SpringerLink
Log in

Spatial decrease of synaptic density in amnestic mild cognitive impairment follows the tau build-up pattern

  • Article
  • Published:
Molecular Psychiatry Submit manuscript

Abstract

Next to amyloid and tau, synaptic loss is a key pathological hallmark in Alzheimer’s disease, closely related to cognitive dysfunction and neurodegeneration. Tau is thought to cause synaptic loss, but this has not been experimentally verified in vivo. In a 2-year follow-up study, dual tracer PET-MR was performed in 12 amnestic MCI patients using 18F-MK-6240 for tau and 11C-UCB-J for SV2A as a proxy for synaptic density. Tau already accumulated in the neocortex at baseline with progression in Braak V/VI at follow-up. While synaptic loss was limited to limbic regions at baseline, it followed the specific tau pattern to stage IV/V regions two years later, indicating that tau spread might drive synaptic vulnerability. Moreover, synaptic density changes correlated to changes in cognitive function. This study shows for the first time in vivo that synaptic loss regionally follows tau accumulation after two years, providing a disease-modifying window of opportunity for (combined) tau-targeting therapies.

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

Access this article

Log in via an institution

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1: Spatial progression of gray matter concentration, p-τ deposition and synaptic loss.
Fig. 2: Voxel-based longitudinal paired changes in gray matter concentration, 18F-MK-6240 binding and 11C-UCB-J binding in patients with aMCI.
Fig. 3: VOI-based longitudinal paired changes in 18F-MK-6240 and 11C-UCB-J binding in patients with aMCI.
Fig. 4: Negative correlation between baseline 18F-MK-6240 binding and 11C-UCB-J binding at 2-year follow-up in patients with aMCI.
Fig. 5: Correlation of PET measures with clinical disease progression.

Similar content being viewed by others

Data availability

Anonymized data will be deposited in an access-controlled file server used by the academic research PET imaging group, which will be shared upon reasonable request from any qualified investigator on approval by the Ethics Committee of the local university hospital.

References

  1. Villemagne VL, Lopresti BJ, Doré V, Tudorascu D, Ikonomovic MD, Burnham S, et al. What is T+? a gordian knot of tracers, thresholds, and topographies. J Nucl Med. 2021;62:614–9.

    PubMed  Google Scholar 

  2. Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimer’s Dement. 2018;14:535–62.

    Google Scholar 

  3. Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, et al. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement. 2012;8:1–13.

    PubMed  PubMed Central  Google Scholar 

  4. Aragão Gomes L, Andrea Hipp S, Rijal Upadhaya A, Balakrishnan K, Ospitalieri S, Koper MJ, et al. Aβ-induced acceleration of Alzheimer-related τ-pathology spreading and its association with prion protein. Acta Neuropathol. 2019;138:913–41.

    Google Scholar 

  5. Naseri NN, Wang H, Guo J, Sharma M, Luo W. The complexity of tau in Alzheimer’s disease. Neurosci Lett. 2019;705:183–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. McInnes J, Wierda K, Snellinx A, Bounti L, Wang Y, Stancu I, et al. Synaptogyrin-3 mediates presynaptic dysfunction induced by tau. Neuron. 2018;97:823–35.

    CAS  PubMed  Google Scholar 

  7. Zhou L, McInnes J, Wierda K, Holt M, Herrmann AG, Jackson RJ, et al. Tau association with synaptic vesicles causes presynaptic dysfunction. Nat Commun. 2017;8:15295.

