Relationships between sulcal morphology, neuropathology, and cognition in aging and Alzheimer's disease

Project Summary Large-scale changes in brain structure occur in aging and Alzheimer's Disease (AD) that demonstrate sulcal vulnerability to age-related atrophy and AD-related amyloid-β (Aβ) deposition. Recent work has shown that the morphology of tertiary sulci (the shallowest and latest-developing cortical indentations) is associated with

individual differences in cognitive development and symptoms of various disorders, but these sulci have not been investigated in aging or AD. This project will investigate individual differences in gyrification in multiple brain regions in cognitively normal older adults and adults with AD, and will combine positron emission

tomography (PET) and MRI imaging methods in investigating relationships between tertiary sulci, pathology, and metabolism. All sulci in medial parietal cortex (MPC) and lateral prefrontal cortex (LPFC) will be manually labeled on individual structural MRI scans of younger adults, cognitively normal older adults, and older adults

with AD. Morphological metrics (such as sulcal cortical thickness) will be extracted from these labels in order to investigate their relationship to cognitive decline, AD pathology (Aβ and tau, measured with PET), and glucose metabolism (measured with PET). Aim 1 will investigate changes in sulcal morphology in MPC and LPFC in

aging and AD. Aim 2 will identify how these changes in tertiary sulci relate to cognitive impairment and AD pathology. Aim 3 will determine whether sulcal morphology relates to metabolism in early adulthood and subsequent Aβ deposition in aging, as a putative explanation of how these sulci confer vulnerability to

pathology and neurodegeneration. Overall, this study will investigate whether tertiary sulci can serve as structural markers of early degenerative and pathological changes relating to cognitive decline and AD. This project will provide training in (1) multimodal neuroimaging acquisition and analysis techniques, (2) statistics

and data analysis methods, (3) pathophysiology of AD, (4) scientific communication, (5) teaching and mentorship skills, and (6) career development. The UC Berkeley Helen Wills Neuroscience Institute is an ideal environment for this research, ensuring access to cutting-edge PET and MRI neuroimaging facilities as well as

world-class neuroimaging, biostatistics, and cognitive neuroscience experts to support the project and training goals. Ongoing collaboration with the UCSF Memory and Aging Center will provide additional training in AD pathophysiology and research. The project’s co-sponsors are exceptionally suited to support its successful

completion: Dr. William Jagust is an expert in PET imaging and in applying multimodal neuroimaging techniques to understand underlying mechanisms of aging and AD, and Dr. Kevin Weiner is an expert in tertiary sulci and in linking individual differences in neuroanatomy to cognition. The proposed research and

training plans will provide the applicant with the skills and support necessary to ensure successful completion of the project and a strong foundation to pursue a competitive post-doctoral fellowship and research career investigating factors underlying cognitive decline in aging and dementia.