A Novel Pathway Phenotype of Temporal Lobe Epilepsy and Comorbid Psychiatric Disorders: Results of Precision Nomothetic Medicine

Abstract

No precision medicine models of temporal lobe epilepsy (TLE) and associated mental comorbidities have been developed to date. This observational study aimed to develop a precision nomothetic, data-driven comorbid TLE model with endophenotype classes and pathway phenotypes that may have prognostic and therapeutical implications. We recruited forty healthy controls and 108 TLE patients for this research and assessed TLE and psychopathology (PP) features as well as oxidative stress (OSTOX, e.g., malondialdehyde or MDA, lipid hydroperoxides, and advanced oxidation protein products) and antioxidant (paraoxonase 1 or PON1 status, -SH groups, and total radical trapping potential or TRAP) biomarkers. A large part (57.2%) of the variance in a latent vector (LV) extracted from the above TLE and PP features was explained by these OSTOX and antioxidant biomarkers. The PON1 Q192R genetic variant showed indirect effects on this LV, which were completely mediated by PON1 activity and MDA. Factor analysis showed that a common core could be extracted from TLE, PP, OSTOX and antioxidant scores, indicating that these features are manifestations of a common underlying construct, i.e., a novel pathway phenotype of TLE. Based on the latter, we constructed a new phenotype class that is characterized by increased severity of TLE, PP and OSTOX features and lowered antioxidant defenses. A large part of the variance in episode frequency was explained by increased MDA, lowered antioxidant, and nitric oxide metabolite levels. In conclusion, (a) PP symptoms belong to the TLE phenome, and the signal increased severity; and (b) cumulative effects of aldehyde formation and lowered antioxidants determine epileptogenic kindling.

Evaluation of the Antioxidant Activity of Levetiracetam in a Temporal Lobe Epilepsy Model

“…In the development of TLE, the involvement of OS and neuroinflammation have been well established as important factors, in part because the large amount of energy required by the brain is considered to be a possible mechanism involved in epileptogenesis [ 12 , 21 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ]. In recent studies, it was observed that the specific inhibition of NADPH oxidase (NOX), the main producer of OS through O 2 •− synthesis, modified chronic epilepsy in a TLE rat model, preventing ROS generation, mitochondrial depolarization, and neuronal death.…”

Research and Diagnostic Algorithmic Rules (RADAR) for mood disorders, recurrence of illness, suicidal behaviors, and the patient’s lifetime trajectory

“…Previous research has shown that ROI is strongly predicted by gene (paraoxonase 1 or PON1 Q192R gene) X ACE interactions and the resulting deficits in PON1-high density lipoprotein (HDL) cholesterol complex (Maes et al, 2018; 2019), as well as with an increased immune and growth factor responsiveness in unipolar depression (Maes et al, 2022b), and dysfunctional T regulatory activities in bipolar disorder (Maes et al, 2021b). Interestingly, the frequency of seizures (kindling) in temporal lobe epilepsy is related with oxidative pathways and decreased antioxidant defenses, particularly PON1 activity and sulfhydryl groups (Maes et al, 2022a). Previous research revealed that oxidative and inflammatory indicators, as well as specific pro-inflammatory cytokines, predicted the recurrence of episodes, hospitalizations, and suicide attempts (Maes et al, 2001; Celik et al, 2010; Maes et al, 2012; Grande et al, 2014; Hope et al, 2013; Siwek et al, 2017; Sowa-Kucma et al, 2018).…”

“…Thus, the model developed here demonstrates that ROI (and the pathophysiology behind ROI) drives suicidal behaviors and the phenome and thus treatment resistance, both in the acute phase of depression (as indicated by the severity of the phenome) and over time (as indicated by ROI). One can wonder how psychotherapy could affect the major neuro-immune and neuro-oxidative pathophysiology, which includes genetic polymorphisms (PON1 Q192R genotype) sensitization of the immune network, T regulatory dysfunctions, autoimmunity and hypernitrosylation (Maes et al, 2018; 2019; 2022a; 2022b). As discussed in our limitations section, antidepressants have no effect on ROI, and furthermore, antidepressants have extremely detrimental effects on the immune system, causing increased vulnerability to injuries and stress (Maes et al, TBS).…”

Increased malondialdehyde and nitric oxide formation, lowered total radical trapping capacity coupled with psychological stressors largely predict the phenome of first-episode mild depression in undergraduate students

“…All inter-assay coefficients of variation were <10.0%). PON1 status was determined by AREase and CMPAase activity and PON1 Q192R genotypes in the present investigation (Brinholi et al, 2023;Maes et al, 2022;Matsumoto et al, 2021;Moreira et al, 2017;. We investigated the rate of phenylacetate hydrolysis at low salt concentration by measuring the activity of AREase and CMPAase (Sigma, St. Louis, MO, USA) ( (Brinholi et al, 2023;Maes et al, 2022;Matsumoto et al, 2021;Moreira et al, 2017;.…”