Clinical value of neurofilament and phospho-tau/tau ratio in the frontotemporal dementia spectrum

Meeter, Lieke H.H.; Vijverberg, Everard G.B.; Campo, Marta Del; Rozemüller, Annemieke; Kaat, Laura Donker; Jong, Frank Jan de; Flier, Wiesje M. van der; Teunissen, Charlotte E.; Swieten, John C. van; Pijnenburg, Yolande A.L.

doi:10.1212/wnl.0000000000005261

Cited by 102 publications

(136 citation statements)

References 42 publications

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“…Patients with high NfL experienced the steepest annual decline in both clinical rating scales and MRI measurements. These findings are consistent with previous studies establishing the prognostic value of both CSF7, 8, 36 and plasma7, 9 NfL in genetic FTD syndromes. Within our bvFTD and nfvPPA cohorts, median CSF NfL levels (4.1 × 10 3 pg/mL and 5.17 × 10 3 pg/mL, respectively) separated patients into subgroups with clinically significant annual change and clinically negligible annual change.…”

Section: Discussionsupporting

confidence: 93%

“…Alternatively, our findings may reflect the pathogenicity of early comorbid A β 1‐42 deposition in FTD, preceding frank biomarker‐positive Alzheimer's disease. Consistent with previous studies,36, 37 patients with FTLD‐TDP had relatively low p‐tau/t‐tau ratios compared to patients with FTLD‐tau, and a cutoff ratio of 0.29 gave modest sensitivity and specificity in detecting FTLD‐TDP en vivo. It should be noted that our FTLD‐TDP and FTLD‐tau cohorts did not include patients with svPPA (due to the limitations of our data), and our FTLD‐TDP cohort had a high burden of motor neuron disease.…”

Section: Discussionsupporting

confidence: 88%

“…A Bonferroni correction was used to correct for multiple pairwise comparisons across five differing CSF measures ( α = 0.05/5 = 0.01). In light of previously published studies,36, 37 we also used a receiver operating characteristic (ROC) analysis to investigate the utility of p‐tau/t‐tau ration in detecting FTLD‐TDP pathology en vivo.…”

Section: Methodsmentioning

confidence: 99%

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Cerebrospinal fluid biomarkers predict frontotemporal dementia trajectory

Ljubenkov

Staffaroni

Rojas

et al. 2018

Ann Clin Transl Neurol

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ObjectiveThe prognostic value of cerebrospinal fluid neurofilament light chain, total tau, phosphorylated tau181, and amyloid beta1‐42 was examined in frontotemporal dementia subtypes.MethodsWe compared baseline biomarkers between 49 controls, 40 patients with behavioral variant frontotemporal dementia, 24 with semantic variant primary progressive aphasia, and 26 with nonfluent variant primary progressive aphasia. Linear mixed effect models were used to assess the value of baseline biomarkers in predicting clinical and radiographic change in patient cohorts over multiple yearly follow up visits.ResultsNeurofilament light chain concentrations were lowest in controls. Elevated baseline neurofilament light chain predicted faster worsening in clinical severity, frontotemporal volume and frontotemporal fractional anisotropy in patients with behavioral variant frontotemporal dementia and nonfluent variant primary progressive aphasia. High total tau similarly predicted faster progression in nonfluent variant primary progressive aphasia. In behavioral variant frontotemporal dementia, higher phosphorylated tau181 predicted faster clinical progression whereas lower amyloid beta1‐42 predicted faster volumetric and fractional anisotropy reduction. Neurofilament light chain and phosphorylated tau181 were of greater predictive value in patients with tau pathology as compared to TDP‐43 pathology. Baseline neurofilament light chain correlated with baseline clinical severity and frontotemporal volume in behavioral variant frontotemporal dementia. Baseline total tau correlated with baseline clinical severity in semantic variant primary progressive aphasia.InterpretationHigh cerebrospinal fluid neurofilament light chain predicts more aggressive disease in behavioral variant frontotemporal dementia and nonfluent variant primary progressive aphasia. Total tau, phosphorylated tau181, and amyloid beta1‐42 also predict some measures of disease aggressiveness in frontotemporal dementia.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 88%

Section: Methodsmentioning

confidence: 99%

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Cerebrospinal fluid biomarkers predict frontotemporal dementia trajectory

Ljubenkov

Staffaroni

Rojas

et al. 2018

Ann Clin Transl Neurol

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“…Using a subset of cases for which NfL measurements were available (FTLD = 92, CON = 28), we observed that the FTLD vs. CON model (AUC:0.94; P < 0.0001) performed similar to NfL alone (AUC:0.94 P < 0.0001, Fig. S3), a non‐disease specific marker that optimally discriminate FTLD cases from controls 27, 32, 33, 34…”

