Journal of the Neurological Sciences 328 (2013) 58–63

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Journal of the Neurological Sciences

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Diffusion-weighted lesions after carotid artery stenting are associated withcognitive impairment

Paola Maggio a, Claudia Altamura a, Doriana Landi a, Simone Migliore a, Domenico Lupoi b, Filomena Moffa c,Livia Quintiliani a, Stefano Vollaro a, Paola Palazzo a, Riccardo Altavilla a, Patrizio Pasqualetti d,e,Yuri Errante f, Carlo Cosimo Quattrocchi f, Francesco Tibuzzi c, Francesco Passarelli c, Roberto Arpesani b,Guido di Giambattista b, Francesco Rosario Grasso f, Giacomo Luppi f, Fabrizio Vernieri a,⁎a Neurology Unit, Università Campus Bio-Medico di Roma, Italyb Radiology Unit, Ospedale FatebeneFratelli, Isola Tiberina, Roma, Italyc Neurology Unit, Ospedale FatebeneFratelli, Isola Tiberina, Roma, Italyd SeSMIT (Service for Medical Statistics & IT), FatebeneFratelli Association for Research, Isola Tiberina, Roma, Italye Epidemiology and Biostatistics, San Raffaele-Cassino, Italyf Radiology Unit, Università Campus Bio-Medico di Roma, Italy

⁎ Corresponding author at: Neurology Unit, UniversitàVia Alvaro del Portillo 200, Roma 00128, Italy. Tel.: +06225411936.

E-mail address: f.vernieri@unicampus.it (F. Vernieri)

0022-510X/$ – see front matter © 2013 Elsevier B.V. Alhttp://dx.doi.org/10.1016/j.jns.2013.02.019

a b s t r a c t

a r t i c l e i n f o

Article history:Received 5 October 2012Received in revised form 24 January 2013Accepted 21 February 2013Available online 17 March 2013

Keywords:Carotid artery stentingCognitive performanceDWI lesion

The effect of carotid artery stenting (CAS) on cognitive function is still debated. Cerebral microembolism, detect-able by post-procedural diffusion-weighted imaging (DWI) lesions, has been suggested to predispose to cogni-tive decline. Our study aimed at evaluating the effect of CAS on cognitive profile focusing on the potential roleof cerebralmicroembolic lesions, taking into consideration the impact of factors potentially influencing cognitivestatus (demographic features, vascular risk profile, neuropsychological evaluation at baseline and magnetic res-onance (MR)markers of brain structural damage). Thirty-sevenpatientswith severe carotid artery stenosiswereenrolled. Neurological assessment, neuropsychological evaluation and brain MR were performed the day beforeCAS (E0). Brain MR with DWI was repeated the day after CAS (E1), while neuropsychological evaluation wasdone after a 14-month median period (E2). Volumes of both white matter hyperintensities and whole brainwere estimated at E0 on axial MR FLAIR and T1w-SE sequences, respectively. Unadjusted ANOVA analysisshowed a significant CAS∗DWI interaction for MMSE (F = 7.154(32), p = .012). After adjusting for factors po-tentially influencing cognitive status CAS∗DWI interactionwas confirmed forMMSE (F = 7.092(13), p = .020).Patients with DWI lesions showed a mean E2–E0 MMSE reduction of −3.1, while group without DWI lesionsshowed a mean E2–E0MMSE of +1.1. Our study showed that peri-procedural brain microembolic load impactsnegatively on cognitive functions, independently from the influence of patients-related variables.

© 2013 Elsevier B.V. All rights reserved.

1. Introduction

The effect of carotid artery stenting (CAS) on cognitive function isstill debated. Independent studies reported different findings: improve-ment [1], deterioration [2], or stability of cognitive performance follow-ing CAS [3]. Although cerebral microembolism, detectable by earlypost-procedural diffusion-weighted imaging (DWI) lesions, has beensuggested to predispose to cognitive decline [4], the reported resultsare conflicting [5], probably due to methodological and patient-relatedvariables discrepancy [6].

