Cerebrospinal fluid neurofilament concentration reflects disease severity in frontotemporal degeneration

Scherling, Carole; Hall, Tracey; Berisha, Flora; Klepac, Kristen; Karydas, Anna; Coppola, Giovanni; Kramer, Joel H.; Rabinovici, Gil D.; Ahlijanian, Michael K.; Miller, Bruce L.; Seeley, William W.; Grinberg, Lea T.; Rosen, Howard J.; Meredith, Jere E.; Boxer, Adam L.

doi:10.1002/ana.24052

Cited by 233 publications

(302 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%

“…CSF samples were collected via lumbar puncture into sterile polypropylene tubes, using a previously described protocol 8. Within 30 min of collection, CSF samples were centrifuged at 2000 g at room temperature (20–25°C) for 5 min, aliquoted into 500 μ L cryovials and stored at −80°C, until further analysis.…”

Section: Methodsmentioning

confidence: 99%

“…Neurofilament light‐chain (NfL) levels were quantified using the Uman Diagnostics enzyme‐linked immunosorbent assay kit (Umea, Sweden). All NfL samples were performed using a 1:4 dilution as specified in the Uman Diagnostic kit instructions, and were otherwise performed using previously described kit methods 8. NfL concentrations were first assessed on 7/26/2012 and 4/24/2013 by a clinical research organization, Bristol‐Myers Squibb (BMS), in an initial cohort of 27 patients (14 with bvFTD, 8 with nfvPPA, and 5 with svPPA).…”

Section: Methodsmentioning

confidence: 99%

“…NfL concentrations were first assessed on 7/26/2012 and 4/24/2013 by a clinical research organization, Bristol‐Myers Squibb (BMS), in an initial cohort of 27 patients (14 with bvFTD, 8 with nfvPPA, and 5 with svPPA). Data obtained from BMS (along with contemporaneous clinical and volumetric data) were previously used in separately published cross‐sectional analyses 8. In order to expand our sample size, NfL concentrations in a larger cohort of patients (26 with bvFTD, 22 with nfvPPA, 19 with svPPA, 49 controls) were measured on 7/15/2015 and 1/12/16 by the Fagan lab, Washington University, St. Louis.…”

Section: Methodsmentioning

confidence: 99%

“…Recent studies in FTD suggest that serum and CSF neurofilament‐light chain (NfL), an intermediate cytoskeletal element that elevates upon neuronal injury,6 is a reliable marker of disease onset,7 clinical severity,7, 8, 9 disease prognosis,7, 10 and brain atrophy rates 7, 9. Few studies, however, have addressed the relative value of NfL in prediction of disease progression in different FTD cohorts.…”

Section: Introductionmentioning

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: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Cerebrospinal fluid biomarkers predict frontotemporal dementia trajectory

Ljubenkov

Staffaroni

Rojas

et al. 2018

Ann Clin Transl Neurol

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Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients With Progranulin Gene Haploinsufficiency

Ljubenkov¹,

Edwards²,

Iaccarino³

et al. 2021

JAMA Netw Open

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IMPORTANCE Histone deacetylase inhibitors have been repeatedly shown to elevate progranulin levels in preclinical models. This report describes the first randomized clinical trial of a histone deacetylase inhibitor in frontotemporal dementia (FTD) resulting from progranulin (GRN) gene variations. OBJECTIVE To characterize the safety, tolerability, plasma pharmacokinetics, and pharmacodynamic effects of oral FRM-0334 on plasma progranulin and other exploratory biomarkers, including fluorodeoxyglucose (FDG)-positron emission tomography (PET), in individuals with GRN haploinsufficiency. DESIGN, SETTING, AND PARTICIPANTS In this randomized, double-blind, placebo-controlled, dose-escalating, phase 2a safety, tolerability, and pharmacodynamic clinical study, 2 doses of a histone deacetylase inhibitor (FRM-0334) were administered to participants with prodromal to moderate FTD with granulin variations. Participants were recruited from January 13, 2015, to April 13, 2016. The study included 27 participants with prodromal (n = 8) or mild-to-moderate symptoms of FTD (n = 19) and heterozygous pathogenic variations in GRN and was conducted at multiple centers in North America, the UK, and the European Union. Data were analyzed from June 9, 2019, to May 13, 2021. INTERVENTIONS Daily oral placebo (n = 5), 300 mg of FRM-0334 (n = 11), or 500 mg of FRM-0334 (n = 11) was administered for 28 days. MAIN OUTCOMES AND MEASURES Primary outcomes were safety and tolerability of FRM-0334 and its peripheral pharmacodynamic effect on plasma progranulin. Secondary outcomes were the plasma pharmacokinetic profile of FRM-0334 and its pharmacodynamic effect on cerebrospinal fluid progranulin. Exploratory outcomes were FDG-PET, FTD clinical severity, and cerebrospinal fluid biomarkers (neurofilament light chain [NfL], amyloid β 1-42, phosphorylated tau 181, and total tau [ttau]). RESULTS A total of 27 participants (mean [SD] age, 56.6 [10.5] years; 16 women [59.3%]; 26 White participants [96.3%]) with GRN variations were randomized and completed treatment. FRM-0334was safe and well tolerated but did not affect plasma progranulin (4.3 pg/mL per day change after treatment; 95% CI, -10.1 to 18.8 pg/mL; P = .56), cerebrospinal fluid progranulin (0.42 pg/mL per day; 95% CI, -0.12 to 0.95 pg/mL; P = .13), or exploratory pharmacodynamic measures. Plasma (continued)

