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Dissecting IWG-2 typical and atypical Alzheimer’s disease: insights from cerebrospinal fluid analysis

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Abstract

Pathobiological factors underlying phenotypic diversity in Alzheimer’s disease (AD) are incompletely understood. We used an extended cerebrospinal fluid (CSF) panel to explore differences between “typical” with “atypical” AD and between amnestic, posterior cortical atrophy, logopenic aphasia and frontal variants. We included 97 subjects fulfilling International Working Group-2 research criteria for AD of whom 61 had “typical” AD and 36 “atypical” syndromes, and 30 controls. CSF biomarkers included total tau (T-tau), phosphorylated tau (P-tau), amyloid β1-42, amyloid βX-38/40/42, YKL-40, neurofilament light (NFL), and amyloid precursor proteins α and β. The typical and atypical groups were matched for age, sex, severity and rate of cognitive decline and had similar biomarker profiles, with the exception of NFL which was higher in the atypical group (p = 0.03). Sub-classifying the atypical group into its constituent clinical syndromes, posterior cortical atrophy was associated with the lowest T-tau [604.4 (436.8–675.8) pg/mL], P-tau (79.8 ± 21.8 pg/L), T-tau/Aβ1-42 ratio [2.3 (1.4–2.6)], AβX-40/X-42 ratio (22.1 ± 5.8) and rate of cognitive decline [1.9 (0.75–4.25) MMSE points/year]. Conversely, the frontal variant group had the highest levels of T-tau [1185.4 (591.7–1329.3) pg/mL], P-tau (116.4 ± 45.4 pg/L), T-tau/Aβ1-42 ratio [5.2 (3.3–6.9)] and AβX-40/X-42 ratio (27.9 ± 7.5), and rate of cognitive decline. Whilst on a group level IWG-2 “typical” and “atypical” AD share similar CSF profiles, which are very different from controls, atypical AD is a heterogeneous entity with evidence for subtle differences in amyloid processing and neurodegeneration between different clinical syndromes. These findings also have practical implications for the interpretation of clinical CSF biomarker results.

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Acknowledgments

We gratefully acknowledge the support of our patients and their families, the Leonard Wolfson Experimental Neurology Centre, Alzheimer’s Research UK and Iceland Foods Ltd. This work was supported by the National Institute for Health Research Queen Square Dementia Biomedical Research Unit, University College London Hospitals Biomedical Research Centre and the Swedish Research Council. HZ is a Wallenberg Academy Fellow. SC is supported by an Alzheimer’s Research UK Senior Research Fellowship and ESRC/NIHR grant (ES/K006711/1). The authors have no conflicts of interest that are directly relevant to the content of this article.

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Authors and Affiliations

  1. Dementia Research Centre, UCL Institute of Neurology, London, UK

    Ross W. Paterson, Jason D. Warren, Cath J. Mummery, Martin N. Rossor, Sebastian J. Crutch, Nick C. Fox & Jonathan M. Schott

  2. Reta Lila Weston Institute, UCL Institute of Neurology, London, UK

    Catherine F. Slattery & Nadia K. Magdalinou

  3. Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK

    Jamie Toombs & Henrik Zetterberg

  4. Department of Medical Statistics, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK

    Jennifer M. Nicholas

  5. Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden

    Ulf Andreasson, Kaj Blennow & Henrik Zetterberg

  6. Department of Clinical Neuroimmunology, National Hospital for Neurology and Neurosurgery, London, UK

    Michael P. Lunn

  7. Box 16 National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK

    Jonathan M. Schott

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  1. Ross W. Paterson
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Correspondence to Jonathan M. Schott.

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H. Zetterberg and J. M. Schott are Joint Senior Authors.

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Paterson, R.W., Toombs, J., Slattery, C.F. et al. Dissecting IWG-2 typical and atypical Alzheimer’s disease: insights from cerebrospinal fluid analysis. J Neurol 262, 2722–2730 (2015). https://doi.org/10.1007/s00415-015-7904-3

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  • DOI: https://doi.org/10.1007/s00415-015-7904-3

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