Altered Cortical Synaptic Plasticity in Response to 5-Hz Repetitive Transcranial Magnetic Stimulation as a New Electrophysiological Finding in Amnestic Mild Cognitive Impairment Converting to Alzheimer's Disease: Results from a 4-year Prospective Cohort Study

Alessandro Trebbastoni, Floriana Pichiorri, Fabrizia D'Antonio, Alessandra Campanelli, Emanuela Onesti, Marco Ceccanti, Carlo de Lena, Maurizio Inghilleri, Alessandro Trebbastoni, Floriana Pichiorri, Fabrizia D'Antonio, Alessandra Campanelli, Emanuela Onesti, Marco Ceccanti, Carlo de Lena, Maurizio Inghilleri

Abstract

Introduction: To investigate cortical excitability and synaptic plasticity in amnestic mild cognitive impairment (aMCI) using 5 Hz repetitive transcranial magnetic stimulation (5 Hz-rTMS) and to assess whether specific TMS parameters predict conversion time to Alzheimer's disease (AD).

Materials and methods: Forty aMCI patients (single- and multi-domain) and 20 healthy controls underwent, at baseline, a neuropsychological examination and 5 Hz-rTMS delivered in trains of 10 stimuli and 120% of resting motor threshold (rMT) intensity over the dominant motor area. The rMT and the ratio between amplitude of the 1st and the 10th motor-evoked potential elicited by the train (X/I-MEP ratio) were calculated as measures of cortical excitability and synaptic plasticity, respectively. Patients were followed up annually over a period of 48 months. Analysis of variance for repeated measures was used to compare TMS parameters in patients with those in controls. Spearman's correlation was performed by considering demographic variables, aMCI subtype, neuropsychological test scores, TMS parameters, and conversion time.

Results: Thirty-five aMCI subjects completed the study; 60% of these converted to AD. The baseline rMT and X/I-MEP ratio were significantly lower in patients than in controls (p = 0.04 and p = 0.01). Spearman's analysis showed that conversion time correlated with the rMT (0.40) and X/I-MEP ratio (0.51).

Discussion: aMCI patients displayed cortical hyperexcitability and altered synaptic plasticity to 5 Hz-rTMS when compared with healthy subjects. The extent of these changes correlated with conversion time. These alterations, which have previously been observed in AD, are thus present in the early stages of disease and may be considered as potential neurophysiological markers of conversion from aMCI to AD.

Keywords: Alzheimer’s disease; N-methyl-d-aspartate acid receptor; cortical excitability; mild cognitive impairment; synaptic plasticity; transcranial magnetic stimulation.

Figures

Figure 1
Figure 1
Study design. At the baseline (T0), all the participants enrolled underwent a neuropsychological evaluation (NPS), a physical examination (PE), blood samples (Lab), and 5 Hz-rTMS. The cohort of aMCI subjects then started the longitudinal observational period. At each time point, the patients were reassessed in order to determine whether they had converted to dementia. Subjects who fulfilled the diagnostic criteria for aMCI (non-converters) at each time point continued the study to the subsequent follow-up visit. Converters were instead excluded from the study.
Figure 2
Figure 2
Average motor-evoked potential (MEP) amplitude across trains of 5 Hz-rTMS in the two groups. Vertical bars denote 0.95 confidence intervals. Repeated measures ANOVA showed a significant interaction of factors “Number of Stimulus” (x-axis) and “Group” (healthy vs. aMCI). Bonferroni’s correction revealed that while there was no significant difference across stimuli in the MCI group, there was a significant increase in MEP amplitude in healthy controls from the seventh stimulus onward.
Figure 3
Figure 3
Scatter plots of resting motor threshold (rMT) (A), X/I-MEP ratio (B) and time of conversion to AD in the 21 converters. Spearman’s rank correlation index (rs) is shown for each variable.

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