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All sourcesNASA NTRSDOE OSTI
DOE OSTI2013

Aging phenotypes in cultured normal human mammary epithelial cells are correlated with decreased telomerase activity independent of telomere length

Shortening of telomeres, which are essential for maintenance of genomic integrity, is a mechanism commonly associated with the aging process. Here we ascertained whether changes in telomere lengths or telomerase activity correlated with age in normal human mammary epithelial cells (HMEC), or with phenotypes of aging in breast. Accordingly, flow cytometry fluorescence in situ hybridization (flowFISH) was used to determine relative telomere lengths (RTL), and telomerase activity was measured by the telomeric repeat amplification protocol (TRAP), in a collection of 41 primary HMEC strains established from women aged 16 to 91 years. RTL measurements of HMEC strains that were heterogeneous with respect to lineage composition revealed no significant associations between telomere length with age, maximum observed population doublings, or with lineage composition of the strains. However, within strains, luminal epithelial and cKit-expressing epithelial progenitor cells that were flow cytometry-enriched from individual HMEC strains exhibited significantly shorter telomeres relative to isogenic myoepithelial cells (P < 0.01). In unsorted strains, detectable telomerase activity did not correlate with RTL. Telomerase activity declined with age; the average age of strains that exhibited TRAP activity was 29.7 ± 3.9y, whereas the average age of strains with no detectable TRAP activity was 49.0 ± 4.9y (P < 0.01). Non-detectable TRAP activity also was correlated with phenotypes of aging previously described in HMEC strains; increased proportions of CD227-expressing luminal epithelial cells (P < 0.05) and cKit-expressing progenitor cells (P < 0.05). Telomere shortening did not correlate with the chronological ages of HMEC strains, whereas decreased telomerase activity correlated with age and with lineage distribution phenotypes characteristic of aging.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2002

Activity Tracking for Pilot Error Detection from Flight Data

This report presents an application of activity tracking for pilot error detection from flight data, and describes issues surrounding such an application. It first describes the Crew Activity Tracking System (CATS), in-flight data collected from the NASA Langley Boeing 757 Airborne Research Integrated Experiment System aircraft, and a model of B757 flight crew activities. It then presents an example of CATS detecting actual in-flight crew errors.

Callantine, Todd J.↗
NASA NTRS1999

Detection of endogenous alkaline phosphatase activity in intact cells by flow cytometry using the fluorogenic ELF-97 phosphatase substrate

BACKGROUND: The alkaline phosphatase (AP) substrate 2-(5'-chloro-2'-phosphoryloxyphenyl)-6-chloro-4-(3H)-quinazolinone (ELF((R))-97 for enzyme-labeled fluorescence) has been found useful for the histochemical detection of endogenous AP activity and AP-tagged proteins and oligonucleotide probes. In this study, we evaluated its effectiveness at detecting endogenous AP activity by flow cytometry. METHODS: The ELF-97 phosphatase substrate was used to detect endogenous AP activity in UMR-106 rat osteosarcoma cells and primary cultures of chick chondrocytes. Cells were labeled with the ELF-97 reagent and analyzed by flow cytometry using an argon ultraviolet (UV) laser. For comparison purposes, cells were also assayed for AP using a Fast Red Violet LB azo dye assay previously described for use in detecting AP activity by flow cytometry. RESULTS: The ELF-97 phosphatase substrate effectively detected endogenous AP activity in UMR-106 cells, with over 95% of the resulting fluorescent signal resulting from AP-specific activity (as determined by levamisole inhibition of AP activity). In contrast, less than 70% of the fluorescent signal from the Fast Red Violet LB (FRV) assay was AP-dependent, reflecting the high intrinsic fluorescence of the unreacted components. The ELF-97 phosphatase assay was also able to detect very low AP activity in chick chondrocytes that was undetectable by the azo dye method. CONCLUSIONS: The ELF-97 phosphatase assay was able to detect endogenous AP activity in fixed mammalian and avian cells by flow cytometry with superior sensitivity to previously described assays. This work also shows the applicability of ELF-97 to flow cytometry, supplementing its previously demonstrated histochemical applications. Copyright 1999 Wiley-Liss, Inc.

