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At least 217 records · Page 12

Regional Tau Effects on Prospective Cognitive Change in Cognitively Normal Older Adults

Studies suggest that tau deposition starts in the anterolateral entorhinal cortex (EC) with normal aging, and that the presence of β-amyloid (Aβ) facilitates its spread to neocortex, which may reflect the beginning of Alzheimer's disease (AD). Functional connectivity between the anterolateral EC and the anterior-temporal (AT) memory network appears to drive higher tau deposition in AT than in the posterior-medial (PM) memory network. Here, we investigated whether this differential vulnerability to tau deposition may predict different cognitive consequences of EC, AT, and PM tau. Using 18 F-flortaucipir (FTP) and 11 C-Pittsburgh compound-B (PiB) positron emission tomography (PET) imaging, we measured tau and Aβ in 124 cognitively normal human older adults (74 females, 50 males) followed for an average of 2.8 years for prospective cognition. We found that higher FTP in all three regions was individually related to faster memory decline, and that the effects of AT and PM FTP, but not EC, were driven by Aβ+ individuals. Moreover, when we included all three FTP measures competitively in the same model, only AT FTP significantly predicted memory decline. Our data support a model whereby tau, facilitated by Aβ, transits from EC to cortical regions that are most closely associated with the anterolateral EC, which specifically affects memory in the initial stage of AD. Memory also appears to be affected by EC tau in the absence of Aβ, which may be less clinically consequential. These findings may provide clarification of differences between normal aging and AD, and elucidate the transition between the two stages. SIGNIFICANCE STATEMENT Tau and β-amyloid (Aβ) are hallmarks of Alzheimer's disease (AD) but are also found in cognitively normal people. It is unclear whether, and how, this early deposition of tau and Aβ may affect cognition in normal aging and the asymptomatic stage of AD. We show that tau deposition in the entorhinal cortex (EC), which is common in advanced age, predicts memory decline in older adults independent of Aβ, likely reflecting normal, age-related memory loss. In contrast, tau in anterior-temporal (AT) regions is most predictive of memory decline in Aβ+ individuals. These data support the idea that tau preferentially spreads to specific cortical regions, likely through functional connections, which plays a primary role in memory decline in the early stage of AD.

60 APPLIED LIFE SCIENCES↗

HIV influences microtubule associated protein-2: potential marker of HIV-associated neurocognitive disorders

Postmortem brains of patients diagnosed with HIV-1-associated neurocognitive disorders (HAND) exhibit loss of dendrites. However, the mechanisms by which synapses are damaged are not fully understood. Dendrite length and remodeling occurs via microtubules, the dynamics of which are regulated by microtubule-binding proteins, including microtubule-associated protein 2 (MAP2). The HIV protein gp120 is neurotoxic and interferes with neuronal microtubules. We measured MAP2 concentrations in human cerebrospinal fluid (CSF) and MAP2 immunoreactivity in rat cortical neurons exposed to HIV and gp120. First, we examined whether HIV affects MAP2 levels by analyzing the CSF of 27 persons living with HIV (PLH) whose neurocognitive performance had been characterized. We then used rat cortical neurons to study the mechanisms of HIV-mediated dendritic loss. PLH who had HAND had greater MAP2 concentrations within the CSF than cognitive normal PLH. In cortical neurons, the deleterious effect of HIV on MAP2-positive dendrites occurred through a gp120-mediated mechanism. The neurotoxic effect of HIV was blocked by a CCR5 antagonist and prevented by Helix-A, a peptide that displaces gp120 from binding to microtubules, conjugated to a nanolipoprotein particle delivery platform. Our findings support that HIV at least partially effects its neurotoxicity via neuronal cytoskeleton modifications and provide evidence of a new therapeutic compound that could be used to prevent the HIV-associated neuropathology.

