Hematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy.

Blood-brain barrier disruption marks the onset of cerebral adrenoleukodystrophy (CALD), a devastating cerebral demyelinating disease caused by loss of ABCD1 gene function. The underlying mechanism are not well understood, but evidence suggests that microvascular dysfunction is involved. We analyzed cerebral perfusion imaging in boys with CALD treated with autologous hematopoietic stem-cells transduced with the Lenti-D lentiviral vector that contains ABCD1 cDNA as part of a single group, open-label phase 2-3 safety and efficacy study (NCT01896102) and patients treated with allogeneic hematopoietic stem cell transplantation. We found widespread and sustained normalization of white matter permeability and microvascular flow. We demonstrate that ABCD1 functional bone marrow-derived cells can engraft in the cerebral vascular and perivascular space. Inverse correlation between gene dosage and lesion growth suggests that corrected cells contribute long-term to remodeling of brain microvascular function. Further studies are needed to explore the longevity of these effects.

Global white matter structural integrity mediates the effect of age on ischemic stroke outcomes.

BACKGROUND: The relationship of global white matter microstructural integrity and ischemic stroke outcomes is not well understood. AIMS: To investigate the relationship of global white matter microstructural integrity with clinical variables and functional outcomes after acute ischemic stroke. METHODS: A retrospective analysis of neuroimaging data from 300 acute ischemic stroke patients with magnetic resonance imaging brain obtained within 48 hours of stroke onset and long-term functional outcomes (modified Rankin, mRS) was performed. Peak width of skeletonized mean diffusivity (PSMD), as a measure of global white matter microstructural injury, was calculated in the hemisphere contralateral to the acute infarct. Multivariable linear and logistic regression analyses were performed to identify variables associated with PSMD and excellent functional outcome (mRS < 2) at 90 days, respectively. Mediation analysis was then pursued to characterize how PSMD mediates the effect of age on acute ischemic stroke functional outcomes. RESULTS: White matter hyperintensity volume, age, pre-stroke disability, and normal-appearing white matter mean diffusivity were independently associated with increased PSMD. In logistic regression analysis, increased infarct volume and PSMD were independent predictors of excellent functional outcome. Additionally, the effect of age on functional outcomes was indirectly mediated by PSMD (P < 0.001). CONCLUSIONS: As a marker of global white matter microstructural injury, increased PSMD mediates the effect of increased age to contribute to poor acute ischemic stroke functional outcomes. PSMD could serve as a putative radiographic marker of brain age for stroke outcomes prognostication.

Neurotoxicity of subarachnoid Gd-based contrast agent accumulation: a potential complication of intraoperative MRI?

OBJECTIVE: Intraoperative MRI with Gd-based contrast agent (GBCA) improves the extent of resection of contrast-enhancing brain tumors. Signal changes of CSF due to perioperative GBCA leakage in the subarachnoid space have been reported. However, although GBCA potentially exhibits neurotoxic effects, so far no associated complications have been described. In this case series, the authors report a single-center cohort of patients with subarachnoid GBCA extravasation after intraoperative MRI and discuss potential neurotoxic complications and potential ways of avoiding them. METHODS: All patients with CSF signal increase on unenhanced T1-weighted and FLAIR images on postoperative MRI, who had previously undergone tumor resection with use of intraoperative MRI, were retrospectively included and compared with a control cohort. The control group was matched in age, tumor characteristics, and extent of resection; comparisons were made regarding postoperative seizures and ICU stay. A subgroup with initially diagnosed malignant glioma was additionally analyzed for potential delay of initiation of adjuvant treatment and overall survival. RESULTS: Seven patients with postoperative GBCA accumulation in the subarachnoid space were identified; 5 presented with focal seizures and altered mental status postoperatively. Poor patient condition led to extended ICU stay and prolonged delay of the initiation of adjuvant treatment in patients with newly diagnosed malignant glioma. Overall survival was reduced compared to the matched control group. CONCLUSIONS: The results suggest that there might be a risk of neurotoxic complications if GBCA that is intravenously applied during neurosurgery leaks into the subarachnoid space. Patients with highly vascularized tumors with intraoperative bleeding seem to be especially at risk for GBCA accumulation and neurotoxic complications. Therefore, awareness of the potential risk of complicating GBCA leakage is mandatory in the application of intraoperative GBCA.

