The AD-CSF-Index Discriminates Alzheimer's Disease Patients from Healthy Controls: A Validation Study

Article type: Research Article

Authors: Molinuevo, Jose L.^{a; b; c; 1; *} | Gispert, Juan Domingo^{c; 1} | Dubois, Bruno^d | Heneka, Michael T.^e | Lleo, Alberto^f | Engelborghs, Sebastiaan^g | Pujol, Jesús^h | de Souza, Leonardo Cruz^d | Alcolea, Daniel^f | Jessen, Frankⁱ | Sarazin, Marie^d | Lamari, Foudil^j | Balasa, Mircea^a | Antonell, Anna^{a; b} | Rami, Lorena^{a; b}

Affiliations: [a] Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic, Barcelona, Spain | [b] Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain | [c] BarcelonaBeta Brain Research Centre, Pasqual Maragall Foundation, Barcelona, Spain | [d] Alzheimer Institute, Research and Resource Memory Centre, AP-HP, Pitié-Salpêtrière Hospital, Paris, France | [e] Neurology Department, University of Bonn, Germany | [f] Neurology Department, Hospital Sant Pau, Barcelona, CIBERNED, Spain | [g] Reference Centre for Biological Markers of Dementia (BIODEM), University of Antwerp, Antwerp, Belgium | [h] CRC-Mar, Hospital del Mar, CRC Corporació Sanitària, Barcelona, Spain | [i] Department of Psychiatry, University of Bonn, Bonn, Germany | [j] Department of Metabolic Biochemistry, AP-HP, Pitiá-Salpêtrière Hospital, Paris, France

Correspondence: [*] Both authors contributed equally to this manuscript. Correspondence to: José Luis Molinuevo, M.D., Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clínic, Villarroel 170, and Fundació Pasqual Maragall, 08036, Barcelona, Spain. Tel.: +34 932275785; Fax: +34 932275783; E-mail: jlmoli@clinic.ub.es.

Note: [1] Both authors contributed equally to this manuscript.

Abstract: Background:Cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) show an acceptable diagnostic sensitivity and specificity; however, their interpretation and ease of use is far from optimal. Objective:To study and validate the diagnostic accuracy of an easy-to-use normalized CSF biomarker index, the AD-CSF-index, in different European populations. Methods:A total of 342 subjects, 103 healthy controls and 239 AD patients, from four European memory clinics were included. The AD-CSF-index was constructed from the addition of normalized values between the minimum and maximum of amyloid and tau protein levels. The diagnostic accuracy, receiver operating characteristic, and regression analysis of the AD-CSF-index and other composite indices were evaluated in this study. Results:AD patients presented a significantly higher AD-CSF-index than healthy subjects (control = 0.5204; AD = 1.2272; p < 0.001). The AD-CSF-index obtained a sensitivity of 88.6% at 85% specificity and also showed a significantly higher diagnostic power (p < 0.05) than the individual CSF biomarkers and other studied indices. The performance of the AD-CSF-index was very similar between ELISA and MesoScale measurements. Cut-off values of approximately 0.75 provided the lowest achievable overall classification errors and a cut-off point of about 0.95 consistently provided specificities above 85%. Conclusion:The AD-CSF-index represents a novel approach, combining normalized CSF values, for the biological diagnosis of AD. The AD-CSF-index presents an optimal AUC with high sensitivity and specificity and seems to be a simple and intuitive way to interpret AD CSF biomarker results even from different analytical platforms.

Keywords: Alzheimer's disease, biomarkers, cerebrospinal fluid, diagnostic accuracy, sensitivity, specificity

DOI: 10.3233/JAD-130203

Journal: Journal of Alzheimer's Disease, vol. 36, no. 1, pp. 67-77, 2013