Plasma β-III tubulin, neurofilament light chain and glial fibrillary acidic protein are associated with neurodegeneration and progression in schizophrenia

Abstract

Schizophrenia is a progressive disorder characterized by multiple psychotic relapses. After every relapse, patients may not fully recover, and this may lead to a progressive loss of functionality. Pharmacological treatment represents a key factor to minimize the biological, psychological and psychosocial impact of the disorder. The number of relapses and the duration of psychotic episodes induce a potential neuronal damage and subsequently, neurodegenerative processes. Thus, a comparative study was performed, including forty healthy controls and forty-two SZ patients divided into first-episode psychosis (FEP) and chronic SZ (CSZ) subgroups, where the CSZ sub group was subdivided by antipsychotic treatment. In order to measure the potential neuronal damage, plasma levels of β-III tubulin, neurofilament light chain (Nf-L), and glial fibrillary acidic protein (GFAP) were performed. The results revealed that the levels of these proteins were increased in the SZ group compared to the control group (P < 0.05). Moreover, multiple comparison analysis showed highly significant levels of β-III tubulin (P = 0.0002), Nf-L (P = 0.0403) and GFAP (P < 0.015) in the subgroup of CSZ clozapine-treated. In conclusion, β-III tubulin, Nf-L and GFAP proteins may be potential biomarkers of neurodegeneration and progression in SZ. Schizophrenia (SZ) is a complex, severe and heterogeneous disorder. Unfortunately, its aetiology and pathophysiology remains unclear 1. Although schizophrenia can occur at any age, the average age of onset tends to be in the late teens to the early 20s for men, and the late 20s to early 30s for women, and its deteriorating course makes SZ the most disabling psychiatric disorder 2. SZ has been explained both by neurodevelopmental and neurodegenerative models, which include neuronal damage and grey matter abnormalities 3,4. Both models may be complementary, and four stages can be proposed in the course of SZ 5-11 (Fig. 1). Moreover, the duration of untreated psychosis (DUP) is a critical period during schizophrenia course. Accumulating evidence suggests that a longer DUP is associated with clinical deterioration, including increased symptoms severity, cognitive and functioning declines, and poorer response to antipsychotics 12,13. SZ patients treated immediately after the FEP will suffer less cognitive impairment and disability 14-17. Cognitive deficits are considered part of the core symptoms of SZ 18. Both abnormalities in prenatal life and in the early childhood neurodevelopment are associated with SZ, and they may explain the early cognitive decline that characterizes this disorder 8,19. Pathological neurodevelopment described in SZ patients may be explained

The 2022 Lady Estelle Wolfson lectureship on neurofilaments

“…Higher Nf concentrations are observed with neurodegeneration. It is, therefore, interesting to note that there is a small increase in Nf concentrations in Depression (Bavato et al, 2021; Chen, Liu, et al, 2021; Zhao et al, 2020), Schizophrenia (Bavato et al, 2021; Rodrigues‐Amorim et al, 2020) and with Psychosis (Katisko et al, 2019). Future research will need to investigate how much of this is due to neuro‐axonal loss or potential side effects of treatments.…”

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

“…(Al Shweiki et al, 2019;Bavato et al, 2021;Katisko et al, 2020;Rodrigues-Amorim et al, 2020;Zerr et al, 2018) However, these studies had smaller numbers, less comprehensively characterised patients, mixed psychiatric cohorts rather than specifically exploring schizophrenia, and did not include many people with severe and treatment-resistant schizophrenia, and people on clozapine.…”

“…We found no statistically significant differences between different primary psychiatric disorders and controls, but lower levels in primary psychiatric disorders compared with neurological and neurodegenerative disorders (Eratne et al, 2020a, 2020b). Several studies have included or explored NfL levels in patients with schizophrenia, many comparing them to neurodegenerative disorders such as frontotemporal dementia (Al Shweiki et al, 2019; Bavato et al, 2021; Katisko et al, 2020; Rodrigues-Amorim et al, 2020; Zerr et al, 2018). However, these studies had smaller numbers, less comprehensively characterised patients, mixed psychiatric cohorts rather than specifically exploring schizophrenia, and did not include many people with severe and TRS, and people on clozapine.…”

“…Elevated levels in cerebrospinal fluid (CSF) and blood have been demonstrated in a wide range of neurological and neurodegenerative conditions, with NfL functioning as a biomarker to identify and grade neuroaxonal injury, as well as for staging, prognosis and treatment response in many conditions (Ashton et al, 2021;Bridel et al, 2019;Gaetani et al, 2019;Khalil et al, 2018). A recent study explored plasma NfL in 42 people with schizophrenia (including nine on clozapine), and reported slightly higher NfL levels in schizophrenia compared to controls, and higher levels in clozapine-treated patients compared to controls (Rodrigues-Amorim et al, 2020). This study did not use ultrasensitive technology however, unlike more recent plasma NfL studies.…”

Association between CpG island DNA methylation in the promoter region of RELN and positive and negative types of schizophrenia

“…The neurodevelopmental disorder hypothesis is one of the most important pathological hypotheses of schizophrenia. 1 Reelin (encoded by RELN ) is an extracellular glycoprotein composed of 3461 amino acid residues, with a molecular weight of approximately 420 kD. It is involved in signal regulation in neurotransmission, information formation, and synaptic plasticity, and regulates the migration and localization of neural stem cells during brain development.…”