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