Timothy J. Carroll

BACKGROUND AND OBJECTIVES: It is not clear whether changes in lesion volume might represent a clinically relevant and statistically advantageous outcome parameter in early phase trials aimed at preventing bleeding in cerebral cavernous malformations (CCM). METHODS: We examined prospective changes in CCM lesion volume in the double-blinded AT CASH EPOC trial (clinicaltrials.gov NCT02603328). We correlated these with symptomatic hemorrhage (SH) events, contemporaneously assessed changes in lesional iron content by quantitative susceptibility mapping (QSM) on MRI, and objective (modified Rankin Scale (mRS)) and subjective (Euro-QoL Visual Analog Scale [EQ-VAS]) functional status. We also simulated sample sizes needed to detect potential effects on lesion volume. RESULTS: There was excellent correlation between independently assessed maximum lesion diameter and CCM lesion volume (R ² = 0.68, P < .0001). The mean (SD) percentage change in lesion volume per year was +6 (65) and +18 (94) in atorvastatin and placebo patients, respectively ( P = .43). All cases with SH had increases in lesion volume and increases in mean lesional iron content by QSM, and most had declines in functional status on mRS and EQ-VAS, but there were no overall meaningful correlations of changes in lesion volume with concomitant changes in mean lesional QSM, mRS, or EQ-VAS (all R/R ² < 0.5 and Bonferroni corrected P > .05), including in brainstem lesions analyzed separately. Sample size simulations indicate larger case numbers needed to demonstrate an effect on change in lesion volume than those needed to detect an effect on QSM change with α = 0.05 and β = 0.8, and even larger samples to detect effects on the number of cases with increased or decreased lesion volume. CONCLUSION: Changes in lesion volume occur frequently in CCM lesions after recent SH, but do not correlate with biomarkers of lesional bleeding, nor reflect functional changes, and are not statistically advantageous compared with QSM measures in detecting potential drug effects.

BACKGROUND: Acute intermittent hypoxia (AIH) is a novel therapeutic intervention that facilitates recovery of function, but the tolerability and effectiveness have not been tested in people living with chronic stroke. The purpose here was to examine whether AIH is tolerable and effective in this population. METHODS: Ten participants with a unilateral, hemispheric stroke were assessed before and after 4 sessions of AIH separated by ≥48 hours in a case series at Shirley Ryan AbilityLab (Chicago). Physician-assessed signs and symptoms (assessed via: repeated symptom reviews, National Institutes of Health Stroke Scale, cranial nerve assessment, a muscle strength test, the Brunnstrom scale, sensory changes, reflexes, assessment of heart and lung status, Fugl-Meyer test, Chedoke-McMaster Stroke Assessment, Modified Ashworth Scale for Spasticity, and Delis Kaplan Executive Function System Color-Word Interference Test) and bilateral upper limb strength (grip and elbow flexion) were assessed before, ≈15 to 30 minutes, and ≈60 minutes after the intervention. RESULTS: AIH was well-tolerated and there were no adverse events observed. After AIH, grip strength (12.91% and 16.53% improvement at 30 and 60 minutes post-AIH, respectively) and elbow flexion force (5.87% and 7.01% improvement at 30 and 60 minutes post-AIH, respectively) improved in the more-affected limb. CONCLUSIONS: AIH is potentially safe and effective for improving strength in the more-affected limb in people living with hemiparetic stroke. Future work should explore the use of AIH to enhance task-specific training-induced plasticity. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04019522.

