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

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 A beta(42), 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 /A beta(42) ratio showed the best diagnostic performance. No statistically significant effects of the confounders were observed. Nonetheless, the p-tau /A beta(42) 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 /A beta(42) ratio for more cognitively impaired patients (low MMSE scores). Conclusion: The p-tau /A beta(42) 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.