Salience and frontoparietal network impairments across disease stages in dementia with Lewy bodies: A comparative functional MRI study with Alzheimer's disease
Restricted accessResearch articleFirst published online December, 2025
Salience and frontoparietal network impairments across disease stages in dementia with Lewy bodies: A comparative functional MRI study with Alzheimer's disease
Resting-state functional magnetic resonance imaging (fMRI) studies in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) have described connectivity alterations in large-scale brain networks. However, little is known about functional changes across disease stages, particularly in DLB.
Objective
To investigate functional connectivity of key brain networks in DLB patients at different stages, compare them to AD patients and healthy controls (HC), and examine associations with core clinical symptoms.
Methods
Ninety DLB patients (63 with mild cognitive impairment [MCI-DLB] and 27 with dementia [d-DLB]), 25 AD patients (11 MCI-AD and 14 d-AD) and 34 HC underwent clinical, neuropsychological and resting-state fMRI assessments. Region of interest (ROI)-to-ROI analyses were performed using the CONN toolbox (pFDR < 0.05).
Results
The overall DLB group showed reduced functional connectivity within the salience network (SN) compared to HC, but not to the overall AD group. At the subgroup level, d-DLB patients showed reduced SN and frontoparietal network (FPN) connectivity compared to both HC and the overall AD group, whereas MCI-DLB did not significantly differ from either group. In the overall DLB group, SN connectivity correlated with fluctuation severity and FPN connectivity correlated with both REM sleep behavior disorder and cognitive decline. In the overall AD group, decreased default mode network (DMN) connectivity was associated with lower Mini-Mental State Examination scores.
Conclusions
SN and FPN connectivity impairments relate to disease progression and core clinical features in DLB, whereas DMN connectivity is linked to cognitive decline in AD. These distinct patterns highlight divergent paths of network dysfunction in the two diseases.
Clinical Trial: This study is part of the AlphaLewyMA cohort, registered on ClinicalTrials.gov (identifier: NCT01876459; registered on June 12, 2013).
McKeithIGBoeveBFDicksonDW, et al.Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium. Neurology2017; 89: 88–100.
2.
McKeithIGFermanTJThomasAJ, et al.Research criteria for the diagnosis of prodromal dementia with Lewy bodies. Neurology2020; 94: 743–755.
3.
ChabranERoquetDGounotD, et al.Functional disconnectivity during inter-task resting state in dementia with Lewy bodies. Dement Geriatr Cogn Disord2018; 45: 105–120.
4.
LowtherERO’BrienJTFirbankMJ, et al.Lewy body compared with Alzheimer dementia is associated with decreased functional connectivity in resting state networks. Psychiatry Res Neuroimaging2014; 223: 192–201.
5.
KucikovaLKalabizadehHMotsiKG, et al.A systematic literature review of fMRI and EEG resting-state functional connectivity in dementia with Lewy bodies: underlying mechanisms, clinical manifestation, and methodological considerations. Ageing Res Rev2024; 93: 102159.
6.
ChabranENobletVLoureiro De SousaP, et al.Changes in gray matter volume and functional connectivity in dementia with Lewy bodies compared to Alzheimer’s disease and normal aging: implications for fluctuations. Alzheimers Res Ther2020; 12: 9.
7.
PerazaLRKaiserMFirbankM, et al.fMRI resting state networks and their association with cognitive fluctuations in dementia with Lewy bodies. Neuroimage Clin2014; 4: 558–565.
8.
PerazaLRCollobySJFirbankMJ, et al.Resting state in Parkinson’s disease dementia and dementia with Lewy bodies: commonalities and differences. Int J Geriatr Psychiatry2015; 30: 1135–1146.
9.
SchumacherJPerazaLRFirbankM, et al.Functional connectivity in dementia with Lewy bodies: a within- and between-network analysis. Hum Brain Mapp2018; 39: 1118–1129.
10.
SeeleyWWMenonVSchatzbergAF, et al.Dissociable intrinsic connectivity networks for salience processing and executive control. J Neurosci2007; 27: 2349–2356.
11.
SalaACaminitiSPIaccarinoL, et al.Vulnerability of multiple large-scale brain networks in dementia with Lewy bodies. Hum Brain Mapp2019; 40: 4537–4550.
12.
VincentJLKahnISnyderAZ, et al.Evidence for a frontoparietal control system revealed by intrinsic functional connectivity. J Neurophysiol2008; 100: 3328–3342.
