Bohnen et al.1 correlated slowing of gait with cortical cholinergic denervation, rather than nigral dopaminergic denervation, in patients with Parkinson disease (PD). This solidifies the current opinion that PD is the result of more than an isolated dopamine deficit. There was also no correlation with pedunculopontine nucleus (PPN)–thalamic denervation. The benefit of PPN-targeted deep brain stimulation on gait in PD is unclear.2 The authors suggested that enhancement of cortical cholinergic function might improve gait disorders in patients with PD. There are scarce but promising data to support this suggestion.
A small open-label study of 9 patients with Alzheimer disease (AD) on galantamine for 6 months showed no improvement when patients only walked, yet it showed improvement when they walked and counted out loud.3 This confirms that the effect of denervation of the cholinergic system on gait might be through impairment of the attention and cognition (cortical), rather than the direct locomotion (PPN), network. However, these results could not be replicated in a smaller open-label study of 6 patients with AD treated with donepezil and 8 untreated patients with mild cognitive impairment serving as controls.4 Larger, randomized studies are needed.
Author Response
We agree with Dr. Mehanna that the clinical effects of acetylcholinesterase inhibitor drugs (AChEIs) are modest at best. Several factors may explain the limited effectiveness of AChEIs. First, our previous in vivo imaging studies have shown that in up to 60% of subjects with Alzheimer disease, AChEI-induced cerebral acetylcholinesterase inhibition may be too low to induce a relevant effect.5 Furthermore, when AChEIs elevate levels of acetylcholine in the brain, high synaptic and extrasynaptic acetylcholine levels may generate unwelcome effects, including inhibition of presynaptic cholinergic signaling by stimulation of presynaptic muscarinic type 2 receptors and nonphysiologic, tonic stimulation of postsynaptic nicotinic and muscarinic receptors.6 Despite these limitations, mobility benefits of AChEIs have been reported in PD.7
Preliminary data in animal studies suggest that drugs that selectively stimulate α4β2(*) nicotinic receptors not only have excellent entry into the brain but also may improve mobility functions in rats with dual dopaminergic and cholinergic lesions.8 Such selective agonists are superior to the nonselective nicotine mother drug because nicotine interferes with the phasic cholinergic activity that is essential for cognitive function.9 Further investigation of this class of drugs to treat mobility problems in PD is necessary.
- © 2014 American Academy of Neurology
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