Background: Pyroglutamate-3 Aβ (pGlu-3 Aβ) is an N-terminally truncated and post-translationally modified Aβ species found in Alzheimer’s disease (AD) brain. Its increased peptide aggregation propensity and toxicity make it an attractive emerging treatment strategy for AD. We address the question of how the effector function of an anti-pGlu-3 Aβ antibody influences the efficacy of immunotherapy in mouse models with AD-like pathology. Methods: We compared two different immunoglobulin (Ig) isotypes of the same murine anti-pGlu-3 Aβ mAb (07/1 IgG1 and 07/2a IgG2a) and a general N-terminal Aβ mAb (3A1 IgG1) for their ability to clear Aβ and protect cognition in a therapeutic passive immunotherapy study in aged, plaque-rich APP_SWE/PS1ΔE9 transgenic (Tg) mice. We also compared the ability of these antibodies and a CDC-mutant form of 07/2a (07/2a-k), engineered to avoid complement activation, to clear Aβ in an ex vivo phagocytosis assay and following treatment in APP_SLxhQC double Tg mice, and to activate microglia using longitudinal microPET imaging with TSPO-specific ¹⁸F-GE180 tracer following a single bolus antibody injection in young and old Tg mice. Results: We demonstrated significant cognitive improvement, better plaque clearance, and more plaque-associated microglia in the absence of microhemorrhage in aged APP_SWE/PS1ΔE9 Tg mice treated with 07/2a, but not 07/1 or 3A1, compared to PBS in our first in vivo study. All mAbs cleared plaques in an ex vivo assay, although 07/2a promoted the highest phagocytic activity. Compared with 07/2a, 07/2a-k showed slightly reduced affinity to Fcγ receptors CD32 and CD64, although the two antibodies had similar binding affinities to pGlu-3 Aβ. Treatment of APP_SLxhQC mice with 07/2a and 07/2a-k mAbs in our second in vivo study showed significant plaque-lowering with both mAbs. Longitudinal ¹⁸F-GE180 microPET imaging revealed different temporal patterns of microglial activation for 3A1, 07/1, and 07/2a mAbs and no difference between 07/2a-k and PBS-treated Tg mice. Conclusion: Our results suggest that attenuation of behavioral deficits and clearance of amyloid is associated with strong effector function of the anti-pGlu-3 Aβ mAb in a therapeutic treatment paradigm. We present evidence that antibody engineering to reduce CDC-mediated complement binding facilitates phagocytosis of plaques without inducing neuroinflammation in vivo. Hence, the results provide implications for tailoring effector function of humanized antibodies for clinical development.

Background: Single photon emission computed tomography (SPECT) has limited ability to identify multivessel and microvascular coronary artery disease. Gamma cameras with cadmium zinc telluride detectors allow the quantification of absolute myocardial blood flow (MBF) and myocardial flow reserve (MFR). However, evidence of its accuracy is limited, and of its reproducibility is lacking. We aimed to validate ^99m Tc-sestamibi SPECT MBF and MFR using standard and spline-fitted reconstruction algorithms compared with ¹³ N-ammonia positron emission tomography in a cohort of patients with known or suspected coronary artery disease and to evaluate the reproducibility of this technique. Methods: Accuracy was assessed in 34 participants who underwent dynamic ^99m Tc-sestamibi SPECT and ¹³ N-ammonia positron emission tomography and reproducibility in 14 participants who underwent 2 ^99m Tc-sestamibi SPECT studies, all within 2 weeks. A rest/pharmacological stress single-day SPECT protocol was performed. SPECT images were reconstructed using a standard ordered subset expectation maximization (OSEM) algorithm with (N=21) and without (N=30) application of spline fitting. SPECT MBF was quantified using a net retention kinetic model‚ and MFR was derived as the stress/rest MBF ratio. Results: SPECT global MBF with splines showed good correlation with ¹³ N-ammonia positron emission tomography (r=0.81, P <0.001) and MFR estimates (r=0.74, P <0.001). Correlations were substantially weaker for standard reconstruction without splines (r=0.61, P <0.001 and r=0.34, P =0.07, for MBF and MFR, respectively). Reproducibility of global MBF estimates with splines in paired SPECT scans was good (r=0.77, P <0.001), while ordered subset expectation maximization without splines led to decreased MBF (r=0.68, P 0.05 for all). Conclusions: MBF and MFR quantification using ^99m Tc-sestamibi cadmium zinc telluride SPECT with spatiotemporal spline fitting improved the correlation with ¹³ N-ammonia positron emission tomography flow estimates and test/retest reproducibility. The use of splines may represent an important step toward the standardization of SPECT flow estimation.