Magnetic resonance (MR) studies described higher incidence ofclinically silent DWI lesions in patients with vascular dementia and

Campus Bio-Medico di Roma,39 06225411889; fax: +39

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recent cognitive deterioration [7]. Furthermore, silent microemboliccerebral injury seems to be associated to cognitive impairment occur-ring after cardiac catheterization and surgical procedures [8].

In patients undergoing CAS also vascular risk factors for dementia,such as hypertension, diabetes, hypercholesterolemia and smoking,might influence cognitive profile [9] or act synergically with carotiddisease to induce cognitive impairment [10].

Carotid disease is associated with MR indices of brain vasculardamage, such as white matter hyperintensities (WMH) detected byfluid attenuated inversion recovery (FLAIR) [11]. Moreover, WMHvolume is related with an increased risk of dementia [12] and globalbrain atrophy although it is not yet clear whether this association isindependent of shared risk factors [13].

Our study aimed at evaluating the effect of CAS on cognitive profileand the potential role of cerebral microembolism, embodied by post-procedural DWI lesions. The impact of patient-related factors potential-ly influencing cognitive status (demographic features, vascular risk

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profile, neuropsychological evaluation at baseline and MR markers ofbrain structural damage) was also investigated.

2. Methods

Thirty-seven patients (mean age 72.9 ± 7.9 years, 13 female)with severe (i.e. greater than 70%) carotid artery stenosis, diagnosedin our ultrasound laboratory according to standardized criteria [14]and selected for carotid angioplasty with stent placement, underwentthis procedure at the Interventional Radiology of our institution fromJanuary 2007 to November 2011.

Plaque characteristics and degree of stenosiswere always confirmedby computed-tomographic angiography of the neck vessels. Intracranialvessels were also examined with transcranial color-coded sonographyandMR angiography: no patient had significant stenosis of the large in-tracranial arteries.

All patients underwent electrocardiogram and cardiological exami-nation at admission. Neurological assessment including National Insti-tutes of Health Stroke Scale (NIHSS), neuropsychological evaluationand brain MR were performed the day before CAS (E0). No patienthad recent (b3 months) stroke or transient ischemic attack or possibleor probable embolizing cardiopathy. Three patients had a mild stroke6 months before the procedure: two patients had a NIHSS score = 1point, the third one had a NIHSS score = 3 points at E0.

CAS procedures were performed according to the European guide-lines [15].

The day after the procedure (E1), clinical assessment and brainMR were repeated and color-coded duplex sonography of the neckvessels was performed to evaluate CAS good outcome. In addition,all patients underwent continuous electrocardiographic monitoringin the first 48 h following CAS to detect possible arrhythmias (in par-ticular, new onset of atrial fibrillation or bradycardia b40 bpm).

Therapy with ASA 100 mg plus clopidogrel 75 mg as tablets once aday was initiated at least 5 days before CAS in all patients. Clopidogrelwas continued for 6 months after CAS and ASA was administered in-definitely. Each patient received the best medical therapy to controlvascular risk factors. Patients were followed-up by telephone inter-view every 3 months and clinically re-evaluated after 6 months.

The study was approved by the institutional review committeeand was performed according to the ethical standards laid down inthe 1964 Declaration of Helsinki. All the patients gave their informedwritten consent.

2.1. MR imaging

MR was performed with an Achieva 1.5 T scanner (Philips MedicalSystems, Best, the Netherlands) and an 8 channel head phase-arraycoil with parallel imaging capabilities (SENSE). The following brainMR sequences were collected both at E0 and E1: axial plane T1w-SE(T1w-spin echo; TR = 550, TE = 15, slice thickness = 3 mm, interslicegap = 0), FLAIR (TR = 8000, TE = 125, TI = 2500; slice thickness =3 mm, interslice gap = 0), and DWI (TR = 3220, TE = 88, b value =1000, slice thickness = 5 mm, interslice gap = 1 mm) with apparentdiffusion coefficient (ADC).

Total WMH volume was computed on FLAIR axial images at E0,after having segmented lesional region of interests (ROIs) through asemi-automated local thresholding approach (Osirix® software V.3.9.4)(Fig. 1) [16].

Whole brain volume (WBV) normalized for subject head size wasestimated with SIENAX [17] version 2.6 (part of FSL 4.1.9, FMRIB'ssoftware library) on the axial T1w-SE sequences acquired at E0.

