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Corresponding author. Department of General and Vascular Surgery, Central Clinic of Athens, 24, Alexander Papagou street, Neo Irakleio, 14122, Athens, Greece.
The aim was to evaluate the relationship between asymptomatic carotid stenosis (ACS) of any severity and cognitive impairment and to determine whether there is evidence supporting an aetiological role for ACS in the pathophysiology of cognitive impairment.
Data sources
PubMed/Medline, Embase, Scopus, and the Cochrane library.
Review methods
This was a systematic review (35 cross sectional or longitudinal studies)
Results
Study heterogeneity confounded data interpretation, largely because of no standardisation regarding cognitive testing. In the 30 cross sectional and six longitudinal studies (one included both), 33/35 (94%) reported an association between any degree of ACS and one or more tests of impaired cognitive function (20 reported one to three tests with poorer cognition; 11 reported four to six tests with poorer cognition, while three studies reported seven or more tests with poorer cognition). There was no evidence that ACS caused cognitive impairment via silent cortical infarction, or via involvement in the pathophysiology of lacunar infarction or white matter hyperintensities. However, nine of 10 studies evaluating cerebral vascular reserve (CVR) reported that ACS patients with impaired CVR were significantly more likely to have cognitive impairment and that impaired CVR was associated with worsening cognition over time. Patients with severe ACS but normal CVR had cognitive scores similar to controls.
Conclusion
Notwithstanding significant heterogeneity within the constituent studies, which compromised overall interpretation, 94% of studies reported an association between ACS and one or more tests of cognitive impairment. However, “significant association” does not automatically imply an aetiological relationship. At present, there is no clear evidence that ACS causes cognitive impairment via silent cortical infarction (but very few studies have addressed this question) and no evidence of ACS involvement in the pathophysiology of white matter hyperintensities or lacunar infarction. There is, however, better evidence that patients with severe ACS and impaired CVR are more likely to have cognitive impairment and to suffer further cognitive decline with time.
Study heterogeneity confounded data interpretation, largely because there is no standardisation regarding cognitive testing. However, 94% of studies reported an association between asymptomatic carotid stenosis (ACS) and one or more tests of cognitive impairment. The review found no clear evidence that ACS caused cognitive impairment via silent cortical infarction (few studies addressed this question), or by involvement in the pathophysiology of lacunar infarction or white matter hyperintensities. There was, however, better evidence suggesting that patients with severe ACS and impaired cerebral vascular reserve were more likely to have cognitive impairment and to suffer further cognitive decline with time.
Introduction
The management of patients with asymptomatic carotid stenosis (ACS) is controversial. While randomised controlled trials showed a small but significant benefit regarding the role of carotid endarterectomy (CEA) in late stroke prevention,
MRC Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial.
these data are now somewhat historical, and the 2017 European Society for Vascular Surgery (ESVS) guidelines advise that carotid interventions should now be reserved for a smaller subset of patients with imaging/clinical criteria that make them higher risk of stroke on medical therapy.
ESVS Guidelines Committee. Editor-s Choice – Management of Atherosclerotic Carotid and Vertebral Artery Disease: 2017 Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS).
A growing controversy relating to ACS is its potential involvement in the pathophysiology of cognitive impairment and dementia. A 2013 systematic review reported that nine of 10 studies (eight cross sectional, two community based), reported a significant association between ACS and cognitive impairment,
raising the question of whether carotid interventions might prevent or reverse cognitive decline in these patients. However, a “significant association” does not necessarily mean there is a direct aetiological relationship.
The aims of the current systematic review were to analyse the literature regarding the relationship between any degree of ACS severity and cognitive function and to establish whether there was evidence supporting a direct aetiological role for ACS in the development of cognitive decline (e.g., via silent cortical infarcts, silent embolisation, involvement in the pathophysiology of lacunar infarction or white matter hyperintensities or by causing cognitive impairment via a haemodynamic aetiology).
