Highlights
- •Accurate diagnosis of behavioural variant frontotemporal dementia is challenging.
- •bvFTD is commonly misdiagnosed, and distinguishing from non-progressor mimics is challenging.
- •The biomarker of neuronal injury, neurofilament light, improves diagnostic confidence in bvFTD.
Abstract
Background: Distinguishing behavioural variant frontotemporal dementia (bvFTD) from non-neurodegenerative
‘non-progressor’ mimics of frontal lobe dysfunction, can be one of the most challenging
clinical dilemmas. A biomarker of neuronal injury, neurofilament light chain (NfL),
could reduce misdiagnosis and delay.
Methods: Cerebrospinal fluid (CSF) NfL, amyloid beta 1–42 (AB42), total and phosphorylated
tau (T-tau, P-tau) levels were examined in patients with an initial diagnosis of bvFTD.
Based on follow-up information, patients were categorised as Progressors or Non-Progressors:
further subtyped into Non-Progressor Revised (non-neurological/neurodegenerative final
diagnosis), and Non-Progressor Static (static deficits, not fully explained by non-neurological/neurodegenerative
causes).
Results: Forty-three patients were included: 20 Progressors, 23 Non-Progressors (15 Non-Progressor
Revised, 8 Non-Progressor Static), and 20 controls. NfL concentrations were lower
in Non-Progressors (Non-Progressors Mean, M = 554 pg/mL, 95%CI:[461, 675], Non-Progressor
Revised M = 459 pg/mL, 95%CI:[385, 539], and Non-Progressor Static M = 730 pg/mL,
95%CI:[516, 940]), compared to Progressors (M = 2397 pg/mL, 95%CI:[1607, 3332]). NfL
distinguished Progressors from Non-Progressors with the highest accuracy (area under
the curve 0.92, 90%/87% sensitivity/specificity, 86%/91% positive/negative predictive
value, 88% accuracy). Non-Progressor Static tended to have higher T-tau and P-tau
levels compared to Non-Progressor Revised Diagnoses.
Conclusion: This study demonstrated strong diagnostic utility of CSF NfL to distinguish bvFTD
from non-progressor variants, at baseline, with high accuracy, in a real-world clinical
setting. This has important clinical implications, to improve outcomes for patients
and clinicians facing this challenging clinical dilemma, healthcare services, and
clinical trials. Further research is required to investigate heterogeneity within
the non-progressor group and potential diagnostic algorithms, and prospective studies
are underway assessing plasma NfL.
Keywords
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References
- Time to diagnosis in younger-onset dementia and the impact of a specialist diagnostic service.Int. Psychogeriatr. 2020; : 1-9https://doi.org/10.1017/S1041610220001489
- Time to diagnosis in young-onset dementia and its determinants: the INSPIRED study.International Journal of Geriatric Psychiatry. 2016; 31: 1217-1224https://doi.org/10.1002/gps.4430
- Missed and delayed diagnosis of dementia in primary care: prevalence and contributing factors.Alzheimer Dis. Assoc. Disord. 2009; 23: 306-314https://doi.org/10.1097/WAD.0b013e3181a6bebc
- The diagnostic challenge of psychiatric symptoms in neurodegenerative disease: rates of and risk factors for prior psychiatric diagnosis in patients with early neurodegenerative disease.J. Clin. Psychiatry. 2011; 72: 126-133https://doi.org/10.4088/JCP.10m06382oli
- Identifying specific clinical symptoms of behavioral variant frontotemporal dementia versus differential psychiatric disorders in patients presenting with a late-onset frontal lobe syndrome.J. Clin. Psychiatry. 2016; 77: 1189-1200https://doi.org/10.4088/JCP.15r10174
- The diagnostic challenge of the late-onset frontal lobe syndrome: clinical predictors for primary psychiatric disorders versus behavioral variant frontotemporal dementia.J. Clin. Psychiatry. 2017; 78: e1197-e1203https://doi.org/10.4088/JCP.16m11078
- Diagnostic accuracy of the frontotemporal dementia consensus criteria in the late-onset frontal lobe syndrome.Dement. Geriatr. Cogn. Disord. 2016; 41: 210-219https://doi.org/10.1159/000444849
