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Meeting ReportNeurosciences

Study of ALS and RAGE Using [11C]PBR28: Mechanisms and Therapeutic Opportunities

Jiacheng Wang, Michael MacLean, Zakia Youss, Orin Mishkit, Dillon Clancy, Raul Jackson, Judyta Juranek, Giuseppe Carlucci, Ann Marie Schmidt and Yu-Shin Ding
Journal of Nuclear Medicine May 2020, 61 (supplement 1) 212;
Jiacheng Wang
1New York University School of Medicine New York NY United States
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Michael MacLean
1New York University School of Medicine New York NY United States
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Zakia Youss
1New York University School of Medicine New York NY United States
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Orin Mishkit
1New York University School of Medicine New York NY United States
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Dillon Clancy
2NYU Medical College New York City NY United States
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Raul Jackson
1New York University School of Medicine New York NY United States
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Judyta Juranek
1New York University School of Medicine New York NY United States
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Giuseppe Carlucci
3NYU School of Medicine, Department of Radiology New York NY United States
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Ann Marie Schmidt
1New York University School of Medicine New York NY United States
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Yu-Shin Ding
1New York University School of Medicine New York NY United States
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Abstract

212

Objectives: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder that is characterized by selective degeneration of both upper and lower motor neurons, resulting in paralysis of skeletal muscle and respiratory failure, with death occurring within 2-5 years of diagnosis. 90% of cases are sporadic, and of the 10% that are familial more than 20 genes (>150 mutations) have been found to be associated with ALS, most notably copper/zinc superoxide dismutase (SOD1). SOD1 mutant proteins are believed to cause toxicities in degenerating neurons. Studies suggest that the neuronal and non-neuronal cell contributions to the onset and progression of ALS are complex. It was proposed that there are two phases of neuroinflammation in the spinal cord - the first being an early neuroprotective phase followed by a second late neurotoxic phase. One of the challenges in the study of neuroinflammation is that it is difficult to serially track the disease process, as there are no bona fide biomarkers for onset and progression in ALS. For this reason, we use PET with [11C]PBR28 to track microglial neuroinflammation in the brain and spinal cord. We and others have shown that the receptor for advanced glycation end products (RAGE) is highly expressed in human ALS spinal cord, particularly in microglia, and to an increased degree compared to that of age-matched control subjects. Our previous studies with myeloid/microglia deletion of Ager and treatment with sRAGE (soluble RAGE) suggested that RAGE impairs survival and motor function in Sod1G93A mice. The ultimate goal is to test the hypothesis that RAGE inhibition in either initiation or progression phases of the ALS will prolong survival and maintain motor function in adult Sod1G93A mice.

Methods: MicroPET/CT (Inveon, Siemens) with [11C]PBR28 was used to track and compare microglial neuroinflammation in the brain and spinal cord of WT vs. ALS mice (110-120 day old), also after treatment with RAGE inhibitors (subject identity was blind to study investigator and data analyst). Using IRW (Inveon Research Workplace, Siemens), several ROIs in the thoracic and lumbar spinal cord (T13, L1, L2, L3) were drawn on the fused PET/CT images to obtain the regional SUVs. An automated atlas-based methodology using Firevoxel (https://wp.nyu.edu/Firevoxel) that we previously developed was used for brain mapping and segmentation to derive regional time-activity curves (TAC) and SUVs for 20 brain regions.

Results: Dynamic regional SUV [11C]PBR28 binding data were obtained and averaged SUVs derived from the last 5 frames (with steady and less variable intensity levels) were compared. Results derived from both spinal cord and brain regions displayed a similar trend with two obvious clusters. Reduced binding was observed for ALS group as compared to WT. RAGE inhibitor-treated ALS mi­­ce showed increased binding (brain SUV avg. 0.402±0.0382 over 20 ROIs) as compared to vehicle-treated (0.157±0.0339), suggesting that RAGE inhibition may contribute to the restoration of homeostasis in ALS animals (i.e., their bindings after treatment were closer to those in WT (0.485±0.171)). Notably, hypothalamus, brain stem, and olfactory bulb consistently exhibited higher binding, suggesting their role in this regulation.

Conclusions: Inconsistent outcomes have been reported in the literature when comparing TSPO ligand binding for imaging neuroinflammation. Our data are consistent with findings from several recent studies; i.e., reduced PBR28 binding was associated with disease state (e.g., in patients with PTSD or alcoholism). A notion that the reduced binding might reflect competition from endogenous TSPO ligands such as cholesterol can’t be excluded. The strategies described here will test the hypothesis that pharmacological antagonism of RAGE signal transduction in either initiation or progression phases of the ALS will prolong survival and maintain motor function in adult Sod1G93A mice.

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Journal of Nuclear Medicine
Vol. 61, Issue supplement 1
May 1, 2020
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Study of ALS and RAGE Using [11C]PBR28: Mechanisms and Therapeutic Opportunities
Jiacheng Wang, Michael MacLean, Zakia Youss, Orin Mishkit, Dillon Clancy, Raul Jackson, Judyta Juranek, Giuseppe Carlucci, Ann Marie Schmidt, Yu-Shin Ding
Journal of Nuclear Medicine May 2020, 61 (supplement 1) 212;

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Study of ALS and RAGE Using [11C]PBR28: Mechanisms and Therapeutic Opportunities
Jiacheng Wang, Michael MacLean, Zakia Youss, Orin Mishkit, Dillon Clancy, Raul Jackson, Judyta Juranek, Giuseppe Carlucci, Ann Marie Schmidt, Yu-Shin Ding
Journal of Nuclear Medicine May 2020, 61 (supplement 1) 212;
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