Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Current Neurology and Neuroscience Reports
Published in: Current Neurology and Neuroscience Reports 10/2014

01-10-2014 | Neuroimaging (DJ Brooks, Section Editor)

Disruption of Resting Functional Connectivity in Alzheimer’s Patients and At-Risk Subjects

Authors: Lenka Krajcovicova, Radek Marecek, Michal Mikl, Irena Rektorova

Published in: Current Neurology and Neuroscience Reports | Issue 10/2014

Login to get access

Abstract

The resting brain exhibits continuous intrinsic activity, which is correlated between groups of regions forming resting state networks. Evaluating resting connectivity is a popular approach for studying brain diseases. Several hundred studies are now available that address integrity of resting connectivity in patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI), as well as preclinical at-risk subjects. Most studies focus on the default mode network, a system of specific brain areas showing strong connected resting activity that attenuates during goal-directed behavior. The extent of intrinsic brain activity tends to be strongly correlated with cognitive processes and is specifically disrupted in AD and MCI patients and at-risk subjects, with changes seeming to evolve during the transition between the disease stages. In this study, we review the current findings in default mode network and other resting state network studies in AD and MCI patients and at-risk subjects as assessed by resting state functional magnetic resonance imaging.
Literature
1.
Buckner RL, Vincent JL. Unrest at rest: default activity and spontaneous network correlations. Neuroimage. 2007;37(4):1091–6.PubMedCrossRef
2.
van den Heuvel MP, Mandl RC, Kahn RS, Hulshoff Pol HE. Functionally linked resting-state networks reflect the underlying structural connectivity architecture of the human brain. Hum Brain Mapp. 2009;30(10):3127–41.PubMedCrossRef
3.
Rektorova I. Resting-state networks in Alzheimer's disease and Parkinson's disease. Neurodegener Dis. 2014;13(2–3):186–8.PubMed
4.
He Y, Chen Z, Gong G, Evans A. Neuronal networks in Alzheimer's disease. Neuroscientist. 2009;15(4):333–50.PubMedCrossRef
5.
Supekar K, Menon V, Rubin D, Musen M, Greicius MD. Network analysis of intrinsic functional brain connectivity in Alzheimer's disease. Plos Computational Biol. 2008;4(6).
6.
Buckner RL, Sepulcre J, Talukdar T, Krienen FM, Liu HS, Hedden T, et al. Cortical hubs revealed by intrinsic functional connectivity: mapping, assessment of stability, and relation to Alzheimer's disease. J Neurosci. 2009;29(6):1860–73.PubMedPubMedCentralCrossRef
7.
Bai F, Shi Y, Yuan Y, Wang Y, Yue C, Teng Y, et al. Altered self-referential network in resting-state amnestic type mild cognitive impairment. Cortex. 2012;48(5):604–13.PubMedCrossRef
8.
Yao H, Liu Y, Zhou B, Zhang Z, An N, Wang P, et al. Decreased functional connectivity of the amygdala in Alzheimer's disease revealed by resting-state fMRI. Eur J Radiol. 2013;82(9):1531–8.PubMedCrossRef
9.
Gour N, Ranjeva JP, Ceccaldi M, Confort-Gouny S, Barbeau E, Soulier E, et al. Basal functional connectivity within the anterior temporal network is associated with performance on declarative memory tasks. Neuroimage. 2011;58(2):687–97.PubMedCrossRef
10.
Li R, Wu X, Chen K, Fleisher AS, Reiman EM, Yao L. Alterations of directional connectivity among resting-state networks in Alzheimer disease. AJNR Am J Neuroradiol. 2013;34(2):340–5.PubMedPubMedCentralCrossRef
11.
