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Role of tau versus TDP-43 pathology on medial temporal lobe atrophy in aging and Alzheimer's disease

Hippocampal atrophy on magnetic resonance imaging is an important biomarker in Alzheimer's disease (AD). While hippocampal atrophy was thought to result from tau tangles in AD, different neuropathologies can lead to hippocampal atrophy, especially TAR DNA-binding protein 43 (TDP-43) pathology. In this narrative review, we evaluate existing studies on the relative contribution of tau and TDP-43 pathology to medial temporal lobe (MTL) atrophy. We report a clear association of both tau and TDP-43 neuropathology with MTL atrophy, even after correcting for other neuropathologies. Next, we discuss a potential synergism between tau and TDP-43 and the relative timing of the effects of both neuropathologies. Finally, avenues for future research will be discussed. A better understanding of the interplay between tau and TDP-43 neuropathologies and their effect on atrophy will help with the development of more specific biomarkers for limbic-predominant age-related TDP-43 encephalopathy and pinpointing of the optimal timing for testing anti-tau and anti-TDP-43 treatments in trials.

60 APPLIED LIFE SCIENCES↗

Deep learning for Alzheimer's disease: Mapping large-scale histological tau protein for neuroimaging biomarker validation

Abnormal tau inclusions are hallmarks of Alzheimer's disease and predictors of clinical decline. Several tau PET tracers are available for neurodegenerative disease research, opening avenues for molecular diagnosis in vivo. However, few have been approved for clinical use. Understanding the neurobiological basis of PET signal validation remains problematic because it requires a large-scale, voxel-to-voxel correlation between PET and (immuno) histological signals. Large dimensionality of whole human brains, tissue deformation impacting co-registration, and computing requirements to process terabytes of information preclude proper validation. We developed a computational pipeline to identify and segment particles of interest in billion-pixel digital pathology images to generate quantitative, 3D density maps. The proposed convolutional neural network for immunohistochemistry samples, IHCNet, is at the pipeline's core. We have successfully processed and immunostained over 500 slides from two whole human brains with three phospho-tau antibodies (AT100, AT8, and MC1), spanning several terabytes of images. Our artificial neural network estimated tau inclusion from brain images, which performs with ROC AUC of 0.87, 0.85, and 0.91 for AT100, AT8, and MC1, respectively. Introspection studies further assessed the ability of our trained model to learn tau-related features. We present an end-to-end pipeline to create terabytes-large 3D tau inclusion density maps co-registered to MRI as a means to facilitate validation of PET tracers.

60 APPLIED LIFE SCIENCES↗

Improved Neutron Lifetime Measurement with UCN$\tau$

In this work, we report an improved measurement of the free neutron lifetime $\tau_n$ using the UCN$\tau$ apparatus at the Los Alamos Neutron Science Center. We count a total of approximately 38×10 6 surviving ultracold neutrons (UCNs) after storing in UCN$\tau$’s magnetogravitational trap over two data acquisition campaigns in 2017 and 2018. We extract $\tau$ n from three blinded, independent analyses by both pairing long and short storage time runs to find a set of replicate $\tau$ n measurements and by performing a global likelihood fit to all data while self-consistently incorporating the β-decay lifetime. Both techniques achieve consistent results and find a value $\tau$ n =877.75±0.28 stat +0.22/–0.16 syst s. With this sensitivity, neutron lifetime experiments now directly address the impact of recent refinements in our understanding of the standard model for neutron decay.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗

Search for squarks and gluinos in pp collisions at $\sqrt{s} = 13$ TeV and 13.6 TeV in events with $\tau$-leptons, jets and missing transverse momentum using the ATLAS detector

A search for R-parity-conserving supersymmetry in events with large missing transverse momentum, jets and at least one hadronically decaying $\tau$-lepton is presented. Both gluino and squark pair production are considered, with the cascade decay of each gluino or squark producing either a $\tau$-slepton or a $\tau$-sneutrino. Three channels are examined, requiring either exactly one hadronically decaying $\tau$-lepton and no other leptons, exactly one hadronically decaying $\tau$-lepton and at least one other lepton, or two or more hadronically decaying $\tau$-leptons. Analyses in the three channels are optimised independently and combined statistically. Two separate analysis strategies, either a cut-and-count or machine-learning approach, are used. The search uses 140 and 51.8 of pp collision data recorded by the ATLAS detector at the Large Hadron Collider during 2015–2018 at TeV and 2022–2023 at TeV, respectively. Gluino masses below 2.25 TeV and squark masses up to 1.7 TeV are excluded