Cerebrovascular Disease Progression in Patients With ACTA2 Arg179 Pathogenic Variants.

OBJECTIVE: To establish progression of imaging biomarkers of stroke, arterial steno-occlusive disease, and white matter injury in patients with smooth muscle dysfunction syndrome caused by mutations in the ACTA2 gene, we analyzed 113 cerebral MRI scans from a retrospective cohort of 27 patients with ACTA2 Arg179 pathogenic variants. METHODS: Systematic quantifications of arterial ischemic strokes and white matter lesions were performed on baseline and follow-up scans using planimetric methods. Critical stenosis and arterial vessel diameters were quantified applying manual and semiautomated methods to cerebral magnetic resonance angiograms. We then assessed correlations between arterial abnormalities and parenchymal injury. RESULTS: We found characteristic patterns of acute white matter ischemic injury and progressive internal carotid artery stenosis during infancy. Longitudinal analysis of patients older than 1.2 years showed stable white matter hyperintensities but increased number of cystic-like lesions over time. Progressive narrowing of the terminal internal carotid artery occurred in 80% of patients and correlated with the number of critical stenoses in cerebral arteries and arterial ischemic infarctions. Arterial ischemic strokes occurred in same territories affected by critical stenosis. CONCLUSIONS: We found characteristic, early, and progressive cerebrovascular abnormalities in patients with ACTA2 Arg179 pathogenic variants. Our longitudinal data suggest that while steno-occlusive disease progresses over time and is associated with arterial ischemic infarctions and cystic-like white matter lesions, white matter hyperintensities can remain stable over long periods. The evaluated metrics will enable diagnosis in early infancy and be used to monitor disease progression, guide timing of stroke preventive interventions, and assess response to current and future therapies.

Cerebral Small Vessel Diseases and Sleep Related Strokes.

BACKGROUND AND PURPOSE: Sleep related Stroke (SRS) is common and has been associated with cerebral small vessel diseases (SVD) in ischemic strokes (ISs). We tested the hypothesis that SRS is associated with SVD in both ischemic and hemorrhagic stroke. METHODS: Prospectively collected data from patients consecutively enrolled after intracerebral hemorrhage (ICH) related to SVD or after IS were analyzed. Symptom onset was recorded as SRS versus awake. Each ICH was grouped according to lobar and deep locations. The IS cohort was etiologically characterized based on the Causative Classification of Stroke system. Frequencies of SRS within and between ICH and IS cohorts as well as its associations (etiology, risk factors) were analyzed. RESULTS: We analyzed 1812 IS (mean age 67.9 years ± 15.9 years, 46.4% female) and 1038 ICH patients (mean age 72.5 years ± 13.0 years, 45.4% female). SRS was significantly more common among SVD-related ICH patients (n = 276, 26.6%) when compared to all IS (n = 363, 20.0%, P < .001) and in both, small artery occlusion (SAO) related IS and lobar ICH within the respective IS and ICH cohorts (16.3% SRS versus 9.1% awake for SAO within all IS, P < .001; and 57.1% SRS versus 47.7% awake for lobar bleeds within all ICH, P = .008). These associations remained significant after controlling for age, sex and risk factors. CONCLUSIONS: SRS was associated with SVD. The SAO etiology and cerebral amyloid angiopathy related lobar ICH suggest that the presence of SVD can interact with sleep or arousal related hemodynamic changes to cause ischemic and hemorrhagic stroke.

Signal variance-based collateral index in DSC perfusion: A novel method to assess leptomeningeal collateralization in acute ischaemic stroke.