Materials and methods
A systematic review was conducted according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement
(Fig. 1). PubMed/Medline, Embase, Scopus, and the Cochrane library were independently searched by two teams of investigators (K.I.P., S.A./G.F.) until 1 November 2020 to identify studies focusing on the association between ACS and cognitive function. The following combinations of search terms were used: “asymptomatic carotid stenosis AND cognitive impairment”, “asymptomatic carotid stenosis AND cognitive function”, “carotid stenosis AND cognitive impairment” and “carotid stenosis AND cognitive function”. Any degree of carotid stenosis severity was included, but not studies involving measurement of carotid intima-media thickness. In addition, manual searches of references in the relevant papers were performed. Review articles, commentaries and conference abstracts were excluded, as were single case reports or case series with five or less patients and studies where there was no differentiation regarding cognitive test scores between symptomatic and asymptomatic patients. The results of the two independent searches were compared and discussed. Any discrepancies were resolved by the senior author (A.R.N.).
Figure 1Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flow diagram of studies on asymptomatic carotid stenosis and cognitive impairment.
A total of 1 211 potential studies were identified. After excluding duplicate publications, 574 were screened and 158 excluded (Fig. 1). A total of 416 articles were assessed for eligibility, abstracts reviewed, and, when relevant, full text articles were retrieved. A total of 35 studies
Discrepancy analysis between crystallized and fluid intelligence tests: a novel method to detect mild cognitive impairment in patients with asymptomatic carotid stenosis.
Impairments in brain perfusion, metabolites, functional connectivity, and cognition in severe asymptomatic carotid stenosis patients: an integrated MRI study.
Carotid atherosclerotic plaque instability and cognition determined by ultrasound-measured plaque strain in asymptomatic patients with significant stenosis.
Influence of collateral circulation on cerebral blood flow and frontal lobe cognitive function in patients with severe internal carotid artery stenosis.
which is based on three domains (selection of study group, comparability of groups, and reporting of outcomes). N-O scores are detailed in Table 1; the score was 5/9 in three studies, 6/9 in eight studies, 7/9 in nine studies, and 8/9 in 15 studies. Due to the heterogeneous nature of the constituent studies, formal meta-analyses were not undertaken.
Table 1Principle findings from the constituent studies on asymptomatic carotid stenosis and cognitive impairment
Study (N-O score)
Exclusion criteria
Adjusted for
Carotid disease
Significant cognitive test findings including OR/HR (95% CI)
Patients with 70–100% ACS were significantly more probably to have MMSE <24 vs. MMSE ≥24 (p<.001). Compared with 1–69% ACS, 70–100% ACS had significantly worse cognitive scores for Fuld objective memory, rapid verbal retrieve, WAIS-digit symbol, WAIS block design (all p<.050)
ACS patients with 70–100% ACS had significantly worse cognitive scores compared with patients with 1–69% ACS
The incidence of >50% ACS was 15% in dementia patients and 21% in controls (p=ns)The incidence of >70% ACS was 3% in dementia patients and 6.9% in controls (p=ns)The incidence of venous-arterial shunts was 30% in dementia patients and 21% in controls (p=ns)
Incidence of >70% ACS (5%) in embolising dementia patients vs. 3% in non-embolising dementia patients (p=ns)
Discrepancy analysis between crystallized and fluid intelligence tests: a novel method to detect mild cognitive impairment in patients with asymptomatic carotid stenosis.
Impairments in brain perfusion, metabolites, functional connectivity, and cognition in severe asymptomatic carotid stenosis patients: an integrated MRI study.
Cognitive impairment in 8/96 (8.3%) with 50–69% ACS no different to controls (OR 1.4 [0.6–3.2]). Cognitive impairment in 5/27 (18.5%) with 70–99% ACS (OR 3.8 [1.2–11.4] p=.023)
70–99% ACS more probably to have cognitive impairment than 50–69%
Carotid atherosclerotic plaque instability and cognition determined by ultrasound-measured plaque strain in asymptomatic patients with significant stenosis.
Impaired TMT-A and complex motor/executive function with increased lateral plaque strain (p=.010). Low scores on WAIS Digit Symbol (p<.001) and block design (p=.019) with max plaque shear strain. High axial strain associated with reduced performance in language, motor function, memory, visual-motor construction, executive function (all p<.050)
Influence of collateral circulation on cerebral blood flow and frontal lobe cognitive function in patients with severe internal carotid artery stenosis.