Wen X, Wu X, Li R, Fleisher AS, Reiman EM, Chen K, et al. Alzheimer's disease-related changes in regional spontaneous brain activity levels and inter-region interactions in the default mode network. Brain Res. 2013;1509:58–65.PubMedCrossRef
12.••
Jones DT, Machulda MM, Vemuri P, McDade EM, Zeng G, Senjem ML, et al. Age-related changes in the default mode network are more advanced in Alzheimer disease. Neurology. 2011;77(16):1524–31. Age-associated connectivity declines in the posterior DMN are greater in the AD group, whereas the anterior DMN age-associated connectivity changes in the frontal lobe lose specificity in the AD group, which displayed diffuse frontal lobe increases in connectivity. Greater connectivity in the frontal lobe (an older and AD pattern of connectivity) was found in subjects with poorer performance.PubMedPubMedCentralCrossRef
13.
Wu X, Li R, Fleisher AS, Reiman EM, Guan XT, Zhang YM, et al. Altered default mode network connectivity in Alzheimer's disease‒a resting functional MRI and Bayesian Network Study. Hum Brain Mapp. 2011;32(11):1868–81.PubMedPubMedCentralCrossRef
14.
Allen EA, Erhardt EB, Damaraju E, Gruner W, Segall JM, Silva RF, et al. A baseline for the multivariate comparison of resting-state networks. Front Syst Neurosci. 2011;5:2.PubMedPubMedCentral
15.
Binnewijzend MA, Adriaanse SM, Van der Flier WM, Teunissen CE, de Munck JC, Stam CJ, et al. Brain network alterations in Alzheimer's disease measured by eigenvector centrality in fMRI are related to cognition and CSF biomarkers. Hum Brain Mapp. 2014;35(5):2383–93.PubMedCrossRef
16.
Yao Z, Zhang Y, Lin L, Zhou Y, Xu C, Jiang T. Abnormal cortical networks in mild cognitive impairment and Alzheimer's disease. PLoS Comput Biol. 2010;6(11):e1001006.PubMedPubMedCentralCrossRef
17.
Han Y, Wang J, Zhao Z, Min B, Lu J, Li K, et al. Frequency-dependent changes in the amplitude of low-frequency fluctuations in amnestic mild cognitive impairment: a resting-state fMRI study. Neuroimage. 2011;55(1):287–95.PubMedCrossRef
18.
Zhang Z, Liu Y, Jiang T, Zhou B, An N, Dai H, et al. Altered spontaneous activity in Alzheimer's disease and mild cognitive impairment revealed by regional homogeneity. Neuroimage. 2012;59(2):1429–40.PubMedCrossRef
19.
Warsi MA, Molloy W, Noseworthy MD. Correlating brain blood oxygenation level dependent (BOLD) fractal dimension mapping with magnetic resonance spectroscopy (MRS) in Alzheimer's disease. Magma. 2012;25(5):335–44.PubMedCrossRef
20.
Liu CY, Krishnan AP, Yan L, Smith RX, Kilroy E, Alger JR, et al. Complexity and synchronicity of resting state blood oxygenation level-dependent (BOLD) functional MRI in normal aging and cognitive decline. J Magn Reson Imaging. 2013;38(1):36–45.PubMedPubMedCentralCrossRef
21.
Laufs H, Krakow K, Sterzer P, Eger E, Beyerle A, Salek-Haddadi A, et al. Electroencephalographic signatures of attentional and cognitive default modes in spontaneous brain activity fluctuations at rest. Proc Natl Acad Sci U S A. 2003;100(19):11053–8.PubMedPubMedCentralCrossRef
22.
Zhou Y, Dougherty Jr JH, Hubner KF, Bai B, Cannon RL, Hutson RK. Abnormal connectivity in the posterior cingulate and hippocampus in early Alzheimer's disease and mild cognitive impairment. Alzheimers Dement. 2008;4(4):265–70.PubMedCrossRef
23.
24.
Xia M, Wang Z, Dai Z, Liang X, Song H, Shu N, et al. Differentially disrupted functional connectivity in posteromedial cortical subregions in Alzheimer's disease. J Alzheimers Dis. 2014;39(3):527–43.PubMed
25.•