- Comparing neurocognition in severe chronic schizophrenia and frontotemporal dementia.Australian and New Zealand Journal of Psychiatry. 2014; https://doi.org/10.1177/0004867414529477
- Frontotemporal dementia presenting as schizophrenia-like psychosis in young people: Clinicopathological series and review of cases.Br. J. Psychiatry. 2009; 194: 298-305https://doi.org/10.1192/bjp.bp.108.057034
- Psychiatric diagnoses underlying the phenocopy syndrome of behavioural variant frontotemporal dementia.J. Neurol. Neurosurg. Psychiatry. 2016; 87: 64-68https://doi.org/10.1136/jnnp-2014-308284
- Recommendations to distinguish behavioural variant frontotemporal dementia from psychiatric disorders.Brain. 2020; 143: 1632-1650https://doi.org/10.1093/brain/awaa018
- The diagnostic challenge of young-onset dementia syndromes and primary psychiatric diseases: results from a retrospective 20-year cross-sectional study.J Neuropsychiatry Clin Neurosci. 2021; https://doi.org/10.1176/appi.neuropsych.20100266
- The behavioral variant frontotemporal dementia Phenocopy syndrome: a review.J. Geriatr. Psychiatry Neurol. 2021; 34: 196-208https://doi.org/10.1177/0891988720924708
- Phenocopy frontotemporal dementia: a case series from a National Memory Clinic and a review of the literature.Eur psychiatr. 2017; 41: S636-S637https://doi.org/10.1016/j.eurpsy.2017.01.1046
- Can progressive and non-progressive behavioural variant frontotemporal dementia be distinguished at presentation?.J. Neurol. Neurosurg. Psychiatry. 2009; 80: 591-593https://doi.org/10.1136/jnnp.2008.163873
- Executive function in progressive and nonprogressive behavioral variant frontotemporal dementia.Neurology. 2008; 71: 1481-1488https://doi.org/10.1212/01.wnl.0000334299.72023.c8
- The behavioural variant frontotemporal dementia phenocopy syndrome is a distinct entity - evidence from a longitudinal study.BMC Neurol. 2018; 18https://doi.org/10.1186/s12883-018-1060-1
- Progression in behavioral variant frontotemporal dementia: a longitudinal study.JAMA Neurology. 2015; 72: 1501https://doi.org/10.1001/jamaneurol.2015.2061
- Phenocopy or variant: a longitudinal study of very slowly progressive frontotemporal dementia.Case Reports. 2013; (bcr2012008077–bcr2012008077)https://doi.org/10.1136/bcr-2012-008077
- Novel cerebrospinal fluid biomarkers of axonal degeneration in frontotemporal dementia.Mol. Med. Rep. 2008; 1: 757-761https://doi.org/10.3892/mmr-00000025
- Functional connectivity and microstructural white matter changes in phenocopy frontotemporal dementia.Eur. Radiol. 2017; 27: 1352-1360https://doi.org/10.1007/s00330-016-4490-4
- Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion.J. Neurol. Neurosurg. Psychiatry. 2012; 83: 358-364https://doi.org/10.1136/jnnp-2011-301883
- Clinical heterogeneity of the C9orf72 genetic mutation in frontotemporal dementia.Neurocase. 2015; 21: 535-541https://doi.org/10.1080/13554794.2014.951058
- Structural and functional brain abnormalities place phenocopy frontotemporal dementia (FTD) in the FTD spectrum.NeuroImage: Clinical. 2016; 11: 595-605https://doi.org/10.1016/j.nicl.2016.03.019
- The bvFTD phenocopy syndrome: a clinicopathological report.J. Neurol. Neurosurg. Psychiatry. 2016; 87: 1155-1156https://doi.org/10.1136/jnnp-2015-312826
- Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.Brain. 2011; 134: 2456-2477https://doi.org/10.1093/brain/awr179
- Identifying bvFTD within the wide Spectrum of late onset frontal lobe syndrome: a clinical approach.Am. J. Geriatr. Psychiatry. 2015; 23: 1056-1066https://doi.org/10.1016/j.jagp.2015.04.002
- Neurofilaments as biomarkers in neurological disorders.Nat. Rev. Neurol. 2018; 14: 577-589https://doi.org/10.1038/s41582-018-0058-z
- Neurofilaments and neurofilament proteins in health and disease.Cold Spring Harb. Perspect. Biol. 2017; 9: 1-24https://doi.org/10.1101/cshperspect.a018309
- Diagnostic value of cerebrospinal fluid Neurofilament light protein in neurology: a systematic review and Meta-analysis.JAMA Neurology. 2019; 76: 1035-1048https://doi.org/10.1001/jamaneurol.2019.1534
