In vivo targeting and multimodal imaging of cerebral amyloid-ß aggregates using hybrid GdF3 nanoparticles.

Aim: To propose a new multimodal imaging agent targeting amyloid-ß (Aß) plaques in Alzheimer's disease. Materials & methods: A new generation of hybrid contrast agents, based on gadolinium fluoride nanoparticles grafted with a pentameric luminescent-conjugated polythiophene, was designed, extensively characterized and evaluated in animal models of Alzheimer's disease through MRI, two-photon microscopy and synchrotron x-ray phase-contrast imaging. Results & conclusion: Two different grafting densities of luminescent-conjugated polythiophene were achieved while preserving colloidal stability and fluorescent properties, and without affecting biodistribution. In vivo brain uptake was dependent on the blood-brain barrier status. Nevertheless, multimodal imaging showed successful Aß targeting in both transgenic mice and Aß fibril-injected rats.

The design and study of a new contrast agent targeting amyloid-ß (Aß) plaques in Alzheimer's disease (AD) is proposed. Aß plaques are the earliest pathological sign of AD, silently appearing in the brain decades before the symptoms of the disease are manifested. While current detection of Aß plaques is based on nuclear medicine (a technique using a radioactive agent), a different kind of contrast agent is here evaluated in animal models of AD. The contrast agent consists of a nanoparticle made of gadolinium and fluorine ions (core), and decorated with a molecule previously shown to bind to Aß plaques (grafting). The core is detectable with MRI and x-ray imaging, while the grafting molecule is detectable with fluorescence imaging, thus allowing different imaging methods to be combined to study the pathology. In this work, the structure, stability and properties of the contrast agent have been verified in vitro (in tubes and on brain sections). Then the ability of the contrast agent to bind to Aß plaques and provide a detectable signal in MRI, x-ray or fluorescence imaging has been demonstrated in vivo (in rodent models of AD). This interdisciplinary research establishes the proof of concept that this new class of versatile agent contrast can be used to target pathological processes in the brain.

Characteristics of diffuse hemispheric gliomas, H3 G34-mutant in adults.

BACKGROUND: Diffuse hemispheric gliomas, H3 G34-mutant (DHG H3G34-mutant) constitute a distinct type of aggressive brain tumors. Although initially described in children, they can also affect adults. The aims of this study were to describe the characteristics of DHG H3G34-mutant in adults and to compare them to those of established types of adult WHO grade IV gliomas. METHODS: The characteristics of 17 adult DHG H3G34-mutant, 32 H3.3 K27M-mutant diffuse midline gliomas (DMG), 100 IDH-wildtype, and 36 IDH-mutant glioblastomas were retrospectively analyzed. RESULTS: Median age at diagnosis in adult DHG H3G34-mutant was 25 years (range: 19-33). All tumors were hemispheric. For 9 patients (56%), absent or faint contrast enhancement initially suggested another diagnosis than a high-grade glioma, and diffusion-weighted imaging seemed retrospectively more helpful to suspect an aggressive tumor than MR-spectroscopy and perfusion MRI. All cases were IDH-wildtype. Most cases were immunonegative for ATRX (93%) and Olig2 (100%) and exhibited MGMT promoter methylation (82%). The clinical and radiological presentations of adult DHG H3G34-mutant were different from those of established types of adult grade IV gliomas. Median overall survival of adult DHG H3G34-mutant was 12.4 months compared to 19.6 months (P = .56), 11.7 months (P = .45), and 50.5 months (P = .006) in H3.3 K27M-mutant DMG, IDH-wildtype, and IDH-mutant glioblastomas, respectively. CONCLUSIONS: Adult DHG H3G34-mutant are associated with distinct characteristics compared to those of established types of adult WHO grade IV gliomas. This study supports considering these tumors as a new type of WHO grade IV glioma in future classifications.

Impact of Collateral Status on Neuroprotective Effect of Cyclosporine A in Acute Ischemic Stroke.

