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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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All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Intermittent fasting enhances long-term memory consolidation, adult hippocampal neurogenesis, and expression of longevity gene Klotho

Daily calorie restriction (CR) and intermittent fasting (IF) enhance longevity and cognition but the effects and mechanisms that differentiate these two paradigms are unknown. We examined whether IF in the form of every-other-day feeding enhances cognition and adult hippocampal neurogenesis (AHN) when compared to a matched 10% daily CR intake and ad libitum conditions. After 3 months under IF, female C57BL6 mice exhibited improved long-term memory retention. IF increased the number of BrdU-labeled cells and neuroblasts in the hippocampus, and microarray analysis revealed that the longevity gene Klotho (Kl) was upregulated in the hippocampus by IF only. Furthermore, we found that downregulating Kl in human hippocampal progenitor cells led to decreased neurogenesis, whereas Kl overexpression increased neurogenesis. Finally, histological analysis of Kl knockout mice brains revealed that Kl is required for AHN, particularly in the dorsal hippocampus. These data suggest that IF is superior to 10% CR in enhancing memory and identifies Kl as a novel candidate molecule that regulates the effects of IF on cognition likely via AHN enhancement.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18–72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18–73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19; I 2 = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen’s d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Model metamers reveal divergent invariances between biological and artificial neural networks

Deep neural network models of sensory systems are often proposed to learn representational transformations with invariances like those in the brain. To reveal these invariances, we generated ‘model metamers’, stimuli whose activations within a model stage are matched to those of a natural stimulus. Metamers for state-of-the-art supervised and unsupervised neural network models of vision and audition were often completely unrecognizable to humans when generated from late model stages, suggesting differences between model and human invariances. Targeted model changes improved human recognizability of model metamers but did not eliminate the overall human–model discrepancy. The human recognizability of a model’s metamers was well predicted by their recognizability by other models, suggesting that models contain idiosyncratic invariances in addition to those required by the task. Metamer recognizability dissociated from both traditional brain-based benchmarks and adversarial vulnerability, revealing a distinct failure mode of existing sensory models and providing a complementary benchmark for model assessment.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Tau PET positivity in individuals with and without cognitive impairment varies with age, amyloid-β status, APOE genotype and sex

Abstract Tau positron emission tomography (PET) imaging allows in vivo detection of tau proteinopathy in Alzheimer’s disease, which is associated with neurodegeneration and cognitive decline. Understanding how demographic, clinical and genetic factors relate to tau PET positivity will facilitate its use for clinical practice and research. Here we conducted an analysis of 42 cohorts worldwide (N = 12,048), including 7,394 cognitively unimpaired (CU) participants, 2,177 participants with mild cognitive impairment (MCI) and 2,477 participants with dementia. We found that from age 60 years to 80 years, tau PET positivity in a temporal composite region increased from 1.1% to 4.4% among CU amyloid-β (Aβ)-negative participants and from 17.4% to 22.2% among CU Aβ-positive participants. Across the same age span, tau PET positivity decreased from 68.0% to 52.9% in participants with MCI and from 91.5% to 74.6% in participants with dementia. Age, Aβ status,APOEε4 carriership and female sex were all associated with a higher prevalence of tau PET positivity across groups.APOEε4 carriership in CU individuals lowered the age at onset of both Aβ positivity and tau positivity by decades. Finally, we replicated these associations in an independent autopsy dataset (N = 5,072 from 3 cohorts).

Neurosciences & Neurology↗
DOE OSTI2024

Diagnosis of Alzheimer’s disease using plasma biomarkers adjusted to clinical probability

Abstract Recently approved anti-amyloid immunotherapies for Alzheimer’s disease (AD) require evidence of amyloid-β pathology from positron emission tomography (PET) or cerebrospinal fluid (CSF) before initiating treatment. Blood-based biomarkers promise to reduce the need for PET or CSF testing; however, their interpretation at the individual level and the circumstances requiring confirmatory testing are poorly understood. Individual-level interpretation of diagnostic test results requires knowledge of disease prevalence in relation to clinical presentation (clinical pretest probability). Here, in a study of 6,896 individuals evaluated from 11 cohort studies from six countries, we determined the positive and negative predictive value of five plasma biomarkers for amyloid-β pathology in cognitively impaired individuals in relation to clinical pretest probability. We observed that p-tau217 could rule in amyloid-β pathology in individuals with probable AD dementia (positive predictive value above 95%). In mild cognitive impairment, p-tau217 interpretation depended on patient age. Negative p-tau217 results could rule out amyloid-β pathology in individuals with non-AD dementia syndromes (negative predictive value between 90% and 99%). Our findings provide a framework for the individual-level interpretation of plasma biomarkers, suggesting that p-tau217 combined with clinical phenotyping can identify patients where amyloid-β pathology can be ruled in or out without the need for PET or CSF confirmatory testing.