    PubMed  PubMed Central  Google Scholar 

  8. Ruan Z, Delpech J-C, Kalavai SV, Enoo AAVan, Hu J, Ikezu S, et al. P2RX7 inhibitor suppresses exosome secretion and disease phenotype in P301S tau transgenic mice. Mol Neurodegener. 2020;15:47.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Becker G, Dammicco S, Bahri MA, Salmon E. The rise of synaptic density PET imaging. Molecules 2020;25:2303.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Leuzy A, Chiotis K, Lemoine L, Gillberg PG, Almkvist O, Rodriguez-Vieitez E, et al. Tau PET imaging in neurodegenerative tauopathies—still a challenge. Mol Psychiatry. 2019;24:1112–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Lemoine L, Leuzy A, Chiotis K, Rodriguez-Vieitez E, Nordberg A. Tau positron emission tomography imaging in tauopathies: the added hurdle of off-target binding. Alzheimer’s Dement Diagnosis Assess Dis Monit. 2018;10:232–6.

    Google Scholar 

  12. Gogola A, Minhas DS, Villemagne VL, Cohen AD, Mountz JM, Pascoal TA, et al. Direct comparison of the tau PET tracers [18 F]flortaucipir and [18 F]MK-6240 in human subjects. J Nucl Med. 2022;63:108–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Aguero C, Dhaynaut M, Normandin MD, Amaral AC, Guehl NJ, Neelamegam R. et al. Autoradiography validationof novel tau PET tracer [F-18]-MK-6240 on human postmortem brain tissue. Acta Neuropathol Commun. 2019;7:37

    PubMed  PubMed Central  Google Scholar 

  14. Salinas C, Lohith TG, Purohit A, Struyk A, Sur C, Bennacef I, et al. Test–retest characteristic of [18F]MK-6240 quantitative outcomes in cognitively normal adults and subjects with Alzheimer’s disease. J Cereb Blood Flow Metab. 2020;40:2179–87.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  16. Braak H, Del Tredici K. The preclinical phase of the pathological process underlying sporadic Alzheimer’s disease. Brain. 2015;138:2814–33.

    PubMed  Google Scholar 

  17. Cho H, Lee HS, Choi JY, Lee JH, Ryu YH, Lee MS, et al. Predicted sequence of cortical tau and amyloid-β deposition in Alzheimer disease spectrum. Neurobiol Aging. 2018;68:76–84.

    CAS  PubMed  Google Scholar 

  18. Pascoal TA, Benedet AL, Tudorascu DL, Therriault J, Mathotaarachchi S, Savard M, et al. Longitudinal 18 F-MK-6240 tau tangles accumulation follows Braak stages. Brain. 2021;27:1592–9.

    CAS  Google Scholar 

  19. Vogel JW, Iturria-Medina Y, Strandberg OT, Smith R, Levitis E, Evans AC, et al. Spread of pathological tau proteins through communicating neurons in human Alzheimer’s disease. Nat Commun. 2020;11:2612.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Pascoal TA, Therriault J, Benedet AL, Savard M, Lussier FZ, Chamoun M, et al. 18F-MK-6240 PET for early and late detection of neurofibrillary tangles. Brain. 2020;143:2818–30.

    PubMed  Google Scholar 

  21. Therriault J, Pascoal TA, Lussier FZ, Tissot C, Chamoun M, Bezgin G, et al. Biomarker modeling of Alzheimer’s disease using PET-based Braak staging. Nat Aging. 2022;2:526–35.

  22. Bajjalieh SM, Frantz GD, Weimann JM, McConnell SK, Scheller RH. Differential expression of synaptic vesicle protein 2 (SV2) isoforms. J Neurosci. 1994;14:5223–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Finnema SJ, Nabulsi NB, Eid T, Detyniecki K, Lin SF, Chen MK, et al. Imaging synaptic density in the living human brain. Sci Transl Med. 2016;8:1–10.

    Google Scholar 

  24. Delva A, Michiels L, Koole M, Van Laere K, Vandenberghe W. Synaptic damage and its clinical correlates in people with early huntington disease: a PET study. Neurology. 2022;98:e83-e94.

  25. Holmes SE, Scheinost D, Finnema SJ, Naganawa M, Davis MT, DellaGioia N, et al. Lower synaptic density is associated with depression severity and network alterations. Nat Commun. 2019;10:1529.

