Assessment of Small Vessel Function Using 7T MRI in Patients With Sporadic Cerebral Small Vessel Disease: The ZOOM@SVDs Study.

BACKGROUND AND OBJECTIVES: Cerebral small vessel disease (cSVD) is a major cause of stroke and dementia, but little is known about disease mechanisms at the level of the small vessels. 7T-MRI allows assessing small vessel function in vivo in different vessel populations. We hypothesized that multiple aspects of small vessel function are altered in patients with cSVD and that these abnormalities relate to disease burden. METHODS: Patients and controls participated in a prospective observational cohort study, the ZOOM@SVDs study. Small vessel function measures on 7T-MRI included perforating artery blood flow velocity and pulsatility index in the basal ganglia and centrum semiovale, vascular reactivity to visual stimulation in the occipital cortex, and reactivity to hypercapnia in the gray and white matter. Lesion load on 3T-MRI and cognitive function were used to assess disease burden. RESULTS: Forty-six patients with sporadic cSVD (mean age ± SD 65 ± 9 years) and 22 matched controls (64 ± 7 years) participated in the ZOOM@SVDs study. Compared with controls, patients had increased pulsatility index (mean difference 0.09, p = 0.01) but similar blood flow velocity in basal ganglia perforating arteries and similar flow velocity and pulsatility index in centrum semiovale perforating arteries. The duration of the vascular response to brief visual stimulation in the occipital cortex was shorter in patients than in controls (mean difference -0.63 seconds, p = 0.02), whereas reactivity to hypercapnia was not significantly affected in the gray and total white matter. Among patients, reactivity to hypercapnia was lower in white matter hyperintensities compared with normal-appearing white matter (blood-oxygen-level dependent mean difference 0.35%, p = 0.001). Blood flow velocity and pulsatility index in basal ganglia perforating arteries and reactivity to brief visual stimulation correlated with disease burden. DISCUSSION: We observed abnormalities in several aspects of small vessel function in patients with cSVD indicative of regionally increased arteriolar stiffness and decreased reactivity. Worse small vessel function also correlated with increased disease burden. These functional measures provide new mechanistic markers of sporadic cSVD.

Sex Differences in Plaque Composition and Morphology Among Symptomatic Patients With Mild-to-Moderate Carotid Artery Stenosis.

BACKGROUND AND PURPOSE: Incidence of ischemic stroke differs between men and women, with substantially higher rates in men. The underlying mechanism of this difference remains poorly understood but may be because of differences in carotid atherosclerosis. Using an in-depth imaging-based approach, we investigated differences between carotid plaque composition and morphology in male and female patients with stroke, taking into account differences in total plaque burden. Additionally, we investigated all possible within-artery combinations of plaque characteristics to explore differences between various plaque phenotypes. METHODS: We included 156 men and 68 women from the PARISK (Plaque At Risk) study, a prospective cohort study of patients with recent ischemic cerebrovascular symptoms and <70% ipsilateral carotid stenosis. Plaque characteristics (intraplaque hemorrhage [IPH], lipid-rich necrotic core [LRNC], calcifications, thin-or-ruptured fibrous cap, ulcerations, total plaque volume) were assessed with magnetic resonance imaging and multidetector-row computed tomography angiography. We used multivariable logistic and linear regression analyses to assess sex differences in plaque characteristics. RESULTS: We found significant difference in total plaque volume between men and women (ß=22.9 mm3 [95% CI, 15.4-30.5]; mean volume in men 1399±425 mm3, in women 1011±242 mm3). Additionally, men were more likely to have IPH (odds ratio [OR]=2.8 [95% CI, 1.3-6.3]; IPH proportion in men 49%, in women 16%) and LRNC (OR=2.4 [95% CI, 1.2-4.7]; LRNC proportion in men 73%, in women 41%) even after adjustment for total plaque volume. We found no sex-specific differences in plaque volume-corrected volumes of IPH, LRNC, and calcifications. In terms of coexistence of plaque characteristics, we found that men had more often a plaque with coexistence of calcifications, LRNC, and IPH (OR=2.7 [95% CI, 1.2-7.0]), with coexistence of thin-or-ruptured fibrous cap/ulcerations, LRNC, and IPH (OR=2.4 [95% CI, 1.1-5.9]), and with coexistence of all plaque characteristics (OR=3.0 [95% CI, 1.2-8.6]). CONCLUSIONS: In symptomatic patients with mild-to-moderate carotid stenosis, men are more likely to have a high-risk carotid plaque with IPH and LRNC than women, regardless of total plaque burden. Men also have more often a plaque with multiple vulnerable plaque components, which could comprise an even higher stroke risk. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01208025.

