Tuesday, January 14, 2025
1/14/2025
ABSTRACT/ SUMMARY This R01 study will apply neurocognitive, brain, and plasma biomarkers to quantify prodromal signs of dementia in autistic adults ages 40-65. Autism spectrum disorder (ASD) is a lifelong condition that continuously demands precision diagnosis, targeted treatment, and high-quality care. Emerging clinical and epidemiological studies suggest that autistic adults are more vulnerable to developing early-onset dementia than the general population as they age. Robust pilot data from our group show accelerated verbal memory and executive function deterioration in middle-aged autistic adults. Our free-water diffusion MRI (FWdMRI) data show FW accumulations in the hippocampal and frontotemporal areas relevant to these behavioral deficits in ASD. Our amyloid PET scans highlight early amyloid load in Phase 1 (i.e., neocortices) Thal regions and elevated amyloid burden in Phase 2 (e.g., entorhinal cortex, hippocampus, and amygdala) Thal regions in autistic adults, accompanied with cortical thinning and volume reductions of these affected areas. Our preliminary plasma biomarkers also show significant increases in amyloid β42 (Aβ42), Aβ40, total Tau, and neurofilament light chain (NfL) in autistic adults relative to controls. Despite promising findings from our lab and others, studies focused on neurodegenerative comorbidities in ASD are scant. We are still far from a systematic understanding of dementia onset, manifestation, and progression in ASD. To address this critical scientific gap, we plan to acquire cross-sectional data to quantify established neurocognitive, brain, and plasma biomarkers of dementia in autistic adults and compare these markers with age- and sex-matched cognitively normal controls. Forty-five autistic adults and 45 controls ages 40-65 will be recruited. Aim 1 will quantify verbal memory retention and executive function impairments in ASD. Aim 2 will quantify dementia-related brain degenerations in autistic adults using T1 weighted MRI, FWdMRI, and amyloid PET. Regions of interest will focus on the hippocampus, hippocampal input and output tracts, and frontotemporal areas. Aim 3 will focus on quantifying plasma Amyloid/Tau/Neurodegeneration (A/T/N) biomarkers in autistic adults, including Aβ40, Aβ42, Aβ42/Aβ40 ratio, phosphorylated Tau (pTau), NfL, and glial fibrillary acidic protein (GFAP). The relationships among cognitive (Aim1), brain (Aim2), and plasma (Aim 3) biomarkers will be explored to achieve a multi-dimensional evaluation of dementia pathophysiology in ASD. This work holds significant promise to develop a foundational understanding of the pathophysiological mechanisms underlying dementia in ASD across outcome measures at multiple levels.
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