60 APPLIED LIFE SCIENCES↗

Evaluation of Classifier Complexity for Delay Tolerant Network Routing

The growing popularity of small cost effective satellites (SmallSats, CubeSats, etc.) creates the potential for a variety of new science applications involving multiple nodes functioning together or independently to achieve a task, such as swarms and constellations. As this technology develops and is deployed for missions in Low Earth Orbit and beyond, the use of delay tolerant networking (DTN) techniques may improve communication capabilities within the network. In this paper, a network hierarchy is developed from heterogeneous networks of SmallSats, surface vehicles, relay satellites and ground stations which form an integrated network. There is a tradeoff between complexity, flexibility, and scalability of user defined schedules versus autonomous routing as the number of nodes in the network increases. To address these issues, this work proposes a machine learning classifier based on DTN routing metrics. A framework is developed which will allow for the use of several categories of machine learning algorithms (decision tree, random forest and deep learning) to be applied to a dataset of historical network statistics, which allows for the evaluation of algorithm complexity versus performance to be explored. We develop the emulation of a hierarchical network, consisting of tens of nodes which form a cognitive network architecture. CORE (Common Open Research Emulator) is used to emulate the network using bundle protocol and DTN IP neighbor discovery.

Dudukovich, Rachel↗

A multi-ancestry genetic study of pain intensity in 598,339 veterans

Chronic pain is a common problem, with more than one-fifth of adult Americans reporting pain daily or on most days. It adversely affects the quality of life and imposes substantial personal and economic costs. Efforts to treat chronic pain using opioids had a central role in precipitating the opioid crisis. Despite an estimated heritability of 25–50%, the genetic architecture of chronic pain is not well-characterized, in part because studies have largely been limited to samples of European ancestry. To help address this knowledge gap, we conducted a cross-ancestry meta-analysis of pain intensity in 598,339 participants in the Million Veteran Program, which identified 126 independent genetic loci, 69 of which are new. Pain intensity was genetically correlated with other pain phenotypes, level of substance use and substance use disorders, other psychiatric traits, education level and cognitive traits. Integration of the genome-wide association studies findings with functional genomics data shows enrichment for putatively causal genes (n = 142) and proteins (n = 14) expressed in brain tissues, specifically in GABAergic neurons. Drug repurposing analysis identified anticonvulsants, β-blockers and calcium-channel blockers, among other drug groups, as having potential analgesic effects. Our results provide insights into key molecular contributors to the experience of pain and highlight attractive drug targets.

59 BASIC BIOLOGICAL SCIENCES↗

Ten questions concerning low-cost indoor air quality sensors: Perspectives from research and practice

Low-cost indoor air quality (IAQ) sensors are increasingly being used in homes and commercial and public buildings, driven by growing concerns about the impact of air on health, cognitive performance, and occupant wellbeing. These sensors offer a potentially transformative opportunity to increase spatial and temporal coverage of IAQ monitoring at a fraction of the cost of conventional reference instruments. However, their widespread use raises questions around accuracy, calibration, placement, data handling and interpretation, and integration into existing standards and workflows. This paper presents ten critical questions concerning the use of low-cost IAQ sensors in buildings, drawing on the latest empirical research, field deployments, and emerging practice. It discusses potential frameworks for deployment and evaluation, examines current sensor capabilities for measuring common pollutants, identifies methodological gaps in validation and uncertainty quantification, and outlines the extent to which existing IAQ standards can accommodate sensor-based evidence. The paper also explores how monitoring needs and deployment models vary by building type, the potential of real-time IAQ data to support building operations, and the ethical and legal implications of widespread sensor use. While significant challenges remain in ensuring data quality and building stakeholder trust, new applications are emerging through open data initiatives and advances in analytics and visualization. As the technology, science, and standards co-evolve, low-cost IAQ sensors are poised to become integral to routine building operation, building science, and environmental health research.

