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All sources NASA NTRS DOE OSTI

DOE OSTI2024

Eucalyptus Wood Smoke Extract Elicits a Dose-Dependent Effect in Brain Endothelial Cells

The frequency, duration, and size of wildfires have been increasing, and the inhalation of wildfire smoke particles poses a significant risk to human health. Epidemiological studies have shown that wildfire smoke exposure is positively associated with cognitive and neurological dysfunctions. However, there is a significant gap in knowledge on how wildfire smoke exposure can affect the blood–brain barrier and cause molecular and cellular changes in the brain. Our study aims to determine the acute effect of smoldering eucalyptus wood smoke extract (WSE) on brain endothelial cells for potential neurotoxicity in vitro. Primary human brain microvascular endothelial cells (HBMEC) and immortalized human brain endothelial cell line (hCMEC/D3) were treated with different doses of WSE for 24 h. WSE treatment resulted in a dose-dependent increase in IL-8 in both HBMEC and hCMEC/D3. RNA-seq analyses showed a dose-dependent upregulation of genes involved in aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (NRF2) pathways and a decrease in tight junction markers in both HBMEC and hCMEC/D3. When comparing untreated controls, RNA-seq analyses showed that HBMEC have a higher expression of tight junction markers compared to hCMEC/D3. In summary, our study found that 24 h WSE treatment increases IL-8 production dose-dependently and decreases tight junction markers in both HBMEC and hCMEC/D3 that may be mediated through the AhR and NRF2 pathways, and HBMEC could be a better in vitro model for studying the effect of wood smoke extract or particles on brain endothelial cells.

60 APPLIED LIFE SCIENCES↗

NASA NTRS1997

Robotic multimodality stereotactic brain tissue identification: work in progress

Real-time identification of tissue would improve procedures such as stereotactic brain biopsy (SBX), functional and implantation neurosurgery, and brain tumor excision. To standard SBX equipment has been added: (1) computer-controlled stepper motors to drive the biopsy needle/probe precisely; (2) multiple microprobes to track tissue density, detect blood vessels and changes in blood flow, and distinguish the various tissues being penetrated; (3) neural net learning programs to allow real-time comparisons of current data with a normative data bank; (4) three-dimensional graphic displays to follow the probe as it traverses brain tissue. The probe can differentiate substances such as pig brain, differing consistencies of the 'brain-like' foodstuff tofu, and gels made to simulate brain, as well as detect blood vessels imbedded in these substances. Multimodality probes should improve the safety, efficacy, and diagnostic accuracy of SBX and other neurosurgical procedures.

Brain/anatomy & histology/surgery↗

NASA NTRS1992

Evidence for a membrane defect in Alzheimer disease brain

To determine whether neurodegeneration in Alzheimer disease brain is associated with degradation of structural cell membrane molecules, we measured tissue levels of the major membrane phospholipids and their metabolites in three cortical areas from postmortem brains of Alzheimer disease patients and matched controls. Among phospholipids, there was a significant (P less than 0.05) decrease in phosphatidylcholine and phosphatidylethanolamine. There were significant (P less than 0.05) decreases in the initial phospholipid precursors choline and ethanolamine and increases in the phospholipid deacylation product glycerophosphocholine. The ratios of glycerophosphocholine to choline and glycerophosphoethanolamine to ethanolamine were significantly increased in all examined Alzheimer disease brain regions. The activity of the glycerophosphocholine-degrading enzyme glycerophosphocholine choline-phosphodiesterase was normal in Alzheimer disease brain. There was a near stoichiometric relationship between the decrease in phospholipids and the increase of phospholipid catabolites. These data are consistent with increased membrane phospholipid degradation in Alzheimer disease brain. Similar phospholipid abnormalities were not detected in brains of patients with Huntington disease, Parkinson disease, or Down syndrome. We conclude that the phospholipid abnormalities described here are not an epiphenomenon of neurodegeneration and that they may be specific for the pathomechanism of Alzheimer disease.

