Recovery from aphasia in the first year after stroke.

Most individuals who experience aphasia after a stroke recover to some extent, with the majority of gains taking place in the first year. The nature and time course of this recovery process is only partially understood, especially its dependence on lesion location and extent, which are the most important determinants of outcome. The aim of this study was to provide a comprehensive description of patterns of recovery from aphasia in the first year after stroke. We recruited 334 patients with acute left hemisphere supratentorial ischaemic or haemorrhagic stroke and evaluated their speech and language function within 5 days using the Quick Aphasia Battery (QAB). At this initial time point, 218 patients presented with aphasia. Individuals with aphasia were followed longitudinally, with follow-up evaluations of speech and language at 1 month, 3 months, and 1 year post-stroke, wherever possible. Lesions were manually delineated based on acute clinical MRI or CT imaging. Patients with and without aphasia were divided into 13 groups of individuals with similar, commonly occurring patterns of brain damage. Trajectories of recovery were then investigated as a function of group (i.e. lesion location and extent) and speech/language domain (overall language function, word comprehension, sentence comprehension, word finding, grammatical construction, phonological encoding, speech motor programming, speech motor execution, and reading). We found that aphasia is dynamic, multidimensional, and gradated, with little explanatory role for aphasia subtypes or binary concepts such as fluency. Patients with circumscribed frontal lesions recovered well, consistent with some previous observations. More surprisingly, most patients with larger frontal lesions extending into the parietal or temporal lobes also recovered well, as did patients with relatively circumscribed temporal, temporoparietal, or parietal lesions. Persistent moderate or severe deficits were common only in patients with extensive damage throughout the middle cerebral artery distribution or extensive temporoparietal damage. There were striking differences between speech/language domains in their rates of recovery and relationships to overall language function, suggesting that specific domains differ in the extent to which they are redundantly represented throughout the language network, as opposed to depending on specialized cortical substrates. Our findings have an immediate clinical application in that they will enable clinicians to estimate the likely course of recovery for individual patients, as well as the uncertainty of these predictions, based on acutely observable neurological factors.

Vascular space occupancy asymmetric spin echo (VASO-ASE) for non-invasive quantification of cerebral oxygen extraction fraction.

PURPOSE: Asymmetric spin echo (ASE) MRI is a method for measuring regional oxygen extraction fraction (OEF); however, extravascular tissue models have been shown to under-estimate OEF. The hypothesis investigated here is that the addition of a vascular-space-occupancy (VASO) pre-pulse will more fully suppress blood water signal and provide global OEF values more consistent with physiological expectation and 15 O positron emission tomography (PET)-validated T2 -relaxation-under-spin-tagging (TRUST) OEF measures. METHODS: Healthy adults (n = 14; age = 27.7 ± 5.2 y; sex = 7/7 male/female) were scanned at 3.0T. Multi-echo ASE without inter-readout refocusing (ASERF- ), multi-echo ASE with inter-readout refocusing (ASERF+ ), and single-echo VASO-ASE were acquired twice each with common spatial resolution = 3.44 × 3.44 × 3.0 mm and τ = 0-20 ms (interval = 0.5 ms). TRUST was acquired twice sequentially for independent global OEF assessment (τCPMG  = 10 ms; effective TEs = 0, 40, 80, and 160 ms; spatial resolution = 3.4 × 3.4 × 5 mm). OEF intraclass-correlation-coefficients (ICC), summary statistics, and group-wise differences were assessed (Wilcoxon rank-sum; significance: two-sided p < 0.05). RESULTS: ASERF+ (OEF = 36.8 ± 1.9%) and VASO-ASE (OEF = 34.4 ± 2.3%) produced OEF values similar to TRUST (OEF = 36.5 ± 4.6%, human calibration model; OEF = 32.7 ± 4.9%, bovine calibration model); however, ASERF- yielded lower OEF (OEF = 26.1 ± 1.0%; p < 0.01) relative to TRUST. VASO-ASE (ICC = 0.61) yielded lower ICC compared to other ASE variants (ICC >0.89). CONCLUSION: VASO-ASE and TRUST provide similar OEF values; however, VASO-ASE spatial coverage and repeatability improvements are required.

Elevated Aortic Pulse Wave Velocity Relates to Longitudinal Gray and White Matter Changes.

