Plasma neurofilament light chain protein is not increased in treatment-resistant schizophrenia and first-degree relatives

Abstract

Objective: Schizophrenia, a complex psychiatric disorder, is often associated with cognitive, neurological and neuroimaging abnormalities. The processes underlying these abnormalities, and whether a subset of people with schizophrenia have a neuroprogressive or neurodegenerative component to schizophrenia, remain largely unknown. Examining fluid biomarkers of diverse types of neuronal damage could increase our understanding of these processes, as well as potentially provide clinically useful biomarkers, for example with assisting with differentiation from progressive neurodegenerative disorders such as Alzheimer and frontotemporal dementias. Methods: This study measured plasma neurofilament light chain protein (NfL) using ultrasensitive Simoa technology, to investigate the degree of neuronal injury in a well-characterised cohort of people with treatment-resistant schizophrenia on clozapine ( n = 82), compared to first-degree relatives (an at-risk group, n = 37), people with schizophrenia not treated with clozapine ( n = 13), and age- and sex-matched controls ( n = 59). Results: We found no differences in NfL levels between treatment-resistant schizophrenia (mean NfL, M = 6.3 pg/mL, 95% confidence interval: [5.5, 7.2]), first-degree relatives (siblings, M = 6.7 pg/mL, 95% confidence interval: [5.2, 8.2]; parents, M after adjusting for age = 6.7 pg/mL, 95% confidence interval: [4.7, 8.8]), controls (M = 5.8 pg/mL, 95% confidence interval: [5.3, 6.3]) and not treated with clozapine (M = 4.9 pg/mL, 95% confidence interval: [4.0, 5.8]). Exploratory, hypothesis-generating analyses found weak correlations in treatment-resistant schizophrenia, between NfL and clozapine levels (Spearman’s r = 0.258, 95% confidence interval: [0.034, 0.457]), dyslipidaemia ( r = 0.280, 95% confidence interval: [0.064, 0.470]) and a negative correlation with weight ( r = −0.305, 95% confidence interval: [−0.504, −0.076]). Conclusion: Treatment-resistant schizophrenia does not appear to be associated with neuronal, particularly axonal degeneration. Further studies are warranted to investigate the utility of NfL to differentiate treatment-resistant schizophrenia from neurodegenerative disorders such as behavioural variant frontotemporal dementia, and to explore NfL in other stages of schizophrenia such as the prodome and first episode.

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

“…Participants were from the Cooperative Research Centre (CRC) Psychosis Study, a cross-sectional study that recruited people aged 18-65 years from inpatient and outpatient services in Melbourne, Australia, between 2012-2017 (n=82), who were on clozapine and had a diagnosis of treatment- resistant schizophrenia (TRS), defined as failure to respond to adequate trials of two or more antipsychotics, as previously described (Bousman et al, 2019; Eratne et al, 2021; Mostaid et al, 2017) The TRS biobank is detailed here: https://researchdata.ands.org.au/treatment-resistant-schizophrenia-biobank/1325206…”

“…Samples and data were pooled from healthy people (n=96) with no current or past psychiatric or neurological illness, from the CRC Psychosis Study (healthy controls age-matched to TRS, and healthy parents and siblings of participants with TRS), as described previously (Eratne et al, 2021).…”

“…This data was not available for Cohorts 1 and 2. More detailed information on recruitment and eligibility criteria have been published previously (Berk et al, 2019; Bousman et al, 2019; Dean et al, 2014, 2017; Eratne et al, 2021; Mostaid et al, 2017; Ooi et al, 2022; Simrén et al, 2022).…”

“…Higher serum NfL levels were seen in bipolar depression (Aggio et al, 2022). Mixed findings have also been seen in psychotic disorders: some studies reported no differences between controls and schizophrenia (Al Shweiki et al, 2019; Bavato et al, 2021) and between controls and treatment-resistant clozapine-treated schizophrenia (Eratne et al, 2021) while one study reported slightly higher NfL levels in both schizophrenia and clozapine- treated patients compared to controls (Rodrigues-Amorim et al, 2020). A recent study found higher serum NfL levels in psychosis associated with anti-NMDA receptor encephalitis, compared to psychosis due to primary psychiatric illness, of particular relevance to patients in psychiatric settings (Guasp et al, 2022).…”

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

“…Neurofilament light (NfL) is one of three subunits of a neuroaxonal cytoskeletal protein common to myelinated axons, with elevated levels in cerebrospinal fluid (CSF) and blood associated with neuronal injury and a marker of diagnosis, staging and prognosis, in a diverse range of neurological and neurodegenerative disorders [25][26][27][28][29][30][31]. Numerous studies have demonstrated elevated CSF and blood NfL in bvFTD compared to controls, as well as primary psychiatric disorders [29][30][31][32][33][34][35][36][37][38]. Recent expert consensus guidelines and recommendations have recommended NfL as a biomarker to assist with differentiating bvFTD from primary psychiatric disorders [11].…”