- 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.
- 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.
|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|
|Vo, An; Volpe, Bruce T; Tang, Chris C et al. (2014) Regional brain metabolism in a murine systemic lupus erythematosus model. J Cereb Blood Flow Metab 34:1315-20|
|Chang, Eric H; Frattini, Stephen A; Robbiati, Sergio et al. (2013) Construction of microdrive arrays for chronic neural recordings in awake behaving mice. J Vis Exp :e50470|
|Cohen-Solal, J F G; Diamond, B (2011) [Neuropsychiatric lupus and autoantibodies against ionotropic glutamate receptor (NMDAR)]. Rev Med Interne 32:130-2|
|Cohen-Solal, Joel; Diamond, Betty (2011) Lessons from an anti-DNA autoantibody. Mol Immunol 48:1328-31|
|Bloom, Ona; Cheng, Kai Fan; Cheng, Kai Fen et al. (2011) Generation of a unique small molecule peptidomimetic that neutralizes lupus autoantibody activity. Proc Natl Acad Sci U S A 108:10255-9|
|Diamond, B; Bloom, O; Al Abed, Y et al. (2011) Moving towards a cure: blocking pathogenic antibodies in systemic lupus erythematosus. J Intern Med 269:36-44|
|Aranow, Cynthia; Diamond, Betty; Mackay, Meggan (2010) Glutamate receptor biology and its clinical significance in neuropsychiatric systemic lupus erythematosus. Rheum Dis Clin North Am 36:187-201, x-xi|
|Faust, Thomas W; Chang, Eric H; Kowal, Czeslawa et al. (2010) Neurotoxic lupus autoantibodies alter brain function through two distinct mechanisms. Proc Natl Acad Sci U S A 107:18569-74|
|Diamond, Betty (2010) Antibodies and the Brain: Lessons from Lupus. J Immunol 185:2637-2640|
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