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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 163 records · Page 9
All sourcesNASA NTRSDOE OSTI
DOE OSTI2025

Cognitive aging outcomes are related to both tau pathology and maintenance of cingulate cortex structure

Abstract INTRODUCTION Successful cognitive aging is related to both maintaining brain structure and avoiding Alzheimer's disease (AD) pathology, but how these factors interplay is unclear. METHODS A total of 109 cognitively normal older adults (70+ years old) underwent amyloid beta (Aβ) and tau positron emission tomography (PET) imaging, structural magnetic resonance imaging (MRI), and cognitive testing. Cognitive aging was quantified using the cognitive age gap (CAG), subtracting chronological age from predicted cognitive age. RESULTS Lower CAG (younger cognitive age) was related to slower decline in episodic memory, multi‐domain cognition, and atrophy of the midcingulate cortex (MCC). Lower entorhinal cortical tau was linked to slower decline in episodic memory, multi‐domain cognition, and hippocampal atrophy. DISCUSSION These results suggest that aging outcomes may be influenced by two independent pathways: one associated with tau accumulation, affecting primarily memory and hippocampal atrophy, and another involving tau‐independent structural preservation of the MCC, benefiting multi‐domain cognition over time. Highlights Younger cognitive age (lower cognitive age gap [CAG]) is related to slower cognitive decline. Lower CAG is linked to slower midcingulate cortex (MCC) atrophy. Reduced tau in the entorhinal cortex is related to less hippocampal atrophy and cognitive decline. Structural preservation of the MCC benefits multi‐domain cognition over time. Two independent pathways influence cognitive aging: tau accumulation and MCC preservation.

Neurosciences & Neurology↗
DOE OSTI2025

Exploring inflammation‐related protein expression and its relationship with TSPO PET in Alzheimer's disease

Abstract INTRODUCTION To understand the role of neuroinflammation in Alzheimer's disease (AD), we characterized immune‐related proteins in central and peripheral biofluids. METHODS Selection of participants from the Translational Biomarker of Aging and Dementia (TRIAD) cohort with available translocator protein (TSPO) positron emission tomography (PET), cerebrospinal fluid (CSF) (n = 97), and plasma (n = 165). Biofluid samples analyzed with Olink technology (368 inflammation proteins). RESULTS Elevated proteins levels in CSF of TSPO‐positive individuals were identified. Functional enrichment analysis of CSF proteins revealed processes implicated in AD (MAPK, ERK cascades, cytokine, and leukocyte signaling). Selected candidates (CXCL1 and TNFRSF11B) showed high correlation with each other in CSF and with TSPO PET signal, but weaker associations with amyloid and tau PET. No significantly changed proteins in plasma between TSPO groups were found. DISCUSSION This explorative study identified two potential targets in CSF showing correlations with TSPO, amyloid and tau PET, suggesting a direct link between neuroinflammation, expression of these proteins and their potential implication in AD. Highlights Several proteins are elevated in CSF of TSPO PET‐positive individuals, linking them to neuroinflammation. Elevated CSF proteins were enriched in pathways such as MAPK, ERK, and cytokine signaling, linking them to the AD pathophysiology. Candidate proteins (CXCL1 and TNFRSF11B) correlated strongly with TSPO PET, particularly in brain regions known to be affected in AD. Although none of the plasma proteins remained significant after multiple comparisons correction when comparing their expression between TSPO groups, as done for CSF, candidate CSF proteins were found to correlate with plasmatic proteins, highlighting the complexity of the immune system.