NASA Discipline Regulatory Physiology↗

DOE OSTI2025

Investigating the FLASH Effect in a Rat Brain Organotypic Model With a Novel High-Energy Electron Beam

Ultrahigh dose rate (FLASH) radiation therapy is reported to reduce normal tissue toxicity while maintaining tumor control; however, mechanism(s) remain obscure. To study FLASH mechanisms in brain tissue, we developed a novel experimental platform featuring a specialized high-energy electron linear accelerator, High Intensity Gamma Ray Source (HIGS), paired with an organotypic ex vivo brain metastasis model. We varied interpulse spacing to modulate the mean dose rate (MDR) of our unique 35 MeV electron beam, while maintaining extremely high instantaneous dose rate (IDR). We characterized dosimetry and targeting accuracy of the FLASH beam with film dosimetry. We combined this FLASH beam with an organotypic rat brain slice/breast carcinoma coculture model of brain metastasis to assess effects on normal and neoplastic tissues. Live-cell and bioluminescence imaging demonstrated cancer cell growth effects, whereas normal tissue responses and immune activation were assessed using live-cell imaging, cytokine profiles, and confocal microscopy. Here, we performed comparison experiments with 20 MeV electrons from a Varian clinical linear accelerator (VCLA) using conventional dose rates. The highest IDR of the FLASH beam to date was 20.7 ± 0.6 MGy/s, with maximum MDR of 20.7 MGy/s delivered in 1 pulse of 1 µs duration. Beam targeting was accurate to <1 mm and reproducible. HIGS-FLASH and VCLA dose rates equivalently decreased cancer cell growth. HIGS-FLASH irradiation significantly increased tumor necrosis factor α and fractalkine levels and confocal microscopy revealed distinct changes in microglial morphology slices suggesting microglia activation. Our novel experimental platform produces extremely high dose rates and rapid normal/neoplastic tissue readouts for mechanistic research into the effects of FLASH radiation in the brain. HIGS-FLASH irradiation induces comparable cancer cell growth inhibition but differential effects on cytokines and microglial morphology, suggesting that acute innate immune responses may be involved in FLASH normal tissue effects in the brain.

Kay, Tyler V. [Duke University, Durham, NC (United↗

DOE OSTI2024

Deciphering ApoE Genotype-Driven Proteomic and Lipidomic Alterations in Alzheimer’s Disease Across Distinct Brain Regions

Alzheimer’s disease (AD) is a neurodegenerative disease with a complex etiology influenced by confounding factors such as genetic polymorphisms, age, sex, and race. Traditionally, AD research has not prioritized these influences, resulting in dramatically skewed cohorts such as three times the number of Apolipoprotein E (APOE) e4-allele carriers in AD relative to healthy cohorts. Thus, the resulting molecular changes of AD have previously been complicated by the influence of apolipoprotein E disparities. To explore how apolipoprotein E polymorphism influences AD progression, 62 post-mortem patients consisting of 33 Alzheimer’s disease (AD) and 29 controls (Ctrl) were studied to balance the number of e4-allele carriers and facilitate a molecular comparison of the apolipoprotein E genotype. Lipid and protein perturbations were assessed across AD diagnosed brains compared to Ctrl brains, e4 allele carriers (APOE4+ for those carrying 1 or 2 e4s and APOE4- for non-e4 carriers), and differences in e3e3 and e3e4 Ctrl brains across two brain regions (frontal cortex (FCX) and cerebellum (CBM)). In conclusion, the region-specific influences of apolipoprotein E on AD mechanisms showcased mitochondrial dysfunction and cell proteostasis at the core of AD pathophysiology in the post-mortem brains, indicating these two processes may be influenced by genotypic differences and brain morphology.

Alzheimer’s disease↗

DOE OSTI2021

Structural diverseness of neurons between brain areas and between cases

The cerebral cortex is composed of multiple cortical areas that exert a wide variety of brain functions. Although human brain neurons are genetically and areally mosaic, the three-dimensional structural differences between neurons in different brain areas or between the neurons of different individuals have not been delineated. Here we report a nanometer-scale geometric analysis of brain tissues of the superior temporal gyrus of schizophrenia and control cases. The results of the analysis and a comparison with results for the anterior cingulate cortex indicated that (1) neuron structures are significantly dissimilar between brain areas and that (2) the dissimilarity varies from case to case. The structural diverseness was mainly observed in terms of the neurite curvature that inversely correlates with the diameters of the neurites and spines. The analysis also revealed the geometric differences between the neurons of the schizophrenia and control cases. The schizophrenia cases showed a thin and tortuous neuronal network compared with the controls, suggesting that the neuron structure is associated with the disorder. The area dependency of the neuron structure and its diverseness between individuals should represent the individuality of brain functions.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2024

X-ray fluorescence mapping of brain tissue reveals the profound extent of trace element dysregulation in stroke pathophysiology