BACKGROUND: Neuroprotection for acute ischemic stroke remains an elusive goal. Intracranial collaterals may favor neuroprotective drugs delivery at the acute stage of ischemic stroke. A recent phase 2 study showed that cyclosporine A (CsA) reduced ischemic damage in patients with a proximal occlusion who experienced effective recanalization. Collateral flow may improve this benefit. MATERIALS & METHODS: Collateral supply was assessed using dynamic susceptibility contrast MRI in 47 patients among the 110 patients from the original study and were graded in two groups: good collaterals and poor collaterals. Patients with good collaterals had significantly smaller initial infarct in both CsA group (p = 0.003) and controls (p = 0.016). Similarly, the final lesion volume was significantly lower in patients with good collaterals in both groups. RESULTS: In patients with either good or poor collaterals CsA showed no additional benefit on ischemic lesion progression and final infarct size at day 30. CONCLUSION: We failed to demonstrate any significant additional benefit of CsA in patients with good collateral circulation.

Clinical Imaging of Choroid Plexus in Health and in Brain Disorders: A Mini-Review.

The choroid plexuses (ChPs) perform indispensable functions for the development, maintenance and functioning of the brain. Although they have gained considerable interest in the last years, their involvement in brain disorders is still largely unknown, notably because their deep location inside the brain hampers non-invasive investigations. Imaging tools have become instrumental to the diagnosis and pathophysiological study of neurological and neuropsychiatric diseases. This review summarizes the knowledge that has been gathered from the clinical imaging of ChPs in health and brain disorders not related to ChP pathologies. Results are discussed in the light of pre-clinical imaging studies. As seen in this review, to date, most clinical imaging studies of ChPs have used disease-free human subjects to demonstrate the value of different imaging biomarkers (ChP size, perfusion/permeability, glucose metabolism, inflammation), sometimes combined with the study of normal aging. Although very few studies have actually tested the value of ChP imaging biomarkers in patients with brain disorders, these pioneer studies identified ChP changes that are promising data for a better understanding and follow-up of diseases such as schizophrenia, epilepsy and Alzheimer's disease. Imaging of immune cell trafficking at the ChPs has remained limited to pre-clinical studies so far but has the potential to be translated in patients for example using MRI coupled with the injection of iron oxide nanoparticles. Future investigations should aim at confirming and extending these findings and at developing translational molecular imaging tools for bridging the gap between basic molecular and cellular neuroscience and clinical research.

Conventional MRI radiomics in patients with suspected early- or pseudo-progression.

BACKGROUND: After radiochemotherapy, 30% of patients with early worsening MRI experience pseudoprogression (Psp) which is not distinguishable from early progression (EP). We aimed to assess the diagnostic value of radiomics in patients with suspected EP or Psp. METHODS: Radiomics features (RF) of 76 patients (53 EP and 23 Psp) retrospectively identified were extracted from conventional MRI based on four volumes-of-interest. Subjects were randomly assigned into training and validation groups. Classification model (EP versus Psp) consisted of a random forest algorithm after univariate filtering. Overall (OS) and progression-free survivals (PFS) were predicted using a semi-supervised principal component analysis, and forecasts were evaluated using C-index and integrated Brier scores (IBS). RESULTS: Using 11 RFs, radiomics classified patients with 75.0% and 76.0% accuracy, 81.6% and 94.1% sensitivity, 50.0% and 37.5% specificity, respectively, in training and validation phases. Addition of MGMT promoter status improved accuracy to 83% and 79.2%, and specificity to 63.6% and 75%. OS model included 14 RFs and stratified low- and high-risk patients both in the training (hazard ratio [HR], 3.63; P = .002) and the validation (HR, 3.76; P = .001) phases. Similarly, PFS model stratified patients during training (HR, 2.58; P = .005) and validation (HR, 3.58; P = .004) phases using 5 RF. OS and PFS forecasts had C-index of 0.65 and 0.69, and IBS of 0.122 and 0.147, respectively. CONCLUSIONS: Conventional MRI radiomics has promising diagnostic value, especially when combined with MGMT promoter status, but with moderate specificity. In addition, our results suggest a potential for predicting OS and PFS.

Impact of the Thrombectomy Trials on the Management and Outcome of Large Vessel Stroke: Data From the Lyon Stroke Center.

