Hartley, Sigan L PHD

The proposed supplement is relevant to the INCLUDE project, in which the parent grant focuses on adults with Down Syndrome (DS), specifically, associations between hearing status, auditory function, cognition, language and brain imaging through functional and structural approaches. This supplement aims to collect pilot data in children with DS, as there is a paucity of auditory studies in this population, with known incidence of hearing loss in infants and children with being much higher than in the general population. This supplement will provide pilot data in children with DS, establishing feasibility for a new parent R01 on auditory function and its association with cognition, language and brain structure and function in children with DS.

The Metabolic Health, Lifestyle, and Risk of Co-Occurring Health Conditions in Down Syndrome (MET-DS) study is a five-year, longitudinal deep-phenotyping study of factors driving the risk and severity of co-occurring conditions in children, adolescents, and young adults with Down syndrome, funded by the NIH INCLUDE Project (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE). The study involves a rigorous protocol for understanding the complex interplay between trisomy 21, metabolic dysregulation, obesity, lifestyle, and the development of co-occurring conditions across childhood, adolescence, and into young adulthood in people with Down syndrome. This effort will enroll 200 participants (ages 6-24 years of age) with Down syndrome from four clinical performance sites, and track conditions and variables across 3 data collection cycles.

Down syndrome (DS) is a leading known cause of intellectual disability and a highly recognized genetic syndrome that involves multiple medical co-morbidities; hearing deficits in DS are estimated to occur at a rate of 80-90% and are thought to be caused by a combination of structural and functional abnormalities in the external and/or inner ear. This project aims to tackle a timely and significant question regarding the role of hearing loss in DS on auditory function, cognition, language, and structural integrity of brain regions that are important for hearing, meeting the programmatic objectives of INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndrome. Results will provided information regarding clinical diagnosis and intervention to facilitate treatment of hearing disorders in individuals with DS, and more long-term impact will be identification of measures that may be used to evaluate effectiveness of pharmaceutical and therapeutic trials.

Adults with Down syndrome experience an early age of onset and increased risk for Alzheimer's disease. The proposed study addresses this public health crisis and advances science by providing the first longitudinal investigation of the effect of four lifestyle factors (physical activity, sleep, cognitive stimulation, and social engagement) on the age of onset of early Alzheimer's neurodegeneration and on the timing of the transition to clinical dementia in adults with Down syndrome. These lifestyle factors may be important modifiable resiliency mechanisms for delaying Alzheimer's disease in adults with Down syndrome despite their genetic risk.

Adults with Down syndrome are at high risk of developing Alzheimer’s disease. The parent R01 addresses this public health crisis by investigating the effect of modifiable aspects of lifestyle (physical activity, sleep, cognitive stimulation, and social engagement) on biomarkers of Alzheimer’s disease and cognitive decline in adults with Down syndrome. This supplement builds on this effort by increasing the sample size and diversity and employing new innovative mediational analyses and methods for non-invasive biomarkers of sleep and physical activity in everyday life.

The goal of this Administrative Supplement is to expand on the parent R01AG70028 “Lifestyle Risk and Resiliency Factors and Alzheimer’s Disease in Down syndrome” project by examining the effect of adverse childhood events (e.g., parent divorce, abuse/neglect, poverty) and recent life stressors (e.g., job termination, new staff, death of family member) on the timing of Alzheimer’s disease pathology and symptomology in people with Down syndrome. To accomplish this goal, the current project will include a new measure into the Lifestyle R01 protocol to capture adverse childhood experiences (ACEs); 2) use a new coding technique to capture stressful life events in adulthood; and 3) conduct new analyses to determine the association between stressful childhood and adult life experiences and Alzheimer’s disease imaging and biofluid biomarkers and cognitive performance measures. These analyses will investigate the direct effect of stressful life experiences on biomarkers of Alzheimer’s disease and cognitive impairments and the indirect effects through inflammation (e.g., plasma IL-6) and co-occurring health conditions (e.g., obesity, depression, cardiovascular disease, and disordered sleep).