As a determinant of the progression rate of the ischaemic process in acute large-vessel stroke, the degree of collateralization is a strong predictor of the clinical outcome after reperfusion therapy and may influence clinical decision-making. Therefore, the assessment of leptomeningeal collateralization is of major importance. The purpose of this study was to develop and evaluate a quantitative and observer-independent method for assessing leptomeningeal collateralization in acute large-vessel stroke based on signal variance characteristics in T2*-weighted dynamic susceptibility contrast (DSC) perfusion-weighted MR imaging (PWI). Voxels representing leptomeningeal collateral vessels were extracted according to the magnitude of signal variance in the PWI raw data time series in 55 patients with proximal large-artery occlusion and an intra-individual collateral vessel index (CVIPWI) was calculated. CVIPWI correlated significantly with the initial ischaemic core volume (rho = -0.459, p = 0.0001) and the PWI/DWI mismatch ratio (rho = 0.494, p = 0.0001) as an indicator of the amount of salvageable tissue. Furthermore, CVIPWI was significantly negatively correlated with NIHSS and mRS at discharge (rho = -0.341, p = 0.015 and rho = -0.305, p = 0.023). In multivariate logistic regression, CVIPWI was an independent predictor of favourable functional outcome (mRS 0-2) (OR = 16.39, 95% CI 1.42-188.7, p = 0.025). CVIPWI provides useful rater-independent information on the leptomeningeal collateral supply in acute stroke.

Frequency of early rapid improvement in stroke severity during interfacility transfer.

BACKGROUND: As interfacility transfer of patients with stroke becomes increasingly common, understanding fluctuations in deficits during transfer may help predict resource needs. We sought to characterize changes in NIH Stroke Scale (NIHSS) scores during transfer and identify factors associated with early rapid improvement (ERI). METHODS: We used prospectively collected data from our Comprehensive Stroke Center's (CSCs) stroke and telestroke network databases. We calculated changes in NIHSS scores for all patients transferred to our CSC after an initial telestroke evaluation from January 2010 to December 2015. Logistic regression identified factors associated with ERI, controlling for patient characteristics available on arrival. RESULTS: Among the 505 patients included, the median initial NIHSS score was 11 (interquartile range [IQR] 5-18), and on CSC arrival, it was 9 (IQR 3-17), with a median change of 0 (-3 to -0). Of note, 74.5% of scores changed by fewer than 4 points (7% increased ≥4 points, and 19% decreased ≥4). In 85% of cases, the NIHSS score change did not cross a threshold to alter eligibility for thrombectomy. In multivariable modeling, ERI was associated with ability to ambulate before the index stroke (odds ratio [OR] 5.79, p = 0.02) and higher initial NIHSS (OR 1.06 per point, p = 0.001). CONCLUSIONS: These findings may be valuable for resource planning and for inclusion in thrombectomy alert activation processes at the receiving hospital.

MRI brain lesions in asymptomatic boys with X-linked adrenoleukodystrophy.

OBJECTIVE: To describe the brain MRI findings in asymptomatic patients with childhood cerebral adrenoleukodystrophy (CCALD). METHODS: We retrospectively reviewed a series of biochemically or genetically confirmed cases of adrenoleukodystrophy followed at our institution between 2001 and 2015. We identified and analyzed 219 brain MRIs from 47 asymptomatic boys (median age 6.0 years). Patient age, MRI scan, and brain lesion characteristics (e.g., contrast enhancement, volume, and Loes score) were recorded. The rate of lesion growth was estimated using a linear mixed effect model. RESULTS: Sixty percent of patients (28/47) showed brain lesions (median Loes score of 3.0 points; range 0.5-11). Seventy-nine percent of patients with CCALD (22/28) had contrast enhancement on first lesional or subsequent MRI. Lesion progression (Loes increase of ≥0.5 point) was seen in 50% of patients (14/28). The rate of lesion growth (mL/mo) was faster in younger patients (r = -0.745; p < 0.0001). Older patients (median age 14.4 y/o) tended to undergo spontaneous arrest of disease. Early lesions grew 46× faster when still limited to the splenium, genu of the corpus callosum, or the brainstem (p = 0.001). CONCLUSION: We provide a description of CCALD lesion development in a cohort of asymptomatic boys. Understanding the early stages of CCALD is crucial to optimize treatments for children diagnosed by newborn screening.

White Matter Integrity and Early Outcomes After Acute Ischemic Stroke.

