Introduction:Neuropsychiatric symptoms (NPS) are common in neurocognitive disorders (NCD) and are known to negatively impact patient's functional abilities. However, our understanding of the relationship between individual NPS and functional decline in patients with NCD across the spectrum of cognitive impairment is limited. Here we examine the relationship between specific NPS to characterize their effects on patient's function within and across different etiologies. Method:Longitudinal observational study using the National Alzheimer's Coordinating Center Uniform Data Set (NACCUDS). We examined NPS as characterized by expert clinicians and report its impact on the outcome of functional decline, measured by the Functional Assessment Questionnaire (FAQ), a standardized assessment of activities of daily living, by dementia etiology (Alzheimer's disease (AD, N = 11,044), Lewy Body Disease (LBD, N = 921), and behavioral variant frontal temporal lobe dementia (bvFTD, N = 933)). Results:We find apathy was the most commonly endorsed and the most persistent symptom across dementia types in all groups and was associated with more rapid functional decline in AD and bvFTD. On the contrary, depression, occurring in 40% or more of all groups, was not associated with worsening functional impairment in any group. We identified patterns that indicated higher rates of disinhibition and persistent disinhibition in bvFTD compared to AD and LBD. Psychosis had unique impact on functional decline in AD and LBD as did agitation in AD. Discussion:Differential impact of individual NPS across dementia etiologies and their impact on functional decline may have important consequences for clinical trial designs for the treatment of these symptoms.

Many Veterans who experienced blast-related traumatic brain injuries (TBI) during their military service suffer from chronic cognitive and mental health problems including post-traumatic stress disorder (PTSD). Male rats exposed to repetitive low-level blast injuries designed to mimic the type of blast-related mild TBI that was so common in the conflicts in Iraq and Afghanistan develop delayed and persistent cognitive and PTSD-related traits that remain present for over 1 year after exposure. Boldine, an alkaloid derived from the Chilean Boldo tree (Peumus boldus), is a widely used herbal remedy with anti-oxidant, anti-inflammatory, hepatoprotective, and connexin hemichannel-blocking properties. We studied whether oral administration of boldine prevented development of PTSD-related behavioral traits in rats exposed to repetitive low-level blast. Treatment with boldine prevented appearance of the blast-induced PTSD-like phenotype including object recognition deficits and exaggerated cued fear learning. Boldine also prevented blast-induced elevation of the metabotropic glutamate receptor 2 (mGluR2) and the N-methyl-D-aspartate receptor 2b (NMDAR2b), but did not reverse decreases in the serotonin 5-HT2A receptor. Iba1 immunofluorescence staining suggested that boldine reduced blast-associated microglial process retraction (indicative of activation) in the somatosensory cortex. Transcriptomics analysis of hippocampus mRNA did not identify individual genes that remained significant after FDR correction. Exploratory analysis of 85 nominally significant candidates suggested that boldine induced coordinated transcriptional changes related to GO terms “Cognition” and “Neurotransmitter Transport,” consistent with modulation of activity-regulated transcription factors and neuroimmune signaling. These studies suggest that boldine may be beneficial for the neurobehavioral syndromes that follow blast exposure in military Veterans.

Repetitive low-level blast exposures in rats induce the development of a post-traumatic stress disorder (PTSD)-like phenotype and evolving chronic brain vascular alterations. These alterations included atherogenic-like lesions characterized by increased extravasation of blood elements into the arterial subendothelial layers, nuclear expression of c-Fos in endothelial and vascular smooth muscle cells, vascular hyperplasia, foam cell formation, and ultimately vascular rupture. Foam cells were mainly of macrophage/microglial or of vascular smooth muscle cell origin with upregulated expression of MHC II and of its co-stimulatory molecule CD86, which is characteristic of antigen-presenting cells. Foam cells also upregulated the lysosomal CD68 marker, indicating macrophage/microglial phagocytic and inflammatory activity. Foam cells of vascular smooth muscle cell origin were present at arteriolar bends, kinks, and bifurcations and were associated with a progressive arterial network degeneration in regions with enlarged perivascular spaces. Foam cell inclusions also contained the gelatinase MMP-9, which is involved in extracellular matrix degradation, and the pro-inflammatory cytokine TNF-α that further induces foam cell formation. These findings indicate that the chronic atherogenic lesions associated with blast-induced vascular degeneration may trigger a progressive pro-inflammatory state and expand the progressive vascular degeneration associated with the PTSD-like phenotype.