Damoiseaux JS, Prater KE, Miller BL, Greicius MD. Functional connectivity tracks clinical deterioration in Alzheimer's disease. Neurobiol Aging. 2012;33(4):828.e19–30. Authors found decreased connectivity in the posterior DMN and increased connectivity in both the ventral and anterior DMN in AD patients. After follow-up (35.5+/- 11.5 months), AD showed significantly decreased connectivity in all resting state networks. The compensatory increases in connectivity in the frontal cortex (that is relatively preserved early in the disease) become targeted by AD pathology as the disease progresses and its connectivity also declines.CrossRef
26.
Hagmann P, Cammoun L, Gigandet X, Meuli R, Honey CJ, Wedeen VJ, et al. Mapping the structural core of human cerebral cortex. PLoS Biol. 2008;6(7):e159.PubMedPubMedCentralCrossRef
27.
Bullmore E, Sporns O. Complex brain networks: graph theoretical analysis of structural and functional systems. Nat Rev Neurosci. 2009;10(3):186–98.PubMedCrossRef
28.
Wang L, Zang YF, He Y, Liang M, Zhang XQ, Tian LX, et al. Changes in hippocampal connectivity in the early stages of Alzheimer's disease: evidence from resting state fMRI. Neuroimage. 2006;31(2):496–504.PubMedCrossRef
29.
He Y, Wang L, Zang Y, Tian L, Zhang X, Li K, et al. Regional coherence changes in the early stages of Alzheimer's disease: a combined structural and resting-state functional MRI study. Neuroimage. 2007;35(2):488–500.PubMedCrossRef
30.
Schwindt GC, Chaudhary S, Crane D, Ganda A, Masellis M, Grady CL, et al. Modulation of the default-mode network between rest and task in Alzheimer's Disease. Cereb Cortex. 2013;23(7):1685–94.PubMedCrossRef
31.
Cha J, Jo HJ, Kim HJ, Seo SW, Kim HS, Yoon U, et al. Functional alteration patterns of default mode networks: comparisons of normal aging, amnestic mild cognitive impairment and Alzheimer's disease. Eur J Neurosci. 2013;37(12):1916–24.PubMedPubMedCentralCrossRef
32.
Binnewijzend MAA, Schoonheim MM, Sanz-Arigita E, Wink AM, van der Flier WM, Tolboom N, et al. Resting-state fMRI changes in Alzheimer's disease and mild cognitive impairment. Neurobiol Aging. 2012;33(9):2018–28.PubMedCrossRef
33.
Franciotti R, Falasca NW, Bonanni L, Anzellotti F, Maruotti V, Comani S, et al. Default network is not hypoactive in dementia with fluctuating cognition: an Alzheimer disease/dementia with Lewy bodies comparison. Neurobiol Aging. 2013;34(4):1148–58.PubMedCrossRef
34.
Krajcovicova L, Mikl M, Marecek R, Rektorova I.Disturbed default mode network connectivity patterns in Alzheimer's disease associated with visual processing. J Alzheimers Dis. 2014;41(4):1229-38.
35.
Zhang HY, Wang SJ, Liu B, Ma ZL, Yang M, Zhang ZJ, et al. Resting brain connectivity: changes during the progress of Alzheimer disease. Radiology. 2010;256(2):598–606.PubMedCrossRef
36.••
Agosta F, Pievani M, Geroldi C, Copetti M, Frisoni GB, Filippi M. Resting state fMRI in Alzheimer's disease: beyond the default mode network. Neurobiol Aging. 2012;33(8):1564–78. AD showed decresed resting state connectivity in the DMN and increased connectivity in frontal networks compared with both MCI and healthy subjects. MCI showed reduced connectivity in the precuneus; reduction in precuneus resting state intrinsic activity seems to be present since the early phase of AD.PubMedCrossRef
37.•
Koch W, Teipel S, Mueller S, Benninghoff J, Wagner M, Bokde ALW, et al. Diagnostic power of default mode network resting state fMRI in the detection of Alzheimer's disease. Neurobiol Aging. 2012;33(3):466–78. Authors used both ICA and signal time course analysis to evaluate DMN in AD and MCI. Interconnectivity of almost all DMN regions was lower in AD patients than in healthy controls; differences were most accentuated in parietal cortex and the superior frontal cortex. With multivariate analyses combining both methods of analysis, the diagnostic power fo AD could be increased.PubMedCrossRef
