Abstract
Cognitive fluctuations are a characteristic and distressing disturbance of attention and consciousness seen in patients with Dementia with Lewy bodies and Parkinson’s disease dementia. It has been proposed that fluctuations result from disruption of key neuromodulatory systems supporting states of attention and wakefulness which are normally characterised by temporally variable and highly integrated functional network architectures. In this study, patients with DLB (n = 25) and age-matched controls (n = 49) were assessed using dynamic resting state fMRI. A dynamic network signature of reduced temporal variability and integration was identified in DLB patients compared to controls. Reduced temporal variability correlated significantly with fluctuation-related measures using a sustained attention task. A less integrated (more segregated) functional network architecture was seen in DLB patients compared to the control group, with regions of reduced integration observed across dorsal and ventral attention, sensorimotor, visual, cingulo-opercular and cingulo-parietal networks. Reduced network integration correlated positively with subjective and objective measures of fluctuations. Regions of reduced integration and unstable regional assignments significantly matched areas of expression of specific classes of noradrenergic and cholinergic receptors across the cerebral cortex. Correlating topological measures with maps of neurotransmitter/neuromodulator receptor gene expression, we found that regions of reduced integration and unstable modular assignments correlated significantly with the pattern of expression of subclasses of noradrenergic and cholinergic receptors across the cerebral cortex. Altogether, these findings demonstrate that cognitive fluctuations are associated with an imaging signature of dynamic network impairment linked to specific neurotransmitters/neuromodulators within the ascending arousal system, highlighting novel potential diagnostic and therapeutic approaches for this troubling symptom.
Highlights
Lewy body dementia, which comprises Dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), is a common neurodegenerative disease with a higher morbidity, socioeconomic cost and caregiver burden relative to other dementias[1]
We show that compared to healthy agematched controls, DLB patients demonstrate a functional signature of reduced network-integration and low temporal variability
We found that the diversity of observed brain activation patterns was reduced in DLB, as demonstrated by significantly higher global state-to-state correlation (SG) across the imaging period compared to controls (0.32 ± 0.06 versus 0.19 ± 0.05; P < 0.001, Cohen’s d = 1.6; Fig. 1c)
Summary
Lewy body dementia, which comprises Dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), is a common neurodegenerative disease with a higher morbidity, socioeconomic cost and caregiver burden relative to other dementias[1]. Integrated and temporally variable states have been shown to correlate with awareness and consciousness[15,18,19,20], and with better performance on cognitive tasks[16,21,22]. Such network-level characteristics have been linked to the influence of distinct neuromodulatory neurotransmitters forming part of the ascending reticular activating system[23]. By correlating our topological fMRI connectivity measures with data from established receptor gene expression maps, we confirm an explicit link between noradrenaline and acetylcholine neurotransmission and the pathophysiology of altered brain dynamics that underlie the cognitive fluctuations observed in DLB
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