Skip to main content

Advertisement

SpringerLink
Log in

High-resolution functional connectivity of the default mode network in young adults with down syndrome

  • Original Research
  • Published:
Brain Imaging and Behavior Aims and scope Submit manuscript

Abstract

Studies of resting-state functional connectivity MRI in Alzheimer’s disease suggest that disease stage plays a role in functional changes of the default mode network. Individuals with the genetic disorder Down syndrome show an increased incidence of early-onset Alzheimer’s-type dementia, along with early and nearly universal neuropathologic changes of Alzheimer’s disease. The present study examined high-resolution functional connectivity of the default mode network in 11 young adults with Down syndrome that showed no measurable symptoms of dementia and 11 age- and sex-matched neurotypical controls. We focused on within-network connectivity of the default mode network, measured from both anterior and posterior aspects of the cingulate cortex. Sixty-eight percent of connections to the posterior cingulate and 26% to the anterior cingulate showed reduced strength in the group with Down syndrome (p < 0.01). The Down syndrome group showed increased connectivity strength from the anterior cingulate to the bilateral inferior frontal gyri and right putamen (p < 0.005). In an exploratory analysis, connectivity in the group with Down syndrome showed regional relationships to plasma measures of inflammatory markers and t-tau. In non-demented adults with Down syndrome, functional connectivity within the default mode network may be analogous to changes reported in preclinical Alzheimer’s disease, and warrants further investigation as a measure of dementia risk.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

ACC:

anterior cingulate cortex

AD:

Alzheimer’s disease

APP:

amyloid precursor protein

Aβ:

beta-amyloid

DAMES:

Down’s syndrome Attention, Memory and Executive function battery

DLD:

Dementia Questionnaire for People with Learning Disabilities

DMN:

default mode network

DS:

Down Syndrome

DSQIID:

Dementia Screening Questionnaire for Individuals with Intellectual Disabilities

FDR:

false discovery rate

GM:

grey matter

ITG:

inferior temporal gyrus

PCC:

posterior cingulate cortex

PCFT:

Prudhoe Cognitive Function Test

ROI:

region of interest

rsfMRI:

resting-state functional MRI connectivity

sTREM2:

soluble cleavage product of triggering receptor expressed in myeloid cells-2

WM:

white matter

References

  • Anderson, J. S., Nielsen, J. A., Ferguson, M. A., Burback, M. C., Cox, E. T., Dai, L., Gerig, G., Edgin, J. O., & Korenberg, J. R. (2013). Abnormal brain synchrony in down syndrome. NeuroImage: Clinical, 2, 703–715.

    Google Scholar 

  • Andrews-Hanna, J. R., Smallwood, J., & Spreng, R. N. (2014). The default network and self-generated thought: Component processes, dynamic control, and clinical relevance. Annals of the New York Academy of Sciences, 1316(29), 52.

    Google Scholar 

  • Avants, B. B., Epstein, C. L., Grossman, M., & Gee, J. C. (2008). Symmetric Diffeomorphic image registration with cross-correlation: Evaluating automated labeling of elderly and neurodegenerative brain. Medical Image Analysis, 12(1), 26–41.

    CAS  PubMed  Google Scholar 

  • Beacher, F., Daly, E., Simmons, A., Prasher, V., Morris, R., Robinson, C., Lovestone, S., Murphy, K., & Murphy, D. G. M. (2009). Alzheimer’s disease and Down’s syndrome: An in vivo MRI study. Psychological Medicine, 39, 675–684.

    CAS  PubMed  Google Scholar 

  • Beall, E. B., & Lowe, M. J. (2014). SimPACE: Generating simulated motion corrupted BOLD data with synthetic-navigated acquisition for the development and evaluation of SLOMOCO: a new, highly effective slicewise motion correction. Neuroimage, 101, 21–34.

    PubMed  Google Scholar 

  • Binney, R. J., Embleton, K. V., Jefferies, E., Parker, G. J., & Ralph, M. A. (2010). The ventral and inferolateral aspects of the anterior temporal lobe are crucial in semantic memory: Evidence from a novel direct comparison of distortion-corrected fMRI, rTMS, and semantic dementia. Cerebral Cortex, 20(11), 2728–2738.

    PubMed  Google Scholar 

  • Cox, R. (1996). AFNI: Software for analysis and visualization of functional magnetic resonance neuroimages. Computers and Biomedical Research, 29, 162–173.