Chronic white matter structural injury is a risk factor for poor long-term outcomes after acute ischemic stroke (AIS). However, it is unclear how white matter structural injury predisposes to poor outcomes after AIS. To explore this question, in 42 AIS patients with moderate to severe white matter hyperintensity (WMH) burden, we characterized WMH and normal-appearing white matter (NAWM) diffusivity anisotropy metrics in the hemisphere contralateral to acute ischemia in relation to ischemic tissue and early functional outcomes. All patients underwent brain MRI with dynamic susceptibility contrast perfusion and diffusion tensor imaging within 12 h and at day 3-5 post stroke. Early neurological outcomes were measured as the change in NIH Stroke Scale score from admission to day 3-5 post stroke. Target mismatch profile, percent mismatch lost, infarct growth, and rates of good perfusion were measured to assess ischemic tissue outcomes. NAWM mean diffusivity was significantly lower in the group with early neurological improvement (ENI, 0.79 vs. 0.82 × 10-3, mm2/s; P = 0.02). In multivariable logistic regression, NAWM mean diffusivity was an independent radiographic predictor of ENI (ß = - 17.6, P = 0.037). Median infarct growth was 118% (IQR 26.8-221.9%) despite good reperfusion being observed in 65.6% of the cohort. NAWM and WMH diffusivity metrics were not associated with target mismatch profile, percent mismatch lost, or infarct growth. Our results suggest that, in AIS patients, white matter structural integrity is associated with poor early neurological outcomes independent of ischemic tissue outcomes.

Complete Restitution of the Ischemic Penumbra after Successful Thrombectomy : A Pilot Study Using Quantitative MRI.

PURPOSE: Endovascular thrombectomy is highly effective in patients with proximal large artery occlusion but the relevance of reperfusion injury after recanalization is a matter of debate. The aim of this study was to investigate potential residual metabolic distress and microstructural tissue damage or edema after reperfusion using quantitative oxygen-sensitive T2' and T2-mapping in patients successfully treated by thrombectomy. METHODS: Included in this study were 11 patients (mean age 70 ± 11.4 years) with acute ischemic stroke due to internal carotid artery and/or middle cerebral artery occlusion. Quantitative T2 and T2' (1/T2' = 1/T2* - 1/T2) were determined within the ischemic core and hypoperfused but salvaged tissue with delayed time-to-peak (TTP) in patients before and after successful thrombectomy and compared to a control region within the unaffected hemisphere. RESULTS: Decreased T2' values within hypoperfused tissue before thrombectomy showed a normalization after recanalization (p < 0.01). In formerly hypoperfused but salvaged tissue, T2 values increased significantly after thrombectomy (p < 0.05) but did not differ from reference values in the control region. In salvaged tissue, increases of quantitative T2' and T2 to follow-up were more pronounced in areas with severe TTP delay. CONCLUSION: After successful recanalization, T2' re-increased back to normal in formerly hypoperfused areas as a sign of prompt normalization of oxygen metabolism. Furthermore, quantitative T2 in the formerly hypoperfused tissue did not differ from reference values in unaffected tissue. These results indicate complete restitution of salvaged tissue after reperfusion and support the overall safety of endovascular thrombectomy with respect to microstructural tissue integrity.

Introducing the New 3.5/28 Microstent Retriever for Recanalization of Distal Cerebral Arteries in Acute Stroke: Preliminary Results.

BACKGROUND AND PURPOSE: To describe our first experience using a small stent retriever specifically designed for thrombectomy in cerebral arteries with a small caliber (Acandis APERIO® 3.5/28) in patients with acute ischemic stroke. MATERIALS AND METHODS: All patients with an acute ischemic stroke, who underwent endovascular recanalization using the APERIO® thrombectomy device with a diameter of 3.5 mm, were identified in retrospect and included in the present analysis. Demographic and clinical data as well as data on the procedures performed were collected (patient sex, mean age, NIHSS, mRS, TICI score, and complications). RESULTS: Stent retriever-based thrombectomy with the Aperio® 3.5/28 alone (n = 10 vessels) or in combination with other devices (n = 13 vessels) was performed in 22 acute stroke patients with embolic occlusions of distal branches of the anterior and posterior circulations (median NIHSS = 8.5). For vessels treated with the Aperio® 3.5/28, we achieved a TICI 2b/3 reperfusion rate of 73.9%. One patient suffered a symptomatic intracerebral hemorrhage after thrombectomy; otherwise, no procedure-related complications were seen. CONCLUSION: Our data suggest that mechanical thrombectomy of distal cerebral artery occlusions with the Aperio® 3.5/28 is feasible and in general safe, thus offering a promising option for endovascular stroke therapy. However, multicentric studies with larger patient cohorts are necessary to evaluate the clinical benefit.

