Where Should I Draw the Line: PET-Driven, Data-Driven, or Manufacturer Cut-Off?

Article type: Research Article

Authors: Sánchez-Soblechero, Antonio^{a; *} | López-García, Sara^{b; d; e} | Lage, Carmen^{b; d; e} | Fernández-Matarrubia, Marta^{b; d; e} | Irure, Juan^{c; d; g} | López-Hoyos, Marcos^{c; d; g} | Jiménez-Bonilla, Julio^{d; f} | Quirce, Remedios^{d; f} | de Arcocha-Torres, María^{d; f} | Cuenca-Vera, Oriana^f | Martín-Arroyo, Juan^b | Martínez-Dubarbie, Francisco^{b; d; e} | Pozueta, Ana^{b; e} | García-Martínez, María^{b; e} | Infante, Jon^{b; d; e; g} | Sánchez-Juan, Pascual^{d; e; h} | Rodríguez-Rodríguez, Eloy^{b; d; e; g}

Affiliations: [a] Neurology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain | [b] Neurology Department, Cognitive Impairment Unit, ‘Marqués de Valdecilla’ University Hospital, Santander, Spain | [c] Immunology Department, ‘Marqués de Valdecilla’ University Hospital, Santander, Spain | [d] Institute for Research ’Marqués de Valdecilla’ (IDIVAL), Santander, Spain | [e] Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain | [f] Nuclear Medicine Department, ‘Marqués de Valdecilla’ University Hospital, Santander, Spain | [g] Department of Medicine and Psychiatry, University of Cantabria, Santander, Spain | [h] Alzheimer’s Centre Reina Sofia-CIEN Foundation-ISCIII, Madrid, Spain

Correspondence: [*] Correspondence to: Antonio Sánchez Soblechero, MD, Neurology Department. Hospital General Universitario Gregorio Marañón. C/Doctor Esquerdo 46, 28007, Madrid, España. Tel.: +34 915868339; E-mails: antonio.sanchez.s@hotmail.com; asoblechero@salud.madrid.org.

Abstract: Background:The optimal cut-off for Alzheimer’s disease (AD) CSF biomarkers remains controversial. Objective:To analyze the performance of cut-off points standardized by three methods: one that optimized the agreement between 11C-Pittsburgh compound B PET (a-PET) and CSF biomarkers (Aβ1–42, pTau, tTau, and Aβ1–42/Aβ1–40 ratio) in our population, called PET-driven; an unbiased cut-off using data from a healthy research cohort, called data-driven, and that provided by the manufacturer. We also compare changes in ATN classification. Methods:CSF biomarkers measured by the LUMIPULSE G600II platform and qualitative visualization of amyloid positron emission tomography (a-PET) were performed in all the patients. We established a cut-off for each single biomarker and Aβ1–42/Aβ1–40 ratio that optimized their agreement with a-PET using ROC curves. Sensitivity, Specificity, and Overall Percent of Agreement are assessed using a-PET or clinical diagnosis as gold standard for every cut-off. Also, we established a data-driven cut-off from our cognitively unimpaired cohort. We then analyzed changes in ATN classification. Results:One hundred and ten patients were recruited. Sixty-six (60%) were a-PET positive. PET-driven cut-offs were: pTau > 57, tTau > 362.62, Aβ1–42/Aβ1–40 < 0.069. For a single biomarker, pTau showed the highest accuracy (AUC 0.926). New PET-driven cut-offs classified patients similarly to manufacturer cut-offs (only two patients changed). However, 20 patients (18%) changed when data-driven cut-offs were used. Conclusions:We established our sample’s best CSF biomarkers cut-offs using a-PET as the gold standard. These cut-offs categorize better symptomatic subjects than data-driven in ATN classification, but they are very similar to the manufacturer’s.

Keywords: Alzheimer’s disease, amyloid positron emission tomography (a-PET), ATN classification, cerebrospinal fluid biomarkers (tTau, pTau, Aβ_1–42 and Aβ_1–42/Aβ_1–40), ¹¹C-Pittsburgh compound B, cut-off, data-driven cut-off, PET-driven cut-off

DOI: 10.3233/JAD-230678

Journal: Journal of Alzheimer's Disease, vol. 98, no. 3, pp. 957-967, 2024