Abstract The brain is a privileged organ with regard to its trace element composition and maintains a robust barrier system to sequester this specialized environment from the rest of the body and the vascular system. Stroke is caused by loss of adequate blood flow to a region of the brain. Without adequate blood flow ischaemic changes begin almost immediately, triggering an ischaemic cascade, characterized by ion dysregulation, loss of function, oxidative damage, cellular degradation, and breakdown of the barrier that helps maintain this environment. Ion dysregulation is a hallmark of stroke pathophysiology and we observe that most elements in the brain are dysregulated after stroke. X-ray fluorescence-based detection of physiological changes in the neurometallome after stroke reveals profound ion dysregulation within the lesion and surrounding tissue. Not only are most elements significantly dysregulated after stroke, but the level of dysregulation cannot be predicted from a cell-level description of dysregulation. X-ray fluorescence imaging reveals that the stroke lesion retains <25% of essential K+ after stroke, but this element is not concomitantly elevated elsewhere in the organ. Moreover, elements like Na+, Ca2+, and Cl− are vastly elevated above levels available in normal brain tissue (>400%, >200%, and >150%, respectively). We hypothesize that weakening of the blood–brain barrier after stroke allows elements to freely diffuse down their concentration gradient so that the stroke lesion is in equilibrium with blood (and the compartments containing brain interstitial fluid and cerebrospinal fluid). The change observed for the neurometallome likely has consequences for the potential to rescue infarcted tissue, but also presents specific targets for treatment.

Biochemistry & Molecular Biology↗

DOE OSTI2024

Associations between regional blood-brain barrier permeability, aging, and Alzheimer’s disease biomarkers in cognitively normal older adults

Background Increased blood-brain barrier permeability (BBBp) has been hypothesized as a feature of aging that may lead to the development of Alzheimer’s disease (AD). We sought to identify the brain regions most vulnerable to greater BBBp during aging and examine their regional relationship with neuroimaging biomarkers of AD. Methods We studied 31 cognitively normal older adults (OA) and 10 young adults (YA) from the Berkeley Aging Cohort Study (BACS). Both OA and YA received dynamic contrast-enhanced MRI (DCE-MRI) to quantify K trans values, as a measure of BBBp, in 37 brain regions across the cortex. The OA also received Pittsburgh compound B (PiB)-PET to create distribution volume ratios (DVR) images and flortaucipir (FTP)- PET to create partial volume corrected standardized uptake volume ratios (SUVR) images. Repeated measures ANOVA assessed the brain regions where OA showed greater BBBp than YA. In OA, K trans values were compared based on sex, Aβ positivity status, and APOE4carrier status within a composite region across the areas susceptible to aging. We used linear models and sparse canonical correlation analysis (SCCA) to examine the relationship between K trans and AD biomarkers. Results OA showed greater BBBp than YA predominately in the temporal lobe, with some involvement of parietal, occipital and frontal lobes. Within an averaged ROI of affected regions, there was no difference in K trans values based on sex or Aβ positivity, but OA who were APOE4carriers had significantly higher K trans values. There was no direct relationship between averaged K trans and global Aβ pathology, but there was a trend for an Ab status by tau interaction on K trans in this region. SCCA showed increased K trans was associated with increased PiB DVR, mainly in temporal and parietal brain regions. There was not a significant relationship between K trans and FTP SUVR. Discussion Our findings indicate that the BBB shows regional vulnerability during normal aging that overlaps considerably with the pattern of AD pathology. Greater BBBp in brain regions affected in aging is related to APOE genotype and may also be related to the pathological accumulation of Aβ.

Science & Technology - Other Topics↗

DOE OSTI2022

Correlation of Injury Simulation with Clinical Assessment of Traumatic Brain Injury

This report contains a summary of our efforts to correlate head injury simulations predicting intracranial fluid cavitation with clinical assessments of brain injury from blunt impact to the head. Magnetic resonance imaging (MRI) data, collected on traumatic brain injury (TBI) subjects by researchers at the MIND Institute of New Mexico, was acquired for the current work. Specific blunt impact TBI case histories were selected from the TBI data for further study and possible correlation with simulation. Both group and single-subject case histories were examined. We found one single-subject case that was particularly suited for correlation with simulation. Diffusion tensor image (DTI) analysis of the TBI subject identified white matter regions within the brain displaying reductions in fractional anisotropy (FA), an indicator of local damage to the white matter axonal structures. Analysis of functional magnetic resonance image (fMRI) data collected on this individual identified localized regions of the brain displaying hypoactivity, another indicator of brain injury. We conducted high fidelity simulations of head impact experienced by the TBI subject using the Sandia head-neck-torso model and the shock physics computer code CTH. Intracranial fluid cavitation predictions were compared with maps of DTI fractional anisotropy and fMRI hypoactivity to assess whether a possible correlation exists. The ultimate goal of this work is to assess whether one can correlate simulation predictions of intracranial fluid cavitation with the brain injured sites identified by the fMRI and DTI analyses. The outcome of this effort is described in this report.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