OBJECTIVE: To determine whether baseline aortic stiffness, measured by aortic pulse wave velocity (PWV), relates to longitudinal cerebral gray or white matter changes among older adults. Baseline cardiac magnetic resonance imaging will be used to assess aortic PWV while brain magnetic resonance imaging will be used to assess gray matter and white matter hyperintensity (WMH) volumes at baseline, 18 months, 3 years, 5 years, and 7 years. Approach and Results: Aortic PWV (m/s) was quantified from cardiac magnetic resonance. Multimodal 3T brain magnetic resonance imaging included T1-weighted imaging for quantifying gray matter volumes and T2-weighted fluid-attenuated inversion recovery imaging for quantifying WMHs. Mixed-effects regression models related baseline aortic PWV to longitudinal gray matter volumes (total, frontal, parietal, temporal, occipital, hippocampal, and inferior lateral ventricle) and WMH volumes (total, frontal, parietal, temporal, and occipital) adjusting for age, sex, race/ethnicity, education, cognitive diagnosis, Framingham stroke risk profile, APOE (apolipoprotein E)-ε4 carrier status, and intracranial volume. Two hundred seventy-eight participants (73±7 years, 58% male, 87% self-identified as non-Hispanic White, 159 with normal cognition, and 119 with mild cognitive impairment) from the Vanderbilt Memory & Aging Project (n=335) were followed on average for 4.9±1.6 years with PWV measurements occurring from September 2012 to November 2014 and longitudinal brain magnetic resonance imaging measurements occurring from September 2012 to June 2021. Higher baseline aortic PWV was related to greater decrease in hippocampal (ß=-3.6 [mm3/y]/[m/s]; [95% CI, -7.2 to -0.02] P=0.049) and occipital lobe (ß=-34.2 [mm3/y]/[m/s]; [95% CI, -67.8 to -0.55] P=0.046) gray matter volume over time. Higher baseline aortic PWV was related to greater increase in WMH volume over time in the temporal lobe (ß=17.0 [mm3/y]/[m/s]; [95% CI, 7.2-26.9] P<0.001). All associations may be driven by outliers. CONCLUSIONS: In older adults, higher baseline aortic PWV related to greater decrease in gray matter volume and greater increase in WMHs over time. Because of unmet cerebral metabolic demands and microvascular remodeling, arterial stiffening may preferentially affect certain highly active brain regions like the temporal lobes. These same regions are affected early in the course of Alzheimer disease.

Higher Aortic Stiffness Is Related to Lower Cerebral Blood Flow and Preserved Cerebrovascular Reactivity in Older Adults.

BACKGROUND: Mechanisms underlying the association between age-related arterial stiffening and poor brain health remain elusive. Cerebral blood flow (CBF) homeostasis may be implicated. This study evaluates how aortic stiffening relates to resting CBF and cerebrovascular reactivity (CVR) in older adults. METHODS: Vanderbilt Memory & Aging Project participants free of clinical dementia, stroke, and heart failure were studied, including older adults with normal cognition (n=155; age, 72±7 years; 59% male) or mild cognitive impairment (n=115; age, 73±7 years; 57% male). Aortic pulse wave velocity (PWV; meters per second) was quantified from cardiac magnetic resonance. Resting CBF (milliliters per 100 g per minute) and CVR (CBF response to hypercapnic normoxia stimulus) were quantified from pseudocontinuous arterial spin labeling magnetic resonance imaging. Linear regression models related aortic PWV to regional CBF, adjusting for age, race/ethnicity, education, Framingham Stroke Risk Profile (diabetes mellitus, smoking, left ventricular hypertrophy, prevalent cardiovascular disease, atrial fibrillation), hypertension, body mass index, apolipoprotein E4 ( APOE ε4) status, and regional tissue volume. Models were repeated testing PWV× APOE ε4 interactions. Sensitivity analyses excluded participants with prevalent cardiovascular disease and atrial fibrillation. RESULTS: Among participants with normal cognition, higher aortic PWV related to lower frontal lobe CBF (ß=-0.43; P=0.04) and higher CVR in the whole brain (ß=0.11; P=0.02), frontal lobes (ß=0.12; P<0.05), temporal lobes (ß=0.11; P=0.02), and occipital lobes (ß=0.14; P=0.01). Among APOE ε4 carriers with normal cognition, findings were more pronounced with higher PWV relating to lower whole-brain CBF (ß=-1.16; P=0.047), lower temporal lobe CBF (ß=-1.81; P=0.004), and higher temporal lobe CVR (ß=0.26; P=0.08), although the last result did not meet the a priori significance threshold. Results were similar in sensitivity models. Among participants with mild cognitive impairment, higher aortic PWV related to lower CBF in the occipital lobe (ß=-0.70; P=0.02), but this finding was attenuated when participants with prevalent cardiovascular disease and atrial fibrillation were excluded. Among APOE ε4 carriers with mild cognitive impairment, findings were more pronounced with higher PWV relating to lower temporal lobe CBF (ß=-1.20; P=0.02). CONCLUSIONS: Greater aortic stiffening relates to lower regional CBF and higher CVR in cognitively normal older adults, especially among individuals with increased genetic predisposition for Alzheimer's disease. Central arterial stiffening may contribute to reductions in regional CBF despite preserved cerebrovascular reserve capacity.