    CAS  PubMed  Google Scholar 

  • Damoiseaux, J. S., Prater, K., Miller, B. L., & Greicius, M. D. (2012). Functional connectivity tracks clinical deterioration in Alzheimer's disease. Neurobiol Aging, 33(4), 828.e819–828.e830.

    Google Scholar 

  • Deb, S., Hare, M., Prior, L., & Bhaumik, S. (2007). Dementia screening questionnaire for individuals with intellectual disabilities. The British Journal of Psychiatry, 190, 440–444.

    PubMed  Google Scholar 

  • Evenhuis, H. M. (1996). Further evaluation of the dementia questionnaire for persons with mental retardation. Journal of Intellectual Disability Research, 40(4), 369–373.

    PubMed  Google Scholar 

  • Fortea, J., Carmona-Iragui, M., Benejam, B., Fernández, S., Videla, L., Barroeta, I., Alcolea, D., Pegueroles, J., Muñoz, L., Belbin, O., de Leon, M. J., Maceski, A. M., Hirtz, C., Clarimón, J., Videla, S., Delaby, C., Lehmann, S., Blesa, R., & Lleó, A. (2018). Plasma and CSF biomarkers for the diagnosis of Alzheimer's disease in adults with down syndrome: a cross-sectional study. Lancet Neurology, 17(10), 860–869.

    CAS  PubMed  Google Scholar 

  • Freesurfer. (2017). version 6.0.0. http://surfer.nmr.mgh.harvard.edu/.

  • Glover, G. H., Li, T., & Ress, D. (2000). Image-based method for retrospective correction of physiological motion effects in fMRI: RETROICOR. Magnetic Resonance in Medicine, 44, 162–167.

    CAS  PubMed  Google Scholar 

  • Greicius, M. D., Krasnow, B., Reiss, A. L., & Menon, V. (2003). Functional connectivity in the resting brain: A network analysis of the default mode hypothesis. PNAS, 100(1), 253–258.

    CAS  PubMed  Google Scholar 

  • Hedden, T., Van Dijk, K. R. A., Becker, J. A., Mehta, A., Sperling, R. A., Johnson, K. A., & Buckner, R. L. (2009). Disruption of functional connectivity in clinically Normal older adults harboring amyloid burden. J Neurocience, 29(40), 12686–12694.

    CAS  Google Scholar 

  • Horn, A., Ostwald, D., Reisert, M., & Blankenburg, F. (2014). The structural-functional connectome and the default mode network of the human brain. Neuroimage, 102(1), 142–151.

    PubMed  Google Scholar 

  • Iulita, M. F., Ower, A., Barone, C., Pentz, R., Gubert, P., Romano, C., Cantarella, R. A., Elia, F., Buono, S., Recupero, M., Romano, C., Castellano, S., Bosco, P., Di Nuovo, S., Drago, F., Caraci, F., & Cuello, A. C. (2016). An inflammatory and trophic disconnect biomarker profile revealed in down syndrome plasma: Relation to cognitive decline and longitudinal evaluation. Alzheimers Dementia, 12(11), 1132–1148.

    Google Scholar 

  • Kesslak, J. P., Nagata, S. F., Lott, I. T., & Nalcioglu, O. (1994). MRI analysis of age-related changes in the brains of individuals with DS. Neurology, 44, 1039–1045.

    CAS  PubMed  Google Scholar 

  • Lamar, M., Foy, C. M. L., Beacher, F., Daly, E., Poppe, M., Archer, N., Prasher, V., Murphy, K. C., Morris, R. G., Simmons, A., Lovestone, S., & Murphy, D. G. M. (2011). Down syndrome with and without dementia: An in vivo proton magnetic resonance spectroscopy study with implications for Alzheimer's disease. Neuroimage, 57, 63–68.

    PubMed  Google Scholar 

  • Lemere, C. A., Blusztajn, J. K., Yamaguchi, H., Wisniewski, T., Saido, T. C., & Selkoe, D. J. (1996). Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in down syndrome: Implications for initial events in amyloid plaque formation. Neurobiology of Disease, 3(1), 16–32.

    CAS  PubMed  Google Scholar 

  • Leverenz, J. B., & Raskind, M. A. (1998). Early amyloid deposition in the medial temporal lobe of young down syndrome patients: a regional quantitative analysis. Experimental Neurology, 150(2), 296–304.

