Synergic cholinergic and dopaminergic role in motor symptoms of sporadic Parkinson’s disease

277 

Abstract Submission 

Peng Ren^1,2

¹Fudan University, Shanghai, Shanghai, ²Harbin Institute of Technology, Heilongjiang, China

Peng Ren  
Fudan University|Harbin Institute of Technology
Shanghai, Shanghai|Heilongjiang, China

Parkinson's Disease (PD) is a dominant neurodegenerative disease, characterized with various motor symptoms.[1] Despite the prevailing dopaminergic treatments for PD motor symptoms,[2] no disease-modifying drugs exist,[3] which implicates the potential involvement of non-dopaminergic neurotransmitter systems. Previous autopsy study indicated that the α-synuclein deposition in nucleus basalis of Meynert (NbM) occurs as early as the Lewy bodies formation and dopaminergic neurons loss in substantia nigra (SN).[4] However, existing works usually explore the association between cholinergic/dopaminergic subcomponents and specific motor symptoms.[5-7] To date, there is a lack of systematic exploration for the relationship between all cholinergic/dopaminergic components and various motor symptoms. Here, using imaging data from Parkinson's Progression Markers Initiative (PPMI), we characterize the cross-sectional and longitudinal role of multimodal cholinergic/dopaminergic regional measurements in motor symptoms. By dividing the PD patients into those present stable (Any) or no/unstable (Never) non-motor symptoms, we also explore the impact of non-motor symptoms on the roles of cholinergic/dopaminergic system.

We used longitudinal T1w, T2w and DAT SPECT images from PPMI, including 151 subjects (31 control/120 PD) for voxel-based morphometric and DAT striatal binding ratios (SBR) analysis and 176 subjects (49 controls/127 PD) for T1w/T2w analysis. We calculated regional volume, SBR and T1w/T2w of cholinergic (NbM, Medial septum-diagonal band of Broca (MS/DB) and pedunculopontine nucleus (PPN)) and dopaminergic (SN, putamen, caudate, globus pallidus (GP) and ventral tegmental area (VTA)) components for each subject and time point. Baseline cross-sectional group differences were detected by appropriate tests. Linear mixed effect models were performed to examine group difference of longitudinal change, the association between longitudinal change of regional measurements and motor symptoms, as well as whether baseline regional measurements are predictors of motor symptoms progression. The baseline age, gender, education year, intracranial volume, disease duration and baseline motor severity were controlled as appropriate. Finally, in exploring the impact of non-motor symptoms on the discovered cholinergic/dopaminergic role, we repeated the above statistical analyses in the Never and Any group, separately.

Cross-sectionally, we found that PD patients showed worsen global motor symptoms and subscores (bradykinesia, rigidity, gait and tremor), reduced SBR in putamen and caudate (Fig.1B).
Longitudinally, PD patients showed greater decline of global motor symptom, bradykinesia, rigidity and caudate volume (Fig.1C). In addition, longitudinal increase of global motor symptom was associated with reduction of volume and SBR in putamen and caudate, T1w/T2w in NbM, PPN, SN, putamen, caudate, GP and VTA. Similar results were discovered for bradykinesia, rigidity and gait. No longitudinal associations were observed for tremor. The baseline T1w/T2w ratio of NbM predicted longitudinal increase of global motor symptom, bradykinesia and PIGD, while caudate volume, MS/DB T1w/T2w, caudate T1w/T2w and caudate SBR were additional predictors of PIGD. No significant baseline predictors were found for tremor (Fig.1D).
In subgroup cross-sectional analysis, the Any group showed the least DAT SBR in putamen and caudate, followed by the Never group. Longitudinally, similar longitudinal results were only found in the Any group, but not the Never group (Fig.2).

The T1w/T2w ratio of both cholinergic and dopaminergic regions showed potential for being biomarker of PD progression and prognosis beyond regional volume and SBR. Additionally, this role is more significant with the existing of non-motor symptoms. These new findings may advance the understanding of the development of PD pathology and optimize future clinical treatment.

Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) ¹

Motor Behavior Other

Transmitter Systems

Anatomical MRI ²

PET

Dopamine

Movement Disorder

Neurotransmitter