Vessel wall and lumen characteristics with age in healthy participants using 3T intracranial vessel wall magnetic resonance imaging.

BACKGROUND: Intracranial vessel wall imaging (VWI) at a clinical field strength of 3T has become more widely available. However, how vessel measurements change with age and sex, over an age range spanning a typical lifespan, are needed. PURPOSE/HYPOTHESIS: To assess for identifiable changes in arterial wall thickness, outer vessel wall diameter, and lumen diameter with age cross-sectionally in healthy controls without cerebrovascular disease risk factors at the spatial resolution afforded by currently recommended 3T VWI approaches. STUDY TYPE: Prospective. POPULATION/SUBJECTS: Healthy subjects (n = 82; age = 8-79 years). FIELD STRENGTH/SEQUENCE: 3T intracranial VWI, angiography, and T1 -weighted anatomical imaging. ASSESSMENT: Two readers measured lumen and outer wall diameters of the supraclinoid internal carotid artery (ICA) and distal basilar artery. Wall thickness and intraclass correlation coefficients (ICCs) were calculated. STATISTICAL TESTS: Separate linear regressions were performed to understand the relationship between wall measurements (lumen diameter, outer vessel wall diameter, and wall thickness) and age, gender, side (left or right); significance: two-sided P < 0.05. RESULTS: Readers showed excellent agreement for lumen and outer wall diameters (ICC 0.83-094). Linear regression of supraclinoid ICA wall measurements showed a statistically significant increase in wall thickness (P = 0.00051) and outer vessel wall diameter (P = 0.030) with age. ICA lumen and outer vessel wall diameters were statistically greater in males vs. females (lumen diameter 3.69 ± 0.41 vs. 3.54 ± 0.35 mm, P = 0.026; outer wall diameter 5.78 ± 0.52 vs. 5.56 ± 0.44 mm, P = 0.0089) with a trend toward increase in wall thickness (1.05 ± 0.12 vs. 1.01 ± 0.10 mm, P = 0.055). No significant difference was found in basilar artery wall thickness (P = 0.45, P = 0.72), lumen diameter (P = 0.15, P = 0.42), or outer vessel wall diameter (P = 0.34, P = 0.41) with age or gender, respectively. DATA CONCLUSION: Intracranial vessel wall measurements were shown to be consistent between readers. At the available spatial resolution of 3T intracranial VWI sequences, supraclinoid ICA vessel wall thickness and outer vessel wall diameter appear to mildly increase with age. There was no detectable change in basilar artery vessel wall characteristics with age. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;50:1452-1460.

Cerebral blood flow territory instability in patients with atherosclerotic intracranial stenosis.

BACKGROUND: Stroke risk stratification in patients with symptomatic intracranial atherosclerotic arterial disease (ICAD) remains an important clinical objective owing to the high 14-19% recurrent stroke rate in these patients on standard-of-care medical management. There thus remains a need for hemodynamic markers that may allow for the selection of personalized therapies for high-risk symptomatic patients. PURPOSE: To determine if shifting of cerebral blood flow (CBF) territories in response to changes in cerebral perfusion pressure (CPP) may provide a marker for stroke risk in ICAD patients. STUDY TYPE: Prospective. POPULATION: Twenty ICAD patients who experienced a stroke within 45 days of study enrollment and 10 healthy controls. SEQUENCE: 3.0T MRI including anatomical imaging (T1 -weighted, T2 -weighted/FLAIR), 3D MR angiography, and normocapnic and hypercapnic vessel-encoded CBF-weighted arterial spin labeling. ASSESSMENT: Patients were scanned within 45 days of overt stroke and monitored (duration = 13.2 ± 4.4 months) for the endpoint of non-cardioembolic stroke or transient ischemic attack. Flow territory shifting (shifting index) was calculated from the first scan by determining whether a voxel shifted from its primary arterial source from normocapnia to hypercapnia. STATISTICAL TESTS: A Mann-Whitney U-test (significance: P < 0.05) was performed to determine whether patients meeting the endpoint had greater shifting indices relative to controls or patients not meeting the endpoint. RESULTS: Shifting indices (mean ± standard error) were significantly higher in patients meeting endpoint criteria relative to controls (P = 0.0057; adjusted P = 0.036) and patients not meeting endpoint criteria (P = 0.0047; adjusted P = 0.036). DATA CONCLUSION: Flow territory shifting may provide a marker of recurrent stroke risk in symptomatic ICAD patients on standard-of-care medical management therapies. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1441-1451.

Variable impact of CSF flow suppression on quantitative 3.0T intracranial vessel wall measurements.