    PubMed  PubMed Central  Google Scholar 

  26. Matuskey D, Tinaz S, Wilcox KC, Naganawa M, Toyonaga T, Dias M, et al. Synaptic changes in Parkinson disease assessed with in vivo imaging. Ann Neurol. 2020;87:329–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Onwordi EC, Halff EF, Whitehurst T, Mansur A, Cotel M-C, Wells L, et al. Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats. Nat Commun. 2020;11:246.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Chen M-K, Mecca AP, Naganawa M, Finnema SJ, Toyonaga T, Lin S, et al. Assessing synaptic density in Alzheimer disease with synaptic vesicle glycoprotein 2A positron emission tomographic imaging. JAMA Neurol. 2018;75:1215–24.

    PubMed  PubMed Central  Google Scholar 

  29. Bastin C, Bahri MA, Meyer F, Manard M, Delhaye E, Plenevaux A, et al. In vivo imaging of synaptic loss in Alzheimer’s disease with [18F] UCB-H positron emission tomography. Eur J Nucl Med Mol Imaging. 2020;47:390–402.

    CAS  PubMed  Google Scholar 

  30. Mecca AP, Chen MK, O’Dell RS, Naganawa M, Toyonaga T, Godek TA, et al. In vivo measurement of widespread synaptic loss in Alzheimer’s disease with SV2A PET. Alzheimer’s Dement. 2020;16:974–82.

    Google Scholar 

  31. Vanhaute H, Ceccarini J, Michiels L, Koole M, Sunaert S, Lemmens R, et al. In vivo synaptic density loss is related to tau deposition in amnestic mild cognitive impairment. Neurology. 2020;95:e545–53.

    CAS  PubMed  Google Scholar 

  32. O’Dell RS, Mecca AP, Chen MK, Naganawa M, Toyonaga T, Lu Y, et al. Association of Aβ deposition and regional synaptic density in early Alzheimer’s disease: a PET imaging study with [11C]UCB-J. Alzheimer’s Res Ther. 2021;13:11.

    Google Scholar 

  33. Coomans EM, Schoonhoven DN, Tuncel H, Verfaillie SCJ, Wolters EE, Boellaard R, et al. In vivo tau pathology is associated with synaptic loss and altered synaptic function. Alzheimer’s Res Ther. 2021;13:35.

    CAS  Google Scholar 

  34. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. 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 Dement. 2011;7:270–9.

    Google Scholar 

  35. Nabulsi NB, Mercier J, Holden D, Carré S, Najafzadeh S, Vandergeten M-C, et al. Synthesis and preclinical evaluation of 11 C-UCB-J as a PET tracer for imaging the synaptic vesicle glycoprotein 2A in the brain. J Nucl Med. 2016;57:777–84.

    CAS  PubMed  Google Scholar 

  36. Collier TL, Yokell DL, Livni E, Rice PA, Celen S, Serdons K, et al. cGMP production of the radiopharmaceutical [18 F]MK-6240 for PET imaging of human neurofibrillary tangles. J Label Compd Radiopharm. 2017;60:263–9.

    CAS  Google Scholar 

  37. Mertens N, Michiels L, Vanderlinden G, Vandenbulcke M, Lemmens R, Van Laere K, et al. Impact of meningeal uptake and partial volume correction techniques on [18 F] MK-6240 binding in aMCI patients and healthy controls. J Cereb Blood Flow Metab. 2022;42:1236–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Koole M, Van Aalst J, Devrome M, Mertens N, Serdons K, Lacroix B, et al. Quantifying SV2A density and drug occupancy in the human brain using [11 C]UCB-J PET imaging and subcortical white matter as reference tissue. Eur J Nucl Med Mol Imaging. 2019;46:396–406.