Parkinson, Thomas↗

Low-Latency Lunar Surface Telerobotics from Earth-Moon Libration Points

Concepts for a long-duration habitat at Earth-Moon LI or L2 have been advanced for a number of purposes. We propose here that such a facility could also have an important role for low-latency telerobotic control of lunar surface equipment, both for lunar science and development. With distances of about 60,000 km from the lunar surface, such sites offer light-time limited two-way control latencies of order 400 ms, making telerobotic control for those sites close to real time as perceived by a human operator. We point out that even for transcontinental teleoperated surgical procedures, which require operational precision and highly dexterous manipulation, control latencies of this order are considered adequate. Terrestrial telerobots that are used routinely for mining and manufacturing also involve control latencies of order several hundred milliseconds. For this reason, an Earth-Moon LI or L2 control node could build on the technology and experience base of commercially proven terrestrial ventures. A lunar libration-point telerobotic node could demonstrate exploration strategies that would eventually be used on Mars, and many other less hospitable destinations in the solar system. Libration-point telepresence for the Moon contrasts with lunar telerobotic control from the Earth, for which two-way control latencies are at least six times longer. For control latencies that long, telerobotic control efforts are of the "move-and-wait" variety, which is cognitively inferior to near real-time control.

Lester, Daniel↗

Closing transdisciplinary collaboration gaps of food-energy-water nexus research

The nexus of food, energy, and water (FEW) systems is key to ensuring global sustainability in the face of climate change, population growth, and urbanization. To address FEW resources inequity among different regions and countries, transdisciplinary research networking becomes increasingly important for tackling this intractable, complex grand challenge. In contrast to interdisciplinary or multidisciplinary research, transdisciplinary research emphasizes the interactions of scientific, cognitive, and social factors from a top-down view. Intellectual and strategic integrations entail weaving scientific, socioeconomic, and political perspectives together into a new convergence model and fostering a shared vision and comparable assessment, though these goals might not be realistically achievable in the short term. This article summarizes major barriers to transdisciplinary research on FEW nexus grand challenges and possible solutions to be implemented at multiple levels of distinct social systems. Implementation of the solutions relies on not only top-down incentives of governments but also bottom-up initiatives of academic communities and individual researchers. The relevance of shared interests and visions between the research communities and the public is emphasized.

29 ENERGY PLANNING, POLICY, AND ECONOMY↗

Therapeutic targeting of membrane-associated proteins in central nervous system tumors

The activity of the most complex system, the central nervous system (CNS) is profoundly regulated by a huge number of membrane-associated proteins (MAP). A minor change stimulates immense chemical changes and the elicited response is organized by MAP, which acts as a receptor of that chemical or channel enabling the flow of ions. Slight changes in the activity or expression of these MAPs lead to severe consequences such as cognitive disorders, memory loss, or cancer. CNS tumors are heterogeneous in nature and hard-to-treat due to random mutations in MAPs; like as overexpression of EGFRvIII/TGFβR/VEGFR, change in adhesion molecules α5β3 integrin/SEMA3A, imbalance in ion channel proteins, etc. Extensive research is under process for developing new therapeutic approaches using these proteins such as targeted cytotoxic radiotherapy, drug-delivery, and prodrug activation, blocking of receptors like GluA1, developing viral vector against cell surface receptor. The combinatorial approach of these strategies along with the conventional one might be more potential. Henceforth, our review focuses on in-depth analysis regarding MAPs aiming for a better understanding for developing an efficient therapeutic approach for targeting CNS tumors.

60 APPLIED LIFE SCIENCES↗

Proteomic and metabolomic profiling of acute and chronic stress events associated with military exercises

By characterizing physiological changes that occur in warfighters during simulated combat, we can start to unravel the key biomolecular components that are linked to physical and cognitive performance. Viable field-based sensors for the warfighter must be rapid and noninvasive. In an effort to facilitate this, we applied a multiomics pipeline to characterize the stress response in the saliva of warfighters to correlate biomolecular changes with overall performance and health. In this study, two different stress models were observed – one of chronic stress and one of acute stress. In both models, significant perturbations in the immune, metabolic, and protein manufacturing/processing systems were observed. However, when differentiating between stress models, specific metabolites associated with the “fight or flight” response and protein folding were seen to be discriminate of the acute stress model.