Neurosciences & Neurology↗
DOE OSTI2025

Plasma GFAP for populational enrichment of clinical trials in preclinical Alzheimer's disease

Abstract INTRODUCTION Cognitively unimpaired (CU) amyloid beta (Aβ)+ individuals with elevated plasma glial fibrillary acidic protein (GFAP) have an increased risk of Alzheimer's disease (AD)‐related progression. We tested the utility of plasma GFAP for population enrichment CU populations in clinical trials. METHODS We estimated longitudinal progression, effect size, and costs of hypothetical clinical trials designed to test an estimated 25% drug effect on reducing tau positron emission tomography (PET) accumulation in the medial temporal lobe (MTL) and temporal neocortical region (NEO‐T). RESULTS CU GFAP+/Aβ+ individuals present an increased annual rate of change and effect size in tau PET MTL and tau PET NEO‐T compared to the other groups. An enrichment strategy selecting CU GFAP+/Aβ+ individuals would require a smaller sample size (≈ 57% reduction) and fewer Aβ PET scans (≈ 74% reduction) than trials enriched with Aβ PET alone, reducing total clinical trial costs by up to 64%. DISCUSSION Our results suggest that clinical trials focusing on preclinical AD recruiting Aβ+ individuals with elevated GFAP levels would improve cost effectiveness. Highlights Cognitively unimpaired (CU) glial fibrillary acidic protein (GFAP)+/amyloid beta (Aβ)+ shows increased changes in tau positron emission tomography (PET) . CU GFAP+/Aβ+ enriched clinical trials require a reduced sample size compared to Aβ+ only. CU GFAP+/Aβ+ enrichment reduces Aβ PET scans required and costs. CU GFAP+/Aβ+ enrichment allows the selection of individuals at early stages of the Alzheimer's disease continuum.

Neurosciences & Neurology↗
DOE OSTI2025

Calibration of multisite raters for prospective visual reads of amyloid PET scans

Abstract INTRODUCTION In multicenter Alzheimer's disease studies, amyloid positron emission tomography (PET) visual reads are typically performed centrally by a few experts. Incorporating a broader reader network enhances scalability and generalizability. METHODS Ten neuroimaging experts from eight Alzheimer's Disease Research Centers (ADRCs) visually read 180 amyloid PET scans (30 scans and 15 duplicate scans for each of four tracers, imaged across a wide variety of scanners), using preferred reading software without anatomical imaging or quantitation. Scans were classified as elevated or non‐elevated per tracer‐specific criteria. Inter‐ and intra‐rater agreement was assessed. RESULTS Inter‐rater agreement was substantial (Fleiss’κ = 0.78), with full consensus on 69% of scans. Inter‐rater reliability was substantial to perfect across tracers (Fleiss’κ = 0.70–0.87). Intra‐rater agreement was substantial to perfect (Cohen'sκ = 0.79‐1). Scans with intermediate (10–40 Centiloid) quantitation had lower reader agreement. DISCUSSION A multicenter expert network achieved substantial agreement classifying amyloid PET scans. These scans provide a standard for reader training and reliability assurance in future studies. Highlights Calibration methods ensure reliable amyloid positron emission tomography (PET) visual reads across multiple raters. Substantial agreement is possible across readers using their preferred tools. Agreement is also substantial regardless of the amyloid PET tracer used. Scans with intermediate (10–40 Centiloid) quantitation have lower reader agreement. The calibration set will become a training tool for amyloid PET visual read studies.

Neurosciences & Neurology↗
DOE OSTI2024

Distinct cellular expression and subcellular localization of Kv2 voltage‐gated K + channel subtypes in dorsal root ganglion neurons conserved between mice and humans

Abstract The distinct organization of Kv2 voltage‐gated potassium channels on and near the cell body of brain neurons enables their regulation of action potentials and specialized membrane contact sites. Somatosensory neurons have a pseudounipolar morphology and transmit action potentials from peripheral nerve endings through axons that bifurcate to the spinal cord and the cell body within ganglia including the dorsal root ganglia (DRG). Kv2 channels regulate action potentials in somatosensory neurons, yet little is known about where Kv2 channels are located. Here, we define the cellular and subcellular localization of the Kv2 paralogs, Kv2.1 and Kv2.2, in DRG somatosensory neurons with a panel of antibodies, cell markers, and genetically modified mice. We find that relative to spinal cord neurons, DRG neurons have similar levels of detectable Kv2.1 and higher levels of Kv2.2. In older mice, detectable Kv2.2 remains similar, while detectable Kv2.1 decreases. Both Kv2 subtypes adopt clustered subcellular patterns that are distinct from central neurons. Most DRG neurons co‐express Kv2.1 and Kv2.2, although neuron subpopulations show preferential expression of Kv2.1 or Kv2.2. We find that Kv2 protein expression and subcellular localization are similar between mouse and human DRG neurons. We conclude that the organization of both Kv2 channels is consistent with physiological roles in the somata and stem axons of DRG neurons. The general prevalence of Kv2.2 in DRG as compared to central neurons and the enrichment of Kv2.2 relative to detectable Kv2.1 in older mice, proprioceptors, and axons suggest more widespread roles for Kv2.2 in DRG neurons.

