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

Foiani, Martha S. ; Cicognola, Claudia LU orcid ; Ermann, Natalia ; Woollacott, Ione O.C. ; Heller, Carolin ; Heslegrave, Amanda J. ; Keshavan, Ashvini ; Paterson, Ross W. ; Ye, Keqiang and Kornhuber, Johannes , et al. (2019) In Journal of Neurology, Neurosurgery and Psychiatry 90(7). p.740-746
Abstract

Background Frontotemporal 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. Methods 86 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... (More)

Background Frontotemporal 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. Methods 86 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 Aβ 42 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. Results Significantly 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. Conclusions Despite 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.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
CSF, frontotemporal dementia, tau
in
Journal of Neurology, Neurosurgery and Psychiatry
volume
90
issue
7
pages
7 pages
publisher
BMJ Publishing Group
external identifiers
  • scopus:85064352651
  • pmid:30981993
ISSN
0022-3050
DOI
10.1136/jnnp-2018-319266
language
English
LU publication?
no
id
a4f4945f-499b-4006-b727-fd4306e5766c
date added to LUP
2020-02-25 09:48:02
date last changed
2024-05-15 07:33:59
@article{a4f4945f-499b-4006-b727-fd4306e5766c,
  abstract     = {{<p>Background Frontotemporal 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. Methods 86 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 Aβ 42 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. Results Significantly 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 &lt;0.109. Conclusions Despite 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.</p>}},
  author       = {{Foiani, Martha S. and Cicognola, Claudia and Ermann, Natalia and Woollacott, Ione O.C. and Heller, Carolin and Heslegrave, Amanda J. and Keshavan, Ashvini and Paterson, Ross W. and Ye, Keqiang and Kornhuber, Johannes and Fox, Nick C. and Schott, Jonathan M. and Warren, Jason D. and Lewczuk, Piotr and Zetterberg, Henrik and Blennow, Kaj and Höglund, Kina and Rohrer, Jonathan D.}},
  issn         = {{0022-3050}},
  keywords     = {{CSF; frontotemporal dementia; tau}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{7}},
  pages        = {{740--746}},
  publisher    = {{BMJ Publishing Group}},
  series       = {{Journal of Neurology, Neurosurgery and Psychiatry}},
  title        = {{Searching for novel cerebrospinal fluid biomarkers of tau pathology in frontotemporal dementia : An elusive quest}},
  url          = {{http://dx.doi.org/10.1136/jnnp-2018-319266}},
  doi          = {{10.1136/jnnp-2018-319266}},
  volume       = {{90}},
  year         = {{2019}},
}