Characterizing the Neurophysiological Correlates of Age-Related Cognitive Decline with Corticomotor Transcranial Magnetic Stimulation

Abstract

The field of Alzheimer's Disease and Related Dementia (ADRD) is currently in a state of flux, with a push to disarticulate the pathobiological and clinico-behavioral facets of the disease. Concurrently, the same tailwinds propelling this reconceptualization have provoked increased attention on the preclinical stages of the disease continuum. These changes are, in part, driven by necessity. Repeated clinical failures underscore that 1) care must be taken to disambiguate the relatively imprecise clinical phenotype of amnestic dementia by focusing on more specific pathobiological entities, and 2) the manifestation of clinico-behavioral impairment represents the late stages of the ADRD continuum that are likely medically refractory conditions necessitating earlier intervention. As the field continues to shift focus toward the nascent, preclinical stages of the disease, there is an urgent unmet need to better characterize risk profiles for cognitive deterioration. Beyond the hallmark proteinopathies of AD, complementary neurophysiological features of cortical excitability and neural plasticity may add depth and precision to forecasting an individual's clinical trajectory along this continuum. Corticomotor Transcranial Magnetic Stimulation (TMS) may have utility in this regard as a tool capable of generating an array of relevant proxy measures in this domain. The following dissertation explores this potential utility by characterizing TMS-derived neurophysiological correlates of cognitive aging. Chapter 1 provides in-depth discussions introducing the capabilities of corticomotor TMS and describing the current landscape of ADRD research. Chapter 2 details the first cross-sectional study I completed in this area of investigation, where we generated novel findings suggestive of diminished homeostatic metaplasticity in this population of interest. Chapter 3 entails a systematic review and meta-analysis I co-authored, where we quantitively assessed the extant literature reporting on corticomotor TMS proxy measures in Mild Cognitive Impairment and AD. Chapter 4 details the final study in this series of works, where we took lessons learned from the preceding meta-analysis and attempted to fill in the gaps that we identified in the literature. In Chapter 5, I tie these works together in a discussion that also addresses limitations and looks ahead to future directions.