Cell Biology↗
DOE OSTI2023

Determinants of cognitive and brain resilience to tau pathology: a longitudinal analysis

Mechanisms of resilience against tau pathology in individuals across the Alzheimer’s disease spectrum are insufficiently understood. Longitudinal data are necessary to reveal which factors relate to preserved cognition (i.e. cognitive resilience) and brain structure (i.e. brain resilience) despite abundant tau pathology, and to clarify whether these associations are cross-sectional or longitudinal. We used a longitudinal study design to investigate the role of several demographic, biological and brain structural factors in yielding cognitive and brain resilience to tau pathology as measured with PET. In this multicentre study, we included 366 amyloid-β-positive individuals with mild cognitive impairment or Alzheimer’s disease dementia with baseline 18 F-flortaucipir-PET and longitudinal cognitive assessments. A subset (n = 200) additionally underwent longitudinal structural MRI. We used linear mixed-effects models with global cognition and cortical thickness as dependent variables to investigate determinants of cognitive resilience and brain resilience, respectively. Models assessed whether age, sex, years of education, APOE-ε4 status, intracranial volume (and cortical thickness for cognitive resilience models) modified the association of tau pathology with cognitive decline or cortical thinning. We found that the association between higher baseline tau-PET levels (quantified in a temporal meta-region of interest) and rate of cognitive decline (measured with repeated Mini-Mental State Examination) was adversely modified by older age (Stβ interaction = -0.062, P = 0.032), higher education level (Stβ interaction = -0.072, P = 0.011) and higher intracranial volume (Stβ interaction = -0.07, P = 0.016). Younger age, higher education and greater cortical thickness were associated with better cognitive performance at baseline. Greater cortical thickness was furthermore associated with slower cognitive decline independent of tau burden. Higher education also modified the negative impact of tau-PET on cortical thinning, while older age was associated with higher baseline cortical thickness and slower rate of cortical thinning independent of tau. Our analyses revealed no (cross-sectional or longitudinal) associations for sex and APOE-ε4 status on cognition and cortical thickness. In this longitudinal study of clinically impaired individuals with underlying Alzheimer’s disease neuropathological changes, we identified education as the most robust determinant of both cognitive and brain resilience against tau pathology. The observed interaction with tau burden on cognitive decline suggests that education may be protective against cognitive decline and brain atrophy at lower levels of tau pathology, with a potential depletion of resilience resources with advancing pathology. Finally, we did not find major contributions of sex to brain nor cognitive resilience, suggesting that previous links between sex and resilience might be mainly driven by cross-sectional differences.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

New cyclophilin D inhibitor rescues mitochondrial and cognitive function in Alzheimer’s disease

Abstract Mitochondrial dysfunction is an early pathological feature of Alzheimer disease and plays a crucial role in the development and progression of Alzheimer’s disease. Strategies to rescue mitochondrial function and cognition remain to be explored. Cyclophilin D (CypD), the peptidylprolyl isomerase F (PPIase), is a key component in opening the mitochondrial membrane permeability transition pore, leading to mitochondrial dysfunction and cell death. Blocking membrane permeability transition pore opening by inhibiting CypD activity is a promising therapeutic approach for Alzheimer’s disease. However, there is currently no effective CypD inhibitor for Alzheimer’s disease, with previous candidates demonstrating high toxicity, poor ability to cross the blood–brain barrier, compromised biocompatibility and low selectivity. Here, we report a new class of non-toxic and biocompatible CypD inhibitor, ebselen, using a conventional PPIase assay to screen a library of ∼2000 FDA-approved drugs with crystallographic analysis of the CypD-ebselen crystal structure (PDB code: 8EJX). More importantly, we assessed the effects of genetic and pharmacological blockade of CypD on Alzheimer’s disease mitochondrial and glycolytic bioenergetics in Alzheimer’s disease-derived mitochondrial cybrid cells, an ex vivo human sporadic Alzheimer’s disease mitochondrial model, and on synaptic function, inflammatory response and learning and memory in Alzheimer’s disease mouse models. Inhibition of CypD by ebselen protects against sporadic Alzheimer’s disease- and amyloid-β-induced mitochondrial and glycolytic perturbation, synaptic and cognitive dysfunction, together with suppressing neuroinflammation in the brain of Alzheimer’s disease mouse models, which is linked to CypD-related membrane permeability transition pore formation. Thus, CypD inhibitors have the potential to slow the progression of neurodegenerative diseases, including Alzheimer’s disease, by boosting mitochondrial bioenergetics and improving synaptic and cognitive function.

