Chronic carotid or cerebral artery severe (>70%) stenosis or occlusion disease are the common causes of chronic cerebral hypoperfusion (CCH) (1–5), which has been positively identified as a key mechanism leading to vascular cognitive impairment and dementia (2, 6–9). Many studies have shown the changes in the structure, brain network, cognitive function, and their relationships in patients with chronic carotid artery severe stenosis or occlusion disease (10–16). One study showed neither a clear pattern of reduced cortical thickness nor an association of cortical thickness with cognitive function in patients with severe asymptomatic carotid stenosis (SACS) (17). These patients can be clinically asymptomatic or symptomatic. Symptoms include sensorimotor, pure sensory, and cognitive impairment and depression. Furthermore, patients with subtle cognitive impairment (including attention, memory, processing speed, and executive function) may be neglected due to normal-appearing white matter in general MRI and little attention in the clinical setting. However, the cognitive impairment can gradually progress, and finally lead to subsequent dementia (3). However, the underlying pathophysiology remains unclear and is multifactorial.

Despite promising results revealing the changes in the structure and network in patients with severe asymptomatic carotid stenosis, studies have some shortcomings. A major limitation is that current diffusion tensor imaging (DTI) studies cannot provide a direct comprehensive analysis of the structural connectivity of the whole cortex. A recent technique named fiber connectivity density (FiCD) mapping was proposed to map the structural connectivity properties (e.g., fractional anisotropy, or mean diffusivity) to the cortical surface, to create a common space for comparison with results from brain functional analysis and cortical thickness analysis, which can automatically identify brain regions with significant differences at the whole-brain level without defining ROIs (18, 19). Studies had shown that FiCD values were significantly changed in cerebral small-vessel disease (CSVD) patients (20) with mild cognitive impairment (MCI) and in patients with end-stage renal disease (ESRD) (21). FC can reveal brain activity, which has become an important tool in the study of neurological diseases (22), and numerous studies proved that decreased FC was related to impaired cognition in various diseases.

For another aspect, diffusion and metabolic changes in regions of cerebral artery obstruction in patients with symptomatic MCA steno-occlusive disease (defined as >70% stenosis on maximum intensity projection images or a complete signal loss of the middle cerebral artery trunk on magnetic resonance angiography) and normal-appearing white matter have been revealed (23, 24). Nonetheless, structural changes, FiCD values, FC, and the relationships between them and cognitive function in these patients have not been investigated, which would likely provide more pathophysiological information that can lead to a better understanding of the mechanisms of cognitive impairment in these patients.

In this study, we recruited a group of patients with asymptomatic MCA steno-occlusive disease and normal-appearing white matter. Multimodal MRI (structural, diffusion, and resting-state functional MRI) measures were compared for brain volume, cortical thickness, fiber connectivity density (FiCD) value, and functional connectivity (FC) between patients and an age-, sex-, and education-matched healthy control (NC) group. The associations between abnormal cortical thicknesses, FiCD values, and functional connectivities with the neurobehavioral assessments were performed.

This study systematically conducted a cross-sectional neuroimaging analysis of asymptomatic MCA steno-occlusive disease patients with NAWM to increase knowledge about the possible changes in brain volume, cortical thickness, FiCD value, FC, and cognition associated with this condition. Our study focused on the main effects of groups than on the differences between the left and right sides of the brain on account of the effect of the dominant hemisphere.

We found that brain structural volume quantification showed no difference among the left group, right group, and NC group. Nevertheless, the left group showed significant thinning of the left superior parietal lobule, while the right group showed significant thinning of the right superior parietal lobule and caudal portion of the right middle frontal gyrus in cortical thickness. This phenomenon may be caused by hypoperfusion and different susceptibility to hypoperfusion. First, with respect to hypoperfusion, previous investigations confirmed that patients with the carotid steno-occlusive disease had an increased risk of cerebral hypoperfusion (3, 4, 16, 34–36), which, gradually, may lead to cerebral atrophy (11, 14, 37, 38). Second, Marshall et al. (16) found that even if the posterior circulation regions also showed hypoperfusion in vertebrobasilar disease, the occipital and cerebellar cortices were barely affected, which led them to speculate that the anterior circulation region, but not the posterior circulation, is susceptible to hypoperfusion. Moreover, we only found two regions with decreased cortical thickness in our study, which may reflect the different susceptibility to hypoperfusion in different cerebral regions and even the same regions in different hemispheres. Ordinarily, neurodegenerative diseases tend to begin with a single vulnerable brain region, followed by trans-synaptic spread (39). Therefore, further longitudinal follow-up studies are needed. Studies have shown that atrophy of different regions in patients with CAS may result in different kinds of cognitive impairments (2, 14, 37, 38) and plenty of studies had reported memory decline in patients with CAS (40, 41). In our study, patient groups had lower scores in AVLT-H, suggesting memory decline, whereas no correlations were found between cortical thickness and AVLT-H scores. It may be related to a small sample size, or our neurobehavioral assessments could not discover their subtle cognitive impairments related to these regions with cortical thickness thinning, which needs further study.

