Title : Metabolic connectomics targeting brain pathology in dementia with Lewy bodies Short title : FDG-PET connectomics in DLB

DLB is characterized by α-synuclein accumulation and degeneration of dopaminergic and cholinergic pathways. To gain an overview of brain systems affected by neurodegeneration, we characterized the [18F]FDG-PET metabolic connectome in 42 DLB patients, as compared to 42 healthy controls, using SICE method and graphtheory. We performed whole-brain and anatomically-driven analyses, targeting cholinergic and dopaminergic pathways, and the α-synuclein spreading. The first revealed substantial alterations in connectivity indexes, brain modularity and hubs configuration. Namely, decreases in local metabolic connectivity within occipital cortex, thalamus, and cerebellum, and increases within frontal, temporal, parietal and basal ganglia regions. There were also long-range disconnections among these brain regions, all supporting a disruption of the functional hierarchy characterizing the normal brain. The anatomically-driven analysis revealed alterations within brain structures early affected by α-synuclein pathology, supporting Braak’s early pathological staging in DLB. The dopaminergic striato-cortical pathway was severely affected, as well as the cholinergic networks, with an extensive decrease in connectivity in Ch1-Ch2, Ch5-Ch6 networks and the lateral Ch4 capsular network significantly towards the occipital cortex. These altered patterns of metabolic connectivity unveil a new in vivo scenario for DLB underlying pathology in terms of changes in whole brain metabolic connections, spreading of α-synuclein, and neurotransmission impairment.