Introduction: Randomized trials (RT) have recently validated the superiority of thrombectomy over standard medical care, including intravenous thrombolysis (IVT). However, data on their impact on routine clinical care remains scarce. Methods: Using a prospective observational registry, we assessed: (1) the clinical and radiological characteristics of all consecutive patients treated with thrombectomy; (2) the outcome of all patients with M1 occlusion (treated with thrombectomy or IVT alone). Two periods were compared: before (2013-2014) and after (2015-2016) the publication of RT. Results: Endovascular procedures significantly increased between the two periods (N = 82 vs. 314, p < 0.0001). In 2015-2016, patients were older (median [IQR]: 69 [57-80]; vs. 66 [53-74]; p = 0.008), had shorter door-to-clot times (69 [47-95]; vs. 110 [83-155]; p < 0.0001) resulting in a trend toward shorter delay from symptom onset to reperfusion (232 [185-300]; vs. 250 [200-339]; p = 0.1), with higher rates of reperfusion (71 vs. 48%; p = 0.0001). Conversely, no significant differences in baseline NIHSS scores, ASPECTS, delay to IVT or intracranial hemorrhage were found. In 2015-2016, patients with M1 occlusion were treated with thrombectomy more often than in 2013-2014 (87 vs. 32%, respectively; p < 0.0001), with a significant improvement in clinical outcome (shift analysis, lower modified Rankin scale scores: OR = 1.68; 95% CI: 1.10-2.57; p = 0.017). Conclusion: Following the publication of RT, thrombectomy was rapidly implemented with significant improvements in intrahospital delay and reperfusion rates. Treatment with thrombectomy increased with better clinical outcomes in patients with M1 occlusion.

Collateral circulation assessment within the 4.5 h time window in patients with and without DWI/FLAIR MRI mismatch.

OBJECTIVES: The aim of the present study was to assess the association between collateral status and DWI-FLAIR mismatch in patients with acute ischemic stroke within the 4.5 h time-window. METHODS: We analysed DWI, FLAIR, and PWI data in patients within 4.5 h after symptom onset from the I-KNOW European database. Collateral flow maps were graded by analyzing contrast 'staining' extent over the early, mid and late perfusion phases. ADC values, DWI lesion volume, and normalised perfusion parameters (CBV,Tmax) within DWI lesions were determined. Visibility of parenchymal hyperintensivty on FLAIR was evaluated ("FLAIR positive"), and DWI-FLAIR mismatch was assessed. Spontaneously reperfused regions were defined as voxels with Tmax <6 s within the DWI lesion. Final infarct size was assessed on day-30 FLAIR images. RESULTS: Of the 168 patients included in I-KNOW database, 87 were eligible for this study. DWI-FLAIR mismatch was present in 69 patients. There was no difference between poor and good collaterals status according to age, sex, baseline NIHSS score, time to MRI and DWI lesion volume. Collateral status was significantly better in the FLAIR positive group (p = .001). Patients with poor collaterals had significantly increased Tmax (p = .005). Baseline DWI lesion volume and final lesion volume were significantly smaller in patients with good collateral status (p < .001 and 0.01, respectively). CONCLUSIONS: We found that patients with early FLAIR lesion visibility have a better collateral status. This finding has implications for the management of stroke patients with unknown time-of-onset, and more widely should be considered in the current context of extending the therapeutic window.

Post-Thrombolysis Recanalization in Stroke Referrals for Thrombectomy: Incidence, Predictors, and Prediction Scores.

