We report on white matter alterations assessed by FBA in a large population-based sample of individuals at risk of cerebrovascular disease and in early stages of CSVD. Our study has two main findings: first, higher extent of WMH was accompanied by changes of FBA metrics capturing white matter alterations on a microscopic and macroscopic level at the corpus callosum, superior longitudinal fasciculus and corticospinal tract, whereas DTI metrics showed a less specific and more general pattern of changes. Second, FBA and DTI metrics were associated with lower performance in the TMT indicating impaired frontal-executive cognitive functions. These results promote FBA metrics as a novel imaging marker of microstructural white matter alterations linked to clinical behavior in early stages of CSVD.
Conceptually, the application of FBA offers several advantages compared to DTI-based methods. The fibre tract-specific model provides measures more directly interpretable regarding disturbed structural connectivity as compared to voxel-average measures such as FA. FBA promotes statistical testing beyond the confinement of a white matter ‘skeleton’ of classical tract-based statistics, which can be limited by reduced detection accuracy compared to whole-brain analysis 43,44. Furthermore, FBA is helpful to guard against potential misleading findings in brain areas with complex crossing fibre architecture, that are known to result in erroneously unchanged or increased values of voxel-average DTI metrics such as FA as demonstrated recently in a comparative investigation of patients with Alzheimer’s disease 45,46.
In our population-based sample of individuals with an overall low amount of WMH (median WMH load in WMH-Q1 = 0.007%), we identified regions of reduced FD, indicating microstructural fibre-specific axonal loss, reduced FC, indicating macroscopic tract atrophy, and reduced FDC, indicating combined pathology of fiber-specific axonal loss and tract atrophy. Our findings complement the existing body of imaging-based and histopathological research shedding light on the microscopical structural changes induced by CSVD which are already present at an early stage of the disease, such as axonal loss, demyelination and gliosis in WMH 47,48. Compared to FBA metrics, changes of DTI metrics appeared in a less specific anatomical distribution indicating changes of white matter integrity throughout large sections of the white matter skeleton. These findings are in line with previous studies revealing an increased MD as well as a decreased FA in patients with CSVD 49–51. Lacking histopathological correlates for validation, we can only speculate on the differing results. In TBSS, false positives may be responsible for our findings, having been shown to arise from method-inherent issues like considerable noise dependency and projection inaccuracies in regions of crossing fibres 43. Similarly, false-negative findings by FBA have to be considered as a cause, potentially arising from the relatively low b-value (b = 1000mm/s²) leading to insufficient suppression of the extraaxonal compartment 52.
Looking at regions with significantly differing FBA-metrics between participants with low and high extent of WMH, we identify specific white matter tracts that were preferentially affected: We found reduced FD in the corpus callosum, inferior and superior longitudinal fasciculus indicating a loss of diverse white matter fibre populations. A reduced FC and FDC in the corpus callosum, corticospinal tract inferior and superior longitudinal fasciculus further indicated white matter atrophy in these tracts. As suggested by consistent results from all analyses, the corpus callosum specifically appeared to be affected by fibre-specific axonal loss and atrophy. In accordance with these results, previous evidence and our own DTI analysis show significantly reduced FA and increased MD in callosal regions accompanying CSVD, a pattern which is coherent with DTI metric alterations in WMH and surrounding NAWM 4,53.
The pronounced involvement of long-range white matter tracts such as the superior longitudinal fasciculus to chronic vascular injury in CSVD appears plausible due to their hemisphere-centric position which is the region of highest WMH frequency and fixel alterations in our analysis. The axons of these long fascicles are typically densely packed and of pronounced myelination which makes them a critical target of blood supply owing to their high metabolic maintenance costs 54. Their vulnerability may be caused by their distance from well-perfused pericortical areas rendering them reliant on the branches of small perforators. These small-caliber vessels, however, show critical pathology in CSVD and are therefore eponymous. Inter alia, they feature arteriolosclerosis, lipohyalinosis and fibrinoid necrosis which coincide with impaired blood-brain barrier function and vasoreactivity 55–58. Taken together, our findings match previous evidence in this sample showing disturbed structural connectivity preferentially in long-range fibre tracts in participants with higher CSVD burden 23. In summary, widespread white matter alterations can be detected even at an early disease stage. Since the progression of CSVD appears to be modifiable by pharmacological intervention and lifestyle changes – e.g., antihypertensive therapy and smoking cessation – early disease characterization might enable more effective disease management and thus prevention of symptom emergence 55.
Several imaging and histopathological studies have suggested that microstructural alterations in CSVD spread across lesions detectable in T2-images 48,49,51,59,60. On that basis, recent longitudinal evidence indicates that WMH are being preceded by subvisible alterations leading to the hypothesis that CSVD manifestations lie on an injury continuum with WMH marking regions of more advanced pathology 9,13,61,62. Our findings are in line with this conception. We found that tracts identified as affected by our tract of interest analysis – the corpus callosum, corticospinal tract, inferior longitudinal fasciculus and superior longitudinal fasciculus - exhibited higher amounts of WMH load in the tract-wise assessment. In the whole-brain FBA, FDC changes consistently overlapped with regions of frequent WMH appearance.
Impairment of frontal-executive cognitive functions is one of the main clinical characteristics of vascular cognitive impairment – conditions for which CSVD is regarded as a key cause 63. In our study, adjusted fixel- and voxel-wise linear models indicated an association between reduced FD (FBA) and increased MD (DTI) with longer processing times (determined by TMT-delta) in white matter tracts such as the superior longitudinal fasciculus, arcuate fasciculus and inferior longitudinal fasciculus. These findings are in line with the dependency of executive brain functions on large-scale brain networks integrating processes from remote brain regions 64. Therefore, our results would support the relevance of long-range fibres for integrating distinct brain functions distributed throughout the neuronal anatomy. Previous investigations demonstrated an association of the superior longitudinal fasciculus’ integrity as detected by DTI metrics and cognitive function in CSVD 54,55. We did not observe a statistically significant association between FA and TMT performance. A similar observation has been reported before 65.
This study has several additional limitations. Due to the cross-sectional study design, this work captures only a snapshot of disease characteristics. Therefore, there is considerable potential to elucidate the progression of white matter alteration utilizing a longitudinal fixel framework 66,67. When interpreting our results, it should be considered that we acquired diffusion-weighted images at a b-value of b = 1000 s/mm². Chosen as a compromise between a high signal-to-noise ratio and proper suppression of the extra-axonal compartment this is relatively low compared to what is recommended for quantifying fibre density 19. However, we note that FBA was able to generate pathophysiologically plausible results in our dataset. Also, the effects of lower b-values should be attenuated by the application of single-shell 3-tissue constrained spherical deconvolution during processing in our analysis.