DOE OSTI2024

Enhancing Acute Migraine Treatment: Exploring Solid Lipid Nanoparticles and Nanostructured Lipid Carriers for the Nose-to-Brain Route

Migraine has a high prevalence worldwide and is one of the main disabling neurological diseases in individuals under the age of 50. In general, treatment includes the use of oral analgesics or non-steroidal anti-inflammatory drugs (NSAIDs) for mild attacks, and, for moderate or severe attacks, triptans or 5-HT1B/1D receptor agonists. However, the administration of antimigraine drugs in conventional oral pharmaceutical dosage forms is a challenge, since many molecules have difficulty crossing the blood-brain barrier (BBB) to reach the brain, which leads to bioavailability problems. Efforts have been made to find alternative delivery systems and/or routes for antimigraine drugs. In vivo studies have shown that it is possible to administer drugs directly into the brain via the intranasal (IN) or the nose-to-brain route, thus avoiding the need for the molecules to cross the BBB. In this field, the use of lipid nanoparticles, in particular solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), has shown promising results, since they have several advantages for drugs administered via the IN route, including increased absorption and reduced enzymatic degradation, improving bioavailability. Furthermore, SLN and NLC are capable of co-encapsulating drugs, promoting their simultaneous delivery to the site of therapeutic action, which can be a promising approach for the acute migraine treatment. This review highlights the potential of using SLN and NLC to improve the treatment of acute migraine via the nose-to-brain route. First sections describe the pathophysiology and the currently available pharmacological treatment for acute migraine, followed by an outline of the mechanisms underlying the nose-to-brain route. Afterwards, the main features of SLN and NLC and the most recent in vivo studies investigating the use of these nanoparticles for the treatment of acute migraine are presented.

Torres, Joana (ORCID:0000000327276229)↗

NASA NTRS1999

GCR Transport in the Brain: Assessment of Self-Shielding, Columnar Damage, and Nuclear Reactions on Cell Inactivation Rates

Radiation shield design is driven by the need to limit radiation risks while optimizing risk reduction with launch mass/expense penalties. Both limitation and optimization objectives require the development of accurate and complete means for evaluating the effectiveness of various shield materials and body-self shielding. For galactic cosmic rays (GCR), biophysical response models indicate that track structure effects lead to substantially different assessments of shielding effectiveness relative to assessments based on LET-dependent quality factors. Methods for assessing risk to the central nervous system (CNS) from heavy ions are poorly understood at this time. High-energy and charge (HZE) ion can produce tissue events resulting in damage to clusters of cells in a columnar fashion, especially for stopping heavy ions. Grahn (1973) and Todd (1986) have discussed a microlesion concept or model of stochastic tissue events in analyzing damage from HZE's. Some tissues, including the CNS, maybe sensitive to microlesion's or stochastic tissue events in a manner not illuminated by either conventional dosimetry or fluence-based risk factors. HZE ions may also produce important lateral damage to adjacent cells. Fluences of high-energy proton and alpha particles in the GCR are many times higher than HZE ions. Behind spacecraft and body self-shielding the ratio of protons, alpha particles, and neutrons to HZE ions increases several-fold from free-space values. Models of GCR damage behind shielding have placed large concern on the role of target fragments produced from tissue atoms. The self-shielding of the brain reduces the number of heavy ions reaching the interior regions by a large amount and the remaining light particle environment (protons, neutrons, deuterons. and alpha particles) may be the greatest concern. Tracks of high-energy proton produce nuclear reactions in tissue, which can deposit doses of more than 1 Gv within 5 - 10 cell layers. Information on rates of cell killing from GCR, including patterns of cell killing from single particle tracks. can provide useful information on expected differences between proton and HZE tracks and clinical experiences with photon irradiation. To model effects on cells in the brain, it is important that transport models accurately describe changes in the GCR due to interactions in the cranium and proximate tissues. We describe calculations of the attenuated GCR particle fluxes at three dose-points in the brain and associated patterns of cell killing using biophysical models. The effects of the brain self-shielding and bone-tissue interface of the skull in modulating the GCR environment are considered. For each brain dose-point, the mass distribution in the surrounding 4(pi) solid angle is characterized using the CAM model to trace 512 rays. The CAM model describes the self-shielding by converting the tissue distribution to mass-equivalent aluminum, and nominal values of spacecraft shielding is considered. Particle transport is performed with the proton, neutron, and heavy-ion transport code HZETRN with the nuclear fragmentation model QMSFRG. The distribution of cells killed along the path of individual GCR ions is modeled using in vitro cell inactivation data for cells with varying sensitivity. Monte Carlo simulations of arrays of inactivated cells are considered for protons and heavy ions and used to describe the absolute number of cell killing events of various magnitude in the brain from the GCR. Included are simulations of positions of inactivated cells from stopping heavy ions and nuclear stars produced by high-energy ions most importantly, protons and neutrons.

