Cholinergic Dysfunction and Gait Disturbance in Parkinson’s Disease
Cholinergic Dysfunction and Gait Disturbance in Parkinson’s Disease
Abstract & Commentary
By Alexander Shtilbans, MD, PhD, Assistant Professor of Neurology, Weill Cornell Medical College. Dr. Shtilbans reports no financial relationships relevant to this field of study.
Synopsis: Cholinergic system dysfunction, as measured by short latency afferent inhibition, might contribute to gait abnormality in early stages of Parkinson’s disease.
Source: Rochester L, et al. Cholinergic dysfunction contributes to gait disturbance in early Parkinson’s disease. Brain 2012;135:2779-2788.
Gait dysfunction usually occurs later in the course of Parkinson’s disease (PD) unless it affects a lower limb first. Postural instability and gait dysfunction, such as freezing of gait, rarely respond to dopaminergic therapies and can cause significant disability due to risk of falls. Cholinergic dysfunction is believed to contribute to the gait dysfunction, and these authors studied utility of short latency afferent inhibition (SAI) as a marker of such dysfunction in PD. SAI is a noninvasive tool that can evaluate inhibitory circuits in the sensorimotor cortex. The authors hypothesized that SAI could be an independent predictor of impaired gait in the early stage of PD.
Twenty-two patients with early PD (< 36 months) and 22 age-matched controls were recruited. All PD patients were on dopaminergic medications. Continuous gait was evaluated in both groups using a 7-meter instrumented walkway. Surface EMG and somatosensory-evoked potentials were recorded in all participants. Additionally, they underwent transcranial magnetic stimulation of motor cortex and SAI was calculated. Since SAI could not be measured in a presence of background EMG activity, the PD patients with significant tremor were excluded from the study. Results showed that SAI was significantly reduced in PD patients. However, only slower gait speed and shorter stride length were significantly correlated with reduced SAI in PD. Cognitive function was found to be more impaired in these patients as well. The authors concluded that cholinergic dysfunction makes an independent and significant contribution to gait dysfunction in patients with PD, which was observed early in the disease course. They also concluded that SAI could be used as a putative marker of cholinergic dysfunction. The authors also found that “attention” was an independent explanatory characteristic of gait speed in early PD, suggesting that gait dysfunction might be predominantly mediated through cognitive impairment. As a practical consequence of their study, the authors suggested that early treatment with cholinesterase inhibitors might delay the onset of falls in PD.
Commentary
Previous studies showed reduced SAI in patients with Alzheimer’s disease where cholinergic interneurons degenerate. The authors of this paper found reduced SAI in PD patients with gait dysfunction early in the disease course, suggesting that cholinergic dysfunction makes a contribution to gait dysfunction early on. This is an important study that highlights the role of cholinergic dysfunction in the pathophysiology of gait disturbance in PD, and shows a way that such dysfunction can be measured. There are several limitations of this study, however. Patient selection is biased due to exclusion of the tremor-predominant phenotype of the disease. Moreover, the presence of gait dysfunction early in the disease, and lack of tremor and cognitive dysfunction observed in the study group, could be indicative of atypical parkinsonism such as progressive supranuclear palsy, multiple system atrophy, or corticobasal degeneration, yet the PD diagnoses were only clinical and no functional imaging tests were performed to ensure that only idiopathic PD patients were enrolled. A previous study of SAI in PD by Sailer et al demonstrated that only patients taking dopaminergic medications had reduced SAI and those off the medications did not.1 All of the PD patients in Rochester’s study were on dopaminergic medications, which the authors recognized as a limitation. It is unknown if SAI would be changed in similarly medicated controls. Furthermore, the authors evaluated continuous gait to capture steady-state locomotion and avoid acceleration and deceleration. This minimized the occurrences of “freezing of gait,” which was not evaluated but is prevalent in PD and represents a gait dysfunction. The authors concluded that cholinergic dysfunction makes a contribution to gait dysfunction in PD, yet it could be a correlation, not a cause. Furthermore, the authors recommend early treatment with cholinesterase inhibitors to prevent falls, even though there are no large randomized, placebo-controlled trials demonstrating any evidence of delay or reduction in falls in PD patients taking cholinesterase inhibitors. A larger study of SAI in various phenotypes of idiopathic PD patients, on and off dopaminergic medications, will be needed to confirm the above findings. Also, a large randomized trial is warranted to evaluate the role of cholinesterase inhibitors in fall prevention in PD.
Reference
1. Sailer A, et al. Short and long latency afferent inhibition in Parkinson’s disease. Brain 2003;126(Pt 8):1883-1894.
Cholinergic system dysfunction, as measured by short latency afferent inhibition, might contribute to gait abnormality in early stages of Parkinsons disease.Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.