After the procedure (E1) DWI was looked over for areas of restrict-ed diffusion (DWI lesions) (Fig. 2). If present, total number and ana-tomical localization of DWI lesions were considered. They werefurther classified according to the side of the treated artery (ipsilater-al or contralateral), vascular territory (anterior cerebral artery—ACA,

posterior cerebral artery—PCA, and middle cerebral artery—MCA, orborder zones) and cortical or subcortical location. Border zones wereconsidered as external (cortical), if located at the junctions of ACA,PCA and MCA territories, or internal (subcortical), at the junctions ofthe three cerebral artery territories with the Heubner, lenticulostriate,and anterior choroidal artery [18].

MR imaging analysis was conducted by the consensus of two in-vestigators blind to clinical patients' data.

2.2. Neuropsychological evaluation

Memory, attention, executive functions and language were evaluat-ed at E0 and after a median of 14 months (min 4–max 41) from CAS(E2). Cognitive global function was assessed by Mini-Mental State Ex-amination (MMSE). Episodic verbal memory was studied with Rey'sAuditorial Verbal Learning Test (RAVLT). The numbers ofwords recalledafter the first presentation of a 15-word list was used as a marker ofshort term verbal memory (RAVLT—Immediate, RAVLT-I), while thenumber of words recalled after an interference visuo-spatial task wasconsidered a marker of long-term verbal memory (RAVLT—Delayed,RAVLT-D). Recall of Rey–Osterrieth Complex Figure Test (RROF) wasused as an index of long-term episodic visual memory. Attention wasexamined by Double Barrage Test (DBT), expressed in seconds neededto perform the task. The linguistic skills were evaluated with batteryfor the analysis of the aphasic deficit subtest (oral denominationnames—ND), while executive functionswere examined by Raven's pro-gressive matrices test (RPM).

For each administered test appropriate adjustments for age andeducation were applied according to normative data of the Italianpopulation [19]. Available cut-off scores of normality (95% of thelower tolerance limit of the normal population distribution) were ap-plied. The difference between post-procedural and pre-proceduralvalues was computed (E2–E0).

2.3. Statistical analysis

The differences between post-procedural and pre-procedural values(E2–E0) of each cognitive domain were compared between DWI andnon-DWI group by means of independent Student's t-test.

For differences in MMSE, non-parametric descriptive (median,min–max) and inferential (Mann–Whitney test) statisticswere applied.

To assess the effects of CAS (two levels: E2, and E0), DWI (occurrenceof newDWI lesions) and their interaction on cognitivemeasures, ANOVAfor repeatedmeasureswas appliedwith CAS aswithin-subjects factor andDWI as between-subjects factor. To take into account the influence of de-mographic variables (age, and years of education), vascular risk factors(smoking, hypertension, diabetes, and hypercholesterolemia), follow-uplength, and basalMRfindings (WMHvolume andWBV) on cognitive pro-file, these variables were entered as covariates in the adjusted ANOVAmodel. Moreover, E0 cognitive domain scores were added as covariatesin adjusted ANOVA analysis for each corresponding cognitive test. To pro-vide information about the changes that occurred, 95% confidence inter-vals were also computed. Chi-square and independent samples t-testwere used to compare groups based on DWI lesions.

A formal power analysis was not performed in advance. If DWI lesionoccurrence reached 50%, a sample size of 30 patients provides a power of0.80 to recognize as statistically significant (at bilateral alpha level 0.05)only large effect sizes. The power decreases if DWI lesion occurrence isless. Thus, this study should be considered as explorative, being notable to detect smaller yet clinically relevant differences. Statistical analy-sis was performed with SPSS software (version 19) for Windows.

3. Results

Table 1 shows patients' demographic and lifestyle characteristics,atherosclerosis burden, MR findings and cognitive status at baseline.

Fig. 1. Total WMH volume has been computed on FLAIR axial images (left) by segmenting lesional region of interests (ROIs) through a semi-automated local thresholding approach(Osirix® software V.3.9.4) (right). An example of white matter lesion load in non-DWI (A, and a) and DWI (B, and b) patients.