Collateral patterns: AcoA, PcoA, OA. MCAV significantly lower in ACS v controls (p<.001). Highest MCAVs in AcoA>PcoA>OA. Word fluency was lower in PcoA, OA vs. controls (p<.050). Digit span lower in AcoA, PcoA, OA vs. controls (p<.050)
Cognitive function influenced by collateral flow patterns
Unilat/bilat 50–69%: significant deficits across all RBANS domains (all p<.050)Unilat/bilat 70–99%: significant deficits across all RBANS domains, apart from language (all p<.050)Unilat/bilat occlusion: significant deficits across all RBANS domains except immediate memory (all p<.050)
No difference in cognitive test scores relative to stenosis severity (occlusion)
LICA/RACS >70% + normal CVR: no diff to controlsLACS >70% + impaired CVR: impaired verbal fluency test (p<.050)RACS >70% + imp CVR: impaired Coloured Progressive matrices test and complex figure test copy (both p<.050)
Patients with >70% ACS and normal CVR had normal NP testing, compared with controls
BACS + unilateral ACS: worse cognitive scores than controls (p<.050)BACS + LACS + impaired CVR did worse on phonemic verbal fluency vs. controls (p<.050)BACS + RACS with impaired CVR did worse on coloured progression matrices and complex figure copy test vs. controls (p<.050)
No difference in cognitive performance between BACS or unilateral ACS vs. controls in absence of impaired CVR
ACS: Declines in cognitive composite score (p=.020); learning and memory (p=.020); motor and processing (p=.010)Imp CVR vs. normal CVR cognitive composite score (p=.040); learning and memory (p=.010)
Stenosis severity, plaque area, GSM and emboli did not influence outcomes
Progression to severe AD (MMSE<21) at 12 mo (vs. 0–59% ACS)(R) 60–99%: impaired CVR vs. normal CVR (HR 3.56 [2.08–6.07])(L) 60–99%: impaired CVR vs. normal CVR (HR 2.84 [1.76–4.58])
>60% and normal CVR were significantly less probably to progress to severe AD than patients with impaired CVR
MMSE decrease by three points at 3 yControls 7% vs. 24.8% patients (OR 4.2 [1.9–9.1] p<.001). Of the 52 ACS patients whose MMSE score decreased by three pts, 87% had impaired CVR, vs. 13.5% with normal CVR (OR 14.7 [7.5–28.6] p<.001)
MMSE <80: LICA >75% vs. control (OR 6.7 [2.4–1.8]); no MRI infarct: LICA >75% vs. control (OR 14 [2.3–86]); MRI infarct: LICA >75% vs. control (OR 8.8 [1.7–45])Cog decline: LICA>75% vs. control (OR 2.6 [1.1–6.3])
No association 1–74% ACS vs. no ACS for cognitive impairment (OR 1.3 [0.92-1.7]). Significant worse with >75% ACS
CI = confidence interval; AcoA = anterior communicating artery; ACS = asymptomatic stenosis; BACS = bilateral asymptomatic stenosis; BMI = body mass index; CAS = carotid stenting; CEA = carotid endarterectomy; DXT = radiotherapy; EY = education year; HR = hazard ratio; imp CVR = impaired cerebral vascular reserve; GSM = Gray-Scale Median; LACI = lacunar infarct; LACS = left asymptomatic stenosis; MMD = major medical disease; MMSE = Mini Mental State Examination; MoCA = Montreal Cognitive Score; ND = neurological diseases; N-O = Newcastle Ottawa score; ns = not significant; OA = ophthalmic artery; occ = occlusion; OR = odds ratio; PcoA = posterior communicating artery; PD = psychiatric disease; RACS = right asymptomatic stenosis; RBANS = repeatable battery for assessment of neuropsychological status; SCI = silent cerebral infarction; Str/TIA = stroke/transient ischaemic attack; TM-A/B = Trail making test A and B; WMH = white matter hyperintensity; VB/IC = vertebrobasilar and intracranial disease; VRF = vascular risk factor.
Discrepancy analysis between crystallized and fluid intelligence tests: a novel method to detect mild cognitive impairment in patients with asymptomatic carotid stenosis.