We did not find any decreased FiCD value in the left and right groups. We interpreted the lack of decrease in FiCD value as an indicator of the robustness of the white matter to CCH, which may benefit from the lower oxygen demand compared with gray matter. Furthermore, compensatory circulation and neurovascular coupling may help maintain white matter’s structural and functional metabolism. Besides, the left group showed increased FiCD values in the superior frontal region of the left hemisphere, which reflected the increased fibrous connections in this region. This may be a compensatory mechanism in the brain that has not been reported previously. Otherwise, we were not sure whether it was caused by a small sample size, other confounding factors, or an analytical method in our study. Thus, further studies are needed to evaluate this speculation.

With regard to FC, we observed that functional connectivity of many interhemispheric and intrahemispheric regions showed decrements, especially between interhemispheric regions and intrahemispheric regions of the stenotic side in the left and right groups. Compatible with our current findings, one article about patients with asymptomatic MCA steno-occlusive disease indicated significant decreases in network strength, global efficiency, and the clustering coefficient, as well as a longer characteristic path length (42). We found many functional connectivity profiles were positively correlated with AVLT-H scores, thus we speculated that the subtle cognitive impairment may be attributed to the combined effect of the decreased FC profiles. Many studies showing decreased functional connectivity and increased risk of cognitive fragility in patients with SACS (12, 13, 15, 36, 43, 44) confirmed our speculation. Moreover, we found hyper-connectivity in many brain regions between the ipsilateral and bilateral hemispheres of patients in our study, reflecting compensatory effects for maintaining better cognitive function. Studies had reported compensatory hyper-connectivity in the healthy hemisphere and a few hyper-connectivity in the stenotic sides of patients with SACS (45, 46). Thus, we speculated that hyper-connectivity may be an important mechanism that maintains clinical asymptomatic performance and better cognition function. In addition, the collateral network (primary and secondary) may be another compensatory mechanism, which had not been discovered in our study and needs further research. Furthermore, we found that the decrement of FC in the right group was much more diffuse than that in the left group, which may also reflect the different susceptibility to hypoperfusion in different cerebral regions. The effect of the dominant hemisphere may be another explanation because we only recruited right-handed patients, therefore, further studies involving left-handed patients are needed to evaluate this speculation. Otherwise, one study also showed that part of the FC alterations gradually recovered to the normal condition after carotid artery stenting in patients with carotid stenosis (46). So, FC may be used as a biomarker of disease progression and therapeutic efficacy evaluation in these patients’ chronic cerebrovascular steno-occlusive disease. Notably, it was difficult to directly compare these studies because the functional measures differed.

In the present study, we found numerous regions with decreased FC in regions without declined cortical thickness and FiCD value, thus, we speculated that decreases in FC may exist prior to the structural changes including white and gray matter, which represented a higher sensitivity of FC. The alterations in FC may be an important mechanism underlying the neurodegenerative process in patients with carotid or cerebral arterial diseases causing early cognition impairment, which may promote the detection of network alterations, helping provide guidance for early clinical interventions in advance and reduce the impairment of higher brain functions in patients with carotid or cerebral arterial diseases.

There were several limitations in this study. First, our number of patients was small, limiting the statistical ability to identify small effect size variations. Second, our neurobehavioral assessments were relatively simple, and more elaborate neurological scales could be conducted in the future. Third, we did not evaluate the small vessels or microvessels of the patients, because the interval time between perfusion imaging and multimodal MRI was too long. Finally, the acquisition time of r-fMRI in this study was relatively short, and longer scanning time is preferred to provide more robust information on functional connectivity.

Even if the patients with MCA steno-occlusive disease were asymptomatic and had normal-appearing white matter, their cognitive function, structural and functional profiles had changed, especially the FC. And, alterations in FC in patients with asymptomatic MCA steno-occlusive disease occurred before structural changes. Hyper-connectivity may act as the compensation factor in neuroplasticity, maintaining clinical asymptomatic performance and better cognitive function. So, FC assessment may promote the detection of network alterations, which may be used as a biomarker of disease progression and therapeutic efficacy evaluation in patients with chronic cerebrovascular steno-occlusive disease.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

The studies involving humans were approved by Medical Ethics Committee of the Qilu Hospital (Qingdao) of Shandong University. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

XM conceived and designed the research. ZH performed the experiments. ZH, XX, and SG collected the data. ZH, XX, LS, and YL performed the imaging analysis. ZH and XX wrote, reviewed, and edited the manuscript. GG, JZ, and LS reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.

This research was supported by Qingdao Key Clinical Specialty Project Fund (QDZDZK-2022-097) and Qingdao Natural Science Foundation (23-2-1-201-zyyd-jch).

LS is the director of BrainNow Medical Technology Limited and YL is now employed by BrainNow Medical Technology Limited.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.