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

Abstract

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.

Plasma neurofilament light protein provides evidence of accelerated brain ageing in treatment-resistant schizophrenia

“…It also is a marker of potential neuronal injury. While some studies have observed increased NfL in schizophrenia and depression 7,8 , recent studies from our group using ultrasensitive technology to measure plasma NfL levels found no evidence of increased NfL in treatment-resistant schizophrenia (TRS) or major depressive disorder (MDD), but a slight increase in individuals with bipolar affective disorder (BPAD) 9,10 . However, these studies did not examine whether age trajectories of NfL in psychiatric disorders differed from those seen in healthy individuals, where higher NfL levels are associated with increasing age 11 .…”

“…NfL Z-scores were calculated from age-adjusted percentiles from the large reference cohort (Control Group 2), derived using generalised additive models for location, scale, and shape 9 .…”

Elevated plasma neurofilament light & glial fibrillary acidic protein in epilepsy versus non-epileptic seizures & non-epileptic disorders

“…NfL levels from all patient cohorts were compared to a large reference control cohort. This cohort and models and methodology have been described in detail previously(16,28). Briefly, this cohort included 1,926 people aged 5–90 years, with no history or clinical symptoms or signs of neurological disorder, with plasma NfL analysed using the Quanterix Simoa HD-X platform.…”

“…We hypothesised that NfL and GFAP levels would be higher in patients with epilepsy compared to those with non-epileptic disorders. We further compared NfL levels against a large reference cohort to examine for any associations between NfL and clinical variables in patients with epilepsy(16,28). A similar reference cohort is not available for GFAP levels.…”

“…There is an increasing body of research examining the use of blood biomarkers in the diagnosis and differen'al diagnoses of a range of neurological and neurodegenera've disorders (11)(12)(13). Recent research has iden'fied that biomarkers such as neurofilament light chain protein (NfL), a marker of neuronal injury, can be used to dis'nguish neurological and neurodegenera've disorders, from primary psychiatric and nonneurodegenera've disorders (13)(14)(15)(16).…”