Oxidative stress, indicated by skin Advanced Glycation End products, and tobacco smoking in relation to psychotic experiences and cognitive symptoms

Oxidative stress and inflammation are thought to underly the development of psychotic disorders 
(also called schizophrenia-spectrum disorders [SSD]) (Fraguas et al., 2018). Oxidative stress implies 
an imbalance between reactive oxygen species and antioxidants (redox dysregulation). Depletion of 
glutathione, an important antioxidant in the brain, due to high levels of oxidative stress or 
inadequate synthesis of glutathione are thought to cause decreased activity of the NMDA-receptor in 
the medial prefrontal cortex. This results in dysregulation of the dopaminergic system which in turn 
can cause psychotic symptoms (Perkins et al., 2020). Thus far, an association of redox dysregulation 
and severity of negative symptoms (i.e. diminished emotional expression or avolition) has been 
found (Matsuzawa et al., 2008). No other clinical parameter has been found to be associated with 
(peripheral) biomarkers indicating oxidative stress in patients suffering from SSD (Flatow et al., 
2013). 
Advanced Glycation End products (AGEs) are oxidated and glycated proteins and lipids that play a 
role in the cascade linking oxidative stress and neuroinflammation (Perkins et al., 2020). Skin 
autofluorescence (SAF) measures of AGEs serve as indicator of cumulative oxidative stress and 
increased levels have been demonstrated in individuals suffering from SSD (Hagen et al., 2017; 
Kouidrat et al., 2013), as well as in those suffering from affective disorders (Hagen et al., 2020)
compared to a healthy control group. Investigation of the association between SAF and self-reported 
psychotic symptoms in the general population can help further elucidate the relation between redox 
regulation and psychotic symptoms. Furthermore, genetic risk of psychosis, operationalised as 
polygenic risk score of schizophrenia (PRS-SZ), could confound the association between SAF and 
psychotic symptoms. Therefore, adjustment for PRS-SZ is warranted when detangling of the 
association between above mentioned factors.
Tobacco smoke is a well-known external source of reactive oxygen species. Tobacco smoking is 
related with psychotic symptoms in patients with psychosis (Vermeulen et al., 2019) as well as in the 
general population (Bhavsar et al., 2018). Although a pathophysiological role of redox dysregulation 
and oxidative stress seems plausible, different mechanisms could be dominant. For instance, 
overlapping genetic influence to psychosis, smoking behaviour and psychotic experiences could 
confound this association (Barkhuizen et al., 2021). Therefore, also the association between tobacco 
smoking and self-reported psychotic symptoms needs to be investigated, again taking into account 
genetic factors. 
Main research questions of this study are to what extent SAF and tobacco smoking are associated 
with self-reported psychotic experiences in the general population? We hypothesize that, in the 
general population, there are positive associations between SAF and psychotic symptoms and 
similarly between tobacco smoking and psychotic symptoms and that these associations are only 
partly dependent on PRS-SZ.
Cognitive impairment associated with SSD has been described extensively (Velthorst et al., 2021). 
Cognitive impairment in this population might be a direct result of (redox dysregulation-related) 
reduced activity of the NMDA-receptor, a hypothesis that is supported by findings of an association 
Application form data, biomaterials and linkage
Date 09-01-2023
For questions about this application form, please contact us or check www.lifelines.nl Page 6 of 11
between different biomarkers indicating oxidative stress including plasma AGEs and cognitive 
functioning in SDD (Gares-Caballer et al., 2022; Kobori et al., 2021; Wang et al., 2021). In an elderly 
population, associations between SAF and other biomarkers indicating redox regulation and 
cognitive functioning have been demonstrated cross-sectionally (Chen et al., 2021). However, 
described associations in the general population are much weaker compared to in individuals with 
SDD (ref). Furthermore, longitudinal associations were attenuated and therefore reverse causation 
cannot be excluded. Notably, research has focused mainly on elderly populations and individuals 
with diabetes mellitus type II, in whom different pathological mechanisms may be prevalent. 
In line with the hypothesis that redox dysregulation is a driving cause of cognitive impairment, 
duration and severity of tobacco smoking (an external source of reactive oxygen species) was 
associated with the severity of cognitive impairment in the general population (Mons et al., 2013). A 
negative association between tobacco smoking and cognitive performance has been demonstrated 
in both patients with SDD and controls (Mallet et al., 2022). Smoking cessation (with co-occurrent 
decrease in oxidative stress) is associated with improvements in processing speed in patients with 
psychosis (Vermeulen et al., 2018). 
Differences in cognitive profiles between individuals with clinical and non-clinical psychotic 
experiences (Mollon et al., 2016) suggests the need to adjust for genetic factors whilst investigating 
the associations between SAF and cognitive functioning symptoms, and similarly between tobacco 
smoking and cognitive functioning in the general population. Presence and effects of both genetic 
and environmental factors need to be investigated to gain a more thorough understanding of the 
underlying process. Adjustment for PRS-SZ could help detangle different plausible mechanisms in the 
association between redox regulation and cognition. Our other main research question is to what 
extent SAF and tobacco smoking are associated with (change in) cognitive functioning? We 
hypothesize that in the general population there are positive associations between SAF and cognitive 
functioning and similarly between tobacco smoking and cognitive functioning and that these 
associations are not completely explained by PRS-SZ.