Aad, G. [CNRS/IN2P3] (ORCID:0000000266654934)↗

Evaluation of partial volume correction and analysis of longitudinal [ 18 F]GTP1 tau PET imaging in Alzheimer's disease using linear mixed-effects models

Purpose: We evaluated the impact of partial volume correction (PVC) methods on the quantification of longitudinal [ 18 F]GTP1 tau positron-emission tomography (PET) in Alzheimer's disease and the suitability of describing the tau pathology burden temporal trajectories using linear mixed-effects models (LMEM). Methods: We applied van Cittert iterative deconvolution (VC), 2-compartment, and 3-compartment, and the geometric transfer matrix plus region-based voxelwise methods to data acquired in an Alzheimer's disease natural history study over 18 months at a single imaging site. We determined the optimal PVC method by comparing the standardized uptake value ratio change (%ΔSUVR) between diagnostic and tau burden–level groups and the longitudinal repeatability derived from the LMEM. The performance of LMEM analysis for calculating %ΔSUVR was evaluated in a natural history study and in a multisite clinical trial of semorinemab in prodromal to mild Alzheimer's disease by comparing results to traditional per-visit estimates. Results: The VC, 2-compartment, and 3-compartment PVC methods had similar performance, whereas region-based voxelwise overcorrected regions with a higher tau burden. The lowest within-subject variability and acceptable group separation scores were observed without PVC. The LMEM-derived %ΔSUVR values were similar to the per-visit estimates with lower variability. Conclusion: The results indicate that the tested PVC methods do not offer a clear advantage or improvement over non-PVC images for the quantification of longitudinal [ 18 F]GTP1 PET data. LMEM offers a robust framework for the longitudinal tau PET quantification with low longitudinal test–retest variability. Clinical trial registration: NCT02640092 and NCT03289143.

60 APPLIED LIFE SCIENCES↗

A robust and interpretable machine learning approach using multimodal biological data to predict future pathological tau accumulation

The early stages of Alzheimer’s disease (AD) involve interactions between multiple pathophysiological processes. Although these processes are well studied, we still lack robust tools to predict individualised trajectories of disease progression. Here, we employ a robust and interpretable machine learning approach to combine multimodal biological data and predict future pathological tau accumulation. In particular, we use machine learning to quantify interactions between key pathological markers (β-amyloid, medial temporal lobe atrophy, tau and APOE 4) at mildly impaired and asymptomatic stages of AD. Using baseline non-tau markers we derive a prognostic index that: (a) stratifies patients based on future pathological tau accumulation, (b) predicts individualised regional future rate of tau accumulation, and (c) translates predictions from deep phenotyping patient cohorts to cognitively normal individuals. Our results propose a robust approach for fine scale stratification and prognostication with translation impact for clinical trial design targeting the earliest stages of AD.

60 APPLIED LIFE SCIENCES↗

Neuronally-derived tau is increased in experienced breachers and is associated with neurobehavioral symptoms

Military and law enforcement breachers are exposed to many low-level blasts during their training and occupational experiences in which they detonate explosives to force entry into secured structures. There is a concern that exposure to these repetitive blast events in career breachers could result in cumulative neurological effects. This study aimed to determine concentrations of neurofilament light (NF-L), tau, and amyloid-beta 42 (Aβ42) in serum and in neuronal-derived extracellular vesicles (EVs) in an experienced breacher population, and to examine biomarker associations with neurobehavioral symptoms. Thirty-four participants enrolled in the study: 20 experienced breachers and 14 matched military or civilian law enforcement controls. EV tau concentrations were significantly elevated in experienced breachers (0.3301 ± 0.5225) compared to controls (–0.4279 ± 0.7557; F = 10.43, p = 0.003). No statistically significant changes were observed in EV levels of NF-L or Aβ42 or in serum levels of NF-L, tau, or Aβ42 (p’s > 0.05). Elevated EV tau concentrations correlated with increased Neurobehavioral Symptom Inventory (NSI) score in experienced breachers (r = 0.596, p = 0.015) and predicted higher NSI score (F(1,14) = 7.702, p = 0.015, R 2 = 0.355). These findings show that neuronal-derived EV concentrations of tau are significantly elevated and associated with neurobehavioral symptoms in this sample of experienced breachers who have a history of many low-level blast exposures.