Non-NASA Center↗
DOE OSTI2022

Discriminating Types of Volcanic Electrical Activity: Toward an Eruption Detection Algorithm

Abstract We present a method for classification of the two distinct types of electrical activity that occur during an explosive volcanic eruption: vent discharges and lightning. Vent discharges occur at the onset of an explosion and create a distinctive radio frequency signature called continual radio frequency. Seconds to minutes after the onset of the eruption, lightning begins to occur throughout the eruption column. We use logistic regression to classify a radio frequency impulse as being part of either a lightning flash or a period of continual radio frequency. The classifier uses the number of peaks in the amplitude envelope from 1 ms windows before and after the impulsive very high frequency waveform, with an average accuracy of 97.9%. We propose that this method could be used in an algorithm to determine when explosive eruptions occurred by identification of the distinctive signatures of vent discharges and lightning.

58 GEOSCIENCES↗
NASA NTRS2001

Use of Acoustic Wind Profilers for Uninhabited Aerial Vehicle Flight Test Activities

Sonic detection and ranging (SODAR) systems provide crucial information to meteorologists for advising uninhabited aerial vehicle (UAV) flight crews and mission directors on historical, current, and forecasted wind and turbulence conditions. The SODAR system provided advanced warning of increasing surface winds for an X-38 flight on February 6, 1999. The SODAR system has also provided important postflight data for X-38 engineers to review the performance of the parafoil in the presence of strong wind shears near the surface at landing.

Donnohue, Casey J.↗
DOE OSTI2015

Temperature admittance spectroscopy of boron doped chemical vapor deposition diamond

Precision admittance spectroscopy measurements over wide temperature and frequency ranges were carried out for chemical vapor deposition epitaxial diamond samples doped with various concentrations of boron. It was found that the experimentally detected boron activation energy in the samples decreased from 314 meV down to 101 meV with an increase of B/C ratio from 600 to 18000 ppm in the gas reactants. For the heavily doped samples, a transition from thermally activated valence band conduction to hopping within the impurity band (with apparent activation energy 20 meV) was detected at temperatures 120–150 K. Numerical simulation was used to estimate the impurity DOS broadening. Accurate determination of continuously altering activation energy, which takes place during the transformation of conduction mechanisms, was proposed by numerical differentiation of the Arrhenius plot. With increase of boron doping level the gradual decreasing of capture cross section from 3 × 10{sup −13} down to 2 × 10{sup −17} cm{sup 2} was noticed. Moreover, for the hopping conduction the capture cross section becomes 4 orders of magnitude less (∼2 × 10{sup −20} cm{sup 2}). At T > T{sub room} in doped samples the birth of the second conductance peak was observed. We attribute it to a defect, related to the boron doping of the material.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗
NASA NTRS1992

Detection of TeV photons from the active galaxy Markarian 421

The detection of TeV energy photons from the giant elliptical galaxy Markarian 421 using the Whipple Observatory gamma-ray telescope is reported. The signal has a statistical significance of 6 sigma above background and the flux above 0.5 TeV is 0.3 of that from the Crab Nebula. The source location agrees with the position of Mk 421 within the angular uncertainty of the Whipple instrument.

Punch, M.↗
DOE OSTI2018

Automatic Imagery Data Analysis for Proactive Computer-Based Workflow Management during Nuclear Power Plant Outages