38.
Dai Z, Yan C, Wang Z, Wang J, Xia M, Li K, et al. Discriminative analysis of early Alzheimer's disease using multi-modal imaging and multi-level characterization with multi-classifier (M3). Neuroimage. 2012;59(3):2187–95.PubMedCrossRef
39.
Chhatwal JP, Schultz AP, Johnson K, Benzinger TL, Jack Jr C, Ances BM, et al. Impaired default network functional connectivity in autosomal dominant Alzheimer disease. Neurology. 2013;81(8):736–44.PubMedPubMedCentralCrossRef
40.
Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, et al. Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci. 2005;25(34):7709–17.PubMedCrossRef
41.
Wermke M, Sorg C, Wohlschläger AM, Drzezga A. A new integrative model of cerebral activation, deactivation and default mode function in Alzheimer's disease. Eur J Nucl Med Mol Imaging. 2008;35(Suppl 1):S12–24.
42.
Zarei M, Beckmann CF, Binnewijzend MA, Schoonheim MM, Oghabian MA, Sanz-Arigita EJ, et al. Functional segmentation of the hippocampus in the healthy human brain and in Alzheimer's disease. Neuroimage. 2012;66c:28–35.PubMed
43.
Zhang HY, Wang SJ, Xing J, Liu B, Ma ZL, Yang M, et al. Detection of PCC functional connectivity characteristics in resting-state fMRI in mild Alzheimer's disease. Behav Brain Res. 2009;197(1):103–8.PubMedCrossRef
44.•
Esposito R, Mosca A, Pieramico V, Cieri F, Cera N, Sensi SL. Characterization of resting state activity in MCI individuals. PeerJ. 2013;1:e135. MCI subjects showed increased intrinsic connectivity in the DMN (namely the PCC and left inferior parietal lobule) and in the sensorimotor network. During the three years follow-up, the subset of MCI AD-converted patients showed increased connectivity only in the right IPL, (ie, the connectivity in PCC diminished with the disease progression).
45.
Zamboni G, Wilcock GK, Douaud G, Drazich E, McCulloch E, Filippini N, et al. Resting functional connectivity reveals residual functional activity in Alzheimer's disease. Biol Psychiatry. 2013;74(5):375–83.PubMedCrossRef
46.
Wang K, Liang M, Wang L, Tian L, Zhang X, Li K, et al. Altered functional connectivity in early Alzheimer's disease: a resting-state fMRI study. Hum Brain Mapp. 2007;28(10):967–78.PubMedCrossRef
47.•
Brier MR, Thomas JB, Snyder AZ, Benzinger TL, Zhang D, Raichle ME, et al. Loss of intranetwork and internetwork resting state functional connections with Alzheimer's disease progression. J Neurosci. 2012;32(26):8890–9. Authors analyzed 5 resting state networks - DMN, dorsal attention network, salience network, control network and sensorimotor network comparing the AD patients in various CDR stage. All RSNs were affected with increasing AD severity.PubMedPubMedCentralCrossRef
48.
Li R, Wu X, Fleisher AS, Reiman EM, Chen K, Yao L. Attention-related networks in Alzheimer's disease: A resting functional MRI study. Hum Brain Mapp. 2012;33(5):1076–88.PubMedPubMedCentralCrossRef
49.
Liu Z, Zhang Y, Bai L, Yan H, Dai R, Zhong C, et al. Investigation of the effective connectivity of resting state networks in Alzheimer's disease: a functional MRI study combining independent components analysis and multivariate Granger causality analysis. NMR Biomed. 2012;25(12):1311–20.PubMedCrossRef
50.
Song J, Qin W, Liu Y, Duan Y, Liu J, He X, et al. Aberrant functional organization within and between resting-state networks in AD. PLoS One. 2013;8(5).
