Skip to main content

Advertisement

SpringerLink
Log in

Depressive symptoms accelerate cognitive decline in amyloid-positive MCI patients

  • Original Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Late-life depression even in subsyndromal stages is strongly associated with Alzheimer’s disease (AD). Furthermore, brain amyloidosis is an early biomarker in subjects who subsequently suffer from AD and can be sensitively detected by amyloid PET. Therefore, we aimed to compare amyloid load and glucose metabolism in subsyndromally depressed subjects with mild cognitive impairment (MCI).

Methods

[18F]AV45 PET, [18F]FDG PET and MRI were performed in 371 MCI subjects from the Alzheimer’s Disease Neuroimaging Initiative Subjects were judged β-amyloid-positive (Aβ+; 206 patients) or β-amyloid-negative (Aβ−; 165 patients) according to [18F]AV45 PET. Depressive symptoms were assessed by the Neuropsychiatric Inventory Questionnaire depression item 4. Subjects with depressive symptoms (65 Aβ+, 41 Aβ−) were compared with their nondepressed counterparts. Conversion rates to AD were analysed (mean follow-up time 21.5 ± 9.1 months) with regard to coexisting depressive symptoms and brain amyloid load.

Results

Aβ+ depressed subjects showed large clusters with a higher amyloid load in the frontotemporal and insular cortices (p < 0.001) with coincident hypermetabolism (p < 0.001) in the frontal cortices than nondepressed subjects. Faster progression to AD was observed in subjects with depressive symptoms (p < 0.005) and in Aβ+ subjects (p < 0.001). Coincident depressive symptoms additionally shortened the conversion time in all Aβ+ subjects (p < 0.005) and to a greater extent in those with a high amyloid load (p < 0.001).

Conclusion

Our results clearly indicate that Aβ+ MCI subjects with depressive symptoms have an elevated amyloid load together with relative hypermetabolism of connected brain areas compared with cognitively matched nondepressed individuals. MCI subjects with high amyloid load and coexistent depressive symptoms are at high risk of faster conversion to AD.

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
Fig. 3

Similar content being viewed by others

References

  1. Ziegler-Graham K, Brookmeyer R, Johnson E, Arrighi HM. Worldwide variation in the doubling time of Alzheimer’s disease incidence rates. Alzheimers Dement. 2008;4:316–23. doi:10.1016/j.jalz.2008.05.2479.

    Article  PubMed  Google Scholar 

  2. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–59.

    Article  CAS  PubMed  Google Scholar 

  3. Lim YY, Ellis KA, Pietrzak RH, Ames D, Darby D, Harrington K, et al. Stronger effect of amyloid load than APOE genotype on cognitive decline in healthy older adults. Neurology. 2012;79:1645–52. doi:10.1212/WNL.0b013e31826e9ae6.

    Article  CAS  PubMed  Google Scholar 

  4. Lim YY, Maruff P, Pietrzak RH, Ellis KA, Darby D, Ames D, et al. Abeta and cognitive change: examining the preclinical and prodromal stages of Alzheimer’s disease. Alzheimer’s Dement. 2014;10:743–51. doi:10.1016/j.jalz.2013.11.005.

    Article  Google Scholar 

  5. Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D. Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry. 2006;63:530–8. doi:10.1001/archpsyc.63.5.530.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Olin JT, Katz IR, Meyers BS, Schneider LS, Lebowitz BD. Provisional diagnostic criteria for depression of Alzheimer disease: rationale and background. Am J Geriatr Psychiatry. 2002;10:129–41.

    Article  PubMed  Google Scholar 

  7. Steenland K, Karnes C, Seals R, Carnevale C, Hermida A, Levey A. Late-life depression as a risk factor for mild cognitive impairment or Alzheimer’s disease in 30 US Alzheimer’s disease centers. J Alzheimer’s Dis. 2012;31:265–75. doi:10.3233/JAD-2012-111922.

    CAS  Google Scholar 

  8. Butters MA, Klunk WE, Mathis CA, Price JC, Ziolko SK, Hoge JA, et al. Imaging Alzheimer pathology in late-life depression with PET and Pittsburgh compound-B. Alzheimer Dis Assoc Disord. 2008;22:261–8. doi:10.1097/WAD.0b013e31816c92bf.