Shavers, M. R.↗

NASA NTRS2015

Increased Brain Activation for Foot Movement During 70-Day 6 Deg Head-Down Bed Rest (HDBR): Evidence from Functional Magnetic Resonance Imaging (fMRI)

Bed rest has been widely used as a simulation of weightlessness in studying the effects of microgravity exposure on human physiology and cognition. Changes in muscle function and functional mobility have been reported to be associated with bed rest. Understanding the effect of bed rest on neural control of movement would provide helpful information for spaceflight. In the current study, we evaluated how the brain activation for foot movement changed as a function of bed rest. Eighteen healthy men (aged 25 to 39 years) participated in this HDBR study. They remained continuously in the 6deg head‐down tilt position for 70 days. Functional MRI was acquired during 1‐Hz right foot tapping, and repeated at 7 time points: 12 days pre‐, 8 days pre‐, 7 days in‐, 50 days in‐, 70 days in‐, 8 days post‐, and 12 days post‐ HDBR. In all 7 sessions, we observed increased activation in the left motor cortex, right cerebellum and right occipital cortex during foot movement blocks compared to rest. Compared to the pre‐HDBR baseline (1st and 2nd sessions), foot movement‐induced activation in the left hippocampus increased during HDBR. This increase emerged in the 4th session, enlarged in the 5th session, and remained significant in the 6th and 7th sessions. Furthermore, increased activation relative to the baseline in left precuneus was observed in the 5th, 6th and 7th sessions. In addition, in comparison with baseline, increased activation in the left cerebellum was found in the 4th and 5th sessions, whereas increased activation in the right cerebellum was observed in the 4th, 6th and 7th sessions. No brain region exhibited decreased activation during bed rest compared to baseline. The increase of foot movement related brain activation during HDBR suggests that in a long‐term head‐down position, more neural control is needed to accomplish foot movements. This change required a couple of weeks to develop in HDBR (between 3rd and 4th sessions), and did not return to baseline even 12 days after HDBR. The observed effect of bed rest on brain activation during a foot tapping task could be linked to HDBR related changes in brain structure that we have recently reported. The relationship between pre‐ and post‐ HDBR changes in brain activation and performance in a functional mobility test will also be presented.

Yuan, P.↗

NASA NTRS2017

Behavioral, Brain Imaging and Genomic Measures to Predict Functional Outcomes Post-Bed Rest and Space Flight