    CAS  PubMed  Google Scholar 

  39. Betthauser TJ, Cody KA, Zammit MD, Murali D, Converse AK, Barnhart TE, et al. In vivo characterization and quantification of neurofibrillary Tau PET radioligand 18 F-MK-6240 in humans from Alzheimer disease dementia to young controls. J Nucl Med. 2019;60:93–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Visser D, Wolters EE, J Verfaillie SC, Coomans EM, Timmers T, Tuncel H, et al. Tau pathology and relative cerebral blood flow are independently associated with cognition in Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2020;47:3165–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Wolters EE, Ossenkoppele R, Verfaillie SCJ, Coomans EM, Timmers T, Visser D, et al. Regional [18F]flortaucipir PET is more closely associated with disease severity than CSF p-tau in Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2020;47:2866–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Schöll M, Lockhart SN, Schonhaut DR, O’Neil JP, Janabi M, Ossenkoppele R, et al. PET imaging of tau deposition in the aging human brain. Neuron. 2016;89:971–82.

    PubMed  PubMed Central  Google Scholar 

  43. Chandra A, Dervenoulas G, Politis M, Initiative for the ADN. Magnetic resonance imaging in Alzheimer’s disease and mild cognitive impairment. J Neurol. 2019;266:1293–302.

    PubMed  Google Scholar 

  44. Kreisl WC, Lao PJ, Johnson A, Tomljanovic Z, Klein J, Polly K, et al. Patterns of tau pathology identified with 18F-MK-6240 PET imaging. Alzheimer’s Dement. 2022;18:272–82.

  45. La Joie R, Visani AV, Baker SL, Brown JA, Bourakova V, Cha J, et al. Prospective longitudinal atrophy in Alzheimer’s disease correlates with the intensity and topography of baseline tau-PET. Sci Transl Med. 2020;12:eaau5732.

  46. Krishnadas N, Doré V, Robertson J, Ward L, Fowler C, Masters CL, et al. Rates of regional tau accumulation in ageing and across the Alzheimer’s disease continuum: An AIBL 18F-MK6240 PET study. medRxiv. 2022.03.11.22272240.

  47. Jack CR, Wiste HJ, Schwarz CG, Lowe VJ, Senjem ML, Vemuri P, et al. Longitudinal tau PET in ageing and Alzheimer’s disease. Brain. 2018;141:1517–28.

    PubMed  PubMed Central  Google Scholar 

  48. Harrison TM, La Joie R, Maass A, Baker SL, Swinnerton K, Fenton L, et al. Longitudinal tau accumulation and atrophy in aging and alzheimer disease. Ann Neurol. 2019;85:229–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Pontecorvo MJ, Devous MD, Kennedy I, Navitsky M, Lu M, Galante N, et al. A multicentre longitudinal study of flortaucipir (18 F) in normal ageing, mild cognitive impairment and Alzheimer’s disease dementia. Brain 2019;142:1723–35.

    PubMed  PubMed Central  Google Scholar 

  50. Cho H, Choi JY, Lee HS, Lee JH, Ryu YH, Lee MS, et al. Progressive tau accumulation in Alzheimer disease: 2-year follow-up study. J Nucl Med. 2019;60:1611–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Csukly G, Sirály E, Fodor Z, Horváth A, Salacz P, Hidasi Z, et al. The differentiation of amnestic type MCI from the non-amnestic types by structural MRI. Front Aging Neurosci. 2016;8:52.

  52. Bowen J, Teri L, Kukull W, McCormick W, McCurry SM, Larson EB. Progression to dementia in patients with isolated memory loss. Lancet. 1997;349:763–5.

    CAS  PubMed  Google Scholar 

  53. Forsberg A, Varrone A. Timing is everything: tau imaging across stages of Alzheimer’s disease. Brain. 2020;143:2634–6.

    Google Scholar 

  54. Holland N, Malpetti M, Rittman FRCPT, Mak EE, Passamonti MRCPL, Kaalund SS, et al. Molecular pathology and synaptic loss in primary tauopathies: [18 F]AV-1451 and [11 C]UCB-J PET study. Brain. 2022;145:340–8.

