Functional Connectivity Alterations in Early-Stage Cognitive Decline: An MRI-Based Study
DOI:
https://doi.org/10.5281/zenodo.22849447Keywords:
functional connectivity, resting-state fMRI, mild cognitive impairment, default mode network, Alzheimer's disease biomarkersAbstract
Resting-state functional MRI has become one of the most actively studied candidate tools for detecting brain changes in Alzheimer's disease before the structural atrophy visible on conventional imaging emerges. This article synthesizes the literature on functional connectivity alterations in early-stage cognitive decline, from healthy older adults at biomarker-defined risk through mild cognitive impairment (MCI). We trace the field from the methodological foundations of intrinsic connectivity networks and graph-theoretic analysis, through the now well-replicated finding that default mode network (DMN) connectivity is reduced in at-risk and MCI populations, to whole-brain graph-theoretic evidence that this disruption preferentially targets hub regions such as the hippocampus and degrades global network efficiency rather than remaining confined to a single pathway. We review how successive diagnostic frameworks, from Petersen's original MCI criteria through the NIA-AA biomarker-based Research Framework, have progressively refined the populations these studies examine, and how multi-site cohort infrastructure such as ADNI has supported more generalizable findings. Read together, the evidence supports default mode network hypoconnectivity as a genuine, reproducible early functional signature of the Alzheimer's disease continuum, while leaving longitudinal validation of its predictive value, biomarker-based stratification of study populations, and the diagnostic utility of dynamic (non-stationary) connectivity measures as an active research agenda rather than a settled question.
References
Fox, M.D., Raichle, M.E. (2007) Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nature Reviews Neuroscience, 8(9): 700-711. DOI: 10.1038/nrn2201
Raichle, M.E., MacLeod, A.M., Snyder, A.Z., Powers, W.J., Gusnard, D.A., Shulman, G.L. (2001) A default mode of brain function. Proceedings of the National Academy of Sciences, 98(2): 676-682. DOI: 10.1073/pnas.98.2.676
Sperling, R.A., LaViolette, P.S., O'Keefe, K., O'Brien, J., Rentz, D.M., Pihlajamaki, M., Marshall, G., Hyman, B.T., Selkoe, D.J., Hedden, T., Buckner, R.L., Becker, J.A., Johnson, K.A. (2009) Amyloid deposition is associated with impaired default network function in older persons without dementia. Neuron, 63(2): 178-188. DOI: 10.1016/j.neuron.2009.07.003
Calhoun, V.D., Adali, T., Pearlson, G.D., Pekar, J.J. (2001) A method for making group inferences from functional MRI data using independent component analysis. Human Brain Mapping, 14(3): 140-151. DOI: 10.1002/hbm.1048
Rubinov, M., Sporns, O. (2010) Complex network measures of brain connectivity: Uses and interpretations. NeuroImage, 52(3): 1059-1069. DOI: 10.1016/j.neuroimage.2009.10.003
Bullmore, E., Sporns, O. (2009) Complex brain networks: Graph theoretical analysis of structural and functional systems. Nature Reviews Neuroscience, 10(3): 186-198. DOI: 10.1038/nrn2575
Greicius, M.D., Srivastava, G., Reiss, A.L., Menon, V. (2004) Default-mode network activity distinguishes Alzheimer's disease from healthy aging: Evidence from functional MRI. Proceedings of the National Academy of Sciences, 101(13): 4637-4642. DOI: 10.1073/pnas.0308627101
Sorg, C., Riedl, V., Muhlau, M., Calhoun, V.D., Eichele, T., Laer, L., Drzezga, A., Forstl, H., Kurz, A., Zimmer, C., Wohlschlager, A.M. (2007) Selective changes of resting-state networks in individuals at risk for Alzheimer's disease. Proceedings of the National Academy of Sciences, 104(47): 18760-18765. DOI: 10.1073/pnas.0708803104