Impairments in brain perfusion, metabolites, functional connectivity, and cognition in severe asymptomatic carotid stenosis patients: an integrated MRI study.
Carotid atherosclerotic plaque instability and cognition determined by ultrasound-measured plaque strain in asymptomatic patients with significant stenosis.
Influence of collateral circulation on cerebral blood flow and frontal lobe cognitive function in patients with severe internal carotid artery stenosis.
Table S1 details patient/control numbers, mean age, vascular risk factors (VRFs) (hypertension, diabetes, current smoking), and education years. Full details regarding VRFs were provided in 24 studies, while two others provided partial details. Details regarding education years were missing in 11 studies. There were control subjects in 28 studies. Table1 details patterns of carotid disease; 10 used a threshold of > 50%; six used > 60%; 11 used > 70%, and two used > 80%. Three studies included any degree of stenosis severity,
Exclusion criteria are also detailed in Table 1. Dementia was an exclusion criterion in eight studies, while a very low Mini-Mental State Examination score (MMSE) or Montreal Cognitive Assessment (MoCA) score (indicating severe cognitive impairment) was an exclusion criterion in 12 studies. In effect, 20/35 studies excluded patients with dementia or severe cognitive impairment. Ten studies included bilateral ACS (BACS), while 11 specifically excluded BACS (Table 1). Three studies included carotid occlusion, while occlusion was an exclusion criterion in five studies. Table 1 also details whether data were adjusted or unadjusted.
Imaging and monitoring techniques
Table S1 provides information on whether transcranial Doppler (TCD), magnetic resonance imaging (MRI), or computed tomography (CT) was undertaken. Twenty-two studies performed CT/MRI. In 11, MRI/CT was used to exclude patients with silent cerebral infarction (SCI) or significant white matter hyperintensities (WMHs). In five studies, MRI/CT evaluated the incidence/severity of SCI/WMHs or microinfarction.
Fourteen studies involved TCD. Two measured mean middle cerebral artery velocity (MCAV), including one which also used TCD to map collateral flow patterns in the circle of Willis (CoW). Two studies counted spontaneous emboli entering the ipsilateral MCA during one hour of TCD monitoring (Table S1). Ten studies (Table 1) used TCD to evaluate cerebral vascular reserve (CVR). As the ACS becomes more severe, patients with poor collateralisation via the CoW compensate by vasodilation of intracranial arterioles in the ipsilateral hemisphere. This maintains cerebral blood flow (CBF), but a point arises where vessels cannot dilate any more i.e., they enter a state of impaired or exhausted CVR, with limited (or no) capacity to dilate further. Thereafter, further increases in stenosis severity result in gradually reduced brain perfusion. There are several methods for measuring CVR. Most studies (9/10) used the breath holding index (BHI), while one used inhaled 5% CO2. Breath holding causes CO2 retention and cerebral arteriolar vasodilation. BHI is defined as the per cent increase in MCAV with breath holding, divided by the time the subject held their breath. Normal BHI is 1.02 – 1.65. Most studies used a BHI of < 0.69 to diagnose impaired CVR.
Cognitive assessment
Table S1 details the neuropsychological (NP) tests used in the 35 studies. A battery of cognitive tests was used in 24 studies (69%), while in one study a diagnosis of dementia had already been made.
Cognitive impairment in asymptomatic carotid stenosis patients
Notwithstanding issues regarding study heterogeneity and the different types of NP testing, both of which reduced the quality of the studies in the systematic review, Table 1 details cognitive test findings that were statistically significant. Overall, 33/35 (94%) reported an association between ACS and tests of cognitive impairment. Twenty reported one to three cognitive tests showing significant impairment; 10 reported four to six tests showing significant impairment, while three studies reported seven or more tests demonstrating significant cognitive impairment.
Discrepancy analysis between crystallized and fluid intelligence tests: a novel method to detect mild cognitive impairment in patients with asymptomatic carotid stenosis.
Impairments in brain perfusion, metabolites, functional connectivity, and cognition in severe asymptomatic carotid stenosis patients: an integrated MRI study.
