Motor cortical excitability and paired-associative stimulation-induced plasticity in amnestic mild cognitive impairment and Alzheimer's disease.

Objective: Synaptopathy including alterations of synaptic plasticity (long-term potentiation, LTP) may precede neurodegeneration in Alzheimer's disease (AD). We studied LTP-like corticospinal plasticity induced by paired-associative stimulation (PAS) in AD and its prodromal stage, amnestic mild cognitive impairment (aMCI).

Methods: 15 AD and 15 aMCI patients, and 23 demographically matched healthy controls (HC) were included. Resting motor threshold (RMT) and stimulus intensity needed to evoke motor evoked potentials (MEP) of 1 mV (SI1mV) were obtained as single-pulse transcranial magnetic stimulation (TMS) measures of corticospinal excitability in a hand muscle at baseline, followed by PAS using standard methodology. MEP amplitude change after PAS normalized to baseline was defined as plasticity effect. All measures were repeated in two visits for examining test-retest reliability.

Results: SI1mV were lower in aMCI compared to HC, while there was no difference between AD and HC. RMT and SI1mV showed excellent test-retest reliability in all groups. PAS indiscriminately did not induce LTP-like plasticity in any of the groups, and expressed poor test-retest reliability.

Conclusions: aMCI shows corticospinal hyperexcitability, consistent with glutamatergic excitotoxicity in early-stage AD. Possible abnormalities of LTP-like plasticity could not be reliably tested with the standard PAS protocol due to massive inter-subject variability even in HC, and poor test-retest reliability.

Significance: Findings indicate corticospinal hyperexcitability in prodromal AD, and reliability of single-pulse TMS measures for identifying such abnormality. In contrast, the standard PAS protocol may not be suitable for assessing LTP-like motor cortical plasticity, given its overall nil effect and poor test-retest reliability.