Neurosciences & Neurology↗
DOE OSTI2023

Treatment of cholinergic‐induced status epilepticus with polytherapy targeting GABA and glutamate receptors

Abstract Despite new antiseizure medications, the development of cholinergic‐induced refractory status epilepticus (RSE) continues to be a therapeutic challenge as pharmacoresistance to benzodiazepines and other antiseizure medications quickly develops. Studies conducted by Epilepsia . 2005;46:142 demonstrated that the initiation and maintenance of cholinergic‐induced RSE are associated with trafficking and inactivation of gamma‐aminobutyric acid A receptors (GABA A R) thought to contribute to the development of benzodiazepine pharmacoresistance. In addition, Dr. Wasterlain's laboratory reported that increased N‐methyl‐ d ‐aspartate receptors (NMDAR) and alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors (AMPAR) contribute to enhanced glutamatergic excitation ( Neurobiol Dis . 2013;54:225; Epilepsia . 2013;54:78). Thus, Dr. Wasterlain postulated that targeting both maladaptive responses of reduced inhibition and increased excitation that is associated with cholinergic‐induced RSE should improve therapeutic outcome. We currently review studies in several animal models of cholinergic‐induced RSE that demonstrate that benzodiazepine monotherapy has reduced efficacy when treatment is delayed and that polytherapy with drugs that include a benzodiazepine (eg midazolam and diazepam) to counter loss of inhibition, concurrent with an NMDA antagonist (eg ketamine) to reduce excitation provide improved efficacy. Improved efficacy with polytherapy against cholinergic‐induced seizure is demonstrated by reduction in (1) seizure severity, (2) epileptogenesis, and (3) neurodegeneration compared with monotherapy. Animal models reviewed include pilocarpine‐induced seizure in rats, organophosphorus nerve agent (OPNA)‐induced seizure in rats, and OPNA‐induced seizure in two mouse models: (1) carboxylesterase knockout (Es1 −/− ) mice which, similarly to humans, lack plasma carboxylesterase and (2) human acetylcholinesterase knock‐in carboxylesterase knockout (KIKO) mice. We also review studies showing that supplementing midazolam and ketamine with a third antiseizure medication (valproate or phenobarbital) that targets a nonbenzodiazepine site rapidly terminates RSE and provides further protection against cholinergic‐induced SE. Finally, we review studies on the benefits of simultaneous compared with sequential drug treatments and the clinical implications that lead us to predict improved efficacy of early combination drug therapies. The data generated from seminal rodent studies of efficacious treatment of cholinergic‐induced RSE conducted under Dr. Wasterlain's guidance suggest that future clinical trials should treat the inadequate inhibition and temper the excess excitation that characterize RSE and that early combination therapies may provide improved outcome over benzodiazepine monotherapy.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Brain‐age prediction: Systematic evaluation of site effects, and sample age range and size