BACKGROUND AND PURPOSE: In acute ischemic stroke, the amount of “local” CBF distal to the occlusion, i.e. all blood flow within a region whether supplied antegrade or delayed and dispersed through the collateral network, may contain valuable information regarding infarct growth rate and treatment response. DSC CBF using a local arterial input function (AIF) is one method of quantifying local CBF (local-qCBF) and correlates with collaterals. Similarly, intravoxel incoherent motion MRI (IVIM) is “local”, with excitation and readout in the same plane, and a potential alternative way to measure local-qCBF. The purpose of this work was to compare IVIM local-qCBF against DSC local-qCBF in the ischemic penumbra, compare measurement of perfusion-diffusion mismatch (PWI/DWI), and examine if local-qCBF may improve prediction of final infarct. MATERIALS AND METHODS: Eight experiments in a pre-clinical canine model of middle cerebral artery occlusion were performed; native collateral circulation was quantified via x-ray DSA 30 minutes post-occlusion, and collateralization was subsequently enhanced in a subset of experiments with simultaneous pressor and vasodilator. IVIM and DSC MRI were acquired 2.5hr post-occlusion. IVIM was post-processed to return local-qCBF from fD*, water transport time (WTT) from D*, diffusion from D, and the PWI/DWI mismatch. These were compared with DSC parameters processed first with a standard global-AIF and then with a local-AIF. These DSC parameters included time-to-maximum, local MTT, standard-qCBF, local-qCBF and PWI/DWI mismatch. Infarct volume was measured with DWI at 2.5hrs and 4hrs post-occlusion. RESULTS: 2.5hr post-occlusion, IVIM local-qCBF in the non-infarcted ipsilateral territory strongly correlated with DSC local-qCBF (slope=1.00, R²=0.69, Lin’s CCC=0.71). Correlation was weaker between IVIM local-qCBF and DSC standard-qCBF (R²=0.13). DSC localqCBF and IVIM local-qCBF in the non-infarcted ipsilateral territory both returned strong prediction of final infarct volume (R²=0.78, R²=0.61 respectively). DSC standard-qCBF was a weaker predictor (R²=0.12). The hypoperfused lesion from DSC local-qCBF and from IVIM local-qCBF both predicted final infarct volume with good sensitivity and correlation (slope=2.08, R²=0.67, slope=2.50, R²=0.68 respectively). The IVIM PWI/DWI ratio was correlated with infarct growth (R²=0.70) and WTT correlated with DSC MTT (R²=0.60). CONCLUSIONS: Non-contrast IVIM measurement of local-qCBF and PWI/DWI mismatch may include collateral circulation and improve prediction of infarct growth. ABBREVIATIONS: AIF: arterial input function, IVIM: intravoxel incoherent motion, qCBF: quantitative cerebral blood flow, WTT: water transport time, MCAO: middle cerebral artery occlusion, MD: mean diffusivity

Traditional guidance for intracranial aneurysm (IA) management is dichotomized by rupture status. Fundamental to ruptured aneurysm management is the detection and treatment of subarachnoid hemorrhage, along with securing the aneurysm by the safest technique. On the other hand, unruptured aneurysms first require a careful assessment of natural history versus treatment risk, including an imaging assessment of aneurysm size, location, and morphology, along with additional evidence-based risk factors such as smoking, hypertension, and family history. Unfortunately, a large proportion of ruptured aneurysms are in the lower risk size category (<7mm), putting a premium on discovering a more refined non-invasive biomarker to detect and stratify aneurysm instability prior to rupture. In this review of aneurysm work-up, we cover the gamut of established imaging modalities (e.g., CT, CTA, DSA, FLAIR, 3D-TOF-MRA, CE-MRA) as well as more novel MR techniques (MR-VWI, DCE-MRI, CFD). Additionally, we evaluate the current landscape of AI software and their integration into diagnostic and risk stratification pipelines for IAs. These advanced MR techniques, increasingly complemented with AI models, offer a paradigm shift by evaluating factors beyond size and morphology, including vessel wall inflammation, permeability, and hemodynamics. Additionally, we provide our institution’s scan parameters for many of these modalities as reference. Ultimately, this review provides an organized, up-to-date summary on the array of available modalities/sequences for IA imaging to help build protocols focused on IA characterization. ABBREVIATIONS: IA = intracranial aneurysm; LP = lumbar puncture; UIA = unruptured intracranial aneurysm; VWI = vessel wall imaging; 3DRA = 3D Rotational Angiography.

BACKGROUND AND PURPOSE: In ischemic stroke, leptomeningeal collaterals can provide delayed and dispersed compensatory blood flow to tissue-at-risk despite an occlusion and can impact treatment response and infarct growth. The purpose of this work is to test the hypothesis that inclusion of this delayed and dispersed flow with an appropriately calculated Local Arterial Input Function (Local-AIF) is needed to quantify the degree of collateral blood supply in tissue distal to an occlusion. MATERIALS AND METHODS: Seven experiments were conducted in a pre-clinical middle cerebral artery occlusion model. Dynamic susceptibility contrast MRI was imaged and post-processed to yield quantitative cerebral blood flow (qCBF) maps with both a traditionally chosen single arterial input function applied globally to the whole brain (i.e. “Global-AIF”) and a delay and dispersion corrected AIF (i.e. “Local-AIF”) that is sensitive to retrograde flow. Leptomeningeal collateral arterial recruitment was quantified with a pial collateral score from x-ray angiograms, and infarct growth calculated from serially acquired diffusion weighted MRI scans. RESULTS: The degree of collateralization at x-ray correlated more strongly with qCBF using the Local-AIF in the ischemic penumbra (R²=0.81) than traditionally chosen Global-AIF (R²=0.05). qCBF using a Local-AIF was negatively correlated (less infarct progression as perfusion increased) with infarct growth (R² = 0.79) more strongly than a Global-AIF (R²=0.02). CONCLUSIONS: In acute stroke, qCBF calculated with a Local-AIF is more accurate for assessing tissue status and collateral supply than traditionally chosen Global-AIFs. These findings support use of a Local-AIF that corrects for delayed and dispersed retrograde flow in determining quantitative tissue perfusion with collateral supply in occlusive disease. ABBREVIATIONS: MRI = magnetic resonance imaging; DSC = dynamic susceptibility contrast; PCS = pial collateral score; MCAO = middle cerebral artery occlusion; MCA = middle cerebral artery; AIF = arterial input function; rCBF = relative cerebral blood flow; qCBF = quantitative cerebral blood flow