    PubMed  Google Scholar 

  55. Hostetler ED, Walji AM, Zeng Z, Miller P, Bennacef I, Salinas C, et al. Preclinical characterization of 18 F-MK-6240, a promising PET tracer for in vivo quantification of human neurofibrillary tangles. J Nucl Med. 2016;57:1599–606.

    CAS  PubMed  Google Scholar 

  56. Menkes-Caspi N, Yamin HG, Kellner V, Spires-Jones TL, Cohen D, Stern EA. Pathological tau disrupts ongoing network activity. Neuron. 2015;85:959–66.

    CAS  PubMed  Google Scholar 

  57. Kaniyappan S, Chandupatla RR, Mandelkow EM, Mandelkow E. Extracellular low-n oligomers of tau cause selective synaptotoxicity without affecting cell viability. Alzheimer’s Dement. 2017;13:1270–91.

    Google Scholar 

  58. Metaxas A, Thygesen C, Briting SRR, Landau AM, Darvesh S, Finsen B. Increased inflammation and unchanged density of synaptic vesicle glycoprotein 2A (SV2A) in the postmortem frontal cortex of Alzheimer’s disease patients. Front Cell Neurosci. 2019;13:1–8.

    Google Scholar 

  59. Heneka MT, Carson MJ, Khoury JEL, Landreth GE, Brosseron F, Feinstein, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14:388–405.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Biasetti L, Rey S, Fowler M, Ratnayaka A, Fennell K, Smith C, et al. Elevated amyloid beta disrupts the nanoscale organization and function of synaptic vesicle pools in hippocampal neurons. Cereb Cortex. 2022;bhac134. Epub ahead of print.

  61. Pickett EK, Henstridge CM, Allison E, Pitstick R, Pooler A, Wegmann S, et al. Spread of tau down neural circuits precedes synapse and neuronal loss in the rTgTauEC mouse model of early Alzheimer’s disease. Synapse. 2017;71:e21965.

  62. Spires-Jones TL, Hyman BT. The intersection of amyloid beta and tau at synapses in Alzheimer’s disease. Neuron. 2014;82:756–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Wu JW, Hussaini SA, Bastille IM, Rodriguez GA, Mrejeru A, Rilett K, et al. Neuronal activity enhances tau propagation and tau pathology in vivo. Nat Neurosci. 2016;19:1085–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Walters ER, Lesk VE. Time of day and caffeine influence some neuropsychological tests in the elderly. Psychol Assess. 2015;27:161–8.

    PubMed  Google Scholar 

  65. Tierney MC, Szalai JP, Snow WG, Fisher RH, Nores A, Nadon G, et al. Prediction of probable Alzheimer’s disease in memory-impaired patients: a prospective longitudinal study. Neurology. 1996;46:661–5.

    CAS  PubMed  Google Scholar 

  66. Michiels L, Delva A, Van Aalst J, Ceccarini J, Vandenberghe W, Vandenbulcke M, et al. Synaptic density in healthy human aging is not influenced by age or sex: a 11 C-UCB-J PET study. Neuroimage. 2021;232:117877.

    CAS  PubMed  Google Scholar 

  67. Mertens N, Maguire RP, Serdons K, Lacroix B, Mercier J, Sciberras D, et al. Validation of parametric methods for [11C]UCB-J PET imaging using subcortical white matter as reference tissue. Mol Imaging Biol. 2020;22:444–52.

    CAS  PubMed  Google Scholar 

  68. Naganawa M, Gallezot J-D, Finnema S, Matuskey D, Mecca A, Nabulsi N, et al. Simplified quantification of 11 C-UCB-J PET evaluated in a large human cohort. J Nucl Med. 2021;62:418–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Lohith TG, Bennacef I, Vandenberghe R, Vandenbulcke M, Salinas CA, Declercq R, et al. Brain imaging of Alzheimer dementia patients and elderly controls with 18 F-MK-6240, a PET tracer targeting neurofibrillary tangles. J Nucl Med. 2019;60:107–14.

