Abstract
Cerebral small vessel disease (CSVD) is a common cause of morbidity and cognitive decline in the elderly population. However, characterizing the disease pathophysiology and its association with potential clinical sequelae in early stages is less well explored. We applied fixel-based analysis (FBA), a novel framework of investigating microstructural white matter integrity by diffusion-weighted imaging, to data of 921 participants of the Hamburg City Health Study, comprising middle-aged individuals with increased cerebrovascular risk in early stages of CSVD. In individuals in the highest quartile of white matter hyperintensity loads (n = 232, median age 63 years; IQR 15.3 years), FBA detected significantly reduced axonal density and increased atrophy of transcallosal fiber tracts, the bilateral superior longitudinal fasciculus, and corticospinal tracts compared to participants in the lowest quartile of white matter hyperintensities (n = 228, mean age 55 years; IQR 10 years). Analysis of all participants (N = 921) demonstrated a significant association between reduced fiber density and worse executive functions operationalized by the Trail Making Test. Findings were confirmed by complementary analysis of diffusion tensor metrics.
Highlights
Cerebral small vessel disease (CSVD) is a common cause of morbidity and cognitive decline in the elderly population
Looking at regions with significantly differing fixel-based analysis (FBA)-metrics between participants with low and high extent of WMH, we identify specific white matter tracts that were preferentially affected: We found reduced fibre density (FD) in the corpus callosum, inferior and superior longitudinal fasciculus indicating a loss of diverse white matter fibre populations
As suggested by consistent results from all analyses, the corpus callosum appeared to be affected by fibre-specific axonal loss and atrophy. In accordance with these results, previous evidence and our own data by tensor imaging (DTI) analysis show significantly reduced fractional anisotropy (FA) and increased mean diffusivity (MD) in callosal regions accompanying CSVD, a pattern which is coherent with DTI metric alterations in WMH and surrounding N AWM4,63
Summary
Cerebral small vessel disease (CSVD) is a common cause of morbidity and cognitive decline in the elderly population. We applied fixel-based analysis (FBA), a novel framework of investigating microstructural white matter integrity by diffusion-weighted imaging, to data of 921 participants of the Hamburg City Health Study, comprising middle-aged individuals with increased cerebrovascular risk in early stages of CSVD. Conventional MRI approaches using T2-weighted sequences are insufficient to detect incipient changes of white matter integrity occurring at the microscopic level during the early stages of CSVD. Drawing its information solely from tissue water diffusion, modern DWI-based methods provide a manifold toolset for characterization of pathophysiological processes in neurological and psychiatric diseases: fibre tractography—i.e., the specific reconstruction of axonal trajectories from DWI information as streamlines—enables the approximation of the human brain network as a structural connectome. Structural connectomics demonstrated as insightful regarding the intricacies of the relationship between CSVD pathophysiology and symptoms[13,14]; analysis of DWI data by tensor imaging (DTI) is commonly applied to infer tissue status. Notwithstanding, traditional DTI-derived metrics such as FA and MD are limited by their relatively low specificity of detecting microstructural changes, in areas of complex fibre architecture present in the majority of white matter connections[17,18,19]
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