59 BASIC BIOLOGICAL SCIENCES↗

Associations between hormone therapy use and tau accumulation in brain regions vulnerable to Alzheimer’s disease

Elucidating the downstream impact of exogenous hormones on the aging brain will have far-reaching consequences for understanding why Alzheimer’s disease (AD) predominates in women almost twofold over men. We tested the extent to which menopausal hormone therapy (HT) use is associated with later-life amyloid-β (Aβ) and tau accumulation using PET onN = 146 baseline clinically normal women, aged 51 to 89 years. Women were scanned over a 4.5-year (SD, 2.1; range, 1.3 to 10.4) and 3.5-year (SD, 1.5; range, 1.2 to 8.1) period for Aβ and tau, respectively, ~14 years after the initiation of HT. In older women (aged >70 years), HT users exhibited faster regional tau accumulation relative to non-users, localized to the entorhinal cortex and the inferior temporal and fusiform gyri, with an indirect effect of HT on cognitive decline through regional tau accumulation. In younger women (aged <70 years), HT associations with tau accumulation were negligible. Findings are relevant for optimizing menopausal treatment guidelines.

Science & Technology - Other Topics↗

Detection of astrophysical tau neutrino candidates in IceCube

High-energy tau neutrinos are rarely produced in atmospheric cosmic-ray showers or at cosmic particle accelerators, but are expected to emerge during neutrino propagation over cosmic distances due to flavor mixing. When high energy tau neutrinos interact inside the IceCube detector, two spatially separated energy depositions may be resolved, the first from the charged current interaction and the second from the tau lepton decay. We report a novel analysis of 7.5 years of IceCube data that identifies two candidate tau neutrinos among the 60 “High-Energy Starting Events” (HESE) collected during that period. The HESE sample offers high purity, all-sky sensitivity, and distinct observational signatures for each neutrino flavor, enabling a new measurement of the flavor composition. The measured astrophysical neutrino flavor composition is consistent with expectations, and an astrophysical tau neutrino flux is indicated at 2.8σ significance.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗

Line identifications in the ultraviolet spectra of Tau Herculis, B5 IV, and Zeta Draconis, B6 III

Tables of the lines found on two tracings each of the ultraviolet spectrum of Tau Her, B5 IV, and Zeta Dra, B6 III, made by the Copernicus satellite and possible identifications are given. The ranges 1025-1451A for Tau Her and 1035 to 1425A for Zeta Dra are covered by the U2 spectrometer at a resolution of 0.2A; the ranges 2028 to 2959A for Tau Her and 2000 to 3000A for Zeta Dra are covered by the V2 spectrometer at a resolution of 0.4A. The observed density of lines in the U2 region is 1.1 lines/A for Tau Her and 1.7 lines/A for Zeta Dra. In the V2 region it is 0.8 lines/A for Tau Her and 0.9 lines/A for Zeta Dra.

Underhill, A. B.↗

Near-Infrared Imaging Polarimetry of Inner Region of GG Tau A Disk

By performing non-masked polarization imaging with Subaru HiCIAO, polarized scattered light from the inner region of the disk around the GGTau A system was successfully detected in the H band, with a spatial resolution of approximately0 07, revealing the complicated inner disk structures around this young binary. This paper reports the observation of an arc-like structure to the north of GG Tau Ab, and part of a circumstellar structure that is noticeable around GG Tau Aa, extending to a distance of approximately 28 au from the primary star. The speckle noise around GG Tau Ab constrains its disk radius to 13 au. Based on the size of the circumbinary ring and the circumstellar disk around GG Tau Aa, these mimajor axis of the binary's orbit is likely to be 62 au. A comparison of the present observations with previous Atacama Large Millimeter Array and near-infrared H2 emission observations suggests that the north arc could be part of a large streamer flowing from the circumbinary ring to sustain the circumstellar disks. According to the previous studies,the circumstellar disk around GG Tau Aa has enough mass and can sustain itself for a duration sufficient for planet formation; thus, our study indicates that planets can form within close (separation 100 au) young binary systems.

non-masked polarization imaging↗

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↗

Locus coeruleus catecholamines link neuroticism and vulnerability to tau pathology in aging

Higher neuroticism is a risk factor for Alzheimer's disease (AD), and is implicated in disordered stress responses. The locus coeruleus (LC)-catecholamine system is activated during perceived threat and is a centerpiece of developing models of the pathophysiology of AD, as it is the first brain region to develop abnormal tau. We examined relationships among the "Big 5" personality traits, LC catecholamine synthesis capacity measured with [ 18 F]Fluoro-m-tyrosine PET, and tau burden measured with [ 18 F]Flortaucipir PET in cognitively normal older adults (n = 47). β-amyloid (Aβ) status was determined using [ 11 C]Pittsburgh compound B PET (n = 14 Aβ positive). Lower LC catecholamine synthesis capacity was associated with higher neuroticism, more depressive symptoms as measured by the Geriatric Depression Scale, and higher amygdala tau-PET binding. Exploratory analyses with other personality traits revealed that low trait conscientiousness was also related to both lower LC catecholamine synthesis capacity, and more depressive symptoms. A significant indirect path linked both high neuroticism and low conscientiousness to greater amygdala tau burden via their mutual association with low LC catecholamine synthesis capacity. Together, these findings reveal LC catecholamine synthesis capacity to be a promising marker of affective health and pathology burden in aging, and identifies candidate neurobiological mechanisms for the effect of personality on increased vulnerability to dementia.

