Vulnerability of multiple large‐scale brain networks in dementia with Lewy bodies

Abstract

Aberrations of large‐scale brain networks are found in the majority of neurodegenerative disorders. The brain connectivity alterations underlying dementia with Lewy bodies (DLB) remain, however, still elusive, with contrasting results possibly due to the pathological and clinical heterogeneity characterizing this disorder. Here, we provide a molecular assessment of brain network alterations, based on cerebral metabolic measurements as proxies of synaptic activity and density, in a large cohort of DLB patients (N = 72). We applied a seed‐based interregional correlation analysis approach (p < .01, false discovery rate corrected) to evaluate large‐scale resting‐state networks' integrity and their interactions. We found both local and long‐distance metabolic connectivity alterations, affecting the posterior cortical networks, that is, primary visual and the posterior default mode network, as well as the limbic and attention networks, suggesting a widespread derangement of the brain connectome. Notably, patients with the lowest visual and attention cognitive scores showed the most severe connectivity derangement in regions of the primary visual network. In addition, network‐level alterations were differentially associated with the core clinical manifestations, namely, hallucinations with more severe metabolic dysfunction of the attention and visual networks, and rapid eye movement sleep behavior disorder with alterations of connectivity of attention and subcortical networks. These multiple network‐level vulnerabilities may modulate the core clinical and cognitive features of DLB and suggest that DLB should be considered as a complex multinetwork disorder.

Brain Molecular Connectivity in Neurodegenerative Conditions

“…In DLB, metabolic connectivity evidence showed a severe involvement of the posterior cortical, the limbic, and the attention networks, consistently with the pathological and clinical heterogeneity intrinsic to this condition [ 98 ]. DLB connectivity alterations in large-scale resting-state networks are strongly related to the clinical symptoms [ 98 ]. Visual hallucinations (VH) are associated with impaired connectivity in posterior DMN, the attention network, and visual networks [ 66 , 98 ].…”

“…Moreover, isolated rapid eye movement (REM) sleep behavior disorder (iRBD) represents the prodromal stage of full-blown alpha-synucleinopathies [ 94 ]. There are several PET metabolic connectivity studies in PD and DLB [ 66 , 95 , 96 , 97 , 98 , 99 , 100 , 101 ], and less evidence in iRBD [ 95 , 102 ] and MSA [ 103 , 104 ].…”

“…As mentioned above, disease-specific brain network alterations, mainly involving the posterior DMN, characterize AD already in the prodromal phase. Conversely, in PD and DLB, connectivity alterations of resting-state large-scale networks revealed a widespread derangement of the brain connectome, suggesting them as multi-network neurodegenerative disorders ( Figure 2 B) [ 96 , 97 , 98 ].…”

“…DLB connectivity alterations in large-scale resting-state networks are strongly related to the clinical symptoms [ 98 ]. Visual hallucinations (VH) are associated with impaired connectivity in posterior DMN, the attention network, and visual networks [ 66 , 98 ]. The biological explanation for these findings points to cholinergic damage, leading to the breakdown of the functional relationship among the calcarine cortex, lateral occipital cortex, and parietal cortex [ 110 ].…”

Correlations of Neuropsychological and Metabolic Brain Changes in Parkinson's Disease and Other α-Synucleinopathies

“…A small study (11 patients) from Fujishiro et al showed that hypometabolism in primary visual cortex can predict DLB in non-demented individuals (120). Furthermore, Sala et al showed disruption of posterior cortical networks in DLB patients, especially in the primary visual network (121). Specific disease-related changes in glucose metabolism can be seen in DLB patients even before the development of distinct clinical picture.…”