Abstract Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain‐age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain‐age has highlighted the need for robust and publicly available brain‐age models pre‐trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain‐age model. Here we expand this work to develop, empirically validate, and disseminate a pre‐trained brain‐age model to cover most of the human lifespan. To achieve this, we selected the best‐performing model after systematically examining the impact of seven site harmonization strategies, age range, and sample size on brain‐age prediction in a discovery sample of brain morphometric measures from 35,683 healthy individuals (age range: 5–90 years; 53.59% female). The pre‐trained models were tested for cross‐dataset generalizability in an independent sample comprising 2101 healthy individuals (age range: 8–80 years; 55.35% female) and for longitudinal consistency in a further sample comprising 377 healthy individuals (age range: 9–25 years; 49.87% female). This empirical examination yielded the following findings: (1) the accuracy of age prediction from morphometry data was higher when no site harmonization was applied; (2) dividing the discovery sample into two age‐bins (5–40 and 40–90 years) provided a better balance between model accuracy and explained age variance than other alternatives; (3) model accuracy for brain‐age prediction plateaued at a sample size exceeding 1600 participants. These findings have been incorporated into CentileBrain ( https://centilebrain.org/#/brainAGE2 ), an open‐science, web‐based platform for individualized neuroimaging metrics.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Connectivity, Pathology, and ApoE4 Interactions Predict Longitudinal Tau Spatial Progression and Memory

ABSTRACT Tau pathology spread into neocortex indicates a transition from healthy aging to Alzheimer's disease (AD). Connectivity between tau epicenters and later accumulating regions of cortex has been proposed as a mechanism of tau spread, but how this relationship changes with greater AD pathology burden or genotype is not understood. We investigated tau accumulation in two key regions, precuneus and inferior temporal cortex, using resting state functional connectivity (rsFC) and longitudinal PET imaging from a multicohort sample of cognitively unimpaired older adults. We examined how baseline tau PET, Aβ PET, and ApoE4 genotype status interact with rsFC between hippocampus and these downstream regions to predict rate of tau accumulation in neocortex. We found that the 3‐way interaction between connectivity, baseline tau, and baseline Aβ or ApoE4 status was associated with neocortical tau accumulation in precuneus and inferior temporal cortex. In addition, baseline tau, Aβ, and ApoE4 status also moderated the association between connectivity and rate of memory decline. Together, these results suggest that the extent and distribution of future tau accumulation may be predicted by the interaction of baseline connectivity, AD pathology, and genetic risk.

Neurosciences & Neurology↗
DOE OSTI2025

Neural Active Manifolds: Nonlinear Dimensionality Reduction for Uncertainty Quantification

We present a new approach for nonlinear dimensionality reduction, specifically designed for computationally expensive mathematical models. We leverage autoencoders to discover a one-dimensional neural active manifold (NeurAM) capturing the model output variability, through the aid of a simultaneously learnt surrogate model with inputs on this manifold. Our method only relies on model evaluations and does not require the knowledge of gradients. The proposed dimensionality reduction framework can then be applied to assist outer loop many-query tasks in scientific computing, like sensitivity analysis and multifidelity uncertainty propagation. In particular, we prove, both theoretically under idealized conditions, and numerically in challenging test cases, how NeurAM can be used to obtain multifidelity sampling estimators with reduced variance by sampling the models on the discovered low-dimensional and shared manifold among models. Several numerical examples illustrate the main features of the proposed dimensionality reduction strategy and highlight its advantages with respect to existing approaches in the literature.

Autoencoders↗
DOE OSTI2024

Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes

Mutations that cause familial Alzheimer’s disease (FAD) are found in amyloid precursor protein (APP) and presenilin, the catalytic component of γ-secretase, that together produce amyloid β-peptide (Aβ). Nevertheless, whether Aβ is the primary disease driver remains controversial. We report here that FAD mutations disrupt initial proteolytic events in the multistep processing of APP substrate C99 by γ-secretase. Cryoelectron microscopy reveals that a substrate mimetic traps γ-secretase during the transition state, and this structure aligns with activated enzyme-substrate complex captured by molecular dynamics simulations. In silico simulations and in cellulo fluorescence microscopy support stabilization of enzyme-substrate complexes by FAD mutations. Neuronal expression of C99 and/or presenilin-1 in Caenorhabditis elegans leads to synaptic loss only with FAD-mutant transgenes. Designed mutations that stabilize the enzyme-substrate complex and block Aβ production likewise led to synaptic loss. Collectively, these findings implicate the stalled process—not the products—of γ-secretase cleavage of substrates in FAD pathogenesis.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Amplitude- and frequency-dependent activation of layer II/III neurons by intracortical microstimulation

