Association of longitudinal white matter degeneration and cerebrospinal fluid biomarkers of neurodegeneration, inflammation and Alzheimer’s disease in late-middle-aged adults

  • Annie M. Racine
  • Andrew P. Merluzzi
  • Nagesh Adluru
  • Derek Norton
  • Rebecca L. Koscik
  • Lindsay R. Clark
  • Sara E. Berman
  • Christopher R. Nicholas
  • Sanjay Asthana
  • Andrew L. Alexander
  • Kaj Blennow
  • Henrik Zetterberg
  • Won Hwa Kim
  • Vikas Singh
  • Cynthia M. Carlsson
  • Barbara B. Bendlin
  • Sterling C. Johnson
Original Research

Abstract

Alzheimer’s disease (AD) is characterized by substantial neurodegeneration, including both cortical atrophy and loss of underlying white matter fiber tracts. Understanding longitudinal alterations to white matter may provide new insights into trajectories of brain change in both healthy aging and AD, and fluid biomarkers may be particularly useful in this effort. To examine this, 151 late-middle-aged participants enriched with risk for AD with at least one lumbar puncture and two diffusion tensor imaging (DTI) scans were selected for analysis from two large observational and longitudinally followed cohorts. Cerebrospinal fluid (CSF) was assayed for biomarkers of AD-specific pathology (phosphorylated-tau/Aβ42 ratio), axonal degeneration (neurofilament light chain protein, NFL), dendritic degeneration (neurogranin), and inflammation (chitinase-3-like protein 1, YKL-40). Linear mixed effects models were performed to test the hypothesis that biomarkers for AD, neurodegeneration, and inflammation, or two-year change in those biomarkers, would be associated with worse white matter health overall and/or progressively worsening white matter health over time. At baseline in the cingulum, phosphorylated-tau/Aβ42 was associated with higher mean diffusivity (MD) overall (intercept) and YKL-40 was associated with increases in MD over time. Two-year change in neurogranin was associated with higher mean diffusivity and lower fractional anisotropy overall (intercepts) across white matter in the entire brain and in the cingulum. These findings suggest that biomarkers for AD, neurodegeneration, and inflammation are potentially important indicators of declining white matter health in a cognitively healthy, late-middle-aged cohort.

Keywords

Preclinical Alzheimer’s disease Cerebrospinal fluid White matter Biomarkers Longitudinal Linear mixed effects 

Abbreviations

DTI

Diffusion Tensor Imaging

WRAP

Wisconsin Registry for Alzheimer’s Prevention

FA

fractional anisotropy

MD

mean diffusivity

APOE ε4

apolipoprotein E gene

FH

(parental) family history

WM

white matter

GM

gray matter

FSL

FMRIB Software Library

ANTS

Advanced Normalization Tools

Cingulum-CC

cingulum adjacent to corpus callosum

Cingulum-HC

hippocampal cingulum

Notes

Acknowledgements

The authors gratefully acknowledge Amy Hawley, Jennifer Oh, Chuck Illingworth, Nancy Davenport-Sis, Sandra Harding, and the support of researchers and staff at the Wisconsin Alzheimer’s Disease Research Center, the Wisconsin Alzheimer’s Institute, the Waisman Center, and the University of Wisconsin-Madison for their assistance in recruitment, data collection, and data analysis. Above all, we wish to thank our dedicated volunteers for their participation in this research.

Compliance with ethical standards

Funding

This research was supported by the National Institutes of Health awards (AG021155, AG027161, AG000213, P50 AG033514, AG037639 and UL1RR025011) to the University of Wisconsin, Madison; by the National Science Foundation Graduate Research Fellowship under Grant No. DGE-1256259 (APM); by the Neuroscience & Public Policy Program (SES-0849122); by the Neuroscience Training Program (T32GM007507); by the Medical Scientist Training Program (T32GM008692); by the Wisconsin Alzheimer’s Institute Lou Holland Fund; and by the Swedish Research Council, the Swedish Brain Foundation, the Knut and Alice Wallenberg Foundation, and Torsten Söderberg’s Foundation to the University of Gothenburg. N.A is supported in part by R01-EB022883, U54-HD090256, U54-AI117924, UF1-AG051216 and R56-AG052698. The project was also supported by the Clinical and Translational Science Award (CTSA) program by the National Center for Advancing Translational Sciences (NCATS) grant UL1TR000427 and NSF CAREER award (1252725). Portions of this research were supported by the Veterans Administration including facilities and resources at the Geriatric Research Education and Clinical Center of the William S. Middleton Memorial Veterans Hospital, Madison, WI. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors(s) and do not necessarily reflect the views of the NIH, the Veterans Administration, or National Science Foundation.

Conflict of interest

KB and HZ are co-founders of Brain Biomarker Solutions in Gothenburg AB, a GU Venture-based platform company at the University of Gothenburg. KB has served as a consultant or at advisory boards for IBL International, Roche Diagnostics, Eli Lilly, Fujirebio Europe, and Novartis. The other authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

11682_2017_9732_MOESM1_ESM.docx (653 kb)
ESM 1(DOCX 652 kb)

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© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Annie M. Racine
    • 1
    • 2
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    • 1
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  • Nagesh Adluru
    • 3
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    • 6
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    • 2
  • Christopher R. Nicholas
    • 6
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    • 3
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    • 9
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    • 9
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  • Won Hwa Kim
    • 12
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  • Vikas Singh
    • 2
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  • Cynthia M. Carlsson
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  1. 1.Neuroscience and Public Policy ProgramUniversity of WisconsinMadisonUSA
  2. 2.Alzheimer’s Disease Research CenterUniversity of Wisconsin School of Medicine and Public HealthMadisonUSA
  3. 3.Waisman Laboratory for Brain Imaging and BehaviorUniversity of Wisconsin-MadisonMadisonUSA
  4. 4.Department of Biostatistics and Medical InformaticsUniversity of Wisconsin – MadisonMadisonUSA
  5. 5.Wisconsin Alzheimer’s InstituteUniversity of Wisconsin School of Medicine and Public HealthMadisonUSA
  6. 6.Geriatric Research Education and Clinical CenterWilliam S. Middleton Memorial VA HospitalMadisonUSA
  7. 7.Department of Medical PhysicsUniversity of Wisconsin School of Medicine and Public HealthMadisonUSA
  8. 8.Department of PsychiatryUniversity of Wisconsin School of Medicine and Public HealthMadisonUSA
  9. 9.Department of Psychiatry and Neurochemistry, Institute of Neuroscience and PhysiologyThe Sahlgrenska Academy at the University of GothenburgMölndalSweden
  10. 10.Clinical Neurochemistry LaboratorySahlgrenska University HospitalMölndalSweden
  11. 11.Institute of NeurologyUniversity College LondonLondonUK
  12. 12.Department of Computer SciencesUniversity of Wisconsin – MadisonMadisonUSA

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