Cerebrospinal fluid neurofilament light chain differentiates behavioural variant frontotemporal dementia progressors from non-progressors

Malpas

et al. 2023

Preprint

Self Cite

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.

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Malpas

et al. 2023

Preprint

Self Cite

“…One of the most challenging clinical distinctions, associated with some of the highest diagnostic uncertainty/instability and misdiagnoses, is distinguishing PPD from behavioural variant frontotemporal dementia (bvFTD), a neurodegenerative condition associated with personality, behavioural and psychiatric changes (Ducharme et al, 2020;Eratne et al, 2022b;Kang et al, 2023;Tsoukra et al, 2022). Previous studies have investigated blood and cerebrospinal fluid (CSF) NfL in bvFTD compared to PPD (Al Shweiki et al, 2019;Ashton et al, 2021;Katisko et al, 2020;Vijverberg et al, 2017), and in bvFTD and range of other neurodegenerative conditions compared to PPD and non-progressive/phenocopy syndromes (Eratne et al, 2020(Eratne et al, , 2022b(Eratne et al, , 2022cLoi et al, 2022), finding significantly elevated levels in neurodegenerative disorders including bvFTD, compared to PPD. There remain significant gaps in our understanding of NfL levels in large, well characterised cohorts of severe PPD that can often present as or 'mimic' conditions like bvFTD, such as bipolar affective disorder (BPAD), MDD, and schizophrenia, which have overlapping clinical features and are common initial misdiagnoses or prodromes of bvFTD, and/or are associated themselves with cognitive and neuroimaging abnormalities.…”

Section: Introductionmentioning

confidence: 99%

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

Malpas

et al. 2023

Aust N Z J Psychiatry

Self Cite

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.

“…Despite the heterogeneity of neurodegenerative and psychiatric disorders, neurofilament light chain (NfL) in CSF has shown promise as a diagnostic discriminator (Eratne et al, 2020;Eratne, Keem, et al, 2022;Eratne, Loi, et al, 2022;Fourier et al, 2020;Karantali et al, 2020). NfL, a neurofilament subunit, makes up the structure of the axonal skeleton expressed in large myelinated axons (Gafson et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Cerebrospinal fluid neurofilament light predicts longitudinal diagnostic change in patients with psychiatric and neurodegenerative disorders

Dobson

et al. 2023

Acta Neuropsychiatr.

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Objective People with neuropsychiatric symptoms often experience delay in accurate diagnosis. Although cerebrospinal fluid neurofilament light (CSF NfL) shows promise in distinguishing neurodegenerative disorders (ND) from psychiatric disorders (PSY), its accuracy in a diagnostically challenging cohort longitudinally is unknown. Methods We collected longitudinal diagnostic information (mean=36 months) from patients assessed at a neuropsychiatry service, categorising diagnoses as ND/mild cognitive impairment/other neurological disorders (ND/MCI/other), and PSY. We pre-specified NfL>582pg/mL as indicative of ND/MCI/other. Results Diagnostic category changed from initial to final diagnosis for 23% (49/212) of patients. NfL predicted the final diagnostic category for 92% (22/24) of these and predicted final diagnostic category overall (ND/MCI/other vs. PSY) in 88% (187/212), compared to 77% (163/212) with clinical assessment alone. Conclusions CSF NfL improved diagnostic accuracy, with potential to have led to earlier, accurate diagnosis in a real-world setting using a pre-specified cut-off, adding weight to translation of NfL into clinical practice.