Project Summary Knee osteoarthritis (OA) is a common disorder among the elderly population. Recent studies with large sample sizes found that knee OA was associated with a significantly increased risk for dementia. Nevertheless, the reason why knee OA is associated with increased dementia risk remains unknown. Recent evidence suggested that dysfunction of the locus coeruleus-noradrenergic system and neuroinflammation mediate both chronic pain and cognition/memory; therefore, these factors may play a significant role in the accelerated cognitive decline in individuals with knee OA. Taking advantage of the recently funded NCCIH/NIH project (R01AT012173-01A1) on brain mechanisms of mind-body and neuromodulation treatment of knee OA, this ancillary application aims to expand our research on mechanisms underlying accelerated cognitive decline in people with knee OA. Specifically, with the support of new funding, we will 1) add a cohort of pain-free individuals with mild cognitive impairment (MCI) and a cohort of pain-free controls who do not have MCI (25 in each group); 2) collect blood samples to assess inflammation markers; and 3) add cognitive measurements to assess the cognitive function of the knee OA patients and new cohorts of participants. With newly collected data, we will 1) investigate the functional and structural changes in the brain associated with the locus coeruleus-noradrenergic system in MCI (individuals with MCI vs. controls) and knee OA (individuals with knee OA vs. pain-free controls) and identify the common functional and structural changes associated with MCI and knee OA; 2) investigate the inflammation markers associated with MCI and knee OA; and 3) explore the association between inflammation markers, brain function and structure, and cognitive function as well as the modulation effect of alternative treatments on the above measurements. Relevance to Alzheimer’s disease and/or its Related Dementia and