- Neurofilament light chain as a biomarker in neurological disorders.J. Neurol. Neurosurg. Psychiatry. 2019; 90: 870-881https://doi.org/10.1136/jnnp-2018-320106
- A multicentre validation study of the diagnostic value of plasma neurofilament light.Nat. Commun. 2021; 12: 3400https://doi.org/10.1038/s41467-021-23620-z
- A pilot study of the utility of cerebrospinal fluid neurofilament light chain in differentiating neurodegenerative from psychiatric disorders: a ‘C-reactive protein’ for psychiatrists and neurologists?.Aust. N. Z. J. Psychiatry. 2020; 54: 57-67https://doi.org/10.1177/0004867419857811
- Cerebrospinal fluid neurofilament light chain is elevated in Niemann–Pick type C compared to psychiatric disorders and healthy controls and may be a marker of treatment response.Aust. N. Z. J. Psychiatry. 2020; 54: 648-649https://doi.org/10.1177/0004867419893431
- CSF neurofilament light differs in neurodegenerative diseases and predicts severity and survival.Neurology. 2014; 83: 1945-1953https://doi.org/10.1212/WNL.0000000000001015
- CSF neurofilaments in frontotemporal dementia compared with early onset Alzheimer’s disease and controls.Dement. Geriatr. Cogn. Disord. 2007; 23: 225-230https://doi.org/10.1159/000099473
- The diagnostic performance of neurofilament light chain in CSF and blood for Alzheimer’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis: a systematic review and meta-analysis.Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring. 2019; 11: 730-743https://doi.org/10.1016/j.dadm.2019.08.009
- The role of neurofilament light chain in frontotemporal dementia: a meta-analysis.Aging Clinical and Experimental Research. 2020; https://doi.org/10.1007/s40520-020-01554-8
- Serum neurofilament light chain is a discriminative biomarker between frontotemporal lobar degeneration and primary psychiatric disorders.J. Neurol. 2020; 267: 162-167https://doi.org/10.1007/s00415-019-09567-8
- Neurofilament light chain as a blood biomarker to differentiate psychiatric disorders from behavioural variant frontotemporal dementia.J. Psychiatr. Res. 2019; 113: 137-140https://doi.org/10.1016/j.jpsychires.2019.03.019
- Plasma neurofilament light chain protein is not increased in treatment-resistant schizophrenia and first-degree relatives.Aust N Z J Psychiatry. 2021; (000486742110586)https://doi.org/10.1177/00048674211058684
- Cerebrospinal fluid neurofilament light chain differentiates primary psychiatric disorders from rapidly progressive, Alzheimer’s disease and frontotemporal disorders in clinical settings.Alzheimers Dement. 2022; : alz.12549https://doi.org/10.1002/alz.12549
- The NUCOG: validity and reliability of a brief cognitive screening tool in neuropsychiatric patients.Aust. N. Z. J. Psychiatry. 2006; 40: 995-1002https://doi.org/10.1111/j.1440-1614.2006.01923.x
- A Hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD.Neuron. 2011; 72: 257-268https://doi.org/10.1016/j.neuron.2011.09.010
- Expanded GGGGCC Hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.Neuron. 2011; 72: 245-256https://doi.org/10.1016/j.neuron.2011.09.011
- The clinical utility of exome sequencing and extended bioinformatic analyses in adolescents and adults with a broad range of neurological phenotypes: an Australian perspective.J. Neurol. Sci. 2021; 420117260https://doi.org/10.1016/j.jns.2020.117260
- Psychiatric Phenocopy syndrome of behavioral frontotemporal dementia: behavioral and cognitive fingerprint.J. Alzheimers Dis. 2019; 72: 1159-1164https://doi.org/10.3233/JAD-190332
- Neurofilament light chain in FTD is elevated not only in cerebrospinal fluid, but also in serum.J. Neurol. Neurosurg. Psychiatry. 2016; 87: 1-4
Article info
Publication history
Published online: September 30, 2022
Accepted:
September 25,
2022
Received in revised form:
September 5,
2022
Received:
June 19,
2022
Identification
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© 2022 Elsevier B.V. All rights reserved.
