The impact of APOE4 on neurological symptoms after exposure to K. brevis neurotoxin.

Introduction: The harmful alga Karenia brevis (K. brevis) releases brevetoxins (PbTx) that cause respiratory and neurological symptoms. The apolipoprotein E (APOE) ε4 allele has been linked to poor neurological outcomes after exposure to environmental toxicants.

PPARγ activation ameliorates cognitive impairment and chronic microglial activation in the aftermath of r-mTBI.

Chronic neuroinflammation and microglial activation are key mediators of the secondary injury cascades and cognitive impairment that follow exposure to repetitive mild traumatic brain injury (r-mTBI). Peroxisome proliferator-activated receptor-γ (PPARγ) is expressed on microglia and brain resident myeloid cell types and their signaling plays a major anti-inflammatory role in modulating microglial responses. At chronic timepoints following injury, constitutive PPARγ signaling is thought to be dysregulated, thus releasing the inhibitory brakes on chronically activated microglia.

Overexpression of pathogenic tau in astrocytes causes a reduction in AQP4 and GLT1, an immunosuppressed phenotype and unique transcriptional responses to repetitive mild TBI without appreciable changes in tauopathy.

Epidemiological studies have unveiled a robust link between exposure to repetitive mild traumatic brain injury (r-mTBI) and elevated susceptibility to develop neurodegenerative disorders, notably chronic traumatic encephalopathy (CTE). The pathogenic lesion in CTE cases is characterized by the accumulation of hyperphosphorylated tau in neurons around small cerebral blood vessels which can be accompanied by astrocytes that contain phosphorylated tau, the latter termed tau astrogliopathy. However, the contribution of tau astrogliopathy to the pathobiology and functional consequences of r-mTBI/CTE or whether it is merely a consequence of aging remains unclear.

Characterizing 1991 Gulf War women veterans from the Boston Biorepository and Integrative Network for Gulf War Illness: Demographics, exposures, neuroimaging and cognitive outcomes.

: Gulf War Illness (GWI) is a debilitating multisymptom condition that affects nearly a third of 1990-91 Gulf War (GW) veterans. Symptoms include pain, fatigue, gastrointestinal issues, and cognitive decrements. Our work has shown that GWI rates and potential causes for symptoms vary between men and women veterans.

Repetitive head trauma and apoE4 induce chronic cerebrovascular alterations that impair tau elimination from the brain.

Repetitive mild traumatic brain injuries (r-mTBI) sustained in the military or contact sports have been associated with the accumulation of extracellular tau in the brain, which may contribute to the pathogenesis of neurodegenerative tauopathies. The expression of the apolipoprotein E4 (apoE4) isoform has been associated with higher levels of tau in the brain, and worse clinical outcomes after r-mTBI, though the influence of apoE genotype on extracellular tau dynamics in the brain is poorly understood. We recently demonstrated that extracellular tau can be eliminated across blood-brain barrier (BBB), which is progressively impaired following r-mTBI.

Frontotemporal disorders: the expansive panoply of syndromes and spectrum of etiologies.

Background: Frontotemporal lobe disorders (FTD) are amongst the most common brain neurodegenerative disorders. Their relatively covert, frequently subtle presentations and diverse etiologies, pose major challenges in diagnosis and treatments. Recent studies have yielded insights that the etiology in the majority are due to environmental and sporadic causes, rather than genetic in origin.

Baseline serum brain-derived neurotrophic factor association with future cognition in community-dwelling older adults undergoing annual memory screening.

Objectives: It has been shown that peripheral measures of brain-derived neurotrophic factor (BNDF), an important neurotrophin instrumental to the biology of learning, may contribute to predicting cognitive decline. However, the two primary forms of BDNF, mature (mBDNF) and pro (proBDNF), and how they contribute to cognition longitudinally has not been well studied.

Methods: Eighty-two older adults (average age 72.

Levels of Arachidonic Acid-Derived Oxylipins and Anandamide Are Elevated Among Military ɛ4 Carriers With a History of Mild Traumatic Brain Injury and Post-Traumatic Stress Disorder Symptoms.

Currently approved blood biomarkers detect intracranial lesions in adult patients with mild to moderate traumatic brain injury (TBI) acutely post-injury. However, blood biomarkers are still needed to help with a differential diagnosis of mild TBI (mTBI) and post-traumatic stress disorder (PTSD) at chronic post-injury time points. Owing to the association between phospholipid (PL) dysfunction and chronic consequences of TBI, we hypothesized that examining bioactive PL metabolites (oxylipins and ethanolamides) would help identify long-term lipid changes associated with mTBI and PTSD.