Astronauts experience sensorimotor disturbances during their initial exposure to microgravity and during the re-adaptation phase following a return to an Earth-gravitational environment. These alterations may disrupt crewmembers' ability to perform mission critical functional tasks requiring ambulation, manual control and gaze stability. Interestingly, astronauts who return from spaceflight show substantial differences in their abilities to readapt to a gravitational environment. The ability to predict the manner and degree to which individual astronauts are affected will improve the effectiveness of countermeasure training programs designed to enhance sensorimotor adaptability. For such an approach to succeed, we must develop predictive measures of sensorimotor adaptability that will allow us to foresee, before actual spaceflight, which crewmembers are likely to experience greater challenges to their adaptive capacities. The goals of this project are to identify and characterize this set of predictive measures. Our approach includes: 1) behavioral tests to assess sensory bias and adaptability quantified using both strategic and plastic-adaptive responses; 2) imaging to determine individual brain morphological and functional features, using structural magnetic resonance imaging (MRI), diffusion tensor imaging, resting state functional connectivity MRI, and sensorimotor adaptation task-related functional brain activation; and 3) assessment of genetic polymorphisms in the catechol-O-methyl transferase, dopamine receptor D2, and brain-derived neurotrophic factor genes and genetic polymorphisms of alpha2-adrenergic receptors that play a role in the neural pathways underlying sensorimotor adaptation. We anticipate that these predictive measures will be significantly correlated with individual differences in sensorimotor adaptability after long-duration spaceflight and exposure to an analog bed rest environment. We will be conducting a retrospective study, leveraging data already collected from relevant ongoing or completed bed rest and spaceflight studies. This data will be combined with predictor metrics that will be collected prospectively (as described for behavioral, brain imaging and genomic measures) from these returning subjects to build models for predicting post spaceflight and bed rest adaptive capability. In this presentation we will discuss the optimized set of tests for predictive metrics to be used for evaluating post mission adaptive capability as manifested in their outcome measures. Comparisons of model performance will allow us to better design and implement sensorimotor adaptability training countermeasures against decrements in post-mission adaptive capability that are customized for each crewmember's sensory biases, adaptive ability, brain structure, brain function, and genetic predispositions. The ability to customize adaptability training will allow more efficient use of crew time during training and will optimize training prescriptions for astronauts to mitigate the deleterious effects of spaceflight.

Mulavara, A. P.↗

DOE OSTI2023

Imaging crossing fibers in mouse, pig, monkey, and human brain using small-angle X-ray scattering

Myelinated axons (nerve fibers) efficiently transmit signals throughout the brain via action potentials. Multiple methods that are sensitive to axon orientations, from microscopy to magnetic resonance imaging, aim to reconstruct the brain's structural connectome. As billions of nerve fibers traverse the brain with various possible geometries at each point, resolving fiber crossings is necessary to generate accurate structural connectivity maps. However, doing so with specificity is a challenging task because signals originating from oriented fibers can be influenced by brain (micro)structures unrelated to myelinated axons. X-ray scattering can specifically probe myelinated axons due to the periodicity of the myelin sheath, which yields distinct peaks in the scattering pattern. Here, in this work, we show that small-angle X-ray scattering (SAXS) can be used to detect myelinated, axon-specific fiber crossings. We first demonstrate the capability using strips of human corpus callosum to create artificial double- and triple-crossing fiber geometries, and we then apply the method in mouse, pig, vervet monkey, and human brains. We compare results to polarized light imaging (3D-PLI), tracer experiments, and to outputs from diffusion MRI that sometimes fails to detect crossings. Given its specificity, capability of 3-dimensional sampling and high resolution, SAXS could serve as a ground truth for validating fiber orientations derived using diffusion MRI as well as microscopy-based methods.

59 BASIC BIOLOGICAL SCIENCES↗

NASA NTRS1987

Nutrients affecting brain composition and behavior

This review examines the changes in brain composition and in various brain functions, including behavior, that can follow the ingestion of particular foods or nutrients. It details those that are best understood: the increases in serotonin, catecholamine, or acetylcholine synthesis that can occur subsequent to food-induced increases in brain levels of tryptophan, tyrosine, or choline; it also discusses the various processes that must intervene between the mouth and the synapse, so to speak, in order for a nutrient to affect neurotransmission, and it speculates as to additional brain chemicals that may ultimately be found to be affected by changes in the availability of their nutrient precursors. Because the brain chemicals best known to be nutrient dependent overlap with those thought to underlie the actions of most of the drugs used to treat psychiatric diseases, knowledge of this dependence may help the psychiatrist to understand some of the pathologic processes occurring in his/her patients, particularly those with appetitive symptoms. At the very least, such knowledge should provide the psychiatrist with objective criteria for judging when to take seriously assertions that particular foods or nutrients do indeed affect behavior (e.g., in hyperactive children). If the food can be shown to alter neurotransmitter release, it may be behaviorally-active; however, if it lacks a discernible neurochemical effect, the likelihood that it really alters behavior is small.

