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Default mode network activity and white matter integrity in healthy middle-aged ApoE4 carriers

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Abstract

Alzheimer’s disease (AD) is most commonly detected during old age, but the underlying neuropathologic changes likely appear decades earlier, especially among patients possessing genetic risk factors, such as the isoform E4 of the apolipoprotein E (ApoE4). In this study, we used magnetic resonance imaging (MRI) to assess default mode network (DMN) connectivity in 22 ApoE4 non-carriers and 14 matched ApoE4 carriers as well as white matter fractional anisotropy (FA) in 15 ApoE4 non-carriers and 11 demographically matched ApoE4 carriers. Cognitive tests were also administered. All of the participants were middle-aged adults. The analysis revealed no cognitive or white matter FA differences between carriers and non-carriers. However, in DMN regions previously implicated in AD, we did detect decreased functional connectivity. Our findings suggest that functional MRI abnormalities may be detectable well before cognitive decline or white matter changes among individuals at increased genetic risk for AD.

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References

  • Axelrod, B. N., & Ryan, J. J. (2000). Prorating Wechsler adult intelligence scale-III summary scores. Journal of Clinical Psychology, 56(6), 807–811.

    Article  PubMed  CAS  Google Scholar 

  • Behrens, T. E., Woolrich, M. W., Jenkinson, M., Johansen-Berg, H., Nunes, R. G., Clare, S., et al. (2003). Characterization and propagation of uncertainty in diffusion-weighted MR imaging. Magnetic Resonance in Medicine, 50(5), 1077–88.

    Article  PubMed  CAS  Google Scholar 

  • Bell, A. J., & Sejnowski, T. J. (1995). An information-maximization approach to blind separation and blind deconvolution. Neural Computation, 7(6), 1129–1159.

    Article  PubMed  CAS  Google Scholar 

  • Binnewijzend, M. A, Schoonheim, M. M., Sanz-Arigita, E., Wink, A. M., van der Flier, W. M., Tolboom, N., et al. (2011). Resting-state fMRI changes in Alzheimer’s disease and mild cognitive impairment. Neurobiology of Aging.

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Cherner, M., Suarez, P., Lazzaretto, D., Fortuny, L. A., Mindt, M. R., Dawes, S., et al. (2007). Demographically corrected norms for the Brief Visuospatial Memory Test-revised and Hopkins Verbal Learning Test-revised in monolingual Spanish speakers from the U.S.-Mexico border region. Archives of Clinical Neuropsychology, 22(3), 343–353.

    Article  PubMed  CAS  Google Scholar 

  • Damoiseaux, J. S., Prater, K. E., Miller, B. L., & Greicius, M. D. (2011). Functional connectivity tracks clinical deterioration in Alzheimer’s disease. Neurobiology of Aging.

  • Delis, D., Kaplan, E., & Kramer, J. (2001). Delis Kaplan executive function system. San Antonio: The Psychological Corporation.

    Google Scholar 

  • Filippini, N., MacIntosh, B. J., Hough, M. G., Goodwin, G. M., Frisoni, G. B., Smith, S. M., et al. (2009). Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele. Proceedings of the National Academy of Sciences of the United States of America, 106(17), 7209–7214.

    Article  PubMed  CAS  Google Scholar 

  • Filippini, N., Ebmeier, K. P., MacIntosh, B. J., Trachtenberg, A. J., Frisoni, G. B., Wilcock, G. K., et al. (2011). Differential effects of the APOE genotype on brain function across the lifespan. NeuroImage, 54(1), 602–610.

    Article  PubMed  CAS  Google Scholar 

  • Fleisher, A. S., Sherzai, A., Taylor, C., Langbaum, J. B., Chen, K., & Buxton, R. B. (2009). Resting-state BOLD networks versus task-associated functional MRI for distinguishing Alzheimer’s disease risk groups. NeuroImage, 47(4), 1678–1690.

    Article  PubMed  Google Scholar 

  • 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 of the United States of America, 101(13), 4637–4642.

    Article  PubMed  CAS  Google Scholar 

  • Hampel, H., Prvulovic, D., Teipel, S. J., & Bokde, A. L. (2011). Recent developments of functional magnetic resonance imaging research for drug development in Alzheimer’s disease. Progres in Neurobiology.

  • He, Y., Wang, L., Zang, Y., Tian, L., Zhang, X., Li, K., et al. (2007). Regional coherence changes in the early stages of Alzheimer’s disease: a combined structural and resting-state functional MRI study. NeuroImage, 35(2), 488–500.