Herein, we report the discovery and development of an optimized mGlu2 Negative Allosteric Modulator (NAM) in vivo tool compound, VU6066098, based on a novel, structurally distinct chemotype. VU6066098 is a potent, selective, and CNS-penetrant mGlu2 NAM with excellent rat PK (CLp = 23.9 mL/min/kg, t1/2 = 2.2 h, %F = 100, Kp = 1.28, Kp,uu = 0.25), making it ideal to explore the therapeutic potential of selective mGlu2 inhibition in preclinical rat models. In a rat forced swim test, VU6066098 displayed an oral minimum effective dose (MED) of 1 mg/kg and was equi-efficacious to ketamine. In amphetamine-induced hyperlocomotion, VU6066098 displayed an oral minimum effective dose (MED) of 30 mg/kg. While in the preclinical cognitive tasks of rat novel object recognition and acquisition of contextual fear conditioning, VU6066098 produced robust dose-dependent effects at oral minimum effective doses (MED) of 3 mg/kg and 0.3 mg/kg, respectively. In a blast-related traumatic brain injury (TBI) model, administration of VU6066098 at a dose of 10 mg/kg IP was effective acutely, and the effect on NOR memory was sustained up to 30 days postdose. Thus, mGlu2 NAMs show therapeutic potential for the treatment of a broad range of affective and cognitive symptoms associated with Major Depressive Disorder, Alzheimer's disease, TBI, and acute psychosis; moreover, these data strongly support further optimization of mGlu2 NAMs for future clinical development.

Many Veterans who experienced blast-related traumatic brain injuries (TBIs) 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 chronic cognitive and PTSD-related behavioral traits that are present for more than 1 year after exposure. Psychedelic agents alter cognition as well as mood and agents such as psilocybin have gained attention as possible treatments for the mental health disorders that affect Veterans. The best-known action of psilocybin's metabolite psilocin is to stimulate the serotonin 2A receptor (5-HT2AR). The aim of this study was to determine whether 5-HT2AR levels are altered by blast exposure. 5-HT2AR expression was examined by Western blot in 7 cohorts of rats exposed to low level repetitive blast collected from 2 weeks to 12 months after blast exposure. The analysis included three brain regions (anterior cerebral cortex, hippocampus and amygdala) that were chosen based on being relevant to fear learning and the biological basis of PTSD. Possible correlations between Western blot data and behavioral outcomes were evaluated. 5-HT2AR was chronically decreased in anterior cortex of blast-exposed rats in all cohorts except the one studied at 2 weeks after blast exposure. 5-HT2AR levels were variably affected in the other regions. 5-HT2AR expression correlated differently in blast and control rats in some behavioral parameters. These findings have implications for understanding the neurochemical basis of blast-induced cognitive and behavioral changes. They also suggest 5-HT2AR as a potential therapeutic target for treatment of PTSD-related symptoms that follow blast injury.

In modern war theaters, exposures to blast overpressures are one of the most common causes of brain injury. These pervasive events result in acute and chronic cerebrovascular degenerative processes. Using a rat model of blast-induced mild traumatic brain injury, we identified intramural periarterial hematomas as early primary acute lesions induced by blast exposures. These lesions resulted in intravascular cell death, cell layer reorganization, and plasma leakage into the intraperiarterial basal membranes that constitute the intraperiarterial drainage system (IPAD). Plasma metalloproteases, including MMP-9, in the IPAD basal membranes may degrade extracellular matrix components compromising normal cerebral interstitial fluid drainage, arterial structure and function leading to chronic vascular degenerative processes. Related subacute effects of blast exposure included increased MMP-9 expression in perivascular reactive astrocytes and the extension of astrocytic processes through the layers of affected vessels. These results, in combination with normal levels of proinflammatory cytokines and the absence of proinflammatory MHC II-expressing microglia, suggest an astrocytic role in the clearing of intravascular hematomas and provide further mechanistic evidence that blast-induced vascular degenerative processes may precede the onset of neurovascular inflammation.

Several disease modifying treatment (DMT) in early AD have shown effectiveness in reducing rate of decline on cognition and function. Earlier analyses using participants who are likely targets for clinical trial and treatment showed treatment effects may have important effects on patients’ work capacity and need for informal care. However, amyloid pathology was not examined. This study explores the relationship between amyloid burden and health-related resource use. Participants enrolled in the Mount Sinai Alzheimer’s Disease Research Center with CDR = 0.5 or 1 and clinical diagnosis of MCI or AD. Health-related resource use was self-reported by participant and/or study partner using the Resource Use Inventory (RUI). Amyloid images received a clinical read by a neuro-radiologist who was blinded to patient characteristics used to determine amyloid status. Two-part or hurdle models were used adjusting for age, sex, race/ethnicity, education, comorbidities, baseline CDR Sum of Boxes (CDR-SB), and years of follow up. Sample included 56 participants (28 amyloid positive, 28 negative) who had 1 or more RUI assessments (average follow up = 2.6±1.5 years). At baseline, average age = 73±8, 17±3 years of schooling, 54% female, 66% White, 20% Black, 11% Hispanic. 91% CDR = 0.5, 13% cognitively normal, 63% MCI, 25% AD; MMSE = 26±3, CDR-SB = 1.8±1.8, comorbidities = 5.5±2.5. There were no statistically significant differences (at p = 0.05) in participants' characteristics except that proportion of participants who were White was higher in those who were amyloid positive (86%) than negative (46%) (p = 0.002). No Hispanic participant was amyloid positive. Follow up was longer in those who were amyloid negative (3±1.4 years) than amyloid positive (2.2±1.4 years). Baseline RUI items were not statistically significantly different by amyloid positivity. At baseline, amyloid positivity was associated with lower likelihood of participation in employment/volunteering. Among those who used help, amyloid positivity was associated with higher home health care hours. Over time, likelihood of receiving informal help increased and participation in employment/volunteering decreased. Data did not reveal any interaction between amyloid positivity and time. Results from this small sample of participants that reflects AD clinical trial populations suggest amyloid burden may be associated with higher health-related resource use.

