Age‐ and disease‐specific reference values for neurofilament light presented in an online interactive support interface

Vermunt, Lisa; Otte, Marco; Verberk, Inge M.W.; Killestein, Joep; Lemstra, Afina W.; Flier, Wiesje M. van der; Pijnenburg, Yolande A.L.; Vijverberg, Everard G.B.; Bouwman, Femke H.; Gravesteijn, Gido; Scheltens, Philip; Harten, Argonde C. van; Willemse, Eline A.J.; Teunissen, Charlotte E.

doi:10.1002/acn3.51676

Cited by 41 publications

(33 citation statements)

References 20 publications

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“…The application allows input of an individual’s age and plasma NfL level (generated using technology/assays similar to those used for the reference cohort), providing estimated centiles and z-scores and allowing visualisation on the centiles reference chart, compared to the large reference cohort, Control Group 2. This builds on other similar applications that have been developed recently (Benkert et al, 2022; Vermunt et al, 2022), but to our knowledge this is the first application to use GAMLSS modelling and providing both individualised percentiles and z-scores for plasma NfL. This application could be used for academic and research interests and will be used in studies underway to investigate the clinical and diagnostic utility and validity of such tools, as well as feasibility and utility for clinicians.…”

Section: Discussionmentioning

confidence: 99%

Plasma neurofilament light in behavioural variant frontotemporal dementia compared to mood and psychotic disorders

Eratne

Kang

Malpas

et al. 2023

Preprint

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Objective Blood biomarkers of neuronal injury such as neurofilament light (NfL) are being intensively studied to improve diagnosis and treatment of neurodegenerative disorders, but gaps remain in its ability to assist in distinguishing neurodegenerative from primary psychiatric disorders (PPD) with overlapping clinical presentations that commonly cause diagnostic dilemmas. This study aimed to investigate plasma NfL in a range of PPDs, and the diagnostic utility of plasma NfL in differentiating PPD from behavioural variant frontotemporal dementia (bvFTD), a neurodegenerative disorder commonly misdiagnosed initially as PPD. Furthermore, improved understanding of NfL in a diverse range of PPDs, the role and performance of a large normative/reference data sets and models to facilitate precision interpretation of an individual levels, and the influence of covariates, will be critical for future research and clinical translation. Methods Plasma NfL was analysed using Single molecule array (Simoa) technology in major depressive disorder (MDD, n=42), bipolar affective disorder (BPAD, n=121), treatment-resistant schizophrenia (TRS, n=82), and bvFTD (n=22). Comparisons were made between the four clinical cohort groups, and the reference cohort (Control Group 2, n=1926, using generalised additive models for location, scale, and shape (GAMLSS), and age-matched controls (Control Group 1, n=96, using general linear models), Results Large differences were seen between bvFTD (mean NfL 34.9pg/mL) and all PPDs and controls (all <11pg/mL). Plasma NfL distinguished bvFTD from PPD with high accuracy; a 13.3pg/mLcut-off resulted in 86% sensitivity, 88% specificity. GAMLSS models using the large Control Group 2 performed equally to or outperformed models using local controls. An internet-based application was developed to provide individualised z-scores and percentiles based on this reference cohort, which can facilitate precision interpretation of an individual level. Slightly higher plasma NfL levels were found in BPAD, compared to both control groups, and compared to TRS. Conclusions This study adds further evident on the strong diagnostic utility of NfL to distinguish bvFTD from clinically relevant PPDs, and includes the largest cohort of BPAD to date. The finding of higher plasma NfL levels in the largest cohort of BPAD to date should prompt further investigation. Use of large reference cohorts and GAMLSS modelling may have important implications for future research and clinical translation. Studies are underway investigating clinical and diagnostic utility of plasma NfL and the serviceability of the internet-based application for diverse neurodegenerative and primary psychiatric conditions in real-world primary care and specialist clinical settings.