This report is being submitted for the task “Final Report” of DOE NEUP Project 15-8121 “Automatic Imagery Data Analysis for Proactive Computer-Based Workflow Management during Nuclear Power Plant Outages.” Typical nuclear power plant (NPP) outages always involve thousands of maintenance and refueling activities and a large number of workers in limited workspaces, while having tight schedules and zero-tolerance for accidents. During an outage, thousands of workers will be working in various workspaces across the NPP. High outage costs and expensive delays (approximately 1.5 million dollars of loss per day of delay) in NPP maintenance demand tight outage schedules. In packed workspaces, an automatic system that monitors human behaviors in real-time and provides insights about current and pending schedule deviations from the plan is critical for ensuring: 1) effective collaboration among workers and worker teams from different trades; 2) less waste of time and resources due to the lack of situational awareness; and 3) proactive outage project control. The overall goal of this project is to test the hypothesis that real-time imagery-based object tracking and spatial analysis, as well as human behavior modeling of outage participants, will significantly improve the efficiency of outage control while lowering the rates of accidents and incidents. Three objectives of this project are: 1) Establish real-time object tracking and spatiotemporal analysis methods that automatically assess the productivity of field activities and detect anomalous spatiotemporal relationships among activities that cause inefficiencies and risks; 2) Establish realtime human tracking and human factor modeling methods for automatically diagnosing unexpected actions of and interactions between outage participants, those which cause inefficient collaborations between Advanced Outage Control Center (AOCC), satellite outage centers, NPP workers, and maintenance service providers; and 3) Test the proposed automated object tracking, human behavior modeling, and spatiotemporal analysis methods in outage control case studies in order to characterize the effectiveness of automated imagery-data-driven methods in proactively improving the efficiency and safety of workflows in outage coordination and risk management. Recent studies of detailed human behavior monitoring on construction sites have examined the potential of applying advanced computer vision algorithms in detecting and tracking anomalous workers (i.e., workers who do not wear hard hats or safety vests) for ensuring job site safety. Some studies of human factor studies revealed the importance of modeling detailed interactions between individuals within and across teams in better understanding the impact of human in proactive project control. Other studies in the construction domain have developed computational simulation frameworks that formalize detailed spatiotemporal interactions between tasks in order to simulate the impacts of individual tasks on the performance of workflows. While integrated analyses that combine human factor assessment, as well as image processing and simulation, are in demand for effective decision-making, limited studies have examined the potential of such integrated analyses in NPP outage control. This research project has examined an automatic outage monitoring and control system that integrates human factor analysis, computer vision techniques, and simulation methods in order to enable engineers to better understand the interactions between humans, resources, and workflows during outage processes. The project aims at providing NPP maintenance agencies insights into more efficient use of limited resources in extending the life of a nuclear plant, as well as reducing waste while ensuring sufficient generation of electricity. This study is significant for the safety of nuclear plants, sustainable electricity generation for livable communities, and cost savings for maintaining electricity infrastructures in the United States.

22 GENERAL STUDIES OF NUCLEAR REACTORS↗
NASA NTRS2008

Stereo and Solar Cycle 24

The twin STEREO spacecrafi, launched in October 2006, are in heliocentric orbits near 4 AU with one spacecraft (Ahead) leading Earth in its orbit around the Sun and the other (Behind) trailing Earth. As viewed from the Sun, the STEREO spacecraft are continually separating from one another at about 45 degrees per year with Earth biseding the angle. At present, th@spaser=raft are a bit more than 45 degrees apart, thus they are able to each 'vie@ ground the limb's of the Sun by about 23 degrees, corresponding to about 1.75 days of solar rotation. Both spameraft contain an identical set of instruments including an extreme ultraviolet imager, two white light coronagraphs, tws all-sky imagers, a wide selection of energetic particle detectors, a magnetometer and a radio burst tracker. A snapshot of the real time data is continually broadcast to NOW-managed ground stations and this small stream of data is immediately sent to the STEREO Science Center and converted into useful space weather data within 5 minutes of ground receipt. The resulting images, particle, magnetometer and radio astronomy plots are available at ~ ~ j ~ g ~ ~ ~ i t , : gAs~ timqe~ co~n~ting ue~s ijnto~ ~ ~ ~ ~ . ~ g ~ solar cycle 24, the separation angle becomes 90 degrees in early 2009 and 180 degrees in early 201 1 as the activity heads toward maximum. By the time of solar maximum, STEREO will provide for the first time a view of the entire Sun with the mronagraphs and e*reme ultraviolet instruments. This view wilt allow us to follow the evolution of active regions continuously and also detect new active regions long before they pose a space weather threat to Earth. The in situ instruments will be able to provide about 7 days advanced notice of co-rotating structures in the solar wind. During this same intewal near solar maximum, the wide-angle imagers on STEREB will both be ;able to view EarlCP-dirsted CMEs in their plane-oPsky. When combined with Eat-lhorbiting assets available at that time, it seems solar cycle 24 will mark a great increase in our ability to understand and predict space weather.

