Alzheimer's disease biomarker-guided diagnostic workflow using the added value of six combined cerebrospinal fluid candidates: Aβ1-42, total-tau, phosphorylated-tau, NFL, neurogranin, and YKL-40

Harald Hampel; Nicola Toschi; Filippo Baldacci; Henrik Zetterberg; Kaj Blennow; Ingo Kilimann; Stefan J Teipel; Enrica Cavedo; Antonio Melo Dos Santos; Stéphane Epelbaum; Foudil Lamari; Remy Genthon; Bruno Dubois; Roberto Floris; Francesco Garaci; Simone Lista; Alzheimer Precision Medicine Initiative (APMI)

doi:10.1016/j.jalz.2017.11.015

Alzheimer's disease biomarker-guided diagnostic workflow using the added value of six combined cerebrospinal fluid candidates: Aβ_1-42, total-tau, phosphorylated-tau, NFL, neurogranin, and YKL-40

Alzheimers Dement. 2018 Apr;14(4):492-501. doi: 10.1016/j.jalz.2017.11.015. Epub 2018 Jan 9.

Authors

Harald Hampel¹, Nicola Toschi², Filippo Baldacci³, Henrik Zetterberg⁴, Kaj Blennow⁵, Ingo Kilimann⁶, Stefan J Teipel⁶, Enrica Cavedo⁷, Antonio Melo Dos Santos⁸, Stéphane Epelbaum⁸, Foudil Lamari⁹, Remy Genthon⁸, Bruno Dubois⁸, Roberto Floris¹⁰, Francesco Garaci¹¹, Simone Lista¹; Alzheimer Precision Medicine Initiative (APMI)

Affiliations

¹ AXA Research Fund & Sorbonne Université Chair, Paris, France; Sorbonne Université, AP-HP, GRC n° 21, Alzheimer Precision Medicine (APM), Hôpital de la Pitié-Salpêtrière, Paris, France; Institut du Cerveau et de la Moelle Épinière (ICM), INSERM U 1127, CNRS UMR 7225, Paris, France; Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Département de Neurologie, Hôpital de la Pitié-Salpêtrière, Paris, France.
² Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy; Department of Radiology, "Athinoula A. Martinos" Center for Biomedical Imaging, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
³ AXA Research Fund & Sorbonne Université Chair, Paris, France; Sorbonne Université, AP-HP, GRC n° 21, Alzheimer Precision Medicine (APM), Hôpital de la Pitié-Salpêtrière, Paris, France; Institut du Cerveau et de la Moelle Épinière (ICM), INSERM U 1127, CNRS UMR 7225, Paris, France; Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Département de Neurologie, Hôpital de la Pitié-Salpêtrière, Paris, France; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
⁴ Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK; UK Dementia Research Institute, London, UK.
⁵ Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁶ Department of Psychosomatic Medicine, University of Rostock & DZNE Rostock, Rostock, Germany.
⁷ AXA Research Fund & Sorbonne Université Chair, Paris, France; Sorbonne Université, AP-HP, GRC n° 21, Alzheimer Precision Medicine (APM), Hôpital de la Pitié-Salpêtrière, Paris, France; Institut du Cerveau et de la Moelle Épinière (ICM), INSERM U 1127, CNRS UMR 7225, Paris, France; Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Département de Neurologie, Hôpital de la Pitié-Salpêtrière, Paris, France; IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
⁸ Sorbonne Université, AP-HP, GRC n° 21, Alzheimer Precision Medicine (APM), Hôpital de la Pitié-Salpêtrière, Paris, France; Institut du Cerveau et de la Moelle Épinière (ICM), INSERM U 1127, CNRS UMR 7225, Paris, France; Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Département de Neurologie, Hôpital de la Pitié-Salpêtrière, Paris, France.
⁹ AP-HP, UF Biochimie des Maladies Neuro-métaboliques, Service de Biochimie Métabolique, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
¹⁰ Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy.
¹¹ Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy; Casa di Cura "San Raffaele Cassino", Cassino, Italy.

PMID: 29328927
DOI: 10.1016/j.jalz.2017.11.015

Abstract

Introduction: The diagnostic and classificatory performances of all combinations of three core (amyloid β peptide [i.e., Aβ_1-42], total tau [t-tau], and phosphorylated tau) and three novel (neurofilament light chain protein, neurogranin, and YKL-40) cerebrospinal fluid biomarkers of neurodegeneration were compared among individuals with mild cognitive impairment (n = 41), Alzheimer's disease dementia (ADD; n = 35), frontotemporal dementia (FTD; n = 9), and cognitively healthy controls (HC; n = 21), using 10-fold cross-validation.

Methods: The combinations ranking in the top 10 according to diagnostic accuracy in differentiating between distinct diagnostic categories were identified.

Results: The single biomarkers or biomarker combinations generating the best area under the receiver operating characteristics (AUROCs) were the following: the combination [amyloid β peptide + phosphorylated tau + neurofilament light chain] for distinguishing between ADD patients and HC (AUROC = 0.86), t-tau for distinguishing between ADD and FTD patients (AUROC = 0.82), and t-tau for distinguishing between FTD patients and HC (AUROC = 0.78).

Conclusions: Novel and established cerebrospinal fluid markers perform with at least fair accuracy in the discrimination between ADD and FTD. The classification of mild cognitive impairment individuals was poor.

Keywords: Alzheimer's disease; Alzheimer's disease dementia; Biomarker combination; Cerebrospinal fluid; Clinical diagnosis; Cognitive aging; Diagnostic biomarkers; Frontotemporal dementia; Mild cognitive impairment; Neurodegeneration; Neurofilament light chain; Neurogranin; Pathophysiological pathways; Precision medicine; YKL-40.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Alzheimer Disease / cerebrospinal fluid*
Alzheimer Disease / classification
Amyloid beta-Peptides / cerebrospinal fluid
Area Under Curve
Biomarkers / cerebrospinal fluid
Chitinase-3-Like Protein 1 / cerebrospinal fluid
Cognitive Dysfunction / cerebrospinal fluid
Cognitive Dysfunction / classification
Cross-Sectional Studies
Diagnosis, Differential
Female
Frontotemporal Dementia / cerebrospinal fluid
Frontotemporal Dementia / classification
Humans
Male
Middle Aged
Neurofilament Proteins / cerebrospinal fluid
Nuclear Proteins / cerebrospinal fluid
Peptide Fragments / cerebrospinal fluid
RNA-Binding Proteins
ROC Curve
Retrospective Studies
tau Proteins / cerebrospinal fluid

Substances

Amyloid beta-Peptides
Biomarkers
CHI3L1 protein, human
Chitinase-3-Like Protein 1
MAPT protein, human
NGDN protein, human
Neurofilament Proteins
Nuclear Proteins
Peptide Fragments
RNA-Binding Proteins
amyloid beta-protein (1-42)
neurofilament protein L
tau Proteins