Editor's Choice - Risk of Stroke before Revascularisation in Patients with Symptomatic Carotid Stenosis: A Pooled Analysis of Randomised Controlled Trials.

OBJECTIVE: Current guidelines recommending rapid revascularisation of symptomatic carotid stenosis are largely based on data from clinical trials performed at a time when best medical therapy was potentially less effective than today. The risk of stroke and its predictors among patients with symptomatic carotid stenosis awaiting revascularisation in recent randomised controlled trials (RCTs) and in medical arms of earlier RCTs was assessed. METHODS: The pooled data of individual patients with symptomatic carotid stenosis randomised to stenting (CAS) or endarterectomy (CEA) in four recent RCTs, and of patients randomised to medical therapy in three earlier RCTs comparing CEA vs. medical therapy, were compared. The primary outcome event was any stroke occurring between randomisation and treatment by CAS or CEA, or within 120 days after randomisation. RESULTS: A total of 4 754 patients from recent trials and 1 227 from earlier trials were included. In recent trials, patients were randomised a median of 18 (IQR 7, 50) days after the qualifying event (QE). Twenty-three suffered a stroke while waiting for revascularisation (cumulative 120 day risk 1.97%, 95% confidence interval [CI] 0.75 - 3.17). Shorter time from QE until randomisation increased stroke risk after randomisation (χ2 = 6.58, p = .011). Sixty-one patients had a stroke within 120 days of randomisation in the medical arms of earlier trials (cumulative risk 5%, 95% CI 3.8 - 6.2). Stroke risk was lower in recent than earlier trials when adjusted for time between QE and randomisation, age, severity of QE, and degree of carotid stenosis (HR 0.47, 95% CI 0.25 - 0.88, p = .019). CONCLUSION: Patients with symptomatic carotid stenosis enrolled in recent large RCTs had a lower risk of stroke after randomisation than historical controls. The added benefit of carotid revascularisation to modern medical care needs to be revisited in future studies. Until then, adhering to current recommendations for early revascularisation of patients with symptomatic carotid stenosis considered to require invasive treatment is advisable.

Quantitative assessment of brachial plexus MRI for the diagnosis of chronic inflammatory neuropathies.

OBJECTIVE: This study aimed at developing a quantitative approach to assess abnormalities on MRI of the brachial plexus and the cervical roots in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) and to evaluate interrater reliability and its diagnostic value. METHODS: We performed a cross-sectional study in 50 patients with CIDP, 31 with MMN and 42 disease controls. We systematically measured cervical nerve root sizes on MRI bilaterally (C5, C6, C7) in the coronal [diameter (mm)] and sagittal planes [area (mm2)], next to the ganglion (G0) and 1 cm distal from the ganglion (G1). We determined their diagnostic value using a multivariate binary logistic model and ROC analysis. In addition, we evaluated intra- and interrater reliability. RESULTS: Nerve root size was larger in patients with CIDP and MMN compared to controls at all predetermined anatomical sites. We found that nerve root diameters in the coronal plane had optimal reliability (intrarater ICC 0.55-0.87; interrater ICC 0.65-0.90). AUC was 0.78 (95% CI 0.69-0.87) for measurements at G0 and 0.81 (95% CI 0.72-0.91) for measurements at G1. Importantly, our quantitative assessment of brachial plexus MRI identified an additional 10% of patients that showed response to treatment, but were missed by nerve conduction (NCS) and nerve ultrasound studies. CONCLUSION: Our study showed that a quantitative assessment of brachial plexus MRI is reliable. MRI can serve as an important additional diagnostic tool to identify treatment-responsive patients, complementary to NCS and nerve ultrasound.

