Abstract
Objective Cognitive fluctuations are a core clinical feature of Dementia with Lewy bodies (DLB), and although common and disabling, their pathophysiology is poorly understood. This work aimed to identify novel functional network signatures of cognitive fluctuations and investigate their underlying neurobiology by relating them to neuromodulatory systems.
Methods Patients with DLB and age-matched controls were assessed on both subjective and objective measures of fluctuations and attention. Resting state dynamic functional magnetic resonance imaging was used to identify the temporal and topological signatures of cognitive fluctuations. Abnormal patterns of activation were mapped onto established gene expression atlases to determine associations with specific neuromodulators.
Results DLB patients displayed more stationary brain-state configurations relative controls. This signature of reduced temporal variability correlated significantly with fluctuation-related measures using a sustained attention task (response time variability and drift rate). Topologically, patients with DLB demonstrated a less integrated (more segregated) functional network architecture compared to the control group. Regions of reduced integration were observed across dorsal and ventral attention, sensorimotor, visual, cingulo-opercular and cingulo-parietal networks. Relatively segregated networks correlated positively with subjective and objective measures of fluctuations. Regions of reduced integration and unstable regional assignments were significantly related to the pattern of expression of specific classes of noradrenergic and cholinergic receptors across the cerebral cortex.
Conclusions Cognitive fluctuations in DLB are related to specific dynamic functional network impairments that are linked to the noradrenergic and cholinergic systems. Such systems may be viable targets of future therapies.