59 BASIC BIOLOGICAL SCIENCES↗

Tau tridents at accelerator neutrino facilities

We present the first detailed study of Standard Model neutrino tridents involving tau leptons at the near detectors of accelerator neutrino facilities. The rates of these processes were previously thought to be negligible, even at future facilities. Our full 2 → 4 calculation, including both coherent and incoherent scatterings, reveals that the DUNE near detector could observe a considerable number of tau tridents—an important background to new physics searches. We identify promising kinematic features that may allow distinction of tau tridents from the usual neutrino charged-current background at DUNE, and thus establish the observation of tau tridents for the first time. We also comment on the detection prospects at other accelerator and collider neutrino experiments.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗

The Association of Age-Related and Off-Target Retention with Longitudinal Quantification of [ 18 F]MK6240 Tau PET in Target Regions

6-(fluoro- 18 F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([ 18 F]MK6240) tau PET tracer quantifies the brain tau neurofibrillary tangle load in Alzheimer disease. The aims of our study were to test the stability of common reference region estimates in the cerebellum over time and across diagnoses and evaluate the effects of age-related and off-target retention on the longitudinal quantification of [ 18 F]MK6240 in target regions. Methods: We assessed reference, target, age-related, and off-target regions in 125 individuals across the aging and Alzheimer disease spectrum with longitudinal [ 18 F]MK6240 SUVs and SUV ratios (SUVRs) (mean ± SD, 2.25 ± 0.40 y of follow-up). We obtained SUVR from meninges, exhibiting frequent off-target retention with [ 18 F]MK6240. Additionally, we compared tracer uptake between 37 cognitively unimpaired young (CUY) (mean age, 23.41 ± 3.33 y) and 27 cognitively unimpaired older (CU) adults (amyloid-β–negative and tau-negative, 58.50 ± 9.01 y) to identify possible nonvisually apparent, age-related signal. Two-tailed t testing and Pearson correlation testing were used to determine the difference between groups and associations between changes in region uptake, respectively. Results: Inferior cerebellar gray matter SUV did not differ on the basis of diagnosis and amyloid-β status, cross-sectionally and over time. [ 18 F]MK6240 uptake significantly differed between CUY and CU adults in the putamen or pallidum (affecting ~75% of the region) and in the Braak II region (affecting ~35%). Changes in meningeal and putamen or pallidum SUVRs did not significantly differ from zero, nor did they vary across diagnostic groups. We did not observe significant correlations between longitudinal changes in age-related or meningeal off-target retention and changes in target regions, whereas changes in all target regions were strongly correlated. Conclusion: Inferior cerebellar gray matter was similar across diagnostic groups cross-sectionally and stable over time and thus was deemed a suitable reference region for quantification. Despite not being visually perceptible, [ 18 F]MK6240 has age-related retention in subcortical regions, at a much lower magnitude but topographically colocalized with significant off-target signal of the first-generation tau tracers. The lack of correlation between changes in age-related or meningeal and target retention suggests little influence of possible off-target signals on longitudinal tracer quantification. Nevertheless, the age-related retention in the Braak II region needs to be further investigated. Future postmortem studies should elucidate the source of the newly reported age-related [ 18 F]MK6240 signal, and in vivo studies should further explore its impact on tracer quantification.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Probing the Gaseous Disk of T Tau N with CN 5-4 Lines

We present spectrally resolved observations of the young multiple system T Tau in atomic and molecular lines obtained with the Heterodyne Instrument for the Far Infrared on board Herschel. While CO, H2O, [C ii], and SO lines trace the envelope and the outflowing gas up to velocities of 33 km s(exp −1) with respect to systemic, the CN 5-4 hyperfine structure lines at 566.7, 566.9 GHz show a narrow double-peaked profile centered at systemic velocity, consistent with an origin in the outer region of the compact disk of T Tau N. Disk modeling of the T Tau N disk with the thermo-chemical code ProDiMo produces CN line fluxes and profiles consistent with the observed ones and constrain the size of the gaseous disk (R(sub out) = 110(+10/−20) AU) and its inclination (i = 25 deg +/- 5 deg). The model indicates that the CN lines originate in a disk upper layer at 40-110 AU from the star, which is irradiated by the stellar UV field and heated up to temperatures of 50-700 K. With respect to previously observed CN 2-1 millimeter lines, the CN 5-4 lines appear to be less affected by envelope emission, due to their larger critical density and excitation temperature. Hence, high-J CN lines are a unique confusion-free tracer of embedded disks, such as the disk of T Tau N.