BACKGROUND: Flow suppression techniques have been developed for intracranial (IC) vessel wall imaging (VWI) and optimized using simulations; however, simulation results may not translate in vivo. PURPOSE: To evaluate experimentally how IC vessel wall and lumen measurements change in identical subjects when evaluated using the most commonly available blood and cerebrospinal fluid (CSF) flow suppression modules and VWI sequences. STUDY TYPE: Prospective. POPULATION/SUBJECTS: Healthy adults (n = 13; age = 37 ± 15 years) were enrolled. FIELD STRENGTH/SEQUENCE: A 3.0T 3D T1 /proton density (PD)-weighted turbo-spin-echo (TSE) acquisition with post-readout anti-driven equilibrium module, with and without Delay-Alternating-with-Nutation-for-Tailored-Excitation (DANTE) was applied. DANTE flip angle (8-12°) and TSE refocusing angle (sweep = 40-120° or 50-120°) were varied. ASSESSMENT: Basilar artery and internal carotid artery (ICA) wall thicknesses, CSF signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and signal ratio (SR) were assessed. Measurements were made by two readers (radiology resident and board-certified neuroradiologist). STATISTICAL TESTS: A Wilcoxon signed-rank test was applied with corrected two-sided P < 0.05 required for significance (critical P = 0.008, 0.005, and 0.05 for SNR/CNR, SR, and wall thickness, respectively). RESULTS: A TSE pulse sweep = 40-120° and sweep = 50-120° provided similar (P = 0.55) CSF suppression. Addition of the DANTE preparation reduced CSF SNR from 17.4 to 6.7, thereby providing significant (P < 0.008) improvement in CSF suppression. The DANTE preparation also resulted in a significant (P < 0.008) reduction in vessel wall SNR, but variable vessel wall to CSF CNR improvement (P = 0.87). There was a trend for a difference in blood SNR with vs. without DANTE (P = 0.05). The outer vessel wall diameter and wall thickness values were lower (P < 0.05) with (basilar artery 4.45 mm, 0.81 mm, respectively) vs. without (basilar artery 4.88 mm, 0.97 mm, respectively) DANTE 8°. DATA CONCLUSION: IC VWI with TSE sweep = 40-120° and with DANTE flip angle = 8° provides the best CSF suppression and CNR of the approaches evaluated. However, improvements are heterogeneous, likely owing to intersubject vessel pulsatility and CSF flow variations, which can lead to variable flow suppression efficacy in these velocity-dependent modules. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;48:1120-1128.

Cerebral hemodynamic changes after haploidentical hematopoietic stem cell transplant in adults with sickle cell disease.

ABSTRACT: Preliminary evidence from a series of 4 adults with sickle cell disease (SCD) suggests that hematopoietic stem cell transplant (HSCT) improves cerebral hemodynamics. HSCT largely normalizes cerebral hemodynamics in children with SCD. We tested the hypothesis in adults with SCD that cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) measured using magnetic resonance imaging, normalized to healthy values, comparing measurements from ∼1 month before to 12 to 24 months after HSCT (n = 11; age, 33.3 ± 8.9 years; 389 ± 150 days after HSCT) with age-, race- and sex-matched values from healthy adults without sickle trait (n = 28; age, 30.2 ± 5.6 years). Before transplant, 7 patients had neurological indications for transplant (eg, overt stroke) and 4 had nonneurological reasons for haploidentical bone marrow transplant (haplo-BMT). All received haplo-BMT from first-degree relatives (parent, sibling, or child donor) with reduced-intensity preparation and maintained engraftment. Before transplant, CBF was elevated (CBF, 69.11 ± 24.7 mL/100 g/min) compared with that of controls (P = .004). Mean CBF declined significantly after haplo-BMT (posttransplant CBF, 48.2 ± 13.9 mL/100 g/min; P = .003). OEF was not different from that of controls at baseline and did not change significantly after haplo-BMT (pretransplant, 43.1 ± 6.7%; posttransplant, 39.6 ± 7.0%; P = .34). After transplant, CBF and OEF were not significantly different from controls (CBF, 48.2 ± 13.4 mL/100 g/min; P = .78; and OEF, 39.6 ± 7.0%; P > .99). CMRO2 did not change significantly after haplo-BMT (pretransplant, 3.18 ± 0.87 mL O2/100 g/min; posttransplant, 2.95 ± 0.83; P = .56). Major complications of haplo-BMT included 1 infection-related death and 1 severe chronic graft-versus-host disease. Haplo-BMT in adults with SCD reduces CBF to that of control values and maintains OEF and CMRO2 on average at levels observed in healthy adult controls. The trial was registered at www.clinicaltrials.gov as #NCT01850108.

Cerebrovascular reactivity dispersion as a new biomarker of recent stroke symptomatology in moyamoya.

