Novel diagnostic cerebrospinal fluid biomarkers for pathologic subtypes of frontotemporal dementia identified by proteomics

Teunissen, Charlotte E.; Elias, Naura; Koel-Simmelink, Marleen; Durieux-Lu, Sisi; Malekzadeh, Arjan; Pham, Thang V.; Piersma, Sander R.; Beccari, Tommaso; Meeter, Lieke H.H.; Dopper, Elise G.P.; Swieten, John van; Jiménez, Connie R.; Pijnenburg, Yolande A.L.

doi:10.1016/j.dadm.2015.12.004

Cited by 80 publications

(80 citation statements)

References 52 publications

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“…This reinforces the notion that coincident pathologies, comorbid AD in this case, have an impact on CSF biomarkers 9 18 26. We also found that, in agreement with another study,27 YKL-40 in FTLD-Tau is elevated compared with AD and controls.…”

Section: Discussionsupporting

confidence: 93%

Elevated YKL-40 and low sAPPβ:YKL-40 ratio in antemortem cerebrospinal fluid of patients with pathologically confirmed FTLD

Alcolea

Irwin

Illán-Gala

et al. 2018

J Neurol Neurosurg Psychiatry

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ObjectivesThe combination of high YKL-40 (a glial inflammatory marker) and low sAPPβ (a soluble β fragment of amyloid precursor protein) in cerebrospinal fluid (CSF) has been associated with frontotemporal lobar degeneration (FTLD) in clinical series. We investigate these biomarkers in a neuropathologically confirmed cohort of patients with FTLD.MethodsCSF samples were selected from the Penn FTD Center (University of Pennsylvania). Participants were followed to autopsy and had a neuropathological diagnosis of FTLD-Tau (n=24), transactive response DNA-binding protein with 43 kDa (FTLD-TDP) (n=25) or Alzheimer’s disease (AD, n=97). We compared levels of YKL-40 and sAPPβ between groups and with cognitively normal controls (n=77), and assessed their diagnostic utility using receiver operating characteristic curves. We also investigated the effect of AD copathology and the correlation between these CSF markers and tau burden at autopsy.ResultsBoth FTLD groups had lower levels of sAPPβ, higher levels of YKL-40 and lower sAPPβ:YKL-40 ratio in CSF compared with controls. The group of pure FTLD-Tau (without AD copathology) showed higher levels of YKL-40 than AD and than pure FTLD-TDP. YKL-40 levels correlated with pathological tau burden. The sAPPβ:YKL-40 ratio had an area under the curve (AUC) of 0.91 (95% CI 0.86 to 0.96) to distinguish subjects with FTLD from controls, but lower values to distinguish FTLD from AD (AUC 0.70; 95% CI 0.61 to 0.79) and to discriminate FTLD-Tau from FTLD-TDP (AUC 0.67; 95% CI 0.51 to 0.82).ConclusionsOur study provides pathological confirmation that the combination of low sAPPβ and high YKL-40 in CSF is associated with FTLD. These biomarkers could be useful in particular clinical settings when FTLD is suspected.

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Section: Discussionsupporting

confidence: 93%

Elevated YKL-40 and low sAPPβ:YKL-40 ratio in antemortem cerebrospinal fluid of patients with pathologically confirmed FTLD

Alcolea

Irwin

Illán-Gala

et al. 2018

J Neurol Neurosurg Psychiatry

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“…The CSF YKL40 levels were 1.4 fold higher in the probable/definite bvFTD group compared to those in the primary psychiatric disorders. Of note, although the levels of NfL and YKL40 in the group of psychiatric disorders were lower than in bvFTD, they were higher than levels described in control subjects, which are typically in the range of 254-365 pg/mL for CSF NfL [12,15,35] and around 200 ng/mL for CSF YKL40 [8,36].…”

Section: Levels Of Csf Biomarkersmentioning

confidence: 56%

Cerebrospinal fluid biomarker examination as a tool to discriminate behavioral variant frontotemporal dementia from primary psychiatric disorders

Vijverberg

Dols

Krudop

et al. 2017

Alz & Dem Diag Ass & Dis Mo

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IntroductionTo prospectively determine the diagnostic value of cerebrospinal fluid (CSF) levels total-tau (tau) to amyloid-β1–42 ratio (Aβ1–42) ratio (tau/Aβ1–42 ratio), phosphorylated-tau (p-tau) to tau ratio (p-tau/tau ratio), neurofilament light chain (NfL) and YKL40 in the late-onset frontal lobe syndrome, in particular for the differential diagnosis of behavioral variant frontotemporal dementia (bvFTD) versus primary psychiatric disorders (PSY).MethodWe included patients with a multidisciplinary 2-year-follow-up diagnosis of probable/definite bvFTD (n = 22) or PSY (n = 25), who underwent a detailed neuropsychiatric clinical examination, neuropsychological test battery, and magnetic resonance imaging at baseline. In all cases, CSF was collected through lumbar puncture at baseline. We compared CSF biomarker levels between the two groups and measured the diagnostic accuracy for probable/definite bvFTD, using the follow-up diagnosis as the reference standard.ResultsThe best discriminators between probable/definite bvFTD and PSY were the levels of CSF NfL (area under the curve [AUC] 0.93, P < .001, 95% confidence interval [CI] 0.85–1.00), p-tau/tau ratio (AUC 0.87, P < .001, 95% CI 0.77–0.97), and YKL40 (AUC 0.82, P = .001, 95% CI 0.68–0.97). The combination of these three biomarkers had a sensitivity of 91% (95% CI 66%–100%) at a specificity of 83% (95% CI 65%–95%) with an AUC of 0.94 (P < .001, 95% CI 0.87–1.00) for bvFTD. CSF tau/Aβ1–42 ratio was less accurate in differentiating between bvFTD and PSY.DiscussionWe found a good diagnostic accuracy for higher levels of CSF NfL and YKL40 and reduced p-tau/tau ratio in distinguishing bvFTD from PSY. We advocate the use of these CSF biomarkers as potential additional tools to neuroimaging in the diagnosis of bvFTD versus PSY.

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“…YKL-40 was measured with the MicroVue ELISA from Quidel (USA) 20. GFAP in CSF was determined with an ELISA from BioVendor (Czech Republic) and GFAP in blood was measured with the Simoa GFAP Discovery Kit (Quanterix, USA).…”

Section: Methodsmentioning

confidence: 99%

Different neuroinflammatory profile in amyotrophic lateral sclerosis and frontotemporal dementia is linked to the clinical phase

Oeckl

Weydt

Steinacker

et al. 2018

J Neurol Neurosurg Psychiatry

103

124

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Novel diagnostic cerebrospinal fluid biomarkers for pathologic subtypes of frontotemporal dementia identified by proteomics

Cited by 80 publications

References 52 publications

Elevated YKL-40 and low sAPPβ:YKL-40 ratio in antemortem cerebrospinal fluid of patients with pathologically confirmed FTLD

Elevated YKL-40 and low sAPPβ:YKL-40 ratio in antemortem cerebrospinal fluid of patients with pathologically confirmed FTLD

Cerebrospinal fluid biomarker examination as a tool to discriminate behavioral variant frontotemporal dementia from primary psychiatric disorders

Different neuroinflammatory profile in amyotrophic lateral sclerosis and frontotemporal dementia is linked to the clinical phase

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