Impaired metabolic brain networks associated with neurotransmission systems in the α-synuclein spectrum

Introduction: While the involvement of multiple neurotransmitter systems in α-synucleinopathies is reported, a comprehensive study on their metabolic connectivity reconfiguration in the preclinical and clinical disease-spectrum is lacking. We aimed to investigate shared and disease-specific neural vulnerabilities of the nigro-striato-cortical dopaminergic, noradrenergic and cholinergic networks within the α-synuclein-spectrum, by means of metabolic connectivity approach. Methods: We collected 34 polysomnography-confirmed isolated REM sleep behaviour disorder (iRBD) subjects, 29 idiopathic Parkinson's disease (PD) patients without dementia, 30 patients with probable dementia with Lewy bodies (DLB), and 50 healthy controls for comparisons. Neurotransmission networks' analyses were performed through multivariate partial correlations based on FDG-PET brain metabolic data. Results: We found: a) the nigro-striato-cortical dopaminergic network with a limited reconfiguration in individuals with iRBD, but moderate-to-severe alterations in patients with DLB and PD; b) an extended connectivity alteration of the noradrenergic network in all groups; c) changes within the cholinergic networks connectivity in the whole disease-spectrum, with some differences: PD with only moderate connectivity reconfiguration and DLB with the most severe alterations, some of these shared with iRBD. Conclusions: Synucleinopathies can be considered multisystem disorders, with common and disease-specific neurotransmission networks reconfigurations. The present findings indicate dopaminergic connectivity alterations only when associated with parkinsonism, a very early involvement of noradrenergic networks, occurring in both the iRBD and in symptomatic PD/DLB patients and cholinergic alterations with disease-specific vulnerabilities shared by iRBD and DLB. The latter finding may represent an early biomarker of disease progression to dementia.