Sex-specific differences in white matter microvascular integrity after ischaemic stroke.

Background and purpose: Functional outcomes after ischaemic stroke are worse in women, despite adjusting for differences in comorbidities and treatment approaches. White matter microvascular integrity represents one risk factor for poor long-term functional outcomes after ischaemic stroke. The aim of the study is to characterise sex-specific differences in microvascular integrity in individuals with acute ischaemic stroke. Methods: A retrospective analysis of subjects with acute ischaemic stroke and brain MRI with diffusion-weighted (DWI) and dynamic-susceptibility contrast-enhanced (DSC) perfusion-weighted imaging obtained within 9 hours of last known well was performed. In the hemisphere contralateral to the acute infarct, normal-appearing white matter (NAWM) microvascular integrity was measured using the K2 coefficient and apparent diffusion coefficient (ADC) values. Regression analyses for predictors of K2 coefficient, DWI volume and good outcome (90-day modified Rankin scale (mRS) score <2) were performed. Results: 105 men and 79 women met inclusion criteria for analysis. Despite no difference in age, women had increased NAWM K2 coefficient (1027.4 vs 692.7×10-6/s; p=0.006). In women, atrial fibrillation (ß=583.6; p=0.04) and increasing NAWM ADC (ß=4.4; p=0.02) were associated with increased NAWM K2 coefficient. In multivariable regression analysis, the K2 coefficient was an independent predictor of DWI volume in women (ß=0.007; p=0.01) but not men. Conclusions: In women with acute ischaemic stroke, increased NAWM K2 coefficient is associated with increased infarct volume and chronic white matter structural integrity. Prospective studies investigating sex-specific differences in white matter microvascular integrity are needed.

Subependymomas - Characteristics of a "Leave me Alone" Lesion. / Subependymome ­ Charakteristika einer "leave me alone"-Läsion.

PURPOSE: Intracranial subependymomas are rare, mostly asymptomatic tumours, which are often found incidentally and therefore did not receive much attention in previous literature. By being classified as benign grade I in the WHO classification of tumours of the central nervous system, they are given a special status compared to the other ependymal tumours. Tumor recurrences are a rarity, spinal "drop metastases" do not occur. While etiological, pathological and therapeutic characteristics have been subject of several publications over the last few decades and have meanwhile been well studied, the imaging characteristics are much less well received. MATERIAL AND METHOD: Retrospective analysis of our relatively large group of 33 patients with subependymoma, including 4 patients with a mixture of subependymomas with ependymal cell fractions in terms of imaging and clinical aspects and with reference to a current literature review. RESULTS: Subependymomas have typical image morphologic characteristics that differentiate them from tumors of other entities, however, the rare subgroup of histopathological mixtures of subependymomas with ependymal cell fractions has no distinctly different imaging properties. CONCLUSIONS: Knowing the imaging characteristics of subpendymoma and their differential diagnoses is of particular importance in order to be able to decide between the necessity of follow-up controls, an early invasive diagnosis or, depending on the entity, tumor resection. KEY POINTS: · Subependymomas have typical imaging characteristics that are clearly distinguishable from other entities.. · Increased incidence in middle/ older aged men, most frequent localization: 4th ventricle.. · Symptomatic subependymomas, often located in lateral ventricles, are usually characterized by hydrocephalus.. · Radiological identification of mixed subependymoma with ependymal cell fractions is not possible.. · Image based differentiation from other entities is important for the procedure.. CITATION FORMAT: · Kammerer S, Mueller-Eschner M, Lauer A et al. Subependymomas - Characteristics of a "Leave me Alone" Lesion. Fortschr Röntgenstr 2018; 190: 955 - 966.