    CAS  PubMed  Google Scholar 

  • LeVine, H., Spielmann, P. H., Matveev, S., Cauvi, F. M., Murphy, M. P., Beckett, T. L., McCarty, K., Lott, I. T., Doran, E., Schmitt, F., & Head, E. (2017). Down syndrome: Age-dependence of PiB binding in postmortem frontal cortex across the lifespan. Neurobiology of Aging, 54, 163–169.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lowe, M., Koenig, K., Beall, E., Sakaie, K., Stone, L., Bermel, R., & Phillips, M. (2014). Anatomic connectivity assessed using pathway radial diffusivity is related to functional connectivity in monosynaptic pathways. Brain Connectivity, 4(7), 558–565.

    PubMed  Google Scholar 

  • Lowe, M. J., Mock, B. J., & Sorenson, J. A. (1998). Functional connectivity in single and multislice Echoplanar imaging using resting-state fluctuations. Neuroimage, 7(2), 119–132.

    CAS  PubMed  Google Scholar 

  • Machulda, M. M., Jones, D. T., Vemuri, P., McDade, E., Avula, R., Przybelski, S., Boeve, B. F., Knopman, D. S., Petersen, R. C., & Jack, C. R. (2011). Effect of APOE ε4 status on intrinsic network connectivity in cognitively Normal elderly subjects. Archives of Neurology, 68(9), 1131–1136.

    PubMed  PubMed Central  Google Scholar 

  • Mann, D. M., & Esiri, M. M. (1989). The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down's syndrome. Journal of the Neurological Sciences, 89(2–3), 169–179.

    CAS  PubMed  Google Scholar 

  • Margallo-Lana, M. L., Moore, P. B., Tyrer, S. P., Dawson, H., Jenkins, K., & Kay, D. W. (2003). The Prudhoe cognitive function test, a scale to assess cognitive function in adults with Down’s syndrome: Inter-rater and test-retest reliability. Journal of Intellectual Disability Research, 47(6), 488–492.

  • Margallo-Lana, M. L., Moore, P. B., Kay, D. W. K., Perry, R. H., Reid, B. E., Berney, T. P., & Tyrer, S. P. (2007). Fifteen-year follow-up of 92 hospitalized adults with Down’s syndrome: incidence of cognitive decline, its relationship to age and neuropathology. Journal of Intellectual Disability Research, 51(6), 463–477.

  • Marques, J. P., Kober, T., Krueger, G., van der Zwaag, W., Van de Moortele, P. F., & Gruetter, R. (2010). MP2RAGE, a self bias-field corrected sequence for improved segmentation and T1-mapping at high field. Neuroimage, 49, 1271–1281.

    PubMed  Google Scholar 

  • Palmqvist, S., Schöll, M., Strandberg, O., Mattsson, N., Stomrud, E., Zetterberg, H., Blennow, K., Landau, S., Jagust, W., & Hansson, O. (2017). Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity. Nature Communications, 8, 1214.

    PubMed  PubMed Central  Google Scholar 

  • Patel, K. T., Stevens, M. C., Pearlson, G. D., Winkler, A. M., Hawkins, K. A., Skudlarski, P., & Bauer, L. O. (2013). Default mode network activity and white matter integrity in healthy middle-aged ApoE4 carriers. Brain Imaging and Behavior, 7(1), 60–67.

    PubMed  Google Scholar 

  • Prasher, V., Cumella, S., Natarajan, K., Rolfe, E., Shah, S., & Haque, M. S. (2003). Magnetic resonance imaging, Down’s syndrome and Alzheimer’s disease : Research and clinical implications. Journal of Intellectual Disabilities Research, 47, 90–100.

    CAS  Google Scholar 

  • Pujol, J., del Hoyo, L., Blanco-Hinojo, L., de Sola, S., Macià, D., Martínez-Vilavella, G., Amor, M., Deus, J., Rodríguez, J., Farré, M., Dierssen, M., & de la Torre, R. (2015). Anomalous brain functional connectivity contributing to poor adaptive behavior in down syndrome. Cortex, 64, 148–156.

    PubMed  Google Scholar 

  • Rafii, M. S., Lukic, A. S., Andrews, R. D., Brewer, J., Rissman, R. A., Strother, S. C., Wernick, M. N., Pennington, C., Mobley, W. C., Ness, S., Matthews, D. C., & Initiative, D. S. B. I. a. t. A. s. D. N. (2017). PET imaging of tau pathology and relationship to amyloid, longitudinal MRI, and cognitive change in down syndrome: Results from the down syndrome biomarker Initiative (DSBI). Journal of Alzheimer's Disease, 60(2), 439–450.

