Clinic-Based Validation of Cerebrospinal Fluid Biomarkers with Florbetapir PET for Diagnosis of Dementia

Article type: Research Article

Authors: Álvarez, Ignacio^{a; b} | Aguilar, Miquel^{a; b} | González, Jose Manuel^c | Ysamat, Montse^c | Lorenzo-Bosquet, Carles^d | Alonso, Alvaro^e | Tartari, Juan Pablo^{a; b} | Romero, Silvia^{a; b} | Diez-Fairen, Monica^{a; b} | Carcel, Maria^{a; b} | Pujalte, Francisco^f | Pastor, Pau^{a; b; g; *}

Affiliations: [a] Fundació Docència i Recerca Mútua de Terrassa, Terrassa, Barcelona, Spain | [b] Department of Neurology, Memory Disorders Unit, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain | [c] Centre de Tecnologia Diagnòstica, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain | [d] Servei de Medicina Nuclear, Hospital Universitari Vall d’Hebron, Barcelona, Spain | [e] Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA | [f] Immunology Area, Parc Logístic de Salut, Catlab, Viladecavalls, Barcelona, Spain | [g] CIBERNED, Instituto de Salud Carlos III, Madrid, Spain

Correspondence: [*] Correspondence to: Pau Pastor, MD, PhD, Department of Neurology, University Hospital Mutua de Terrassa, C/Castell, 31, planta -3. 08221 Terrassa, Spain. Tel.: +34 937365050; Fax: +34 937365059; E-mail: pastorpau@gmail.com.

Abstract: Background:Cerebrospinal fluid (CSF) biomarker studies have shown variable accuracy for diagnosis of Alzheimer’s disease (AD); therefore, internal validation is recommended. Objective:To investigate the correlation between CSF biomarkers and cerebral 18-Florbetapir positron emission tomography (Amyloid-PET) and calculate their sensitivity and specificity to obtain the optimal clinical cut-off points to diagnose the etiology of cognitive impairment. Methods:We performed Amyloid-PET scans and CSF biomarker levels analyses in 68 subjects (50 with mild cognitive impairment, 11 with AD dementia, and 7 with non-AD dementia). Visual examination of Amyloid-PET scans was performed. CSF analyses were performed using standard sandwich ELISA. Results:Amyloid-PET was positive in 36 subjects, negative in 26, and inconclusive in 6. Optimal clinical cut-off points for CSF markers were the following: amyloid-β 1–42 (Aβ42) = 629 pg/ml, total tau (t-tau) = 532 pg/ml, phosphorylated tau (p-tau) = 88 pg/ml, and t-tau/Aβ42 ratio = 0.58. T-tau/Aβ42 ratio showed the best sensitivity and specificity (92 and 84%, respectively). T-tau and p-tau CSF levels (r2 = 0.867) followed by the t-tau and t-tau/Aβ42 CSF ratio (r2 = 0.666) showed the strongest inter-marker correlation. Interestingly, subjects with inconclusive Amyloid-PET showed intermediate values for all CSF markers between negative and positive Amyloid-PET groups. Conclusions:CSF t-tau/Aβ42 ratio appears to be the most accurate AD CSF marker. The presence of intermediate values for CSF markers among the subjects with inconclusive Amyloid-PET suggests the presence of other dementias associated with AD pathology or intermediate phenotypes.

Keywords: Alzheimer’s disease, amyloid, apolipoprotein E, cerebrospinal fluid, positron emission tomography

DOI: 10.3233/JAD-170753

Journal: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 135-143, 2018