ApoE4 expression disrupts tau uptake, trafficking, and clearance in astrocytes.

Tauopathies are a collection of neurodegenerative diseases characterized by the accumulation of pathogenic aggregates of the microtubule-associated protein tau. Despite the prevalence and diversity of tau astrogliopathy in tauopathies, the interactions between astrocytes and tau in the brain, and the influence of neurodegenerative genetic risk factors like the apolipoprotein E4 (apoE4) isoform, are largely unknown. Here, we leveraged primary and immortalized astrocytes expressing humanized apoE isoforms to characterize the mechanisms by which astrocytes interact with and eliminate extracellular tau, and the influence of apoE genotype on these processes.

Genetic association between the APOE ε4 allele, toxicant exposures and Gulf war illness diagnosis.

Introduction: Exposure to nerve agents, pyridostigmine bromide (PB), pesticides, and oil-well fires during the 1991 Gulf War (GW) are major contributors to the etiology of Gulf War Illness (GWI). Since the apolipoprotein E (APOE) ε4 allele is associated with the risk of cognitive decline with age, particularly in the presence of environmental exposures, and cognitive impairment is one of the most common symptoms experienced by veterans with GWI, we examined whether the ε4 allele was associated with GWI.

Methods: Using a case-control design, we obtained data on APOE genotypes, demographics, and self-reported GW exposures and symptoms that were deposited in the Boston Biorepository and Integrative Network (BBRAIN) for veterans diagnosed with GWI (n = 220) and healthy GW control veterans (n = 131).

Human amnionic progenitor cell secretome mitigates the consequence of traumatic optic neuropathy in a mouse model.

Traumatic optic neuropathy (TON) is a condition in which acute injury to the optic nerve from direct or indirect trauma results in vision loss. The most common cause of TON is indirect injury to the optic nerve caused by concussive forces that are transmitted to the optic nerve. TON occurs in up to 5% of closed-head trauma patients and there is currently no known effective treatment.

Thrombin, a Key Driver of Pathological Inflammation in the Brain.

Neurodegenerative diseases, including Alzheimer's disease (AD), are major contributors to death and disability worldwide. A multitude of evidence suggests that neuroinflammation is critical in neurodegenerative disease processes. Exploring the key mediators of neuroinflammation in AD, a prototypical neurodegenerative disease, could help identify pathologic inflammatory mediators and mechanisms in other neurodegenerative diseases.

Deletion of PTEN in microglia ameliorates chronic neuroinflammation following repetitive mTBI.

Traumatic brain injury is a leading cause of morbidity and mortality in adults and children in developed nations. Following the primary injury, microglia, the resident innate immune cells of the CNS, initiate several inflammatory signaling cascades and pathophysiological responses that may persist chronically; chronic neuroinflammation following TBI has been closely linked to the development of neurodegeneration and neurological dysfunction. Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that have been shown to regulate several key mechanisms in the inflammatory response to TBI.

supplementation has no effect on serum brain-derived neurotrophic factor levels but beneficially modulates nuclear factor kappa B and cyclic AMP response element-binding protein levels in healthy elderly subjects.

Background And Aim: is an Ayurvedic herb that has been used for multiple conditions, most notably to augment cognition, particularly memory and attention. Multiple mechanisms, including raising brain-derived neurotrophic factor (BDNF), have been proposed and investigated in animal models that require translational studies in humans.

Methods: Bacopa was administered in an open-labeled study to cognitively healthy controls over a 3-month period.

Associations of ApoE4 status and DHA supplementation on plasma and CSF lipid profiles and entorhinal cortex thickness.

Apolipoprotein ε allele 4 (APOE4) influences the metabolism of polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA). The entorhinal cortex (EC) in the brain is affected early in Alzheimer's disease and is rich in DHA. The purpose of this study is to identify the effect of APOE4 and DHA lipid species on the EC.

Age and affect L-carnitine system metabolites in the brain in the APOE-TR model.