Kaise,r Michael L.↗
DOE OSTI2017

Detection and Quantification of Biologically Active Botulinum Neurotoxin Serotypes A and B Using a Förster Resonance Energy Transfer-Based Quantum Dot Nanobiosensor

Botulinum neurotoxin (BoNT) is the most potent toxin known. The ingestion of food contaminated with biologically active BoNT causes foodborne botulism, which can lead to respiratory paralysis, coma, and death after ingestion of as little as 70 mu g for a 70 kg human. Because of its lethality and challenges associated with current detection methods, there is an urgent need for highly sensitive rapid screening techniques capable of detecting biologically active BoNT. Here, we describe a Forster resonance energy transfer-based nanobiosensor that uses quantum dots (QDs) and two specific quencher-labeled peptide probes to detect and differentiate two biologically active forms of BoNT, serotypes A and B, which were responsible for 80% of human foodborne botulism cases in the U.S. from 2012 to 2015. Each peptide probe contains an enzymatic cleavage site specific to only one serotype. QDs were selected based on the spectral overlap with the quenchers. In the presence of the target BoNT serotype, the peptide probe is cleaved and the quenching of QD photoluminescence (PL) is reduced, giving a signal that is easily detected by a PL spectrophotometer. This sensor performance was evaluated with light chains of BoNT/A and BoNT/B (LcA and LcB), catalytic domains of the respective serotypes. LcA and LcB were detected in 3 h with limits of detection of 0.2 and 2 ng/mL, respectively. The specificity of the sensor was evaluated, and no cross-reactivity from nontarget serotypes was observed with 2 h of incubation. Because each serotype-specific peptide is conjugated to a QD with a unique emission wavelength, multiple biologically active BoNT serotypes could be detected in one PL spectrum. The sensor was also shown to be responsive to BoNT/A and BoNT/B holotoxins. Good performance of this sensor implies its potential application as a rapid screening method for biologically active BoNT/A and BoNT/B in the laboratory and in the field.

botulinum neurotoxin↗
DOE OSTI2020

Further Investigation on Chromospheric and Prominence Activity of the RS Canum Venaticorum Star SZ Piscium

To continue our study on chromospheric activity and detection for possible prominence events of the very active RS Canum Venaticorum star SZ Piscium (SZ Psc), long-term high-resolution spectroscopic observations were obtained during several observing runs from 2014 to 2018. Based on the spectral subtraction technique, the chromospheric emission of the Ca ii IRT (λ8662, λ8542, and λ8498), H{sub α}, Na i D{sub 1}, D{sub 2} doublet, H{sub β}, and Ca ii H & K lines is mainly associated with the K1 IV primary star of the SZ Psc system, in good agreement with the previous studies, and the F8 V secondary star also shows some chromospheric emission, implying its active chromosphere. Moreover, an optical flare characterized by the He i D{sub 3} line emission together with stronger emission in the other indicators was detected. Furthermore, two chromospheric active longitudes around the two quadratures of the system were identified for most of the time, and the chromospheric activity shows significant changes during a few orbital cycles. The chromospheric activity level seems to show a long-term variation during our observations. There were some excess absorption features in the subtracted H{sub α} line and the other activity indicators, which would be caused by prominence-like materials associated with the K1 IV primary star of the system. Prominence materials could absorb the chromospheric emission and continuum from the K1 IV primary star and even the F8 V secondary one.

