Tract Specific White Matter Lesion Load Affects White Matter Microstructure and Their Relationships With Functional Connectivity and Cognitive Decline

Abstract

White matter hyperintensities (WMHs) are associated with cognitive decline. Assessing the effect of WMH on WM microstructural changes and its relationships with structural and functional connectivity to multiple cognitive domains are helpful to better understand the pathophysiological processes of cognitive impairment. 65 participants (49 normal and 16 MCI subjects, age: 67.4 ± 8.3 years, 44 females) were studied at 3T. The WMHs and fifty fiber tracts were automatically segmented from the T1/T2-weighted images and diffusion-weighted images, respectively. Tract-profiles of WMH were compared with those of apparent fiber density (AFD). The relationship between AFD and tract connectivity (TC) was assessed. Functional connectivity (FC) between tract ends obtained from resting-state functional MRI was examined in relation to TC. Tract-specific relationships of WMH, TC and FC with a multi-domain neuropsychological test battery and Montreal Cognitive Assessment (MoCA) were also separately assessed by lasso linear regression. Indirect pathways of TC and FC between WMH and multiple cognitive measures were tested using the mediation analysis. Higher WMH loads in WM tracts were locally matched with the reduced AFD, which was related to decrease in TC. However, no direct relationship was found between TC and FC. Tract-specific changes on WMH, TC and FC for each cognitive performance may explain that macro- and microstructural and functional changes are associated differently with each cognitive domain in a fiber specific manner. In these identified tracts, the differences between normal and MCI for WMH and TC were increased, and the relationships of WMH, TC and FC with cognitive outcomes were more significant, compared to the results from all tracts. Indirect pathways of two-step (TC-FC) between WMH and all cognitive domains were significant (p < 0.0083 with Bonferroni correction), while the separated indirect pathways through TC and through FC were different depending on cognitive domain. Deterioration in specific cognitive domains may be affected by alterations in a set of different tracts that are differently associated with macrostructural, microstructural, and function changes. Thus, assessments of WMH and its associated changes on specific tracts help for better understanding of the interrelationships of multiple changes in cognitive impairment.

High‐frequency longitudinal white matter diffusion‐ and myelin‐based MRI database: Reliability and variability

“…This suggests that along-bundle profiling could help to reliably highlight more subtle changes such as the presence of a white matter lesion, which may impact one or more parts of the bundle without affecting the whole bundle. This is supported by a recent study which shows that AFD profiles are affected by the presence of a lesion and are significantly different at the location of WMH in fronto-pontine tracts bundle in mild-cognitive impairment subjects with high WM lesion load (Kim et al, 2022).…”

High-frequency longitudinal white matter diffusion- & myelin-based MRI database: reliability and variability

“…This suggests that along-bundle profiling could help to reliably highlight more subtle changes such as the presence of a white matter lesion, which may impact one or more parts of the bundle without affecting the whole bundle. This is supported by a recent study which shows that AFD profiles are affected by the presence of a lesion and are significantly different at the location of WMH in fronto-pontine tracts bundle in mild-cognitive impairment subjects with high WM lesion load (T. Kim et al, 2022).…”

White matter hyperintensities in Burning Mouth Syndrome assessed according to the Age-Related White Matter Changes scale

“…Structural imaging based on MRI of the brain is a mainstay in the clinical assessment and differential diagnosis of patients with suspected neurological diseases such as AD and VaD ( Moon et al, 2017 ; Kim et al, 2022 ). It can also be effective to exclude neurodegenerative disorders in younger patients with BMS ( Zhang and Meng, 2015 ; Di Stefano et al, 2019 ).…”

“…The role of WMHs in patients with chronic pain is still debated ( Buckalew et al, 2013 ; Binnekade et al, 2019 ). However, they may potentially reflect macrostructural white matter damage, also influencing interconnections among multiple regions of the brain, mainly from the cortical to subcortical areas, which in turn may affect the descending pathway of the modulatory system of pain, playing a significant role in the amplification and processing of the pain ( Wozniak and Lim, 2006 ; Kim et al, 2022 ).…”