Background and Purpose­Whether all acute stroke patients with large vessel occlusion need to undergo intravenous thrombolysis before mechanical thrombectomy (MT) is debated as (1) the incidence of post-thrombolysis early recanalization (ER) is still unclear; (2) thrombolysis may be harmful in patients unlikely to recanalize; and, conversely, (3) transfer for MT may be unnecessary in patients highly likely to recanalize. Here, we determined the incidence and predictors of post-thrombolysis ER in patients referred for MT and derive ER prediction scores for trial design. Methods­Registries from 4 MT-capable centers gathering patients referred for MT and thrombolyzed either on site (mothership) or in a non MT-capable center (drip-and-ship) after magnetic resonance­ or computed tomography­based imaging between 2015 and 2017. ER was identified on either first angiographic run or noninvasive imaging. In the magnetic resonance imaging subsample, thrombus length was determined on T2*-based susceptibility vessel sign. Independent predictors of no- ER were identified using multivariable logistic regression models, and scores were developed according to the magnitude of regression coefficients. Similar registries from 4 additional MT-capable centers were used as validation cohort. Results­In the derivation cohort (N=633), ER incidence was ≈20%. In patients with susceptibility vessel sign (n=498), no-ER was independently predicted by long thrombus, proximal occlusion, and mothership paradigm. A 6-point score derived from these variables showed strong discriminative power for no-ER (C statistic, 0.854) and was replicated in the validation cohort (n=353; C statistic, 0.888). A second score derived from the whole sample (including negative T2* or computed tomography­based imaging) also showed good discriminative power and was similarly validated. Highest grades on both scores predicted no-ER with >90% specificity, whereas low grades did not reliably predict ER. Conclusions­The substantial ER rate underlines the benefits derived from thrombolysis in bridging populations. Both prediction scores afforded high specificity for no-ER, but not for ER, which has implications for trial design.

Multi-site laser Doppler flowmetry for assessing collateral flow in experimental ischemic stroke: Validation of outcome prediction with acute MRI.

High variability in infarct size is common in experimental stroke models and affects statistical power and validity of neuroprotection trials. The aim of this study was to explore cerebral collateral flow as a stratification factor for the prediction of ischemic outcome. Transient intraluminal occlusion of the middle cerebral artery was induced for 90 min in 18 Wistar rats. Cerebral collateral flow was assessed intra-procedurally using multi-site laser Doppler flowmetry monitoring in both the lateral middle cerebral artery territory and the borderzone territory between middle cerebral artery and anterior cerebral artery. Multi-modal magnetic resonance imaging was used to assess acute ischemic lesion (diffusion-weighted imaging, DWI), acute perfusion deficit (time-to-peak, TTP), and final ischemic lesion at 24 h. Infarct volumes and typology at 24 h (large hemispheric versus basal ganglia infarcts) were predicted by both intra-ischemic collateral perfusion and acute DWI lesion volume. Collateral flow assessed by multi-site laser Doppler flowmetry correlated with the corresponding acute perfusion deficit using TTP maps. Multi-site laser Doppler flowmetry monitoring was able to predict ischemic outcome and perfusion deficit in good agreement with acute MRI. Our results support the additional value of cerebral collateral flow monitoring for outcome prediction in experimental ischemic stroke, especially when acute MRI facilities are not available.

MRI Assessment of Ischemic Lesion Evolution within White and Gray Matter.

BACKGROUND: In acute ischemic stroke (AIS), gray matter (GM) and white matter (WM) have different vulnerabilities to ischemia. Thus, we compared the evolution of ischemic lesions within WM and GM using MRI. METHODS: From a European multicenter prospective database (I-KNOW), available T1-weighted images were identified for 50 patients presenting with an anterior AIS and a perfusion weighted imaging (PWI)/diffusion weighted imaging (DWI) mismatch ratio of 1.2 or more. Six lesion compartments were outlined: initial DWI (b = 1,000 s/mm2) lesion, initial PWI-DWI mismatch (Tmax >4 s and DWI-negative), final infarct mapped on 1-month fluid-attenuated inversion recovery (FLAIR) imaging, lesion growth between acute DWI and 1-month FLAIR, DWI lesion reversal at 1 month and salvaged mismatch. The WM and GM were segmented on T1-weighted images, and all images were co-registered within subjects to the baseline MRI. WM and GM proportions were calculated for each compartment. RESULTS: Fifty patients were eligible for the study. Median delay between symptom onset and baseline MRI was 140 min. The percentage of WM was significantly greater in the following compartments: initial mismatch (52.5 vs. 47.5%, p = 0.003), final infarct (56.7 vs. 43.3%, p < 0.001) and lesion growth (58.9 vs. 41.2%, p < 0.001). No significant difference was found between GM and WM percentages within the initial DWI lesion, DWI reversal and salvaged mismatch compartments. CONCLUSIONS: Ischemic lesions may extend preferentially within the WM. Specific therapeutic strategies targeting WM ischemic processes may deserve further investigation.

