| Title: |
Alzheimer’s disease and memantine effects on NMDA-receptor blockade: non-invasive in vivo insights from magnetoencephalography |
| Authors: |
Lanskey, JH; Jafarian, A; Hughes, LE; Karadag, M; Kocagoncu, E; Rouse, MA; Adams, NE; Naessens, M; Raymont, V; Woolrich, M; Singh, KD; Henson, RN; Rowe, JB |
| Publisher Information: |
Springer Nature [academic journals on nature.com] |
| Publication Year: |
2025 |
| Collection: |
Oxford University Research Archive (ORA) |
| Description: |
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 |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1038/s41380-025-03288-3 |
| Availability: |
https://doi.org/10.1038/s41380-025-03288-3; https://ora.ox.ac.uk/objects/uuid:b92e1bef-80ea-4570-bdb5-bbda54fde1d4 |
| Rights: |
info:eu-repo/semantics/openAccess ; CC Attribution (CC BY) |
| Accession Number: |
edsbas.5E585CD1 |
| Database: |
BASE |