Increased glutamate in the hippocampus after galantamine treatment for Alzheimer disease

Galantamine is a cholinesterase inhibitor and allosteric potentiating ligand modulating presynaptic nicotinic acetylcholine receptors that is used in the treatment of Alzheimer disease (AD). The purpose of this study was to determine if galantamine treatment would result in detectable hippocampal metabolite changes that correlated with changes in cognition, as measured by the Mini-Mental State Examination (MMSE) and the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog). Short echo-time proton magnetic resonance (MR) spectra were acquired from within the right hippocampus of ten patients using a 4 Tesla magnetic resonance imaging (MRI) scanner. Spectra were used to quantify absolute metabolite levels for N-acetylaspartate (NAA), glutamate (Glu), choline (Cho), creatine (Cr), and myo-inositol (mI). Patient scans and cognitive tests were performed before and 4 months after beginning galantamine treatment, which consisted of an 8 mg daily dose for the first month and a 16 mg daily dose for the remaining three months. The levels of Glu, Glu/Cr, and Glu/NAA increased after four months of treatment, while there were no changes in MMSE or ADAS-cog scores. Additionally, changes (Δ) in Glu over the four months (ΔGlu) correlated with ΔNAA, and Δ(Glu/Cr) correlated with ΔMMSE scores. Increased Glu and the ratio of Glu to Cr measured by MR spectroscopy after galantamine treatment were associated with increased cognitive performance. The increase in Glu may be related to the action of galantamine as an allosteric potentiating ligand for presynaptic nicotinic acetylcholine receptors, which increases glutamatergic neurotransmission.