Older FMR1 premutation carriers may develop
fragile X-associated tremor/ataxia syndrome (
FXTAS), a
neurodegenerative disorder manifesting cognitive deficits that often subsequently progress to
dementia. To date, there is no specific treatment available for
FXTAS. Studies have demonstrated the premutation-associated overactivation of glutamatergic receptors in neurons.
Memantine, a
NMDA receptor antagonist approved for treatment of
Alzheimer's disease, thus was tested in the first placebo-controlled, double-blind, randomized clinical trial in
FXTAS. Prior event-related brain potential (ERP) studies in
FXTAS found reduced N400 repetition effect, a
glutamate-related electrophysiological marker of semantic priming, and verbal memory processes. This substudy of the randomized clinical trial of
memantine in
FXTAS sought to use the N400 repetition effect to evaluate effects of chronic
memantine treatment on verbal memory. Subsequent recall and recognition memory tests for the experimental stimuli were administered to characterize verbal memory. Data from 41 patients who completed the 1-year
memantine trial (21 on
memantine) and also completed longitudinal ERP studies were analyzed. Results showed treatment-associated benefits on both cued-recall memory and N400 repetition effect amplitude. Importantly, improvement in cued recall was positively correlated with amplitude increase of the N400 repetition effect. The placebo group, in contrast, displayed a significant reduction of the N400 repetition effect after 1 year. These results suggest that
memantine treatment may have beneficial effects on verbal memory in
FXTAS. Additional studies of
memantine, perhaps in combination with other therapeutic agents, appear warranted, as symptomatic treatments and neuroprotective treatments are both needed for this recently recognized
neurodegenerative disorder.