Prediction of Alzheimer’s Dementia in Patients with Amnestic Mild Cognitive Impairment in Clinical Routine: Incremental Value of Biomarkers of Neurodegeneration and Brain Amyloidosis Added Stepwise to Cognitive Status

Article type: Research Article

Authors: Lange, Catharina^{a; b} | Suppa, Per^{a; c} | Pietrzyk, Uwe^{b; d} | Makowski, Marcus R.^e | Spies, Lothar^c | Peters, Oliver^f | Buchert, Ralph^{a; g; *} | for the Alzheimer’s Disease Neuroimaging Initiative¹

Affiliations: [a] Department of Nuclear Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany | [b] School of Mathematics and Natural Science, University of Wuppertal, Wuppertal, Germany | [c] jung diagnostics GmbH, Hamburg, Germany | [d] Institute of Neuroscience and Medicine, Forschungszentrum Jülich, Jülich, Germany | [e] Department of Radiology, Charité – Universitätsmedizin Berlin, Berlin, Germany | [f] Department of Psychiatry and Psychotherapy, Charité – Universitätsmedizin Berlin, Berlin, Germany | [g] Department of Diagnostic and Interventional Radiology and Nuclear Medicine, Center for Radiology and Endoscopy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Correspondence: [*] Correspondence to: Ralph Buchert, Department of Diagnostic and Interventional Radiology and Nuclear Medicine, Center for Radiology and Endoscopy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Tel.: +49 40 7410 54347; Fax: +49 40 7410 40265; E-mail: [email protected].

Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.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.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Abstract: The aim of this study was to evaluate the incremental benefit of biomarkers for prediction of Alzheimer’s disease dementia (ADD) in patients with mild cognitive impairment (MCI) when added stepwise in the order of their collection in clinical routine. The model started with cognitive status characterized by the ADAS-13 score. Hippocampus volume (HV), cerebrospinal fluid (CSF) phospho-tau (pTau), and the FDG t-sum score in an AD meta-region-of-interest were compared as neurodegeneration markers. CSF-Aβ1-42 was used as amyloidosis marker. The incremental prognostic benefit from these markers was assessed by stepwise Kaplan-Meier survival analysis in 402 ADNI MCI subjects. Predefined cutoffs were used to dichotomize patients as ‘negative’ or ‘positive’ for AD characteristic alteration with respect to each marker. Among the neurodegeneration markers, CSF-pTau provided the best incremental risk stratification when added to ADAS-13. FDG PET outperformed HV only in MCI subjects with relatively preserved cognition. Adding CSF-Aβ provided further risk stratification in pTau-positive subjects, independent of their cognitive status. Stepwise integration of biomarkers allows stepwise refinement of risk estimates for MCI-to-ADD progression. Incremental benefit strongly depends on the patient’s status according to the preceding diagnostic steps. The stepwise Kaplan-Meier curves might be useful to optimize diagnostic workflow in individual patients.

Keywords: Alzheimer’s disease, biomarker, cerebrospinal fluid, FDG, magnetic resonance imaging, mild cognitive impairment, neuropsychological testing, positron emission tomography, prediction, white matter hyperintensities

DOI: 10.3233/JAD-170705

Journal: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 373-388, 2018