Cross-sectional and longitudinal assessment of the upper cervical spinal cord in motor neuron disease.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neuromuscular disease characterized by both upper and lower motor neuron degeneration. While neuroimaging studies of the brain can detect upper motor neuron degeneration, these brain MRI scans also include the upper part of the cervical spinal cord, which offers the possibility to expand the focus also towards lower motor neuron degeneration. Here, we set out to investigate cross-sectional and longitudinal disease effects in the upper cervical spinal cord in patients with ALS, progressive muscular atrophy (PMA: primarily lower motor neuron involvement) and primary lateral sclerosis (PLS: primarily upper motor neuron involvement), and their relation to disease severity and grey and white matter brain measurements. METHODS: We enrolled 108 ALS patients without C9orf72 repeat expansion (ALS C9-), 26 ALS patients with C9orf72 repeat expansion (ALS C9+), 28 PLS patients, 56 PMA patients and 114 controls. During up to five visits, longitudinal T1-weighted brain MRI data were acquired and used to segment the upper cervical spinal cord (UCSC, up to C3) and individual cervical segments (C1 to C4) to calculate cross-sectional areas (CSA). Using linear (mixed-effects) models, the CSA differences were assessed between groups and correlated with disease severity. Furthermore, a relationship between CSA and brain measurements was examined in terms of cortical thickness of the precentral gyrus and white matter integrity of the corticospinal tract. RESULTS: Compared to controls, CSAs at baseline showed significantly thinner UCSC in all groups in the MND spectrum. Over time, ALS C9- patients demonstrated significant thinning of the UCSC and, more specifically, of segment C3 compared to controls. Progressive thinning over time was also observed in C1 of PMA patients, while ALS C9+ and PLS patients did not show any longitudinal changes. Longitudinal spinal cord measurements showed a significant relationship with disease severity and we found a significant correlation between spinal cord and motor cortex thickness or corticospinal tract integrity for PLS and PMA, but not for ALS patients. DISCUSSION: Our findings demonstrate atrophy of the upper cervical spinal cord in the motor neuron disease spectrum, which was progressive over time for all but PLS patients. Cervical spinal cord imaging in ALS seems to capture different disease effects than brain neuroimaging. Atrophy of the cervical spinal cord is therefore a promising additional biomarker for both diagnosis and disease progression and could help in the monitoring of treatment effects in future clinical trials.

Effect sizes of BOLD CVR, resting-state signal fluctuations and time delay measures for the assessment of hemodynamic impairment in carotid occlusion patients.

BACKGROUND AND PURPOSE: The BOLD signal amplitude as a response to a hypercapnia stimulus is commonly used to assess cerebrovascular reserve. Despite recent advances, the implementation remains cumbersome and alternative ways to assess hemodynamic impairment are desirable. Resting-state BOLD signal fluctuations (rsBOLD) have been proposed however data on its sensitivity and dependence on baseline venous cerebral blood volume (vCBV) is limited. The primary aim of this study was to compare the effect sizes of resting-state and hypercapnia induced BOLD signal changes in the detection of hemodynamic impairment. The second aim of the study was to assess the dependence of BOLD signal variability on vCBV. MATERIALS AND METHODS: Fifteen patients with internal carotid artery occlusive disease and 15 matched healthy controls were included in this study. The BOLD signal was derived from a dual-echo gradient-echo echo-planar sequence during hypercapnia (HC) and hyperoxia (HO) gas modulations. BOLD (fractional) amplitude of low frequency fluctuations ((f)ALFF) was compared to HC-BOLD, BOLD response delays derived from time delay analysis and ΔBOLD in response to progressively increasing HC. Effect sizes (i.e. the standard mean difference between patients and controls) were calculated. HO-BOLD was used to estimate vCBV, and its contribution to the variability in rsBOLD signal was evaluated. RESULTS: The effect sizes of ALFF and fALFF (0.61 and 0.72) were lower than the effect sizes related to hypercapnia-based hemodynamic assessment analysis; 1.62, 1.56 and 0.90 for HC-BOLD, BOLD response delays and ΔBOLD in response to progressively increasing HC. A moderate relation was found between (f)ALFF and HC-BOLD in controls (R2 of 0.61 and 0.42), but this relation decreased in patients (R2 of 0.33 and 0.15). (f)ALFF did not differ between patients and controls whereas HC-BOLD did (p < 0.005). The ΔBOLD response to progressively increasing HC was significantly different in between patients and controls for ΔEtCO2 values ≥ 2 mmHg (at +2  mmHg F(1, 18) = 5.85, p = 0.026). Up to 31% and 53% of the variance in the ALFF and HC-BOLD spatial distribution could be explained by HO-BOLD. CONCLUSION: ALFF and fALFF demonstrated a moderate effect size to detect hemodynamic impairment whereas the effect size was large for methods employing a hypercapnia-based vascular stress stimulus. Based on our analysis of BOLD signal change as a response to a progressively increasing hypercapnia stimulus we can argue that a hypercapnia stimulus of at least 2 mmHg above baseline EtCO2 is necessary to evaluate hemodynamic impairment. We also demonstrated that a substantial amount of information imbedded in the rsBOLD and HC-BOLD was explained by HO-BOLD. HO-BOLD can serve as a proxy for vCBV and this thus indicates that one should be careful when adopting these techniques in disease cases with compromised CBV.

Brain oxygen saturation assessment in neonates using T2-prepared blood imaging of oxygen saturation and near-infrared spectroscopy.