Does b1000-b0 Mismatch Challenge Diffusion-Weighted Imaging-Fluid Attenuated Inversion Recovery Mismatch in Stroke?

BACKGROUND AND PURPOSE: Our aim was to explore whether the mismatch in lesion visibility between b1000 and b0 images is an alternative to mismatch between diffusion-weighted imaging and fluid-attenuated inversion recovery imaging as a surrogate marker of stroke age. METHODS: We analyzed patients from the European multicenter I-KNOW database. Independent readers assessed the visibility of ischemic lesions of the anterior circulation on b0 and fluid-attenuated inversion recovery imaging images. The signal-intensity ratio for b0 and fluid-attenuated inversion recovery imaging images was also measured from the segmented stroke lesion volume on b1000 images. RESULTS: This study included 112 patients (68 men; mean age, 67.4 years) with stroke onset within (n=85) or longer than (n=27) 4.5 hours. b1000-b0 mismatch identified patients within 4.5 hours of stroke onset with moderate sensitivity (72.9%; 95% confidence interval [CI], 63.5-82.4) and specificity (70.4%; 95% CI, 53.2-87.6), high positive predictive value (88.6%; 95% CI, 81.1-96.0), and low negative predictive value (45.2%; 95% CI, 30.2-60.3). Global comparison of b1000-b0 mismatch with diffusion-weighted imaging-fluid-attenuated inversion recovery imaging mismatch (considered the imaging gold standard) indicated high sensitivity (85.9%; 95% CI, 78.2-93.6), specificity (91.2%; 95% CI, 76.3-98.1), and positive predictive value (96.7%; 95% CI, 88.0-99.1) and moderate negative predictive value (73.8%; 95% CI, 60.5-87.1) of this new approach. b0 signal-intensity ratio (r=0.251; 95% CI, 0.069-0.417; P=0.008) was significantly although weakly correlated with delay between stroke onset and magnetic resonance imaging. CONCLUSIONS: b1000-b0 mismatch may identify patients with ischemic stroke of the within 4.5 hours of onset with high positive predictive value, perhaps constituting an alternative imaging tissue clock.

Evaluation of image quality of DWIBS versus DWI sequences in thoracic MRI at 3T.

PURPOSE: To compare diffusion weighted imaging with background suppression (DWIBS) sequence with classic spectral diffusion sequence (DWI) with and without respiratory gating in mediastinal lymph node analysis at 3T. MATERIALS AND METHODS: 26 patients scheduled for mediastinoscopic lymph node analysis, prospectively undergone a thoracic 3T MRI with DWIBS (FatSat=STIR; TR/TE=6674.1/44.7ms; IR=260 ms) and DWI sequences (FatSat=SPIR; TR/TE=1291/59.6 ms) (b=0-400-800 s/mm2) with and without (free breathing) respiratory gating. Images at b=800 were analyzed by two radiologists. They performed qualitative analysis of fat-sat homogeneity and motion artifacts, rated from 0 to 4, and quantitative evaluation by studying signal to background (STB) of lymph nodes. RESULTS: Quality of fat suppression was significantly higher for DWIBS than for DWI both for free-breathing (score 3.48±0.65 vs. 1.76±0.96, p<0.0001) and respiratory-gated scans (3.17±0.77 vs. 1.72±0.73, p=0.0001). Similarly, artifacts were reduced with DWIBS (3.16±0.47 vs. 1.76±0.59, p<0.0001; 3.0±0.73 vs. 2.04±0.53, p=0.0001). Quantitative analysis showed higher STB with DWIBS (3.26±1.83 vs. 0.98±0.44, p<0.0001; 3.56±, 2.09 vs. 0.92±0.59, p<0.0001). Gating did not improve image quality and STB on DWIBS (p>0.05). CONCLUSION: In thoracic MRI, ungated DWIBS sequence improves fat-sat homogeneity, reduces motion artifacts and increases STB of lymph nodes. Respiratory gating does not improve DWIBS image quality.