Decisions regarding risk stratification and intervention for carotid stenosis have traditionally been based on overt symptomatology in the setting of luminal narrowing. However, mounting evidence has suggested conventional definitions of “symptoms” (eg, stroke, amaurosis fugax, etc.) may miss silent embolic infarcts and chronic hypoperfusion leading to debilitating, albeit subclinical, neurocognitive impairment. Objective identification of global brain dysfunction in asymptomatic carotid stenosis is challenging; however, resting-state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI) have recently been evaluated as tools to assess functional and microstructural connectivity in other neuropsychiatric pathologies. It is against this background that Lin et al evaluated whether functional connectivity measures utilizing fMRI and DTI may be used for early diagnosis of cognitive impairment in patients suffering asymptomatic severe carotid artery stenosis.1 Ideally, these radiographic adjuncts may identify the most appropriate patients for revascularization at pre-symptomatic stages, before the onset of irreversible cognitive dysfunction.
The authors performed a prospective, case-control trial, enrolling healthy volunteers and patients matched for age, sex, cardiovascular risk factors, and education level. Patients included for analysis were between 55 and 80 years of age with incidentally discovered, unilateral ICA stenosis ≥70% on both duplex ultrasonography and MR angiography (according to NASCET criteria). Exclusion criteria were prior cerebrovascular ischemic event(s), contralateral ICA stenosis ≥50%, dementia, functional disability, and major neuropsychiatric and/or systemic disease. A blinded neurologist and neuroradiologist evaluated all images. Radiographic measures included leukoaraiosis, cortical and white matter volumes, fiber tract integrity (ie, fractional anisotropy, FA), and regional functional connectivity (ie, inter-hemispheric connections between homologous regions/networks, Fc). The primary endpoint was mild cognitive impairment, defined as performance 1.5 standard-deviations below matched controls in cognitive test performance (attention, verbal memory, executive function, and visuospatial perception tests).
Thirty consecutive patients and 30 matched-healthy controls were enrolled. Fifty-five percent were male, with an average degree of stenosis of 81%. There were no significant differences in leukoaraiosis or general gray-white matter volumes. However, microstructural white matter integrity and interhemispheric connections among prefrontal, motor, somatosensory, parietal, and insular cortex were profoundly different between cohorts. Patients with carotid stenosis had worse dizziness scores and poorer verbal memory, executive function and complex visuo-spatial performance than controls. Forty percent of the patients harboring so-called “asymptomatic,” severe carotid stenosis met criteria for mild cognitive impairment. Overall, the presence of disrupted white matter integrity and functional connectivity was 92% accurate at predicting cognitive impairment.
These results demonstrate the utility of radiographic connectivity measures as surrogate markers of incipient neurocognitive damage due to severe “asymptomatic” stenosis of the ICA. Furthermore, these data point toward widespread, inter-hemispheric injury as the neural substrate for the observed cognitive decline suffered by patients with clinically silent severe carotid stenosis. The utility of these findings is bolstered by prior work demonstrating measurable functional connectivity and accompanying cognitive improvement following successful carotid revascularization.
This work represents diligent and timely work by the authors; however, several issues remain unresolved. Due to the cross sectional design of this study, a causal relationship was not assessed between radiographic measures and the risk of developing frank ischemic events (stroke, TIA, etc.) or if, in this population, these changes were reversible with revascularization. Prospective, independent evaluation will be needed to validate, and fine-tune which functional networks (frontoparietal, insular, etc.) provide the most robust assessment of injury. This study elegantly demonstrates that patients with severe asymptomatic carotid stenosis may suffer extensive disruption in brain networks even at the pre-symptomatic stage. Radiographic assessment of microstructural integrity and functional connectivity may allow refined risk stratification in patients with carotid stenosis. These techniques may one day identify those in more urgent need of revascularization, before a clinically evident event occurs. Also, longitudinal measurements could provide ongoing assessment of the efficacy of various interventions for the mitigation of cognitive impairment caused by supposedly asymptomatic carotid disease.
1. Lin CJ, Tu PC, Chern CM, et al.. Connectivity features for identifying cognitive impairment in presymptomatic carotid stenosis. PLOS One. 2014;9(1):e85441. doi: 10.1371/journal.pone.0085441.