Understanding the structural, functional, and prognostic implications of cortical excitability in Alzheimer's disease

PROJECT SUMMARY/ABSTRACT
Recent therapeutic drug trials in Alzheimer’s disease (AD) have failed to improve cognitive outcomes
despite improvements on imaging-based targets (e.g., amyloid PET). One possible missing link is a failure to
restore normal neuronal function. Measures of cortical excitability using transcranial magnetic stimulation with
electroencephalography (TMS-EEG) have the potential to fill this gap by measuring the neuronal response to
controlled perturbation. However, practical applications of TMS-EEG measures are currently limited by a
dearth of data from brain regions involved in early-stage AD pathophysiology, and a lack of understanding of
how cortical excitability is related to clinically useful metrics. The long-term goal of this project is to determine
the extent to which cortical excitability is an important prognostic marker and/or treatment target in AD. This
study assesses excitability in both motor cortex—a well-characterized TMS site—and parietal cortex—a brain
involved in the early stages of AD pathogenesis. The objective of the present proposal is to understand how
parietal cortical excitability is related to neuroimaging abnormalities and prognosis in a cohort of early-stage
symptomatic AD participants (early AD). The hypothesis is that increased cortical excitability in parietal cortex
is related to neurodegeneration, decreased network connectivity, and more rapid clinical decline. This will be
tested with three independent Aims to assess how cortical excitability is related to 1) local cortical thickness, 2)
resting state fMRI connectivity; and 3) disease progression. The proposed project is highly innovative, using
TMS-EEG measures to capture local cortical excitability in AD, integrating neuroimaging and neurophysiologic
measurements, and testing the extent to which cortical excitability predicts meaningful clinical outcomes. This
contribution will be significant because it will inform our understanding of how measures of synaptic function
are related to progression of AD pathology. Findings from this study will lay the groundwork for future clinical
trials in AD seeking to measure restoration of neuronal function using novel biomarkers.
The candidate has a strong commitment to a clinical research career in Alzheimer’s disease and
related dementias. She is a practicing cognitive neurologist at Beth Israel Deaconess Medical Center and
Instructor in Neurology at Harvard Medical School. Her training plan and research project are specifically
designed to build her expertise in AD biomarkers, advanced neuroimaging techniques, and biostatistics for AD
clinical trials. Her mentorship team, led by Dr. Daniel Press and Dr. Michael Fox, will provide critical guidance
on the integration of TMS measures with neuroimaging. Additional mentorship will be provided by Dr. Mouhsin
Shafi on TMS-EEG, Dr. Reisa Sperling on AD biomarkers, and Dr. Long Ngo on biostatistics. Completion of
this five-year career development plan will allow the candidate to launch a career as an independent
investigator using novel neurophysiologic tools to advance prognosis and treatment of AD.

Grant Number: 5K23AG068364-05
NIH Institute/Center: NIH
Principal Investigator: Stephanie Buss