Lanskey, Juliette H., Jafarian, Amirhossein, Hughes, Laura E., Karadag, Melek, Kocagoncu, Ece, Rouse, Matthew A., Adams, Natalie E., Naessens, Michelle, Raymont, Vanessa, Woolrich, Mark, Singh, Krish D.  ORCID: https://orcid.org/0000-0002-3094-2475, Henson, Richard N. and Rowe, James B.
2025.
Alzheimer’s disease and memantine effects on NMDA-receptor blockade: non-invasive in vivo insights from magnetoencephalography.
Molecular Psychiatry
10.1038/s41380-025-03288-3
|
Preview |
PDF
- Published Version
Available under License Creative Commons Attribution. Download (1MB) | Preview |
Abstract
To accelerate new treatments for Alzheimer’s disease, there is the need for human pathophysiological biomarkers that are sensitive to treatment and disease mechanisms. In this proof-of-concept study, we assess new biophysical models of non-invasive human MEG imaging to test the pharmacological and disease modulation of NMDA-receptor inhibition. Magnetoencephalography was recorded during an auditory mismatch negativity paradigm from (1) neurologically-healthy people on memantine or placebo (n = 19, placebo-controlled crossover design); (2) people with Alzheimer’s disease at baseline and 16-months (n = 42, amyloid-biomarker positive, longitudinal observational design). Optimised dynamic causal models inferred voltage-dependent NMDA-receptor blockade using Parametric Empirical Bayes to test group effects. The mismatch negativity amplitude was attenuated when Alzheimer’s disease was more severe (lower baseline mini-mental state examination) and after follow-up (versus baseline). Memantine increased NMDA-receptor inhibition, compared to placebo. Alzheimer’s disease reduced NMDA-receptor inhibition in proportion to severity and over time. In line with preclinical studies, we confirm in humans that memantine and Alzheimer’s disease have opposing effects on NMDA-receptor inhibition. The ability to infer such receptor dynamics and pharmacology from non-invasive physiological recordings has wide applications, including the assessment of other neurological disorders and novel drugs intended for symptomatic or disease-modifying treatments.
| Item Type: | Article |
|---|---|
| Date Type: | Published Online |
| Status: | In Press |
| Schools: | Schools > Psychology Research Institutes & Centres > Cardiff University Brain Research Imaging Centre (CUBRIC) |
| Publisher: | Springer Nature [academic journals on nature.com] |
| ISSN: | 1359-4184 |
| Date of First Compliant Deposit: | 20 October 2025 |
| Date of Acceptance: | 23 September 2025 |
| Last Modified: | 21 Oct 2025 08:30 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/181755 |
Actions (repository staff only)
 |
Edit Item |
Altmetric
Altmetric