Carotid artery stenosis without transient ischemic attack (TIA) and stroke is considered as “asymptomatic” (1, 2). However, a number of studies have demonstrated that asymptomatic carotid artery stenosis patients had significantly poorer performance in executive function and memory, indicating that “asymptomatic” carotid stenosis might not be truly asymptomatic (3–7). Carotid endarterectomy (CEA) had been traditionally performed to prevent stroke in patients with high-grade carotid stenosis (8). However, carotid artery stenting (CAS) is now being investigated as an alternative to CEA (9). Although both CEA and CAS have been proven to reduce future strokes, the effect of CEA and CAS on cognition still remained conflicting (9–11).

In past few years, several imaging techniques, such as pulsed arterial spin labeling (pASL) MRI and resting-state functional MRI (R-fMRI), had been increasingly used to study cognitive impairment in humans. In this study, we evaluated the cognition performance in severe asymptomatic carotid artery stenosis patients undergoing CAS and explored the mechanisms underlying the cognition changes by the integrated MRI techniques including pASL MRI and R-fMRI.

From January 2015 to June 2016, successful CAS was performed in 24 asymptomatic carotid artery stenosis patients, and the follow-up study was completed for 16 patients. No vascular complications occurred in these 16 subjects. The inclusion criteria were as follows: (1) age between 55 years and 80 years; (2) unilateral internal carotid artery stenotic degree ≥ 70%; (3) right-hand-dominant; (4) free of stroke, TIA, dementia, and depression; (5) modified Rankin Scale: 0 or 1; (6) no major medical conditions; and (7) obtained written informed consent. The exclusion criteria were as follows: (1) contralateral internal carotid artery stenosis ≥ 50%; (2) posterior circulation diseases; (3) MMSE < 26, which is a cutoff value for mild cognitive impairment; (4) functional disability (modified Rankin Scale ≥ 2); (5) severe systemic diseases and neuropsychiatric diseases (such as congestive heart failure and history of stroke); (6) any contraindications for MRI scan (e.g., metal implants); (7) low education level (<6 years); (8) evidence of carotid dissection; (9) intracranial aneurysm or arteriovenous malformation; and (10) allergy to heparin, aspirin, or clopidogrel. All procedures involved in this study were approved by Zhongnan Hospital Review Board.

After stenting, all final residual diameter stenosis was ≤20%. Systolic blood pressure was carefully maintained between 100 and 140 mmHg, and no complications were found. Aspirin and clopidogrel were continued for at least 3 months after successful intervention.

Cognition assessments were completed within 1 week after MRI scan. The MMSE and MoCA Beijing Version were used to assess the global cognition. In the Digit Symbol Test, subjects were required to translate numbers to symbols in a given time and correct translations within 90 s were recorded. The Rey Auditory Verbal Learning Test was used to evaluate the memory and verbal learning ability. In this test, participants had to recall all the words remembered, and this procedure was repeated five times. These were recorded so that the total number of words was immediately recalled during the first five repeats and the delayed recall of the first list. In the Digit Span Test, participants were required to repeat the orally presented lists of numbers, beginning with a two-number sequence, and each correct performance was followed by one additional number. In the forward span, participants were asked to retell the span in forward order, and in the backward span, the participant was asked to retell the span in reverse order.

MRI images were acquired using a 3.0 T Siemens scanner in Zhongnan Hospital. T1 images were collected using MP-RAGE sequence. Scan parameters were as follows: flip angle = 9°, TR = 2,250 ms, TE = 2.26 ms, slice thickness = 1.0 mm, inversion time = 900 ms, number of slices = 176, data matrix = 215 × 256, and FOV = 256 mm × 224 mm. pASL perfusion images were collected using Q2TIPS II technique. Scan parameters were as follows: TR = 2,500 ms, TE = 11 ms, FOV = 240 mm × 240 mm, matrix = 64 × 64, FA = 90°, and slice thickness = 6 mm. R-fMRI was acquired using EPI sequence: repetition time = 2,000 ms, echo time = 30 ms, flip angle = 90°, number of slices = 33, slice thickness = 3.8 mm, gap = 1 mm, data matrix = 64 × 64, and field of view = 240 mm × 240 mm.

Part 1: Table 1 shows the demographic information and cognitive test scores at baseline and 3 months after CAS. Significant improvements in the MMSE, Verbal Memory test, and delayed recall were observed. There is no decline in any individual scores (Table 1).

Part 2: Difference in CBF between baseline and 3 months after performance. Compared with baseline, the asymptomatic carotid artery stenosis patients showed the increased CBF mainly in the left frontal gyrus, anterior cingulate, left occipital gyrus, and left cerebellum (Table 2; Figure 1).

