Regional cerebral cholinergic nerve terminal integrity and cardinal motor features in Parkinson’s disease

Abstract

Clinical effects of anti-cholinergic drugs implicate cholinergic systems alterations in the pathophysiology of some cardinal motor impairments in Parkinson's disease. The topography of affected cholinergic systems deficits and motor domain specificity are poorly understood. Parkinson's disease patients (n = 108) underwent clinical and motor assessment and vesicular acetylcholine transporter [18F]-fluoroethoxybenzovesamicol PET imaging. Volumes-of-interest-based analyses included detailed thalamic and cerebellar parcellations. Successful PET sampling for most of the small-sized parcellations was available in 88 patients. A data-driven approach, stepwise regression using the forward selection method, was used to identify cholinergic brain regions with cardinal domain-specific motor ratings. Regressions with motor domain scores for model-selected regions followed by confounder analysis for effects of age of onset, duration of motor disease and levodopa equivalent dose. Among 7 model-derived regions associating with postural instability and gait difficulties domain scores three retained significance in confounder variable analysis: medial geniculate nucleus (standardized β = -0.34, t = -3.78, P = 0.0003), lateral geniculate nucleus (β = -0.32, t = -3.4, P = 0.001) and entorhinal cortex (β = -0.23, t = -2.6, P = 0.011). A sub-analysis of non-episodic postural instability and gait difficulties scores demonstrated significant effects of the medial geniculate nucleus, entorhinal cortex and globus pallidus pars interna. Among 6 tremor domain model-selected regions two regions retained significance in confounder variable analysis: cerebellar vermis section of lobule VIIIb (β = -0.22, t = -2.4, P = 0.021) and the putamen (β = -0.23, t = -2.3, P = 0.024). None of the three model-selected variables for the rigidity domain survived confounder analysis. Two out of the four model-selected regions for the distal limb bradykinesia domain survived confounder analysis: globus pallidus pars externa (β = 0.36, t = 3.9, P = 0.0097) and the paracentral lobule β = 0.26, t = 2.5, P = 0.013. Emphasizing the utility of a systems-network conception of the pathophysiology of Parkinson's disease cardinal motor features, our results are consistent with specific deficits in basal forebrain corticopetal, peduncupontine-laterodorsal tegmental complex, and medial vestibular nucleus cholinergic pathways, against the background of nigrostriatal dopaminergic deficits, contributing significantly to postural instability, gait difficulties, tremor and distal limb bradykinesia cardinal motor features of Parkinson's disease. Our results suggest significant and distinct consequences of degeneration of cholinergic peduncupontine-laterodorsal tegmental complex afferents to both segments of the globus pallidus. Non-specific regional cholinergic nerve terminal associations with rigidity scores likely reflect more complex multifactorial signaling mechanisms with smaller contributions from cholinergic pathways.

Cholinergic system changes in Parkinson's disease: emerging therapeutic approaches

“…Postural instability and gait difficulties show spatially distinct cholinergic deficits. Key hubs of the topography associated with non-episodic axial motor impairments include the medial geniculate nucleus and the entorhinal cortex, regions involved in multisensory processing and spatial navigation, respectively (55). Distinct regional vulnerability patterns were seen between patients with falls (right lateral geniculate nucleus, right caudate nucleus) and freezing of gait (similar regions as fallers but with additional prominent bilateral striatal, limbic and prefrontal reductions) (51).…”

“…With disease progression, these episodic disturbances become more frequent. Cholinergic deficits within the medial geniculate nucleus and the entorhinal cortex are robustly associated with non-episodic axial motor impairments (i.e., all axial motor impairments except for falls and freezing of gait) (55). The medial geniculate nucleus is involved in multi-sensory (auditory, vestibular, and proprioceptive) processing.…”

Discussion of Research Priorities for Gait Disorders in Parkinson's Disease

“…49 In particular, the vestibular system, including the cholinergic vestibular projections to the cerebellum (vermis, flocculonodular lobules), are thought to be a significant contributor based on positron emission tomography (PET) imaging studies in patients with PD where the onset of gait disorders was associated with cerebellar and metathalamic cholinergic changes, including the medial geniculate body. 50 The medial geniculate body has intrinsic involvement with processing of pontocerebellar vestibular information that is critical for postural control and navigation. Using a vesicular acetylcholine transporter ligand ( 18 F-FEOBV) for PET, it is now possible to visualize distinct and prominent uptake in the flocculus, nodulus, and vermis regions.…”

“…Turns are a common trigger of FOG, and clearly, the postural control of turning could be a lead mechanism 49 . In particular, the vestibular system, including the cholinergic vestibular projections to the cerebellum (vermis, flocculonodular lobules), are thought to be a significant contributor based on positron emission tomography (PET) imaging studies in patients with PD where the onset of gait disorders was associated with cerebellar and metathalamic cholinergic changes, including the medial geniculate body 50 . The medial geniculate body has intrinsic involvement with processing of pontocerebellar vestibular information that is critical for postural control and navigation.…”

No Dopamine Agonist Modulation of Brain [18F]FEOBV Binding in Parkinson’s Disease

“…21,22 Distribution volume ratios (DVRs) were calculated from a ratio of summed six delayed imaging frames (3 h after injection) for gray matter target and white matter reference tissues. 15,21,22 The [ 11 C]DTBZ DVR of the bilaterally averaged striatum was determined based on the Logan plot graphical analysis method with the supratentorial cortex as the reference region. 23 FreeSurfer software (http://surfer.nmr.mgh.harvard.edu) was used to define cortical and subcortical MR gray volumes-of-interest (VOIs) based on labels from the Mindboggle-101 data set.…”