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Breakdown of lipid homeostasis is thought to contribute to pathological aging, the largest risk factor for neurodegenerative disorders such as Alzheimer's Disease (AD). Cognitive reserve theory posits a role for compensatory mechanisms in the aging brain in preserving neuronal circuit functions, staving off cognitive decline, and mitigating risk for AD. However, the identities of such mechanisms have remained elusive. A screen for hippocampal dentate granule cell (DGC) synapse loss-induced factors identified a secreted phospholipase , Pla2g2f , whose expression increases in DGCs during aging. Pla2g2f deletion in DGCs exacerbates aging-associated pathophysiological changes including synapse loss, inflammatory microglia, reactive astrogliosis, impaired neurogenesis, lipid dysregulation and hippocampal-dependent memory loss. Conversely, boosting Pla2g2f in DGCs during aging is sufficient to preserve synapses, reduce inflammatory microglia and reactive gliosis, prevent hippocampal-dependent memory impairment and modify trajectory of cognitive decline. Ex vivo, neuronal-PLA2G2F mediates intercellular signaling to decrease lipid droplet burden in microglia. Boosting Pla2g2f expression in DGCs of an aging-sensitive AD model reduces amyloid load and improves memory. Our findings implicate PLA2G2F as a compensatory neuroprotective factor that maintains lipid homeostasis to counteract aging-associated cognitive decline.

[ 212 Pb]VMT01 is a melanocortin 1 receptor (MC1R) targeted theranostic ligand in clinical development for alpha particle therapy for melanoma. 212 Pb has an elementally matched gamma-emitting isotope 203 Pb; thus, [ 203 Pb]VMT01 can be used as an imaging surrogate for [ 212 Pb]VMT01. [ 212 Pb]VMT01 human serum stability studies have demonstrated retention of the 212 Bi daughter within the chelator following beta emission of parent 212 Pb. However, the subsequent alpha emission from the decay of 212 Bi into 208 Tl results in the generation of free 208 Tl. Due to the 10.64-hour half-life of 212 Pb, accumulation of free 208 Tl in the injectate will occur. The goal of this work is to estimate the human dosimetry for [ 212 Pb]VMT01 and the impact of free 208 Tl in the injectate on human tissue absorbed doses. Human [ 212 Pb]VMT01 tissue absorbed doses were estimated from murine [ 203 Pb]VMT01 biodistribution data, and human biodistribution values for 201 Tl chloride (a cardiac imaging agent) from published data were used to estimate the dosimetry of free 208 Tl. Results indicate that the dose-limiting tissues for [ 212 Pb]VMT01 are the red marrow and the kidneys, with estimated absorbed doses of 1.06 and 8.27 mGy RBE = 5 /MBq. The estimated percent increase in absorbed doses from free 208 Tl in the injectate is 0.03% and 0.09% to the red marrow and the kidneys, respectively. Absorbed doses from free 208 Tl result in a percent increase of no more than 1.2% over [ 212 Pb]VMT01 in any organ or tissue. This latter finding indicates that free 208 Tl in the [ 212 Pb]VMT01 injectate will not substantially impact estimated tissue absorbed doses in humans.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder that is characterized by episodic yet cumulative heterotopic ossification (HO) in skeletal muscles, tendons, and ligaments over a patient's lifetime. FOP is caused by missense mutations in the type I bone morphogenetic protein (BMP) receptor ACVR1. We have determined that the formation of heterotopic bone in FOP requires activation of mutant ACVR1 by Activin A, in part by showing that prophylactic inhibition of Activin A blocks HO in a mouse model of FOP. Here we piece together a natural history of developing HO lesions in mouse FOP, and determine where in the continuum of HO Activin A is required, using imaging (T2-MRI, μCT, 18 F-NaF PET/CT, histology) coupled with pharmacologic inhibition of Activin A at different times during the progression of HO. First, we show that expansion of HO lesions comes about through growth and fusion of independent HO events. These events tend to arise within a neighborhood of existing lesions, indicating that already formed HO likely triggers the formation of new events. The process of heterotopic bone expansion appears to be dependent on Activin A because inhibition of this ligand suppresses the growth of nascent HO lesions and stops the emergence of new HO events. Therefore, our results reveal that Activin A is required at least up to the point when nascent HO lesions mineralize and further demonstrate the therapeutic utility of Activin A inhibition in FOP. These results provide evidence for a model where HO is triggered by inflammation but becomes "self-propagating" by a process that requires Activin A. © 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc., (© 2017 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.)