60 P. Maggio et al. / Journal of the Neurological Sciences 328 (2013) 58–63

All patients had a complete recanalization after the procedure, con-firmed by means of post-procedural angiography and duplex sonogra-phy at E1. No major complications were observed either during theintervention or during the follow-up period. No patient developed ar-rhythmias. One patient reported transient (lasting less than 2 h) leftupper limbweakness early after CAS. No other patient presented symp-toms suggestive of stroke during the entire follow-up. Neurological ex-amination and NIHSS score did not change during follow-up period forall patients. DWI lesionswere not detected on the basal evaluation. Ninepatients (24%) had at least one DWI lesion at E1 (DWI group), withoutNIHSS score increase.

3.1. DWI lesions after carotid artery stenting

We found a total of 34 DWI lesions. Twenty-six (76%)were ipsilater-al to the treated artery, 8 were contralateral. Twenty-four (71%) werecortical, 8 (23%) were subcortical, and 2 were cortico–subcortical. Elev-en DWI lesions were in MCA territory (32%), 4 (12%) in ACA territory, 2(6%) in PCA territory, and 17 (50%) were located in border zones. Out ofthese 17, 14 (82%) were found in external (cortical), and 3 in internal

(subcortical) border zones. One occurring on right precentral gyruswas symptomatic (transient left upper limb weakness).

3.2. Neuropsychological findings

Table 2 shows the differences between post-procedural andpre-procedural values (E2–E0) of each cognitive domain. Unadjustedand adjusted ANOVA analyses are summarized in Table 3. Cognitiveperformance remained stable after CAS in all patients (for all testp > .05), while a significant CAS∗DWI interaction was found forMMSE (CAS∗DWI: F = 7.154(32), p = .012). DWI group had a meanE2–E0 MMSE reduction of −1.5 (95% CI from −2.8 to −0.2), whilenon-DWI group had a mean E2–E0 MMSE of +0.5 (95% CI from −0.3to +1.3). A trend toward CAS∗DWI interaction was observed for de-layed memory (RAVLT-D) and visual memory (RROF) (respectively:F = 3.651(30), p = .066 and F = 3.985(25), p = .057).

After adjusting for patient-related factors potentially influencingcognitive status a significant CAS∗DWI interaction was confirmed forMMSE (CAS∗DWI: F = 7.092(13), p = .020): DWI group showed amean E2–E0 MMSE reduction of −3.1 (95% CI ranging from −5.8 to

Fig. 2. Axial diffusion-weighted image (left) shows a small hyperintense area in left frontal region which looks hypointense on the corresponding ADC map (right) due to local tis-sue ischemia.

61P. Maggio et al. / Journal of the Neurological Sciences 328 (2013) 58–63

−0.5), while non-DWI group showed a mean E2–E0 MMSE of +1.1(95% CI from −0.3 to +2.5, see Fig. 3).

Baseline characteristics of patients grouped according to DWI aresummarized in Table 4. Comparing E0 neuropsychological findings,DWI group had worse cognitive performance in short and long-term

Table 1Baseline characteristicsa of patients undergoing CAS.

Demography and lifestyle

Age, years, (SD) 72.9 (7.9)Years of education, (SD) 8.7 (4.4)Gender, female 35%Hypertension 81%Diabetes 40%Hypercholesterolemia 78%Smoking habit 35%

Ultrasound findings

Side carotid artery stenosis, right 59%Degree of stenosis, %(SD) 77 (8)Contralateral internal artery stenosisb30% 38%30–45% 38%50–65% 19%>70% 5%

MR findings

White matter hyperintensities, cm3 (SD) 4.21 (5.2)Whole brain volume, cm3 (SD) 1422.08 (87.2)

Neuropsychological findings

MMSE median (min–max) 27 (14–30)Immediate memory (RAVLT-I) (SD) 37.6 (7.1)Delayed memory (RAVLT-D) (SD) 7.5 (1.7)Visual memory (RROF) (SD) 8 (5.2)Attention (DBT) (SD) 91.5 (11.5)Language (ND) (SD) 27.6 (3.2)Executive functions (RPM) (SD) 25.6 (5.6)Time interval, months: median (min–max) 14 (4–41)