Although near-infrared spectroscopy is increasingly being used to monitor cerebral oxygenation in neonates, it has a limited penetration depth. The T2-prepared Blood Imaging of Oxygen Saturation (T2-BIOS) magnetic resonance sequence provides an oxygen saturation estimate on a voxel-by-voxel basis, without needing a respiratory calibration experiment. In 15 neonates, oxygen saturation measured by T2-prepared blood imaging of oxygen saturation and near-infrared spectroscopy were compared. In addition, these measures were compared to cerebral blood flow and venous oxygen saturation in the sagittal sinus. A strong linear relation was found between the oxygen saturation measured by magnetic resonance imaging and the oxygen saturation measured by near-infrared spectroscopy ( R2 = 0.64, p < 0.001). Strong linear correlations were found between near-infrared spectroscopy oxygen saturation, and magnetic resonance imaging measures of frontal cerebral blood flow, whole brain cerebral blood flow and venous oxygen saturation in the sagittal sinus ( R2 = 0.71, 0.50, 0.65; p < 0.01). The oxygen saturation obtained by T2-prepared blood imaging of oxygen saturation correlated with venous oxygen saturation in the sagittal sinus ( R2 = 0.49, p = 0.023), but no significant correlations could be demonstrated with frontal and whole brain cerebral blood flow. These results suggest that measuring oxygen saturation by T2-prepared blood imaging of oxygen saturation is feasible, even in neonates. Strong correlations between the various methods work as a cross validation for near-infrared spectroscopy and T2-prepared blood imaging of oxygen saturation, confirming the validity of using of these techniques for determining cerebral oxygenation.

Effects of carotid endarterectomy or stenting on arterial diameters in the circle of Willis.

BACKGROUND: In patients with internal carotid artery (ICA) stenosis, the circle of Willis (CoW) is the primary collateral pathway. We compared luminal diameters in the CoW before and after carotid revascularization and compared the effects of carotid endarterectomy (CEA) and stenting on these diameters. METHODS: At a single center in the International Carotid Stenting Study, 139 patients with symptomatic ICA stenosis of 50% or more were randomized to stenting (n = 81) or CEA (n = 58). The diameters of all segments of the CoW were assessed on computed tomography angiography (CTA), before and 30 days after revascularization. All evaluations were performed blinded to treatment allocation and order of CTA. RESULTS: A .10-mm increase (95% confidence interval [CI], .02-.17; 7%; P = .01) in diameter after revascularization occurred in the ipsilateral precommunicating anterior cerebral artery (A1), whereas both the ipsilateral and contralateral posterior communicating arteries decreased in diameter by .12 mm (95% CI, .04-.21; 14%; P = .01) and .08 mm (95% CI, .00-.17; 10%; P = .05), respectively. The increase in diameter of the A1 was larger after stenting (.15 mm; 95% CI, .07-.24; P = .001) than after CEA (.02 mm; 95% CI, -.11 to .15; P = .79). Only in patients treated with CEA, the diameters of the contralateral A1 and ipsilateral precommunicating posterior cerebral artery were reduced after revascularization. CONCLUSIONS: Carotid revascularization improves anterior collateralization and reduces reliance on posterior collateral pathways via the CoW. Carotid stenting and endarterectomy appear to have different early effects on collateralization.

Assessment of the contribution of the external carotid artery to brain perfusion in patients with internal carotid artery occlusion.

BACKGROUND AND PURPOSE: The purpose of this study was to prospectively investigate the contribution of the ipsilateral external carotid artery (ECA) to cerebral perfusion in patients with internal carotid artery occlusion. METHODS: Institutional Review Board approval and informed consent were obtained. Thirty functionally independent patients (24 men, 6 women; mean age, 63 years) with an angiographically proven unilateral internal carotid artery occlusion and transient or minor disabling ischemic attacks ipsilateral to the side of the internal carotid artery occlusion were included. Grading of ECA collateral flow was performed with intraarterial digital subtraction angiography. The contribution of the ECA to regional cerebral blood flow was assessed with selective arterial spin labeling MRI. Differences in regional cerebral blood flow were analyzed with Student t test. RESULTS: Twenty percent of the patients had ECA Grade 0 collateral flow (no filling of ophthalmic artery), 20% Grade 1 (filling of carotid siphon), and 60% Grade 2 (filling of anterior and/or middle cerebral artery) as demonstrated on digital subtraction angiography. Although in the Grade 1 group, the ECA supplied a smaller region of the brain compared with the Grade 2 group, the mean regional cerebral blood flow of the perfusion territory supplied by the ECA is similar (P=0.70) in the Grade 1 group (mean+/-SD 57+/-16 mL/min/100 g) and the Grade 2 group (60+/-12 mL/min/100g). CONCLUSIONS: In patients with symptomatic internal carotid artery occlusion, focal brain regions may strongly depend on the contribution to cerebral perfusion of the ECA ipsilateral to the side of the internal carotid artery occlusion, even in patients with limited ECA collateral supply as demonstrated on digital subtraction angiography.