Delays in the Air or Ground Transfer of Patients for Endovascular Thrombectomy.

BACKGROUND AND PURPOSE: For suspected large vessel occlusion patients efficient transfer to centers that provide endovascular therapy (ET) is critical to maximizing treatment opportunity. Our objective was to examine associations between transfer time, modes of transfer, ET, and outcomes within a hub-and-spoke telestroke network. METHODS: Patients with ischemic stroke were included if transferred to a single hub hospital between January 2011 and October 2015 with National Institutes of Health Stroke Scale>6, onset<12 hours from hub arrival with complete clinical, imaging, and transfer data. Transfer time was the interval between initiation of telestroke consult and arrival at the hub. Algorithms were created for ideal transfer times; ideal time was subtracted from actual time to calculate delay. We examined bivariate relationships between transfer time and several clinical outcomes and used multivariable regression modeling to explore possible predictors of delay. RESULTS: Of 234 patients that met inclusion criteria, 51% were transferred by ambulance and 49% by helicopter; 27% underwent ET (36% achieved modified Rankin Scale score of 0-2 at 90 days). Median actual transfer time was 132 minutes (interquartile range, 103-165), compared with median ideal transfer time at 102 minutes (interquartile range, 96-123). Longer transfer time was associated with decreased likelihood of undergoing ET (odds ratio, 0.990; P=0.003). Nocturnal transfer (18:00 to 06:00 hours) was associated with significantly longer delay (ß=20.5; P<0.0005), whereas intravenous tissue-type plasminogen activator (tPA) delivery at spoke hospital was not. The median delay for nocturnal transfer was 31 minutes (interquartile range, 11-51), compared with daytime at 14 minutes (interquartile range, -9 to 36). CONCLUSIONS: Within a large telestroke network, there was an association between longer transfer time and decreased likelihood of undergoing ET. Nocturnal transfers were associated with a substantial delay relative to daytime transfers. In contrast, delivery of tPA was not associated with delays, underscoring the impact of effective protocols at spoke hospitals. More efficient transfer may enable higher ET treatment rates. Metrics and protocols for transfer, especially at night, may improve transfer times.

Intravenous thrombolysis in unwitnessed stroke onset: MR WITNESS trial results.

OBJECTIVE: Most acute ischemic stroke (AIS) patients with unwitnessed symptom onset are ineligible for intravenous thrombolysis due to timing alone. Lesion evolution on fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) correlates with stroke duration, and quantitative mismatch of diffusion-weighted MRI with FLAIR (qDFM) might indicate stroke duration within guideline-recommended thrombolysis. We tested whether intravenous thrombolysis ≤4.5 hours from the time of symptom discovery is safe in patients with qDFM in an open-label, phase 2a, prospective study (NCT01282242). METHODS: Patients aged 18 to 85 years with AIS of unwitnessed onset at 4.5 to 24 hours since they were last known to be well, treatable within 4.5 hours of symptom discovery with intravenous alteplase (0.9mg/kg), and presenting with qDFM were screened across 14 hospitals. The primary outcome was the risk of symptomatic intracranial hemorrhage (sICH) with preplanned stopping rules. Secondary outcomes included symptomatic brain edema risk, and functional outcomes of 90-day modified Rankin Scale (mRS). RESULTS: Eighty subjects were enrolled between January 31, 2011 and October 4, 2015 and treated with alteplase at median 11.2 hours (IQR = 9.5-13.3) from when they were last known to be well. There was 1 sICH (1.3%) and 3 cases of symptomatic edema (3.8%). At 90 days, 39% of subjects achieved mRS = 0-1, as did 48% of subjects who had vessel imaging and were without large vessel occlusions. INTERPRETATION: Intravenous thrombolysis within 4.5 hours of symptom discovery in patients with unwitnessed stroke selected by qDFM, who are beyond the recommended time windows, is safe. A randomized trial testing efficacy using qDFM appears feasible and is warranted in patients without large vessel occlusions. Ann Neurol 2018;83:980-993.

Diffuse microvascular dysfunction and loss of white matter integrity predict poor outcomes in patients with acute ischemic stroke.