MMSE: mini-mental state examination; RAVLT-I: Rey's Auditorial Verbal LearningTest—Immediate; RAVLT-D: Rey's Auditorial Verbal Learning Test—Delayed; RROF:Recall of Rey–Osterrieth Complex Figure Test; DBT: Double Barrage Test; ND: OralDenomination Names; and RPM: Raven's Progressive Matrices Test.

a For continuous variables, values were expressed as mean ± SD; for categoricalvariables, percent were used. MMSE was expressed as median (min–max range).

memory tests (RAVLT-I and RAVLT-D) than non-DWI one (p b .05).Moreover, DWI group showed higher WMH volume (see Fig. 1),although not statistically significant.

4. Discussion

The main finding of our study is that CAS-induced brainmicroembolism, evidenced by post-procedural DWI lesions, impactsnegatively on cognitive functions. This result was confirmed afteradjusting for patient-related factors potentially influencing cognitivestatus (demographic features, vascular risk profile, baseline neuropsy-chological evaluation and MR findings of brain structural damage).

CAS is known to induce new ischemic lesions detectable bypost-procedural DWI MR, whose incidence ranges from 10 to 40%[20]. CAS-related DWI lesions often occur in the cerebral cortex,mostly in watershed territories [21]. In our sample DWI lesion inci-dence was 24%; they were mostly cortical and lied in border zonesin half cases, in line with previous reports [20,21].

Table 2Differences between post-procedural and pre-procedural neuropsychological findings(E2–E0).

Cognitive domaina Non-DWI DWI p-Value

MMSE median (min/max)b 0 (−3/+6) −1 (−5/+3) .017Verbal immediate memory(RAVLT-I)

+2.08 (7.0) −1.20 (4.3) .202

Verbal delayed memory(RAVLT-D)

+0.80 (1.8) −0.70 (1.6) .066

Visual delayed memory (RROF) +1.38 (4.0) −2.40 (2.5) .057Attention (DBT) −3.66 (60.9) +29.40 (75.2) .469Language (ND) −0.12 (1.1) −0.50 (1.9) .501Executive functions (RPM) −0.56 (5.2) −1.47 (4.0) .656

MMSE: Mini-mental State Examination; RAVLT-I: Rey's Auditorial Verbal LearningTest—Immediate; RAVLT-D: Rey's Auditorial Verbal Learning Test—Delayed; RROF:recall of Rey–Osterrieth Complex Figure Test; DBT: Double Barrage Test; ND: OralDenomination Names; and RPM: Raven's Progressive Matrices Test. Significant (p b .05)interactions are evidenced in bold.

a Differences are expressed as E2–E0 age- and education-corrected mean (SD)scores, but attention (DBT) that is expressed as E2–E0 age- and education-correctedmean (SD) seconds needed to perform the task.

b Median E2–E0 MMSE (min/max range) for non-DWI and DWI groups and p-Valueof non-parametric statistics (Mann–Whitney test).

Table 3Unadjusted and adjusted ANOVA analysis of CAS (E2–E0), DWI and CAS∗DWI effectson cognitive tests.

Cognitive function Sources ofvariation

Unadjusted Adjusteda

F(df) p-Value F(df) p-Value

MMSE CAS 1.604(32) .214 .300(13) .593DWI 10.228(32) .003 7.092(13) .020CAS∗DWI 7.154(32) .012 7.092(13) .020

Verbal immediatememory(RAVLT-I)

CAS .123(32) .728 .155(13) .700DWI 14.355(32) .001 .011(13) .920CAS∗DWI 1.699(32) .202 .011(13) .920

Verbal delayedmemory(RAVLT-D)

CAS .017(30) .898 2.650(11) .132DWI 11.452(30) .002 .058(11) .814CAS∗DWI 3.651(30) .066 .058(11) .814

Visual delayedmemory(RROF)

CAS .289(25) .596 .313(8) .591DWI .188(25) .669 1.370 (8) .276CAS∗DWI 3.985(25) .057 1.370 (8) .276

Attention(DBT)

CAS .712(27) .406 .176(9) .685DWI 3.832 (27) .061 2.042(9) .187CAS∗DWI .539 (27) .469 2.042(9) .187

Language(ND)

