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Patients with cerebral small-vessel disease (CSVD) exhibit perturbed end-artery function and have an increased risk for stroke and age-related cognitive decline. Here, we used targeted genome-wide association (GWA) analysis and defined a CSVD locus adjacent to the forkhead transcription factor FOXC1. Moreover, we determined that the linked SNPs influence FOXC1 transcript levels and demonstrated that patients as young as 1 year of age with altered FOXC1 function exhibit CSVD. MRI analysis of patients with missense and nonsense mutations as well as FOXC1-encompassing segmental duplication and deletion revealed white matter hyperintensities, dilated perivascular spaces, and lacunar infarction. In a zebrafish model, overexpression or morpholino-induced suppression of foxc1 induced cerebral hemorrhage. Inhibition of foxc1 perturbed platelet-derived growth factor (Pdgf) signaling, impairing neural crest migration and the recruitment of mural cells, which are essential for vascular stability. GWA analysis also linked the FOXC1-interacting transcription factor PITX2 to CSVD, and both patients with PITX2 mutations and murine Pitx2-/- mutants displayed brain vascular phenotypes. Together, these results extend the genetic etiology of stroke and demonstrate an increasing developmental basis for human cerebrovascular disease.

Background Bronchopulmonary dysplasia (BPD) remains a main complication of extreme prematurity and currently lacks efficient treatment. Rat bone marrow-derived mesenchymal stem cells (MSC) prevent lung injury in an oxygen-induced model of BPD. Human cord is an advantageous source of stem cells that is especially appealing for the treatment of neonatal diseases. The therapeutic benefit after established lung injury and long-term safety of cord-derived stem cells is unknown. Methods Human cord-derived perivascular cells (PCs) or cord blood-derived MSCs were delivered prophylactically or after established alveolar injury into the airways of newborn rats exposed to hyperoxia, a well-established BPD model. Results Rat pups exposed to hyperoxia showed the characteristic arrest in alveolar growth with air space enlargement and loss of lung capillaries. PCs and MSCs partially prevented and rescued lung function and structure. Despite therapeutic benefit, cell engraftment was low, suggesting that PCs and MSCs act via a paracrine effect. Accordingly, cell free-derived conditioned media from PCs and MSCs also exerted therapeutic benefit when used either prophylactically or therapeutically. Finally, long-term (6 months) assessment of stem cell or conditioned media therapy showed no adverse lung effects of either strategy, with persistent improvement in exercise capacity and lung structure. Conclusions Human umbilical cord-derived PCs and MSCs exert short- and long-term therapeutic benefit without adverse lung effects in this experimental model and offer new therapeutic options for lung diseases characterised by alveolar damage.

Zaeem et al discuss the case study of a 36-year-old man with fulminant multiple sclerosis. The man has a 9-year history of stable, relapsing-remitting multiple sclerosis (MS) who presented to the emergency department with a 1-week history of blurred vision, vertigo, perioral numbness, difficulty walking, aggression and confusion. Symptoms persisted despite the patient having started prednisolone 3 days before presentation. Several months previously, he had discontinued his maintenance therapy for MS--dimethyl fumarate, a nuclear factor erythroid 2-reIated factor 2 activator--owing to severe diarrhea.

Quantitative susceptibility mapping (QSM) measures bulk susceptibilities in the brain, which can arise from many sources. In iron-rich subcortical gray matter (GM), non-heme iron is a dominant susceptibility source. We evaluated the use of QSM for iron mapping in subcortical GM by direct comparison to tissue iron staining. We performed in situ or in vivo QSM at 4.7T combined with Perls' ferric iron staining on the corresponding extracted subcortical GM regions. This histochemical process enabled examination of ferric iron in complete slices that could be related to susceptibility measurements. Correlation analyses were performed on an individual-by-individual basis and high linear correlations between susceptibility and Perls' iron stain were found for the three multiple sclerosis (MS) subjects studied (R2=0.75, 0.62, 0.86). In addition, high linear correlations between susceptibility and transverse relaxation rate (R2*) were found (R2=0.88, 0.88, 0.87) which matched in vivo healthy subjects (R2=0.87). This work validates the accuracy of QSM for brain iron mapping and also confirms ferric iron as the dominant susceptibility source in subcortical GM, by demonstrating high linear correlation of QSM to Perls' ferric iron staining. [Display omitted] •In situ or in vivo QSM is compared with Perls' iron stain in subcortical gray matter.•Full slice Perls' iron staining enabled spatial maps of ferric iron to relate directly to MRI.•High linear correlations are found between QSM and Perls' iron stain in postmortem subjects with multiple sclerosis.•High linear correlations are also found between QSM and R2* for both postmortem and in vivo subjects.

