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Level of education mitigates the impact of tau pathology on neuronal function

  • Merle C. HoenigEmail author
  • Gérard N. Bischof
  • Özgür A. Onur
  • Juraj Kukolja
  • Frank Jessen
  • Klaus Fliessbach
  • Bernd Neumaier
  • Gereon R. Fink
  • Elke Kalbe
  • Alexander Drzezga
  • Thilo van Eimeren
  • for the Alzheimer’s Disease Neuroimaging Initiative
Original Article
Part of the following topical collections:
  1. Neurology

Abstract

Purpose

Using PET imaging in a group of patients with Alzheimer’s disease (AD), we investigated whether level of education, a proxy for resilience, mitigates the harmful impact of tau pathology on neuronal function.

Methods

We included 38 patients with mild-to-moderate AD (mean age 67 ± 7 years, mean MMSE score 24 ± 4, mean years of education 14 ± 4; 20 men, 18 women) in whom a [18F]AV-1451 scan (a measure of tau pathology) and an [18F]FDG scan (a measure of neuronal function) were available. The preprocessed PET scans were z-transformed using templates for [18F]AV-1451 and [18F]FDG from healthy controls, and subsequently thresholded at a z-score of ≥3.0, representing an one-tailed p value of 0.001. Next, three volumes were computed in each patient: the tau-specific volume (tau pathology without neuronal dysfunction), the FDG-specific volume (neuronal dysfunction without tau pathology), and the overlap volume (tau pathology and neuronal dysfunction). Mean z-scores and volumes were extracted and used as dependent variables in regression analysis with years of education as predictor, and age and MMSE score as covariates.

Results

Years of education were positively associated with tau-specific volume (β = 0.362, p = 0.022), suggesting a lower impact of tau pathology on neuronal function in patients with higher levels of education. Concomitantly, level of education was positively related to tau burden in the overlap volume (β = 0.303, p = 0.036) implying that with higher levels of education more tau pathology is necessary to induce neuronal dysfunction.

Conclusion

In patients with higher levels of education, tau pathology is less paralleled by regional and remote neuronal dysfunction. The data suggest that early life-time factors such as level of education support resilience mechanisms, which ameliorate AD-related effects later in life.

Keywords

Glucose metabolism Brain reserve Brain maintenance Resilience [18F]AV-1451 [18F]FDG 

Notes

Acknowledgments

ÖAO, JK and GRF are grateful for the support of the Marga and Walter Boll foundation. 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).

Author’s contributions

M.C.H. had 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. M.C.H., G.N.B., A.D. and T.vanE. were involved in the conception and design of the study, analysis of the data and drafting the manuscript. E.K. was involved in the conception of the study and drafting the manuscript. Ö.A.O., J.K., F.J., K.F., G.R.F. and B.N. were involved in the acquisition of the data and drafting the manuscript.

Funding

This study was supported by funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, DR 445/9-1). MH’s position is funded by the DFG - 233886668/ GRK1960. ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; 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.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. 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 Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

Compliance with ethical standards

Conflicts of interest

MH, GNB, ÖAO, JK, FJ, KF, and BN have no conflict of interest. GRF received honoraria for speaking engagements from Bayer, Desitin, Ergo DKV, Forum für medizinische Fortbildung FomF GmbH, GSK, Medica Academy Messe Düsseldorf, Medicbrain Healthcare, Novartis, Pfizer, and Sportärztebund NRW. EK received grants from the German Ministry of Education and Research, the German ParkinsonFonds, and the German Parkinson Society as well as honoraria from Oticon GmbH, Hamburg, Germany; Lilly Pharma GmbH, Bad Homburg, Germany; Bernafon AG, Bern, Switzerland; Desitin GmbH, Hamburg, Germany. AD reports having received consulting and speaker honoraria as well as research support from Siemens Healthcare, AVID Radiopharmaceuticals, Lilly, Piramal (now Life Molecular Imaging) and GE Healthcare. TvE reports having received consulting and speaker honoraria as well as research support from Siemens Healthcare, AVID Radiopharmaceuticals, Lilly, Shire Germany, Piramal (now Life Molecular Imaging) and GE Healthcare. Data used in preparation of this article were obtained from the ADNI database (http://adni.loni.usc.edu/). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in 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.

Ethical approval

All procedures performed in this study were in accordance with the ethical standards of the Ethics Committee of the University Cologne and with the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. For this type of study formal consent was not required.

Informed consent

Informed consent was obtained from all individual participants included in this research project as part of the study for the scientific evaluation of the AV-1451 tracer.

Supplementary material

259_2019_4342_MOESM1_ESM.docx (43 kb)
ESM 1 (DOCX 43.2 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Merle C. Hoenig
    • 1
    • 2
    Email author
  • Gérard N. Bischof
    • 1
    • 3
  • Özgür A. Onur
    • 4
    • 5
  • Juraj Kukolja
    • 6
  • Frank Jessen
    • 7
    • 8
  • Klaus Fliessbach
    • 8
    • 9
  • Bernd Neumaier
    • 10
    • 11
  • Gereon R. Fink
    • 4
    • 5
  • Elke Kalbe
    • 12
  • Alexander Drzezga
    • 1
    • 2
    • 8
  • Thilo van Eimeren
    • 1
    • 4
    • 8
  • for the Alzheimer’s Disease Neuroimaging Initiative
  1. 1.Multimodal Neuroimaging, Department of Nuclear Medicine, Medical Faculty and University HospitalUniversity Hospital CologneCologneGermany
  2. 2.Molecular Organization of the Brain, Institute of Neuroscience and Medicine (INM-2)Research Center JülichJülichGermany
  3. 3.Faculty of Mathematics and Natural SciencesUniversity of CologneCologneGermany
  4. 4.Department of Neurology, Medical Faculty and University HospitalUniversity of CologneCologneGermany
  5. 5.Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3)Research Center JülichJülichGermany
  6. 6.Department of Neurology and Clinical NeurophysiologyHelios University Hospital WuppertalWuppertalGermany
  7. 7.Department of Psychiatry, Medical Faculty and University HospitalUniversity of CologneCologneGermany
  8. 8.German Center for Neurodegenerative Diseases (DZNE)Bonn/CologneGermany
  9. 9.Department of Neurodegenerative Diseases and Geriatric PsychiatryUniversity Hospital BonnBonnGermany
  10. 10.Nuclear Chemistry, Institute of Neuroscience and Medicine (INM-5)Research Center JülichJülichGermany
  11. 11.Institute of Radiochemistry and Experimental Molecular Imaging, Medical Faculty and University HospitalUniversity of CologneCologneGermany
  12. 12.Department of Medical Psychology | Neuropsychology and Gender Studies & Center for Neuropsychological Diagnostics and Intervention (CeNDI), Medical Faculty and University HospitalUniversity of CologneCologneGermany

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