Thalamic cholinergic innervation and postural sensory integration function in Parkinson’s disease

Abstract

The pathophysiology of postural instability in Parkinson's disease remains poorly understood. Normal postural function depends in part on the ability of the postural control system to integrate visual, proprioceptive, and vestibular sensory information. Degeneration of cholinergic neurons in the brainstem pedunculopontine nucleus complex and their thalamic efferent terminals has been implicated in postural control deficits in Parkinson's disease. Our aim was to investigate the relationship of cholinergic terminal loss in thalamus and cortex, and nigrostriatal dopaminergic denervation, on postural sensory integration function in Parkinson's disease. We studied 124 subjects with Parkinson's disease (32 female/92 male; 65.5 ± 7.4 years old; 6.0 ± 4.2 years motor disease duration; modified Hoehn and Yahr mean stage 2.4 ± 0.5) and 25 control subjects (10 female/15 male, 66.8 ± 10.1 years old). All subjects underwent (11)C-dihydrotetrabenazine vesicular monoaminergic transporter type 2 and (11)C-methylpiperidin-4-yl propionate acetylcholinesterase positron emission tomography and the sensory organization test balance platform protocol. Measures of dopaminergic and cholinergic terminal integrity were obtained, i.e. striatal vesicular monoaminergic transporter type 2 binding (distribution volume ratio) and thalamic and cortical acetylcholinesterase hydrolysis rate per minute (k3), respectively. Total centre of pressure excursion (speed), a measure of total sway, and sway variability were determined for individual sensory organization test conditions. Based on normative data, principal component analysis was performed to reduce postural sensory organization functions to robust factors for regression analysis with the dopaminergic and cholinergic terminal data. Factor analysis demonstrated two factors with eigenvalues >2 that explained 52.2% of the variance, mainly reflecting postural sway during sensory organization test Conditions 1-3 and 5, respectively. Regression analysis of the Conditions 1-3 postural sway-related factor [R(2)adj = 0.123, F(5,109) = 4.2, P = 0.002] showed that decreased thalamic cholinergic innervation was associated with increased centre of pressure sway speed (β = -0.389, t = -3.4, P = 0.001) while controlling for covariate effects of cognitive capacity and parkinsonian motor impairments. There was no significant effect of cortical cholinergic terminal deficits or striatal dopaminergic terminal deficits. This effect could only be found for the subjects with Parkinson's disease. We conclude that postural sensory integration function of subjects with Parkinson's disease is modulated by pedunculopontine nucleus-thalamic but not cortical cholinergic innervation. Impaired integrity of pedunculopontine nucleus cholinergic neurons and their thalamic efferents play a role in postural control in patients with Parkinson's disease, possibly by participating in integration of multimodal sensory input information.

Effects of Donepezil on Extrapyramidal Symptoms in Patients with Dementia with Lewy Bodies: A Secondary Pooled Analysis of Two Randomized-Controlled and Two Open-Label Long-Term Extension Studies

“…The absence of an influence of ChEIs, including donepezil, on parkinsonism has been reported in previous studies, along with improvement in a few of these studies, which reinforces the interpretations drawn from this analysis [7,10,11,22,34]. Our finding is also in accordance with accumulating evidence of cholinergic involvement in PD; degeneration of multiple cholinergic projection systems occurs early in PD [35], cholinergic degeneration plays a role in some aspects of motor symptoms including postural control [36] and gait [37], and treatment with donepezil produces reductions in the number of falls in frequently falling patients with PD [38]. …”

Are Cholinesterase Inhibitors Effective in Improving Balance in Parkinson’s Disease?

“…Increased postural sway has been associated with thalamic cholinergic denervation in subjects with PD [22]. The effects specifically on SOT condition 4 support a role for the PPN-thalamic cholinergic projections in sensory integration [22]. The decreased ML RMS in the active phase of the study during one of the most problematic balance conditions for PD is when the sensory integration is between somatosensory altered information and visual-vestibular information.…”

“…Perhaps the fall reduction seen in the study of Chung et al could be attributable to improvements in both balance and executive function since an increase in mediolateral postural sway has been associated with falls [20,21] and cognitive impairments have been associated with falls [14]. Increased postural sway has been associated with thalamic cholinergic denervation in subjects with PD [22]. The effects specifically on SOT condition 4 support a role for the PPN-thalamic cholinergic projections in sensory integration [22].…”

Investigation of Proposed Activity of Clarithromycin at GABAA Receptors Using [11C]Flumazenil PET

“…16 Cholinergic system dysfunction has been implicated in some components of postural instability and gait difficulties (PIGD) in PD, in particular falls and sensory processing during postural control, but not with overall severity of axial motor impairments. 17 Postural control and gait functions are mediated by widespread neural networks that cannot be captured by a simplistic model of single neurotransmitter system changes. There is increasing interest in dysfunction of colocalized neurotransmitter functions in PD to better understand the complexity of the multisystem nature of neurodegeneration.…”

“…19−21 Excessive GABAergic activity in the pons has been confirmed by in vivo MR spectroscopy in patients with PD. 22 As the pedunculopontine nucleus is the major modulator of the thalamus and its related central role of postural control in PD, 17 the presence of overactive GABAergic inhibition in the brainstem in PD would auger novel pharmacological approaches to block excessive GABAergic inhibition in PD. In particular, intravenous FMZ has been shown to rapidly improve motor impairments in PD patients.…”