Background: Moyamoya disease (MMD) is a non-atherosclerotic intracranial steno-occlusive condition placing patients at high risk for ischemic stroke. Direct and indirect surgical revascularization can improve blood flow in MMD; however, randomized trials demonstrating efficacy have not been performed and biomarkers of parenchymal hemodynamic impairment are needed to triage patients for interventions and evaluate post-surgical efficacy. We test the hypothesis that hypercapnia-induced maximum cerebrovascular reactivity (CVR MAX ) and the more novel indicator cerebrovascular reactivity (CVR) response time (CVR DELAY ), both assessed from time-regression analyses of non-invasive hypercapnic imaging, correlate with recent focal ischemic symptoms. Methods: Hypercapnic reactivity medical resonance imaging (blood oxygenation level-dependent; echo time=35ms; spatial resolution=3.5×3.5×3.5mm) and catheter angiography assessments of cortical reserve capacity and vascular patency, respectively, in MMD participants (n=73) were performed in sequence. Time regression analyses were applied to quantify CVR MAX and CVR DELAY . Symptomatology information for each hemisphere (n=109) was categorized into symptomatic (ischemic symptoms within six months) or asymptomatic (no history of ischemic symptoms) and logistic regression analysis assessed the association of CVR metrics with ischemic symptoms after controlling for age and sex. Results: Symptomatic hemispheres displayed lengthened CVR DELAY (p<0.001), which was more discriminatory between hemispheres than CVR MAX (p=0.037). CVR DELAY (p<0.001), but not CVR MAX (p=0.127), was found to be sensitively related to age in asymptomatic tissue (0.33-unit increase/year); age-dependent normative ranges are presented to enable quantitative assessment of patient-specific impairment. Furthermore, the area under the receiver operating characteristic curves shows that CVR DELAY predicts ischemic symptoms (p<0.001), whereas CVR MAX does not (p=0.056). Conclusion: Findings support that CVR metrics are uniquely altered in hemispheres with recent ischemic symptoms, motivating the investigation of CVR as a surrogate of ischemic symptomatology and treatment efficacy.

Distribution of Silent Cerebral Infarcts in Adults With Sickle Cell Disease.

BACKGROUND AND OBJECTIVES: Previously we demonstrated that 90% of infarcts in children with sickle cell anemia occur in the border zone regions of cerebral blood flow (CBF). We tested the hypothesis that adults with sickle cell disease (SCD) have silent cerebral infarcts (SCIs) in the border zone regions, with a secondary hypothesis that older age and traditional stroke risk factors would be associated with infarct occurrence in regions outside the border zones. METHODS: Adults with SCD 18-50 years of age were enrolled in a cross-sectional study at 2 centers and completed a 3T brain MRI. Participants with a history of overt stroke were excluded. Infarct masks were manually delineated on T2-fluid-attenuated inversion-recovery MRI and registered to the Montreal Neurological Institute 152 brain atlas to generate an infarct heatmap. Border zone regions between anterior, middle, and posterior cerebral arteries (ACA, MCA, and PCA) were quantified using the Digital 3D Brain MRI Arterial Territories Atlas, and logistic regression was applied to identify relationships between infarct distribution, demographics, and stroke risk factors. RESULTS: Of 113 participants with SCD (median age 26.1 years, interquartile range [IQR] 21.6-31.4 years, 51% male), 56 (49.6%) had SCIs. Participants had a median of 5.5 infarcts (IQR 3.2-13.8). Analysis of infarct distribution showed that 350 of 644 infarcts (54.3%) were in 4 border zones of CBF and 294 (45.6%) were in non-border zone territories. More than 90% of infarcts were in 3 regions: the non-border zone ACA and MCA territories and the ACA-MCA border zone. Logistic regression showed that older participants have an increased chance of infarcts in the MCA territory (odds ratio [OR] 1.08; 95% CI 1.03-1.13; p = 0.001) and a decreased chance of infarcts in the ACA-MCA border zone (OR 0.94; 95% CI 0.90-0.97; p < 0.001). The presence of at least 1 stroke risk factor did not predict SCI location in any model. DISCUSSION: When compared with children with SCD, in adults with SCD, older age is associated with expanded zones of tissue infarction that stretch beyond the traditional border zones of CBF, with more than 45% of infarcts in non-border zone regions.

Multivariate lesion symptom mapping for predicting trajectories of recovery from aphasia.