60 APPLIED LIFE SCIENCES↗

Optimizing quantification of MK6240 tau PET in unimpaired older adults

Accurate measurement of Alzheimer's disease (AD) pathology in older adults without significant clinical impairment is critical to assessing intervention strategies aimed at slowing AD-related cognitive decline. The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (POINTER) is a 2-year randomized controlled trial to evaluate the effect of multicomponent risk reduction strategies in older adults (60-79 years) who are cognitively unimpaired but at increased risk for cognitive decline/dementia due to factors such as cardiovascular disease and family history. The POINTER Imaging ancillary study is collecting tau-PET ([ 18 F]MK6240), beta-amyloid (Aβ)-PET ([ 18 F]florbetaben [FBB]) and MRI data to evaluate neuroimaging biomarkers of AD and cerebrovascular pathophysiology in this at-risk sample. Here 481 participants (70.0±5.0; 66% F) with baseline MK6240, FBB and structural MRI scans were included. PET scans were coregistered to the structural MRI which was used to create FreeSurfer-defined reference regions and target regions of interest (ROIs). We also created off-target signal (OTS) ROIs to examine the magnitude and distribution of MK6240 OTS across the brain as well as relationships between OTS and age, sex, and race. OTS was unimodally distributed, highly correlated across OTS ROIs and related to younger age and sex but not race. Aiming to identify an optimal processing approach for MK6240 that would reduce the influence of OTS, we compared our previously validated MRI-guided standard PET processing and 6 alternative approaches. The alternate approaches included combinations of reference region erosion and meningeal OTS masking before spatial smoothing as well as partial volume correction. To compare processing approaches we examined relationships between target ROIs (entorhinal cortex (ERC), hippocampus or a temporal meta-ROI (MetaROI)) SUVR and age, sex, race, Aβ and a general cognitive status measure, the Modified Telephone Interview for Cognitive Status (TICSm). Overall, the processing approaches performed similarly, and none showed a meaningful improvement over standard processing. Across processing approaches we observed previously reported relationships with MK6240 target ROIs including positive associations with age, an Aβ+> Aβ- effect and negative associations with cognition. In sum, we demonstrated that different methods for minimizing effects of OTS, which is highly correlated across the brain within subject, produced no substantive change in our performance metrics. This is likely because OTS contaminates both reference and target regions and this contamination largely cancels out in SUVR data. Caution should be used when efforts to reduce OTS focus on target or reference regions in isolation as this may exacerbate OTS contamination in SUVR data.

60 APPLIED LIFE SCIENCES↗

Lead Service Line Inventory at the Materials and Fuels Complex

In 1986, Congress amended the Safe Drinking Water Act prohibiting the use of lead in pipes for providing water. This was due to research on lead poisoning showing lead was extremely detrimental to the development of kids and cognitive abilities in adults. Now, because of the amendment of 1986, the EPA 2021 Lead and Copper Rule Revision came out since then to promote progress in the inventory and elimination of lead pipes. The Idaho Department of Environmental Quality(IDEQ) adopted this rule for the state which means every water system in Idaho fall under the new regulation. By October 16, 2024, the INL must report to the IDEQ, the pipe materials in a Lead Service Line Inventory(LSLI) in hopes of finding lead. If lead is found, a Lead Service Line Replacement Plan is required. This poster only specifically talks about the results for the largest site out on the desert, Materials and Fuels Complex(MFC), as the INL also consists of ATR, INTEC, SMC, and CFA.

54 ENVIRONMENTAL SCIENCES↗

Short term treatment with a cocktail of rapamycin, acarbose and phenylbutyrate delays aging phenotypes in mice

Pharmaceutical intervention of aging requires targeting multiple pathways, thus there is rationale to test combinations of drugs targeting different but overlapping processes. In order to determine if combining drugs shown to extend lifespan and healthy aging in mice would have greater impact than any individual drug, a cocktail diet containing 14 ppm rapamycin, 1000 ppm acarbose, and 1000 ppm phenylbutyrate was fed to 20-month-old C57BL/6 and HET3 4-way cross mice of both sexes for three months. Mice treated with the cocktail showed a sex and strain-dependent phenotype consistent with healthy aging including decreased body fat, improved cognition, increased strength and endurance, and decreased age-related pathology compared to mice treated with individual drugs or control. The severity of age-related lesions in heart, lungs, liver, and kidney was consistently decreased in mice treated with the cocktail compared to mice treated with individual drugs or control, suggesting an interactive advantage of the three drugs. This study shows that a combination of three drugs, each previously shown to enhance lifespan and health span in mice, is able to delay aging phenotypes in middle-aged mice more effectively than any individual drug in the cocktail over a 3-month treatment period.

