Acetylcholinesterase inhibitors and gait: a steadying hand?
Authors: Caroline Moreau, David Devos, Luc Defebvre
Journal: The Lancet Neurology (2016)

Cognitive impairment, complex movement disorders, and high risk of falls are all inter-related, 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 deficits other than the loss of nigrostriatal dopaminergic neurons, especially deficits 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.1Bohnen NI Albin RL The cholinergic system and Parkinson disease.Behav Brain Res. 2011; 221: 564-573Crossref PubMed Scopus (371) Google Scholar Although the pathological importance of this degeneration was first 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 quantified until the 1980s (with depletion of up to 80%).2Liu AKL Chang RCC Pearce RKB Gentleman SM Nucleus basalis of Meynert revisited: anatomy, history and differential involvement in Alzheimer's and Parkinson's disease.Acta Neuropathol. 2015; 129: 527-540Crossref PubMed Scopus (186) Google Scholar However, cholinergic denervation also occurs in patients with Parkinson's disease without dementia. Therefore, although it might make specific contributions to the clinical phenotype of Parkinson's disease dementia, the effect of denervation seems diverse, for instance, central limbic cholinergic denervation might be associated with the progressive impairment of odour identification.1Bohnen NI Albin RL The cholinergic system and Parkinson disease.Behav Brain Res. 2011; 221: 564-573Crossref PubMed Scopus (371) Google Scholar 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.1Bohnen NI Albin RL The cholinergic system and Parkinson disease.Behav Brain Res. 2011; 221: 564-573Crossref PubMed Scopus (371) Google Scholar 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.3Takakusaki K Tomita N Yano M Substrates for normal gait and pathophysiology of gait disturbances with respect to the basal ganglia dysfunction.J Neurol. 2008; 255: 19-29Crossref PubMed Scopus (116) Google Scholar, 4Karachi C Grabli D Bernard FA et al.Cholinergic mesencephalic neurons are involved in gait and postural disorders in Parkinson disease.J Clin Invest. 2010; 120: 2745-2754Crossref PubMed Scopus (322) Google Scholar Trials of PPN-directed deep-brain stimulation in human beings have mostly targeted freezing of gait, and have yielded inconsistent results. 5Ferraye MU Debû B Fraix V et al.Effects of pedunculopontine nucleus area stimulation on gait disorders in Parkinson's disease.Brain. 2010; 133: 205-214Crossref PubMed Scopus (370) Google Scholar 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 deficit 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.6Bohnen NI Müller MLTM Koeppe RA et al.History of falls in Parkinson disease is associated with reduced cholinergic activity.Neurology. 2009; 73: 1670-1676Crossref PubMed Scopus (292) Google Scholar In The Lancet Neurology, Emily Henderson and colleagues7Henderson EJ Lord SR Brodie MA et al.Rivastigmine for gait stability in patients with Parkinson's disease (ReSPonD): a randomised, double-blind, placebo-controlled, phase 2 trial.Lancet Neurol. 2016; (published online Jan 12.)http://dx.doi.org/10.1016/S1474-4422(15)00389-0PubMed Google Scholar report findings from the randomised ReSPonD trial, which studied the effects of 32 weeks of high-dose rivastigmine versus placebo in 130 patients with Parkinson's disease without dementia. Patients had a high fall rate (median five falls) in the year before inclusion and so were a population at risk of future falls. Patients assigned to rivastigmine showed better gait stability at 32 weeks than did those assigned to placebo. Rivastigmine was associated with a 28% (95% CI 11–42; p=0·002) greater reduction in adjusted step time variability (used to measure gait instability8Hausdorff JM Cudkowicz ME Firtion R Wei JY Goldberger AL Gait variability and basal ganglia disorders: stride-to-stride variations of gait cycle timing in Parkinson's disease and Huntington's disease.Mov Disord. 