Introduction Cerebral small vessel disease (CSVD) encompasses several diseases affecting the small arteries, arterioles, venules, and capillaries of the brain and refers to several pathological processes and etiologies. Neuroimaging is considered the gold standard for detecting CSVD, which can present diverse features on MRI. Cerebral microbleeds (CMBs), one of the characteristic MRI features, are most easily observed in T2-weighted gradient-recalled echo (GRE) or susceptibility-weighted imaging (SWI) sequences, usually as round or ovoid small hypointense areas with associated blooms seen on GRE scans.¹ CMBs affect the total CSVD score, and have been demonstrated to play a synergistic role in both cerebrovascular and neurodegenerative pathology. Considering previous studies on brain structural abnormalities in CSVD, in the present study, we aimed to explore altered spontaneous brain activity among CSVD patients using amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF) and regional homogeneity (ReHo) methods based on resting-state functional MRI. The combination of the three approaches may provide more detailed information about intrinsic activity across the whole brain.
Methods In this study, we recruited 24 CSVD patients with CMBs (CSVD-c), 42 CSVD patients without CMBs (CSVD-n) and 36 healthy controls from outpatient clinics in Shandong Provincial Hospital affiliated with Shandong First Medical University between September 2018 and June 2019. All subjects underwent 3-T MRI, including three-dimensional T1-weighted (T1W), blood oxygen level-dependent (BOLD) and susceptibility-weighted imaging (SWI). Anatomic structures were segmented, ALFF/fALFF values were calculated, and ReHo maps were generated. Further statistical analysis was applied to study the difference in ALFF/fALFF/ReHo among the three groups and the association between ALFF/fALFF/ReHo changes in different brain regions and clinical characteristics.
Results Twenty-four CSVD-c patients (age: 67.54±6.00 years, 10 females), 42 CSVD-n patients (age: 66.33±5.25 years, 22 females) and 36 healthy subjects (age: 64.14±8.57 years, 19 females) were evaluated. The demographic and clinical characteristics of each group are summarized (Figure 1). Compared with controls, the CSVD-c group showed significantly increased ALFF values in the right insula, putamen and left precuneus; decreased fALFF values in the right precentral gyrus and postcentral gyrus; and increased ReHo values in the left precuneus, fusiform gyrus, right supplementary motor area, and superior frontal gyrus (Figure 2/3). No significant difference was found between the CSVD-n group and the control group. Notably, the mean ALFF values of the right insula and putamen were not only significantly related to all clinical parameters but also demonstrated the best performance in ROC curve analysis (Figure 4/5).
Discussion Only CSVD-c patients had apparent increased/decreased ALFF/fALFF/ReHo in different brain regions compared with controls and CSVD-n patients. A previous study suggested that leakage of the blood-brain barrier (BBB) is often considered to be the original mechanism of CSVD, which can lead to immune cell infiltration and inflammation and result in a variety of pathological processes.² As one of the manifestations of CSVD, there is a close relationship between microbleeding and vascular inflammation markers. The greater burden of CMBs is often accompanied by increased markers of vascular inflammation/endothelial dysfunction and systemic inflammation.³ All inflammatory markers were at higher levels in CMBs patients, and compared with CSVD-n patients, CSVD-c patients had more severe pathological changes.⁴ This also explains why the CSVD-c group showed elevated ALFF values compared with those of the CSVD-n group, and the changed area was similar to the changed area of the controls but slightly less. Therefore, compared with controls, only the ALFF/fALFF/ReHo values of CSVD-c patients changed significantly. CSVD-c patients showed increased ReHo in some regions compared with that of CSVD-n patients.
Compared with controls, CSVD-c patients showed increased ALFF in some regions that link with various neural pathways and networks to influence cognitive control processes, sensorimotor processing and affective processes, executive function in the CSVD-c group compared with controls.^5-8 Significantly decreased fALFF values were found in the right precentral gyrus and postcentral gyrus in CSVD-c patients compared with controls. The postcentral gyrus serves as a key region in the somatosensory network, participates in daily activities and governs the learning of early motor skills acquisition.^9,10 Therefore, CSVD-c patients may experience reduced motor learning ability compared to the control group. Brain regions with increased ReHo values are associated with facial recognition, resting-state regulation, working memory compared with controls/CSVD-n patients.^11-17 Therefore, changes in the ALFF/fALFF/ReHo value of these areas impair related cognitive function parameters.
Conclusion In the current study, we investigated the possible pathogenesis of CSVD by analyzing resting-state spontaneous brain activity based on ALFF, fALFF and ReHo values in CSVD patients. The results suggested that abnormal changes in spontaneous brain activity in the default mode Network, somatosensory network, sensorimotor network, and frontoparietal network may explain the changes in clinical parameters in CSVD patients, especially in CSVD-c patients. The correlation between altered spontaneous neuronal activity and clinical parameters provides early useful diagnostic biomarkers for CSVD.

Acknowledgements

We thank all of the volunteers and patients for their participation in our study.

References

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