BACKGROUND AND PURPOSE: Analysis of vessel wall contrast kinetics (ie, wash-in/washout) is a promising method for the diagnosis and risk-stratification of intracranial atherosclerotic disease plaque (ICAD-P) and the intracranial aneurysm walls (IA-W). We used black-blood MR imaging or MR vessel wall imaging to evaluate the temporal relationship of gadolinium contrast uptake kinetics in ICAD-Ps and IA-Ws compared with normal anatomic reference structures. MATERIALS AND METHODS: Patients with ICAD-Ps or IAs who underwent MR vessel wall imaging with precontrast, early postcontrast (5–15 minutes), and delayed postcontrast (20–30 minutes) 3D T1-weighted TSE sequences were retrospectively studied. ROIs of a standardized diameter (2 mm) were used to measure the signal intensities of the cavernous sinus, pituitary infundibulum, temporalis muscle, and choroid plexus. Point ROIs were used for ICAD-Ps and IA-Ws. All ROI signal intensities were normalized to white matter signal intensity obtained using ROIs of 10-mm diameter. Measurements were acquired on precontrast, early postcontrast, and delayed postcontrast 3D T1 TSE sequences for each patient. RESULTS: Ten patients with 17 symptomatic ICAD-Ps and 30 patients with 34 IA-Ws were included and demonstrated persisting contrast uptake (P < .001) of 7.21% and 10.54% beyond the early phase (5–15 minutes postcontrast) and in the delayed phase (20–30 minutes postcontrast) on postcontrast MR vessel wall imaging. However, normal anatomic reference structures including the pituitary infundibulum and cavernous sinus demonstrated a paradoxical contrast washout in the delayed phase. In both ICAD-Ps and IA-Ws, the greatest percentage of quantitative enhancement (>70%–90%) occurred in the early phase of postcontrast imaging, consistent with the rapid contrast uptake kinetics of neurovascular pathology. CONCLUSIONS: Using standard MR vessel wall imaging techniques, our results demonstrate the effects of gadolinium contrast uptake kinetics in ICAD-Ps and IA-Ws with extended accumulating enhancement into the delayed phase (> 15 minutes) as opposed to normal anatomic reference structures that conversely exhibit decreasing enhancement. Because these relative differences are used to assess qualitative patterns of ICAD-P and IA-W enhancement, our findings highlight the importance of standardizing acquisition time points and MR vessel wall imaging protocols to interpret pathologic enhancement for the risk stratification of cerebrovascular pathologies.

BACKGROUND AND PURPOSE: Ischemic stroke disrupts functional connectivity within the brain9s resting-state networks (RSNs), impacting recovery. This study evaluates the effects of NEH (Norepinephrine and Hydralazine), a cerebral perfusion augmentation therapy, on RSN integrity in a hyper-acute canine stroke model. MATERIALS AND METHODS: Fifteen adult purpose-bred mongrel canines, divided into treatment and control (natural history) groups, underwent endovascular induction of acute middle cerebral artery occlusion (MCAO). Post-occlusion, the treatment group received intra-arterial Norepinephrine (0.1-1.52 μg/kg/min, adjusted for 25-45 mmHg above baseline mean arterial pressure) and Hydralazine (20mg). Resting-state fMRI data were acquired with a 3.0 T scanner using a BOLD-sensitive EPI sequence (TR/TE=1400 ms/20ms, 2.5 mm slices, 300 temporal positions). Preprocessing included motion correction, spatial smoothing (2.5 mm FWHM), and high-pass filtering (0.01 Hz cutoff). Functional connectivity within RSNs were analyzed through group-level independent component analysis (ICA) and weighted whole-brain ROI-to-ROI connectome, pre-and post-MCAO. RESULTS: NEH therapy significantly maintained connectivity post-MCAO in the Higher-order Visual and Parietal RSNs, as evidenced by thresholded statistical mapping (TFCE p-corr > 0.95). However, this preservation was network-dependent, with no significant changes in the Primary Visual and Sensorimotor networks. CONCLUSIONS: NEH demonstrates potential as a proof-of-concept therapy for maintaining RSN functional connectivity following ischemic stroke, emphasizing the therapeutic promise of perfusion augmentation. These insights reinforce the role of functional connectivity as a measurable endpoint for stroke intervention efficacy, suggesting clinical translatability for patients with insufficient collateral circulation. ABBREVIATIONS: NEH＝ Norepinephrine and Hydralazine; RSN＝ Resting-State Network; ICA = Independent Component Analysis; rsfMRI = resting-state Functional Magnetic Resonance Imaging; MCAO = Middle Cerebral Artery Occlusion; TFCE = Threshold-Free Cluster Enhancement