Intracortical microstimulation (ICMS) has been used for the development of brain machine interfaces. However, further understanding about the spatiotemporal responses of neurons to different electrical stimulation parameters is necessary to inform the design of optimal therapies. In this study, we employed in vivo electrophysiological recording, two-photon calcium imaging, and electric field simulation to evaluate the acute effect of ICMS on layer II/III neurons. Our results show that stimulation frequency non-linearly modulates neuronal responses, whereas the magnitude of responses is linearly correlated to the electric field strength and stimulation amplitude before reaching a steady state. Temporal dynamics of neurons’ responses depends more on stimulation frequency and their distance to the stimulation electrode. In addition, amplitude-dependent post-stimulation suppression was observed within ~500 μm of the stimulation electrode, as evidenced by both calcium imaging and local field potentials. These findings provide insights for selecting stimulation parameters to achieve desirable spatiotemporal specificity of ICMS.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Correlative nano-imaging of metals and proteins in primary neurons by synchrotron X-ray fluorescence and STED super resolution microscopy: Experimental validation

It is becoming increasingly clear that biological metals such as iron, copper or zinc are involved in synaptic functions, and in particular in the mechanisms of synaptogenesis and subsequent plasticity. Understanding the role of metals on synaptic functions is a difficult challenge due to the very low concentration of these elements in neurons and to the submicrometer size of synaptic compartments. To address this challenge we have developed a correlative nano-imaging approach combining metal and protein detection. First, stimulated emission depletion (STED) microscopy, a super resolution optical microscopy technique, is applied to locate fluorescently labeled proteins. Then, synchrotron radiation induced X-ray fluorescence (SXRF) is performed on the same regions of interest, e.g. synaptic compartments. Here, we present here the principle scheme that allows this correlative nano-imaging and its experimental validation. We applied this correlative nano-imaging to the study of the physiological distribution of metals in synaptic compartments of primary rat hippocampal neurons. We thus compared the nanometric distribution of metals with that of synaptic proteins, such as PSD95 or cytoskeleton proteins. Compared to correlative imaging approaches currently used to characterize synaptic structures, such as electron microscopy correlated with optical fluorescence, our approach allows for ultra-sensitive detection of trace metals using highly focused synchrotron radiation beams. We provide proof-of-principle for correlative imaging of metals and proteins at the synaptic scale and discuss the present limitations and future developments in this area.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Association Between Dispatch Complaint and Critical Prehospital Time Intervals in Suspected Stroke 911 Activations in the National Emergency Medical Services Information System, 2012–2016

Emergency Medical Services can help improve stroke outcomes by recognizing stroke symptoms, establishing response priority for 911 calls, and minimizing prehospital delays. This study examines 911 stroke events and evaluates associations between events dispatched as stroke and critical EMS time intervals. Data from the National Emergency Medical Services Information System, 2012 to 2016, were analyzed. Activations from 911 calls with a primary or secondary provider impression of stroke were included for adult patients transported to a hospital destination. Three prehospital time intervals were evaluated: (1) response time (RT) ≤8 min, (2) on-scene time (OST) ≤15 min, and (3) transport time (TT) ≤12 min. Associations between stroke dispatch complaint and prehospital time intervals were assessed using multivariate regression to estimate adjusted risk ratios (ARR) and 95% confidence intervals (CIs). Approximately 37% of stroke dispatch complaints were identified by EMS as a suspected stroke. Compared to stroke events without a stroke dispatch complaint, median OST was shorter for events with a stroke dispatch (16 min vs. 14 min, respectively). In adjusted analyses, events dispatched as stroke were more likely to meet the EMS time benchmark for OST ≤15 min (OST, 1.20 [1.20–1.21]), but not RT or TT (RT, [1.00–1.01]; TT, 0.95 [0.94–0.95]). Furthermore, our results indicate that dispatcher recognition of stroke symptoms reduces the time spent on-scene by EMS personnel. These findings can inform future EMS stroke education and quality improvement efforts to emphasize dispatcher recognition of stroke signs and symptoms, as EMS dispatchers play a crucial role in optimizing the prehospital response.

59 BASIC BIOLOGICAL SCIENCES↗