Cholinergic dysfunction contributes to gait disturbance in early Parkinson's disease
ABSTRACT Gait disturbance is an early feature in Parkinson's disease. Its pathophysiology is poorly understood; however, cholinergic dysfunction may be a non-dopaminergic contributor to gait. Short-latency afferent inhibition is a surrogate measure of cholinergic activity, allowing the contribution of cholinergic dysfunction to gait to be evaluated. We hypothesized that short-latency afferent inhibition would be an independent predictor of gait dysfunction in early Parkinson's disease. Twenty-two participants with Parkinson's disease and 22 age-matched control subjects took part in the study. Gait was measured objectively using an instrumented walkway (GAITRite), and subjects were asked to walk at their preferred speed for 2 min around a 25-m circuit. Spatiotemporal characteristics (speed, stride length, stride time and step width) and gait dynamics (variability described as the within subject standard deviation of: speed, stride time, stride length and step width) were determined. Short-latency afferent inhibition was measured by conditioning motor evoked potentials, elicited by transcranial magnetic stimulation of the motor cortex, with electrical stimuli delivered to the contralateral median nerve at intervals ranging from N20 (predetermined) to N20 + 4 ms. Short-latency afferent inhibition was determined as the percentage difference between test and conditioned response for all intervals and was described as the group mean. Participants were optimally medicated at the time of testing. Participants with Parkinson's disease had significantly reduced gait speed (P = 0.002), stride length (P = 0.008) and stride time standard deviation (P = 0.001). Short-latency afferent inhibition was also significantly reduced in participants with Parkinson's disease (P = 0.004). In participants with Parkinson's disease, but not control subjects, significant associations were found between gait speed, short-latency afferent inhibition, age and postural instability and gait disorder score (Movement Disorders Society Unified Parkinson's Disease Rating Scale) and attention, whereas global cognition and depression were marginally significant. No other gait variables were associated with short-latency afferent inhibition. A multiple hierarchical regression model explored the contribution of short-latency afferent inhibition to gait speed, controlling for age, posture and gait symptoms (Postural Instability and Gait Disorder score-Movement Disorders Society Unified Parkinson's Disease Rating Scale), attention and depression. Regression analysis in participants with Parkinson's disease showed that reduced short-latency afferent inhibition was an independent predictor of slower gait speed, explaining 37% of variability. The final model explained 72% of variability in gait speed with only short-latency afferent inhibition and attention emerging as independent determinants. The results suggest that cholinergic dysfunction may be an important and early contributor to gait dysfunction in Parkinson's disease. The findings also point to the contribution of non-motor mechanisms to gait dysfunction. Our study provides new insights into underlying mechanisms of non-dopaminergic gait dysfunction, and may help to direct future therapeutic approaches.
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ABSTRACT: The current study evaluated the effects of disease severity on the control of obstacle crossing in people with idiopathic Parkinson's disease (PD). Forty-five subjects participated in the study, including 15 patients with mild PD (classified as stage 1 to 1.5 of the Hoehn and Yahr Rating Scale), 15 patients with moderate PD (classified as stage 2 to 3 of the Hoehn and Yahr Rating Scale), and 15 neurologically healthy individuals. Groups were matched by sex, age, body mass, and body height. The obstacle crossing task required participants to walk along a pathway and step over an obstacle (half of the knee height, positioned in the middle of the pathway). Patients were tested in a typically medicated state. Kinematic data were recorded using an optoelectronic tridimensional system. The outcome measures included spatiotemporal measures of obstacle avoidance. There were no significant differences between patients with mild PD and healthy individuals. Patients with moderate PD exhibited shorter distances for leading toe clearance and leading foot placement after the obstacle than did healthy individuals. Patients with moderate PD tended to exhibit a lower leading horizontal mean velocity during obstacle crossing than did healthy individuals. We found significant negative relationships between obstacle crossing measures and disease severity (score on the motor section of the Unified Parkinson's Disease Rating Scale). These findings suggest that disease severity affects locomotor behavior during obstacle crossing in PD. Specifically, obstacle avoidance was not affected in the early stages of PD; however, bradykinesia and hypometria influenced obstacle crossing in patients with moderate PD.Gait & posture 05/2014; 40(1). DOI:10.1016/j.gaitpost.2014.03.003 · 2.30 Impact Factor
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- "Our results support a recent theory about the cholinergic systems role in some symptoms of Parkinson's disease, especially gait impairment and postural instability, which do not respond to dopaminergic treatment (Bohnen and Albin 2011; Rochester et al. 2012; Yarnall et al. 2011). Severe nigrostriatal dopaminergic denervation develops secondarily to the formation and deposition of Lewy body inclusions in Parkinson's disease and it has been considered to be the crucial point of the pathophysiology. "
ABSTRACT: The central cholinergic system is believed to be involved in the control of many physiological functions and is an important pharmacological target for numerous neurological pathologies. Here, we summarize our recent observations regarding this topic that we obtained by studying genetically modified mice devoid of particular cholinesterase molecular forms. Our results, collected from mice with deficits of functional cholinesterases in the brain, suggest that the increase in the level of acetylcholine (ACh) has an impact on cognition only in the situation when extracellular ACh is low. Furthermore, we confirmed the central control of movement coordination, which could be of importance for the management of motor problems in patients with Parkinson's disease. At last, we provide clear evidence that while the hypothermic effect of the muscarinic agonist oxotremorine is based on a central mechanism, in contrast, the acetylcholinesterase inhibitor donepezil decreases body temperature by its action in the periphery.Journal of Molecular Neuroscience 11/2013; 53(3). DOI:10.1007/s12031-013-0164-8 · 2.76 Impact Factor
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- "These receptors have been studied in relation to disorders associated with aging and neurodegenerative phenomena, especially Parkinson's disease and Alzheimer's disease. In the latter two neurodegenerative disorders there is a diminished expression of muscarinic acetylcholine receptors as well as a disruption in their capability to bind to endogenous ligands and/or activate coupled G-protein signaling       . "
ABSTRACT: In the last few years, there have been important new insights into the structural biology of G-protein coupled receptors. It is now known that allosteric binding sites are involved in the affinity and selectivity of ligands for G-protein coupled receptors, and that signaling by these receptors involves both G-protein dependent and independent pathways. The present review outlines the physiological and pharmacological implications of this perspective for the design of new drugs to treat disorders of the central nervous system. Specifically, new possibilities are explored in relation to allosteric and orthosteric binding sites on dopamine receptors for the treatment of Parkinson's disease, and on muscarinic receptors for Alzheimer's disease. Future research can seek to identify ligands that can bind to more than one site on the same receptor, or simultaneously bind to two receptors and form a dimer. For example, the design of bivalent drugs that can reach homo/hetero-dimers of D2 dopamine receptor holds promise as a relevant therapeutic strategy for Parkinson's disease. Regarding the treatment of Alzheimer's disease, the design of dualsteric ligands for mono-oligomeric rinic receptors could increase therapeutic effectiveness by generating potent compounds that could activate more than one signaling pathway.Neural Regeneration Research 08/2013; 8(24):2290-302. DOI:10.3969/j.issn.1673-5374.2013.24.009 · 0.23 Impact Factor