Part 3: Differences in ALFF between baseline and 3 months after treatment. After treatment, the asymptomatic carotid artery stenosis patients showed significantly increased ALFF predominantly in the right precentral gyrus. The asymptomatic carotid artery stenosis patients also showed decreased ALFF mainly in the left and right cerebellum anterior lobe (Table 3; Figure 2).

Part 4: Differences in FC to PCC between baseline and 3 months after intervention. After intervention, the asymptomatic carotid artery stenosis patients showed the increased connectivity to the PCC mainly in the right supra frontal gyrus. There was no region showing decreased connectivity to the PCC (Table 4; Figure 3).

Part 5: Relationship between imaging changes and cognition scores. No significant correlation was found between imaging differences and cognition scores (P > 0.05 for all).

In this study, we found that CAS could improve global cognition (assessed by MMSE) and memory (assessed by Verbal Memory test and delayed recall test) in asymptomatic carotid artery stenosis patients, which is agreed with previous reports (12, 13). Since cognitive impairment could also predict mortality, it may be misleading that using stroke as the only outcome marker in CEA and CAS (14).

Silent infarction and cerebral hypoperfusion are the main mechanisms in the development of cognitive decline in asymptomatic carotid artery stenosis patients, indicating that cognition may be improved by reducing silent infarction and restoring CBF. Our results showed the increased regional CBF mainly in the left frontal gyrus, anterior cingulate, left occipital gyrus, and left cerebellum after CAS. The increased CBF found in the occipital gyrus and cerebellum could be explained by the presence of functional circle of Willis. Since frontal gyrus and anterior cingulate consisted of regions that mediated memory and executive function, increased CBF in these regions may contribute to the cognitive improvement after CAS.

In recent years, more and more studies had demonstrated that cognition output was not dependent on the individual brain region, but dependent on network regions (15). A number of studies had already demonstrated this opinion in patients with neurodegenerative diseases (16, 17). The default mode network (DMN) was one of them (18). By functional MRI and PET studies, the most common DMN components are the PCC, the medial prefrontal cortex, the anterior cingulate cortex, the inferior parietal lobule, and other regions (19, 20). The DMN was suggested to play important role in cognition, such as reviewing past knowledge and processing memory (18, 21–23). Another reason selecting DMN for analysis was that previous study had demonstrated that DMN was especially easily affected by hypoperfusion (24). The PCC, supplied by the precuneal artery from its origins at the ICA, had been shown to be a key point in DMN and involved in cognitive decline (19).

Among the indexes utilized in R-fMRI, ALFF was a useful index to reflect spontaneous neuronal activities (25–28). We noted that the asymptomatic carotid artery stenosis patients showed increased ALFF mainly in the right precentral gyrus after CAS, which belonged to the DMN. Thus, cognitive improvement after CAS could also be partially attributed to the increased activities in these regions. Since previous studies had indicated that the cerebellum not only regulated motor control but also involved in cognition tasks (29, 30). The decreased ALFF in the cerebellum anterior lobe may further illustrate the cognition role of cerebellum, but the mechanisms had not been illustrated exactly and needed further more studies.

We compared the FC to the PCC before and after CAS treatment and found that the asymptomatic carotid artery stenosis patients showed increased connectivity to the PCC mainly in the right supra frontal gyrus after CAS. There was no region showing decreased connectivity to the PCC. The increased regions were also overlapped with the anterior part of the DMN. Since the anterior part of the DMN was specially associated with executive function and memory, the cognitive improvement could also be partially attributed to the increased FC to the PCC in the anterior part of DMN, but no significant correlation was found (31, 32).

Nevertheless, several limitations in this study should be discussed. First, the sample size was not big enough. Second, it was extremely difficult to define the stenosis timing. Longer occlusion duration may potentially affect the cognition reversibility. Third, the follow-up interval was relatively short. Fourth, no control group was included.

In summary, this prospective study demonstrated that successful CAS could partly improve cognition dysfunction in asymptomatic carotid artery stenosis patients. By the integrated MRI techniques including pASL MRI and R-fMRI, we also found increased perfusion in the left frontal gyrus and anterior cingulate, increased ALFF in the right precentral gyrus, and enhanced connectivity to the PCC in the right supra frontal gyrus after CAS. Since these regions are overlapped with DMN, the cognition improvement by CAS in asymptomatic carotid artery stenosis patients may be partly attributed to these changes.

This study was carried out in accordance with the recommendations of “Zhongnan Hospital Review Board” with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the “Zhongnan Hospital Review Board.”

TW: analysis and interpretation of data. DS, YL, BM, HL, and SZ: acquisition of data. JZ: study concept and design.

The 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.