Cerebrospinal Fluid Biomarkers for the Differential Diagnosis between Alzheimer’s Disease and Frontotemporal Lobar Degeneration: Systematic Review, HSROC Analysis, and Confounding Factors

Article type: Research Article

Authors: Rivero-Santana, Amado^{a; b; c} | Ferreira, Daniel^d | Perestelo-Pérez, Lilisbeth^{b; c; e; *} | Westman, Eric^d | Wahlund, Lars-Olof^d | Sarría, Antonio^{b; f} | Serrano-Aguilar, Pedro^{b; c; e}

Affiliations: [a] Canarian Foundation for Health Research (FUNCANIS), Tenerife, Spain | [b] Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Tenerife, Spain | [c] Center for Biomedical Research of the Canary Islands (CIBICAN), Tenerife, Spain | [d] Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden | [e] Evaluation Unit of the Canary Islands Health Service (SESCS), Tenerife, Spain | [f] Agency for Health Technology Assessment (AETS), Institute of Health Carlos III, Madrid, Spain

Correspondence: [*] Correspondence to: Lilisbeth Perestelo-Perez, MPsych, PhD, Servicio de Evaluación del Servicio Canario de la Salud, Camino Candelaria, s/n. 38109, El Rosario, S/C de Tenerife, Spain. Tel.: +34 922 68 40 19 / Ext.: 241; E-mails: [email protected]; [email protected].

Abstract: Background: Differential diagnosis in dementia is at present one of the main challenges both in clinical practice and research. Cerebrospinal fluid (CSF) biomarkers are included in the current diagnostic criteria of Alzheimer’s disease (AD) but their clinical utility is still unclear. Objective: We performed a systematic review of studies analyzing the diagnostic performance of CSF Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) in the discrimination between AD and frontotemporal lobar degeneration (FTLD) dementias. Methods: The following electronic databases were consulted until May 2016: Medline and PreMedline, EMBASE, PsycInfo, CINAHL, Cochrane Library, and CRD. For the first-time in the field, a Hierarchical Summary Receiver Operating Characteristic (HRSOC) model was applied, which avoids methodological problems of meta-analyses based on summary points of sensitivity and specificity values. We also investigated relevant confounders of CSF biomarkers’ diagnostic performance such as age, disease duration, and global cognitive impairment. Results: The p-tau/Aβ42 ratio showed the best diagnostic performance. No statistically significant effects of the confounders were observed. Nonetheless, the p-tau/Aβ42 ratio may be especially indicated for younger patients. P-tau may be preferable for less cognitively impaired patients (high MMSE scores) and the t-tau/Aβ42 ratio for more cognitively impaired patients (low MMSE scores). Conclusion: The p-tau/Aβ42 ratio has potential for being implemented in the clinical routine for the differential diagnosis between AD and FTLD. It is of utmost importance that future studies report information on confounders such as age, disease duration, and cognitive impairment, which should also stimulate understanding of the role of these factors in disease mechanisms and pathophysiology.

Keywords: Age, Alzheimer’s disease, cerebrospinal fluid markers, confounding factor, disease duration, frontotemporal lobar degeneration, HSROC analysis, Mini-Mental State Examination, systematic review

DOI: 10.3233/JAD-160366

Journal: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 625-644, 2017