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Objective: Cortical thinning has been reported in patients with cerebrovascular disease and degenerative dementia, but the direct impact of regional hypoperfusion on cortical pathology has been difficult to establish. We examined the association between regional cerebral blood flow (rCBF) and regional cortical thickness (rCT) in a cohort of patients with unilateral high-grade internal carotid artery (ICA) disease without history of stroke. Methods: Twenty-seven patients age 73±10yrs, 11F with unilateral ICA stenosis ≥80% or occlusion but no stroke underwent MRI, including high resolution T1 (MPRAGE) and tissue specific pseudocontinuous arterial spin labeling (ts-pCASL) to assess cortical thickness and gray matter resting CBF. Cortical thickness was measured in each hemisphere in the primary motor cortex (M1--Brodmann Area 4) by a blinded investigator using Freesurfer software ( http://surfer.nmr.mgh.harvard.edu/ ), and in visual cortex (V1, Brodmann area 17) as a control for nonspecific effects in the posterior circulation. Paired t-tests were used to assess hemispheral asymmetry for rCBF and for rCT in M1 on the occluded vs unoccluded side. Linear regression was used to predict the effect of rCBF on rCT in M1 on the occluded side. Results: Cortex was 0.08mm thinner on the side of ICA occlusion in M1 (95%CI=0.04-0.11, p=0.0003). There was no rCT asymmetry in V1 (p=.276). rCBF was 9.3 ml/100gm*min -1 lower in M1 of the occluded hemisphere (95%CI=5.1-13.5, p2 =.128, p=.038). Conclusion: Cortical thinning occurred in M1 on the side of carotid occlusion in the absence of stroke, and correlated with lower rCBF. Brodmann area 4 was chosen to represent the distal field of the carotid artery. Our finding demonstrates an important effect of chronically reduced blood flow on brain pathology, and suggests that a broader definition of “symptomatic” carotid artery disease may be needed.

Background: Cerebral blood flow (CBF) regulation is a critical element in cerebrovascular pathophysiology, particularly in large vessel disease. Different methods to assess hemodynamics may represent different aspects of blood flow regulation, however, uniquely affecting outcomes and management. We examined 4 different blood-flow related measures in patients with high-grade unilateral carotid disease, assessing asymmetry between the occluded vs non-occluded side, and the correlations among the measures. Methods: Thirty-three patients (age 50-93, 19M) with unilateral 80-100% ICA occlusion but no stroke underwent: 1) quantitative resting CBF using continuous arterial spin labeling (CASL) MRI, 2) mean flow velocity (MFV) in both middle cerebral arteries (MCAs) by transcranial Doppler, 3). Vasomotor reactivity (VMR) in response to 2 minutes of 5% CO2 inhalation, and 4) Dynamic cerebral autoregulation (DCA) using continuous insonation of both MCAs for 10 minutes at depth 56mm with a standard head frame. Phase shift (PS) between spontaneous oscillations in blood pressure (measured with finger photoplethysmography) and MCA MFV at frequencies .06-.12 Hz was calculated for each hemisphere using transfer function analysis. Lower PS indicated worse autoregulation. Paired T-tests and Pearson correlations were used to look for side-to-side differences within each measure, and correlations between measures (SPSS v.22). Results: CASL CBF (p=.001), MFV (p0.09). Conclusions: These 4 measures showed high sensitivity to the occluded carotid artery, but appear to represent independent aspects of cerebral blood flow (CASL: resting gray matter CBF; MFV: whole-hemisphere CBF; VMR: cerebrovascular reserve, and DCA: homeostatic blood flow regulation) suggesting that any given measure only partially characterizes hemodynamic state. Further investigation will use these 4 measures to predict outcomes including vascular cognitive impairment.

Background: High grade internal carotid artery (ICA) disease can alter cerebral autoregulation and thus increase risk for ischemia. We aimed to differentiate two types of autoregulation - dynamic cerebral autoregulation (DCA), thought to be a homeostatic process, and vasomotor reactivity (VMR), which determines cerebrovascular reserve - in patients with asymptomatic ICA stenosis. Methods: Twenty-two patients (age 50-93, 16M) with unilateral 80-100% ICA occlusion but no stroke underwent quantitative CBF measurements using continuous arterial spin labeling (CASL) MRI. DCA was performed by continuous insonation of both middle cerebral arteries with transcranial Doppler for 10 minutes at depth 56mm using a standard head frame. Phase shift (PS) between spontaneous oscillations in blood pressure (measured with finger photoplethysmography (Finapres)) and MCA mean flow velocities (MFV) at frequencies .06-.12 Hz was calculated for each hemisphere using transfer function analysis. Lower degree of PS indicated worse autoregulation (abnormal Results: MCA MFV (p Conclusions: DCA but not VMR correlated with a low flow state produced by high grade ICA disease in asymptomatic patients. Our results suggest that in ICA stenosis dynamic/homeostatic mechanisms may be affected without substantially altering the static/protective mechanism of cerebrovascular reserve. Ongoing studies will investigate the effect of these two autoregulatory mechanisms on vascular cognitive impairment. 1 Ortega-Gutierrez S, et al. J Neuroimaging. 2014 24:379-86

Background: High grade carotid stenosis produces hemodynamic effects on the brain, but the relationship between cerebral autoregulation, absolute CBF and neurovascular coupling has not been well-delineated. Methods: Twelve subjects (age 74±9, 3F) with unilateral ICA stenosis (80-100% occluded) but no infarct (asymptomatic or TIA only) underwent dynamic cerebral autoregulation (DCA) testing with transcranial Doppler by comparing phase shift (PS) of spontaneous oscillations in blood pressure (measured with finger photoplethysmography (Finapres)) versus MCA flow velocities at frequencies .06-.12 Hz using transfer function analysis, lower degree of PS indicating worse autoregulation.Neurovascular coupling was assessed by amplitude of absolute increase in CBF in bilateral Brodman area (BA) 4 during a bilateral repetitive hand closure task using continuous arterial spin labeling (CASL) MRI. Four activation (ON) periods were averaged and subtracted from 4 rest (OFF) periods. Resting CBF for each hemisphere’s motor cortex was determined by averaging the OFF periods. Results: All subjects showed: 1) hemispheric asymmetry in baseline CBF with the occluded side being on average 25mL/100g*min (+/- 14 mL/100g*min) lower than the unoccluded hemisphere. 2) hemispheric asymmetry in motor activation: unoccluded hemisphere average activation (mean_CBF_ON - mean_CBF_OFF) in BA4 was 23.7mL/100g*min, representing a 21% increase in local CBF due to activation; occluded hemisphere mean activation was 14 mL/100g*min, representing 18% percent increase in local CBF. 3) Hemispheric asymmetry in DCA, PS=33.1 deg ± 31 on the occluded side vs. 43.5 deg±23 on the non-occluded side. Both the hemispheral difference in baseline CBF (impaired flow) and the difference in DCA measurement (impaired autoregulation) were good predictors of the lower activation (neurovascular coupling) on the occluded hemisphere: R 2 = 0.85 and 0.80, respectively. Conclusion: Both impaired resting CBF and impaired cerebral autoregulation appear to contribute to decreased neurovascular coupling in carotid artery occlusive disease, representing a potential mechanism for occult neuronal dysfunction such as mild cognitive impairment in this patient population.