Carotid atherosclerotic plaque instability and cognition determined by ultrasound-measured plaque strain in asymptomatic patients with significant stenosis.
Influence of collateral circulation on cerebral blood flow and frontal lobe cognitive function in patients with severe internal carotid artery stenosis.
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).
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.
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.
Stenosis severity, emboli, and plaque morphology
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,
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.
Influence of collateral circulation on cerebral blood flow and frontal lobe cognitive function in patients with severe internal carotid artery stenosis.
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).
Influence of collateral circulation on cerebral blood flow and frontal lobe cognitive function in patients with severe internal carotid artery stenosis.
Data interpretation was confounded by considerable heterogeneity within the constituent studies, especially regarding the spectrum of NP testing adopted. Over 90% of studies reported an association between ACS and one or more tests suggesting cognitive impairment. However, a “significant association” does not automatically mean that ACS has a direct aetiological role in the pathophysiology of cognitive dysfunction. There are a number of potential mechanisms whereby ACS might cause cognitive impairment directly. These include (1) silent cerebral infarction (SCI), (2) silent embolisation; (3) involvement in the pathophysiology of WMHs, or (4) via a haemodynamic aetiology.
Silent brain infarction
Hypothesis
If ACS was responsible for cognitive impairment secondary to SCI, there should be a significantly higher incidence of SCI in ACS patients with cognitive impairment vs. controls.
Cortical and lacunar silent cerebral infarctions combined
In the Framingham Study, 15.5% had cortical/lacunar SCI on MRI.
After adjusting for VRFs and time between performing duplex ultrasound (DUS), MRI, and cognitive testing (up to four years apart), the increased prevalence of SCI remained statistically significant in patients with > 50% ACS, who were also more likely to have cognitive impairment (OR 3.07, 95% CI 1.46 – 6.42, p = .003).
Given the lack of any other direct evidence on cognitive function in ACS patients with silent cortical/lacunar SCI (not aided by the fact that 10/35 studies specifically excluded patients with SCI from their study cohorts), what other indirect evidence is available? At first sight, the data are conflicting. A meta-analysis of 11 studies compared 2 110 ACS patients (of varying severity) vs. 10 237 with no ACS.
However, virtually none of the published studies have analysed SCI rates ipsilateral to ACS. One study not included in Finn’s meta-analysis was a subgroup analysis of 848 patients randomised within ACAS with no history of stroke/transient ischaemic attack.
Overall, 15% had evidence of SCI, with 72% being “small and deeply placed” (i.e., probably LACI). Only 43% of SCIs were ipsilateral to the randomised artery, while 44% were contralateral.
A meta-analysis of 30 studies (with/without ACS) reported that most showed a significant association between cortical/lacunar SCI and impaired tests of executive function and processing speed.
The same systematic review found no association between SCI at baseline and the incident risk of developing minor cognitive impairment in the future (HR 0.83, 95% CI 0.4 – 1.72), but SCI was associated with a significantly higher risk of dementia (HR 1.27, 95% CI 1.06 – 1.51).
However, in a second meta-analysis (nine studies; 10 772 patients with/without ACS), SCI was initially associated with a significantly increased risk of dementia (HR 1.29, 95% CI 1.02 – 1.6%), but after correcting for repeat NP testing, statistical significance disappeared.
These two meta-analyses actually showed very similar findings in dementia patients, being only separated by the lower 95% CI being slightly above 1 in one meta-analysis
It is well recognised that the “retest” phenomenon biases interpretation of cognitive impairment studies and this may explain why the second meta-analysis found no evidence of a significant link between SCI and dementia, after correcting for retesting.
An important study not included in the two meta-analyses was the NeuroVISION study, which evaluated the incidence of acute SCI after non-cardiac surgery in 1 114 patients.
Compared with the pre-operative MRI scan, post-operative MRI revealed 7% had a new SCI, of whom 42% developed cognitive impairment at one year, compared with 29% in patients without SCI (HR 1.98, 95% CI 1.22 – 3.2).
