ABSTRACT Cognitive dysfunction (CD) is a common neuropsychiatric manifestation of childhood-onset systemic lupus erythematosus (cSLE) that remains poorly diagnosed and undertreated. CD and other neuropsychiatric symptoms of cSLE can negatively impact school function, self-management, and psychosocial health, as well as lifelong health-related quality of life and occupational opportunity during adulthood. While prior studies in patients with cSLE point to the association of CD with volumetric reductions of gray and white matter, the functional neurobiological aberrancies underlying CD and their relationship to negative health-related behaviors remain largely understudied. Furthermore, in a heightened inflammatory state, the homeostasis of the CNS is likely compromised, implicating neuroimmune systems such as the choroid plexus, which serve as blood- cerebral spinal fluid or immunological barriers. Disruptions localized to the choroid plexus may initiate a range of outcomes, including neuroinflammation, alterations in gray and white matter structural properties, or neuropsychiatric manifestations including CD. The goal of this R21 is to characterize the biobehavioral basis of CD in cSLE by cross-sectional interrogation of (i) prefrontal and parietal cortices with fNIRS and fMRI, (ii) microstructural white matter properties using diffusion tensor imaging (DTI), (iii) volumetric properties of the choroid plexus using high-resolution structural MRI, (iv) neurometabolite (e.g., choline (Cho) and myo-inositol (mIns)) concentrations using single-voxel MRS, (iv) cognitive function using the Pediatric Automated Neuropsychological Assessment Metrics (PedANAM) and supplementary cognitive tests (e.g., Digit span task)40, 41, and (v) psychiatric symptom (brief psychiatric rating scale [BPRS]42) and disease (SLE Disease Activity Index- 2K [SLEDAI-2K]43) severities. We will prospectively enroll 20 cSLE patients (12-18 years old, male or female) and 20 age-sex matched healthy controls (HCs). To better understand the role of comorbid mood symptoms in cSLE, we will also enroll 20 children with depressive or anxiety disorders. We will leverage existing structural MRI datasets (30 cSLE patients + 30 matched HCs). Our hypothesis is that CD in cSLE is underpinned by a combination of dysfunction of the prefrontal cortex, altered white matter microstructure, and compromised choroid plexus barrier function marked by morphological change. Understanding the biological basis and behavioral outcomes of CD can improve recognition of neuropsychiatric cSLE and realign therapeutic strategies with neurobiological phenotypes. We propose the following Specific Aims: Aim 1: Investigate functional CNS properties associated with CD in cSLE. Aim 2: Determine the associations among white matter microstructure with severity of CD in cSLE. Aim 3: Quantify the choroid plexus volume in cSLE and its relationship with CD, glial activity, and disease activity. To carry out this work, we assemb...