Excess tau PET ligand retention in elderly patients with major depressive disorder


Depression is one of the common psychiatric disorders in old age. Major depressive disorder (MDD) has been identified as a risk factor or prodrome for neurodegenerative dementias, suggesting neuropathological overlaps and a continuum between MDD and neurodegenerative disorders. In this study, we examined tau and amyloid-β (Aβ) accumulations in the brains of MDD and healthy controls using positron emission tomography (PET) to explore pathological substrates of this illness. Twenty MDD and twenty age-matched, healthy controls were examined by PET with a tau radioligand, [11C]PBB3, and an Aβ radioligand, [11C]PiB. Radioligand retentions were quantified as a standardized uptake value ratio (SUVR). We also assessed clinical manifestations of the patients using the 17-item Hamilton Depression Scale, the Geriatric Depression Scale, and psychotic symptoms. Mean cortical [11C]PBB3 SUVRs in MDD patients were significantly higher than those of healthy controls. These values were higher in MDD patients with psychotic symptoms than in those without any. The present findings indicate that tau depositions may underlie MDD, and especially in patients with psychotic symptoms. PET detection of tau accumulations may provide mechanistic insights into neuronal dysfunctions in these cases and could serve as predictions of their clinical consequences.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: [11C]PBB3 SUVRs in MDD and healthy controls.
Fig. 2: [11C]PiB SUVRs in MDD and healthy controls.


  1. 1.

    Gottfries CG. Late life depression. Eur Arch Psychiatry Clin Neurosci. 2001;251 Suppl 2:II57–61.

    PubMed  Google Scholar 

  2. 2.

    Murphy E. The prognosis of depression in old age. Br J Psychiatry. 1983;142:111–9.

    CAS  PubMed  Google Scholar 

  3. 3.

    Woolley JD, Khan BK, Murthy NK, Miller BL, Rankin KP. The diagnostic challenge of psychiatric symptoms in neurodegenerative disease: rates of and risk factors for prior psychiatric diagnosis in patients with early neurodegenerative disease. J Clin Psychiatry. 2011;72:126–33.

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Pose M, Cetkovich M, Gleichgerrcht E, Ibanez A, Torralva T, Manes F. The overlap of symptomatic dimensions between frontotemporal dementia and several psychiatric disorders that appear in late adulthood. Int Rev Psychiatry. 2013;25:159–67.

    PubMed  Google Scholar 

  5. 5.

    Byers AL, Yaffe K. Depression and risk of developing dementia. Nat Rev Neurol. 2011;7:323–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Diniz BS, Butters MA, Albert SM, Dew MA, Reynolds CF 3rd. Late-life depression and risk of vascular dementia and Alzheimer’s disease: systematic review and meta-analysis of community-based cohort studies. Br J Psychiatry. 2013;202:329–35.

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Galimberti D, Dell’Osso B, Altamura AC, Scarpini E. Psychiatric symptoms in frontotemporal dementia: epidemiology, phenotypes, and differential diagnosis. Biol Psychiatry. 2015;78:684–92.

    PubMed  Google Scholar 

  8. 8.

    Saito Y, Ruberu NN, Sawabe M, Arai T, Tanaka N, Kakuta Y, et al. Staging of argyrophilic grains: an age-associated tauopathy. J Neuropathol Exp Neurol. 2004;63:911–8.

    PubMed  Google Scholar 

  9. 9.

    Polanco JC, Li C, Bodea LG, Martinez-Marmol R, Meunier FA, Gotz J. Amyloid-beta and tau complexity—towards improved biomarkers and targeted therapies. Nat Rev Neurol. 2018;14:22–39.

    CAS  PubMed  Google Scholar 

  10. 10.

    Srivareerat M, Tran TT, Alzoubi KH, Alkadhi KA. Chronic psychosocial stress exacerbates impairment of cognition and long-term potentiation in beta-amyloid rat model of Alzheimer’s disease. Biol Psychiatry. 2009;65:918–26.

    CAS  PubMed  Google Scholar 

  11. 11.

    Carroll JC, Iba M, Bangasser DA, Valentino RJ, James MJ, Brunden KR, et al. Chronic stress exacerbates tau pathology, neurodegeneration, and cognitive performance through a corticotropin-releasing factor receptor-dependent mechanism in a transgenic mouse model of tauopathy. J Neurosci. 2011;31:14436–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Santos LE, Beckman D, Ferreira ST. Microglial dysfunction connects depression and Alzheimer’s disease. Brain Behav Immun. 2016;55:151–65.

    CAS  PubMed  Google Scholar 

  13. 13.

    Nordberg A. PET imaging of amyloid in Alzheimer’s disease. Lancet Neurol. 2004;3:519–27.

    CAS  PubMed  Google Scholar 

  14. 14.

