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Evaluation of the methoxy-X04 derivative BSC4090 for diagnosis of prodromal and early Alzheimer’s disease from bioptic olfactory mucosa

  • Hannah Pellkofer
  • Friedrich Ihler
  • Bernhard G. Weiss
  • Janina Trothe
  • Harindranath Kadavath
  • Monika Chongtham
  • Marcel Kunadt
  • Dietmar Riedel
  • Finn Lornsen
  • Petra Wilken
  • Claudia Bartels
  • Sina Hirschel
  • Sebastian G. Russo
  • Elke Stransky
  • Lutz Trojan
  • Boris Schmidt
  • Eckhardt Mandelkow
  • Markus Zweckstetter
  • Martin Canis
  • Anja SchneiderEmail author
Original Paper
  • 167 Downloads

Abstract

Alzheimer’s disease (AD) pathology precedes the onset of clinical symptoms by several decades. Thus, biomarkers are required to identify prodromal disease stages to allow for the early and effective treatment. The methoxy-X04-derivative BSC4090 is a fluorescent ligand which was designed to target neurofibrillary tangles in AD. BSC4090 staining was previously detected in post-mortem brains and olfactory mucosa derived from AD patients. We tested BSC4090 as a potential diagnostic marker of prodromal and early AD using olfactory mucosa biopsies from 12 individuals with AD, 13 with mild cognitive impairment (MCI), and 10 cognitively normal (CN) controls. Receiver-operating curve analysis revealed areas under the curve of 0.78 for AD versus CN and of 0.86 for MCI due to AD versus MCI of other causes. BSC4090 labeling correlated significantly with cerebrospinal fluid levels of tau protein phosphorylated at T181. Using NMR spectroscopy, we find that BSC4090 binds to fibrillar and pre-fibrillar but not to monomeric tau. Thus, BSC4090 may be an interesting candidate to detect AD at the early disease stages.

Keywords

Alzheimer’s disease Biomarker Tau Olfactory epithelia Methoxy-X04 

Abbreviations

AD

Alzheimer’s disease

AUC

Area under the curve

CERAD

Consortium to Establish a Registry for Alzheimer’s Disease

CN

Cognitively normal

CSF

Cerebrospinal fluid

FCS

Fetal calf serum

FPLC

Fast protein liquid chromatography

HSQC

Heteronuclear single quantum coherence

MMSE

Mini-mental state examination

NIA-AA

National Institute on Aging–Alzheimer’s Association

NFT

Neurofibrillary Tangles

NINCDS-ADRDA

National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association

NMR

Nuclear magnetic resonance

OE

Olfactory epithelia

PET

Positron emission tomography

ROC

Receiver-operating curve

SUVR

Standard uptake value ratio

STD

Saturation-transfer difference

Notes

Acknowledgements

We are grateful to Angela Dettmar, DZNE Göttingen, for expert technical assistance and to Sabrina Hübschmann, DZNE Bonn, for preparation of recombinant tau proteins. A.S. and M.Z. were supported by grants from the German Research foundation Cluster of Excellence “Nanoscale Microscopy and Molecular Physiology of the Brain” (CNMPB) and the Center for Molecular Physiology of the Brain (CMPB). A.S. received funding by the German Research Foundation (Deutsche Forschungsgemeinschaft) grants SCHN1265 2-1 and 1-1. B.S. thanks Hans-und-Ilse-Breuerstiftung for support.

Author contributions

HP, MaC, MZ, EM, and AS: conception and design of the study. FI, BW, JT, HK, MC, MK, DR, FL, PW, CB, SH, SR, ES, LT, BS, MZ, MoC, and AS: acquisition and analysis of data. MZ, EM, and AS: drafting the manuscript. All authors read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

Dr. Schneider received research support from Actelion which was unrelated to the present study. She is a principal investigator in industry-sponsored clinical trials for Merck MSD, Eli Lilly, Biogen and Ionis. Dr. Pellkofer Dr. Ihler, Dr. Weiss, J. Trothe, Dr. Kadavath, M. Chongtham, Dr. Kunadt, Dr. Riedel, F. Lornsen, Dr. Wilken, Dr. Bartels, S. Hirschel, S. Russo, E. Stransky, Dr.Trojan, Dr. Schmidt, Dr. Mandelkow, Dr. Zweckstetter, and Dr. Canis reported no potential conflicts of interest relevant to this manuscript.

Supplementary material

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Supplementary material 1 (TIF 4365 KB)
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Supplementary material 3 (TIF 9511 KB)
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Supplementary material 4 (DOCX 21 KB)
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Supplementary material 5 (DOCX 13 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Hannah Pellkofer
    • 1
  • Friedrich Ihler
    • 2
  • Bernhard G. Weiss
    • 2
  • Janina Trothe
    • 3
    • 4
  • Harindranath Kadavath
    • 3
  • Monika Chongtham
    • 3
  • Marcel Kunadt
    • 5
  • Dietmar Riedel
    • 6
  • Finn Lornsen
    • 5
  • Petra Wilken
    • 5
  • Claudia Bartels
    • 5
  • Sina Hirschel
    • 5
  • Sebastian G. Russo
    • 6
  • Elke Stransky
    • 7
  • Lutz Trojan
    • 8
  • Boris Schmidt
    • 9
  • Eckhardt Mandelkow
    • 10
    • 11
    • 12
  • Markus Zweckstetter
    • 1
    • 3
    • 4
  • Martin Canis
    • 2
  • Anja Schneider
    • 10
    • 13
    Email author
  1. 1.Department of NeurologyUniversity Medical CenterGöttingenGermany
  2. 2.Department of Otorhinolaryngology, Head and Neck SurgeryUniversity Medical CenterGöttingenGermany
  3. 3.German Center for Neurodegenerative DiseasesDZNE GöttingenGöttingenGermany
  4. 4.Max-Planck-Institute for Biophysical ChemistryGöttingenGermany
  5. 5.Department of Psychiatry and PsychotherapyUniversity Medical CenterGöttingenGermany
  6. 6.Department of AnaesthesiologyUniversity Medical CenterGöttingenGermany
  7. 7.Department of NeurologyUniversity TübingenTübingenGermany
  8. 8.Department of UrologyUniversity Medical CenterGöttingenGermany
  9. 9.Clemens Schoepf-Institute of Organic Chemistry and BiochemistryTechnische Universität DarmstadtDarmstadtGermany
  10. 10.German Center for Neurodegenerative DiseasesDZNE BonnBonnGermany
  11. 11.Center of Advanced European Studies and ResearchBonnGermany
  12. 12.Max Planck Institute for Metabolism ResearchHamburgGermany
  13. 13.Department of Neurodegenerative Diseases and Geriatric PsychiatryUniversity BonnBonnGermany

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