CAS 1.232(31) .276 3.077(12) .105DWI 3.146(31) .086 1.301(12) .276CAS∗DWI .463(31) .501 1.301(12) .276

Executive functions(RPM)

CAS 1.007(30) .324 .709(12) .416DWI 3.311 (30) .079 .548(12) .473CAS∗DWI .202(30) .656 .548(12) .473

MMSE: Mini-mental State Examination; RAVLT-I: Rey's Auditorial Verbal LearningTest—Immediate; RAVLT-D: Rey's Auditorial Verbal Learning Test—Delayed; RROF:recall of Rey–Osterrieth Complex Figure Test; DBT: Double Barrage Test; ND: OralDenomination Names; and RPM: Raven's Progressive Matrices Test. Significant (p b .05)interactions are evidenced in bold.

a The following covariates were considered: age, years of education, smoking, hyper-tension, diabetes, hypercholesterolemia, white matter hyperintensities, whole brainvolume, follow-up length, and cognitive function at baseline (respectively MMSE,RAVLT-I, RAVLT-D, RROF, DBT, ND, and RPM).

Table 4Comparison of baseline characteristics between DWI and non-DWI groups.

Characteristicsa Non-DWI DWI p-Value

Demography and lifestyleAge, years (SD) 72.6 (8.3) 74 (7.5) .678Years of education (SD) 9.8 (4.4) 6.7 (3.2) .073Gender, female 40% 22% .439Hypertension 80% 77.8% .999Diabetes 28% 66.7% .057Hypercholesterolemia 80% 66.7% .649Smoking habit 36% 44.4% .704

Ultrasound findingsDegree of stenosis, %(SD) 78.6 (8.2) 76.1 (6.9) .426Side of stenosis, right 68% 44.4% .254

MR findingsWhite matter hyperintensities, cm3 (SD) 2.95 (3.8) 8 (7.2) .092Whole brain volume, cm3 (SD) 1431.54

(85.3)1399.52(101)

.431

Neuropsychological findingsMMSE median (min–max)b 27 (20–30) 27 (14–29) .140Verbal immediate memory (RAVLT-I)(SD)

39.9 (5.6) 31.6 (8.8) .003

Verbal delayed memory (RAVLT-D) (SD) 7.9 (1.6) 6.1 (1.6) .015Visual delayed memory (RROF) (SD) 8.5 (4.5) 7.8 (6.9) .751Attention (DBT) (SD) 93.4 (9.1) 83 (18.8) .130Language (ND) (SD) 28.4 (1.6) 26.6 (4.3) .578Executive functions (RPM) (SD) 27.4 (4.3) 24.2 (5.7) .109Time interval, monthsmedian (min–max)

14 (4–40) 14 (4–41) .784

MMSE: Mini-mental State Examination; RAVLT-I: Rey's Auditorial Verbal LearningTest—Immediate; RAVLT-D: Rey's Auditorial Verbal Learning Test—Delayed; RROF:recall of Rey–Osterrieth Complex Figure Test; DBT: Double Barrage Test; ND: OralDenomination Names; and RPM: Raven's Progressive Matrices Test. Significant (p b .05)interactions are evidenced in bold.

a For continuous variables, values were expressed as mean ± SD; for categoricalvariables, percent were used.

b Baseline median MMSE (min–max range), for non-DWI and DWI groups andp-value of non-parametric statistics (Mann–Whitney test).

62 P. Maggio et al. / Journal of the Neurological Sciences 328 (2013) 58–63

Post-mortem studies showed that in vascular dementia brainmicroinfarcts are mostly visible in the cerebral cortex, particularly inwatershed areas [22]. Moreover, cortical rather than subcortical cere-bralmicroinfarcts are independently associatedwith the risk of demen-tia also after controlling for larger brain infarcts [23]. DWI areas arelikely prone to turn into brain ischemic microdamage detectable invivo by T2-weighted MR sequence [24]. On this basis, it is reasonableto hypothesize that CAS-induced cortical microischemic lesion loadcould be the main pathogenic determinant of cognitive impairment.

