Date Published: March 20, 2018
Publisher: BioMed Central
Author(s): Ross W. Paterson, Catherine F. Slattery, Teresa Poole, Jennifer M. Nicholas, Nadia K. Magdalinou, Jamie Toombs, Miles D. Chapman, Michael P. Lunn, Amanda J. Heslegrave, Martha S Foiani, Philip S. J. Weston, Ashvini Keshavan, Jonathan D. Rohrer, Martin N. Rossor, Jason D. Warren, Catherine J. Mummery, Kaj Blennow, Nick C. Fox, Henrik Zetterberg, Jonathan M. Schott.
Cerebrospinal fluid (CSF) biomarkers are increasingly being used to support a diagnosis of Alzheimer’s disease (AD). Their clinical utility for differentiating AD from non-AD neurodegenerative dementias, such as dementia with Lewy bodies (DLB) or frontotemporal dementia (FTD), is less well established. We aimed to determine the diagnostic utility of an extended panel of CSF biomarkers to differentiate AD from a range of other neurodegenerative dementias.
We used immunoassays to measure conventional CSF markers of amyloid and tau pathology (amyloid beta (Aβ)1–42, total tau (T-tau), and phosphorylated tau (P-tau)) as well as amyloid processing (AβX-38, AβX-40, AβX-42, soluble amyloid precursor protein (sAPP)α, and sAPPβ), large fibre axonal degeneration (neurofilament light chain (NFL)), and neuroinflammation (YKL-40) in 245 patients with a variety of dementias and 30 controls. Patients fulfilled consensus criteria for AD (n = 156), DLB (n = 20), behavioural variant frontotemporal dementia (bvFTD; n = 45), progressive non-fluent aphasia (PNFA; n = 17), and semantic dementia (SD; n = 7); approximately 10% were pathology/genetically confirmed (n = 26). Global tests based on generalised least squares regression were used to determine differences between groups. Non-parametric receiver operating characteristic (ROC) curves and area under the curve (AUC) analyses were used to quantify how well each biomarker discriminated AD from each of the other diagnostic groups (or combinations of groups). CSF cut-points for the major biomarkers found to have diagnostic utility were validated using an independent cohort which included causes of AD (n = 104), DLB (n = 5), bvFTD (n = 12), PNFA (n = 3), SD (n = 9), and controls (n = 10).
There were significant global differences in Aβ1–42, T-tau, T-tau/Aβ1–42 ratio, P-tau-181, NFL, AβX-42, AβX-42/X-40 ratio, APPα, and APPβ between groups. At a fixed sensitivity of 85%, AβX-42/X-40 could differentiate AD from controls, bvFTD, and SD with specificities of 93%, 85%, and 100%, respectively; for T-tau/Aβ1–42 these specificities were 83%, 70%, and 86%. AβX-42/X-40 had similar or higher specificity than Aβ1–42. No biomarker or ratio could differentiate AD from DLB or PNFA with specificity > 50%. Similar sensitivities and specificities were found in the independent validation cohort for differentiating AD and other dementias and in a pathology/genetically confirmed sub-cohort.
CSF AβX-42/X-40 and T-tau/Aβ1–42 ratios have utility in distinguishing AD from controls, bvFTD, and SD. None of the biomarkers tested had good specificity at distinguishing AD from DLB or PNFA.
The online version of this article (10.1186/s13195-018-0361-3) contains supplementary material, which is available to authorized users.
Cerebrospinal fluid (CSF) biomarkers are increasingly used to support a diagnosis of Alzheimer’s disease (AD). CSF amyloid beta (Aβ)1–42, total tau (T-tau), and phosphorylated tau (P-tau) have utility in differentiating AD from controls and in predicting conversion from mild cognitive impairment (MCI) to AD dementia [1, 2]. Consequently, these measures are included in clinical  and research diagnostic criteria .
The study was conducted in accordance with relevant clinical research regulations, and with ethical approvals in place (Queen Square ethics committee approval reference numbers 13 LO 1155 and 12 LO 1504). Written informed consent was obtained from participants where appropriate.
In this single centre, primarily clinic-based study we show that some biomarkers with proven ability to distinguish AD from healthy controls  also have utility for differentiating AD from other neurodegenerative dementias in clinical practice. In particular, T-tau/Aβ1–42 and AβX-42/X-40 ratios combine high sensitivity (85%) and good specificity (> 70%) for distinguishing AD not only from controls but also from SD and bvFTD; Aβ1–42 performed similarly well for distinguishing AD from controls and SD. In contrast, none of the biomarkers, or models with multiple biomarkers, could reliably differentiate AD from DLB or PNFA with high specificity.
Biomarkers in routine clinical use (particularly AβX-42/X-40 and T-tau/Aβ1–42 ratios) not only have utility in distinguishing AD from controls, but also from bvFTD and SD. These measures, and the other biomarkers tested, have less utility in differentiating AD from DLB and PNFA, likely reflecting varying degrees of AD (amyloid) pathology in these conditions. This study provides an evidence base for the use of CSF biomarkers for the differential diagnosis of AD, highlights the potential utility of the AβX-42/X-40 ratio, and shows that novel biomarkers specific for other non-AD disorders are required.