We sought to investigate the relationship between blood-brain barrier (BBB) permeability and microstructural white matter integrity, and their potential impact on long-term functional outcomes in patients with acute ischemic stroke (AIS). We studied 184 AIS subjects with perfusion-weighted MRI (PWI) performed <9 h from last known well time. White matter hyperintensity (WMH), acute infarct, and PWI-derived mean transit time lesion volumes were calculated. Mean BBB leakage rates (K2 coefficient) and mean diffusivity values were measured in contralesional normal-appearing white matter (NAWM). Plasma matrix metalloproteinase-2 (MMP-2) levels were studied at baseline and 48 h. Admission stroke severity was evaluated using the NIH Stroke Scale (NIHSS). Modified Rankin Scale (mRS) was obtained at 90-days post-stroke. We found that higher mean K2 and diffusivity values correlated with age, elevated baseline MMP-2 levels, greater NIHSS and worse 90-day mRS (all p < 0.05). In multivariable analysis, WMH volume was associated with mean K2 ( p = 0.0007) and diffusivity ( p = 0.006) values in contralesional NAWM. In summary, WMH severity measured on brain MRI of AIS patients is associated with metrics of increased BBB permeability and abnormal white matter microstructural integrity. In future studies, these MRI markers of diffuse cerebral microvascular dysfunction may improve prediction of cerebral tissue infarction and functional post-stroke outcomes.

ABCD1 dysfunction alters white matter microvascular perfusion.

Cerebral X-linked adrenoleukodystrophy is a devastating neurodegenerative disorder caused by mutations in the ABCD1 gene, which lead to a rapidly progressive cerebral inflammatory demyelination in up to 60% of affected males. Selective brain endothelial dysfunction and increased permeability of the blood-brain barrier suggest that white matter microvascular dysfunction contributes to the conversion to cerebral disease. Applying a vascular model to conventional dynamic susceptibility contrast magnetic resonance perfusion imaging, we demonstrate that lack of ABCD1 function causes increased capillary flow heterogeneity in asymptomatic hemizygotes predominantly in the white matter regions and developmental stages with the highest probability for conversion to cerebral disease. In subjects with ongoing inflammatory demyelination we observed a sequence of increased capillary flow heterogeneity followed by blood-brain barrier permeability changes in the perilesional white matter, which predicts lesion progression. These white matter microvascular alterations normalize within 1 year after treatment with haematopoietic stem cell transplantation. For the first time in vivo, our studies unveil a model to assess how ABCD1 alters white matter microvascular function and explores its potential as an earlier biomarker for monitoring disease progression and response to treatment.

Structural Integrity of Normal Appearing White Matter and Sex-Specific Outcomes After Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Women have worse poststroke outcomes than men. We evaluated sex-specific clinical and neuroimaging characteristics of white matter in association with functional recovery after acute ischemic stroke. METHODS: We performed a retrospective analysis of acute ischemic stroke patients with admission brain MRI and 3- to 6-month modified Rankin Scale score. White matter hyperintensity and acute infarct volume were quantified on fluid-attenuated inversion recovery and diffusion tensor imaging MRI, respectively. Diffusivity anisotropy metrics were calculated in normal appearing white matter contralateral to the acute ischemia. RESULTS: Among 319 patients with acute ischemic stroke, women were older (68.0 versus 62.7 years; P=0.004), had increased incidence of atrial fibrillation (21.4% versus 12.2%; P=0.04), and lower rate of tobacco use (21.1% versus 35.9%; P=0.03). There was no sex-specific difference in white matter hyperintensity volume, acute infarct volume, National Institutes of Health Stroke Scale, prestroke modified Rankin Scale score, or normal appearing white matter diffusivity anisotropy metrics. However, women were less likely to have an excellent outcome (modified Rankin Scale score <2: 49.6% versus 67.0%; P=0.005). In logistic regression analysis, female sex and the interaction of sex with fractional anisotropy, radial diffusivity, and axial diffusivity were independent predictors of functional outcome. CONCLUSIONS: Female sex is associated with decreased likelihood of excellent outcome after acute ischemic stroke. The correlation between markers of white matter integrity and functional outcomes in women, but not men, suggests a potential sex-specific mechanism.