Age-Related Modifications of Diffusion Tensor Imaging Parameters and White Matter Hyperintensities as Inter-Dependent Processes

Abstract

Microstructural changes of White Matter (WM) associated with aging have been widely described through Diffusion Tensor Imaging (DTI) parameters. In parallel, White Matter Hyperintensities (WMH) as observed on a T2-weighted MRI are extremely common in older individuals. However, few studies have investigated both phenomena conjointly. The present study investigates aging effects on DTI parameters in absence and in presence of WMH. Diffusion maps were constructed based on 21 directions DTI scans of young adults (n = 19, mean age = 33 SD = 7.4) and two age-matched groups of older adults, one presenting low-level-WMH (n = 20, mean age = 78, SD = 3.2) and one presenting high-level-WMH (n = 20, mean age = 79, SD = 5.4). Older subjects with low-level-WMH presented modifications of DTI parameters in comparison to younger subjects, fitting with the DTI pattern classically described in aging, i.e., Fractional Anisotropy (FA) decrease/Radial Diffusivity (RD) increase. Furthermore, older subjects with high-level-WMH showed higher DTI modifications in Normal Appearing White Matter (NAWM) in comparison to those with low-level-WMH. Finally, in older subjects with high-level-WMH, FA, and RD values of NAWM were associated with to WMH burden. Therefore, our findings suggest that DTI modifications and the presence of WMH would be two inter-dependent processes but occurring within different temporal windows. DTI changes would reflect the early phase of white matter changes and WMH would appear as a consequence of those changes.

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

“…In accordance, recent tractography studies have shown that cingulum tract crossing WMH compared to tract not crossing showed changes in the diffusion measures, in particular increase of RD (Reginold et al, 2016), and suggested that these modifications could extend beyond the lesion to the unaffected portion by the WMHs (Maillard et al, 2014;Promjunyakul et al, 2016;Reginold et al, 2018). Moreover, previous DTI studies reported that WMH were associated with white matter microstructure modifications occurring in the normal-appearing white matter (Leritz et al, 2014;Maillard et al, 2014;Pelletier et al, 2015;Promjunyakul et al, 2016), indicating that individuals with higher WMH burden were more susceptible to present lower FA (Birdsill et al, 2014;Sala et al, 2012;Svärd et al, 2017) and higher diffusion metrics (Iverson et al, 2011;Lange et al, 2014;Pelletier et al, 2015;Svärd et al, 2017). Taken together these results suggest that small focal WMH burden have local and distal effects large enough to affect the white matter diffusion properties on the whole cingulum tract and as a result can impact cognition.…”

“…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).…”

“…Recently, WMHs were associated with changes in white matter composition, indicative of altered water content in white matter fibers (Alber et al, 2019;Ji et al, 2017). Moreover, several recent studies investigating the relationship between WMH and DTI parameters estimate that WMH constitute the ending stage of an histopathological continuum (Maillard et al, 2011;William Reginold et al, 2018), with modifications of DTI parameters in normal appearing white matter may represent the early stage (Maillard et al, 2014;Maniega et al, 2015;Pelletier et al, 2015). Furthermore, tractography studies in aging (Jiang et al, 2018;William Reginold et al, 2018) and in patients with gliomas (Leote, Nunes, Cerqueira, Loução, & Ferreira, 2018) showed a detrimental effect of WMH on fiber tracking algorithms.…”

Statins and Brain Health: Alzheimer’s Disease and Cerebrovascular Disease Biomarkers in Older Adults

“…WMHs, representing a later consequence of the effects of cerebrovascular disease on white matter [24, 25], were segmented from FLAIR images as described previously [34, 35] and were normalized to yield a percentage of total intracranial white matter volume.…”

“…Important neuroimaging biomarkers relevant for cognitive aging research in the general population are reflected in the Amyloid (A)/Tau (T)/Neurodegeneration (N) classification scheme [18, 19], and include measures of amyloid deposition via amyloid positron emission tomography (PET), tau pathology via tau PET, and neurodegeneration via FDG PET and structural magnetic resonance imaging (MRI). In addition, cerebrovascular disease is a well-established independent contributor to neurodegeneration and clinical decline in older adults [20–22], and MRI biomarkers with particular focus on white matter changes can be useful for assessing these changes [23–25]. Therapies to alter these biomarkers of brain health represent crucial potential avenues toward the ultimate goal of modifying the risk and progression of cognitive impairment in aging and dementia.…”