Far Infrared↗

Distinct effects of beta-amyloid and tau on cortical thickness in cognitively healthy older adults

Published reports of associations between β-amyloid (Aβ) and cortical integrity conflict. Tau biomarkers may help elucidate the complex relationship between pathology and neurodegeneration in aging. We measured cortical thickness using magnetic resonance imaging, Aβ using Pittsburgh compound B positron emission tomography (PiB-PET), and tau using flortaucipir (FTP)-PET in 125 cognitively normal older adults. We examined relationships among PET measures, cortical thickness, and cognition. Cortical thickness was reduced in PiB+/FTP+ participants compared to the PiB+/FTP– and PiB–/FTP– groups. Continuous PiB associations with cortical thickness were weak but positive in FTP– participants and negative in FTP+. FTP strongly negatively predicted thickness regardless of PiB status. FTP was associated with memory and cortical thickness, and mediated the association of PiB with memory. Past findings linking Aβ and cortical thickness are likely weak due to opposing effects of Aβ on cortical thickness relative to tau burden. Tau, in contrast to Aβ, is strongly related to cortical thickness and memory.

60 APPLIED LIFE SCIENCES↗

Measurement of the Higgs boson production rate in association with top quarks in final states with electrons, muons, and hadronically decaying tau leptons at $\sqrt{s} =$ 13 TeV

The rate for Higgs (${\mathrm{H}} $) bosons production in association with either one (${\mathrm{t}} {\mathrm{H}} $) or two (${\mathrm{t}} {{\overline{{{\mathrm{t}}}}}} {\mathrm{H}} $) top quarks is measured in final states containing multiple electrons, muons, or tau leptons decaying to hadrons and a neutrino, using proton–proton collisions recorded at a center-of-mass energy of $13\,\text {Te}\text {V} $ by the CMS experiment. The analyzed data correspond to an integrated luminosity of 137$\,\text {fb}^{-1}$. The analysis is aimed at events that contain ${\mathrm{H}} \rightarrow {\mathrm{W}} {\mathrm{W}} $, ${\mathrm{H}} \rightarrow {\tau } {\tau } $, or ${\mathrm{H}} \rightarrow {\mathrm{Z}} {\mathrm{Z}} $ decays and each of the top quark(s) decays either to lepton+jets or all-jet channels. Sensitivity to signal is maximized by including ten signatures in the analysis, depending on the lepton multiplicity. The separation among ${\mathrm{t}} {\mathrm{H}} $, ${\mathrm{t}} {{\overline{{{\mathrm{t}}}}}} {\mathrm{H}} $, and the backgrounds is enhanced through machine-learning techniques and matrix-element methods. The measured production rates for the ${\mathrm{t}} {{\overline{{{\mathrm{t}}}}}} {\mathrm{H}} $ and ${\mathrm{t}} {\mathrm{H}} $ signals correspond to $0.92 \pm 0.19\,\text {(stat)} ^{+0.17}_{-0.13}\,\text {(syst)} $ and $5.7 \pm 2.7\,\text {(stat)} \pm 3.0\,\text {(syst)} $ of their respective standard model (SM) expectations. The corresponding observed (expected) significance amounts to 4.7 (5.2) standard deviations for ${\mathrm{t}} {{\overline{{{\mathrm{t}}}}}} {\mathrm{H}} $, and to 1.4 (0.3) for ${\mathrm{t}} {\mathrm{H}} $ production. Assuming that the Higgs boson coupling to the tau lepton is equal in strength to its expectation in the SM, the coupling $y_{{\mathrm{t}}}$ of the Higgs boson to the top quark divided by its SM expectation, $\kappa _{{\mathrm{t}}}=y_{{\mathrm{t}}}/y_{{\mathrm{t}}}^{\mathrm {SM}}$, is constrained to be within $-0.9< \kappa _{{\mathrm{t}}}< -0.7$ or $0.7< \kappa _{{\mathrm{t}}}< 1.1$, at 95% confidence level. This result is the most sensitive measurement of the ${\mathrm{t}} {{\overline{{{\mathrm{t}}}}}} {\mathrm{H}} $ production rate to date.

72 PHYSICS OF ELEMENTARY PARTICLES AND FIELDS↗