Individuals with post-stroke aphasia tend to recover their language to some extent; however, it remains challenging to reliably predict the nature and extent of recovery that will occur in the long term. The aim of this study was to quantitatively predict language outcomes in the first year of recovery from aphasia across multiple domains of language and at multiple timepoints post-stroke. We recruited 217 patients with aphasia following acute left hemisphere ischaemic or haemorrhagic stroke and evaluated their speech and language function using the Quick Aphasia Battery acutely and then acquired longitudinal follow-up data at up to three timepoints post-stroke: 1 month (n = 102), 3 months (n = 98) and 1 year (n = 74). We used support vector regression to predict language outcomes at each timepoint using acute clinical imaging data, demographic variables and initial aphasia severity as input. We found that ∼60% of the variance in long-term (1 year) aphasia severity could be predicted using these models, with detailed information about lesion location importantly contributing to these predictions. Predictions at the 1- and 3-month timepoints were somewhat less accurate based on lesion location alone, but reached comparable accuracy to predictions at the 1-year timepoint when initial aphasia severity was included in the models. Specific subdomains of language besides overall severity were predicted with varying but often similar degrees of accuracy. Our findings demonstrate the feasibility of using support vector regression models with leave-one-out cross-validation to make personalized predictions about long-term recovery from aphasia and provide a valuable neuroanatomical baseline upon which to build future models incorporating information beyond neuroanatomical and demographic predictors.

Enlarged perivascular space burden associations with arterial stiffness and cognition.

Enlarged perivascular spaces (ePVS) are difficult to quantify, and their etiologies and consequences are poorly understood. Vanderbilt Memory and Aging Project participants (n = 327, 73 ± 7 years) completed 3T brain MRI to quantify ePVS volume and count, longitudinal neuropsychological assessment, and cardiac MRI to quantify aortic stiffness. Linear regressions related (1) PWV to ePVS burden and (2) ePVS burden to cross-sectional and longitudinal neuropsychological performance adjusting for key demographic and medical factors. Higher aortic stiffness related to greater basal ganglia ePVS volume (ß = 7.0×10-5, p = 0.04). Higher baseline ePVS volume was associated with worse baseline information processing (ß = -974, p = 0.003), executive function (ß = -81.9, p < 0.001), and visuospatial performances (ß = -192, p = 0.02) and worse longitudinal language (ß = -54.9, p = 0.05), information processing (ß = -147, p = 0.03), executive function (ß = -10.9, p = 0.03), and episodic memory performances (ß = -10.6, p = 0.02). Results were similar for ePVS count. Greater arterial stiffness relates to worse basal ganglia ePVS burden, suggesting cardiovascular aging as an etiology. ePVS burden is associated with adverse cognitive trajectory, emphasizing the clinical relevance of ePVS.

Silent infarction in sickle cell disease is associated with brain volume loss in excess of infarct volume.

Introduction: Sickle cell disease (SCD) increases cerebral infarct risk, but reported effects on brain volume have varied. More detailed information using larger cohorts and contemporary methods could motivate the use of longitudinal brain volume assessment in SCD as an automated marker of disease stability or future progression. The purpose of this study was to rigorously evaluate whether children and young adults with SCD have reduced gray matter volume (GMV) and white matter volume (WMV) compared to healthy controls using high-resolution MRI. We tested the hypotheses that (i) elevated CBF, a marker of cerebral hemodynamic compensation in SCD, is associated with global and regional brain atrophy, and (ii) silent cerebral infarct burden is associated with brain atrophy in excess of infarct volume. Methods: Healthy controls (n = 49) and SCD participants without overt stroke (n = 88) aged 7-32 years completed 3 T brain MRI; pseudocontinuous arterial spin labeling measured CBF. Multivariable linear regressions assessed associations of independent variables with GMV, WMV, and volumes of cortical/subcortical regions. Results: Reduced hemoglobin was associated with reductions in both GMV (p = 0.032) and WMV (p = 0.005); reduced arterial oxygen content (CaO2) was also associated with reductions in GMV (p = 0.035) and WMV (p = 0.006). Elevated gray matter CBF was associated with reduced WMV (p = 0.018). Infarct burden was associated with reductions in WMV 30-fold greater than the infarct volume itself (p = 0.005). Increased GM CBF correlated with volumetric reductions of the insula and left and right caudate nuclei (p = 0.017, 0.017, 0.036, respectively). Infarct burden was associated with reduced left and right nucleus accumbens, right thalamus, and anterior corpus callosum volumes (p = 0.002, 0.002, 0.009, 0.002, respectively). Discussion: We demonstrate that anemia and decreased CaO2 are associated with reductions in GMV and WMV in SCD. Increased CBF and infarct burden were also associated with reduced volume in subcortical structures. Global WMV deficits associated with infarct burden far exceed infarct volume itself. Hemodynamic compensation via increased cerebral blood flow in SCD seems inadequate to prevent brain volume loss. Our work highlights that silent cerebral infarcts are just a portion of the brain injury that occurs in SCD; brain volume is another potential biomarker of brain injury in SCD.

Leukoaraiosis Is Not Associated With Recovery From Aphasia in the First Year After Stroke.

