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CSF biomarker associations with change in hippocampal volume and precuneus thickness: implications for the Alzheimer’s pathological cascade

  • ADNI: Friday Harbor 2011 Workshop SPECIAL ISSUE
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Abstract

Neurofibrillary tangles (NFT) and amyloid plaques are hallmark neuropathological features of Alzheimer’s disease (AD). There is some debate as to which neuropathological feature comes first in the disease process, with early autopsy studies suggesting that NFT develop first, and more recent neuroimaging studies supporting the early role of amyloid beta (Aβ) deposition. Cerebrospinal fluid (CSF) biomarkers of Aβ42 and hyperphosphorylated tau (p-tau) have been shown to serve as in vivo proxy measures of amyloid plaques and NFT, respectively. The aim of this study was to examine the association between CSF biomarkers and rate of atrophy in the precuneus and hippocampus. These regions were selected because the precuneus appears to be affected early and severely by Aβ deposition, and the hippocampus similarly by NFT pathology. We predicted (1) baseline Aβ42 would be related to accelerated rate of cortical thinning in the precuneus and volume loss in the hippocampus, with the latter relationship expected to be weaker, (2) baseline p-tau181p would be related to accelerated rate of hippocampal atrophy and cortical thinning in the precuneus, with the latter relationship expected to be weaker. Using all ADNI cohorts, we fitted separate linear mixed-effects models for changes in hippocampus and precuneus longitudinal outcome measures with baseline CSF biomarkers modeled as predictors. Results partially supported our hypotheses: Both baseline p-tau181p and Aβ42 were associated with hippocampal atrophy over time. Neither p-tau181p nor Aβ42 were significantly related to cortical thinning in the precuneus over time. However, follow-up analyses demonstrated that having abnormal levels of both Aβ42 and p-tau181p was associated with an accelerated rate of atrophy in both the hippocampus and precuneus. Results support early effects of Aβ in the Alzheimer’s disease process, which are less apparent than and perhaps dependent on p-tau effects as the disease progresses. However, amyloid deposition alone may be insufficient for emergence of significant morphometric changes and clinical symptoms.

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Acknowledgments

This manuscript was a collaborative effort from the 2011 Friday Harbor Advanced Psychometrics Workshop, funded by the National Institute on Aging R13 AG030995. Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; F. Hoffmann-LaRoche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. 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 (http://www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129, K01 AG030514, P30 AG008017, R01 AG029672-01A1 and the Dana Foundation.

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There were no actual or potential conflicts of interest for any of the authors.

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Authors and Affiliations

  1. Psychology Service, VA Boston Healthcare System, Boston, MA, USA

    Nikki H. Stricker

  2. Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA

    Nikki H. Stricker

  3. Department of Neurology, Oregon Health & Sciences University, Portland, OR, USA

    Hiroko H. Dodge

  4. Department of Biostatistics & Medical Informatics, University of Wisconsin, Madison, WI, USA

    N. Maritza Dowling

  5. Department of Behavioral Sciences, Rush University Medical Center, Chicago, IL, USA

    S. Duke Han

  6. Department of Statistics and School of Social Work, University of Washington, Seattle, WA, USA

    Elena A. Erosheva

  7. Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, USA

    William J. Jagust

  8. Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA

    William J. Jagust

  9. VA Boston Medical Center (116B), 150 S. Huntington Ave, Boston, MA, 02130, USA

    Nikki H. Stricker

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  1. Nikki H. Stricker
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Correspondence to Nikki H. Stricker.

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For the Alzheimer’s Disease Neuroimaging Initiative—Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.ucla.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.ucla.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

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Stricker, N.H., Dodge, H.H., Dowling, N.M. et al. CSF biomarker associations with change in hippocampal volume and precuneus thickness: implications for the Alzheimer’s pathological cascade. Brain Imaging and Behavior 6, 599–609 (2012). https://doi.org/10.1007/s11682-012-9171-6

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