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Cerebrospinal Fluid Patterns and the Risk of Future Dementia in Early, Incident Parkinson Disease

et al. 2015

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IMPORTANCE Alterations in cerebrospinal fluid (CSF) have been found in Parkinson disease (PD) and in PD dementia (PDD), but the prognostic importance of such changes is not well known. In vivo biomarkers for disease processes in PD are important for future development of disease-modifying therapies.OBJECTIVE To assess the diagnostic and prognostic value of a panel of CSF biomarkers in patients with early PD and related disorders. DESIGN, SETTING, AND PARTICIPANTS Regional population-based, prospective cohort study of idiopathic parkinsonism that included patients diagnosed between January 1, 2004, and April 30, 2009, by a movement disorder team at a university hospital that represented the only neurology clinic in the region. Participants were 128 nondemented patients with new-onset parkinsonism (104 with PD, 11 with multiple system atrophy, and 13 with progressive supranuclear palsy) who were followed up for 5 to 9 years. At baseline, CSF from 30 healthy control participants was obtained for comparison. MAIN OUTCOMES AND MEASURESCerebrospinal fluid concentrations of neurofilament light chain protein, Aβ1-42, total tau, phosphorylated tau, α-synuclein, and heart fatty acid-binding protein were quantified by 2 blinded measurements (at baseline and after 1 year). Follow-up included an extensive neuropsychological assessment. As PD outcome variables, mild cognitive impairment and incident PDD were diagnosed based on published criteria. RESULTS Among the 128 study participants, the 104 patients with early PD had a different CSF pattern compared with the 13 patients with progressive supranuclear palsy (baseline area under the receiver operating characteristic curve, 0.87; P < .0001) and the 30 control participants (baseline area under the receiver operating characteristic curve, 0.69; P = .0021). A CSF biomarker pattern associated with the development of PDD was observed. In PD, high neurofilament light chain protein, low Aβ1-42, and high heart fatty acid-binding protein at baseline were related to future PDD as analyzed by Cox proportional hazards regression models. Combined, these early biomarkers predicted PDD with high accuracy (hazard ratio, 11.8; 95% CI, 3.3-42.1; P = .0001) after adjusting for possible confounders. CONCLUSIONS AND RELEVANCEThe analyzed CSF biomarkers have potential usefulness as a diagnostic tool in patients with parkinsonism. In PD, high neurofilament light chain protein, low Aβ1-42, and high heart fatty acid-binding protein were related to future PDD, providing new insights into the etiology of PDD.

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Cerebrospinal fluid neurofilament concentration reflects disease severity in frontotemporal degeneration

Cited by 233 publications

References 42 publications

Cerebrospinal fluid biomarkers predict frontotemporal dementia trajectory

Cerebrospinal fluid biomarkers predict frontotemporal dementia trajectory

Effect of the Histone Deacetylase Inhibitor FRM-0334 on Progranulin Levels in Patients With Progranulin Gene Haploinsufficiency

Cerebrospinal Fluid Patterns and the Risk of Future Dementia in Early, Incident Parkinson Disease

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