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Parametric fMRI of paced motor responses uncovers novel whole-brain imaging biomarkers in spinocerebellar ataxia type 3.

Machado‐Joseph Disease, inherited type 3 spinocerebellar ataxia (SCA3), is the most common form worldwide. Neuroimaging and neuropathology have consistently demonstrated cerebellar alterations. Here we aimed to discover whole‐brain functional biomarkers, based on parametric performance‐level‐dependent signals. We assessed 13 patients with early SCA3 and 14 healthy participants. We used a combined parametric behavioral/functional neuroimaging design to investigate disease fingerprints, as a function of performance levels, coupled with structural MRI and voxel‐based morphometry. Functional magnetic resonance imaging (fMRI) was designed to parametrically analyze behavior and neural responses to audio‐paced bilateral thumb movements at temporal frequencies of 1, 3, and 5 Hz. Our performance‐level‐based design probing neuronal correlates of motor coordination enabled the discovery that neural activation and behavior show critical loss of parametric modulation specifically in SCA3, associated with frequency‐dependent cortico/subcortical activation/deactivation patterns. Cerebellar/cortical rate‐dependent dissociation patterns could clearly differentiate between groups irrespective of grey matter loss. Our findings suggest functional reorganization of the motor network and indicate a possible role of fMRI as a tool to monitor disease progression in SCA3. Accordingly, fMRI patterns proved to be potential biomarkers in early SCA3, as tested by receiver operating characteristic analysis of both behavior and neural activation at different frequencies. Discrimination analysis based on BOLD signal in response to the applied parametric finger‐tapping task significantly often reached >80% sensitivity and specificity in single regions‐of‐interest.Functional fingerprints based on cerebellar and cortical BOLD performance dependent signal modulation can thus be combined as diagnostic and/or therapeutic targets in hereditary ataxia. Hum Brain Mapp 37:3656–3668, 2016.

Endothelial progenitor cells enhance blood–brain barrier permeability in subacute stroke

Objective To study the association among endothelial progenitor cells (EPCs), subacute blood–brain barrier (BBB) permeability, and clinical outcome after ischemic stroke, determining the micro RNAs of EPCs responsible for good clinical outcome. Methods We included consecutive patients with nonlacunar acute ischemic strokes in the territory of a middle cerebral artery and ages between 18 and 80 years. Clinical outcome was defined as modified Rankin Scale score at 3 months. Neuroimaging was performed at day 0 and 7 by MRI, including assessment of BBB permeability by dynamic contrast enhancement. EPCs were isolated from peripheral venous blood, quantified, and submitted to in vitro functional tests, including migratory and angiogenic assays. Stroke hemodynamics were evaluated serially by ultrasound. Statistical significance was set at p < 0.05. Results We included 45 patients; mean age was 70.0 ± 10.0 years. The in vitro functional properties of EPCs were associated with BBB permeability, particularly at day 7. The number of each EPC subset at both timepoints was not associated with BBB permeability. Permeability of BBB at day 7 was independently associated with improved clinical outcome (odds ratio 0.897; 95% confidence interval 0.816–0.986; p = 0.025). The EPCs (CD34+ cell subset) of patients with good clinical outcome showed 24 differentially expressed miRNAs, with a common effect on adherens junction pathway. Conclusions The functional properties of EPCs are associated with enhanced subacute permeability of BBB and improved clinical outcome after acute ischemic stroke.

Different locations but common associations in subcortical hypodensities of presumed vascular origin: cross-sectional study on clinical and neurosonologic correlates.

BackgroundSubcortical hypodensities of presumed vascular etiology (SHPVO) are a clinical, radiological and neuropathological syndrome with a still largely unexplained pathophysiology. Parallel to the clinical heterogeneity, there is also recognised cerebral topographical diversity with undetermined etiological implications. Our aim is to assess clinical and neurosonological predictors of SHPVO according to their location.MethodsCross sectional analysis of consecutive patients that underwent neurosonologic evaluation and head CT within one month, during a one year period. We excluded patients with absent temporal sonographic window, any pathology with a possible confounding effect on cerebral arterial pulsatility, atrial fibrillation and other etiologies of white matter diseases. The mean pulsatility index (PI) of both middle cerebral arteries was measured in the middle third of the M1 segment; intima media thickness was evaluated in the far wall of both common carotid arteries. SHPVO were rated by analysis of head CT in deep white matter (DWMH), periventricular white matter (PVWMH) and basal ganglia (BGH). We conducted a multivariate ordinal logistic regression model including all clinical, demographic and ultrasonographic characteristics to determine independent associations with SHPVO.ResultsWe included 439 patients, mean age 63.47 (SD: 14.94) years, 294 (67.0%) male. The independent predictors of SHPVO were age (OR = 1.067, 95% CI: 1.047-1.088, p < 0.001 for DWMH; OR = 1.068, 95% CI: 1.049-1.088, p < 0.001 for PVWMH; OR = 1.05, 95% CI: 1.03-1.071, p < 0.001 for BGH), hypertension (OR = 1.909, 95% CI: 1.222-2.981, p = 0.004 for DWMH; OR = 1.907, 95% CI: 1.238-2.938, p = 0.003 for PVWMH; OR = 1.775, 95% CI: 1.109-2.843, p = 0.017 for BGH) and PI (OR = 17.994, 95% CI: 6.875-47.1, p < 0.001 for DWMH; OR = 5.739, 95%CI: 2.288-14.397, p < 0.001 for PVWMH; OR = 11.844, 95% CI: 4.486-31.268, p < 0.001 for BGH) for all locations of SHPVO.ConclusionsAge, hypertension and intracranial pulsatility are the main independent predictors of SHPVO across different topographic involvement and irrespective of extracranial atherosclerotic involvement.

