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) show promise to improve diagnosis of neurodegenerative disorders and distinguish neurodegenerative from primary psychiatric disorders (PPD). This study investigated the diagnostic utility of plasma NfL to differentiate behavioural variant frontotemporal dementia (bvFTD, a neurodegenerative disorder commonly misdiagnosed initially as PPD), from PPD, and performance of large normative/reference data sets and models. Methods: Plasma NfL was analysed in major depressive disorder (MDD, n = 42), bipolar affective disorder (BPAD, n = 121), treatment-resistant schizophrenia (TRS, n = 82), bvFTD ( n = 22), and compared to the reference cohort (Control Group 2, n = 1926, using GAMLSS modelling), and age-matched controls (Control Group 1, n = 96, using general linear models). Results: Large differences were seen between bvFTD (mean NfL 34.9 pg/mL) and all PPDs and controls (all < 11 pg/mL). NfL distinguished bvFTD from PPD with high accuracy, sensitivity (86%), and specificity (88%). GAMLSS models using reference Control Group 2 facilitated precision interpretation of individual levels, while performing equally to or outperforming models using local controls. Slightly higher NfL levels were found in BPAD, compared to controls and TRS. Conclusions: This study adds further evidence on the diagnostic utility of NfL to distinguish bvFTD from PPD of high clinical relevance to a bvFTD differential diagnosis, and includes the largest cohort of BPAD to date. Using large reference cohorts, GAMLSS modelling and the interactive Internet-based application we developed, may have important implications for future research and clinical translation. Studies are underway investigating utility of plasma NfL in diverse neurodegenerative and primary psychiatric conditions in real-world clinical settings.

Diagnostic utility of plasma ptau217, ptau181, GFAP for Alzheimer disease in a heterogeneous younger onset dementia clinical cohort

“…An important point is that the A-T-patients in this study include people with various neurodegenerative and primary psychiatric diagnoses, so this group is not comparable to AD-focused studies where the A-T-group is equivalent or almost equivalent to healthy controls. This would be the main explanation of our (expected) finding a lack of utility of NfL to distinguish from A+T+ from diverse non-AD conditions, given even the A-T-group included many people with a neurodegenerative disorder known to be associated with elevated NfL levels [12,31]. The findings of this study fit with existing work demonstrating promise in using NfL as a higher level or first tier test to distinguish neurodegenerative from non-neurodegenerative and primary psychiatric conditions [12,31], with more specific tests such as ptau217 being more appropriately used to distinguish AD from other neurodegenerative conditions.…”

“…This would be the main explanation of our (expected) finding a lack of utility of NfL to distinguish from A+T+ from diverse non-AD conditions, given even the A-T-group included many people with a neurodegenerative disorder known to be associated with elevated NfL levels [12,31]. The findings of this study fit with existing work demonstrating promise in using NfL as a higher level or first tier test to distinguish neurodegenerative from non-neurodegenerative and primary psychiatric conditions [12,31], with more specific tests such as ptau217 being more appropriately used to distinguish AD from other neurodegenerative conditions. Identifying optimal biomarkers for such tiered testing is particularly useful as precision medicine approaches and diagnostic algorithms for timely and accurate diagnosis of dementia emerge.…”

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 .…”

“…Participant samples and data, described in detail previously 9,[13][14][15][16] , were included from three patient cohorts and two control groups. Patient cohorts included individuals with BPAD (n = 121), MDD; n = 42, and TRS, n = 82.…”

Neurofilament light and glial fibrillary acidic protein in mood and anxiety disorders: A systematic review and meta-analysis

“…Numerous studies have shown that NfL, in both CSF and blood, is a valuable marker for diagnosing, assessing disease severity, and predicting prognosis in a diverse range of neurodegenerative conditions, including Alzheimer’s disease and frontotemporal lobar degeneration (5–7). NfL can also distinguish neurodegenerative disorders from primary psychiatric disorders within memory clinics and neuropsychiatry services (8–10). More recently, glial fibrillary acidic protein (GFAP), a component of glial cell cytoskeleton, has emerged as a sensitive measure of astrogliosis and neuroinflammation, demonstrating superior prognostic accuracy to NfL in multiple sclerosis (11,12).…”