Space radiation presents a substantial threat to travel beyond Earth. Relatively low doses of high-energy particle radiation cause physiological and behavioral impairments in rodents and may pose risks to human spaceflight. There is evidence that ⁵⁶Fe irradiation, a significant component of space radiation, may be more harmful to males than to females and worsen Alzheimer’s disease pathology in genetically vulnerable models. Yet, research on the long-term, sex- and genotype-specific effects of ⁵⁶Fe irradiation is lacking. Here, we irradiated 4-month-old male and female, wild-type and Alzheimer’s-like APP/PS1 mice with 0, 0.10, or 0.50 Gy of ⁵⁶Fe ions (1GeV/u). Mice underwent microPET scans before and 7.5 months after irradiation, a battery of behavioral tests at 11 months of age and were sacrificed for pathological and biochemical analyses at 12 months of age. ⁵⁶Fe irradiation worsened amyloid-beta (Aβ) pathology, gliosis, neuroinflammation and spatial memory, but improved motor coordination, in male transgenic mice and worsened fear memory in wild-type males. Although sham-irradiated female APP/PS1 mice had more cerebral Aβ and gliosis than sham-irradiated male transgenics, female mice of both genotypes were relatively spared from radiation effects 8 months later. These results provide evidence for sex-specific, long-term CNS effects of space radiation.

Objective The goal of our study is to assess the role of microglial activation in MS-associated fatigue (MSAF) using [F-18]PBR06-PET. Methods Fatigue severity was measured using the Modified Fatigue Impact Scale (MFIS) in 12 subjects with MS (7 relapsing-remitting and 5 secondary progressive) and 10 healthy control participants who underwent [F-18]PBR06-PET. The MFIS provides a total fatigue score as well as physical, cognitive, and psychosocial fatigue subscale scores. Standardized Uptake Value (SUV) 60–90 minute frame PET maps were coregistered to 3T MRI. Voxel-by-voxel analysis using Statistical Parametric Mapping and atlas-based regional analyses were performed. SUV ratios (SUVRs) were global brain normalized. Results Peak voxel-based level of significance for correlation between total fatigue score and PET uptake was localized to the right substantia nigra (T-score 4.67, p = 0.001). Similarly, SUVRs derived from atlas-based segmentation of the substantia nigra showed significant correlation with MFIS (r = 0.76, p = 0.004). On multiple regression, the right substantia nigra was an independent predictor of total MFIS (p = 0.02) and cognitive MFIS subscale values (p = 0.007), after adjustment for age, disability, and depression. Several additional areas of significant correlations with fatigue scores were identified, including the right parahippocampal gyrus, right precuneus, and juxtacortical white matter (all p < 0.05). There was no correlation between fatigue scores and brain atrophy and lesion load in patients with MS. Conclusion Substantia nigra microglial activation is linked to fatigue in MS. Microglial activation across key brain regions may represent a unifying mechanism for MSAF, and further evaluation of neuroimmunologic basis of MSAF is warranted.

Purpose: This study aimed to evaluate the prognostic value of metabolic parameters on ¹⁸F-FDG PET/CT and tumor dose (TD) on posttreatment ⁹⁰Y PET/CT in patients with hepatocellular carcinoma (HCC) who underwent ⁹⁰Y transarterial radioembolization (TARE). Patients and Methods: Forty-seven HCC patients treated with ⁹⁰Y TARE were retrospectively enrolled between January 2013 and October 2018. ¹⁸F-FDG PET/CT was performed before treatment. Maximum tumor SUV–to–mean normal liver SUV ratio (TLR), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured for each patient. Voxel dosimetry was performed on ⁹⁰Y PET/CT images to measure TD. The prognostic significance of metabolic parameters on ¹⁸F-FDG PET/CT, TD on ⁹⁰Y PET/CT, and clinical factors for overall survival (OS) was evaluated. In addition, TD on ⁹⁰Y PET/CT was analyzed in relation to the administered dose of ⁹⁰Y-labeled microspheres and metabolic parameters on ¹⁸F-FDG PET/CT. Results: The median patient age was 57 years, and 37 patients (78.7%) were men. During the follow-up period, 25 patients (53.2%) died. In univariable analysis, Barcelona Clinic Liver Cancer stage C, Child-Pugh score, TD on ⁹⁰Y PET/CT, TLR, MTV, and TLG were significant prognostic factors affecting OS (P < 0.05). In multivariable analysis, Barcelona Clinic Liver Cancer stage C and high TLG on ¹⁸F-FDG PET/CT were independent prognostic factors for OS (P < 0.05). The 1-year OS rates were 72.9% in patients with low TLG and 33.3% in patients with high TLG (P < 0.05). We also found that TD on ⁹⁰Y PET/CT was not correlated with the administered dose of ⁹⁰Y-labeled microspheres, but negatively correlated with TLG on pretreatment ¹⁸F-FDG PET/CT (P < 0.05). Conclusions: TLG, a parameter incorporating both the degree of ¹⁸F-FDG uptake and amount of metabolically active tumor volume on pretreatment ¹⁸F-FDG PET/CT, is a better prognostic factor than TD on ⁹⁰Y PET/CT for predicting OS in HCC patients treated with ⁹⁰Y TARE.