- PROJECT 2 Reported prevalence of cognitive impairment in SLE ranges from 30-80% and behavioral alterations range from 17-75% with significant effects on quality of life and individual productivity. A hypothesis of this Program Grant is that autoantibodies cross-reactive with dsDNA and NMDA receptors, DNRAbs, contribute to cognitive and behavioral impairment in SLE patients. The goals of Project 2 are to continue development of FDG-PET as a biomarker for cognitive and behavioral impairment in NPSLE and to utilize other novel imaging techniques to enhance our understanding of pathologic mechanisms related to DNRAb effects on the brain. Cross-sectional FDG-PET studies of resting brain glucose metabolism demonstrate abnormal hypermetabolism in the hippocampus of SLE subjects. Hippocampus hypermetabolism and elevated serum titers of DNRAb combined have a higher predictive value for memory impairment than either variable alone. This is the first example of a consistent and robust imaging finding that reflects both impaired functional status and a proposed pathogenic mechanism in NPSLE. The longitudinal study proposed in Project 2 will validate and extend these associations. Subjects in the SLE cohort will be selected to have a range of serum DNRAb titers that is equally distributed across a spectrum of normal to high titers. The proposed longitudinal study will inform us about correlates of cognitive and behavioral change over time using FDG-PET imaging (Aim 1). Additionally, we will explore NMDAR biology in human subjects with a novel PET ligand, [11C]-CNS5161, used to localize and quantify NMDAR activation (Aim 2) and explore the role of blood brain barrier (BBB) integrity in cognitive and behavioral impairment (Aim 3). These studies complement the studies proposed in Project 1 that will explore the molecular and cellular basis for the hippocampal hypermetabolism in mouse models where tissue is readily available. In conducting these longitudinal studies, we will also determine the best biomarker with sensitivity for disease progression that can be used as a metric for a clinical trial.

Public Health Relevance

- PROJECT 2 Cognitive and behavioral impairment is present in many, if not most, patients with lupus. Animal studies have elegantly demonstrated the toxic effects of certain autoantibodies on neurons in the brain resulting in cognitive and behavioral abnormalities, however, clear correlations have been lacking in human studies. The proposed studies have the potential to inform us about autoantibody-mediated immune mechanisms that contribute to cognitive and behavioral impairment in human SLE. Improvement in cognition in SLE patients can result in improved quality of life and increased productivity that would benefit society as a whole.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
2P01AI073693-06A1
Application #
8741188
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2014-07-03
Project End
2019-06-30
Budget Start
2014-07-03
Budget End
2015-06-30
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Huerta, Patricio T; Robbiati, Sergio; Huerta, Tomás Salvador et al. (2016) Preclinical models of overwhelming sepsis implicate the neural system that encodes contextual fear memory. Mol Med 22:
Honig, Gerard; Mader, Simone; Chen, Huiyi et al. (2016) Blood-Brain Barrier Deterioration and Hippocampal Gene Expression in Polymicrobial Sepsis: An Evaluation of Endothelial MyD88 and the Vagus Nerve. PLoS One 11:e0144215
Vingtdeux, Valérie; Chang, Eric H; Frattini, Stephen A et al. (2016) CALHM1 deficiency impairs cerebral neuron activity and memory flexibility in mice. Sci Rep 6:24250
Dhawan, Vijay; Robeson, William; Bjelke, David et al. (2015) Human Radiation Dosimetry for the N-Methyl-D-Aspartate Receptor Radioligand 11C-CNS5161. J Nucl Med 56:869-72
Huerta, Patricio T; Gibson, Elizabeth L; Rey, Carson et al. (2015) Integrative neuroscience approach to neuropsychiatric lupus. Immunol Res 63:11-7
Kowal, Czeslawa; Athanassiou, Andrew; Chen, Huiyi et al. (2015) Maternal antibodies and developing blood-brain barrier. Immunol Res 63:18-25
Chang, Eric H; Volpe, Bruce T; Mackay, Meggan et al. (2015) Selective Impairment of Spatial Cognition Caused by Autoantibodies to the N-Methyl-d-Aspartate Receptor. EBioMedicine 2:755-64
Mackay, Meggan; Tang, Chris C; Volpe, Bruce T et al. (2015) Brain metabolism and autoantibody titres predict functional impairment in systemic lupus erythematosus. Lupus Sci Med 2:e000074
Jeganathan, Venkatesh; Peeva, Elena; Diamond, Betty (2014) Hormonal milieu at time of B cell activation controls duration of autoantibody response. J Autoimmun 53:46-54
Braniste, Viorica; Al-Asmakh, Maha; Kowal, Czeslawa et al. (2014) The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med 6:263ra158

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