Resting Motor Threshold – Towards a TMS biomarker of Cognitive Decline in Alzheimer’s Disease

Abstract

The growing burden of dementia due to Alzheimer's Disease (AD) across the globe is currently one of the primary geriatric health concerns. The past decades have observed inspiring progress in understanding the fundamental neuropathological changes contributing to AD causation and progression. Several genetic, physiological & neuroimaging biomarkers have been identified for predicting the diagnosis, monitoring the prognosis and evaluating the treatments. The multifactorial nature of the disease necessitates markers that capture specific aspects of the brain pathology and serve different functions. The primary premise of this thesis is the proposal of a novel marker of cognitive decline in AD. Transcranial magnetic stimulation (TMS) is a technique employed for non-invasive measurement of the cortical excitability in humans. A specific contributor of the total cortical excitability is the excitability of the axonal membranes in the neuronal systems, which in the case of the motor cortex, can be measured by the TMS resting motor threshold (RMT). We present an evaluation of RMT as an independent neurophysiological marker of the cognitive decline in the AD, analyzed across multiple cohorts (group comparison cohort, multicentre disease cohort & group of past studies) in diverse experimental settings (research facilitation and clinical setting) by multiplex statistical strategies (extensive cross-sectional correlational analyses & meta-analyses). While the notion of cortical hyperexcitability in the AD is prevalent, one of the significant contributions of the thesis is an original biological rationale specific for the abnormal RMT in AD compared to healthy aging. The thesis further extends to test the effect size of the RMT abnormality in a broader quantitative synthesis of published studies.