Childhood Trauma Clusters, Klotho, Matrix Metalloproteinase-9, and Cognitive Function in Adolescents with Major Affective Disorders

Introduction: Childhood trauma is common among adolescents with major affective disorders (MADs), including bipolar disorder and major depressive disorder. The relationships between childhood trauma subtypes, cognitive function, and the anti-aging protein Klotho and matrix metalloproteinase-9 (MMP-9) in adolescents with MADs remain unknown. Methods: We enrolled 95 adolescents with MADs (48 bipolar disorder, 47 major depressive disorder) and 45 healthy controls. Childhood trauma was assessed using the Childhood Trauma Questionnaire-Short Form. A k-means cluster analysis identified trauma-based subgroups among patients. Serum Klotho and MMP-9 levels and cognitive functions (working memory, Wisconsin Card Sorting Test, and Go/No-Go task) were assessed. Group differences were examined using generalized linear models adjusting for demographic variables, clinical symptoms, and medication use. Results: Three trauma clusters were identified: low trauma (n = 40), emotional neglect (EN)-focused (n = 47), and multi-trauma (n = 8) groups. The EN-focused group exhibited significantly lower Klotho levels than healthy controls and higher MMP-9 levels than all other groups. Cognitively, the EN-focused group showed reduced working memory accuracy and more trials to complete the first category on the Wisconsin Card Sorting Test, whereas the multi-trauma group demonstrated increased working memory errors and reduced Go/No-Go accuracy. Conclusion: Adolescents with EN-focused trauma displayed a distinct biological-cognitive profile characterized by lower serum Klotho, higher MMP-9, and executive dysfunction. These findings suggest that deprivation-related adversity may be associated with convergent Klotho-MMP-9 alterations and neurobiological vulnerability in MADs. Longitudinal studies are warranted to clarify causal mechanisms.