Quantitative Assessment of Cortical Excitability in Alzheimer’s Dementia and Its Association with Clinical Symptoms: A Systematic Review and Meta-Analyses

Article type: Research Article

Authors: Joseph, Shaylyn^{a; b} | Patterson, Rachel^{a; b} | Wang, Wei^a | Blumberger, Daniel M.^{a; b} | Rajji, Tarek K.^{a; b; c} | Kumar, Sanjeev^{a; b; *}

Affiliations: [a] Centre for Addiction and Mental Health, Toronto, Canada | [b] University of Toronto, Toronto, Canada | [c] Toronto Dementia Research Alliance, Toronto, Canada

Correspondence: [*] Correspondence to: Sanjeev Kumar, # 6324, 80 Workman Way, Toronto, Ontario M6J1H4, Canada. Tel.: +1 416 535 8501/Ext: 39384; E-mail: Sanjeev.Kumar@camh.ca.

Abstract: Background:Alzheimer’s disease (AD) is characterized by cognitive and neuropsychiatric symptoms (NPS) due to underlying neurodegenerative pathology. Some studies using electroencephalography (EEG) have shown increased epileptiform and epileptic activity in AD. Objective:This review and meta-analyses aims to synthesize the existing evidence for quantitative abnormalities of cortical excitability in AD and their relationship with clinical symptoms. Methods:We systematically searched and reviewed publications that quantitatively assessed cortical excitability, using transcranial magnetic stimulation (TMS) resting motor threshold (rMT), active motor threshold (aMT), motor evoked potential (MEP) or directly from the cortex using TMS-EEG via TMS-evoked potential (TEP). We meta-analyzed studies that assessed rMT and aMT using random effects model. Results:We identified 895 publications out of which 37 were included in the qualitative review and 30 studies using rMT or aMT were included in the meta-analyses. The AD group had reduced rMT (Hedges’ g = –0.99, 95% CI [–1.29, –0.68], p < 0.00001) and aMT (Hedges’ g = –0.87, 95% CI [–1.50, –0.24], p < 0.00001) as compared with control groups, indicative of higher cortical excitability. Qualitative review found some evidence of increased MEP amplitude, whereas findings related to TEP were inconsistent. There was some evidence supporting an inverse association between cortical excitability and global cognition. No publications reported on the relationship between cortical excitability and NPS. Conclusion:There is strong evidence of increased motor cortex excitability in AD and some evidence of an inverse association between excitability and cognition. Future studies should assess cortical excitability from non-motor areas using TMS-EEG and examine its relationship with cognition and NPS.

Keywords: Alzheimer’s disease, cognition, cortical excitability, electrophysiology, neuropsychiatric symptoms, transcranial magnetic stimulation

DOI: 10.3233/JAD-210311

Journal: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 867-891, 2022