79 ASTRONOMY AND ASTROPHYSICS↗
DOE OSTI2023

A Graph Convolutional Network for Active Distribution System Anomaly Detection Considering Measurement Spatial-Temporal Correlations

The accuracy of distribution system state estimation may be significantly impacted by the existence of bad measure-ments and unexpected topology errors. This paper proposes a data-driven Graph Convolutional Network (GCN) for anomaly detection, including bad measurements and topology change events. Compared to many existing machine learning approaches, the proposed approach embeds both spatial-temporal measure-ment correlations, which allows us to detect and distinguish different anomalies. Numerical results carried out on the IEEE 37-node system demonstrate that the proposed-based method can obtain high accuracy in detecting bad data and topology changes as compared to other approaches, even in the presence of high PV penetrations.

active distribution system↗
NASA NTRS2014

Management and Climate Contributions to Satellite-Derived Active Fire Trends in the Contiguous United States

Fires in croplands, plantations, and rangelands contribute significantly to fire emissions in the United States, yet are often overshadowed by wildland fires in efforts to develop inventories or estimate responses to climate change. Here we quantified decadal trends, interannual variability, and seasonality of Terra Moderate Resolution Imaging Spectroradiometer (MODIS) observations of active fires (thermal anomalies) as a function of management type in the contiguous U.S. during 2001-2010. We used the Monitoring Trends in Burn Severity database to identify active fires within the perimeter of large wildland fires and land cover maps to identify active fires in croplands. A third class of fires defined as prescribed/other included all residual satellite active fire detections. Large wildland fires were the most variable of all three fire types and had no significant annual trend in the contiguous U.S. during 2001-2010. Active fires in croplands, in contrast, increased at a rate of 3.4 percent per year. Cropland and prescribed/other fire types combined were responsible for 77 percent of the total active fire detections within the U.S and were most abundant in the south and southeast. In the west, cropland active fires decreased at a rate of 5.9 percent per year, likely in response to intensive air quality policies. Potential evaporation was a dominant regulator of the interannual variability of large wildland fires, but had a weaker influence on the other two fire types. Our analysis suggests it may be possible to modify landscape fire emissions within the U.S. by influencing the way fires are used in managed ecosystems.

Satellite-derived↗
DOE OSTI2026

Connecting Current and Future Dual Active Galactic Nucleus Searches to LISA and Pulsar Timing Array Gravitational-wave Detections

Abstract Dual active galactic nuclei (DAGN) mark the observable stage of massive black hole (MBH) pairing during galaxy mergers and are the progenitors of the MBH binaries that generate low-frequency gravitational waves. Using the large-volume ASTRID cosmological simulation, we construct mock DAGN catalogs tailored to the selection functions of current (COSMOS-Web and DESI) and forthcoming (Nancy Grace Roman Space Telescope (Roman) and Lynx X-ray Observatory (Lynx)) surveys, enabling direct comparisons between simulations and observations. With realistic observational selections, ASTRID reproduces the observed dual fractions, projected separations, and host-galaxy properties across redshifts. We predict a substantial population of small-separation (<5 kpc) duals that remain inaccessible to current surveys, demonstrating that the apparent paucity of subkiloparsec systems in COSMOS-Web is primarily a consequence of observational selection rather than an intrinsic absence. Following each simulated dual to coalescence, we show that DAGN are effective tracers of MBH mergers: ∼30%–70% merge within ≲1 Gyr, and 20%–60% of these mergers produce gravitational-wave signals detectable by the Laser Interferometer Space Antenna (LISA). Duals observable with Roman and Lynx are the progenitors of ∼10%–50% of low-redshift LISA sources and contribute ∼30% of the PTA-band stochastic gravitational-wave background. We further identify massive green-valley galaxies hosting moderate-luminosity active galactic nuclei (AGN), together with massive star-forming galaxies containing bright quasars at z > 1, as the environments most likely to host imminent MBH binaries. These results establish a unified cosmological framework connecting DAGN demographics, MBH binary evolution, and gravitational-wave sources, while identifying high-priority targets for coordinated electromagnetic and multimessenger observations in the coming decade.