ChenotQLepronEDe BoissezonX, et al.Functional connectivity within the fronto-parietal network predicts complex task performance: a fNIRS study. Front Neuroergonomics2021; 2: 718176.
15.
YangXWuHSongY, et al.Functional MRI-specific alterations in frontoparietal network in mild cognitive impairment: an ALE meta-analysis. Front Aging Neurosci2023; 15: 1165908.
16.
RaichleME. The brain’s default mode network. Annu Rev Neurosci2015; 38: 433–447.
17.
GreiciusMDSrivastavaGReissAL, et al.Default-mode network activity distinguishes Alzheimer’s disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci U S A2004; 101: 4637–4642.
18.
BucknerRLAndrews-HannaJRSchacterDL. The brain’s default network: anatomy, function, and relevance to disease. Ann N Y Acad Sci2008; 1124: 1–38.
19.
BadhwarATamADansereauC, et al.Resting-state network dysfunction in Alzheimer’s disease: a systematic review and meta-analysis. Alzheimers Dement (Amst)2017; 8: 73–85.
20.
MevelKChételatGEustacheF, et al.The default mode network in healthy aging and Alzheimer’s disease. Int J Alzheimers Dis2011; 2011: 535816.
21.
SchumacherJGunterJLPrzybelskiSA, et al.Dementia with Lewy bodies: association of Alzheimer pathology with functional connectivity networks. Brain2021; 144: 3212–3225.
22.
PetersenRCSmithGEWaringSC, et al.Mild cognitive impairment: clinical characterization and outcome. Arch Neurol1999; 56: 303.
23.
SchumacherJTaylorJ-PHamiltonCA, et al.Functional connectivity in mild cognitive impairment with Lewy bodies. J Neurol2021; 268: 4707–4720.
24.
FermanTJSmithGEBoeveBF, et al.DLB Fluctuations: specific features that reliably differentiate DLB from AD and normal aging. Neurology2004; 62: 181–187.
25.
FénelonGSoulasTZenasniF, et al.The changing face of Parkinson’s disease-associated psychosis: a cross-sectional study based on the new NINDS-NIMH criteria. Mov Disord2010; 25: 763–766.
26.
BallardCMcKeithLBurnD, et al.The UPDRS scale as a means of identifying extrapyramidal signs in patients suffering from dementia with Lewy bodies. Acta Neurol Scand2009; 96: 366–371.
27.
GjerstadMDBoeveBWentzel-LarsenT, et al.Occurrence and clinical correlates of REM sleep behaviour disorder in patients with Parkinson’s disease over time. J Neurol Neurosurg Psychiatry2008; 79: 387–391.
28.
AlbertMSDeKoskySTDicksonD, et al.The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the national institute on aging-Alzheimer’s association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement2011; 7: 270–279.
29.
DuboisBFeldmanHHJacovaC, et al.Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol2014; 13: 614–629.
30.
ChuangK-HVan GelderenPMerkleH, et al.Mapping resting-state functional connectivity using perfusion MRI. Neuroimage2008; 40: 1595–1605.
31.
Whitfield-GabrieliSNieto-CastanonA. Conn: a functional connectivity toolbox for correlated and anticorrelated brain networks. Brain Connect2012; 2: 125–141.
32.
DesikanRSSégonneFFischlB, et al.An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage2006; 31: 968–980.
33.
FoxMDSnyderAZVincentJL, et al.The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc Natl Acad Sci U S A2005; 102: 9673–9678.
34.
CorbettaMShulmanGL. Control of goal-directed and stimulus-driven attention in the brain. Nat Rev Neurosci2002; 3: 201–215.
35.
SridharanDLevitinDJMenonV. A critical role for the right fronto-insular cortex in switching between central-executive and default-mode networks. Proc Natl Acad Sci U S A2008; 105: 12569–12574.
36.
MenonVUddinLQ. Saliency, switching, attention and control: a network model of insula function. Brain Struct Funct2010; 214: 655–667.
37.
UddinLQ. Salience processing and insular cortical function and dysfunction. Nat Rev Neurosci2015; 16: 55–61.
38.
RachidiIMinottiLMartinG, et al.The insula: a stimulating island of the brain. Brain Sci2021; 11: 1533.
39.
WatsonRCollobySJBlamireAM, et al.Assessment of regional gray matter loss in dementia with Lewy bodies: a surface-based MRI analysis. Am J Geriatr Psychiatry2015; 23: 38–46.
40.
BlancFCollobySJCretinB, et al.Grey matter atrophy in prodromal stage of dementia with Lewy bodies and Alzheimer’s disease. Alzheimers Res Ther2016; 8: 31.