Neuropsychiatric symptoms (NPS) are core features of Alzheimer’s disease (AD) and have significant impact on patients, caregivers, and families. Worse NPS scores are associated with worse function and higher need for care. It is unclear if individual NPS symptoms may differentially affect functional decline and may be more effectively targeted to improve patient outcomes. Data are drawn from participants enrolled in the National Alzheimer’s Coordinating Center Uniform Data Set (9/2005-11/2022). Participants were diagnosed with Mild Cognitive Impairment or AD at baseline, had a primary etiologic diagnosis of AD, and had at least one annual follow-up visit (average follow-up = 4 years). Participants’ function was measured using the Functional Assessment Questionnaire (FAQ). NPS were reported by ADC study clinicians using the “Clinician Judgment of Symptoms” (Form B9) evaluating whether each of the following symptoms manifested as a meaningful change in behavior (yes = 1, no = 0): apathy-withdrawal, depressed mood, visual or auditory hallucinations, delusions, disinhibition, irritability, agitation, and anxiety. Dementia severity was measured using the CDR. Multivariable analyses of the effects of each NPS on decline in function were performed using linear mixed models. Covariates included baseline age, gender, race/ethnicity, education, referral source, number of visits, comorbidities, APOE genotype, and number of medications. Baseline sample characteristics (N = 9,358): mean age = 74±9, 47% male, 78% non-Hispanic white, 11% black, 8% Hispanic, education = 15±4; 52% CDR = 0.5, 35% CDR = 1, and 13% CDR≥2; FAQ = 12±9. Baseline presence of NPS: apathy (34%), depressed mood (33%), anxiety (31%), irritability (28%), agitation (13%), disinhibition (10%), delusions (9%), and hallucinations (5%). Apathy was the most persistent of NPS with 37% of all participants had clinician endorsed apathy in ≥50% all of their visits, followed by depressed mood (28%), irritability (27%), anxiety (21%), agitation (14%), disinhibition (11%), delusions (9%), and hallucinations (5%). Functional decline was faster in those with persistent (≥50% of all visits) apathy, agitation, and delusions. Different behavioral symptoms have differential effects on functional decline, a major driver of caregiver stress and institutionalization. Better understanding of these differential effects on function is crucial in designing trials for treatment in AD. Assessing for these behavioral symptoms should be a standard component of cognitive evaluations.

Introduction:Many military Veterans who experienced blast-related traumatic brain injuries (TBI) in the conflicts in Iraq and Afghanistan currently suffer from chronic cognitive and mental health problems including post-traumatic stress disorder (PTSD). Rats exposed to repetitive low level blast injury exhibit chronic PTSD-related behavioral traits. Inflammation has long been suspected of playing a role in blast-induced brain injury and rats exposed to repetitive low-level blast develop chronic inflammatory changes. Minocycline is a tetracycline antibiotic that besides having antibacterial properties has anti-inflammatory activity. The aim of this study was to determine whether minocycline could reverse PTSD related behavioral traits in rats exposed to repetitive low level blast exposure. Methods:Rats were exposed to three 74.5 kPa blast exposures administered one per day for three consecutive days. We tested two cohorts of blast-exposed rats at 8-8.5 months after blast exposure. Rats were tested in a novel object recognition (NOR) task, elevated zero maze (EZM) and cued fear learning paradigm. In one experiment rats were treated with five doses of minocycline over a 9-day period. In the second experiment blast-exposed rats were treated with a 4-week course of minocycline with the drug administered 11 times. After the second experiment blast-induced effects on expression of the serotonin receptor 2A (5-HT2AR) and the post-synaptic density protein-95 (PSD-95) were examined by Western blotting. Microglial morphology was examined by Iba1 immunostaining. Results:In both experiments, cognitive changes in NOR and anxiety in an EZM were reversed by minocycline. However, in neither experiment was exaggerated fear learning rescued. Minocycline did not reverse blast induced effects on expression of 5-HT2AR or PSD-95 although it did appear to modulate blast-induced effects on microglial morphology. Conclusions:These studies have implications for understanding the nature of blast-induced behavioral traits, some of which may be the direct result of inflammatory effects, while others may be independent of inflammation or if the result of inflammation, not reversible once downstream structural or neurochemical changes are established.