    Tateno A, Sakayori T, Higuchi M, Suhara T, Ishihara K, Kumita S, et al. Amyloid imaging with [18F]florbetapir in geriatric depression: early-onset versus late-onset. Int J Geriatr Psychiatry. 2015;30:720–8.

    PubMed  Google Scholar 

  15. 15.

    Wu KY, Liu CY, Chen CS, Chen CH, Hsiao IT, Hsieh CJ, et al. Beta-amyloid deposition and cognitive function in patients with major depressive disorder with different subtypes of mild cognitive impairment: 18F-florbetapir (AV-45/Amyvid) PET study. Eur J Nucl Med Mol Imaging. 2016;43:1067–76.

    CAS  PubMed  Google Scholar 

  16. 16.

    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.

    CAS  PubMed  Google Scholar 

  17. 17.

    De Winter FL, Emsell L, Bouckaert F, Claes L, Jain S, Farrar G, et al. No association of lower hippocampal volume with Alzheimer’s disease pathology in late-life depression. Am J Psychiatry. 2017;174:237–45.

    PubMed  Google Scholar 

  18. 18.

    Kumar A, Kepe V, Barrio JR, Siddarth P, Manoukian V, Elderkin-Thompson V, et al. Protein binding in patients with late-life depression. Arch Gen Psychiatry. 2011;68:1143–50.

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Villemagne VL, Dore V, Burnham SC, Masters CL, Rowe CC. Imaging tau and amyloid-beta proteinopathies in Alzheimer disease and other conditions. Nat Rev Neurol. 2018;14:225–36.

    CAS  PubMed  Google Scholar 

  20. 20.

    Maruyama M, Shimada H, Suhara T, Shinotoh H, Ji B, Maeda J, et al. Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron. 2013;79:1094–108.

    CAS  PubMed  Google Scholar 

  21. 21.

    Shimada H, Kitamura S, Shinotoh H, Endo H, Niwa F, Hirano S, et al. Association between Abeta and tau accumulations and their influence on clinical features in aging and Alzheimer’s disease spectrum brains: a [11C]PBB3-PET study. Alzheimers Dement. 2017;6:11–20.

    Google Scholar 

  22. 22.

    Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993;43:2412–4.

    CAS  Google Scholar 

  23. 23.

    Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey M, et al. Development and validation of a geriatric depression screening scale: a preliminary report. J Psychiatr Res. 1982;17:37–49.

    PubMed  Google Scholar 

  26. 26.

    Hashimoto H, Kawamura K, Igarashi N, Takei M, Fujishiro T, Aihara Y, et al. Radiosynthesis, photoisomerization, biodistribution, and metabolite analysis of 11C-PBB3 as a clinically useful PET probe for imaging of tau pathology. J Nucl Med. 2014;55:1532–8.

    CAS  PubMed  Google Scholar 

  27. 27.

    Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N, et al. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage. 2002;15:273–89.

    CAS  PubMed  Google Scholar 

  28. 28.

    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.

    PubMed  Google Scholar 

  29. 29.

    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.

    PubMed  Google Scholar 

  30. 30.

    Wilson RS, Boyle PA, Capuano AW, Shah RC, Hoganson GM, Nag S, et al. Late-life depression is not associated with dementia-related pathology. Neuropsychology. 2016;30:135–42.

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Tsopelas C, Stewart R, Savva GM, Brayne C, Ince P, Thomas A, et al. Neuropathological correlates of late-life depression in older people. Br J Psychiatry. 2011;198:109–14.

    PubMed  Google Scholar 

  32. 32.

    Jaaskelainen E, Juola T, Korpela H, Lehtiniemi H, Nietola M, Korkeila J, et al. Epidemiology of psychotic depression—systematic review and meta-analysis. Psychol Med. 2018;48:905–18.

    CAS  PubMed  Google Scholar 

  33. 33.

    Farber NB, Rubin EH, Newcomer JW, Kinscherf DA, Miller JP, Morris JC, et al. Increased neocortical neurofibrillary tangle density in subjects with Alzheimer disease and psychosis. Arch Gen Psychiatry. 2000;57:1165–73.

    CAS  PubMed  Google Scholar 

  34. 34.

    Kawakami I, Hasegawa M, Arai T, Ikeda K, Oshima K, Niizato K, et al. Tau accumulation in the nucleus accumbens in tangle-predominant dementia. Acta Neuropathol Commun. 2014;2:40.

    PubMed  PubMed Central  Google Scholar 

  35. 35.

    Nagao S, Yokota O, Ikeda C, Takeda N, Ishizu H, Kuroda S, et al. Argyrophilic grain disease as a neurodegenerative substrate in late-onset schizophrenia and delusional disorders. Eur Arch Psychiatry Clin Neurosci. 2014;264:317–31.

