Ultrasound Imaging Markers of Carotid Atherosclerosis are Associated with Cognition Through Cerebral Small Vessel Disease on MRI
Taylor Ariko1, Botagoz Aimagambetova2, Hannah Gardener3, Bonnie Levin3, Xiaoyan Sun3, Digna Cabral3, Carolina Gutierrez3, Weizhao Zhao1, Noam Alperin4, Consuelo Mora-McLaughlin5, Mitchell Elkind5, Jose Gutierrez5, Clinton Wright6, Ralph Sacco3, Tatjana Rundek2
1Department of Biomedical Engineering, University of Miami, 2Evelyn F. McKnight Brain Insititute, 3Department of Neurology, 4Department of Radiology, University of Miami Miller School of Medicine, 5Department of Neurology, Columbia University, 6National Institute of Neurological Disorders and Stroke
Objective:
Determine whether markers of carotid atherosclerosis are associated with cognitive function through the burden of white matter disease.
Background:
Atherosclerosis is a risk factor for cognitive decline. Ultrasonographic measures of carotid atherosclerosis (plaque and intima-media thickness) and MRI measures of small vessel disease (white matter hyperintensity volume) are subclinical markers of cerebrovascular disease that are associated with cognitive dysfunction. 
Design/Methods:
We included 1290 subjects from the racially and ethnically diverse Northern Manhattan Study (age 64+/-8years, 60% women, 67% Hispanic, 18% Black, 15% White, education 10+/-5years). We assessed total plaque area (TPA) and intima-media thickness (cIMT) measures on carotid ultrasound and measures of white matter hyperintensity volume (WMHV) on MRI. Participants underwent neurocognitive evaluation to estimate global cognitive performance and domains of episodic memory, executive function, semantic memory, and processing speed. Associative mediation models were employed to determine if WMHV mediates the association of TPA and cIMT on global and domain-specific cognitive performance adjusting for age, sex, race, ethnicity, education, ApoE4 status, hypertension, hypercholesteremia, diabetes, and smoking.
Results:
Of the 1290 participants, 675 had carotid plaque (TPA 21+/-22mm2, cIMT 0.95+/-0.09mm, and WMHV 0.77+/-0.93%TIV). WMHV(log) mediated the association of TPA on global cognition [b(indirect-effect)=-0.001, p<0.05], episodic memory [b(indirect-effect)=-0.001, p<0.05], and processing speed [b(indirect-effect)=-0.001, p<0.05)] after adjustment. WMHV(log) volume mediated the association of cIMT on global cognition [b(indirect-effect)=-0.073, p<0.05], episodic memory [b(indirect-effect)=-0.112, p<0.05], and processing speed [b(indirect-effect)=-0.097, p<0.05] after adjustment. No associations were present for executive function and semantic memory.
Conclusions:
Ultrasound measures of extracranial carotid arteriosclerosis are related to intracranial MRI measures of small vessel disease and associated with cognitive performance. White matter hyperintensity volume may be an important factor in understanding the biological link between atherosclerosis and cognitive dysfunction in middle to older age population. More research is needed to better understand vascular imaging biomarkers of age-related cognitive dysfunction. 
10.1212/WNL.0000000000202087