Re-examining age-related differences in white matter microstructure with free-water corrected diffusion tensor imaging

Abstract

Diffusion tensor imaging (DTI) has been used extensively to investigate white matter (WM) microstructural changes during healthy adult aging. However, WM fibers are known to shrink throughout the lifespan, leading to larger interstitial spaces with age. This could allow more extracellular free water molecules to bias DTI metrics, which are relied upon to provide WM microstructural information. Using a cohort of 212 participants, we demonstrate that WM microstructural changes in aging are potentially less pronounced than previously reported once the free water compartment is eliminated. After free water elimination, DTI parameters show age-related differences that match histological evidence of myelin degradation and debris accumulation. The fraction of free water is further shown to associate better with age than any of the conventional DTI parameters. Our findings suggest that DTI analyses involving free water are likely to yield novel insight into retrospective re-analysis of data and to answer new questions in ongoing DTI studies of brain aging.

Diffusion MRI free water is a sensitive marker of age-related changes in the cingulum

“…Moreover, this non-zero value of free water suggests that despite its distance from the ventricles there is an accumulation of free water in the extracellular space within the cingulum bundle. This is consistent with recent studies reporting a fraction of free water on whole white matter in the elderly (Albi et al, 2017;Chad et al, 2018;Papadaki et al, 2019). In addition, in our subjects no association between free water fraction within cingulum and CSF volumes was found (data not shown), while a negative association between free water fraction and cingulum volume was observed (i.e.…”

“…In accordance with recent findings in young (Sepehrband et al, 2019), older adults (Chad et al, 2018) and clinical samples (Bergamino, Pasternak, Farmer, Shenton, & Paul Hamilton, 2016;Ji et al, 2017), FWcorrection was associated with an increase in FA, and a decrease in diffusion metrics (MD, RD and AD) in both groups. These changes of DTI metrics after elimination of the free water compartment suggested not only a nonzero volume of the extracellular water (Hoy, Kecskemeti, & Alexander, 2015;Ji et al, 2017;Madden et al, 2012;Pasternak et al, 2009), but also indicate that white matter microstructural changes were less pronounced than previously suggested by conventional DTI metrics (Bennett & Madden, 2014;Bennett et al, 2017;Lockhart & DeCarli, 2014;Pelletier et al, 2015).…”

“…Ji and colleagues showed in sample of 85 subjects with Alzheimer's Disease or vascular dementia that high free water fraction was associated with the symptom severity (Clinical Dementia Rating) and poor cognitive performance (Ji et al, 2017). Together, these results and ours support the idea that beyond the elimination of CSF contamination, free water would provide additional structural information as an index of physiological tissue changes within the white matter (Chad et al, 2018;Hoy et al, 2015Hoy et al, , 2017. However, the underlying microcellular events associated to this index is far from being fully understood; its increase could be related to different pathophysiological processes such as microvascular degeneration (Ji et al, 2017;Rydhög et al, 2017), reduction in myelin content (Oestreich et al, 2016;Papadaki et al, 2019) or modulation of the permeability of the blood-brain barrier .…”

“…It has been shown that elimination of extracellular free water contamination improves the sensitivity and specificity of most measures derived from conventional DTI (Albi et al, 2017;Salminen et al, 2016;Sepehrband et al, 2019). Although this correction techniques exist and have been used in pathological conditions (Bergamino, Kuplicki, Victor, Cha, & Paulus, 2017;Dumont et al, 2019;Ji et al, 2017;Ofori et al, 2017;Tanner et al, 2019) to date the majority of diffusion MRI studies do not consider free water effects on heathy aging brain (Albi et al, 2017;Chad, Pasternak, Salat, & Chen, 2018). Moreover, while FWE was initially developed to correct DTI derived metrics, it has recently been shown that the extracellular free water fraction may be a sensitive marker of age-related microstructural changes (Chad et al, 2018).…”

“…Although this correction techniques exist and have been used in pathological conditions (Bergamino, Kuplicki, Victor, Cha, & Paulus, 2017;Dumont et al, 2019;Ji et al, 2017;Ofori et al, 2017;Tanner et al, 2019) to date the majority of diffusion MRI studies do not consider free water effects on heathy aging brain (Albi et al, 2017;Chad, Pasternak, Salat, & Chen, 2018). Moreover, while FWE was initially developed to correct DTI derived metrics, it has recently been shown that the extracellular free water fraction may be a sensitive marker of age-related microstructural changes (Chad et al, 2018). Indeed, aging is associated with grey and white matter tissue loss, and the resulting enlargement of interstitial space can lead to increase in free water (unhindered) (Aboitiz, Rodriguez, Olivares, & Zaidel, 1996;Barkhof, Fox, Bastos-Leite, & Scheltens, 2011;Meier-Ruge, Ulrich, Brühlmann, & Meier, 1992;Tang, Nyengaard, Pakkenberg, & Gundersen, 1997).…”