After a stroke, individuals with aphasia often recover to a certain extent over time. This recovery process may be dependent on the health of surviving brain regions. Leukoaraiosis (white matter hyperintensities on MRI reflecting cerebral small vessel disease) is one indication of compromised brain health and is associated with cognitive and motor impairment. Previous studies have suggested that leukoaraiosis may be a clinically relevant predictor of aphasia outcomes and recovery, although findings have been inconsistent. We investigated the relationship between leukoaraiosis and aphasia in the first year after stroke. We recruited 267 patients with acute left hemispheric stroke and coincident fluid attenuated inversion recovery MRI. Patients were evaluated for aphasia within 5 days of stroke, and 174 patients presented with aphasia acutely. Of these, 84 patients were evaluated at ∼3 months post-stroke or later to assess longer-term speech and language outcomes. Multivariable regression models were fit to the data to identify any relationships between leukoaraiosis and initial aphasia severity, extent of recovery, or longer-term aphasia severity. We found that leukoaraiosis was present to varying degrees in 90% of patients. However, leukoaraiosis did not predict initial aphasia severity, aphasia recovery, or longer-term aphasia severity. The lack of any relationship between leukoaraiosis severity and aphasia recovery may reflect the anatomical distribution of cerebral small vessel disease, which is largely medial to the white matter pathways that are critical for speech and language function.

Safety of 3 Tesla Magnetic Resonance Imaging in Patients with Sickle Cell Disease.

Sickle cell disease (SCD) is a well-characterized hemoglobinopathy affecting more than 20 million individuals worldwide and carries an increased risk of cerebral vasculopathy, cerebral infarct, and stroke. As mechanisms of cerebral infarction in SCD are partly attributable to microvascular vaso-occlusive crises, manifesting as altered cerebral blood flow and associated impaired oxygen delivery, magnetic resonance imaging (MRI) methods that can quickly provide a comprehensive perspective on structural and functional disease status, without exogenous contrast administration or ionizing radiation, have emerged as crucial clinical tools for surveillance. However, early ex vivo MRI work in suspended erythrocytes containing hemoglobin S at 0.35 Tesla (T) suggested that sickled erythrocytes can orient preferentially in the presence of an external magnetic field, and as such, it was suggested that MRI exams in sickle cell hemoglobinopathy could induce vaso-occlusion. While this observation has generally not impacted clinical imaging in individuals with SCD, it has led to resistance for some sickle cell studies within the engineering community among some imaging scientists as this early observation has never been rigorously shown to be unconcerning. Here, we performed MRI at the clinical field strength of 3 T in 172 patients with SCD, which included standard anatomical and angiographic assessments together with gold standard diffusion-weighted imaging (DWI; spatial resolution = 1.8 × 1.8 × 4 mm; b-value = 1000 s/mm2) for acute infarct assessment (performed approximately 20 min after patient introduction to the field isocenter). The presence of vasculopathy, as well as chronic and acute infarcts, was evaluated by two independent board-certified radiologists using standard clinical criteria. In these patients (52.3% female; mean age = 19.6 years; age range = 6-44 years), hematocrit (mean = 25.8%; range = 15-36%), hemoglobin phenotype (87.8% HbSS variant), presence of silent infarct (44.2%), and overt chronic infarct (13.4%) were consistent with a typical SCD population; however, no participants exhibited evidence of acute infarction. These findings are consistent with 3 T MRI not inducing acute infarction or vaso-occlusion in individuals with SCD and suggest that earlier low-field ex vivo work of erythrocytes in suspension is not a sufficient cause to discourage MRI scans in patients with SCD.

Intracranial and Extracranial Vascular Stenosis as Risk Factors for Stroke in Sickle Cell Disease.

BACKGROUND: Prevalence and contribution of intracranial and extracranial arterial stenosis to stroke risk were assessed prospectively in children and young adults with sickle cell disease. METHODS: In this cross-sectional study, children and young adults (mean = 19.4 years) with sickle cell disease underwent neurological examination, brain MRI, and magnetic resonance angiography of the head and neck. Two neuroradiologists independently recorded infarcts and arterial stenosis. Clinical features and stroke outcomes were compared between participants with and without stenosis and between children and young adults. Logistic regression analysis assessed the association of variables of interest with overt stroke and silent cerebral infarct. RESULTS: Of 167 participants (79 children and 88 young adults), 20 (12.0%) had intracranial stenosis, all in the anterior circulation, and nine had concurrent extracranial stenosis. No participants had isolated extracranial stenosis. Participants with intracranial stenosis were more likely than those without stenosis to have an overt stroke (70% vs 5%, P < 0.001) or silent cerebral infarct (95% vs 35%, P < 0.001). Logistic regression analysis indicated that intracranial stenosis was strongly associated with overt stroke when compared with participants with silent cerebral infarct alone and strongly associated with silent cerebral infarct when compared with participants with normal brain MRI; male sex and age were also significant predictors of silent cerebral infarct. CONCLUSIONS: Intracranial stenosis was strongly associated with both overt stroke and silent cerebral infarct; prevalence of intracranial stenosis was similar to prior estimates in sickle cell disease. Extracranial stenosis without concurrent intracranial stenosis did not occur and thus could not be evaluated as an independent risk factor for stroke.

