Mapping brain metabolism, connectivity and neurotransmitters topography in early and late onset dementia with Lewy bodies

Abstract

Background: Early- and late-onset dementia with Lewy bodies (EO-DLB and LO-DLB) are similar in terms of core symptoms. However, LO-DLB presents with more amnestic deficits, while EO-DLB shows a rapid cognitive decline and more severe neuropsychiatric symptoms at onset. A contribution of neurotransmitter dysfunction was suggested but never explored, as a possible factor contributing to the reported clinical differences. By using FDG-PET brain metabolism imaging, we aimed to assess the differences between EO-DLB and LO-DLB regarding brain hypometabolism, related neurotransmitter functional topography, and metabolic connectivity. Methods: We included a total of 62 patients, 21 EO-DLB and 41 LO-DLB patients. Statistical parametric mapping (SPM) voxel-wise comparison with a validated dataset of healthy controls (N=112) provided brain hypometabolism patterns. A metabolic connectivity analysis assessed whole-brain and resting-state network (RSN) alterations. Furthermore, we used the JuSpace toolbox to evaluate the correlations between neurotransmitter pathways topography and brain hypometabolism. Results: Both EO- and LO-DLB groups showed typical bilateral occipito-parieto-frontal hypometabolism. Direct between-group comparison revealed a more severe hypometabolism in posterior cingulate cortex (PCC), precuneus, and occipital cortex for EO-DLB and a more severe hypometabolism in fronto-insular cortices for LO-DLB. Metabolic connectivity analysis showed significant reductions in posterior brain regions in both clinical groups compared to controls, as well as connectivity increases in the EO-DLB only. There were differences in the involvement of temporo-parietal and occipital pathological nodes. Specific RSN vulnerabilities were observed in the executive, default mode and limbic networks for EO-DLB and in the attentional network for LO-DLB. The spatial association analysis based on the metabolic differences in neurotransmission showed significant correlations with acetylcholine, gamma-aminobutyric acid (GABA), serotonin, dopamine maps, and hypometabolism in both EO and LO-DLB groups. Of note, the between-group comparison showed a higher correlation for the EO-DLB in the presynaptic serotonergic system. Overall, this indicates the biochemical involvement of metabolic impairment. Conclusions: This metabolic imaging study indicates similarities and differences between EO- and LO-DLB, both in terms of brain hypometabolism, across different neurotransmission networks, and altered connectivity, adding novel biological evidence to the DLB syndromes.