Purpose: One approach to preclinical single-photon emission computed tomography (SPECT) imaging that provides both high resolution and high sensitivity is based on imaging a mouse inside a collimating tube; many magnified pinhole projection images from a small target region, e.g., the heart, can be recorded simultaneously on multiple detectors with little multiplexing since each pinhole aperture's opening angle is restricted to view mostly the target organ. However, to obtain complete data for reconstruction, it may be necessary to scan the mouse through the target region of the tube. The authors are developing a different approach based on acquisition and reconstruction of both low-resolution and high-resolution projection data acquired sequentially through many pinholes embedded in two tungsten tube sections of different diameters, a "scout" section and a high-resolution section, placed end-to-end along the axis of a triple-head clinical SPECT scanner. This paper describes the design procedures used to determine the geometric parameters of two new collimator-tube sections, as well as one approach for joint reconstruction of data acquired from both sections., Methods: The high-resolution section was designed by projecting as many pinhole views of a simulated mouse heart as possible over each detector's camera, with no overlapping of heart projections and minimal overlapping between adjacent "hot" organ and cardiac projections. The authors then jointly optimized the geometric design of the scout section for a triple-detector camera system, as well as the number of maximum-likelihood expectation maximization (MLEM) iterations required to provide minimum mean-squared error of reconstructed voxel counts throughout a 7-cm axial range, with the constraints of fixed, 2.4-mm scout system resolution at the tube center for all apertures, limited multiplexing, and no detector motion. Simulated mouse projection data from both tube sections were then reconstructed to illustrate a simple approach for using high-resolution data to improve the whole-body scout images within a cylindrical region surrounding the heart., Results: The 2-cm-inner-radius high-resolution tube section accommodated 87 platinum-iridium pinhole inserts, each with a 0.3-mm square aperture; their radial distances from the centerline of the system ranged from 2.2 to 3.0 cm. The optimal radial distance to the closest scout pinhole and optimal number of MLEM iterations were 4.4 cm and 35 iterations, respectively, and the radial distances of the 39 scout pinholes ranged from 4.4 to 4.8 cm; aperture sizes ranged from 1.1 to 1.7 mm transaxially and 0.9-1.5 mm axially. After including data from the high-resolution section viewing the heart region into whole-body mouse reconstructions from scout data, the authors obtained high-resolution images of the heart, embedded within lower resolution images of the body, with minimal artifacts., Conclusions: The authors have optimized a dual-resolution collimator tube that provides both whole-body projections of a mouse and more targeted projections centered on the heart that can be jointly reconstructed to obtain high-resolution images of the heart embedded within lower-resolution whole-body images.

Purpose: The authors are currently developing a dual-resolution multiple-pinhole microSPECT imaging system based on three large NaI(Tl) gamma cameras. Two multiple-pinhole tungsten collimator tubes will be used sequentially for whole-body "scout" imaging of a mouse, followed by high-resolution (hi-res) imaging of an organ of interest, such as the heart or brain. Ideally, the whole-body image will be reconstructed in real time such that data need only be acquired until the area of interest can be visualized well-enough to determine positioning for the hi-res scan. The authors investigated the utility of the origin ensemble (OE) algorithm for online and offline reconstructions of the scout data. This algorithm operates directly in image space, and can provide estimates of image uncertainty, along with reconstructed images. Techniques for accelerating the OE reconstruction were also introduced and evaluated., Methods: System matrices were calculated for our 39-pinhole scout collimator design. SPECT projections were simulated for a range of count levels using the MOBY digital mouse phantom. Simulated data were used for a comparison of OE and maximum-likelihood expectation maximization (MLEM) reconstructions. The OE algorithm convergence was evaluated by calculating the total-image entropy and by measuring the counts in a volume-of-interest (VOI) containing the heart. Total-image entropy was also calculated for simulated MOBY data reconstructed using OE with various levels of parallelization., Results: For VOI measurements in the heart, liver, bladder, and soft-tissue, MLEM and OE reconstructed images agreed within 6%. Image entropy converged after ∼2000 iterations of OE, while the counts in the heart converged earlier at ∼200 iterations of OE. An accelerated version of OE completed 1000 iterations in <9 min for a 6.8M count data set, with some loss of image entropy performance, whereas the same dataset required ∼79 min to complete 1000 iterations of conventional OE. A combination of the two methods showed decreased reconstruction time and no loss of performance when compared to conventional OE alone., Conclusions: OE-reconstructed images were found to be quantitatively and qualitatively similar to MLEM, yet OE also provided estimates of image uncertainty. Some acceleration of the reconstruction can be gained through the use of parallel computing. The OE algorithm is useful for reconstructing multiple-pinhole SPECT data and can be easily modified for real-time reconstruction.

