This is a revised application to study cognitive function over time in subjects with Systemic Lupus Erythematosus (SLE) versus a matched group of normal healthy controls. Our prior work demonstrates that the persistent presence of antiphospholipid (aPL), and anti-nbosomal P (anti-P) antibodies are associated with cognitive dysfunction in SLE. Also, Hispanic (HA) ethnicity appears to be a separate risk factor for cognitive dysfunction. This finding is consistent with the more severe disease course overall that has been observed in African American (AA) and HA SLE patients in other studies. In this application we propose to enroll a total of 200 SLE subjects in 3 ethnic groups (HA, AA, and non-Hispanic White [n-HW]) and 200 matched controls from the University of Texas HSC at San Antonio (UTHSCSA), Johns Hopkins Medical Institutions (JHMI) and the Hospital for Special Surgery (HSS). We will test the following Hypotheses: 1a-cognitive functioning over time will be worse in SLE subjects compared to normal controls adjusting for non-SLE related co-morbid conditions associated with cognitive dysfunction (e.g. depression, hypertension, etc.);1b-cognitive function will be worse in both AA and HA SLE subjects compared with n-HW SLE subjects adjusting for age, education, SES, and co-morbid conditions associated with cognitive dysfunction in people with (disease duration, cumulative SLE-related damage, disease activity, medication use) and without SLE (depression, hypertension, etc.); 2a-persistently positive levels of several biomarkers in SLE subjects (aPL, anti-P and anti-glutamate receptor [anti-glutamate receptor [antiNR2] antibodies and matrix metalloproteinase-9 [MMP-9] and its tissue inhibitor [TIMP] will be independently associated with poorer cognitive function after adjusting for age, education, SES, and co-morbid conditions; 2b - cognitive dysfunction will be increased in SLE subjects with abnormal MMP-9/TIMP levels and persistently abnormal levels of some or all of the auto-antibodies. The JHMI Cohort contains equal numbers of AA and n-HW SLE subjects, and HSS has a mixture of HA, AA and n-HW SLE subjects, complementing the primarily HA population at UTHSCSA. Dr. Betty Diamond at The Trustees of Columbia University will collaborate on this project by performing the antibody assays for the anti-NR2 antibodies. A computerized neuropsychological battery (ANAM) will be the primary measure pf cognitive functioning. It is possible that combinations of biomarkers and co-morbidities are needed to lead to the clinical expression of cognitive dysfunction in SLE and that these factors are modified by ethnicity. The information that will be gained from this study is essential for the successful discovery of biological processes that impact on cognitive function in SLE that could be potentially amenable to disease-reversing therapies. ? ? ? ?
