. There is a fundamental gap in understanding the mechanisms underlying the development of pediatric neuropsychiatric systemic lupus erythematosus (pNPSLE), especially pertaining to neurocognitive dysfunction (NCD), and no effective screening tools to help diagnose NCD in children with pediatric SLE (pSLE) are available. This is an important problem because NCD is common among children with pSLE, often resulting in a pervasive decline in attention, visuoconstructional ability and working memory. The long-term goal of our research is to improve the prognosis of children with pSLE through better evidence-based treatments. The objectives of this application are to make an easy-to-use screening tool for NCD available for use in routine clinic settings and to employ advanced imaging techniques to heighten our understanding in how pSLE affects the central nervous system and causes NCD. The central hypotheses to be tested are that pSLE is associated with impaired cognitive growth as reflected by changes in the grey matter functioning detected by functional magnetic resonance imaging (fMRI), alterations of white brain matter tracts seen with Diffusion Tensor Imaging (DTI), and confirmed by formal neuropsychological testing. Additionally, we hypothesize that the Pediatric Automated Neuropsychological Assessment Metrics (Ped-ANAM) has superior measurement properties for the early detection of pSLE-associated NCD over other available self-administered questionnaires of behavior, cognition and executive functioning. Guided by strong preliminary data, these hypotheses will be tested by pursuing the following specific aims: 1) Validate the Ped-ANAM as a measure of cognitive function in pSLE using formal neuropsychological testing as the criterion standard 2) Assess the effects of pSLE on cognitive development during childhood based on formal neuropsychological testing and the Ped-ANAM 3a) Use fMRI to identify grey matter elements of cognitive networks involved in attention, visuoconstructional ability &working memory that are most affected by pSLE;and 3b) Use DTI to estimate white matter changes involved in attention, visuoconstructional ability &working memory that are most affected by pSLE. Forty pSLE subjects and 40 matched 'best-friend'controls will be studied for 1.5 years using the Ped-ANAM and other validated neuropsychological tests. Advanced imaging will be done (fMRI, DTI) with focus on the two most commonly affected neurocognitive domains afflicted by pSLE. The proposed research is innovative, because there are no effective screening tools for pSLE-associated NCD that can be used by clinicians or researchers, and mechanisms leading to NCD and the specific effects of pSLE on the developing brain remain elusive. The expected results are that we will identify grey matter neuronal circuitries and white matter tracts that are associated with pSLE-associated NCD and that the prospective validation of the Ped-ANAM will yield a readily usable screening tool for pSLE-associated NCD. Relevance to Public Health: This is an important and underinvestigated field of investigation as pNPSLE worsens patient morbidity and mortality and decreases patient quality of life. Better diagnostic tests and knowledge about the pathoetiology of NCD is the basis for the future development of targeted therapies for children with pSLE and can likely also be used for adults with SLE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Comprehensive Center (P60)
Project #
5P60AR047784-10
Application #
8382398
Study Section
Special Emphasis Panel (ZAR1-CHW-G)
Project Start
2012-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
10
Fiscal Year
2012
Total Cost
$246,583
Indirect Cost
$62,775
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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Jones, J T; DiFrancesco, M; Zaal, A I et al. (2015) Childhood-onset lupus with clinical neurocognitive dysfunction shows lower streamline density and pairwise connectivity on diffusion tensor imaging. Lupus 24:1081-6
Vega-Fernandez, Patricia; Zelko, Frank A; Klein-Gitelman, Marisa et al. (2014) Value of questionnaire-based screening as a proxy for neurocognitive testing in childhood-onset systemic lupus erythematosus. Arthritis Care Res (Hoboken) 66:943-8
Wallace, Carol A; Giannini, Edward H; Spalding, Steven J et al. (2014) Clinically inactive disease in a cohort of children with new-onset polyarticular juvenile idiopathic arthritis treated with early aggressive therapy: time to achievement, total duration, and predictors. J Rheumatol 41:1163-70
Seid, Michael; Huang, Bin; Niehaus, Stacey et al. (2014) Determinants of health-related quality of life in children newly diagnosed with juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 66:263-9
Gitelman, Darren R; Klein-Gitelman, Marisa S; Ying, Jun et al. (2013) Brain morphometric changes associated with childhood-onset systemic lupus erythematosus and neurocognitive deficit. Arthritis Rheum 65:2190-200
Bennett, Michael; Brunner, Hermine I (2013) Biomarkers and updates on pediatrics lupus nephritis. Rheum Dis Clin North Am 39:833-53
Brunner, Hermine I; Klein-Gitelman, Marisa S; Zelko, Frank et al. (2013) Validation of the Pediatric Automated Neuropsychological Assessment Metrics in childhood-onset systemic lupus erythematosus. Arthritis Care Res (Hoboken) 65:372-81
Ting, Tracy V; Kudalkar, Deepa; Nelson, Shannen et al. (2012) Usefulness of cellular text messaging for improving adherence among adolescents and young adults with systemic lupus erythematosus. J Rheumatol 39:174-9
Seid, Michael (2012) Predictors of health-related quality of life in children and adolescents with juvenile idiopathic arthritis. Arthritis Care Res (Hoboken) 64:652

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