Stress as a mediator of brain alterations in attention-deficit hyperactivity disorder: A systematic review.

OBJECTIVE: Stress is a known risk factor for numerous psychopathologies, whereas evidence is lacking regarding the specific consequences of stress on the neural basis of attention-deficit hyperactivity disorder (ADHD). A systematic literature review was thus conducted to clarify the role of stress in the association between the resulting alterations of brain structure, connectivity, and function in ADHD. METHODS: The study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under identifier CRD42023379809. A systematic search of the PubMed and CINAHL databases was conducted for articles published prior to December 22nd, 2022. Retrieved literature was screened in Rayyan and data extraction was performed with respect to neuroimaging, stress exposure, and ADHD outcomes. The Quality in Prognosis Studies (QUIPS) tool was adapted based on the Conducting Systematic Reviews and Meta-Analyses of Observational Studies of Etiology (COSMOS-E) guidance article to assess risk of bias and quality of studies. Strength of the evidence was assessed under the guidance of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. RESULTS: Screening 25,026 non-duplicate articles yielded 20 eligible studies for inclusion. Exposure to early life trauma, institutionalization, prenatal smoking or alcohol consumption, air pollution, low socioeconomic status, or low birth weight were associated with alterations in brain structure, function, and connectivity in ADHD. However, most studies did not provide strong evidence due to small sample sizes and lack of statistical approaches to determine a direct mediation of the association between stress and ADHD by neural outcomes. CONCLUSION: This systematic review was the first to summarize evidence of structural and functional stress-associated alterations in the brain, which were found to be directly and indirectly associated with ADHD outcomes. Overall, stress requires consideration as a significant determinant of neurodevelopmental outcomes in ADHD. However, extensive further research is warranted due to little available evidence and the difficulty of obtaining clear results. In light of such a complex research question, in order to confirm findings, provide further evidence, and establish causality systematic longitudinal studies would be required. Investigating the topic may provide invaluable information when it comes to tailoring prevention and treatment strategies in ADHD, and should be pursued in order to integrate the factor of stress into a more comprehensive understanding of ADHD.

Polygenic risk for Alzheimer's disease is associated with neuroaxonal damage before onset of clinical symptoms.

INTRODUCTION: Establishing valid diagnostic strategies is a precondition for successful therapeutic intervention in Alzheimer's disease (AD). METHODS: One hundred forty-four healthy 75-year-old participants from the Vienna-Transdanube-Aging longitudinal cohort study were tested for neuroaxonal damage by single molecular array (Simoa) plasma neurofilament light chain (NfL) levels at baseline, 30, 60, and 90 months, and onset of AD dementia. Individual risk for sporadic AD was estimated by continuous shrinkage polygenic risk score (PRS-CS, genome-wide association study). RESULTS: Nineteen participants developed AD after a median of 60 months (interquartile range 30). In participants with AD, baseline NfL plasma levels correlated with PRS-CS (r = 0.75, p < 0.001; difference to controls: Fisher's r-to-z: z = 3.89, p < 0.001). PRS-CS combined with baseline plasma NfL predicted onset of AD (p < 0.01). DISCUSSION: Our data suggest that polygenic risk for AD and plasma NfL closely interact years before onset of clinical symptoms. Peripheral NfL may serve as a diagnostic measure supporting early therapeutic intervention and secondary prevention in AD.

Genetic susceptibility to schizophrenia through neuroinflammatory pathways is associated with retinal thinning: Findings from the UK-Biobank.

The human retina is part of the central nervous system and can be easily and non-invasively imaged with optical coherence tomography. While imaging the retina may provide insights on central nervous system-related disorders such as schizophrenia, a typical challenge are confounders often present in schizophrenia which may negatively impact retinal health. Here, we therefore aimed to investigate retinal changes in the context of common genetic variations conveying a risk of schizophrenia as measured by polygenic risk scores. We used population data from the UK Biobank, including White British and Irish individuals without diagnosed schizophrenia, and estimated a polygenic risk score for schizophrenia based on the newest genome-wide association study (PGC release 2022). We hypothesized that greater genetic susceptibility to schizophrenia is associated with retinal thinning, especially within the macula. To gain additional mechanistic insights, we conducted pathway-specific polygenic risk score associations analyses, focusing on gene pathways that are related to schizophrenia. Of 65484 individuals recruited, 48208 participants with available matching imaging-genetic data were included in the analysis of whom 22427 (53.48%) were female and 25781 (46.52%) were male. Our robust principal component regression results showed that polygenic risk scores for schizophrenia were associated with retinal thinning while controlling for confounding factors (b = -0.03, p = 0.007, pFWER = 0.01). Similarly, we found that polygenic risk for schizophrenia specific to neuroinflammation gene sets revealed significant associations with retinal thinning (b = -0.03, self-contained p = 0.041 (reflecting the level of association), competitive p = 0.05 (reflecting the level of enrichment)). These results go beyond previous studies suggesting a relationship between manifested schizophrenia and retinal phenotypes. They indicate that the retina is a mirror reflecting the genetic complexities of schizophrenia and that alterations observed in the retina of individuals with schizophrenia may be connected to an inherent genetic predisposition to neurodegenerative aspects of the condition. These associations also suggest the potential involvement of the neuroinflammatory pathway, with indications of genetic overlap with specific retinal phenotypes. The findings further indicate that this gene pathway in individuals with a high polygenic risk for schizophrenia could contribute through acute-phase proteins to structural changes in the retina.