Background: Recent technological advances in myocardial perfusion imaging may warrant the use of lower injected activity. We evaluated whether quantitative measures of stress myocardial perfusion defects using Tc-99m sestamibi and low-energy high-resolution (LEHR) collimators are equivalent to lower dose SPECT-CT with cardiac multifocal collimators and software (IQ·SPECT)., Methods: 93 patients underwent one-day rest-stress gated SPECT-CT. Following conventional rest imaging, 925-1100 MBq (25-30 mCi) of Tc-99m sestamibi was injected during stress testing. Stress SPECT-CT images were acquired two ways: with LEHR (13 minutes) and IQ·SPECT (7 minutes). Low-dose IQ·SPECT stress was simulated by subsampling the full-dose data to half-, quarter-, and eighth-count levels. Abnormalities were quantified using the total perfusion deficit (TPD) score and dose-specific databases., Results: The mean ± SD of the differences between LEHR and IQ·SPECT TPD scores were -1.01 ± 5.36%, -0.10 ± 5.81%, 1.78 ± 4.81%, and 1.75 ± 6.05% at full, half, quarter, and eighth doses, respectively. Differences were statistically significant for quarter and eighth doses. Correlation between LEHR and IQ·SPECT was excellent at all doses (R ≥ 0.93). Bland-Altman plots demonstrated minimal bias., Conclusions: With IQ·SPECT, quantitative stress SPECT-CT imaging is possible with half of the standard injected activity in half the time.

Purpose: Noise levels of brain SPECT images are highest in central regions, due to preferential attenuation of photons emitted from deep structures. To address this problem, the authors have designed a novel collimator for brain SPECT imaging that yields greatly increased sensitivity near the center of the brain without loss of resolution. This hybrid collimator consisted of ultrashort cone-beam holes in the central regions and slant-holes in the periphery (USCB). We evaluated this collimator for quantitative brain imaging tasks., Methods: Owing to the uniqueness of the USCB collimation, the hole pattern required substantial variations in collimator parameters. To utilize the lead-casting technique, the authors designed two supporting plates to position about 37 000 hexagonal, slightly tapered pins. The holes in the supporting plates were modeled to yield the desired focal length, hole length, and septal thickness. To determine the properties of the manufactured collimator and to compute the system matrix, the authors prepared an array of point sources that covered the entire detector area. Each point source contained 32 μCi of Tc-99m at the first scan time. The array was imaged for 5 min at each of the 64 shifted locations to yield a 2-mm sampling distance, and hole parameters were calculated. The sensitivity was also measured using a point source placed along the central ray at several distances from the collimator face. High-count projection data from a five-compartment brain phantom were acquired with the three collimators on a dual-head SPECT/CT system. The authors calculated Cramer-Rao bounds on the precision of estimates of striatal and background activity concentration. In order to assess the new collimation system to detect changes in striatal activity, the authors evaluated the precision of measuring a 5% decrease in right putamen activity. The authors also reconstructed images of projection data obtained by summing data from the individual phantom compartments., Results: The sensitivity of the novel cone-beam collimator varied with distance from the detector face; it was higher than that of the fan-beam collimator by factors ranging from 2.7 to 162. Examination of the projections of the point sources revealed that only a few holes were distorted or partially blocked, indicating that the intensive manual fabrication process was very successful. Better reconstructed phantom images were obtained from the USCB+FAN collimator pair than from either LEHR or FAN collimation. For the left caudate, located near the center of the brain, the detected counts were 9.8 (8.3) times higher for UCSB compared with LEHR (FAN), averaged over 60 views. The task-specific SNR for detecting a 5% decrease in putamen uptake was 7.4 for USCB and 3.2 for LEHR., Conclusions: The authors have designed and manufactured a novel collimator for brain SPECT imaging. The sensitivity is much higher than that of a fan-beam collimator. Because of differences between the manufactured collimator and its design, reconstruction of the data requires a measured system matrix. The authors have demonstrated the potential of USCB collimation for improved precision in estimating striatal uptake. The novel collimator may be useful for early detection of Parkinson's disease, and for monitoring therapy response and disease progression.