None of the constituent studies in this review reported that ACS patients with cognitive impairment had higher rates of ipsilateral cortical infarction, but only two of 35 studies
addressed this question. The Tromso Study (which included patients with 35% – 99% ACS) reported that the prevalence of cortical infarction was similar among patients with (6.3%) and without ACS (8.9%) and that cortical infarction had no effect on cognitive function.
In a second study, micro-infarction on MRI (often involving the cortex) was noted in 19% of patients with 30% – 99% ACS, and while these lesions were not associated with reductions in global cognitive score, MoCA, executive function, processing speed or visual memory, there was a significant reduction in visuospatial perception.
Given the paucity of studies evaluating ACS and cortical infarction, is there any other indirect evidence showing that ACS is associated with higher rates of ipsilateral cortical infarction, which (intuitively) one might expect? Once again, the evidence is conflicting. In a meta-analysis, only two sizeable studies were identified. Manolio reported no difference in rates of cortical infarction ipsilateral to a > 50% ACS,
Relationship of cerebral MRI findings to ultrasonographic carotid atherosclerosis in older adults: the Cardiovascular Health Study. CHS Collaborative Research Group.
while Baradaran observed that the incidence of cortical infarction ipsilateral to a > 50% ACS was 15% vs. 4% in the contralateral hemisphere (p = .005).
The Tromso Study reported that patients with 35% – 99% ACS had poorer cognitive function in association with a significantly higher prevalence of LACI (16.9%), vs. 8.9% in controls (p = .030).
In the Osaka Follow up study for Carotid Atherosclerosis, 44% of 506 controls and 47% of 94 ACS patients with normal cognitive function had LACI at baseline. Over the next eight years, 57 (9.5%) were diagnosed with dementia. Cox’s multivariable analysis showed that LACI (at baseline) was independently associated with developing dementia (HR 2.64, 95% CI 1.22 – 6.09), while 50% – 99% ACS was not (HR 1.42, 95% CI 0.58 – 3.22).
Indirect evidence against ACS embolisation being a cause of LACI comes from a meta-analysis on the most likely causes of first ever anterior circulation stroke (2 873 patients in 12 studies).
This showed a significantly lower prevalence of ipsilateral carotid stenosis (OR 0.23, 95% CI 0.19 – 0.29). Only 8.8% of LACI patients had an ipsilateral internal carotid stenosis vs. 25.6% in non-lacunar strokes. After adjustment, there was no significant difference regarding VRFs, suggesting that a non-atheromatous small vessel arteriopathy was responsible for most LACIs.
In a separate study, the overall rate of carotid or cardiac embolisation in 195 patients with LACI was 11%, with the rest being attributed to small vessel disease.
ESVS Guidelines Committee. Editor-s Choice – Management of Atherosclerotic Carotid and Vertebral Artery Disease: 2017 Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS).
there is no currently published evidence that ACS causes cognitive impairment or dementia by its direct involvement in the aetiology of LACI. Evidence linking ACS, cortical infarction and cognitive impairment is lacking, simply because the relationship has been assumed but rarely tested. It will be interesting to see whether CREST-2 (currently randomising ACS patients to CEA/CAS vs. medical therapy) with a substudy evaluating cognitive function, can determine whether there is a causal relationship between ACS, silent cortical infarction and cognitive dysfunction.
Silent embolisation
Hypothesis
ACS patients with spontaneous embolisation on TCD should have poorer cognitive function and/or greater declines in cognitive function over time.
Few studies have been undertaken. A series of 144 dementia patients underwent TCD and cognitive testing every six months for two years.
Spontaneous cerebral micro-embolic signals (MESs) were detected in 44%. There was a significantly faster decline in cognitive functioning, daily living activities in dementia scores and neuropsychological inventory scores in patients who were MES positive. In addition, the presence of spontaneous MES predicted more rapid progression of dementia over two years.
However, while spontaneous MES in dementia patients was associated with worsening cognition over time (OR 3.46, 95% CI 1.84 – 6.52; p < .001), there was no association between ACS prevalence, MES and dementia. Dementia patients who were MES positive rarely had a > 50% ACS (15%), while only 5% had a > 70% ACS.
By contrast, the prevalence of a venous to arterial shunt (diagnosed using TCD insonation of middle cerebral arteries and an intravenous injection of an emulsion of air microbubbles in saline as an ultrasound contrast medium) was present in 32% of AD patients, 29% of vascular dementia patients and 21% of controls.
