Falls are a common and devastating complication of Parkinson’s disease (PD). Whilst tremor, akinesia and rigidity are early motor manifestations, postural instability tends to emerge as the disease progresses. Postural instability, coupled with gait dysfunction, is a major determinant of disability [1
] with mobility and walking limitation cited by patients as the worst aspect of the disease [2
]. Falls are a cause of significant morbidity. The consequences include fractures and injuries [3
], fear of falling [4
], nursing home and hospital admission [5
] carer strain [6
] and increased mortality [7
]. Gait impairment, postural instability and falls are common complications of PD and may have a greater impact on quality of life than motor complications and dyskinesia [8
]. There is currently a lack of pharmacological options of proven efficacy for addressing falls, postural instability, freezing of gait and festination in this high risk population.
The burden of disease complications will inevitably increase as the number of people with Parkinson’s disease in the most populous nations is expected to double from 2005 to 2030 [9
]. A meta-analysis of prospective studies exploring falls in people with Parkinson’s disease demonstrated that 46% of individuals fall at least once over a period of three months [10
]. Twenty years from diagnosis, 87% of people with Parkinson’s disease in the Sydney cohort had fallen with 35% sustaining a fracture [11
]. The peak risk of falls corresponds with Hoehn and Yahr stage three [12
] where people are still mobile but have reduced stability.
Despite increasing recognition of the non-motor features of the disease, the mainstay of pharmacological therapy remains dopaminergic medications. However, disorders of gait and balance in PD are not generally ameliorated by typical dopaminergic medication. During the maintenance and early complications phase of the disease, gait disturbances and end of dose freezing, typically respond to dopaminergic agents. As the condition progresses with associated motor complications, response to treatment becomes less predictable and freezing may develop in the “on” stage [13
]. As Parkinson’s disease advances, “off” freezing becomes unpredictable despite optimisation of medical therapy and levodopa-induced dyskinesias and ‘on’ freezing further contribute to the risk of an individual falling.
Characterisation of the cholinergic neurochemical deficit that is thought to underlie gait disorders and postural instability has aided the search for potential therapeutic targets. The predominantly cholinergic pedunculopontine nucleus (PPN) provides input into the basal ganglia and cortex and undergoes degeneration in PD. The extent of degeneration is correlated with the degree of gait dysfunction [14
]. Cortical and thalamic cholinergic loss, representing projections from the nucleus basalis of Meynert (nbM) and the PPN respectively, is significantly greater in people with PD and a history of falls compared to both those without falls and non-PD controls [15
]. Similarly, the degree of cholinergic neuronal loss is negatively correlated with the Hoehn and Yahr score, which is driven by the progressive emergence of axial impairment [16
Outside of a potential role in gait dysfunction, cholinergic loss manifests as an alteration in attention and cognition [17
]. Furthermore mild cognitive impairment (MCI) is highly prevalent in people with PD and increases with age, duration and severity of PD and affects a range of cognitive domains [18
]. The nbM is the main source of cholinergic projections to the cerebral cortex and degenerates in PD [19
]. Greater cholinergic neuronal loss in the nbM is seen in people with Parkinson’s disease dementia (PDD) than in PD [20
], and neuroimaging evidence of this cholinergic dysfunction is present early in the disease course [21
The observed deficit in cholinergic function in Parkinson’s disease thus accounts, at least to some degree, for the dysfunction seen in both cognitive and gait domains. Historically, gait has been regarded as demanding little or no cognitive resources. The dual-task technique provides a means to examine the extent to which different activities demand attentional capacity, i.e. draw on common central processing resources. In dual-task experiments, a decrement in performance occurring when two tasks are performed simultaneously (relative to baseline performance on each single task) indicates that both tasks demand attention [22
Dual-task paradigms have revealed important insights into the relationship between gait and cognition. Dual-task conditions augment gait impairments seen during normal walking in PD such as reduction in gait speed, stride length and increased stride-to-stride variability [23
]. Furthermore, in PD, a ‘posture second’ strategy seems to be adopted whereby individuals are unable to appropriately prioritise the safety of their walking above other cognitive demands [24
Despite evidence that cholinergic loss may influence both gait and cognitive changes, few have studied the effect of cholinergic augmentation on gait, balance and falls. A small trial of six individuals with Alzheimer’s disease (AD) versus eight controls with MCI examined the effect of a 4 month period of treatment with the acetylcholineseterase inhibitor donepezil. This demonstrated that both gait velocity and variability improved under single and dual-task conditions at follow-up [25
]. Two further studies showed an improvement in stride time [26
] and a reduction in falls with treatment [25
]. A further RCT is currently underway examining these effects on a larger cohort of individuals with MCI [28
]. In Parkinson’s disease, a small cross over trial of donepezil showed a reduction in fall rate, though this was driven primarily by reductions in only those with a history of very frequent falls [27
The aim of this randomised controlled trial is to examine the effect of cholinesterase inhibitor therapy on gait and balance and fall risk in people with Parkinson’s disease with a history of one or more falls in the past year.