Project: 2 Summary/Abstract Project 2 continues our focus on brain imaging studies in human SLE to investigate mechanisms of cognitive dysfunction in patients with this disorder. The proposed study leverages the information gained in the last funding cycle: the presence of consistent elevations in resting metabolic activity (a proxy for local synaptic function) in the hippocampus of SLE patients, which correlated with anti DNA receptor antibody (DNRAb) titers and with performance on cognitive test battery. In the next funding cycle, we plan to use multimodal PET and MRI imaging tools to determine the mechanistic basis for cognitive dysfunction in this disorder. New experimental evidence from Project 1 implicates microglial (MG) activation in the hippocampal neurotoxic response to DNRAb. We will therefore use [11C]-PBR28 PET to assess this phenomenon in SLE patients compared to healthy volunteer subjects. To this end, radiotracer uptake will be quantified in the hippocampus and other metabolically active SLE-related brain regions. Using a longitudinal design, we will evaluate regional MG activation over a two-year period, and determine how these changes relate to concurrent assessments of cognitive functioning, DNRAb titers, and resting metabolic activity measured in the same subjects. Likewise, we will use a quantitative MRI approach to evaluate BBB permeability in the hippocampus and in the other SLE-related brain regions. Changes in this measure will similarly be compared with concurrent serological and cognitive assessments, as well as with the other imaging descriptors of the underlying disease process. The broad applicability of this approach may be limited, however, by the invasiveness of some of the imaging methods. To make these assessments more clinically accessible, we will lastly explore the use of newer non- invasive imaging tools as alternative disease markers. In summary, the multimodal imaging approach in Project 2 will provide objective metrics for the assessment of new treatment strategies for SLE-CI.

Project: Narrative This is a study designed to understand the impact of a defined lupus antibody on cognitive function, brain imaging, and the integrity of the blood brain barrier.