In another study involving 108 patients with known dementia, there was no association between the presence of spontaneous MESs and prevalence of SCI on MRI.
In Lal’s study, involving 82 patients with 50% – 99% ACS and 62 age and co-morbidity matched controls, seven patients (9%) had MESs detected during 60 minutes of TCD monitoring. There was no difference in composite cognitive scores between ACS patients with MESs and those with no MESs.
Further indirect evidence against a predictive association between spontaneous MESs and cognitive impairment comes from a study involving 96 elderly patients (mean age 77 years) who had no evidence of dementia at baseline and who underwent TCD for MES detection followed by serial cognitive testing for 2.5 years. At baseline, 12% were MES positive, but there was no association between being MES positive and late cognitive decline.
In summary, while spontaneous embolisation is another of the ESVS imaging criteria for considering CEA in patients with 60% – 99% ACS in order to prevent stroke,
ESVS Guidelines Committee. Editor-s Choice – Management of Atherosclerotic Carotid and Vertebral Artery Disease: 2017 Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS).
or of an increased likelihood of future cognitive decline.
Involvement in the pathogenesis of white matter hyperintensities
Hypothesis
WMHs are associated with a doubling of dementia (HR 1.9, 95% CI 1.3 – 2.8; p = .002), as well as a faster decline in global cognitive performance, executive function and processing speeds.
If WMHs were caused by emboli or reduced CBF associated with ACS, there should be (1) a higher prevalence of WMHs in ACS patients with cognitive impairment; (2) interhemispheric WMH asymmetry reflecting ACS patterns of disease severity, and (3) WMH severity scores should be higher in the hemisphere ipsilateral to a carotid stenosis.
In support; the Framingham study (which included patients with 25% – 99% ACS) reported that 15.5% had WMHs on MRI. Patients with > 50% ACS were significantly more likely to have WMHs (OR 2.26, 95% CI 1.06 – 4.8; p = .030) than patients with < 50% ACS, which remained significant after correction for VRFs and time between DUS, MRI, and cognitive testing.
In Dempsey’s study, 27 patients with 60% – 99% ACS underwent cognitive testing and ultrasound studies of plaque strain. A subset also underwent MES detection and MRI. Impaired cognition scores were associated with indices of increased plaque strain, while increased WMHs were observed in a subset of 13 patients who were MES positive. Increased lateral strain in the plaque was observed in ACS patients with lower cognitive scores. The authors proposed that some WMHs may have followed ACS micro-embolisation.
Carotid atherosclerotic plaque instability and cognition determined by ultrasound-measured plaque strain in asymptomatic patients with significant stenosis.
There is, however, a much greater body of evidence that ACS is not involved in the pathogenesis of WMHs. In the Tromso study, ACS patients (35% – 99%) had significantly poorer cognitive function, but WMH severity was equally distributed amongst patients with and without ACS.
In a cohort of 500 patients who had previously suffered a stroke, 11% had asymmetry of their extracranial carotid stenoses, but 93% had symmetrical interhemispheric WMHs on MRI, suggesting WMH asymmetry is uncommon. There was no association between ACS asymmetry and WMH asymmetry and no association between WMH scores and ipsilateral ACS (whether previously symptomatic or not), which persisted after adjusting for VRFs and ACS laterality. The WMH severity score correlated strongly with increasing age. The authors reported that 11 studies (6 225 patients) had now found no association between WMH and ipsilateral ACS.
Finally, in a series of 108 dementia patients undergoing MES quantification and MRI (to score WMH severity using Schelten’s score), there was no association between being MES positive and severity/extent of WMHs. Patients with venous to arterial shunts had more severe WMH changes across all brain regions.
In summary, there is no published evidence supporting an aetiological role for ACS in the pathophysiology of WMHs. The presence of WMHs is not one of the ESVS imaging criteria for performing CEA in patients with 60% – 99% ACS in order to prevent stroke.
ESVS Guidelines Committee. Editor-s Choice – Management of Atherosclerotic Carotid and Vertebral Artery Disease: 2017 Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS).