Endothelial Progenitor Cells influence acute and subacute stroke hemodynamics

BACKGROUND Endothelial Progenitor Cells (EPCs) are a circulating stem cell population with in vivo capacity of promoting angiogenesis after ischemic events. Despite the promising preclinical data, their potential integration with reperfusion therapies and hemodynamic evolution of stroke patients is still unknown. Our aim was to determine the association of EPCs with acute, subacute and chronic hemodynamic features. METHODS In this prospective study, we included consecutive patients with ages between 18 and 80years and non-lacunar ischemic stroke within the territory of a middle cerebral artery. All patients were subject to hemodynamic evaluation by ultrasound at baseline, seven days and three months. We quantified cerebral blood flow (CBF) and assessed early recanalization and collateral flow. Hemorrhagic transformation was graded in Magnetic Resonance imaging performed at seven days. EPCs were isolated from peripheral venous blood collected in the first 24h and seven days, counted and submitted to functional in vitro tests. RESULTS We included 45 patients with a median age of 70±10years. The angiogenic and migratory capacities of EPCs were associated with increased collateral flow in the acute stage and day seven CBF, without statistically significant associations with recanalization nor haemorrhagic transformation. The number of EPCs was not associated with any hemodynamic variable. CONCLUSIONS The functional properties of EPCs are associated with acute and subacute stroke hemodynamics, with no effect on haemorrhagic transformation.

Neurosonology Accuracy for Isolated Acute Vestibular Syndromes

The clinical approach to acute vestibular syndromes is often complex for the physician. Neurosonology offers a noninvasive method to study the cervicocephalic circulation when a vascular etiology is suspected. We aim to evaluate the diagnostic accuracy of a vascular neurosonological exam in isolated acute vestibular syndrome.

Collateral pial circulation relates to the degree of brain edema on CT 24 hours after ischemic stroke

Background Cerebral edema is frequent in patients with acute ischemic stroke (AIS) who undergo reperfusion therapy and is associated with high mortality. The impact of collateral pial circulation (CPC) status on the development of edema has not yet been determined. Methods We studied consecutive patients with AIS and documented M1–middle cerebral artery (MCA) and/or distal internal carotid artery (ICA) occlusion who underwent reperfusion treatment. Edema was graded on the 24-hour non-contrast computed tomography (NCCT) scan. CPC was evaluated at the acute phase (≤6 hours) by transcranial color-coded Doppler, angiography and/or CT angiography. We performed an ordinal regression model for the effect of CPC on cerebral edema, adjusting for age, baseline National Institutes of Health Stroke Scale, Alberta Stroke Program Early Computed Tomography Score (ASPECTS) on admission, NCCT, parenchymal hemorrhagic transformation at 24 hours and complete recanalization at six hours. Results Among the 108 patients included, 49.1% were male and mean age was 74.2 ± 11.6 years. Multivariable analysis showed a significant association between cerebral edema and CPC status (OR 0.22, 95% CI 0.08–0.59, p = 0.003), initial ASPECTS (OR 0.72, 95% CI 0.57–0.92, p = 0.007) and parenchymal hemorrhagic transformation (OR 23.67, 95% CI 4.56–122.8, p < 0.001). Conclusions Poor CPC is independently associated with greater cerebral edema 24 hours after AIS in patients who undergo reperfusion treatment.

Differentiating Acute and Subacute Vertical Strabismus Using Different Head Positions During the Upright-Supine Test

