Cholinergic relevant functional reactivity is associated with dopamine responsiveness of tremor in Parkinson’s disease

Abstract

Tremor in Parkinson’s disease (PD) has distinct responsiveness to dopamine, which is supposed not be exclusively related to dopamine deficiency but has a close relationship with cholinergic system. This phenomenon indicates that cholinergic system may be an important regulatory for distinct dopamine responsiveness of parkinsonian tremor. Through investigating the alterations of cholinergic and dopaminergic network during levodopa administration, we aimed at exploring the mechanisms of differed dopamine responsiveness of parkinsonian tremor. Fifty-two PD patients with tremor were enrolled. MRI scanning, UPDRS III and its sub-symptom scores were collected in OFF and ON status (dopaminergic challenge test). Then, patients were divided into two groups (dopamine-resistant tremor and dopamine-responsive tremor) according to the tremor change rate median score. Dopaminergic and cholinergic network were obtained. LASSO regression was conducted to identify functional connectivity with distinct reactivity during levodopa administration between groups. Afterwards, detailed group comparisons, interaction and correlation analyses were performed. The reactivity of cholinergic connectivity showed the highest possibility to distinguish two groups, especially connectivity of right basal forebrain 123 to right parietal operculum cortex (R.BF123-R.PO). After levodopa administration, connectivity of R.BF123-R.PO was decreased for dopamine-responsive tremor while which remained unchanged for dopamine-resistant tremor. The reactivity of R.BF123-R.PO was negatively correlated with tremor change rate. Reduced cholinergic connectivity to parietal operculum may be an underlying mechanism for the responsive tremor in PD and the distinct cholinergic reactivity of parietal operculum to levodopa may be a core pathophysiology for the differed DA responsiveness of tremor in PD.

Striatal dopamine depletion drives disease progression and network topology aberrations specifically by impairing left primary motor cortex network

“…Striatal dopamine deficiency was associated with significant alterations of brain functional networks in PD [14], which could be normalized by dopamine replacement [15]. In addition, striatal dopamine deficiency was also associated with significant changes of structural network [16].…”

“…Dopamine also regulates functional connectivity (FC) and functional networks measured by fMRI [12,13]. Striatal dopamine depletion is associated with widespread alterations of brain functional networks in PD [14] while dopamine replacement normalizes aberrations of functional networks in PD [15]. In addition, striatal dopamine depletion is also associated with significant changes of white matter network [16] and gray matter structure [17] in PD.…”

Normalization effect of dopamine replacement therapy on brain functional connectome in Parkinson's disease

“…A total of 382 PD patients were initially diagnosed according to the UK PD Society Brain Bank diagnostic criteria and Movement Disorder Society clinical diagnostic criteria (Hughes et al, 1992 ; Postuma et al, 2015 ). Patients were excluded due to ① cerebrovascular diseases, including severe cerebral atrophy, stroke, and head injury ( N = 43); ② neurological surgical history ( N = 3); ③ treatment with anticholinergic medication ( N = 4) or antidepressants ( N = 2) which might have interactive effects with dopaminergic medication on FC (Wu et al, 2022 ) (Figure 1 ). Drug‐naïve patients with levodopa challenge test were stratified into Group 2 while the others were divided into Group 1.…”