51.
52.
Xie C, Bai F, Yu H, Shi Y, Yuan Y, Chen G, et al. Abnormal insula functional network is associated with episodic memory decline in amnestic mild cognitive impairment. Neuroimage. 2012;63(1):320–7.PubMedCrossRef
53.
Zhou B, Liu Y, Zhang Z, An N, Yao H, Wang P, et al. Impaired functional connectivity of the thalamus in Alzheimer's disease and mild cognitive impairment: a resting-state fMRI study. Curr Alzheimer Res. 2013;10(7):754–66.PubMedCrossRef
54.
Li Y, Qin Y, Chen X, Li W. Exploring the functional brain network of Alzheimer's disease: based on the computational experiment. PLoS One. 2013;8(9):e73186.PubMedPubMedCentralCrossRef
55.
He Y, Chen Z, Evans A. Structural insights into aberrant topological patterns of large-scale cortical networks in Alzheimer's disease. J Neurosci. 2008;28(18):4756–66.PubMedCrossRef
56.
Liu Z, Zhang Y, Yan H, Bai L, Dai R, Wei W, et al. Altered topological patterns of brain networks in mild cognitive impairment and Alzheimer's disease: a resting-state fMRI study. Psychiatry Res. 2012;202(2):118–25.PubMedCrossRef
57.
Sanz-Arigita EJ, Schoonheim MM, Damoiseaux JS, Rombouts S, Maris E, Barkhof F, et al. Loss of 'small-world' networks in Alzheimer's disease: graph analysis of fMRI resting-state functional connectivity. Plos One. 2010;5(11).
58.•
Tijms BM, Moller C, Vrenken H, Wink AM, de Haan W, van der Flier WM, et al. Single-subject grey matter graphs in Alzheimer's disease. PLoS One. 2013;8(3):e58921. AD networks were characterised by a more random topology. Altered path lenght of the parahippocampal and hippocampal gyrus, fusiform gyrus and precuneus showed the strongest relationship with cognitie decline.PubMedPubMedCentralCrossRef
59.
Chen G, Zhang HY, Xie C, Zhang ZJ, Teng GJ, Li SJ. Modular reorganization of brain resting state networks and its independent validation in Alzheimer's disease patients. Front Hum Neurosci. 2013;7:456.PubMedPubMedCentral
60.
Dickerson BC, Sperling RA. Large-scale functional brain network abnormalities in Alzheimer's disease: insights from functional neuroimaging. Behav Neurol. 2009;21(1):63–75.PubMedPubMedCentralCrossRef
61.
62.
Petrella JR, Sheldon FC, Prince SE, Calhoun VD, Doraiswamy PM. Default mode network connectivity in stable vs progressive mild cognitive impairment. Neurology. 2011;76(6):511–7.PubMedPubMedCentralCrossRef
63.
Zaidel L, Allen G, Cullum CM, Briggs RW, Hynan LS, Weiner MF, et al. Donepezil effects on hippocampal and prefrontal functional connectivity in Alzheimer's disease: preliminary report. J Alzheimers Dis. 2012;31 Suppl 3:S221–6.PubMedPubMedCentral
64.
Sole-Padulles C, Bartres-Faz D, Llado A, Bosch B, Pena-Gomez C, Castellvi M, et al. Donepezil treatment stabilizes functional connectivity during resting state and brain activity during memory encoding in Alzheimer's disease. J Clin Psychopharmacol. 2013;33(2):199–205.PubMedCrossRef
65.
Li W, Antuono PG, Xie C, Chen G, Jones JL, Ward BD, et al. Changes in regional cerebral blood flow and functional connectivity in the cholinergic pathway associated with cognitive performance in subjects with mild Alzheimer's disease after 12-week donepezil treatment. Neuroimage. 2012;60(2):1083–91.PubMedPubMedCentralCrossRef
66.
Lorenzi M, Beltramello A, Mercuri NB, Canu E, Zoccatelli G, Pizzini FB, et al. Effect of memantine on resting state default ode network activity in Alzheimer's disease. Drugs Aging. 2011;28(3):205.PubMedCrossRef
67.