60 APPLIED LIFE SCIENCES↗

Editorial: Functional microcircuits in the brain and in artificial intelligent systems

Fundamental principles underlying higher-order cognitive functions remain elusive, but recent breakthroughs in neurophysiology and deep learning offer new perspectives. First, experimental studies have uncovered neural circuit motifs consisting of various neuron types; see Brain Initiative Cell Census Network (https://www.nature.com/collections/cicghheddj). For example, inhibitory neuron types expressing exclusive genes have specific targets and distinct functions (Pfeffer et al., 2013). Furthermore, diverse neuron types in cortex and their connectomes were identified in cortical columns (Jiang et al., 2015); see also Barth et al. (2016) for a debate on neuron types. Second, artificial neural networks were originally inspired by structures of the brain (McCulloch and Pitts, 1943) and could be trained to perform complex functions similar to human perception/cognition by deep learning (DL) (Lecun et al., 2015).

59 BASIC BIOLOGICAL SCIENCES↗

Neuromorphic scaling advantages for energy-efficient random walk computations

Computing stands to be radically improved by neuromorphic computing (NMC) approaches inspired by the brain's incredible efficiency and capabilities. Most NMC research, which aims to replicate the brain's computational structure and architecture in man-made hardware, has focused on artificial intelligence; however, less explored is whether this brain-inspired hardware can provide value beyond cognitive tasks. We demonstrate that high-degree parallelism and configurability of spiking neuromorphic architectures makes them well-suited to implement random walks via discrete time Markov chains. Such random walks are useful in Monte Carlo methods, which represent a fundamental computational tool for solving a wide range of numerical computing tasks. Additionally, we show how the mathematical basis for a probabilistic solution involving a class of stochastic differential equations can leverage those simulations to provide solutions for a range of broadly applicable computational tasks. Despite being in an early development stage, we find that NMC platforms, at a sufficient scale, can drastically reduce the energy demands of high-performance computing platforms.

59 BASIC BIOLOGICAL SCIENCES↗

Evaluation of a visual interpretation method for tau-PET with 18 F-flortaucipir

Introduction: Positron emission tomography targeting tau (tau-PET) is a promising diagnostic tool for the identification of Alzheimer's disease (AD). Currently available data rely on quantitative measures, and a visual interpretation method, critical for clinical translation, is needed. Methods: In this work, we developed a visual interpretation method for 18 F-flortaucipir tau-PET and tested it on 274 individuals (cognitively normal controls, patients with mild cognitive impairment [MCI], AD dementia, and non-AD diagnoses). Two readers interpreted 18 F-flortaucipir PET using two complementary indices: a global visual score and a visual distribution pattern. Results: Global visual scores were reliable, correlated with global cortical 18 F-flortaucipir standardized uptake value ratio (SUVR) and were associated with clinical diagnosis and amyloid status. The AD-like 18 F-flortaucipir pattern had good sensitivity and specificity to identify amyloid-positive patients with AD dementia or MCI. Discussion: This 18 F-flortaucipir visual rating scheme is associated with SUVR quantification, clinical diagnosis, and amyloid status, and constitutes a promising approach to tau measurement in clinical settings.