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Section: Discussionmentioning

confidence: 99%

Plasma neurofilament light in behavioural variant frontotemporal dementia compared to mood and psychotic disorders

Eratne

Kang

Malpas

et al. 2023

Preprint

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“…Interestingly, levels of NfL in CSF differed between the proband and her mother. The latter showed a significative increase in NfL levels, consistent with FTD-related pathology and then supportive of a bvFTD clinical diagnosis, while the proband presented only a moderate rise, which does not suggest underlying pathology of the FTD spectrum, although NfL age-specific and disease-specific reference values have not been established yet [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Young Onset Alzheimer’s Disease Associated with C9ORF72 Hexanucleotide Expansion: Further Evidence for a Still Unsolved Association

Vinceti

Gallingani

Zucchi

et al. 2023

Genes

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Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are recognized as part of a disease continuum (FTD-ALS spectrum), in which the most common genetic cause is chromosome 9 open reading frame 72 (C9ORF72) gene hexanucleotide repeat expansion. The clinical phenotype of patients carrying this expansion varies widely and includes diseases beyond the FTD-ALS spectrum. Although a few cases of patients with C9ORF72 expansion and a clinical or biomarker-supported diagnosis of Alzheimer’s disease (AD) have been described, they have been considered too sparse to establish a definite association between the C9ORF72 expansion and AD pathology. Here, we describe a C9ORF72 family with pleomorphic phenotypical expressions: a 54-year-old woman showing cognitive impairment and behavioral disturbances with both neuroimaging and cerebrospinal fluid (CSF) biomarkers consistent with AD pathology, her 49-year-old brother with typical FTD-ALS, and their 63-year-old mother with the behavioral variant of FTD and CSF biomarkers suggestive of AD pathology. The young onset of disease in all three family members and their different phenotypes and biomarker profiles make the simple co-occurrence of different diseases an extremely unlikely explanation. Our report adds to previous findings and may contribute to further expanding the spectrum of diseases associated with C9ORF72 expansion.

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“…Although sNfL may be a useful biomarker across several aspects of MS care, to date, sNfL has largely been investigated on a group level and only a handful of studies have looked at predictions on an individual level. Interpretations of individual sNfL levels are also complicated by several common factors that associate with higher sNfL levels, including age, body mass index, impaired renal function, diabetes mellitus, and active smoking, underscoring the need for normative sNfL data to correct for these factors [84,87,94]. Prospective clinical use of sNfL on an individual MS patient level has not yet been established.…”

Section: Neurofilament Light Chainmentioning

confidence: 99%

Emerging imaging and liquid biomarkers in multiple sclerosis

et al. 2023

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The advent of highly effective disease modifying therapy has transformed the landscape of multiple sclerosis (MS) care over the last two decades. However, there remains a critical, unmet need for sensitive and specific biomarkers to aid in diagnosis, prognosis, treatment monitoring, and the development of new interventions, particularly for people with progressive disease. This review evaluates the current data for several emerging imaging and liquid biomarkers in people with MS. MRI findings such as the central vein sign and paramagnetic rim lesions may improve MS diagnostic accuracy and evaluation of therapy efficacy in progressive disease. Serum and cerebrospinal fluid levels of several neuroglial proteins, such as neurofilament light chain and glial fibrillary acidic protein, show potential to be sensitive biomarkers of pathologic processes such as neuro‐axonal injury or glial‐inflammation. Additional promising biomarkers, including optical coherence tomography, cytokines and chemokines, microRNAs, and extracellular vesicles/exosomes, are also reviewed, among others. Beyond their potential integration into MS clinical care and interventional trials, several of these biomarkers may be informative of MS pathogenesis and help elucidate novel targets for treatment strategies.

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Age‐ and disease‐specific reference values for neurofilament light presented in an online interactive support interface

Cited by 41 publications

References 20 publications

Plasma neurofilament light in behavioural variant frontotemporal dementia compared to mood and psychotic disorders

Plasma neurofilament light in behavioural variant frontotemporal dementia compared to mood and psychotic disorders

Young Onset Alzheimer’s Disease Associated with C9ORF72 Hexanucleotide Expansion: Further Evidence for a Still Unsolved Association

Emerging imaging and liquid biomarkers in multiple sclerosis

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