This is an application for a K08-Alzheimer's Disease Clinical Scientist Development Award, entitled "FMRI and Pathology of Anterior Cingulate and Frontoinsular Cortex in FTLD and AD." The primary goal of the proposed research is to use novel functional imaging and pathological techniques to probe a neural circuit rooted in anterior cingulate (ACC), anterior insular (Al), and orbital frontoinsular (Fl) regions known to be selectively vulnerable in frontotemporal dementia (FTD) compared with Alzheimer's Disease (AD). Degenerative dementias target specific, functionally-linked neuronal networks. AD begins in medial temporal areas, producing memory dysfunction, while FTD involves the ACC, Al, and Fl, leading to disordered social conduct. The forces that determine these contrasting anatomic patterns remain unknown. The specific aims of the proposed research are (1) To assess resting state fMRI connectivity within the ACCAI- FI network in FTD, AD, and healthy age-matched controls, (2) To explore connectivity of the ACC-AI-FI network to peripheral autonomic markers in FTD and AD, and (3) To determine the relative susceptibility of a recently evolved cellular population-the spindle neurons-within the ACC and Fl in FTD, AD, and nonneurological controls at autopsy. The overarching hypotheses of this research are that FTD patients alone will have diminished, aberrant ACC-AI-FI network connectivity that is uncoupled from autonomic responses, and that FTD patients will exhibit greater absolute and relative spindle neuron losses than those seen in AD. As part of the proposed research, the applicant seeks training in (1) fMRI, including functional connectivity techniques, (2) basic autonomic physiology recording, (3) neuropathology, including methods for quantifying loss of neuronal subtypes within specific brain regions, (4) clinical care of dementia, (5) manuscript preparation and grant writing and (6) the responsible conduct of research. The proposed research plan, didactic courses, and tutorial instruction from mentors and advisors will promote the applicant's development into an independent investigator in the neuroscience of dementia. Degenerative dementias cause immeasurable human suffering and impose a growing strain on health care resources. The proposed research seeks to benefit the public health by clarifying the biological basis of dementia, ultimately promoting earlier diagnosis and better treatments for dementia patients.