The effect of memantine on cortical network function in frontotemporal lobar degeneration is conditional on baseline GABA physiology

Abstract

AbstractBackgroundFrontotemporal lobar degeneration (FTLD) is associated with deficits to GABA and glutamatergic neurotransmitters, particularly in the frontal cortex. While targeting GABAergic systems has shown to restore frontotemporal deficits in FTLD, little is known whether pharmacological probes of glutamatergic functioning have similar effects in these circuits.MethodTwenty participants with a FTLD‐associated syndrome (11 with PSP, 9 with bvFTD) and 20 healthy‐controls undertook two magnetoencephalography (MEG) sessions with a roving auditory oddball paradigm assessing frontotemporal change detection: (1) session on placebo and (2) after 10mg of oral memantine, which aims to blocks glutamatergic ecotoxicity. The mean amplitude of MEG “mismatch negativity” responses (MMN; standard‐deviants, 125‐175ms) was calculated across gradiometer sensors and for bilateral frontotemporal sources. Glutamate and GABA levels were measured using 7T proton magnetic resonance spectroscopy of the right inferior frontal gyrus (IFG). Frequentist and Bayesian ANOVAs assessed the differential mean MMN responses between controls and patients across placebo and drug conditions. Evoked difference waveforms (standard‐deviants) across the peristimulus time‐window were analysed using random field theory (RFT) (crit p=0.05, FWER) for the interaction effects of interest (i.e. drug session x group and drug x MRS levels).ResultPatients and controls did not demonstrate differential mean MMN amplitudes on placebo at the average‐sensor (p=0.95) or source‐level (p>0.27) (BF10=0.3‐0.5). Across sensors, only controls exhibited a differential drug‐dependent MMN, reflected by a steeper rebound of difference waveforms between 206‐288ms on memantine (Fig 1A; pFWER=0.026, cluster‐level). However, no interaction was found for mean MMNs (p>0.053). Notably, RFT (Fig 1B) and linear mixed models (Fig 1C) identified that greater GABA levels in patients are significantly associated with stronger MMN responses in right‐hemisphere areas under memantine. Glutamate levels did not moderate the mean MMN response to memantine (p>0.065).ConclusionOverall, we show that targeting glutamatergic systems may not lead to a restoration of frontotemporal physiology across patients. However, the effects of memantine are conditional on patient's baseline GABA, suggesting a critical balance between glutamatergic and GABA physiology that may underlie the large‐scale neural deficits in FTLD.