Project 2: Assessing Brain Dysfunction in Clinically Quiescent SLE

Abstract – Project 2 The overall goals of Project 2 are to localize and quantify patterns of central nervous system (CNS) dysfunction in SLE patients in long-term clinical remission (SLE-R) and to identify a relevant imaging marker. This has important potential treatment implications as our preliminary data suggest that, despite clinical quiescence, some SLE-R have ongoing CNS dysfunction that may promote progressive cognitive decline and contribute to relapse. Our Specific Aims are: 1. to investigate regional brain metabolism using FDG PET, blood brain barrier permeability (BBBP) using dynamic contrast enhanced MRI (DCE MRI), neuropsychological (NP) performance and serum Quinolinic/Kynurenic acid ratio (Q/K; a marker of CNS pathology) in SLE-R, 2. to investigate microglial (MG) activation in SLE-R using [11C]-PBR28 PET, and 3. to identify and validate a SLE-R functional brain network using resting state functional MRI (rs-fMRI) and to evaluate associations between the SLE-R network and NP performance, Q/K ratios and risk of relapse. A subgroup of eligible subjects from Project 1, 60 SLE-R, 20 SLE with active disease (SLE-A) and 31 healthy controls (HC), will all have imaging studies, NP testing and serum Q/K evaluated at baseline. SLE-R subjects will have repeat evaluations after 18-24 months and/or at the time of clinical relapse. CNS subjects will be recruited at all sites, reflecting significant geographic, ethnic and racial diversity. The planned analyses will allow us to develop neurophenotypes, defined by imaging measures, Q/K ratio and NP performance, for SLE-R. We expect to identify a range of neurophenotypes among SLE-R; some SLE-R will resemble HC, others will resemble SLE-A and perhaps others will have a phenotype that correlates with relapse. In collaboration with the Biostatistics and Data Integration Core we will further explore the heterogeneity among SLE-R neurophenotypes and associations with the immune phenotypes identified in Project 1.