BACKGROUND: Quantitative susceptibility mapping (QSM) and dynamic contrast-enhanced quantitative perfusion (DCEQP) magnetic resonance imaging sequences assessing iron deposition and vascular permeability were previously correlated with new hemorrhage in cerebral cavernous malformations. We assessed their prospective changes in a multisite trial-readiness project. METHODS: Patients with cavernous malformation and symptomatic hemorrhage (SH) in the prior year, without prior or planned lesion resection or irradiation were enrolled. Mean QSM and DCEQP of the SH lesion were acquired at baseline and at 1- and 2-year follow-ups. Sensitivity and specificity of biomarker changes were analyzed in relation to predefined criteria for recurrent SH or asymptomatic change. Sample size calculations for hypothesized therapeutic effects were conducted. RESULTS: We logged 143 QSM and 130 DCEQP paired annual assessments. Annual QSM change was greater in cases with SH than in cases without SH ( P =0.019). Annual QSM increase by ≥6% occurred in 7 of 7 cases (100%) with recurrent SH and in 7 of 10 cases (70%) with asymptomatic change during the same epoch and 3.82× more frequently than clinical events. DCEQP change had lower sensitivity for SH and asymptomatic change than QSM change and greater variance. A trial with the smallest sample size would detect a 30% difference in QSM annual change during 2 years of follow-up in 34 or 42 subjects (1 and 2 tailed, respectively); power, 0.8, α=0.05. CONCLUSIONS: Assessment of QSM change is feasible and sensitive to recurrent bleeding in cavernous malformations. Evaluation of an intervention on QSM percent change may be used as a time-averaged difference between 2 arms using a repeated measures analysis. DCEQP change is associated with lesser sensitivity and higher variability than QSM. These results are the basis of an application for certification by the US Food and Drug Administration of QSM as a biomarker of drug effect on bleeding in cavernous malformations. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03652181.

BACKGROUND: Cerebral cavernous malformation with symptomatic hemorrhage (SH) are targets for novel therapies. A multisite trial-readiness project ( https://www.clinicaltrials.gov ; Unique identifier: NCT03652181) aimed to identify clinical, imaging, and functional changes in these patients. METHODS: We enrolled adult cerebral cavernous malformation patients from 5 high-volume centers with SH within the prior year and no planned surgery. In addition to clinical and imaging review, we assessed baseline, 1- and 2-year National Institutes of Health Stroke Scale, modified Rankin Scale, European Quality of Life 5D-3 L, and patient-reported outcome-measurement information system, Version 2.0. SH and asymptomatic change rates were adjudicated. Changes in functional scores were assessed as a marker for hemorrhage. RESULTS: One hundred twenty-three, 102, and 69 patients completed baseline, 1- and 2-year clinical assessments, respectively. There were 21 SH during 178.3 patient years of follow-up (11.8% per patient year). At baseline, 62.6% and 95.1% of patients had a modified Rankin Scale score of 1 and National Institutes of Health Stroke Scale score of 0 to 4, respectively, which improved to 75.4% ( P =0.03) and 100% ( P =0.06) at 2 years. At baseline, 74.8% had at least one abnormal patient-reported outcome-measurement information system, Version 2.0 domain compared with 61.2% at 2 years ( P =0.004). The most common abnormal European Quality of Life 5D-3 L domains were pain (48.7%), anxiety (41.5%), and participation in usual activities (41.4%). Patients with prospective SH were more likely than those without SH to display functional decline in sleep, fatigue, and social function patient-reported outcome-measurement information system, Version 2.0 domains at 2 years. Other score changes did not differ significantly between groups at 2 years. The sensitivity of scores as an SH marker remained poor at the time interval assessed. CONCLUSIONS: We report SH rate, functional, and patient-reported outcomes in trial-eligible cerebral cavernous malformation with SH patients. Functional outcomes and patient-reported outcomes generally improved over 2 years. No score change was highly sensitive or specific for SH and could not be used as a primary end point in a trial.