Changes in the intracranial volume from early adulthood to the sixth decade of life: A longitudinal study

Abstract

<jats:title>Abstract</jats:title><jats:p>Normal brain-aging occurs at all structural levels. Excessive pathophysiological changes in the brain, beyond the normal one, are implicated in the etiology of brain disorders such as severe forms of the schizophrenia spectrum and dementia. To account for brain-aging in health and disease, it is critical to study the age-dependent trajectories of brain biomarkers at various levels and among different age groups.</jats:p><jats:p>The intracranial volume (ICV) is a key biological marker, and changes in the ICV during the lifespan can teach us about the biology of development, aging, and gene X environment interactions. However, whether ICV changes with age in adulthood is not resolved.</jats:p><jats:p>Applying a semi-automatic in-house-built algorithm for ICV extraction on T1w MR brain scans in the Dutch longitudinal cohort (GROUP), we measured ICV changes. Individuals between the ages of 16 and 55 years were scanned up to three consecutive times with 3.32±0.32 years between consecutive scans (N=482, 359, 302). Using the extracted ICVs, we calculated ICV longitudinal aging-trajectories based on three analysis methods; direct calculation of ICV differences between the first and the last scan, fitting all ICV measurements of individuals to a straight line and applying a global linear mixed model fitting. We report statistically significant increases in the ICV in adulthood until the fourth decade of life (average change +0.03%/y, or about 0.5 ml/y, at age 20), and decreases in the ICV afterward (−0.09%/y, or about −1.2 ml/y, at age 55). To account for previous cross-sectional reports of ICV changes, we analyzed the same data using a cross-sectional approach. Our cross-sectional analysis detected ICV changes consistent with the previously reported cross-sectional effect. However, the reported amount of cross-sectional changes within this age range was significantly larger than the longitudinal changes. We attribute the cross-sectional results to a generational effect.</jats:p><jats:p>In conclusion, the human intracranial volume does not stay constant during adulthood but instead shows a small increase during young adulthood and a decrease thereafter from the fourth decade of life. The age-related changes in the longitudinal setup are smaller than those reported using cross-sectional approaches and unlikely to affect structural brain imaging studies correcting for intracranial volume considerably. As to the possible mechanisms involved, this awaits further study, although thickening of the meninges and skull bones have been proposed, as well as a smaller amount of brain fluids addition above the overall loss of brain tissue.</jats:p>

Proportional intracranial volume correction differentially biases behavioral predictions across neuroanatomical features and populations

“…More recent studies have confirmed greater ICV in males as well as changes in ICV throughout the lifespan (Caspi et al 2020; Mills et al 2016). ICV shows significant increases throughout childhood and adolescence (Mills et al 2016; Dong, Castellanos, et al 2020), followed by gradual increases in early adulthood until the fourth decade of life after which it begins to decrease (Caspi et al 2020). These changes in ICV parallel shifts in cortical expansion (Hill et al 2010), myelination (Grydeland et al 2019), structure-function coupling (Baum et al 2020), and functional maturation of association networks (Dong, Margulies, et al 2020) throughout the lifespan (Sydnor et al 2021).…”

“…The volume of the cranium, typically referred to as intracranial volume (ICV) or estimated total intracranial volume, was historically thought to increase during development and remain stable throughout adulthood (Matsumae et al 1996), with larger volumes in males than in females throughout the lifespan (De Bellis et al 2001; Cosgrove, Mazure, and Staley 2007). More recent studies have confirmed greater ICV in males as well as changes in ICV throughout the lifespan (Caspi et al 2020; Mills et al 2016). ICV shows significant increases throughout childhood and adolescence (Mills et al 2016; Dong, Castellanos, et al 2020), followed by gradual increases in early adulthood until the fourth decade of life after which it begins to decrease (Caspi et al 2020).…”

“…There are marked differences in head size between individuals, presenting a challenge for the measurement of regional volumes and surface areas. Established differences in gray matter volume and ICV between the sexes and throughout the lifespan (Caspi et al 2020; De Bellis et al 2001; Bethlehem et al 2021) have led to widespread implementations of ICV correction when studying brain-behavior relationships across populations. In this present work, we described how proportional ICV correction influences accuracy of behavioral predictions within a population, generalizability of the predictions across populations, and interpretations of the underlying brain-behavior relationships.…”

“…These changes in ICV parallel shifts in cortical expansion (Hill et al 2010), myelination (Grydeland et al 2019), structure-function coupling (Baum et al 2020), and functional maturation of association networks (Dong, Margulies, et al 2020) throughout the lifespan (Sydnor et al 2021). Across development, males exhibit larger ICV relative to females, along with a steeper rate of change during childhood and adolescence, as well as higher reduction rates after the fifth decade of life (Caspi et al 2020). When investigating neuroanatomical properties (and their relationships to behavior) across the sexes and in different age groups, it is standard to correct for variations in ICV (Pintzka et al 2015; Buckner et al 2004), as corrected properties are assumed to be more valid than uncorrected measures (Sanfilipo et al 2004), providing regional anatomical estimates unbiased by global shifts in head size across the population.…”

“…Although these data suggest ICV correction can influence both the results and their subsequent interpretation, it remains to be established whether these effects are consistent between sexes. Moreover, given the unique trajectories of ICV and regional neuroanatomy during development and adulthood (Caspi et al 2020; Voevodskaya et al 2014), it is likely that ICV correction will have differential effects across the lifespan.…”