Alzheimer's Imaging Consortium

Alzheimer's disease (AD) is linked to abnormal cortical excitability. Recent studies have suggested that amyloid-related cortical hyperexcitability may drive faster clinical decline and be related to spreading of tau. However, we lack non-invasive methods to quickly and directly assay cortical excitability in AD patients. We generate an Input-Output response curve (I/O Curve) using transcranial magnetic stimulation (TMS) with electromyography (EMG) to investigate mechanisms of cortical excitability in AD.

Participants included 52 biomarker-positive early AD (CDR=0.5-1, age 70±8, 37% female) and 51 cognitively normal older adults (CN; age 70±6.5, 53% female). Single-pulse TMS was applied to left motor cortex to measure resting motor threshold (RMT). An I/O Curve was generated by delivering 10 pulses each at eight stimulation intensities (30-100% maximum stimulator output (%MSO)). We recorded motor-evoked potentials (MEP) from the right first dorsal interosseous muscle. RMTs were compared between AD and CN using a linear model controlling for scalp-to-cortex distance (SCD) and protocol (i.e., EEG cap). For the I/O curve, stimulation intensity was normalized to RMT (%MSO/RMT) and binned in 15% increments. MEP amplitudes along the I/O Curve were analyzed using a linear mixed effects model with effects of Group, %MSO/RMT, and Group*%MSO/RMT; covariates of age, sex, education, and APOE4 alleles; and participant-level random effects. Contrasts were conducted comparing the groups at each point along the I/O curve.

RMT was lower in AD than in CN (η² p =0.12, medium effect size, p = 0.004, Figure 1); SCD was a significant covariate (p = 0.006). The I/O Curve revealed an increased response in the AD group, with significant effects of Group (η² p =0.10, medium effect size; p = 0.007), %MSO/RMT (η² p =0.71, p <0.001), and Group*%MSO/RMT (η² p =0.05, small effect size, p = 0.013). Covariates were not significant. Increased excitability in AD was greatest at higher stimulation intensities (120-135%MSO/RMT: Cohen's d=0.286, small effect size, p = 0.015; 135-150%MSO/RMT: Cohen's d=0.495, medium effect size, p <0.001, Figure 2).

TMS-EMG confirms evidence of increased cortical excitability in AD. This was evident at lower intensities with the RMT model (implicating voltage-gated Na+ channels) and higher intensities with the I/O Curve (implicating AMPA receptors). TMS may be useful to measure target engagement of novel therapies targeting cortical excitability in AD.