With age the apolipoprotein E () E4 allele (involved in lipid homeostasis) is associated with perturbation of bioenergetics pathways in Alzheimer's disease (AD). We therefore hypothesized that in aging mice genotype would affect the L-carnitine system (central to lipid bioenergetics), in the brain and in the periphery. Using liquid chromatography-mass spectrometry, levels of L-carnitine and associated metabolites: γ-butyrobetaine (GBB), crotonobetaine, as well as acylcarnitines, were evaluated at 10-, 25-, and 50-weeks, in the brain and the periphery, in a targeted replacement mouse model of human (APOE-TR).

Nutritional metabolism and cerebral bioenergetics in Alzheimer's disease and related dementias.

Disturbances in the brain's capacity to meet its energy demand increase the risk of synaptic loss, neurodegeneration, and cognitive decline. Nutritional and metabolic interventions that target metabolic pathways combined with diagnostics to identify deficits in cerebral bioenergetics may therefore offer novel therapeutic potential for Alzheimer's disease (AD) prevention and management. Many diet-derived natural bioactive components can govern cellular energy metabolism but their effects on brain aging are not clear.

APOE ε4 and Alzheimer's disease diagnosis associated differences in L-carnitine, GBB, TMAO, and acylcarnitines in blood and brain.

Background: The apolipoprotein E (APOE) ε4 allele, involved in fatty acid (FA) metabolism, is a major genetic risk factor for Alzheimer's disease (AD). This study examined the influence of APOE genotypes on blood and brain markers of the L-carnitine system, necessary for fatty acid oxidation (FAO), and their collective influence on the clinical and pathological outcomes of AD.

Methods: L-carnitine, its metabolites γ-butyrobetaine (GBB) and trimethylamine-n-oxide (TMAO), and its esters (acylcarnitines) were analyzed in blood from predominantly White community/clinic-based individuals (n = 372) and in plasma and brain from the Religious Order Study (ROS) (n = 79) using liquid chromatography tandem mass spectrometry (LC-MS/MS).

Impact of gulf war toxic exposures after mild traumatic brain injury.

Chemical and pharmaceutical exposures have been associated with the development of Gulf War Illness (GWI), but how these factors interact with the pathophysiology of traumatic brain injury (TBI) remains an area of study that has received little attention thus far. We studied the effects of pyridostigmine bromide (an anti-nerve agent) and permethrin (a pesticide) exposure in a mouse model of repetitive mild TBI (r-mTBI), with 5 impacts over a 9-day period, followed by Gulf War (GW) toxicant exposure for 10 days beginning 30 days after the last head injury. We then assessed the chronic behavioral and pathological sequelae 5 months after GW agent exposure.

Exposure-response relationship between K. brevis blooms and reporting of upper respiratory and neurotoxin-associated symptoms.

In southwest Florida, Karenia brevis (K. brevis) blooms occur frequently, can be very intense and persist over several years. Individuals living in coastal communities around the Gulf of Mexico are particularly vulnerable to brevetoxins released by K.

Subacute and chronic proteomic and phosphoproteomic analyses of a mouse model of traumatic brain injury at two timepoints and comparison with chronic traumatic encephalopathy in human samples.

Repetitive mild traumatic brain injury (r-mTBI) is the most widespread type of brain trauma worldwide. The cumulative injury effect triggers long-lasting pathological and molecular changes that may increase risk of chronic neurodegenerative diseases. R-mTBI is also characterized by changes in the brain proteome, where the majority of molecules altered early post-TBI are different from those altered at more chronic phases.

Characterization of immune profile in an aging multiple sclerosis clinic population.

Background: There is limited data regarding adaptive immunity in older persons with Multiple Sclerosis (MS).

Objective: The aim of the present study was to quantify adaptive immune cells in younger (age less than 50) and older (age greater than 50) with MS in the context of clinical parameters (EDSS, 25-foot walk, SDMT). Subjects were either Untreated (no MS medications in 6 months), taking Injectables (interferons or glatiramer acetate), or Other approved MS treatments.

Exogenous lipase administration alters gut microbiota composition and ameliorates Alzheimer's disease-like pathology in APP/PS1 mice.

Alzheimer's disease (AD) represents the most common form of dementia in the elderly with no available disease modifying treatments. Altered gut microbial composition has been widely acknowledged as a common feature of AD, which potentially contributes to progression or onset of AD. To assess the hypothesis that Candida rugosa lipase (CRL), which has been shown to enhance gut microbiome and metabolite composition, can rebalance the gut microbiome composition and reduce AD pathology, the treatment effects in APPswe/PS1de9 (APP/PS1) mice were investigated.