    CAS  PubMed  Google Scholar 

  70. Pascoal TA, Shin M, Kang MS, Chamoun M, Chartrand D, Mathotaarachchi S, et al. In vivo quantification of neurofibrillary tangles with [18 F]MK-6240. Alzheimer’s Res Ther. 2018;10:74.

    Google Scholar 

  71. Tuncel H, Boellaard R, Coomans EM, de Vries EFJ, Glaudemans AWJM, Feltes PK, et al. Kinetics and 28-day test–retest repeatability and reproducibility of [11C]UCB-J PET brain imaging. J Cereb Blood Flow Metab. 2021;41:1338–50.

    CAS  PubMed  Google Scholar 

  72. Kolinger GD, Vállez García D, Lohith TG, Hostetler ED, Sur C, Struyk A, et al. A dual-time-window protocol to reduce acquisition time of dynamic tau PET imaging using [18F]MK-6240. EJNMMI Res. 2021;11:49.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by an FWO grant (FWO/G093218N) and KU Leuven internal C2 funding (C24-17-063). We thank all the participants for their willingness to participate in this study. We are grateful to the PET-MR technologists, in particular Kwinten Porters and Jef Van Loock for their contribution in data acquisition. We also thank the PET radiopharmacy team and nuclear medicine medical physics team for their skilled contributions.

Author information

Authors and Affiliations

  1. Nuclear Medicine and Molecular Imaging, Imaging Pathology, KU Leuven, Leuven, Belgium

    Greet Vanderlinden, Jenny Ceccarini, Michel Koole & Koen Van Laere

  2. Neuropsychiatry, Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium

    Thomas Vande Casteele & Mathieu Vandenbulcke

  3. Department of Neurosciences, KU Leuven, Leuven, Belgium

    Laura Michiels & Robin Lemmens

  4. Department of Neurology, University Hospitals UZ Leuven, Leuven, Belgium

    Laura Michiels & Robin Lemmens

  5. VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium

    Laura Michiels & Robin Lemmens

  6. Private Practice Neurology, Leuven, Belgium

    Eric Triau

  7. Department of Nuclear Medicine, University Hospitals UZ Leuven, Leuven, Belgium

    Kim Serdons & Koen Van Laere

  8. Department of Geriatric Medicine, University Hospitals UZ Leuven, Leuven, Belgium

    Jos Tournoy

  9. Department of Public Health and Primary Care, Gerontology and Geriatrics, KU Leuven, Leuven, Belgium

    Jos Tournoy

  10. Department of Old-Age Psychiatry, University Hospitals UZ Leuven, Leuven, Belgium

    Mathieu Vandenbulcke

Authors
  1. Greet Vanderlinden
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jenny Ceccarini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas Vande Casteele
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laura Michiels
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robin Lemmens
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eric Triau
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kim Serdons
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jos Tournoy
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michel Koole
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mathieu Vandenbulcke
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Koen Van Laere
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KVL, MV, and GV contributed to study concept and design, KVL and MV supervised the study progression. GV, TVC, LM, ET, JT, and MV recruited study participants. GV, TVC, and LM attributed to data acquisition. GV, JC, LM, MK, MV, KVL contributed to data analysis and interpretation. KVL obtained funding. KS was responsible for tracer synthesis. GV, KVL, and JC drafted the manuscript and manuscript revision was performed by all authors.

Corresponding author

Correspondence to Greet Vanderlinden.

Ethics declarations

Competing interests

JC is a postdoctoral fellow from Flemish Science Foundation (FWO) (FWO/12R1619N), KVL and RL are senior investigators of the FWO.

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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vanderlinden, G., Ceccarini, J., Vande Casteele, T. et al. Spatial decrease of synaptic density in amnestic mild cognitive impairment follows the tau build-up pattern. Mol Psychiatry 27, 4244–4251 (2022). https://doi.org/10.1038/s41380-022-01672-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-022-01672-x

  • Springer Nature Limited

This article is cited by

Search

Navigation