Fox MD, Snyder AZ, Vincent JL, Corbetta M, Van Essen DC, Raichle ME. The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc Natl Acad Sci U S A. 2005;102(27):9673–8.PubMedPubMedCentralCrossRef
68.
Fox MD, Raichle ME. Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nat Rev Neurosci. 2007;8(9):700–11.PubMedCrossRef
69.•
Jack CR, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, et al. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013;12(2):207–16. Review on biomarkers in AD, MCI and preclinical at-risk subjects.PubMedPubMedCentralCrossRef
70.•
Machulda MM, Jones DT, Vemuri P, McDade E, Avula R, Przybelski S, et al. Effect of APOE epsilon4 status on intrinsic network connectivity in cognitively normal elderly subjects. Arch Neurol. 2011;68(9):1131–6. The posterior DMN revealed decreased connectivity and the salience network showed greater connectivity in the APO-E ε4 carriers relative to noncarriers in the absence of structural changes.PubMedPubMedCentralCrossRef
71.
Filippini N, MacIntosh BJ, Hough MG, Goodwin GM, Frisoni GB, Smith SM, et al. Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele. Proc Natl Acad Sci U S A. 2009;106(17):7209–14.PubMedPubMedCentralCrossRef
72.
Seeley WW, Crawford RK, Zhou J, Miller BL, Greicius MD. Neurodegenerative diseases target large-scale human brain networks. Neuron. 2009;62(1):42–52.PubMedPubMedCentralCrossRef
73.•
Wang Z, Yan C, Zhao C, Qi Z, Zhou W, Lu J, et al. Spatial patterns of intrinsic brain activity in mild cognitive impairment and Alzheimer's disease: a resting-state functional MRI study. Hum Brain Mapp. 2011;32(10):1720–40. PCC showed the most significant alterations in resting state intrinsic activity in both AD and MCI. Compared with MCI, AD showed decreased connectivity in the medial prefrontal cortex.PubMedCrossRef
74.
Miao XY, Wu X, Li R, Chen KW, Yao L. Altered connectivity pattern of hubs in default-mode network with Alzheimer's disease: a granger causality modeling approach. Plos One. 2011;6(10).
75.
76.
Rektorova I, Krajcovicova L, Marecek R, Mikl M. Default mode network and extrastriate visual resting state network in patients with Parkinson's disease dementia. Neurodegener Dis. 2012;10(1-4):232-7.
77.
Anderkova L, Rektorova I. Cognitive effects of repetitive transcranial magnetic stimulation in patients with neurodegenerative diseases - clinician's perspective. J Neurol Sci. 2014;339(1-2):15-25.PubMedCrossRef
Metadata
Title
Disruption of Resting Functional Connectivity in Alzheimer’s Patients and At-Risk Subjects
Authors
Lenka Krajcovicova
Radek Marecek
Michal Mikl
Irena Rektorova
Publication date
01-10-2014
Publisher
Springer US
Published in
Current Neurology and Neuroscience Reports / Issue 10/2014
Print ISSN: 1528-4042
Electronic ISSN: 1534-6293
DOI
https://doi.org/10.1007/s11910-014-0491-3

Other articles of this Issue 10/2014

Current Neurology and Neuroscience Reports 10/2014 Go to the issue

Neurotrauma (J Levine, Section Editor)

Inflammation and Immune System Activation After Traumatic Brain Injury

Genetics (V Bonifati, Section Editor)

The Genetics of Primary Familial Brain Calcifications

Demyelinating Disorders (DN Bourdette and V Yadav, Section Editors)

X-Linked Adrenoleukodystrophy: Pathogenesis and Treatment

Demyelinating Disorders (DN Bourdette and V Yadav, Section Editors)

Remyelination and Multiple Sclerosis: Therapeutic Approaches and Challenges

Neurology of Systemic Disease (J Biller, Section Editor)

Neurologic Manifestations of Gastrointestinal and Liver Diseases

Demyelinating Disorders (DN Bourdette and V Yadav, Section Editors)

Gut Microbiome and Multiple Sclerosis