Purpose To report the accuracy and reliability of Cobb angle (CA), axial vertebral rotation (AVR), kyphotic and lordotic angles (KA and LA) measurements on using a new 3D ultrasound (US) system. Methods Forty participants (34 F, 6 M, aged 14.0 ± 2.3 years) were recruited. The first 20 participants were scanned by the validated US system and the new US system. The other 20 participants were scanned with the new US system only. Two raters (R1 and R2) performed the measurements: R1 has 10 years of experience in radiology but is new in ultrasound scoliosis, while R2 has 30 years of scoliosis experience. All US images were measured twice by R1, and once by R2. Forty posteroanterior and 30 lateral standing radiographs were obtained and measured once by R1. Statistical analysis consisted of mean absolute difference (MAD), intraclass correlation coefficient (ICC (2,1)), and Bland-Altman plots. Results R1 showed excellent intra-rater and inter-rater reliability for US measurements with ICCs(2,1) ≥ 0.91. The inter-method reliability was good between the two US systems for all parameters with ICCs(2,1) ≥ 0.85 and maximum MAD of 3.4°. The new US showed good reliability and accuracy compared to radiographs for CA, AVR and KA with ICCs(2,1) ≥ 0.81 and maximum MAD of 5.8°, but poor results for LA with ICCs(2,1) of 0.27–0.35 and MADs of 14.0°-15.4°. Conclusion The new 3D US system showed good reliability and accuracy for CA, AVR and KA measurements, but a large measurement discrepancy on LA. A new measurement method for US LA may need to investigate.

Takayasu’s arteritis (TAK) is a large-vessel vasculitis that targets the aorta and its major branches. Although extracranial vascular involvement is uniformly present in this disease, the frequency of intracranial involvement in TAK has not been well studied. We retrospectively reviewed the clinical and imaging records of patients diagnosed with TAK at a single Canadian university medical centre to determine the prevalence of intracranial vascular involvement. Intracranial vascular and non-vascular findings were described, and a review of the literature was performed. Of 20 patients with TAK, 12 had vascular neuroimaging completed. Intracranial vascular lesions were identified in 4 patients (33.3% of those with imaging available, 20% of all patients). The frequency of intracranial vessel involvement in TAK may be more common than appreciated. Imaging of both the intra- and extra-cranial vessels should be considered in these young patients.

Clot retraction in intracerebral hemorrhage (ICH) has been described and postulated to be related to effective hemostasis and perihematoma edema (PHE) formation. The incidence and quantitative extent of hematoma retraction (HR) is unknown. Our aim was to determine the incidence of HR between baseline and time of admission. We also tested the hypothesis that patients with HR had higher PHE volume and good prognosis. This was a retrospective single-centre study in which serial planimetric volume measurements of the total hematoma volume (parenchymal (IPH) and intraventricular (IVH)) and PHE were performed in ICH patients with baseline non-contrast computed tomography (CT) completed within 6 hours of onset and follow-up CT 24 (±12) hours from symptom onset. HR was defined as a decrease in volume of >3ml or >15%, and hematoma expansion (HE) as an increase of >6ml or >30%. All other patients were categorized as stable hematoma (HS). Good outcome was defined as modified Rankin Scale (mRS) 0-2 at 90 days. A total of 136 patients (mean age = 69.3±13.39 years, 58.1% male) were included. Median (interquartile range) baseline total hematoma volume was 14.96 (7.80, 31.88) ml. HR >3ml and >15% occurred in 6 (4.4%) and 8 (5.9%) patients, respectively. Neither definition of HR was associated with follow-up PHE (p>0.297) or good outcome (p>0.249). IVH was the only independent predictor of HR (p<0.0241). Early HR is rare and associated with IVH, but not with PHE or clinical outcome. There was no relationship between HR, PHE, and patient prognosis. Therefore, HR is unlikely to be a useful endpoint in clinical ICH studies.