Patients with severe ACS in association with impaired CVR will be more prone to developing cognitive impairment (especially if bilateral) and will be more vulnerable to further cognitive decline with time.
Four studies in the systematic review reported no association between increasing stenosis severity and worsening cognitive impairment,
which may explain why a simple measurement of stenosis severity may not be able to predict risk.
Ten studies in the systematic review evaluated the relationship between impaired CVR and cognitive impairment and nine of 10 reported a significant association with one or more tests of impaired cognition. There was evidence of a stepwise increase in the severity of cognitive impairment from normal in patients with severe ACS but no evidence of impaired CVR (bilaterally), through unilateral impaired CVR (increased impairment), with maximum cognitive dysfunction being observed in patients with bilaterally impaired CVR.
More importantly, patients with similarly severe ACS (unilateral or bilateral) but no evidence of impaired CVR had cognitive test scores that were no different to controls.
There was also consistent evidence from longitudinal studies that patients with severe ACS and impaired CVR were significantly more likely to suffer further cognitive decline with time, compared with patients with severe ACS and normal CVR.
In summary, while the systematic review found no evidence that increasing stenosis severity (on its own) was predictive of cognitive impairment, there was better evidence supporting a causal association between cognitive dysfunction in patients with severe ACS who also had impaired CVR. The ESVS guidelines already include impaired CVR as an imaging criterion for considering CEA in patients with 60% – 99% ACS for the prevention of stroke.
ESVS Guidelines Committee. Editor-s Choice – Management of Atherosclerotic Carotid and Vertebral Artery Disease: 2017 Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS).
Meaningful interpretation of the data in this systematic review was confounded by considerable heterogeneity within the constituent studies regarding the spectrum of NP tests involved, the lack of routine functional brain imaging in up to one third of the studies, as well as missing VRF data. Of greatest importance was the lack of consensus regarding the optimal battery of NP tests that should be adopted in cross sectional/longitudinal studies involving ACS patients. There was also no consistency regarding the role of functional brain imaging; 11 studies used CT/MRI to exclude patients with SCI or WMHs, while five used CT/MRI to score the severity of these deficits and their impact on cognition. Moreover, two thirds of studies excluded patients with significant cognitive impairment or dementia and no study corrected for the “learning effect” associated with repeat testing. Finally, it is also possible that the clinical relevance of cognitive function studies involving ACS patients performed more than 20 years ago might lack relevance in the modern era, given improvements in medical therapy in contemporary practice. If nothing else, this systematic review has highlighted the need for well designed longitudinal studies, where patients undergo standardised NP testing, routine MRI imaging as well as other assessments including TCD and CVR evaluation, with correction for repeat testing. This is especially important in order to determine whether there is an aetiological relationship between ACS, silent cortical infarction and the development of cognitive impairment.
Conclusions
Over 90% of studies reported a statistically significant association between ACS and one or more tests of cognitive impairment. While there is currently no published evidence that ACS causes cognitive impairment via silent cortical infarction (but few studies have specifically addressed this question) or via involvement in the pathophysiology of LACI or WMHs, there is better evidence that patients with severe ACS and impaired CVR are more likely to have cognitive impairment and suffer further cognitive decline with time.
Conflict of interest
None.
Funding
None.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
MRC Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial.
ESVS Guidelines Committee. Editor-s Choice – Management of Atherosclerotic Carotid and Vertebral Artery Disease: 2017 Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS).
Discrepancy analysis between crystallized and fluid intelligence tests: a novel method to detect mild cognitive impairment in patients with asymptomatic carotid stenosis.
Impairments in brain perfusion, metabolites, functional connectivity, and cognition in severe asymptomatic carotid stenosis patients: an integrated MRI study.
Carotid atherosclerotic plaque instability and cognition determined by ultrasound-measured plaque strain in asymptomatic patients with significant stenosis.
Influence of collateral circulation on cerebral blood flow and frontal lobe cognitive function in patients with severe internal carotid artery stenosis.
Relationship of cerebral MRI findings to ultrasonographic carotid atherosclerosis in older adults: the Cardiovascular Health Study. CHS Collaborative Research Group.
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