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 _LTP ) 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 _LTP using standard methodology. MEP amplitude change after PAS _LTP 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 _LTP 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 _LTP 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 _LTP protocol may not be suitable for assessing LTP-like motor cortical plasticity, given its overall nil effect and poor test-retest reliability.
Competing Interests: Declaration of Competing Interest A.M. D.D, P.S., C.L., O.P. and C.Z. report no conflicts of interest. U.Z. has received a grant from Janssen Pharmaceutica NV to support conduction of this work. In addition, he has received grants from European Research Council (ERC), German Research Foundation (DFG), German Federal Ministry of Education and Research (BMBF), Bristol Myers Squibb, Servier, Biogen Idec GmbH, and personal fees from Bayer Vital GmbH, Pfizer GmbH, CorTec GmbH, all not related to this work. I.L.-S. has received grants from Janssen Pharmaceutica NV, Michael J Fox Foundation, National Center of Excellence in Research, Luxembourg National Research Fund, European Commission Horizon 2020, International Parkinson Fonds GmbH IPO, all outside the submitted work. D.B. has received grants from Janssen Pharmaceutica NV, German Parkinson’s Disease Association (dPV), BMWi, BMBF, Parkinson Fonds Deutschland gGmbH, UCB Pharma GmbH, EU, Novartis Pharma GmbH, Lundbeck, Damp foundation, and personal fees from Biogen, BIAL, Lundbeck, UCB Pharma GmbH, AbbVie, Biogen, BIAL, Lundbeck, UCB Pharma GmbH Zambon, Desitin, GE, all not related to this work. G.S., K.T., and M.T. are employees of Janssen Research & Development, LLC or Janssen Research and Development, a division of Janssen Pharmaceutica NV, and hold stock/stock options in the company (Johnson & Johnson). G.S., K.T., and M.T. have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in the subject matter or materials discussed in the manuscript apart from those disclosed.
(Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)