    Article  PubMed Central  PubMed  Google Scholar 

  9. Madsen K, Hasselbalch BJ, Frederiksen KS, Haahr ME, Gade A, Law I, et al. Lack of association between prior depressive episodes and cerebral [11C]PiB binding. Neurobiol Aging. 2012;33:2334–42. doi:10.1016/j.neurobiolaging.2011.11.021.

    Article  CAS  PubMed  Google Scholar 

  10. Wu KY, Hsiao IT, Chen CS, Chen CH, Hsieh CJ, Wai YY, et al. Increased brain amyloid deposition in patients with a lifetime history of major depression: evidenced on F-florbetapir (AV-45/Amyvid) positron emission tomography. Eur J Nucl Med Mol Imaging. 2014;41:714–22. doi:10.1007/s00259-013-2627-0.

    Article  CAS  PubMed  Google Scholar 

  11. Smith GS, Kramer E, Hermann C, Ma Y, Dhawan V, Chaly T, et al. Serotonin modulation of cerebral glucose metabolism in depressed older adults. Biol Psychiatry. 2009;66:259–66. doi:10.1016/j.biopsych.2009.02.012.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Smith GS, Kramer E, Ma Y, Kingsley P, Dhawan V, Chaly T, et al. The functional neuroanatomy of geriatric depression. Int J Geriatr Psychiatr. 2009;24:798–808. doi:10.1002/gps.2185.

    Article  Google Scholar 

  13. Marano CM, Workman CI, Kramer E, Hermann CR, Ma Y, Dhawan V, et al. Longitudinal studies of cerebral glucose metabolism in late-life depression and normal aging. Int J Geriatr Psychiatr. 2013;28:417–23. doi:10.1002/gps.3840.

    Article  Google Scholar 

  14. Hirono N, Mori E, Ishii K, Ikejiri Y, Imamura T, Shimomura T, et al. Frontal lobe hypometabolism and depression in Alzheimer’s disease. Neurology. 1998;50:380–3.

    Article  CAS  PubMed  Google Scholar 

  15. Holthoff VA, Beuthien-Baumann B, Kalbe E, Ludecke S, Lenz O, Zundorf G, et al. Regional cerebral metabolism in early Alzheimer’s disease with clinically significant apathy or depression. Biol Psychiatry. 2005;57:412–21. doi:10.1016/j.biopsych.2004.11.035.

    Article  CAS  PubMed  Google Scholar 

  16. Lee DY, Choo IH, Jhoo JH, Kim KW, Youn JC, Lee DS, et al. Frontal dysfunction underlies depressive syndrome in Alzheimer disease: a FDG-PET study. Am J Geriatr Psychiatry. 2006;14:625–8. doi:10.1097/01.JGP.0000214541.79965.2d.

    Article  PubMed  Google Scholar 

  17. Lee HS, Choo IH, Lee DY, Kim JW, Seo EH, Kim SG, et al. Frontal dysfunction underlies depression in mild cognitive impairment: a FDG-PET study. Psychiatr Investig. 2010;7:208–14. doi:10.4306/pi.2010.7.3.208.

    Article  Google Scholar 

  18. Kaufer DI, Cummings JL, Ketchel P, Smith V, MacMillan A, Shelley T, et al. Validation of the NPI-Q, a brief clinical form of the neuropsychiatric inventory. J Neuropsychiatry Clin Neurosci. 2000;12:233–9.

    Article  CAS  PubMed  Google Scholar 

  19. Johnson KA, Minoshima S, Bohnen NI, Donohoe KJ, Foster NL, Herscovitch P, et al. Appropriate use criteria for amyloid PET: a report of the amyloid imaging task force, the society of nuclear medicine and molecular imaging, and the Alzheimer’s association. Alzheimer’s Dement. 2013;9:e-1–16. doi:10.1016/j.jalz.2013.01.002.

