In vivo microstructural heterogeneity of white matter and cognitive correlates in aging using tissue compositional analysis of diffusion magnetic resonance imaging

Abstract Background Age‐related cognitive decline is linked to changes in the brain, particularly the deterioration of white matter (WM) microstructure that accelerates after the age of 60. WM deterioration is associated with mild cognitive impairment and dementia, but the origin and role of white matter signal abnormalities (WMSA) seen in standard MRI remain debated due to their heterogeneity. This study explores the potential of single‐shell 3‐tissue constrained spherical deconvolution (SS3T‐CSD), a novel technique that models diffusion data in terms of gray matter (T G ), white matter (T w ), and cerebrospinal fluid (T C ), to differentiate WMSA from normal‐appearing white matter and better understand the interplay between changes in WM microstructure and decline in cognition. Methods A total of 189 individuals from the GENIC cohort were included. MRI data, including T1‐weighted and diffusion images, were obtained. Preprocessing steps were performed on the diffusion MRI data, followed by the SS3T‐CSD. WMSA were segmented using FreeSurfer. Statistical analyses were conducted to assess the association between age, WMSA volume, 3‐tissue signal fractions (T w , T G , and T C ), and neuropsychological variables. Results Participants above 60 years old showed worse cognitive performance and processing speed compared to those below 60 ( p < .001). Age was negatively associated with T w in normal‐appearing white matter ( p < .001) and positively associated with T G in both WMSA ( p < .01) and normal‐appearing white matter ( p < .001). Age was also significantly associated with WMSA volume ( p < .001). Higher processing speed was associated with lower T w and higher T G , in normal‐appearing white matter ( p < .01 and p < .001, respectively), as well as increased WMSA volume ( p < .001). Similarly, lower MMSE scores correlated with lower T w and higher T G in normal‐appearing white matter ( p < .05). High cholesterol and hypertension were associated with higher WMSA volume ( p < .05). Conclusion The microstructural heterogeneity within normal‐appearing white matter and WMSA is associated with increasing age and cognitive variation, in cognitively unimpaired individuals. Furthermore, the 3‐tissue signal fractions are more specific to potential white matter alterations than conventional MRI measures such as WMSA volume. These findings also support the view that the WMSA volumes may be more influenced by vascular risk factors than the 3‐tissue metrics. Finally, the 3‐tissue metrics were able to capture associations with cognitive tests and therefore capable of capturing subtle pathological changes in the brain in individuals who are still within the normal range of cognitive performance.