fibronectin in PS1-/- endothelial cells is incorporated into a fibrillar network. Supporting the in vivo relevance of this observation fibronectin expression was increased in microvascular preparations isolated from E14.5 to E18.5 PS1-/- embryonic brain. Reintroduction of PS1 into PS1-/- endothelial cells led to a progressive decrease in fibronectin levels showing that the increased fibronectin in PS1-/- endothelial cells was due to loss of PS1. Increases in fibronectin protein in PS1-/- endothelial cells could not be explained by increased levels of fibronectin RNA nor based on metabolic labeling studies by increased protein synthesis. Rather we show based on the rate of turnover of exogenously added biotinylated fibronectin that increased fibronectin in PS1-/- endothelial cells results from a slower degradation of the fibronectin fibrillar matrix on the cell surface., Conclusions: These studies show that PS1 regulates the constitutive turnover of the fibronectin matrix in endothelial cells. These studies provide molecular clues that may help to explain the origin of the vascular dysgenesis that develops in PS1-/- embryonic mice.

Blast related traumatic brain injury (TBI) has been a major cause of injury in the wars in Iraq and Afghanistan. A striking feature of the mild TBI (mTBI) cases has been the prominent association with post-traumatic stress disorder (PTSD). However, because of the overlapping symptoms, distinction between the two disorders has been difficult. We studied a rat model of mTBI in which adult male rats were exposed to repetitive blast injury while under anesthesia. Blast exposure induced a variety of PTSD-related behavioral traits that were present many months after the blast exposure, including increased anxiety, enhanced contextual fear conditioning, and an altered response in a predator scent assay. We also found elevation in the amygdala of the protein stathmin 1, which is known to influence the generation of fear responses. Because the blast overpressure injuries occurred while animals were under general anesthesia, our results suggest that a blast-related mTBI exposure can, in the absence of any psychological stressor, induce PTSD-related traits that are chronic and persistent. These studies have implications for understanding the relationship of PTSD to mTBI in the population of veterans returning from the wars in Iraq and Afghanistan.