Sex is a defining feature of neuroimaging phenotypes in major brain disorders

Abstract

Sex differences are found in the incidence and expression of psychiatric and neurodegenerative conditions, and many studies suggest these differences are influenced by innate biological differences between males and females and risk factors that interact with these differences. However, few studies have used neuroimaging to examine brain signatures of disease separately by sex, and many studies of sex differences have been based on small samples and their findings have not been replicated in larger cohorts. Large-scale neuroimaging initiatives such as the Enhancing NeuroImaging Genetics through Meta-Analyses (ENIGMA) consortium, the UK Biobank, Human Connectome Project, and others offer an unprecedented source of power to address important questions about the role of sex as a risk or protective factor for suboptimal brain health, as well as sex-specific neuroimaging phenotypes in brain-related illnesses. Here we review the existing neuroimaging literature on sex differences in the human brain in healthy adults and those with the most common and debilitating psychiatric and age-related neurodegenerative conditions. Finally, we discuss key gaps in this literature and opportunities of large-scale collaborative efforts to identify, characterize, and explain how biological sex influences the humanbrain in health and disease.

Age and Sex Effects on Advanced White Matter Microstructure Measures in 15,628 Older Adults: A UK Biobank Study

“…Sex differences in other white matter microstructure characteristics – including measures reflecting diffusivity, neurite density, free water, and restriction – depended to a greater extent on the exact region and metric examined. These findings are largely consistent with previous analyses which used DTI or NODDI to assess white matter sex difference (Cox et al, 2016; Jahanshad & Thompson, 2017; Ritchie et al, 2018; Salminen et al, 2020; Toschi et al, 2020); such prior analyses likewise found that males exhibit higher anisotropy and lower fiber dispersion than females, with other microstructure metrics displaying greater variability in their pattern of sex differences. In the current study, we also observed significant sex differences in age effects for a number of regions and microstructure metrics in our cross-sectional sample.…”

“…Our findings expand on this prior work indicating sex differences in age effects among middleaged to older adults. Importantly, a range of neurodegenerative conditions exhibit sex differences in their prevalence and presentation, emphasizing the importance of understanding differences in neural aging between men and women (Salminen et al, 2020).…”

“…Their results further supported the association between age and white matter decline, in addition to indicating a sex difference in the overall number of white matter tracts that exhibited age-related declines in anisotropy (Tseng et al, 2020). Such prior dMRI work robustly demonstrates that multiple aspects of white matter microstructure are significantly associated with participant age and sex (Beck et al, 2020; Cox et al, 2016; Damoiseaux, 2017; Jahanshad & Thompson, 2017; Ritchie et al, 2018; Salminen et al, 2020; Toschi et al, 2020; Tseng et al, 2020; Zavaliangos-Petropulu et al, 2019). However, it remains an open question how age, sex, and their interaction may be related to additional measures of white matter microstructure obtained from other advanced dMRI models such as TDF and MAPMRI, as well as how age effects on microstructure may manifest in middle to late adulthood when using more complex, data-driven statistical approaches for modeling age.…”

“…Previous dMRI studies examining age and sex effects have reported age-related white matter decline and significant sex differences in white matter microstructure (Beck et al, 2020; Cox et al, 2016; Damoiseaux, 2017; Jahanshad & Thompson, 2017; Ritchie et al, 2018; L.E. Salminen et al, 2020; Toschi et al, 2020; Tseng et al, 2020; Zavaliangos-Petropulu et al, 2019). In one of the largest studies to date that investigated age and sex associations with white matter microstructure adults, Cox et al (2016) examined two DTI metrics (fractional anisotropy, FA; mean diffusivity, MD) and three NODDI metrics (orientation dispersion, OD; intra-cellular volume fraction, ICVF; isotropic volume fraction, ISOVF) in 3,513 middle-aged and older subjects from the UK Biobank for a range of white matter tracts across the brain; age was modeled using a linear or quadratic fit, based on the best fit for each tract and metric.…”

“…White matter alterations have been linked to age-related cognitive decline and implicated in neurodegenerative diseases such as Alzheimer’s disease (Bennett & Madden, 2014; Pievani, Filippini, van den Heuvel, Cappa, & Frisoni, 2014). A range of age-associated neurodegenerative diseases also exhibit sex differences in their prevalence and presentation and, similar to age, sex has also been associated with white matter differences (Cox et al, 2016; Jahanshad & Thompson, 2017; Ritchie et al, 2018; Salminen, Tubi, Bright, & Thompson, 2020; Toschi, Gisbert, Passamonti, Canals, & De Santis, 2020). Understanding the brain’s white matter may substantially improve our understanding of aging and sex differences therein, including ultimately the genetic and environmental factors that may influence healthy or diseased aging.…”