Introduction Diffusion tensor imaging (DTI) has shown abnormalities of the fornix and other limbic white matter tracts in multiple sclerosis (MS), mainly focusing on relapsing‐remitting MS. Methods The goal here was to evaluate the fornix, cingulum, and uncinate fasciculus with DTI tractography at 1.7 mm isotropic resolution in three MS subgroups (11 relapsing‐remitting (RRMS), nine secondary progressive (SPMS), eight primary progressive (PPMS)) versus 11 controls, and assess correlations with cognitive and clinical scores. Results The MS group overall showed extensive diffusion abnormalities of the fornix with less volume, lower fractional anisotropy (FA), and higher mean and radial diffusivities, which were similarly affected in all three MS subgroups. The uncinate fasciculus had lower FA only in the secondary progressive subgroup, and the cingulum had no DTI differences in any MS subgroup. The FA and/or volumes of these tracts correlated negatively with larger total lesion volume. The only DTI‐cognitive correlation was lower right cingulum FA and greater depression over the entire MS cohort. Conclusions Diffusion tractography identified abnormalities in the fornix that appears to be affected early and consistently across all three primary MS phenotypes of RRMS, SPMS, and PPMS regardless of Expanded Disability Status Scale, time since diagnosis, or cognitive scores. Multiple sclerosis (MS) often results in cognitive dysfunction, fatigue, and depression, which may have a microstructural basis in limbic white matter tract degradation. High‐resolution diffusion tensor imaging (DTI) tractography at 4.7T assessed the fornix, cingulum, and uncinate fasciculus tracts and their links to clinical/cognitive scores in three MS diagnostic subgroups. The entire MS cohort showed diffusion abnormalities of the fornix with less volume, lower fractional anisotropy (FA), and higher mean and radial diffusivities, which were similarly affected in all three MS subgroups, and FA and/or volumes of these tracts correlated negatively with larger total lesion volume regardless of Expanded Disability Status Scale, time since diagnosis, or cognitive scores.

Background Aggressively lowering blood pressure (BP) in acute intracerebral hemorrhage (ICH) may improve outcome. Although there is no evidence that BP reduction changes cerebral blood flow, retrospective magnetic resonance imaging (MRI) studies have demonstrated sub-acute ischemic lesions in ICH patients. The primary aim of this study is to assess ischemic lesion development in patients randomized to two different BP treatment strategies. We hypothesize aggressive BP reduction is not associated with ischemic injury after ICH. Methods The I ntra c erebral H emorrhage A cutely D ecreasing B lood P ressure T rial II (ICH ADAPT II) is a phase II multi-centre randomized open-label, blinded-endpoint trial. Acute ICH patients ( N  = 270) are randomized to a systolic blood pressure (SBP) target of <140 or <180 mmHg. Acute ICH patients within 6 h of onset and two SBP measurements ≥140 mmHg recorded >2 mins apart qualify. SBP is managed with a pre-defined treatment protocol. Patients undergo MRI at 48 h, Days 7 and 30, with clinical assessment at Day 30 and 90. The primary outcome is diffusion weighted imaging (DWI) lesion frequency at 48 h. Secondary outcomes include cumulative DWI lesion rate frequency within 30 days, absolute hematoma growth, prediction of DWI lesion incidence, 30-day mortality rates, day 90 functional outcome, and cognitive status. Discussion This trial will assess the impact of hypertensive therapies on physiological markers of ischemic injury. The findings of this study will provide evidence for the link, or lack thereof, between BP reduction and ischemic injury in ICH patients. Trial registration This study is registered with clinicaltrials.gov  ( NCT02281838 , first received October 29, 2014).