Neurosciences & Neurology↗
DOE OSTI2025

Plasma phosphorylated tau217 strongly associates with memory deficits in the Alzheimer’s disease spectrum

Abstract Plasma phosphorylated tau (p-tau) biomarkers open unprecedented opportunities for identifying carriers of Alzheimer’s disease pathophysiology in early disease stages using minimally invasive techniques. Plasma p-tau biomarkers are believed to reflect tau phosphorylation and secretion. However, it remains unclear to what extent the magnitude of plasma p-tau abnormalities reflects neuronal network disturbance in the form of cognitive impairment. To address this question, we included 103 cognitively unimpaired elderly and 40 cognitively impaired, amyloid-β-positive individuals from the TRIAD cohort, in addition to 336 cognitively unimpaired and 216 cognitively impaired, amyloid-β-positive older adults from the BioFINDER-2 cohort. Participants had tau PET scans, amyloid PET scans or amyloid CSF, p-tau217, p-tau181 and p-tau231 blood measures, structural T1-MRI and cognitive assessments. In this cross-sectional study, we used regression models and correlation analyses to assess the relationship between plasma biomarkers and cognitive scores. Furthermore, we applied receiver operating characteristic curves to assess cognitive impairment across plasma biomarkers. Finally, we categorized participants into amyloid (A), p-tau (T1) and tau PET (T2) positive (+) or negative (−) profiles and ran non-parametric comparisons to assess differences across cognitive domains. We found that plasma p-tau217 was more associated with cognitive performance than p-tau181 and p-tau231 and that this relationship was particularly strong for memory scores (TRIAD: βp-tau217 = −0.53, βp-tau181 = −0.35 and βp-tau231 = −0.24; BioFINDER-2: βp-tau217 = −0.52, βp-tau181 = −0.24 and βp-tau231 = −0.29). Associations in amyloid-β-positive participants resembled these results, but other cognitive scores also showed strong associations in cognitively impaired individuals. Moreover, plasma p-tau217 outperformed plasma p-tau181 and plasma p-tau231 in identifying memory impairment (area under the curve values for TRIAD: p-tau217 = 0.86, p-tau181 = 0.77 and p-tau231 = 0.75; and for BioFINDER-2: p-tau217 = 0.86, p-tau181 = 0.76 and p-tau231 = 0.81) and in identifying executive function impairment only in the BioFINDER-2 cohort (p-tau217 = 0.82, p-tau181 = 0.76 and p-tau231 = 0.76). Lastly, we showed that subtle memory deficits were present in A+T1+T2− participants for plasma p-tau217 (P = 0.007) and plasma p-tau181 (P = 0.01) in the TRIAD cohort and for all biomarkers across cognitive domains in A+T1+T2− and A+T1+T2− individuals (P < 0.001 in all) in the BioFINDER-2 cohort. The A+T1+T2− individuals showed cognitive deficits in both cohorts (P < 0.001 in all). Together, our results suggest that plasma p-tau217 stands out as a biomarker capable of identifying memory deficits attributable to Alzheimer’s disease and that memory impairment certainly occurs in amyloid-β- and plasma p-tau-positive individuals who have no significant amounts of tau in the neocortex.

Neurosciences & Neurology↗
DOE OSTI2023

Hooks versus Pedicle Screws at the Upper Instrumented Level: An In Vitro Biomechanical Comparison

Study Design. Controlled laboratory study Objective. To compare motions at the upper instrumented vertebra (UIV) and supra-adjacent level (UIV+1) between two fixation techniques in thoracic posterior spinal fusion (PSF) constructs. We hypothesized there would be greater motion at UIV+1 after cyclic loading across all constructs and bilateral pedicle screws (BPS) with posterior ligamentous compromise would demonstrate the greatest UIV+1 range of motion (ROM). Summary of Background Data. Proximal junctional kyphosis (PJK) is a well-recognized complication following long thoraco-lumbar PSF, however its mechanism is poorly understood. Methods. Twenty-seven thoracic functional spine units (FSU) were randomly divided into three UIV fixation groups (n=9): (1) BPS, (2) bilateral transverse process hooks (TPH), and (3) BPS with compromise of the posterior elements between UIV and UIV+1 (BPS-C). Specimens were tested on a servohydraulic materials testing system in native state, following instrumentation, and after cyclic loading. FSUs were loaded in flexion-extension (FE), lateral bending (LB), and axial rotation (AR). Results. After cyclic testing, the TPH group had a mean 29.4% increase in FE ROM at UIV+1 versus 76.6% in the BPS group ( P <0.05). The BPS-C group showed an increased FE of 49.9% and 62.19% with sectioning of the facet joints and interspinous ligament respectively prior to cyclic testing. Conclusion. Bilateral pedicle screws at the UIV led to greater motion at UIV+1 compared to bilateral TPH after cyclic loading. This is likely due to the increased rigidity of BPS compared to TPH leading to a “softer” transition between the TPH construct and native anatomy at the supra-adjacent level. Facet capsule compromise led to a 49.9% increase in UIV+1 motion, underscoring the importance of preserving the posterior ligamentous complex. Clinical studies that account for fusion rates are warranted to determine if constructs with a “soft transition” result in less PJK in vivo.

Neurosciences & Neurology↗