Chen, Nianyi [Max-Planck-Institut für Astrophysik;↗
DOE OSTI2026

The detection of marine microseismic activity with the CUORE tonne-scale cryogenic experiment

Vibrations from experimental setups and the environment are a persistent source of noise for low-temperature calorimeters searching for rare events, including neutrinoless double beta ( 0νββ ) decay or dark matter interactions. Such noise can significantly limit experimental sensitivity to the physics case under investigation. Here, we report the detection of marine microseismic vibrations using mK-scale calorimeters. This study employs a multi-device analysis correlating data from CUORE, the leading experiment in the search for 0νββ decay with mK-scale calorimeters, and the Copernicus Earth Observation program, revealing the seasonal impact of Mediterranean Sea activity on CUORE’s energy thresholds, resolution, and sensitivity over four years. The detection of marine microseisms underscores the need to address faint environmental noise in ultra-sensitive experiments. Understanding how such noise couples to the detector and developing mitigation strategies is essential for next-generation experiments. We demonstrate one such strategy: a noise decorrelation algorithm implemented in CUORE using auxiliary sensors, which reduces vibrational noise and improves detector performance. Enhancing sensitivity to 0νββ decay and to rare events with low-energy signatures requires identifying unresolved noise sources, advancing noise reduction methods, and improving vibration suppression systems, all of which inform the design of next-generation rare event experiments.

experimental nuclear physics↗
DOE OSTI2015

SUPERMASSIVE BLACK HOLES WITH HIGH ACCRETION RATES IN ACTIVE GALACTIC NUCLEI. III. DETECTION OF Fe ii REVERBERATION IN NINE NARROW-LINE SEYFERT 1 GALAXIES

This is the third in a series of papers reporting on a large reverberation-mapping campaign aimed to study the properties of active galactic nuclei (AGNs) with high accretion rates. We present new results on the variability of the optical Fe ii emission lines in 10 AGNs observed by the Yunnan Observatory 2.4 m telescope from 2012 to 2013. We detect statistically significant time lags, relative to the AGN continuum, in nine of the sources. This accurate measurement is achieved using a sophisticated spectral fitting scheme that allows for apparent flux variations of the host galaxy, and several narrow lines, due to the changing observing conditions. Six of the newly detected lags are indistinguishable from the Hβ lags measured in the same sources. Two are significantly longer and one is slightly shorter. Combining these findings with the Fe ii lags reported in previous studies, we find an Fe ii radius–luminosity relationship similar to the one for Hβ, although our sample by itself shows no clear correlation. The results support the idea that Fe ii emission lines originate in photoionized gas, which, for the majority of the newly reported objects, is indistinguishable from the Hβ-emitting gas. We also present a tentative correlation between the lag and intensity of Fe ii and Hβ and comment on its possible origin.

79 ASTRONOMY AND ASTROPHYSICS↗
NASA NTRS1987

The imaging of extra-galactic low-energy gamma-ray sources prospects, techniques, and instrumentation

Improved understanding of the nature of active galaxies will require detailed observations of 10 to 20 sources, while understanding of their gamma ray luminosity function and its evolution will require the detection of approximately 100 sources. Instruments capable of detecting 100 active galaxies at low-energy, gamma ray energies are achievable. The angular resolution of an instrument, as well as its sensitivity, can limit the number of sources it can observe. An investigation of the angular resolution requirements for future low-energy gamma ray instruments is presented. It was found that the strictest requirements arise not from the need to resolve detectable sources, but from the need to control the level of direction-to-direction fluctuations in the diffuse background level. It was concluded that gamma-ray instruments capable of detecting 100 active galaxies must have sub-degree angular resolution. The use of the coded aperture imaging technique is proposed as a method of achieving accurate control of systematic errors and fine angular resolution without unduly increasing the time needed to conduct full sky surveys. An analysis of coded aperture imaging is presented for instruments that employ masks based on hexagonal uniformly redundant arrays. An instrument, the gamma-ray imaging payload, was built that employs these imaging techniques. The design and testing of the instrument is described in detail. Preliminary results from a balloon flight of the instruments are shown, demonstrating its imaging performance.