NASA Program Space Medicine↗

DOE OSTI2022

Herpes simplex virus and rates of cognitive decline or whole brain atrophy in the Dominantly Inherited Alzheimer Network

Abstract Objective To investigate whether herpes simplex virus type 1 (HSV‐1) infection was associated with rates of cognitive decline or whole brain atrophy among individuals from the Dominantly Inherited Alzheimer Network (DIAN). Methods Among two subsets of the DIAN cohort (age range 19.6–66.6 years; median follow‐up 3.0 years) we examined (i) rate of cognitive decline ( N = 164) using change in mini‐mental state examination (MMSE) score, (ii) rate of whole brain atrophy ( N = 149), derived from serial MR imaging, calculated using the boundary shift integral (BSI) method. HSV‐1 antibodies were assayed in baseline sera collected from 2009–2015. Linear mixed‐effects models were used to compare outcomes by HSV‐1 seropositivity and high HSV‐1 IgG titres/IgM status. Results There was no association between baseline HSV‐1 seropositivity and rates of cognitive decline or whole brain atrophy. Having high HSV‐1 IgG titres/IgM was associated with a slightly greater decline in MMSE points per year (difference in slope − 0.365, 95% CI: −0.958 to −0.072), but not with rate of whole brain atrophy. Symptomatic mutation carriers declined fastest on both MMSE and BSI measures, however, this was not influenced by HSV‐1. Among asymptomatic mutation carriers, rates of decline on MMSE and BSI were slightly greater among those who were HSV‐1 seronegative. Among mutation‐negative individuals, no differences were seen by HSV‐1. Stratifying by APOE4 status yielded inconsistent results. Interpretation We found no evidence for a major role of HSV‐1, measured by serum antibodies, in cognitive decline or whole brain atrophy among individuals at high risk of early‐onset AD.

Warren‐Gash, Charlotte↗

DOE OSTI2024

Global brain activity and its coupling with cerebrospinal fluid flow is related to tau pathology

Abstract INTRODUCTION Factors responsible for the deposition of pathological tau in the brain are incompletely understood. This study links macroscale tau deposition in the human brain to cerebrospinal fluid (CSF) flow dynamics using resting‐state functional magnetic resonance imaging (rsfMRI). METHODS Low‐frequency (< 0.1 Hz) resting‐state global brain activity is coupled with CSF flow and potentially reflects CSF dynamics‐related clearance. We examined the correlation between rsfMRI measures of CSF inflow and global activity (gBOLD–CSF coupling) as a predictor, interacting with amyloid beta (Aβ), of tau and cortical thickness (dependent variables) across Alzheimer's Disease Neuroimaging Initiative (ADNI) participants from cognitively unimpaired through mild cognitive impairment (MCI) and Alzheimer's disease (AD). RESULTS Tau deposition in Aβ+ participants, accompanied by cortical thinning and cognitive decline, is associated with decreased gBOLD–CSF coupling. Tau mediates the relationship between coupling and thickness. DISCUSSION Findings suggest that resting‐state global brain activity and CSF movements comodulate Alzheimer's tau deposition, presumably related to CSF clearance. Highlights A non‐invasive functional magnetic resonance imaging (fMRI) assessment of a CSF clearance‐related process is carried out. Global brain activity is coupled with CSF inflow in human fMRI during resting state. Global fMRI–CSF coupling is correlated with tau in Alzheimer's disease (AD). This coupling measure is also associated with cortical thickness, mediated by tau.

Neurosciences & Neurology↗

DOE OSTI2023

Cdk5 mediates rotational force-induced brain injury

Abstract Millions of traumatic brain injuries (TBIs) occur annually. TBIs commonly result from falls, traffic accidents, and sports-related injuries, all of which involve rotational acceleration/deceleration of the brain. During these injuries, the brain endures a multitude of primary insults including compression of brain tissue, damaged vasculature, and diffuse axonal injury. All of these deleterious effects can contribute to secondary brain ischemia, cellular death, and neuroinflammation that progress for weeks, months, and lifetime after injury. While the linear effects of head trauma have been extensively modeled, less is known about how rotational injuries mediate neuronal damage following injury. Here, we developed a new model of repetitive rotational head trauma in rodents and demonstrated acute and prolonged pathological, behavioral, and electrophysiological effects of rotational TBI (rTBI). We identify aberrant Cyclin-dependent kinase 5 (Cdk5) activity as a principal mediator of rTBI. We utilized Cdk5-enriched phosphoproteomics to uncover potential downstream mediators of rTBI and show pharmacological inhibition of Cdk5 reduces the cognitive and pathological consequences of injury. These studies contribute meaningfully to our understanding of the mechanisms of rTBI and how they may be effectively treated.

60 APPLIED LIFE SCIENCES↗