    Article  Google Scholar 

  20. Jack Jr CR, Bernstein MA, Fox NC, Thompson P, Alexander G, Harvey D, et al. The Alzheimer's Disease Neuroimaging Initiative (ADNI): MRI methods. J Magn Reson Imaging. 2008;27:685–91. doi:10.1002/jmri.21049.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Ashburner J, Friston KJ. Unified segmentation. Neuroimage. 2005;26:839–51. doi:10.1016/j.neuroimage.2005.02.018.

    Article  PubMed  Google Scholar 

  22. Muller-Gartner HW, Links JM, Prince JL, Bryan RN, McVeigh E, Leal JP, et al. Measurement of radiotracer concentration in brain gray matter using positron emission tomography: MRI-based correction for partial volume effects. J Cereb Blood Flow Metab. 1992;12:571–83. doi:10.1038/jcbfm.1992.81.

    Article  CAS  PubMed  Google Scholar 

  23. Hammers A, Allom R, Koepp MJ, Free SL, Myers R, Lemieux L, et al. Three dimensional maximum probability atlas of the human brain, with particular reference to the temporal lobe. Hum Brain Mapp. 2003;19:224–247.

  24. Price JL, Drevets WC. Neurocircuitry of mood disorders. Neuropsychopharmacology. 2010;35:192–216. doi:10.1038/npp.2009.104.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Lavretsky H, Siddarth P, Kepe V, Ercoli LM, Miller KJ, Burggren AC, et al. Depression and anxiety symptoms are associated with cerebral FDDNP-PET binding in middle-aged and older nondemented adults. Am J Geriatr Psychiatry. 2009;17:493–502.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Sun X, Steffens DC, Au R, Folstein M, Summergrad P, Yee J, et al. Amyloid-associated depression: a prodromal depression of Alzheimer disease? Arch Gen Psychiatry. 2008;65:542–50. doi:10.1001/archpsyc.65.5.542.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Rapp MA, Schnaider-Beeri M, Grossman HT, Sano M, Perl DP, Purohit DP, et al. Increased hippocampal plaques and tangles in patients with Alzheimer disease with a lifetime history of major depression. Arch Gen Psychiatry. 2006;63:161–7. doi:10.1001/archpsyc.63.2.161.

    Article  PubMed  Google Scholar 

  28. Rapp MA, Schnaider-Beeri M, Purohit DP, Perl DP, Haroutunian V, Sano M. Increased neurofibrillary tangles in patients with Alzheimer disease with comorbid depression. Am J Geriatr Psychiatry. 2008;16:168–74. doi:10.1097/JGP.0b013e31816029ec.

    Article  PubMed  Google Scholar 

  29. Sweet RA, Hamilton RL, Butters MA, Mulsant BH, Pollock BG, Lewis DA, et al. Neuropathologic correlates of late-onset major depression. Neuropsychopharmacology. 2004;29:2242–50. doi:10.1038/sj.npp.1300554.

    Article  PubMed  Google Scholar 

  30. Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA, Salvado O, et al. Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol. 2013;12:357–67. doi:10.1016/S1474-4422(13)70044-9.

    Article  CAS  PubMed  Google Scholar 

  31. Pietrzak RH, Scott JC, Neumeister A, Lim YY, Ames D, Ellis KA, et al. Anxiety symptoms, cerebral amyloid burden and memory decline in healthy older adults without dementia: 3-year prospective cohort study. Br J Psychiatry. 2014;204:400–1. doi:10.1192/bjp.bp.113.134239.

    Article  PubMed  Google Scholar 

  32. Sheline YI, West T, Yarasheski K, Swarm R, Jasielec MS, Fisher JR, et al. An antidepressant decreases CSF abeta production in healthy individuals and in transgenic AD mice. Sci Transl Med. 2014;6:236re4. doi:10.1126/scitranslmed.3008169.

    Article  PubMed Central  PubMed  Google Scholar 

  33. Buckley RF, Saling MM, Irish M, Ames D, Rowe CC, Lautenschlager NT, et al. Personal memory function in mild cognitive impairment and subjective memory complaints: results from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) Study of Ageing. J Alzheimers Dis. 2014;40:551–61. doi:10.3233/JAD-131820.

