Acetylcholinesterase inhibitors and gait: a steadying hand?

Cognitive impairment, complex movement disorders, and high risk of falls are all interrelated , levodopa-unresponsive symptoms in patients with advanced Parkinson's disease. Although Parkinson's disease is conventionally viewed as a motor syndrome that results from nigrostriatal dopaminergic denervation, there is also an intricate interplay between multisystem degeneration and neurotransmitter defi cits other than the loss of nigrostriatal dopaminergic neurons, especially defi cits in the cholinergic system. The degeneration of neurons in the nucleus basalis of Meynert (the source of cholinergic innervation of the cerebral cortex) is a hallmark of late-stage parkinsonian dementia and is at least as severe as that involved in Alzheimer's disease. 1 Although the pathological importance of this degeneration was fi rst recognised by Lewy in his report on a series of patients with Parkinson's disease, neuron loss in the nucleus basalis of Meynert was not quantifi ed until the 1980s (with depletion of up to 80%). 2 However, cholinergic denervation also occurs in patients with Parkinson's disease without dementia. Therefore, although it might make specifi c contributions to the clinical phenotype of Parkinson's disease dementia, the eff ect of denervation seems diverse, for instance, central limbic cholinergic denervation might be associated with the progressive impairment of odour identifi cation. 1 Recent evidence also indicates that subcortical cholinergic denervation (probably caused by degeneration of brainstem pedunculopontine nucleus [PPN] neurons) might be associated with dopamine-refractory gait and balance impairments (including falls) in Parkinson's disease. 1 Indeed, the role of cholinergic neurons within the mesencephalic locomotor area (including the PPN and the cuneiform nucleus) in gait has been emphasised by a range of studies in healthy people and preclinical studies of lesioned cats and primates. 3,4 Trials of PPN-directed deep-brain stimulation in human beings have mostly targeted freezing of gait, and have yielded inconsistent results. 5 In animal models, cholinergic–striatal disruption of attentional–motor pathways in the basal forebrain is a major cause of falls. Additional losses of cholinergic neurons in the PPN can worsen posture and gait control. Thus the correlations between the various patterns of cholinergic denervation and clinical phenotypes in Parkinson's disease remain to be studied. The association between cortical and subcortico-mesencephalic cholinergic defi cit in patients with Parkinson's disease without dementia with high-level gait disorders (such as freezing of gait), postural instability, falls, coupled with dysexecutive syndrome, and apathy warrant further research. 6 In The Lancet Neurology, Emily Henderson and colleagues 7 report fi ndings from …