Editor's Choice – Asymptomatic Carotid Stenosis and Cognitive Impairment: A Systematic Review

Only one of 30 cross sectional studies^{,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,  ,} (Table 1 and Table S1) reported no association between ACS and tests of cognitive impairment. In this study (which only recruited dementia patients), the incidence of > 70% ACS was 3% vs. 6.9% in controls. Dementia patients were more likely to have venous to arterial shunts as a source of silent brain embolisation (30%), than a carotid source.

Six studies were longitudinal^{,  ,  ,  ,  ,}  (Table 1). Five^{,  ,  ,  ,} analysed changes in MMSE at baseline and at one to three years, while the Osaka Follow Up Study for Carotid Atherosclerosis evaluated changes in MMSE and the Clinical Dementia Rating Scale over eight years. In the latter study, 57/600 patients were diagnosed with dementia by eight years. Compared with 506 controls (after adjusting for age, sex, education years, and VRFs), 94 patients with > 50% ACS were not more likely to develop dementia (odds ratio [OR] 1.4, 95% confidence interval [CI] 0.6 – 3.2). By contrast, patients with lacunar infarction (LACI) on baseline MRI were significantly more likely to develop dementia by eight years (OR 2.6, 95% CI 1.2 – 6.1). The Cardiovascular Health Study reported that patients with >75% left ACS were significantly more likely to develop cognitive impairment vs. controls (OR 2.6, 95% CI 1.1 – 6.3). However, there were only 32 with > 75% ACS in an overall cohort of 4 006. The other four longitudinal studies will be discussed in the section on CVR.

Ten studies^{,  ,  ,  ,  ,  ,  ,  ,  ,}  evaluated the effect of impaired CVR on cognitive function (Table 1), including the four remaining longitudinal studies^{,  ,  ,}  and six cross sectional studies.^{,  ,  ,  ,  ,}  In the six cross sectional studies, only one found no association between CVR and cognitive impairment. In the other five cross sectional studies (n = 759), all reported a significant association.^{,  ,  ,  ,} The main findings were that ACS patients with impaired CVR had significant cognitive impairment vs. controls.^{,  ,  ,  ,} Interestingly, patients with unilateral or bilateral ACS but normal CVR had cognitive test scores that were no different to controls.^, Cognitive dysfunction increased in a stepwise manner from normal CVR (normal cognition) through unilateral CVR (some cognitive impairment), with the lowest cognitive scores being observed in patients with bilateral CVR impairment.

Four longitudinal studies examined whether patients with impaired CVR had greater declines in MMSE over one and three years.^{,  ,  ,}  Buratti et al. reported that 22% of 548 patients with unilateral 70% – 99% ACS had a two point decline in MMSE over one year. In ACS patients with impaired CVR; 44% suffered a two point decline in MMSE vs. 9% with normal CVR (p < .001). Silvestrini et al. evaluated 98 patients with 60% – 99% ACS and mild Alzheimer’s disease (AD) compared with 313 mild AD patients with 0 – 59% ACS acting as controls. AD patients with right 60% – 99% ACS and impaired CVR were more likely to progress to severe AD (defined as MMSE < 21) over 12 months (hazard ratio [HR] 3.56, 95% CI 2.08 – 6.07), as were AD patients with left ACS and impaired CVR (HR 2.84, 95% CI 1.76 – 4.58). Balestrini et al. observed that 52/210 patients with unilateral 70% – 99% ACS had a three point decrease in MMSE scores over three years. Of the 52, 87% had impaired CVR vs. 13.5% with normal CVR (OR 14.7, 95% CI 7.5 – 28.6). On a similar theme, Buratti evaluated 159 patients with bilateral 70% – 99% ACS. Patients with normal CVR (bilaterally) did not decrease their MMSE score by three points over three years (HR 0.9, 95% CI 0.5 – 1.27), while there was a stepwise increase in MMSE scores declining by >3 through unilateral CVR impairment on the right (HR 1.8, 95% CI 1.3 – 2.3), unilateral CVR impairment on the left (HR 1.6, 95% CI 1.1 – 2.2), with the greatest proportion decreasing their MMSE score by three points being seen in patients with bilateral CVR impairment (HR 3.1, 95% CI 2.6 – 3.5). Another study (which did not evaluate CVR) reported that the composite z score for cognitive performance decreased linearly below an MCAV of 45 cm/sec. This level of reduced MCAV is more commonly seen in patients with a non-functioning CoW and impaired CVR.

The systematic review included patients with all degrees of ACS severity (Table 1). Four studies reported no association between increasing stenosis severity and worsening cognitive impairment,^,,, while five reported that patients with more severely stenosed arteries had greater cognitive impairment than patients with less severe ACS.^,,,, Only one study reported that patients with bilateral ACS had poorer cognitive function than patients with unilateral ACS. Purandare et al. reported that the 5% incidence of >70% ACS in dementia patients with evidence of spontaneous embolisation on TCD was no different to the 3% incidence of > 70% stenosis in non-embolising dementia patients. Lal et al. also reported that the presence of spontaneous embolisation on TCD, plaque area and grey scale median had no influence on cognitive testing in 82 patients with 50% – 99% ACS. Chu et al. reported that a higher calcification score in the carotid vessels from aortic arch to CoW was associated with poorer cognitive scores. Weiet al. reported that collateral flow patterns in the CoW influenced cognitive function. In 126 patients with 70% – 99% ACS, recruitment of collateral flow via the anterior communicating artery (AcoA), posterior communicating artery (PcoA), or ophthalmic artery (OA) was associated with lower MCAVs vs. controls (p < .001). Word fluency scores were significantly lower in patients recruiting PcoA or OA collaterals (p < .050), while digit span test scores were significantly lower in patients recruiting AcoA, PcoA, and OA collaterals vs. controls (p < .05). Zavireo et al. observed that the greater the number of collateral pathways recruited, the more impaired CVR became and the lower the MoCA score.