    PubMed  Google Scholar 

  36. 36.

    Gatchel JR, Donovan NJ, Locascio JJ, Schultz AP, Becker JA, Chhatwal J, et al. Depressive symptoms and tau accumulation in the inferior temporal lobe and entorhinal cortex in cognitively normal older adults: a pilot study. J Alzheimers Dis. 2017;59:975–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    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;6:236re234.

    Google Scholar 

  38. 38.

    Nelson RL, Guo Z, Halagappa VM, Pearson M, Gray AJ, Matsuoka Y, et al. Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice. Exp Neurol. 2007;205:166–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Ono M, Sahara N, Kumata K, Ji B, Ni R, Koga S, et al. Distinct binding of PET ligands PBB3 and AV-1451 to tau fibril strains in neurodegenerative tauopathies. Brain. 2017;140:764–80.

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Ni R, Ji B, Ono M, Sahara N, Zhang MR, Aoki I, et al. Comparative in vitro and in vivo quantifications of pathologic tau deposits and their association with neurodegeneration in tauopathy mouse models. J Nucl Med. 2018;59:960–6.

    CAS  PubMed  Google Scholar 

  41. 41.

    Meyer JH, Ginovart N, Boovariwala A, Sagrati S, Hussey D, Garcia A, et al. Elevated monoamine oxidase a levels in the brain: an explanation for the monoamine imbalance of major depression. Arch Gen Psychiatry. 2006;63:1209–16.

    CAS  PubMed  Google Scholar 

  42. 42.

    Moriguchi S, Wilson AA, Miler L, Rusjan PM, Vasdev N, Kish SJ, et al. Monoamine oxidase B total distribution volume in the prefrontal cortex of major depressive disorder: an [11C]SL25.1188 positron emission tomography study. JAMA Psychiatry. 2019;76:634–41.

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Carter SF, Scholl M, Almkvist O, Wall A, Engler H, Langstrom B, et al. Evidence for astrocytosis in prodromal Alzheimer disease provided by 11C-deuterium-L-deprenyl: a multitracer PET paradigm combining 11C-Pittsburgh compound B and 18F-FDG. J Nucl Med. 2012;53:37–46.

    CAS  PubMed  Google Scholar 

  44. 44.

    Faul F, Erdfelder E, Buchner A, Lang AG. Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behav Res Methods. 2009;41:1149–60.

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Skaf CR, Yamada A, Garrido GE, Buchpiguel CA, Akamine S, Castro CC, et al. Psychotic symptoms in major depressive disorder are associated with reduced regional cerebral blood flow in the subgenual anterior cingulate cortex: a voxel-based single photon emission computed tomography (SPECT) study. J Affect Disord. 2002;68:295–305.

    PubMed  Google Scholar 

  46. 46.

    Congdon EE, Sigurdsson EM. Tau-targeting therapies for Alzheimer disease. Nat Rev Neurol. 2018;14:399–415.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


We thank Takamasa Maeda and the members of the Brain Disorder Translational Research Group for their support with PET scans, Kazuko Suzuki, and Shizuko Kawakami for their assistance as clinical coordinators, Hiromi Sano and Naoto Sato for their support with MRI scans, the staff of the Department of Radiopharmaceuticals Development for their radioligand synthesis and metabolite analysis, Yoshihide Akine, Bun Yamagata, and Jinichi Hirano for recruiting subjects and Renpei Sengoku in Tokyo Metropolitan Geriatric Hospital, and Institute of Gerontology for accessing Brain Bank data. We also thank Takashi Horiguchi for his assistance as a research administrator. Sho Moriguchi has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.


This research was partly supported by AMED under Grant Number JP17dm0107094.

Author information




Study concept and design: SM, KT, TS, and MM. Acquisition, analysis, or interpretation of data: SM, KT, MK, SK, YK, KT, RT, HT, JHM, MM, and KK. Drafting of the manuscript: SM, KT, MK, TS, and MH. Critical revision of the manuscript for important intellectual content: SM, KT, MK, MM, TS, MH, and SM. Statistical analysis: SM and KT. Obtained funding: KT, TS, and MH. Administrative, technical, or material support: YK, KK, M-RZ, TS, and MH.

Corresponding author

Correspondence to Sho Moriguchi.

Ethics declarations

Conflict of interest

HS, M-RZ, TS, and MH hold a patent on compounds related to the present report (JP 5422782/EP 12 884 742.3). The other authors report no disclosures relevant to the manuscript.

Additional information

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

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Moriguchi, S., Takahata, K., Shimada, H. et al. Excess tau PET ligand retention in elderly patients with major depressive disorder. Mol Psychiatry (2020). https://doi.org/10.1038/s41380-020-0766-9

Download citation