    Article  PubMed  Google Scholar 

  • Heise, V., Filippini, N., Ebmeier, K. P., & Mackay, C. E. (2011). The APOE varepsilon4 allele modulates brain white matter integrity in healthy adults. Molecular Psychiatry, 16(9), 908–916.

    Article  PubMed  CAS  Google Scholar 

  • Honea, R. A., Vidoni, E., Harsha, A., & Burns, J. M. (2009). Impact of APOE on the healthy aging brain: a voxel-based MRI and DTI study. Journal of Alzheimer’s Disease, 18(3), 553–564.

    PubMed  Google Scholar 

  • Jenkinson, M., & Smith, S. (2001). A global optimisation method for robust affine registration of brain images. Medical Image Analysis, 5(2), 143–156.

    Article  PubMed  CAS  Google Scholar 

  • Klein, C., Hagenah, J., Landwehrmeyer, B., Munte, T., & Klockgether, T. (2011). The presymptomatic stage of neurodegenerative disorders. Nervenarzt, 82(8), 994–1001.

    Article  PubMed  CAS  Google Scholar 

  • Klove, H. (1963). Clinical Neuropsychology. In F. M. Forster (Ed.), Medical clinics of North America. New York: Saunders.

    Google Scholar 

  • Li, Y. O., Adali, T., & Calhoun, V. D. (2007). Estimating the number of independent components for functional magnetic resonance imaging data. Human Brain Mapping, 28(11), 1251–1266.

    Article  PubMed  Google Scholar 

  • Likitjaroen, Y., Meindl, T., Friese, U., Wagner, M., Buerger, K., Hampel, H. et al. (2011). Longitudinal changes of fractional anisotropy in Alzheimer’s disease patients treated with galantamine: a 12-month randomized, placebo-controlled, double-blinded study. European Archives of Psychiatry and Clinical Neuroscience.

  • Lind, J., Persson, J., Ingvar, M., Larsson, A., Cruts, M., Van Broeckhoven, C., et al. (2006). Reduced functional brain activity response in cognitively intact apolipoprotein E epsilon4 carriers. Brain, 129(Pt 5), 1240–1248.

    Article  PubMed  Google Scholar 

  • Liu, Y., Wang, K., Yu, C., He, Y., Zhou, Y., Liang, M., et al. (2008). Regional homogeneity, functional connectivity and imaging markers of Alzheimer’s disease: a review of resting-state fMRI studies. Neuropsychologia, 46(6), 1648–1656.

    Article  PubMed  Google Scholar 

  • Medina, D., DeToledo-Morrell, L., Urresta, F., Gabrieli, J. D., Moseley, M., Fleischman, D., et al. (2006). White matter changes in mild cognitive impairment and AD: A diffusion tensor imaging study. Neurobiology of Aging, 27(5), 663–672.

    Article  PubMed  Google Scholar 

  • Nichols, T. E., Holmes, A. P. (2001). Nonparametric permutation tests for functional neuroimaging: a primer with examples. Hum Brain Mapp 15, 1–25.

    Google Scholar 

  • 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 of the United States of America, 98(2), 676–682.

    Article  PubMed  CAS  Google Scholar 

  • Randolph, C. (1998). Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): Test manual. San Antonio: Harcourt Brace and Company.

    Google Scholar 

  • Reiman, E. M., Chen, K., Alexander, G. E., Caselli, R. J., Bandy, D., Osborne, D., et al. (2004). Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer’s dementia. Proceedings of the National Academy of Sciences of the United States of America, 101(1), 284–289.

    Article  PubMed  CAS  Google Scholar 

  • Reitan, R. M. (1958). Validity of the Trail Making Test as an indi- cator of organic brain damage. Perceptual and Motor Skills, 8, 271–276.

    Google Scholar 

  • Rombouts, S. A., 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.

    Article  PubMed  Google Scholar 

  • Ryan, J. J., & Schnakenberg-Ott, S. D. (2003). Scoring reliability on the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III). Assessment, 10(2), 151–159.

    Article  PubMed  Google Scholar 

  • Sheline, Y. I., Morris, J. C., Snyder, A. Z., Price, J. L., Yan, Z., D’Angelo, G., et al. (2010). APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Abeta42. Journal of Neuroscience, 30(50), 17035–17040.

    Article  PubMed  CAS  Google Scholar 

  • Smith, S. M. (2002). Fast robust automated brain extraction. Human Brain Mapping, 17(3), 143–155.