Finger, Mark Harold↗
DOE OSTI2014

Development of Automated Software Program for the Analysis of Alzheimer's Disease Scans: Evaluation of PET imaging with PBR-111 in HV and AD subjects

Study goal: A Phase 1 evaluation of the kinetics, clearance and cerebral distribution of one novel peripheral benzodiazepine receptors(PBR)positron emission tomography (PET) imaging agent, 18F-PBR-111 following intravenous administration in healthy volunteers and Alzheimer's disease (AD) patients. Short title: Evaluation of PET imaging with PBR-111 in HV and AD subjects Proof of Mechanism. Primary Objective: To evaluate the cerebral distribution of PBR-111 positron emission tomography (PET) for detection/exclusion of microglial activation in patients with Alzheimer's disease subjects compared to healthy volunteers. Secondary objectives: - To assess the dynamic uptake and washout of [18F]PBR-111, a potential imaging bio-marker for inflammatory changes in brain, using positron emission tomography in subjects with Alzheimer's disease (AD) and healthy volunteers (HV). - To perform blood metabolite characterization of [18F]PBR-111 in subjects with AD and HV to determine the nature of metabolites in assessment of [18F]-PBR-111 as a PET brain imaging agent. Name of radioactive drug substance: PBR-111 Dose(s): The applied PBR-111 radioactive dose will be up to 5.0 mCi, diluted in a maximum of 10 ml of saline. The radioligand will be administered as a slow intravenous bolus injection (i.e., 6 sec/ml) into a large vein (e.g., antecubital vein). Route of administration: Intravenous injection Duration of treatment: Single administration of a diagnostic agent Indication: PBR-111 positron emission tomography (PET) imaging has the potential to detect microglial activation. In the presence of PBR-111 uptake (representative of microglial activation), inflammation in the brain can be detected. Diagnosis and main criteria for inclusion: Study participants will be HVs and patients diagnosed with probable AD. HVs must be 18 years of age (at least four subjects 50 years of age) and have no evidence of cognitive impairment or other neurologic disease by medical history. The lack of cognitive impairment will also be based on a Clinical Dementia Rating (CDR) of 0. Patients with probable AD must be 50 years of age and must fulfill the National Institute of Neurological and Communicative Disorders and Stroke, Alzheimer's Disease and Related Disorders Association [NINCDS-ADRDA] criteria for probable AD. The CDR score must be 1.0 and 2.0 and have a modified Hachinski of 4. All HVs and all patients with probable AD must be able to comply with all study procedures. Study design: This is a Phase 1, open-label, single-center, non-randomized single dose study to assess the kinetics, clearance and cerebral distribution of PBR-111 PET imaging in detecting microglial activation in the brain in patients with probable AD compared to HVs. All aspects related to image acquisition, processing, and visual as well as quantitative evaluation will be developed, optimized, and validated (where required). Each subject will be required to visit the study center during the screening phase and on the PBR-111 PET imaging day (baseline). A telephone follow-up visit will be performed 7 days (± 3 days) after PBR-111 PET administration. At the screening visit, each subject (or caregiver in the case of AD subjects) will be asked to provide written informed consent or assent. During the screening phase (maximum duration of 60 days) subject medical, neurological, and surgical history, clinical assessments, and a neuro-psychiatric evaluation will be performed on all eligible subjects. Subjects will be allowed to leave the center after all evaluations have been completed. During this period an MRI of the brain will be performed during the screening period. If an MRI of the brain has been performed within six months of the imaging visit using the methods described in the protocol, and there has been no medically significant events in the interim, the previous MRI may be used. During the PBR-111 PET imaging day, all subjects will receive a single intravenous injection of PBR-111 and scanning will be performed over a 3.5 hour period. Each subject will have a telephone follow-up 7 days (± 3 days) thereafter to assess for adverse events. Methodology: - Assessments to provide clinical characterization of the AD subjects will be performed. - After administration of PBR-111, images will be generated with state-of-the-art PET imaging. Images will be assessed quantitatively for the presence of microglial activation by a nuclear physician blinded to clinical data. - Total radioactivity and estimation of the fraction of radioactivity associated to the un-metabolized tracer will be determined. In addition, the metabolite patterns of PBR-111 are determined in venous plasma and arterial samples based on high-performance liquid chromatography (HPLC) analyses. - Arterial sampling will be acquired in the initial two AD and two HV subjects and modeling will be assessed to determine if additional arterial sampling is necessary.

97 MATHEMATICS AND COMPUTING↗