CSF sAPPβ, YKL-40, and neurofilament light in frontotemporal lobar degeneration

Alcolea, Daniel; Vilaplana, Eduard; Suárez‐Calvet, Marc; Illán-Gala, Ignacio; Blesa, Rafael; Clarimón, Jordi; Lladó, Albert; Sánchez‐Valle, Raquel; Molinuevo, José Luís; García‐Ribas, Guillermo; Compta, Yaroslau; Martı́, Marı́a José; Piñol‐Ripoll, Gerard; Amer-Ferrer, Guillermo; Noguera, Aina; García-Martín, Ana; Fortea, Juan; Lleó, Alberto

doi:10.1212/wnl.0000000000004088

Cited by 109 publications

(104 citation statements)

References 36 publications

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“…Our previous study reported that the combination of CSF sAPPβ with YKL-40 in clinically defined patients had a good diagnostic performance in a clinical setting to distinguish frontotemporal dementia from AD and cognitively normal controls 16. The present study extends these findings to patients with neuropathological confirmation.…”

Section: Discussionsupporting

confidence: 73%

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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: 73%

“…In our previous study of these CSF analytes in clinically diagnosed patients,16 we did not detect differences between patients with high likelihood of FTLD-Tau and patients with high likelihood of FTLD-TDP. The present study examines these analytes in patients with neuropathological confirmation.…”

Section: Discussioncontrasting

confidence: 68%

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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“…CSF samples from the SPIN cohort have contributed to several international multicenter CSF biomarker studies [34][35][36][37][38]. The SPIN cohort has contributed to the characterization of different CSF biomarkers such as b-site APP-cleaving enzyme activity [39,40], sAPP-b [6,39,41], neurofilament light chain [41], YKL-40 [6,39,[41][42][43], progranulin [44], a panel of synaptic proteins [45], and mitochondrial DNA [46] in different neurodegenerative diseases. In addition, the collection of paired blood and CSF samples offers the possibility to investigate the correlation of biomarker levels between these two compartments [15,44].…”

Section: Resultsmentioning

confidence: 99%

The Sant Pau Initiative on Neurodegeneration (SPIN) cohort: A data set for biomarker discovery and validation in neurodegenerative disorders

Alcolea

Clarimón

Carmona-Iragui

et al. 2019

A&D Transl Res & Clin Interv

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101

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Introduction The SPIN (Sant Pau Initiative on Neurodegeneration) cohort is a multimodal biomarker platform designed for neurodegenerative disease research following an integrative approach. Methods Participants of the SPIN cohort provide informed consent to donate blood and cerebrospinal fluid samples, receive detailed neurological and neuropsychological evaluations, and undergo a structural 3T brain MRI scan. A subset also undergoes other functional or imaging studies (video‐polysomnogram, 18F‐fluorodeoxyglucose PET, amyloid PET, Tau PET). Participants are followed annually for a minimum of 4 years, with repeated cerebrospinal fluid collection and imaging studies performed every other year, and brain donation is encouraged. Results The integration of clinical, neuropsychological, genetic, biochemical, imaging, and neuropathological information and the harmonization of protocols under the same umbrella allows the discovery and validation of key biomarkers across several neurodegenerative diseases. Discussion We describe our particular 10‐year experience and how different research projects were unified under an umbrella biomarker program, which might be of help to other research teams pursuing similar approaches.

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“…However, CSF NfL is a nonspecific disease biomarker that is upregulated in other disorders such as AD 27, 32, 34. Importantly, recent studies showed that the ratio between NfL and the soluble β fragment of amyloid precursor protein (sAPP β )53 or the combination of TDP43 with p/tTau ratio54 could optimally discriminate FTLD patients from CON in a large cohort, promising data that need to be replicated in independent cohorts. An additional challenge in clinical practice is the differential diagnosis of dementia.…”

Section: Discussionmentioning

confidence: 99%

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

Campo

Galimberti

Elias

et al. 2018

Ann Clin Transl Neurol

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ObjectiveFrontotemporal lobar degeneration (FTLD) is the second most prevalent dementia in young patients and is characterized by the presence of two main protein aggregates in the brain, tau (FTLD‐Tau) or TDP43 (FTLD‐TDP), which likely require distinct pharmacological therapy. However, specific diagnosis of FTLD and its subtypes remains challenging due to largely overlapping clinical phenotypes. Here, we aimed to assess the clinical performance of novel cerebrospinal fluid (CSF) biomarkers for discrimination of FTLD and its pathological subtypes.Methods YKL40, FABP4, MFG‐E8, and the activities of catalase and specific lysosomal enzymes were analyzed in patients with FTLD‐TDP (n = 30), FTLD‐Tau (n = 20), AD (n = 30), DLB (n = 29), and nondemented controls (n = 29) obtained from two different centers. Models were validated in an independent CSF cohort (n = 188).Results YKL40 and catalase activity were increased in FTLD‐TDP cases compared to controls. YKL40 levels were also higher in FTLD‐TDP compared to FTLD‐Tau. We identified biomarker models able to discriminate FTLD from nondemented controls (MFG‐E8, tTau, and Aβ 42; 78% sensitivity and 83% specificity) and non‐FTLD dementia (YKL40, pTau, p/tTau ratio, and age; 90% sensitivity, 78% specificity), which were validated in an independent cohort. In addition, we identified a biomarker model differentiating FTLD‐TDP from FTLD‐Tau (YKL40, MFGE‐8, βHexA together with βHexA/tHex and p/tTau ratios and age) with 80% sensitivity and 82% specificity.InterpretationThis study identifies CSF protein signatures distinguishing FTLD and the two main pathological subtypes with optimal accuracy (specificity/sensitivity > 80%). Validation of these models may allow appropriate selection of cases for clinical trials targeting the accumulation of Tau or TDP43, thereby increasing their efficiency and facilitating the development of successful therapies.

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CSF sAPPβ, YKL-40, and neurofilament light in frontotemporal lobar degeneration

Abstract: This study provides Class III evidence that CSF levels of sAPPβ, YKL-40, and NfL are useful to identify patients with FTLD-related syndromes.

Cited by 109 publications

References 36 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

The Sant Pau Initiative on Neurodegeneration (SPIN) cohort: A data set for biomarker discovery and validation in neurodegenerative disorders

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

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