1998; 13: 428-437Crossref PubMed Scopus (697) Google Scholar) during an 18 m walking task compared with placebo. However, step time variability in a simple dual task (walking while listing words beginning with the same letter) was only somewhat improved (21% [1–38]; p=0·045), and there was no significant difference between groups in the high-level cognitive dual task (walking while listing words beginning with alternating letters; 19% [–9 to 40]; p=0·17). The rivastigmine group had significantly fewer falls than did the placebo group over the trial period (falls per month 1·4 [SD 2·47] vs 2·4 [4·40], respectively). However, the drug did not have significant effects on episodes of freezing of gait or assessed neuropsychological outcomes (ie, fear of falling, anxiety, and depression). Research from Giladi and colleagues has emphasised the rationale for assessment of cholinergic drugs in patients with Parkinson's disease with high-level gait disorders.9Gurevich T Balash Y Merims D et al.Effect of rivastigmine on mobility of patients with higher-level gait disorder: a pilot exploratory study.Drugs R D. 2014; 14: 57-62Crossref PubMed Scopus (6) Google Scholar However, in their open-label pilot study 5 mg per day of rivastigmine did not significantly reduce gait rhythm disorders, despite improved general mobility and lower anxiety being reported by patients. Thus, high-dose rivastigmine seems to have a specific effect on postural instability. These results have been long awaited, since there are no available pharmacological treatments for poor postural stability in Parkinson's disease. A high number of adverse events were reported by both groups in the ReSPonD.7Henderson EJ Lord SR Brodie MA et al.Rivastigmine for gait stability in patients with Parkinson's disease (ReSPonD): a randomised, double-blind, placebo-controlled, phase 2 trial.Lancet Neurol. 2016; (published online Jan 12.)http://dx.doi.org/10.1016/S1474-4422(15)00389-0PubMed Google Scholar Although gastrointestinal disorders were probably causally related to rivastigmine, many of the adverse events could have been due to the high level of comorbidities in the study population. Importantly, cardiac adverse events were not more frequent in the rivastigmine than in the placebo group and the groups did not differ significantly in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score after 32 weeks. Notably, no worsening of resting tremor was noted despite rivastigmine possibly leading to an imbalance within the striatum between lower dopaminergic and higher cholinergic neurotransmission, which is associated with resting tremor. Some questions are yet to be resolved. In particular, did rivastigmine have different effects on static postural stability (assessed by the retropulsion test, item 3.12 of the MDS-UPDRS) versus dynamic postural stability (stride-to-stride variability during gait)? Although Henderson and colleagues assessed mood with the Geriatric Depression Scale, it would have been useful to investigate apathy because an earlier double-blind, placebo-controlled study of patients with Parkinson's disease with pre-dementia apathy showed that rivastigmine treatment was associated with a lower overall apathy score and caregiver burden and greater intellectual curiosity and action initiation.10Devos D Moreau C Maltête D et al.Rivastigmine in apathetic but dementia and depression-free patients with Parkinson's disease: a double-blind, placebo-controlled, randomised clinical trial.J Neurol Neurosurg Psychiatry. 2014; 85: 668-674Crossref PubMed Scopus (106) Google Scholar Overall, the findings of the ReSPonD trial provide valuable arguments in favour of high-dose rivastigmine treatment in patients with high-level gait disorders. These findings must now be confirmated in a larger cohort of patients with a range of cognitive and behavioural profiles, and taking into account the dose effect, and the long-term risk–benefit balance. CM has serves on the Scientific Advisory Board for AbbVie, Aguettant, ApoPharma, and Orkyn and has received research funding from France Parkinson and honoraria from Abbvie and Aguettant for consultancy and lectures. LD has served on the Scientific Advisory Board for Abbvie, Aguettant, and Novartis. DD has served on the Scientific Advisory Board for AbbVie, Aguettant, ApoPharma, Novartis, and Orkyn, and has received projet hospitalier de recherche clinique (PHRC) grants from the French Ministry of Health, research funding from the France Parkinson charity, and honoraria from AbbVie, Aguettant, ApoPharma, and Orkyn for consultancy and lectures. Rivastigmine for gait stability in patients with Parkinson's disease (ReSPonD): a randomised, double-blind, placebo-controlled, phase 2 trialRivastigmine can improve gait stability and might reduce the frequency of falls. A phase 3 study is needed to confirm these findings and show cost-effectiveness of rivastigmine treatment. Full-Text PDF Open Access