IMaging Della PLAcca Carotidea
IMaging Della PLAcca Carotidea
Background-White matter hyperintensities (WMH), patchy areas of hyperintense signal on
 T2-weighted or Fluid Attenuated Inversion Recovery sequences on brain magnetic resonance
 imaging (MRI), are believed to reflect cerebral burden of ischemic damage and are associated
 to incident stroke, dementia and eventually mortality in otherwise healthy subjects. Also
 brain atrophy has been related with presence of carotid atherosclerosis and vascular
 cognitive impairment. Carotid atherosclerosis may contribute to the genesis of WMH. A recent
 meta-analysis by our group comprising 5306 subjects was able to demonstrate an association
 between the presence of carotid atherosclerosis and WMH (odds ratio, OR, 1.42, 95% confidence
 interval [CI] 1.22-1.66).

 Objective-To evaluate the relation between carotid artery plaque characteristics,
 cardiovascular risk factors and brain atrophy/WMH burden analyzed quantitatively as number
 and volume of lesions and as brain volumes, and progression over 18 months of follow up in
 subjects asymptomatic for cerebrovascular disease with a carotid artery stenosis <70%.
-  Ischemic stroke and vascular cognitive impairment pose a massive clinical, social and
 economic burden. Disruption of carotid plaques, often non-obstructive, with subsequent
 thrombosis and distal embolization is one of leading pathogenetic mechanism of ischemic
 stroke. The widespread use of brain magnetic resonance imaging (MRI) has enabled an
 increased recognition, especially in elderly subjects, of cerebral alterations in
 apparently healthy individuals.

 -  Carotid plaque may be causative in the development of white matter hyperintensities
 (WMH, patchy areas of signal hyperintensity on T2-weighted and/or fluid attenuated
 inversion recovery -FLAIR- sequences), silent brain infarcts (SBI) and eventually brain
 atrophy.

 -  The hypothesis of the investigators is that carotid plaques with features of
 vulnerability detected by multimodality imaging (including standard ultrasound, contrast
 enhanced ultrasound -CEUS-, contrast enhanced CT angiography) and larger extent of
 atherosclerotic process, even if determining only an intermediate degree of stenosis,
 could bear a more rapid progression of silent WMH and brain atrophy.

 -  Carotid CT and CEUS allow fast and reproducible evaluation of plaque size and
 morphology, alongside with functional parameters. Plaque density and positive
 remodelling on CT have been repeatedly associated to histological features of plaque
 vulnerability. At the same time, when compared to standard duplex evaluation, CEUS
 allowed a better imaging definition of plaque margins and extension, and to evaluate
 intraplaque neovascularization. The latter associates with local inflammation and plaque
 vulnerability, and might give rise to plaque hematomas, which are among the substrates
 for lesion progression and for the development of atherothrombosis.

 -  In the initial phase of the study also hybrid imaging with positron tomography and
 computed tomography angiography (PET/CTA) using 11C-PK11195 was used to detect and
 quantify intraplaque inflammation in humans.(7) C-PK11195 is a selective ligand for
 translocator protein, 18kDa (TSPO), which is highly expressed on the surface of
 activated monocytes/macrophages. This part of the study was prematurely stopped due to
 problems with the production of the radiotracer with 11[C] (only 13 patients were
 studied with this approach).

 Primary endpoints:

 - The primary endpoint is to identify independent predictors (plaque-related or
 patient-related) with the progression of WMH through multivariable logistic regression
 analysis.

 Progression of WMH was considered as dichotomous variable: progression versus no progression
 of WMH.

 - The co-primary end-point is to identify independent predictors (plaque-related or
 patient-related) with the progression of gray matter (GM)/all brain atrophy through
 multivariable logistic regression analysis. Progression of brain atrophy was considered as
 dichotomous variable: progression versus no progression of GM/all brain atrophy.

 Statistical considerations:

 The investigators calculated the sample size for multivariate logistic regression analysis
 with a power of 0.8 and an alpha of 0.05. The investigators will analyze the highest tertile
 of carotid plaques burden in terms of plaque volume versus others (see Sillesen, 2012). By
 definition, the prevalence of high burden atherosclerosis will be 33%. The investigators
 estimated a clinically relevant probability of progressing in terms of WMH in the high burden
 group to be 50%, while subjects without high burden plaques are estimated to progress in
 terms of WMH as the general population with carotid atherosclerosis in a similar time frame.
 This probability would be estimated to be around 15% (see Dufoil, 2005 and Pico, 2002). The
 estimated sample size would be 58 individuals.
Inclusion Criteria:

 - bearing an asymptomatic carotid stenosis of 30-70% in diameter, as established by
 Doppler-measured peak systolic flow velocity, according to the Society of Radiologists in
 Ultrasound Consensus Conference (Grant et al. Radiology 2003).

 Exclusion Criteria:

 -  pregnancy or possibility of pregnancy,

 -  history of allergic diathesis,

 -  history of stroke or transitory ischemic attack,

 -  previous carotid artery stenting or carotid endarterectomy,

 -  history of autoimmune vasculitis,

 -  History of drug abuse, alcohol abuse or any psychiatric or social condition which may
 contraindicate the participation to a clinical study

 -  life expectancy of less than 18 months due to underlying medical conditions,

 -  presence of cognitive impairment preventing the patient from providing informed
 consent,

 -  Atrial fibrillation or previous cardiac surgery or positioning of intracardiac devices
 (excluded coronary stents) as potential confounding causes of cerebral ischemic
 damage,

 -  Known patent foramen ovale (PFO) necessitating anti-platelet treatment

 -  Current anti-coagulation,

 -  Previous infections to the central nervous system (CNS)

 -  Previous surgery to the CNS

 -  History of anoxic damage to the CNS

 -  Dementia

 -  Contraindications to computed tomography angiography (CTA, estimated Glomerular
 Filtration Rate<60 mL/min; history of allergic reaction to iodinated contrast media),

 -  Specific contraindication to MRI:

 -  Claustrophobia

 -  Sickle cell anemia

 -  Systemic mastocytosis

 -  Implanted cardiac devices (i.e. pacemakers, implantable cardioverter
 defibrillators)

 -  Vascular clips

 -  Vertebral distractors

 -  Infusion pumps

 -  Neurostimulators

 -  Liquor derivations

 -  Any device which could be dispositioned in the presence of a strong magnetic
 field