    PubMed  Google Scholar 

  34. Hermida AP, McDonald WM, Steenland K, Levey A. The association between late-life depression, mild cognitive impairment and dementia: is inflammation the missing link? Expert Rev Neurother. 2012;12:1339–50. doi:10.1586/ern.12.127.

    Article  CAS  PubMed  Google Scholar 

  35. Caroli A, Lorenzi M, Geroldi C, Nobili F, Paghera B, Bonetti M, et al. Metabolic compensation and depression in Alzheimer’s disease. Dement Geriatr Cogn Disord. 2010;29:37–45. doi:10.1159/000257761.

    Article  CAS  PubMed  Google Scholar 

  36. Kreisl WC, Lyoo CH, McGwier M, Snow J, Jenko KJ, Kimura N, et al. In vivo radioligand binding to translocator protein correlates with severity of Alzheimer’s disease. Brain. 2013;136:2228–38. doi:10.1093/brain/awt145.

    Article  PubMed Central  PubMed  Google Scholar 

  37. Lebedeva A, Westman E, Lebedev AV, Li X, Winblad B, Simmons A, et al. Structural brain changes associated with depressive symptoms in the elderly with Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2014;85:930–5. doi:10.1136/jnnp-2013-307110.

    Article  PubMed  Google Scholar 

  38. Lee GJ, Lu PH, Hua X, Lee S, Wu S, Nguyen K, et al. Depressive symptoms in mild cognitive impairment predict greater atrophy in Alzheimer’s disease-related regions. Biol Psychiatry. 2012;71:814–21. doi:10.1016/j.biopsych.2011.12.024.

    Article  PubMed Central  PubMed  Google Scholar 

  39. Alexopoulos GS, Meyers BS, Young RC, Campbell S, Silbersweig D, Charlson M. ‘Vascular depression’ hypothesis. Arch Gen Psychiatry. 1997;54:915–22.

    Article  CAS  PubMed  Google Scholar 

  40. Marshall GA, Donovan NJ, Lorius N, Gidicsin CM, Maye J, Pepin LC, et al. Apathy is associated with increased amyloid burden in mild cognitive impairment. J Neuropsychiatr Clin Neurosci. 2013;25:302–7. doi:10.1176/appi.neuropsych.12060156.

    Article  Google Scholar 

  41. Mori T, Shimada H, Shinotoh H, Hirano S, Eguchi Y, Yamada M, et al. Apathy correlates with prefrontal amyloid beta deposition in Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2014;85:449–55. doi:10.1136/jnnp-2013-306110.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; ; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. The authors acknowledge Inglewood Biomedical Editing for professional editing of the manuscript.

Conflicts of interest

Matthias Brendel reports no disclosures.

Oliver Pogarell reports no disclosures.

Guoming Xiong reports no disclosures.

Andreas Delker reports no disclosures.

Peter Bartenstein received research support from the Federal Ministry of Education and Science (BMBF).

Axel Rominger received research support from the Friedrich-Baur Foundation and SyNergy cluster.

Author information

Authors and Affiliations

  1. Department of Nuclear Medicine, University of Munich, Munich, Germany

    Matthias Brendel, Guoming Xiong, Andreas Delker, Peter Bartenstein & Axel Rominger

  2. Department of Psychiatry, University of Munich, Munich, Germany

    Oliver Pogarell

  3. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

    Peter Bartenstein & Axel Rominger

Authors
  1. Matthias Brendel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Oliver Pogarell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guoming Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andreas Delker
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter Bartenstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Axel Rominger
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

for the Alzheimer’s Disease Neuroimaging Initiative

Corresponding author

Correspondence to Axel Rominger.

Additional information

The data used in the preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). The ADNI investigators contributed to the design and implementation of ADNI and/or provided data but did not participate in the analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 595 kb)

ESM 2

(DOCX 19 kb)

ESM 3

(DOCX 15 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Brendel, M., Pogarell, O., Xiong, G. et al. Depressive symptoms accelerate cognitive decline in amyloid-positive MCI patients. Eur J Nucl Med Mol Imaging 42, 716–724 (2015). https://doi.org/10.1007/s00259-014-2975-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-014-2975-4

Keywords

Search

Navigation