The present study showed that rivastigmine improved gait velocity under dual-task conditions in subjects with mild to moderate AD. Conversely, rivastigmine did not improve gait velocity, cadence, and stride length under single-task conditions. Rivastigmine also significantly improved the MMSE score, but not those of FAST, GDS, and ADCS-ADL. The AChE activity of all subjects was decreased.
AChEIs stabilize cognitive function and delay functional decrease . Although it is not definitely clear by which mechanism AChEIs have this effect, it is recognized that they improve not only cognitive function but also motor function. Acetylcholine has an important role in cognitive function and in controlling gait and balance . AChEIs are thought to contribute to the initiation and maintenance of gait by improving executive function and attention and the control of step length and gait velocity. A limited number of studies have shown that ChEIs improved gait performance in patients with AD. Donepezil significantly improved gait velocity in subjects with mild AD under single- and dual-task conditions measured using an electronic walkway . Galantamine improved dual-task stride time in a small number of patients with moderate AD . In the present study, rivastigmine significantly improved gait velocity under dual-task conditions in 21 subjects with mild to moderate AD.
Cognitive enhancers could improve gait by a number of mechanisms. Cognitive function and neural control of gait share brain cortical networks and neurotransmitters . The neurotransmitter acetylcholine has an important role in cognitive function and in controlling gait and balance . Specifically, thalamic activity derives mainly from the brainstem pedunculopontine nucleus, which plays a central role in the generation of movement, gait, and balance control . Cholinergic forebrain projections from the nucleus basalis of Meynert also have a specific role in the control of selective attention, which is an important factor in the cost of dual-tasking while walking in subjects with AD. ChEIs stabilize and improve attention and executive function in patients with AD and other neurodegenerative disorders . There may be cognitive- and non-cognitive-related enhancement mechanisms by which ChEIs improve gait and potentially improve gait performance. In our study, rivastigmine increased gait velocity in the dual-task trials, but not in the single-task trials. The principle dual-task paradigm involving gait is the creation of an attention-demanding task . A decline in gait performance while performing a dual task when compared to a single task is usually interpreted as interference due to competing demands for attention between both tasks . Thus, gait performance while dual tasking appears to be more dependent on cortical cholinergic levels than while performing a single task , suggesting that cognitive enhancement may have affected the increase of gait velocity in our subjects rather than non-cognitive enhancement.
Some limitations of this study need to be considered. Firstly, the small number of participants from one clinic may be unrepresentative of the general population of patients with AD. Second, we used a single open-label design with no randomization and no placebo group. Third, although we were able to control for changes of gait and treatment, residual confounders might still be present. Four, there is a possibility of a learning effect due to the repetition of the MMSE, which may have affected the results of this test.
Two participants suffered a fracture. The contribution of rivastigmine to fracture cannot be ruled out completely, but we believe that any direct effect is small as both fractures occurred by accidental collision. Furthermore, both participants have not suffered from refracture, even though they continued to use rivastigmine during hospitalization for fracture treatment, and have continued to use rivastigmine for 2 years after the study ended.
In conclusion, rivastigmine improved gait performance, especially gait velocity, in patients with mild to moderate AD. The improvements were modest, but might be clinically meaningful. This efficacy study provides feasibility data and a meaningful size effect to pursue a large prospective, double blind clinical trial testing the effectiveness of rivastigmine on gait in patients with AD.