Rombouts, S.A.R.B., Barkhof, F., Goekoop, R., Stam, C.J., Scheltens, P. (2005) Altered resting state networks in mild cognitive impairment and mild Alzheimer's disease: An fMRI study. Human Brain Mapping, 26(4): 231-239. DOI:
1002/hbm.20160 10. Wang, L., Zang, Y., He, Y., Liang, M., Zhang, X., Tian, L., Wu, T., Jiang, T., Li, K. (2007) Altered functional connectivity in early Alzheimer's disease: A resting-state fMRI study. Human Brain Mapping, 28(10): 967-978. DOI: 10.1002/hbm.20324
Zhou, J., Greicius, M.D., Gennatas, E.D., Growdon, M.E., Jang, J.Y., Rabinovici, G.D., Kramer, J.H., Weiner, M., Miller, B.L., Seeley, W.W. (2010) Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer's disease. Brain, 133(5): 1352-1367. DOI: 10.1093/brain/awq075
Damoiseaux, J.S., Prater, K.E., Miller, B.L., Greicius, M.D. (2012) Functional connectivity tracks clinical deterioration in Alzheimer's disease. Neurobiology of Aging, 33(4): 828.e19-828.e30. DOI: 10.1016/j.neurobiolaging.2011.06.024
Supekar, K., Menon, V., Rubin, D., Musen, M., Greicius, M.D. (2008) Network analysis of intrinsic functional brain connectivity in Alzheimer's disease. PLoS Computational Biology, 4(6): e1000100. DOI: 10.1371/journal.pcbi.1000100
Seeley, W.W., Menon, V., Schatzberg, A.F., Keller, J., Glover, G.H., Kenna, H., Reiss, A.L., Greicius, M.D. (2007) Dissociable intrinsic connectivity networks for salience processing and executive control. Journal of Neuroscience, 27(9): 2349-2356. DOI: 10.1523/jneurosci.5587-06.2007
Greicius, M. (2008) Resting-state functional connectivity in neuropsychiatric disorders. Current Opinion in Neurology, 21(4): 424-430. DOI: 10.1097/WCO.0b013e328306f2c5
Petersen, R.C. (2004) Mild cognitive impairment as a diagnostic entity. Journal of Internal Medicine, 256(3): 183-194. DOI: 10.1111/j.1365-2796.2004.01388.x
Albert, M.S., DeKosky, S.T., Dickson, D., Dubois, B., Feldman, H.H., Fox, N.C., Gamst, A., Holtzman, D.M., Jagust, W.J., Petersen, R.C., Snyder, P.J., Carrillo, M.C., Thies, B., Phelps, C.H. (2011) 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. Alzheimer's & Dementia, 7(3): 270-279. DOI: 10.1016/j.jalz.2011.03.008
Jack, C.R., Bennett, D.A., Blennow, K., Carrillo, M.C., Dunn, B., Haeberlein, S.B., Holtzman, D.M., Jagust, W., Jessen, F., Karlawish, J., Liu, E., Molinuevo, J.L., Montine, T., Phelps, C., Rankin, K.P., Rowe, C.C., Scheltens, P., Siemers, E., Snyder, H.M., Sperling, R. (2018) NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimer's & Dementia, 14(4): 535-562. DOI: 10.1016/j.jalz.2018.02.018
Petersen, R.C., Aisen, P.S., Beckett, L.A., Donohue, M.C., Gamst, A.C., Harvey, D.J., Jack, C.R., Jagust, W.J., Shaw, L.M., Toga, A.W., Trojanowski, J.Q., Weiner, M.W. (2010) Alzheimer's Disease Neuroimaging Initiative (ADNI): Clinical characterization. Neurology, 74(3): 201-209. DOI: 10.1212/WNL.0b013e3181cb3e25
Hutchison, R.M., Womelsdorf, T., Allen, E.A., Bandettini, P.A., Calhoun, V.D., Corbetta, M., Della Penna, S., Duyn, J.H., Glover, G.H., Gonzalez-Castillo, J., Handwerker, D.A., Keilholz, S., Kiviniemi, V., Leopold, D.A., de Pasquale, F., Sporns, O., Walter, M., Chang, C. (2013) Dynamic functional connectivity: Promise, issues, and interpretations. NeuroImage, 80: 360-378. DOI: 10.1016/j.neuroimage.2013.05.079
Dennis, E.L., Thompson, P.M. (2014) Functional brain connectivity using fMRI in aging and Alzheimer's disease. Neuropsychology Review, 24(1): 49-62. DOI: 10.1007/s11065-014-9249-6
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