Disappearing of DWI lesions on follow-up T2-weighted imageshas also been reported [25]. However, only very small DWI-positivefoci did not turn into stable T2-weighted lesions [25], which reliably

Fig. 3. In adjusted ANOVA analysis CAS∗DWI interaction was confirmed for MMSE.DWI group showed a mean E2–E0 MMSE reduction of −3.1 (blue bar) (95% CI rangingfrom −5.8 to −0.5, black segment), while non-DWI group showed a mean E2–E0MMSE of +1.1 (blue bar) (95% CI from −0.3 to +2.5, black segment).

indicate low sensitivity of T2-weighted images in detecting small is-chemic lesions. Moreover, pathological studies observed structuralneuronal injury also in those areas of rapid normalization of restricteddiffusion after transient experimental ischemia [26], suggesting thatDWI lesions vanishing does not mean absence of brain ischemicdamage.

Conversely, although the sensitivity and specificity of DWI for thedetection of acute ischemic lesions exceed 90% [27], false-negativeDWI has been described for very small infarcts [28] especially for cor-tical ones [29]. Thus, microischemic lesions load after CAS might belargely underestimated by current MR techniques, and DWI areasdetected after CAS could represent just the tip of the iceberg of agreater hidden cortical damage. More accurate MR techniques aremandatory to verify this hypothesis.

To our knowledge, this is the first report showing a role of DWI le-sions on cognitive status also after controlling for patient-related var-iables. Vascular risk factors and carotid disease are recognized toinfluence cognitive status [9,10,30]. Moreover, conventional vascularrisk factors [31] and atherosclerosis [32] are associated with WMH,which was in turn related to cognitive function [31], and with subcor-tical and cortical brain atrophy [33]. These complex interactions ulti-mately act together in patients undergoing CAS and may explaincontroversial results obtained to date [6].

Moreover, we performed a pre-procedural comparison betweengroups. Immediate and delayed verbal memory scores (RAVLT-I andRAVLT-D) were found to be significantly impaired in the group withnew ischemic lesions. Furthermore, a higher WMH load was foundin DWI group, although without an overt statistical significance.These results are in agreement with previous findings, reporting an

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independent association between high WMH volume and worse epi-sodic verbal memory scores [34,35]. A pre-existing subtle vascularcognitive impairment involving mostly memory skills in patientswith new DWI lesions could be hypothesized. Whether patientsreportingnew ischemic brain lesions after CAS aremore exposed to vas-cular brain damage and related-cognitive impairment independently ofendovascular procedure has to be clarified. A possible explanation isthat these patients may have a reduced capability of cerebral vesselsof washing-out microemboli originating from carotid plaques [36].This may thus be responsible both for pre-existing and CAS-enhancedbrain microembolism, with consequent higher basal WMH load andsubtle cognitive impairment.

This study presents some limitations. First, the relatively smallnumber of patients with DWI lesions does not allow drawing defini-tive conclusions. In addition, the different length of follow-up neuropsy-chological evaluation might theoretically have affected the analysis.However, after adjusting formonths of follow-up as covariate, our resultswere confirmed. Another limitation of our study is that we did not per-form microembolic signal detection using TCD immediately before, dur-ing and early after CAS. Therefore we cannot prove whether DWIlesions were induced by artery-to-artery embolism or by low perfusionin patients with hemodynamic stenosis. However, performing MR justfew hours before and after CASmakes the latter hypothesis very unlikely.Finally, the presence of mono or bilateral severe internal carotid arterydiseasemay be associatedwith impairment in specific cognitive domainsin relation to the side of the stenosis and its hemodynamic consequences,as demonstrated previously [37,38]. However, this further evaluationwasunfeasible in our study due to the relatively low number of includedsubjects.

In conclusion, our study showed that cognitive function seems notto be influenced by carotid stenting per se but by peri-procedural loadof cerebral microembolic lesions. The impact of DWI areas is con-firmed independently from influence of patient-related variables. Fu-ture studies in larger groups of patients are needed to investigate ifcerebral hemodynamics may predict the risk of micro-embolic braindamage following endovascular procedures and of CAS-induced cog-nitive deterioration.

Disclosure of conflict of interest

None.

Disclosure of sources of funding

None.

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