41.
BlancFCollobySJPhilippiN, et al.Cortical thickness in dementia with Lewy bodies and Alzheimer’s disease: a comparison of prodromal and dementia stages. PLoS One2015; 10: e0127396.
42.
WhitwellJLWeigandSDShiungMM, et al.Focal atrophy in dementia with Lewy bodies on MRI: a distinct pattern from Alzheimer’s disease. Brain2007; 130: 708–719.
43.
SalmonDPGalaskoDHansenLA, et al.Neuropsychological deficits associated with diffuse Lewy body disease. Brain Cogn1996; 31: 148–165.
44.
HabichAWahlundLWestmanE, et al.(Dis-)connected dots in dementia with Lewy bodies—a systematic review of connectivity studies. Mov Disord2023; 38: 4–15.
45.
KrämerUMSolbakkA-KFunderudI, et al.The role of the lateral prefrontal cortex in inhibitory motor control. Cortex2013; 49: 837–849.
46.
FirbankMJPasquiniJBestL, et al.Cerebellum and basal ganglia connectivity in isolated REM sleep behaviour disorder and Parkinson’s disease: an exploratory study. Brain Imaging Behav2024; 18: 1428–1437.
47.
SunwooJ-SChaKSByunJ-I, et al.Abnormal activation of motor cortical network during phasic REM sleep in idiopathic REM sleep behavior disorder. Sleep2019; 42: 10.1093/sleep/zsy227.
48.
PalmqvistSSchöllMStrandbergO, et al.Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity. Nat Commun2017; 8: 1214.
49.
SchultzAPBuckleyRFHamptonOL, et al.Longitudinal degradation of the default/salience network axis in symptomatic individuals with elevated amyloid burden. Neuroimage Clin2020; 26: 102052.
50.
PerazaLRTaylorJ-PKaiserM. Divergent brain functional network alterations in dementia with Lewy bodies and Alzheimer’s disease. Neurobiol Aging2015; 36: 2458–2467.
51.
KennyERO’BrienJTFirbankMJ, et al.Subcortical connectivity in dementia with Lewy bodies and Alzheimer’s disease. Br J Psychiatry2013; 203: 209–214.
52.
WuTHallettM. The cerebellum in Parkinson’s disease. Brain2013; 136: 696–709.
53.
LawnTFfytcheD. Cerebellar involvement in hallucinations may transcend clinical conditions and perceptual modalities. Cortex2021; 143: 290–294.
54.
PezzoliSDe MarcoMZorziG, et al.Functional brain connectivity patterns associated with visual hallucinations in dementia with Lewy bodies. J Alzheimers Dis Rep2021; 5: 311–320.
55.
SinghNAGoodrichAWGraff-RadfordJ, et al.Altered structural and functional connectivity in posterior cortical atrophy and dementia with Lewy bodies. Neuroimage2024; 290: 120564.
56.
GalvinJEPriceJLYanZ, et al.Resting bold fMRI differentiates dementia with Lewy bodies vs Alzheimer disease. Neurology2011; 76: 1797–1803.
57.
FranciottiRFalascaNWBonanniL, et al.Default network is not hypoactive in dementia with fluctuating cognition: an Alzheimer disease/dementia with Lewy bodies comparison. Neurobiol Aging2013; 34: 1148–1158.
58.
Andrews-HannaJRSmallwoodJSprengRN. The default network and self-generated thought: component processes, dynamic control, and clinical relevance. Ann N Y Acad Sci2014; 1316: 29–52.
59.
NicastroNMakESurendranathanA, et al.Altered structural connectivity networks in dementia with Lewy bodies. Brain Imaging Behav2021; 15: 2445–2453.
60.
KobelevaXFirbankMPerazaL, et al.Divergent functional connectivity during attentional processing in Lewy body dementia and Alzheimer’s disease. Cortex2017; 92: 8–18.
61.
LiuYYuCZhangX, et al.Impaired long distance functional connectivity and weighted network architecture in Alzheimer’s disease. Cereb Cortex2014; 24: 1422–1435.
62.
MaW-YYaoQHuG, et al.Dysfunctional dynamics of intra- and inter-network connectivity in dementia with Lewy bodies. Front Neurol2019; 10: 1265.
63.
SchumacherJPerazaLRFirbankM, et al.Dynamic functional connectivity changes in dementia with Lewy bodies and Alzheimer’s disease. Neuroimage Clin2019; 22: 101812.
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