Choroid plexus perfusion in sickle cell disease and moyamoya vasculopathy: Implications for glymphatic flow.

Cerebrospinal fluid (CSF) and interstitial fluid exchange have been shown to increase following pharmacologically-manipulated increases in cerebral arterial pulsatility, consistent with arterial pulsatility improving CSF circulation along perivascular glymphatic pathways. The choroid plexus (CP) complexes produce CSF, and CP activity may provide a centralized indicator of perivascular flow. We tested the primary hypothesis that elevated cortical cerebral blood volume and flow, present in sickle cell disease (SCD), is associated with fractionally-reduced CP perfusion relative to healthy adults, and the supplementary hypothesis that reduced arterial patency, present in moyamoya vasculopathy, is associated with elevated fractional CP perfusion relative to healthy adults. Participants (n = 75) provided informed consent and were scanned using a 3-Tesla arterial-spin-labeling MRI sequence for CP and cerebral gray matter (GM) perfusion quantification. ANOVA was used to calculate differences in CP-to-GM perfusion ratios between groups, and regression analyses applied to evaluate the dependence of the CP-to-GM perfusion ratio on group after co-varying for age and sex. ANOVA yielded significant (p < 0.001) group differences, with CP-to-GM perfusion ratios increasing between SCD (ratio = 0.93 ± 0.28), healthy (ratio = 1.04 ± 0.32), and moyamoya (ratio = 1.29 ± 0.32) participants, which was also consistent with regression analyses. Findings are consistent with CP perfusion being inversely associated with cortical perfusion.

Lower cardiac output is associated with neurodegeneration among older adults with normal cognition but not mild cognitive impairment.

Subclinical cardiac dysfunction is associated with smaller total brain volume on magnetic resonance imaging (MRI). To study whether cardiac output relates to regional measurements of grey and white matter structure, older adults (n = 326) underwent echocardiogram to quantify cardiac output (L/min) and brain MRI. Linear regressions related cardiac output to grey matter volumes measured on T1 and white matter hyperintensities assessed on T2-FLAIR. Voxelwise analyses related cardiac output to diffusion tensor imaging adjusting for demographic, genetic, and vascular risk factors. Follow-up models assessed a cardiac output x diagnosis interaction with stratification (normal cognition, mild cognitive impairment). Cardiac output interacted with diagnosis, such that lower cardiac output related to smaller total grey matter (p = 0.01), frontal lobe (p = 0.01), and occipital lobe volumes (p = 0.01) among participants with normal cognition. When excluding participants with cardiovascular disease and atrial fibrillation, associations emerged with smaller parietal lobe (p = 0.005) and hippocampal volume (p = 0.05). Subtle age-related cardiac changes may disrupt neuronal homeostasis and impact grey matter integrity prior to cognitive impairment.

Vessel Wall and Lumen Features in North American Moyamoya Patients.

PURPOSE: To apply intracranial vessel wall imaging (VWI) to determine changes in vessel wall characteristics between North American moyamoya patients and controls, as well as with standard clinical measures of moyamoya disease severity. METHODS: North American moyamoya patients and controls underwent intracranial 3.0 T VWI. Moyamoya patients also underwent digital subtraction angiography (DSA), from which modified Suzuki scores (mSS) were calculated. Lumen and outer vessel wall diameters of the supraclinoid internal carotid arteries (ICAs) and basilar artery on VWI were measured by two readers from which wall thickness was calculated. Controls and moyamoya patients were compared in logistic regression using disease category (moyamoya or none) as the dependent variable and wall thickness, age, gender, and side as the explanatory variables (significance: two-sided p < 0.05). In moyamoya patients, regression was performed with mSS as the dependent variable and wall thickness, age, gender, and side as the explanatory variables. Analyses were repeated for each lumen diameter and outer vessel wall diameter in place of wall thickness. RESULTS: Patients with moyamoya (n = 23, gender = 3/20 male/female; age = 43 ± 12 years) and controls (n = 23, gender = 3/20 male/female, age = 43 ± 13 years) were included. Moyamoya patients showed a significantly smaller ICA lumen and outer vessel wall diameter compared to controls (p < 0.05) but no significant change in vessel wall thickness. Similarly, ICA lumen and outer vessel wall diameters decreased with increasing mSS (p < 0.05). CONCLUSION: Findings suggest decreased ICA lumen and outer vessel wall diameters, but no significant difference in wall thickness, between patients and controls. Lumen and outer vessel wall diameters also decreased with disease severity.