Background and objectivesApathy 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.MethodsStudy 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).ResultsBaseline 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.DiscussionIn 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.

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.

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.

The long-term effects of exposure to blast overpressure are an important health concern in military personnel. Increase in amyloid beta (A beta) 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 A beta 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 A beta levels, production, and clearance mechanisms in the acute (24 h) and delayed (28 days) phases post-blast exposure in an experimental rat model. A beta and, notably, the highly neurotoxic detergent soluble A beta 42 form, was reduced at 24 h but not 28 days after blast exposure. This reduction was not associated with changes in the levels of A beta oligomers, expression levels of amyloid precursor protein (APP), or increase in enzymes involved in the amyloidogenic cleavage of APP, the beta- and Gamma-secretases BACE1 and presenilin-1, respectively. The levels of ADAM17 alpha-secretase (also known as tumor necrosis factor alpha-converting enzyme) decreased, concomitant with the reduction in brain A beta. 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 A beta 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 A beta.

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 (APPE693Q) transgenic mice, a model of the pathological accumulation of All oligomers found in AD. Herein, we investigated effects of BCI-838 on PS19 male mice that express the tauopathy mutation MAPTP301S associated with human frontotemporal lobar degeneration (FTLD). These mice develop an agingrelated tauopathy without amyloid accumulation. Mice were divided into three experimental groups: (1) nontransgenic 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 BCI838 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.

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 (APPE693Q) 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 MAPTP301S 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.

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.

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.

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.

BackgroundModulation 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 AβE22Q (APPE693Q = “Dutch APP”) reduced learning behavior impairment and anxiety, both of which are associated with the phenotype of Dutch APP mice.Methods3-month-old mice were administered BCI-838 and/or physical exercise for 1 month and then tested in novel object recognition, neurogenesis, and RNAseq.ResultsHere 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 (APPKM670/671NL/PSEN1Δexon9= 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.ConclusionOur 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.

Modulation of physical exercise (PE) represents an intervention that may delay, slow, or prevent mild cognitive impairment (MCI) or dementia due to Alzheimer’s disease (AD). One mechanism proposed to underlie beneficial effects of PE involves the apparent stimulation of adult hippocampal neurogenesis (AHNG). BCI-838 is a pro-drug whose metabolite BCI-632 is one of the most active proneurogenic agents known and is an antagonist at group II metabotropic receptors (mGluR2/3). The drug stimulates AHNG while enhancing learning behavior and exerting anxiolytic and antidepressant properties. We previously demonstrated that the administration of BCI-838 to a mouse model of cerebral and cerebrovascular accumulation of oligomeric Ab E22Q ( APP E693Q = “Dutch” ) reduced learning behavior impairment and anxiety, both of which are associated with the phenotype of Thy1.1- Dutch APP mice (Kim et al., Mol Psych 2014). Herein, we sought to determine whether BCI-838 might substitute for PE, and/or whether treatment with a BCI-838+PE combination might demonstrate synergistic effects in a mouse model of amyloidosis ( APP KM670/671NL /PSEN1 Δexon9 = APP/PS1 ). 3-month-old APP/PS1 mice were treated with either BCI-838, PE (running wheels), or a combination of BCI-838+PE for 1 month. We performed learning behavior tests (novel object recognition and Barnes maze), biochemical, and transcriptomic analyses on the hippocampal dentate gyrus (DG) of APP/PS1 mice. We performed gene set enrichment analysis, drug repurposing, and chemogenomic enrichment analyses to reveal molecular pathways of interest and investigated compounds with transcriptomically similar profiles as well as drug targets and side effects. We report that: (i) BCI-838, PE, or BCI-838+PE combination enhanced AHNG, (ii) BCI-838 alone or associated with PE led to improvement in both spatial and recognition learning behaviors, (iii) BCI-838 treatment increased mRNA levels of BDNF, metabotropic glutamate receptors, and PIK3C2A of the PI3K-MTOR pathway, and decreased EIF5A of ketamine-modulating mTOR activity in the hippocampal DG. qPCR results validated the statistical significance of the association between BCI-838 treatment and increased levels of BDNF. Our study points to BCI-838 as a safe and orally active compound capable of mimicking the beneficial effect of exercise on AHNG, learning behavior, and anxiety in the APP/PS1 mouse model.