    CAS  PubMed  Google Scholar 

  • Raha-Chowdhury, R., Henderson, J. W., Raha, A. A., Vuono, R., Bickerton, A., Jones, E., Fincham, R., Allinson, K., Holland, A., & Zaman, S. H. (2019). Choroid plexus acts as gatekeeper for TREM2, abnormal accumulation of ApoE, and Fibrillary tau in Alzheimer's disease and in down syndrome dementia. Journal of Alzheimer's Disease, 69(1), 91–109.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Saad, Z. S., Glen, D. R., Chen, G., Beauchamp, M. S., Desai, R., & Cox, R. W. (2009). A new method for improving functional-to-structural alignment using local Pearson correlation. Neuroimage, 44, 839–848.

    PubMed  Google Scholar 

  • Sabbagh, M. N., Chen, K., Rogers, J., Fleisher, A. S., Liebsack, C., Bandy, D., Belden, C., Protas, H., Thiyyagura, P., Liu, X., Roontiva, A., Luo, J., Jacobson, S., Malek-Ahmadi, M., Powell, J., & Reiman, E. M. (2015). Florbetapir PET, FDG PET, and MRI in down syndrome individuals with and without Alzheimer's dementia. Alzheimers Dementia, 11(8), 994–1004.

    Google Scholar 

  • Scheff, S. W., Price, D. A., Schmitt, F. A., Scheff, M. A., & Mufson, E. J. (2011). Synaptic loss in the inferior temporal Gyrus in mild cognitive impairment and Alzheimer's disease. Journal of Alzheimer's Disease, 24(3), 547–557.

    PubMed  Google Scholar 

  • Shi, M., Bradner, J., Hancock, A. M., Chung, K. A., Quinn, J. F., Peskind, E. R., Galasko, D., Jankovic, J., Zabetian, C. P., Kim, H. M., Leverenz, J. B., Montine, T. J., Ginghina, C., Kang, U. J., Cain, K. C., Wang, Y., Aasly, J., Goldstein, D., & Zhang, J. (2011). Cerebrospinal fluid biomarkers for Parkinson disease diagnosis and progression. Annals of Neurology, 69(3), 570–580. https://doi.org/10.1002/ana.22311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sullivan, K. D., Evans, D., Pandey, A., Hraha, T. H., Smith, K. P., Markham, N., Rachubinski, A. L., Wolter-Warmerdam, K., Hickey, F., Espinosa, J. M., & Blumenthal, T. (2017). Trisomy 21 causes changes in the circulating proteome indicative of chronic autoinflammation. Scientific Reports, 7, 14818.

    PubMed  PubMed Central  Google Scholar 

  • Teipel, S. J., Alexander, G. E., Schapiro, M. B., Moller, H. J., Rapoport, S. I., & Hampel, H. (2004). Age-related cortical grey matter reductions in non-demented Down's sydrome adults determined by MRI with voxel-based morphometry. Brain, 127, 811–824.

    PubMed  Google Scholar 

  • Teller, J. K., Russo, C., DeBusk, L. M., Angelini, G., Zacceo, D., Dagna-Bricarelli, F., Scartezzini, P., Bertolini, F., Mann, D. M., Tabaton, M., & Gambetti, P. (1996). Presence of soluble amyloid b-peptide precedes amyloid plaque formation in Down's syndrome. Nature Medicine, 2(1), 93–95.

    CAS  PubMed  Google Scholar 

  • Van Dijk, K. R. A., Sabuncu, M. R., & Buckner, R. L. (2012). The influence of head motion on intrinsic functional connectivity MRI. Neuroimage, 59(1), 431–438.

    PubMed  Google Scholar 

  • Vega, J. N., Hohman, T. J., Pryweller, J. R., Dykens, E. M., & Thornton-Wells, T. A. (2015). Resting-state functional connectivity in individuals with down syndrome and Williams syndrome compared with typically developing controls. Brain Connectivity, 5(8), 461–475.

    PubMed  PubMed Central  Google Scholar 

  • Visser, F. E., Aldenkamp, A. P., van Huffelen, A. C., Kuilman, M., Overweg, J., & van Wijk, J. (1997). Prospective study of the Alzheimer-type dementia in institutionalized individuals with down syndrome. Am J of Mental Retardation, 101, 400–412.