Section: Resultsmentioning

confidence: 90%

“…The levels of AD‐related biomarkers (total and phosphorylated tau [t‐Tau and pTau 181 ]) were analyzed in the corresponding sample collection center using the commercially available kits (Emory: INNO‐BIA AlzBio3; Milan: Innotest A β (1‐42), hTAUAg, phosphor‐Tau(181P); Fujiribo, Ghent, Belgium, both using the same antibodies) as previously described 9, 26. The levels of neurofilament light change (NfL) were measured in a subset of cases within the validation cohort using a validated immunoassay ELISA of UmanDiagnostics (Umeå, Sweden) as previously described 27. All biomarkers were analyzed by a single experienced technician blinded to the clinical groups.…”

Section: Methodsmentioning

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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Distinguishing Frontotemporal Lobar Degeneration Tau From TDP-43 Using Plasma Biomarkers

et al. 2022

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ImportanceBiomarkers are lacking that can discriminate frontotemporal lobar degeneration (FTLD) associated with tau (FTLD-tau) or TDP-43 (FTLD-TDP).ObjectiveTo test whether plasma biomarkers glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), or their ratio (GFAP/NfL) differ between FTLD-tau and FTLD-TDP.Design, Setting, and ParticipantsThis retrospective cross-sectional study included data from 2009 to 2020 from the University of Pennsylvania Integrated Neurodegenerative Disease Database, with a median (IQR) follow-up duration of 2 (0.3-4.2) years. The training sample was composed of patients with autopsy-confirmed and familial FTLD; nonimpaired controls were included as a reference group. The independent validation sample included patients with FTD with a clinical diagnosis of progressive supranuclear palsy syndrome (PSPS) associated with tau (PSPS-tau) or amytrophic lateral sclerosis (ALS) associated with TDP-43 (ALS-TDP). In patients with FTLD with autopsy-confirmed or variant-confirmed pathology, receiver operating characteristic (ROC) curves tested the GFAP/NfL ratio and established a pathology-confirmed cut point. The cut point was validated in an independent sample of patients with clinical frontotemporal dementia (FTD). Data were analyzed from February to July 2022.ExposuresClinical, postmortem histopathological assessments, and plasma collection.Main Outcomes and MeasuresROC and area under the ROC curve (AUC) with 90% CIs evaluated discrimination of pure FTLD-tau from pure FTLD-TDP using plasma GFAP/NfL ratio; the Youden index established optimal cut points. Sensitivity and specificity of cut points were assessed in an independent validation sample.ResultsOf 349 participants with available plasma data, 234 met inclusion criteria (31 controls, 141 in the training sample, and 62 in the validation sample). In the training sample, patients with FTLD-tau were older than patients with FTLD-TDP (FTLD-tau: n = 46; mean [SD] age, 65.8 [8.29] years; FTLD-TDP: n = 95; mean [SD] age, 62.3 [7.82] years; t84.6 = 2.45; mean difference, 3.57; 95% CI, 0.67-6.48; P = .02) but with similar sex distribution (FTLD-tau: 27 of 46 [59%] were male; FTLD-TDP: 51 of 95 [54%] were male; χ21 = 0.14; P = .70). In the validation sample, patients with PSPS-tau were older than those with ALS-TDP (PSPS-tau: n = 31; mean [SD] age, 69.3 [7.35] years; ALS-TDP: n = 31; mean [SD] age, 54.6 [10.17] years; t54.6 = 6.53; mean difference, 14.71; 95% CI, 10.19-19.23; P &lt; .001) and had fewer patients who were male (PSPS-tau: 9 of 31 [29%] were male; ALS-TDP: 22 of 31 [71%] were male; χ21 = 9.3; P = .002). ROC revealed excellent discrimination of FTLD-tau from FTLD-TDP by plasma GFAP/NfL ratio (AUC = 0.89; 90% CI, 0.82-0.95; sensitivity = 0.73; 90% CI, 0.65-0.89; specificity = 0.89; 90% CI, 0.78-0.98), which was higher than either GFAP level alone (AUC = 0.65; 90% CI, 0.54-0.76) or NfL levels alone (AUC = 0.75; 90% CI, 0.64-0.85). In the validation sample, there was sensitivity of 0.84 (90% CI, 0.66-0.94) and specificity of 0.81 (90% CI, 0.62-0.91) when applying the autopsy-derived plasma GFAP/NfL threshold.Conclusions and RelevanceThe plasma ratio of GFAP/NfL may discriminate FTLD-tau from FTLD-TDP.

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Clinical value of neurofilament and phospho-tau/tau ratio in the frontotemporal dementia spectrum

Cited by 102 publications

References 42 publications

Cerebrospinal fluid biomarkers predict frontotemporal dementia trajectory

Cerebrospinal fluid biomarkers predict frontotemporal dementia trajectory

Novel CSF biomarkers to discriminate FTLD and its pathological subtypes

Distinguishing Frontotemporal Lobar Degeneration Tau From TDP-43 Using Plasma Biomarkers

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