Gait speed in Parkinson disease correlates with cholinergic degeneration

Abstract

Objective: We investigated dopaminergic and cholinergic correlates of gait speed in Parkinson disease (PD) and non-PD control subjects to test the hypothesis that gait dysfunction in PD may result from multisystem degeneration.Methods: This was a cross-sectional study. Subjects with PD but without dementia (n 5 125, age 65.6 6 7.3 years) and elderly subjects without PD (n 5 32, age 66.0 6 10.6 years) underwent [ 11 C]dihydrotetrabenazine dopaminergic and [11 C]methyl-4-piperidinyl propionate acetylcholinesterase PET imaging, and cognitive and clinical testing, including an 8.5-m walk in the dopaminergic "off" state. The fifth percentile of cortical cholinergic activity in the elderly without PD was used to define normal-range activity in the subjects with PD.Results: Normal-range cortical cholinergic activity was present in 87 subjects with PD (69.6%).Analysis of covariance using gait speed as the dependent variable demonstrated a significant model (F 5 6.70, p , 0.0001) with a significant group effect (F 5 3.36, p 5 0.037) and significant slower gait speed in the low cholinergic PD subgroup (0.97 6 0.22 m/s) with no significant difference between the normal-range cholinergic PD subgroup (1.12 6 0.20 m/s) and control subjects (1.17 6 0.18 m/s). Covariate effects were significant for cognition (F 5 6.58, p 5 0.011), but not for striatal dopaminergic innervation, sex, or age. Conclusion:Comorbid cortical cholinergic denervation is a more robust marker of slowing of gait in PD than nigrostriatal denervation alone. Gait speed is not significantly slower than normal in subjects with PD with relatively isolated nigrostriatal denervation. The cardinal motor symptoms of Parkinson disease (PD) often develop at different times during disease progression. Upper extremity bradykinesia and rigidity typically precede axial and bilateral lower extremity motor changes, such as limitations in gait.1,2 Imaging studies show that nigrostriatal denervation is already severe in early clinical stage PD.3 Increased activity of other brain systems may compensate for nigrostriatal degeneration. 4,5 If gait speed functions are not prominently affected in early PD despite significant dopaminergic losses, subsequent slowing of gait speed implicates later degeneration of nondopaminergic pathways. A recent study suggested that cholinergic dysfunction is an important contributor to gait dysfunction in PD. 6 We reported previously that subjects with PD with combined basal forebrain cholinergic and dopaminergic deficits had lower global cognitive performance, more severe nigrostriatal denervation, and a trend toward more severe motor impairments, including slower gait, when compared to subjects with PD with normal-range cortical cholinergic innervation. 7 In our prior study, there was no comparison with a non-PD control group and findings were not corrected for the degree of nigrostriatal denervation.

Loss of gait control assessed by cognitive-motor dual-tasks: pros and cons in detecting people at risk of developing Alzheimer’s and Parkinson’s diseases

“…From a behavioral point of view, the gait showing results from the inability of PD patients to generate sufficient stride length and arm swing amplitude (i.e., gait hypokinesia) even though cadence control remains intact (Morris et al 1994;Hausdorff 2009), whereas the increased variability in temporal parameters from an alteration of the internal cueing mechanism needed to walk in a rhythmic fashion (Sheridan and Flowers 1990;Morris et al 1994;Ebersbach et al 1999;Schaafsma et al 2003). From a neuropathological point of view, the causes of these gait disorders may result from (i) dopaminergic striatal deficit (Wu et al 2015), (ii) excessive inhibition of the mesopontine locomotion center by the basal ganglia (Sterling et al 2015), and (iii) cortical cholinergic denervation (Bohnen et al 2013;Müller et al 2015).…”

Imaging in Parkinson's Disease

“…However, differences in AChE activity between early and advanced PD patients were nonsignificant, suggesting that cholinergic dysfunction occurs early, but does not progress with the disease (Shimada et al, 2009). Cortical and thalamic cholinergic denervation as measured by [ 11 C]PMP PET were associated with increased falls, slower gait speed, and increased freezing of gait in PD patients, suggesting that cholinergic degeneration is a major factor leading to impaired postural control and gait dysfunction in PD (Bohnen et al, 2014(Bohnen et al, , 2013(Bohnen et al, , 2009.…”

Participation of the pedunculopontine tegmental nucleus in arousal-demanding functions

“…This evidence has led some authors to consider gait and axial disturbances in PD as possible consequences of a disruption of ACh mechanisms in the brainstem rather than of the nigrostriatal dopaminergic system; and the severity of these motor disabilities has been directly related to the degree of ACh neuronal loss in the PPTg [132,133]. However, other neurotransmitters, in particular glutamate are thought to be involved in fibers descending from the PPTg to the spinal cord and to lower brainstem motor structures.…”