    Article  PubMed  Google Scholar 

  • Smith, S. M., & Nichols, T. E. (2009). Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localisation in cluster inference. NeuroImage, 44(1), 83–98.

    Article  PubMed  Google Scholar 

  • Smith, S. M., Jenkinson, M., Johansen-Berg, H., Rueckert, D., Nichols, T. E., Mackay, C. E., et al. (2006). Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data. NeuroImage, 31(4), 1487–1505.

    Article  PubMed  Google Scholar 

  • Spampinato, M. V., Rumboldt, Z., Hosker, R. J., & Mintzer, J. E. (2011). Apolipoprotein E and gray matter volume loss in patients with mild cognitive impairment and Alzheimer disease. Radiology, 258(3), 843–852.

    Article  PubMed  Google Scholar 

  • Trachtenberg, A. J., Filippini, N., Ebmeier, K. P., Smith, S. M., Karpe, F., & Mackay, C. E. (2012). The effects of APOE on the functional architecture of the resting brain. NeuroImage, 59(1), 565–572.

    Article  PubMed  CAS  Google Scholar 

  • Wang, L., Zang, Y., He, Y., Liang, M., Zhang, X., Tian, L., et al. (2006). Changes in hippocampal connectivity in the early stages of Alzheimer’s disease: evidence from resting state fMRI. NeuroImage, 31(2), 496–504.

    Article  PubMed  Google Scholar 

  • Wang, K., Liang, M., Wang, L., Tian, L., Zhang, X., Li, K., et al. (2007). Altered functional connectivity in early Alzheimer’s disease: a resting-state fMRI study. Human Brain Mapping, 28(10), 967–978.

    Article  PubMed  Google Scholar 

  • Ward, B. D. (2000). Simultaneous inference for FMRI data.

  • Westlye, E. T., Lundervold, A., Rootwelt, H., Lundervold, A. J., & Westlye, L. T. (2011). Increased hippocampal default mode synchronization during rest in middle-aged and elderly APOE epsilon4 carriers: relationships with memory performance. Journal of Neuroscience, 31(21), 7775–7783.

    Article  PubMed  CAS  Google Scholar 

  • Wilkinson, G. S. (1993). The wide range achievement test: Manual (3rd ed.). Wilmington, DE: Wide Range.

    Google Scholar 

  • Zhang, Y., Schuff, N., Jahng, G. H., Bayne, W., Mori, S., Schad, L., et al. (2007). Diffusion tensor imaging of cingulum fibers in mild cognitive impairment and Alzheimer disease. Neurology, 68(1), 13–19.

    Article  PubMed  CAS  Google Scholar 

  • Zhang, H. Y., Wang, S. J., Xing, J., Liu, B., Ma, Z. L., Yang, M., et al. (2009). Detection of PCC functional connectivity characteristics in resting-state fMRI in mild Alzheimer’s disease. Behavioural Brain Research, 197(1), 103–108.

    Article  PubMed  Google Scholar 

  • Zhang, H. Y., Wang, S. J., Liu, B., Ma, Z. L., Yang, M., Zhang, Z. J., et al. (2010). Resting brain connectivity: changes during the progress of Alzheimer disease. Radiology, 256(2), 598–606.

    Article  PubMed  Google Scholar 

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Acknowledgements

This research was supported by a research grant from the Connecticut Department of Public Health (Principal Investigator—Lance Bauer, Ph.D., University of Connecticut). Additional support was provided by Public Health Service grant M01RR006192.

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Authors and Affiliations

  1. Olin Neuropsychiatry Research Center, Institute of Living at Hartford Hospital, 200 Retreat Avenue, Hartford, CT, 06106, USA

    Krishna T. Patel, Michael C. Stevens, Godfrey D. Pearlson, Anderson M. Winkler & Pawel Skudlarski

  2. Department of Psychiatry, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA

    Michael C. Stevens, Godfrey D. Pearlson, Anderson M. Winkler, Keith A. Hawkins & Pawel Skudlarski

  3. Department of Neurobiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA

    Godfrey D. Pearlson

  4. Department of Psychiatry, University of Connecticut, 263 Farmington Ave, Farmington, CT, 06030, USA

    Lance O. Bauer

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  1. Krishna T. Patel
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Correspondence to Krishna T. Patel.

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Patel, K.T., Stevens, M.C., Pearlson, G.D. et al. Default mode network activity and white matter integrity in healthy middle-aged ApoE4 carriers. Brain Imaging and Behavior 7, 60–67 (2013). https://doi.org/10.1007/s11682-012-9187-y

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