PROJECT SUMMARY/ABSTRACT Although conceptualized as a neurodevelopmental disorder with present research primarily focused on infants and children, autism spectrum disorder (ASD) has increasingly been recognized as a lifelong condition with the potential to have a detrimental impact on adult functioning and quality of life. Based on clinical observations that mid-to-older aged adults with ASD may be particularly susceptible to neurodegenerative diseases during aging, the proposed studies will test the central hypothesis that the cerebellum and basal ganglia are selectively disrupted in adults with ASD aged 40 to 60 years. And, this disruption is associated with neuromotor impairments and clinical signs of movement disorders. Free-water diffusion magnetic resonance imaging (FWdMRI) will be applied to quantify neuronal degeneration of the cerebellar lobules, dentate, and basal ganglia nuclei and axonal integrity of cerebellar peduncles to determine whether these subcortical targets are disrupted in adults with ASD relative to age-, sex-, and IQ-matched controls. Functional MRI (fMRI) of precision grip will be used to quantify abnormal activations of cortico-subcortical brain targets and whether these alterations underpin grip force production-related impairments in ASD. Using neuromotor tests sensitive in detecting alterations of the cerebellum and basal ganglia, we will clarify the extent to which performance of Romberg stances, quick step initiation, sit-to-stance balance, and goal-directed finger-pointing is compromised in adults with ASD. Guided by strong preliminary data, we will pursue three specific aims: Aim 1) Determine structural alterations in the cerebellum and basal ganglia in adults with ASD using FWdMRI. Aim 2) Determine functional deficits in the cerebellum and basal ganglia in adults with ASD using motor fMRI. Aim 3) Determine neuromotor impairments in adults with ASD. Our group is uniquely qualified to undertake this critical R01 project as it includes investigators with expertise and experience in sensorimotor neurophysiology in ASD, ASD diagnosis, aging and movement disorders, MRI physics and research, and biostatistics. This proposal is scientifically innovative as it will be the first to systematically quantify aging-related neuromotor issues in ASD at the levels of brain, behavioral, and clinical domains. This project is significant as it holds the promise to identify putative non-invasive traits of subcortical brain targets contributing to aging in ASD. If successful, this work will identify new brain and biobehavioral targets that can be tracked to understand, monitor, and treat aging-related conditions in ASD.