59 BASIC BIOLOGICAL SCIENCES↗

Sensory integration for neuroprostheses: from functional benefits to neural correlates

In the field of sensory neuroprostheses, one ultimate goal is for individuals to perceive artificial somatosensory information and use the prosthesis with high complexity that resembles an intact system. To this end, research has shown that stimulation elicited somatosensory information improves prosthesis perception and task performance. While studies strive to achieve sensory integration, a crucial phenomenon that entails naturalistic interaction with the environment, this topic has not been commensurately reviewed. Therefore, here we present a perspective for understanding sensory integration in neuroprostheses. First, we review the engineering aspects and functional outcomes in sensory neuroprosthesis studies. In this context, we summarize studies that have suggested sensory integration. We focus on how they have used stimulation-elicited percepts to maximize and improve the reliability of somatosensory information. Next, we review studies that have suggested multisensory integration. These works have demonstrated that congruent and simultaneous multisensory inputs provided cognitive benefits such that an individual experiences a greater sense of authority over prosthesis movements (i.e., agency) and perceives the prosthesis as part of their own (i.e., ownership). Thereafter, we present the theoretical and neuroscience framework of sensory integration. We investigate how behavioral models and neural recordings have been applied in the context of sensory integration. Sensory integration models developed from intact-limb individuals have led the way to sensory neuroprosthesis studies to demonstrate multisensory integration. Neural recordings have been used to show how multisensory inputs are processed across cortical areas. Lastly, we discuss some ongoing research and challenges in achieving and understanding sensory integration in sensory neuroprostheses. Here, resolving these challenges would help to develop future strategies to improve the sensory feedback of a neuroprosthetic system.

60 APPLIED LIFE SCIENCES↗

A review of non-cognitive applications for neuromorphic computing

Abstract Though neuromorphic computers have typically targeted applications in machine learning and neuroscience (‘cognitive’ applications), they have many computational characteristics that are attractive for a wide variety of computational problems. In this work, we review the current state-of-the-art for non-cognitive applications on neuromorphic computers, including simple computational kernels for composition, graph algorithms, constrained optimization, and signal processing. We discuss the advantages of using neuromorphic computers for these different applications, as well as the challenges that still remain. The ultimate goal of this work is to bring awareness to this class of problems for neuromorphic systems to the broader community, particularly to encourage further work in this area and to make sure that these applications are considered in the design of future neuromorphic systems.

97 MATHEMATICS AND COMPUTING↗

Direct effects of prolonged TNF-α and IL-6 exposure on neural activity in human iPSC-derived neuron-astrocyte co-cultures

Cognitive impairment is one of the many symptoms reported by individuals suffering from long-COVID and other post-viral infection disorders such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). A common factor among these conditions is a sustained immune response and increased levels of inflammatory cytokines. Tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) are two such cytokines that are elevated in patients diagnosed with long-COVID and ME/CFS. In this study, we characterized the changes in neural functionality, secreted cytokine profiles, and gene expression in co-cultures of human iPSC-derived neurons and primary astrocytes in response to prolonged exposure to TNF-α and IL-6. We found that exposure to TNF-α produced both a concentration-independent and concentration-dependent response in neural activity. Burst duration was significantly reduced within a few days of exposure regardless of concentration (1 pg/mL – 100 ng/mL) but returned to baseline after 7 days. Treatment with low concentrations of TNF-α (e.g., 1 and 25 pg/mL) did not lead to changes in the secreted cytokine profile or gene expression but still resulted in significant changes to electrophysiological features such as interspike interval and burst duration. Conversely, treatment with high concentrations of TNF-α (e.g., 10 and 100 ng/mL) led to reduced spiking activity, which may be correlated to changes in neural health, gene expression, and increases in inflammatory cytokine secretion (e.g., IL-1β, IL-4, and CXCL-10) that were observed at higher TNF-α concentrations. Prolonged exposure to IL-6 led to changes in bursting features, with significant reduction in the number of spikes in bursts across a wide range of treatment concentrations (i.e., 1 pg/mL–10 ng/mL). In combination, the addition of IL-6 appears to counteract the changes to neural function induced by low concentrations of TNF-α, while at high concentrations of TNF-α the addition of IL-6 had little to no effect. Conversely, the changes to electrophysiological features induced by IL-6 were lost when the cultures were co-stimulated with TNF-α regardless of the concentration, suggesting that TNF-α may play a more pronounced role in altering neural function. These results indicate that increased concentrations of key inflammatory cytokines associated with long-COVID can directly impact neural function and may be a component of the cognitive impairment associated with long-COVID and other post-viral infection disorders.

60 APPLIED LIFE SCIENCES↗