    CAS  Google Scholar 

  • Weber, G. E., Koenig, K. A., Khrestian, M., Shao, Y., Tuason, E. D., Gramm, M., Lal, D., Leverenz, J. B., & Bekris, L. M. (2020). Altered relationship between soluble TREM2 and inflammatory markers in young adults with down syndrome: A preliminary report. Journal of Immunology., 204, 1111–1118. https://doi.org/10.4049/jimmunol.1901166.

    Article  CAS  Google Scholar 

  • 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 ε4 carriers: Relationships with memory performance. The Journal of Neuroscience, 31(21), 7775–7783.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wilson, L. R., Vatansever, D., Annus, T., Williams, G. B., Hong, Y. T., Fryer, T. D., Nestor, P. J., Holland, A. J., & Zaman, S. H. (2019). Differential effects of Down's syndrome and Alzheimer's neuropathology on default mode connectivity. Human Brain Mapping, 40(15), 4551–4563.

    PubMed  PubMed Central  Google Scholar 

  • Wu, X., Li, R., Fleisher, A. S., Reiman, E. M., Guan, X., Zhang, Y., Chen, K., & Yao, L. (2011). Altered default mode network connectivity in Alzheimer's disease--a resting functional MRI and Bayesian network study. Human Brain Mapping, 32(11), 1868–1881.

    PubMed  PubMed Central  Google Scholar 

  • Yeo, B. T. T., Krienen, F. M., Sepulcre, J., Sabuncu, M. R., Lashkari, D., Hollinshead, M., Roffman, J. L., Smoller, J. W., Zollei, L., Polimeni, J. R., Fischl, B., Liu, H., & Buckner, R. L. (2011). The organization of the human cerebral cortex estimated by intrinsic functional connectivity. Journal of Neurophysiology, 106, 1125–1165.

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  • Zhang, Y., Che, M., Yuan, J., Yu, Y., Cao, C., Qin, X. Y., & Cheng, Y. (2017). Aberrations in circulating inflammatory cytokine levels in patients with down syndrome: a meta-analysis. Oncotarget, 8(48), 84489–84496.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors thank Tobias Kober and Thomas Benner of Siemens Healthineers for use of WIP 944 and WIP 770B.

Funding

This work was supported by Alzheimer’s Association (2016-NIRG-395687). As a trainee of the research education component of the Cleveland Alzheimer’s Disease Research Center, the work of K. Koenig was in part supported by the National Institute on Aging (P30 AG062428 01).

Author information

Authors and Affiliations

  1. Imaging Sciences, Imaging Institute, Cleveland Clinic, 9500 Euclid Ave / U15, Cleveland, OH, 44195, USA

    Katherine A. Koenig, Se-Hong Oh & Sanghoon Kim

  2. Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA

    Lynn M. Bekris, Grace E. Weber & Maria Khrestian

  3. Department of Psychiatry, University Hospitals, Cleveland, OH, USA

    Stephen Ruedrich

  4. Department of Biomedical Engineering, Hankuk University of Foreign Studies, Yongin, Republic of Korea

    Se-Hong Oh

  5. Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA

    Z. Irene Wang

  6. Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA

    James B. Leverenz

Authors
  1. Katherine A. Koenig
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lynn M. Bekris
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephen Ruedrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Grace E. Weber
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maria Khrestian
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Se-Hong Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sanghoon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Z. Irene Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. James B. Leverenz
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Author contributions included conception and study design (KAK, SR, JBL), methodological development (S-HO, SK), data collection or acquisition (KAK, SR, S-HO, SK, ZIW, JBL), statistical analysis (KAK, LMB, GEW, MK), interpretation of results (KAK, LMB, GEW, JBL), drafting the manuscript work or revising it critically for important intellectual content (KAK, LMB, SR, GEW, JBL) and approval of final version to be published and agreement to be accountable for the integrity and accuracy of all aspects of the work (All authors).

Corresponding author

Correspondence to Katherine A. Koenig.

Ethics declarations

All data was collected under a Cleveland Clinic Institutional Review Board-approved protocol. All participants provided written informed consent prior to any study procedures.

Conflict of interest

None of the authors have a conflict of interest to declare.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Koenig, K.A., Bekris, L.M., Ruedrich, S. et al. High-resolution functional connectivity of the default mode network in young adults with down syndrome. Brain Imaging and Behavior 15, 2051–2060 (2021). https://doi.org/10.1007/s11682-020-00399-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11682-020-00399-z

Keywords

Search

Navigation