Searching for novel cerebrospinal fluid biomarkers of tau pathology in frontotemporal dementia: an elusive quest

Abstract

BackgroundFrontotemporal dementia (FTD) is a pathologically heterogeneous neurodegenerative disorder associated usually with tau or TDP-43 pathology, although some phenotypes such as logopenic variant primary progressive aphasia are more commonly associated with Alzheimer’s disease pathology. Currently, there are no biomarkers able to diagnose the underlying pathology during life. In this study, we aimed to investigate the potential of novel tau species within cerebrospinal fluid (CSF) as biomarkers for tau pathology in FTD.Methods86 participants were included: 66 with a clinical diagnosis within the FTD spectrum and 20 healthy controls. Immunoassays targeting tau fragments N-123, N-mid-region, N-224 and X-368, as well as a non-phosphorylated form of tau were measured in CSF, along with total-tau (T-tau) and phospho-tau (P-tau(181)). Patients with FTD were grouped based on their Aβ42 level into those likely to have underlying Alzheimer’s disease (AD) pathology (n=21) and those with likely frontotemporal lobar degeneration (FTLD) pathology (n=45). The FTLD group was then subgrouped based on their underlying clinical and genetic diagnoses into those with likely tau (n=7) or TDP-43 (n=18) pathology.ResultsSignificantly higher concentrations of tau N-mid-region, tau N-224 and non-phosphorylated tau were seen in both the AD group and FTLD group compared with controls. However, none of the novel tau species showed a significant difference between the AD and FTLD groups, nor between the TDP-43 and tau pathology groups. In a subanalysis, normalising for total-tau, none of the novel tau species provided a higher sensitivity and specificity to distinguish between tau and TDP-43 pathology than P-tau(181)/T-tau, which itself only had a sensitivity of 61.1% and specificity of 85.7% with a cut-off of <0.109.ConclusionsDespite investigating multiple novel CSF tau fragments, none show promise as an FTD biomarker and so the quest for in vivo markers of FTLD-tau pathology continues.

Recent advances in understanding frontotemporal degeneration

“…These findings have been confirmed in a few subsequent studies in FTD 40– 44 , as well as in amyotrophic lateral sclerosis (ALS), which frequently is associated with TDP-43 pathology 45 . Conversely, a recent report investigated novel CSF tau fragments (N-123, N-mid-region, N-224, and X-368) in both FTLD-TDP and FTLD-Tau; however, none of the novel tau species showed a significant difference between pathological groups 41 . Similarly, CSF and plasma TDP-43 dosages have not yielded convincing results in differentiating FTLD-TDP from FTLD-Tau 46– 51 .…”

Fluid biomarkers in frontotemporal dementia: past, present and future

“…CSF concentrations of 'total' tau and phosphorylated forms of tau (p-tau181 and p-tau231) are variable in the different forms of FTD, but overall, are generally lower than in AD. Studies of tau protein fragments have so far not yielded any specific primary tauopathy markers 63,64 . More promising assays may arise from the real-time quaking-induced conversion (RT-QuIC) method which is currently under investigation for Pick's disease and the 4R-tauopathies [65][66][67] .…”

Propagation of Tau Pathology: Integrating Insights From Postmortem and In Vivo Studies

“…This is especially evident in AD, while in primary tauopathies concentrations of truncated tau are surprisingly normal or even lower than those of control subjects (134,135). Assays targeting specific tau fragments (e.g., N-123, N-224, x-224, tau 368) have recently been developed and show promise as candidates to add to the AD and primary tauopathies biomarker panel (136).…”