Clinical Trial: Development of a Novel Glutamate Receptor Ligand for PET Scans in Neuropsychiatric Systemic Lupus Erythematosus
Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Observational
Official Title: Development of a Novel Glutamate Receptor Ligand for PET Scans in Neuropsychiatric Systemic Lupus Erythematosus
Brief Summary: Cognitive impairment occurs in as many as 80% of lupus patients and affective disorders, depression and anxiety, are also common. Both of these problems contribute significantly to disease burden and disability. Associations between serum anti-NMDAR Aab and cognitive and behavioral changes in human SLE have remained controversial, however, elevated titers of these Aabs in cerebrospinal fluid (CSF) correlate with severe central nervous system manifestations, such as coma and psychosis. The aim is to study the progression of disease (cognitive and behavioral impairment) over a 2 year period in SLE subjects with neuropsychologic and behavioral testing and correlates of disease progression using resting FDG-PET and serum Anti-NMDAR Aab. The correlations between hippocampal hypermetabolism, Anti-NMDAR Aab and memory impairment observed in the cross-sectional studies will be validated by baseline measurements in the proposed studies.
Detailed Summary:
Neuropsychiatric lupus is comprised of numerous, complex central and peripheral nervous system symptoms whose pathophysiologic mechanisms remain poorly understood. Cross-reactive anti-dsDNA antibodies have been shown to bind NR2A/NR2B subunits of the N-methyl D-aspartate receptor (NMDAR) on neurons and synergize with glutamate in a concentration dependent manner to either modulate receptor function or cause an excitotoxic, non-inflammatory neuronal death. Mice immunized to express anti-NMDAR Aab demonstrate a causal relationship between anti-NMDAR Aab and persistent behavioral and cognitive neuropathology following compromise to the blood brain barrier (BBB) which is necessary for Aab access to the brain.
The investigators' previous cross-sectional FDG-PET studies of resting brain glucose metabolism demonstrate robust hypermetabolism in the hippocampus of SLE subjects that associates independently with serum Anti-NMDAR Aab titer and impaired memory. Moreover, the combination of hippocampus hypermetabolism and elevated serum titers of Anti-NMDAR Aab has a higher predictive value for memory impairment than either variable alone. These significant correlations must be tested in a longitudinal study to evaluate the utility of FDG-PET as a biomarker for Anti-NMDAR Aab-mediated brain damage. The proposed longitudinal studies will inform the investigators about correlates of cognitive and behavioral change over time using FDG-PET imaging (Aim 1). Additionally, the investigators will explore NMDAR biology 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).
Sponsor: Northwell Health
Current Primary Outcome: Changes in brain activity [ Time Frame: hippocampal metabolism from baseline over the 2 years ]
Original Primary Outcome: Same as current
Current Secondary Outcome: Use of PET ligand CNS 5161 tracer as an assessment and imaging biomarker for regional brain dysfunction [ Time Frame: Specific activity of CNS5161, determined by the UV absorbance of the radioactive peak as compared with a standard curve of CNS5161 from baseline over the 2 years ]
Original Secondary Outcome: Same as current
Information By: Northwell Health
Dates:
Date Received: May 15, 2015
Date Started: January 2015
Date Completion: December 2018
Last Updated: January 17, 2017
Last Verified: January 2017
