Sex Differences in Cortical Morphology Across 21 Brain Disorders: a Mega-analysis of 44,000 Subjects
Poster No:
515
Submission Type:
Abstract Submission
Authors:
Ilan Libedinsky1, Marius Gruber2, Jonathan Repple2, Tilo Kircher3, Udo Dannlowski4, Martijn van den Heuvel1
Institutions:
1Vrije Universiteit Amsterdam, Amsterdam, North Holland, 2Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Hesse, 3Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Hesse, 4Institute for Translational Psychiatry, Münster, North Rhine-Westphalia
First Author:
Co-Author(s):
Marius Gruber
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt
Frankfurt, Hesse
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt
Frankfurt, Hesse
Jonathan Repple
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt
Frankfurt, Hesse
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt
Frankfurt, Hesse
Introduction:
Males and females often exhibit distinct clinical profiles in brain disorders (Pinares-Garcia et al., 2018). Neuroimaging studies have extensively examined brain alterations between patients and control populations, but less often is considered how these alterations converge or diverge between sexes (Cosgrove et al., 2007).
Methods:
Cortical thickness was extracted from T1-weighted MRI data collected for 21 brain disorders in 43,765 individuals: 19,743 patients (9,758 females, 9,985 males) and 24,022 controls (12,572 females, 11,450 males). The sample included 41 clinical MRI datasets and 4 large-scale datasets from the general population (e.g., UK Biobank, ABCD Study, Healthy Brain Network, Nathan Kline Institute-Rockland Sample). Disorders included 13 neuropsychiatric, neurodevelopmental, or behavioral conditions (anxiety-related disorders, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, disruptive behavior disorders, eating disorders, insomnia, major depressive disorder, obsessive-compulsive disorder, schizoaffective disorder, schizophrenia, stress-related disorders, and substance abuse disorder) and 8 neurological or neurodegenerative conditions (Alzheimer's disease, cerebrovascular accidents, epilepsy, frontotemporal dementia, migraine, mild cognitive impairment, multiple sclerosis, and Parkinson's disease).
Datasets were harmonized with ComBat (Reynolds et al., 2023), and cortical thickness values were adjusted for age, age2, and intracranial volume. Mega-analyses estimated case-control differences separately for each disorder and sex. P-values were calculated with Student's t-tests and adjusted for multiple comparisons across 219 brain regions using the false discovery rate (FDR). Equivalence testing (two one-sided t-tests [TOST]) (Schuirmann, 1987) assessed spatial similarity in brain alteration patterns between sexes, while permutation testing with shuffled sex labels identified sex-specific differences in patterns and severity (10,000 iterations).
Datasets were harmonized with ComBat (Reynolds et al., 2023), and cortical thickness values were adjusted for age, age2, and intracranial volume. Mega-analyses estimated case-control differences separately for each disorder and sex. P-values were calculated with Student's t-tests and adjusted for multiple comparisons across 219 brain regions using the false discovery rate (FDR). Equivalence testing (two one-sided t-tests [TOST]) (Schuirmann, 1987) assessed spatial similarity in brain alteration patterns between sexes, while permutation testing with shuffled sex labels identified sex-specific differences in patterns and severity (10,000 iterations).
Results:
Cortical thickness alterations were observed in male patients across 13 disorders ([min, max]: d = [-1.58, 0.37], pFDR < 0.05) and in female patients across 11 disorders (d = [-1.33, 0.32], pFDR < 0.05). The most extensive alterations occurred in male patients with schizophrenia (changes in 96% of cortical regions, all pFDR < 0.05) and frontotemporal dementia (88%), and in female patients with Alzheimer's disease (88%), and frontotemporal dementia (86%). Whole-brain patterns were similar between sexes in six disorders: frontotemporal dementia, insomnia, multiple sclerosis, Parkinson's disease, schizoaffective disorder, and schizophrenia (ptost < 0.05, delta = 0.05), indicating comparable disease patterns in males and females. In contrast, sex-divergent disease patterns were found in Alzheimer's disease (p = 7.6 x 10-5, permutation testing), mild cognitive impairment (p = 5.6 x 10-5), cerebrovascular accidents (p = 6 x 10-4), bipolar disorder (p = 5.9 x 10-3), disruptive behavior disorders (p = 4.1 x 10-3), major depressive disorder (p = 3.9 x 10-2), eating disorders (p = 4.4 x 10-2), and autism spectrum disorder (p = 4.7 x 10-2). Furthermore, females showed more pronounced alterations than males in specific regions, with significant sex differences observed in Alzheimer's disease (21% of cortical regions; all p < 0.05, permutation testing), mild cognitive impairment (14%), migraine (10%), and bipolar disorder (8%), while males exhibited more pronounced cortical alterations than females in cerebrovascular accidents (26%), attention-deficit/hyperactivity disorder (24%), disruptive behavior disorders (14%), and eating disorders (13%).
·Sex-stratified mega-analysis of patient-control differences in cortical thickness across 21 brain disorders based on 44,000 subjects
Conclusions:
We provide a comprehensive analysis of sex-specific and shared cortical alterations across brain disorders, highlighting differences in disease impact.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s)
Neurodevelopmental/ Early Life (eg. ADHD, autism)
Psychiatric (eg. Depression, Anxiety, Schizophrenia) 1
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Cortical Anatomy and Brain Mapping
Novel Imaging Acquisition Methods:
Anatomical MRI 2
Keywords:
Affective Disorders
Attention Deficit Disorder
Autism
Cortex
Degenerative Disease
MRI
Neurological
Psychiatric Disorders
Schizophrenia
Other - sex differences
1|2Indicates the priority used for review
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Were any human subjects research approved by the relevant Institutional Review Board or ethics panel? NOTE: Any human subjects studies without IRB approval will be automatically rejected.
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Provide references using APA citation style.
Pinares-Garcia, P., Stratikopoulos, M., Zagato, A., Loke, H., & Lee, J. (2018). Sex: A Significant Risk Factor for Neurodevelopmental and Neurodegenerative Disorders. Brain Sciences, 8(8), 154. https://doi.org/10.3390/brainsci8080154
Reynolds, M., Chaudhary, T., Eshaghzadeh Torbati, M., Tudorascu, D. L., & Batmanghelich, K. (2023). ComBat Harmonization: Empirical Bayes versus fully Bayes approaches. NeuroImage: Clinical, 39, 103472. https://doi.org/10.1016/j.nicl.2023.103472
Schuirmann, D. J. (1987). A comparison of the Two One-Sided Tests Procedure and the Power Approach for assessing the equivalence of average bioavailability. Journal of Pharmacokinetics and Biopharmaceutics, 15(6), 657–680. https://doi.org/10.1007/BF01068419