Importance Accurate clinical differentiation between skew deviation and fourth nerve palsy (4NP) is critical in the acute and subacute settings. Objective To determine the sensitivity and specificity of the upright-supine test to detect vertical misalignment changes using different head positions for the diagnosis of acute or subacute skew deviation vs 4NP. Design, Setting, and Participants This multicenter study enrolled consecutive patients from Coimbra University Hospital Centre, Coimbra, Portugal, and Michigan State University, Lansing, within 2 months of presenting with vertical diplopia and diagnosed as having skew deviation or acquired unilateral 4NP. The study used nonmasked screening and diagnostic test results from June 1, 2013, to December 31, 2016. Data were analyzed from January 1, 2017, to June 30, 2017. Main Outcomes and Measures A 50% or greater change in vertical misalignment between the upright and supine positions, with the head centered and tilted to either side. Measurements included the alternate prism and cover (APC) test, the double Maddox rod test, the APC test change index ([measurement upright − measurement supine] / [measurement upright + measurement supine]), and the APC test sensitivity and specificity. Results Of the 37 included patients, the mean (SD) age was 58 (14) years, and 26 (70%) were male. We enrolled 19 patients (51%) with skew deviation and 18 (49%) with 4NP. Eighteen patients with skew deviation (95%) showed additional ocular motor and/or neurological signs. When moving to the supine position, only 1 patient with skew deviation (5%) showed more than a 50% decrease of hypertropia with the head centered (APC test: sensitivity, 5%; specificity, 100%). Three patients with 4NP (17%) showed more than a 50% decrease of hypertropia with the head tilted toward the hypertropic eye, and 10 patients with 4NP (56%) showed more than a 50% increase of hypertropia with the head tilted toward the hypotropic eye. Change indexes were different between the skew deviation and 4NP groups for head tilt to the hypotropic eye (difference, −0.33 prism diopters; 95% CI, −0.43 to −0.20; P < .001). Cyclotorsion worsened in the supine position only in patients with skew deviation (hypertropic eye: difference, −7.6 prism diopters; 95% CI, −13.00 to −0.75; P = .01; hypotropic eye: difference, 8.2 prism diopters; 95% CI, 0 to 15.75; P = .03). Conclusions and Relevance The upright-supine test with the head centered is not a sensitive method to separate acute or subacute skew deviation from 4NP. Conversion of an incomitant vertical deviation in the upright position to a comitant vertical strabismus in the supine position in all head positions, as well as the absence of additional ocular motor and/or neurologic signs, may constitute a more useful clue.

STROKE34 study protocol: A randomized controlled phase IIa trial of intra-arterial CD34+ cells in acute ischemic stroke

Rationale/aim Despite the increasing efficacy of recanalization therapies for acute ischemic stroke, a large number of patients are left with long-term functional impairment, devoid of efficacious treatments. CD34+ cells comprise a subset of bone marrow-derived mononuclear cells with the capacity to promote angiogenesis in ischemic lesions and have shown promising results in observational and in vitro studies. In this study, we aim to assess the efficacy of an autotransplant of CD34+ cells in acute ischemic stroke. Sample size estimates 30 patients will be randomized for a power of 90% and alpha of 0.05 to detect a difference in 3 months infarct volume. Methods and design We will screen 18–80 years old patients with acute ischemic stroke due to occlusion of a middle cerebral artery (MCA) for randomization. Persistent arterial occlusions, contra-indications to magnetic resonance imaging (MRI), premorbid dependency, or other severe diseases will be excluded. Treatment will involve bone marrow aspiration, selection of CD34+ cells, and their administration intra-arterially in the symptomatic MCA by angiography. Patients will be randomized for treatment at 7 (±2) days, 20 (±5 days) or sham procedure, 10 in each group. Study outcomes The primary outcome will be infarct volume in MRI performed at 3 months. Secondary outcomes will include adverse events and multidimensional functional and neurological measures. Discussion/conclusion STROKE34 is a PROBE design phase IIa clinical trial to assess the efficacy of intra-arterial administration of CD34+ cells 7 and 20 days after acute ischemic stroke. Trial registration (EU Clinical Trials Register) 2017-002456-88.

Blood Pressure Variability in Acute Ischemic Stroke: The Role of Early Recanalization

We performed a retrospective study with the aim of investigating the association between blood pressure (BP) variability in the first 24 h after ischemic stroke and functional outcome, regarding arterial recanalization status. A total of 674 patients diagnosed with acute stroke and treated with revascularization therapies were enrolled. Systolic and diastolic BP values of the first 24 h after stroke were collected and their variation quantified through standard deviation. Recanalization state was evaluated at 6 h and clinical outcome at 3 months was assessed by modified Rankin Scale. In multivariate analyses systolic BP variability in the first 24 h post-stroke showed an association with 3 months clinical outcome in the whole population and non-recanalyzed patients. In recanalyzed patients, BP variability did not show a significant association with functional outcome.

Monitoring Balloon Test Occlusion of the Internal Carotid Artery with Transcranial Doppler: A Case Report and Literature Review

Angiographic balloon test occlusion (BTO) allows preoperative risk evaluation of patients undergoing permanent therapeutic occlusion of the internal carotid artery (ICA). The sensitivity of the BTO can be increased using different complementary techniques. Transcranial Doppler (TCD) stands out as a non-invasive, bedside method providing real-time monitoring of cerebral haemodynamics, therefore accurately identifying patients at risk of stroke. A case of a 30-year-old woman with a giant intracavernous aneurysm of the left ICA presenting with subacute left VI nerve palsy is described. A pre-operative TCD- and EEG-monitored BTO of the left ICA was performed. The 16.7% drop found in the middle cerebral arterys peak systolic velocity (PSVMCA) predicts clinical and haemodynamic tolerance to the permanent loss of that vessel. This case illustrates the potential of TCD monitoring during temporary BTO of the ICA. It highlights its ability to provide a complete preclinical evaluation of collateralization and autoregulatory adaptation to unilateral ICA occlusion. TCD may also decrease the time of occlusion required for the BTO.