Study of Memantine for Gait Disorders And Attention Deficit In Parkinson's Disease
Status:
Completed
Trial end date:
2010-10-01
Target enrollment:
Participant gender:
Summary
Along with cognitive and psychobehavioural disorders, gait disorders represent a major
problem in the treatment of advanced Parkinson's disease (PD). PD can be considered to be a
hyperglutamatergic disease because dopaminergic depletion induces hyperactivity of the
subthalamic nucleus (STN) and the internal pallidum (GPi), with glutamatergic hyperactivity
of the STN's efferent pathway, i.e., the subthalamopallidal, subthalamonigral and
subthalamo-entopeduncular pathways (projecting to the pedunculopontine nucleus (PPN)). Excess
glutamate in the PPN has also been observed in the 6-OHDA rat model of PD. Reduction of this
glutamatergic hyperactivity within the PPN via the systemic or intra-peduncular
administration of glutamate antagonists improves akinesia in drug-induced murine and primate
models of PD, via the NMDA and AMPA receptors. High doses of memantine (10 mg/kg) improve
locomotion in reserpine- and alpha-methyl-p-tyrosine-treated rats. In humans, the PPN may
play a key role in gait, posture control, axial rigidity and attention. It is also involved
in the gating of sensory information involved in the startle reflex, which can be studied via
prepulse inhibition (PPI) of the blink reflex. At present, two uncompetitive NMDA receptor
antagonists are approved for use in humans: amantadine and memantine. Reviews of the recent
literature on these drugs have identified no published studies specifically on severe gait
and attention disorders in PD. Memantine is a partial blocker of open NMDA channels. The
value of memantine relates to the fact that it decreases excessive glutamatergic transmission
by lowering the synaptic noise due to excessive activation of NMDA receptors. In this
double-blind study, the investigators shall seek to demonstrate the presence or absence of an
effect of memantine on gait and attention disorders. In order to study the interaction
between glutamatergic hyperactivity and the dopaminergic system, the investigators shall
study the phenomena both in the absence of L-dopa and following acute administration of the
latter. Twenty eight volunteer, non-demented, late-stage PD patients displaying severe gait
disorders will receive memantine (20 mg/day) or placebo for 3 months. The investigators
expect to see a reduction in gait and attention disorders, together with an improvement in
the blink reflex with PPI under memantine. This pilot study could subsequently be turned into
a double-blind, placebo-controlled multicenter study.