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. 2025 Jul:151:95-106.
doi: 10.1016/j.neurobiolaging.2025.04.007. Epub 2025 Apr 17.

Brain network connectivity underlying neuropsychiatric symptoms in prodromal Lewy body dementia

Laura M Wright  1 , Paul C Donaghy  1 , David J Burn  1 , John-Paul Taylor  1 , John T O'Brien  2 , Alison J Yarnall  3 , Fiona E Matthews  4 , Michael J Firbank  1 , Hilmar P Sigurdsson  1 , Julia Schumacher  5 , Alan J Thomas  1 , Rachael A Lawson  6
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Free article

Brain network connectivity underlying neuropsychiatric symptoms in prodromal Lewy body dementia

Laura M Wright et al. Neurobiol Aging. 2025 Jul.
Free article

Abstract

Neuropsychiatric symptoms (NPS) are prevalent, emerge early, and are associated with poorer outcomes in Lewy body dementia (LBD). Research suggests NPS may reflect LBD-related dysfunction in distributed neuronal networks. This study investigated NPS neural correlates in prodromal LBD using resting-state functional MRI. Fifty-seven participants were included with mild cognitive impairment (MCI) with Lewy bodies (MCI-LB, n = 28) or Parkinson's disease (PD-MCI, n = 29). Functional MRI assessed connectivity within five resting-state networks: primary visual, dorsal attention, salience, limbic, and default mode networks. NPS were measured using the Neuropsychiatric Inventory. Principal component analyses identified three neuropsychiatric factors: affective disorder (apathy, depression), psychosis (delusions, hallucinations) and anxiety. Seed-to-voxel connectivity maps were analysed to determine associations between NPS and network connectivity. In PD-MCI, affective symptoms and anxiety were associated with greater connectivity between limbic orbitofrontal cortex and default mode areas, including medial prefrontal cortex, subgenual cingulate and precuneus, and weaker connectivity between limbic orbitofrontal cortex and the brainstem and between the salience network and medial prefrontal cortex (all pFWE<0.001). Psychosis severity in PD-MCI correlated with connectivity across multiple networks (all pFWE<0.001). In MCI-LB, no significant correlations were found between NPS severity and network connectivity. However, participants with anxiety demonstrated a trend towards greater connectivity within medial prefrontal areas than those without (pFWE=0.046). Altered connectivity within and between networks associated with mood disorders may explain affective and anxiety symptoms in PD-MCI. Neural correlates of NPS in MCI-LB, however, remain unclear, highlighting the need for research in larger, more diverse LBD populations to identify symptomatic treatment targets.

Keywords: Dementia with Lewy bodies; FMRI; Mild cognitive impairment; Neuroimaging; Neuropsychiatry; Parkinson’s disease; Resting-state networks.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: PCD has received grant support by the Medical Research Council, the Lewy Body Society, Alzheimer’s Society and Alzheimer's Research UK. PCD has also received payment (paid to institution) for lectures for the Neurology Academy and has an unpaid leadership role on the Lewy Body Society Specialist Advisory Committee. JPT is supported by the NIHR Newcastle Biomedical Research Centre. JTO has received grant support from Alliance Medical and Merck, consulting fees from Roche and Biogen and lecture fees from GE Healthcare. JTO, also participates on advisory boards for TauRx, Novo Nordisk and chairs the research strategy board for UK Alzheimer's Society. AJY has received grant support from the Dunhill Medical Trust, EU IMI, NIHR, Parkinson’s UK, Michael J Fox Foundation, Weston Brain Institute, Lewy Body Society and Intercept pharmaceuticals. AJY has also received funding and/or honoraria from Britannia, UCB, Abbvie, GSK, Teva-Lundbeck, GE Healthcare and Genus for attending educational events. AJT has received grant funding in the duration of this work from Alzheimer's Research UK (ARUK-PG2015–13). RAL is supported by a Janet Owens Senior Fellowship grant from Parkinson's UK (F-1801) and has received grant support from the Lewy Body Society. LMW has received grant support from Alzheimer’s Research UK (ARUK-ECRBF2023B-006). The remaining authors have no competing interests to declare.

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