A Cellular Ground Truth to Develop MRI Signatures in Glioma Models by Correlative Light Sheet Microscopy and Atlas-Based Coregistration.

Glioblastoma is the most common malignant primary brain tumor with poor overall survival. Magnetic resonance imaging (MRI) is the main imaging modality for glioblastoma but has inherent shortcomings. The molecular and cellular basis of MR signals is incompletely understood. We established a ground truth-based image analysis platform to coregister MRI and light sheet microscopy (LSM) data to each other and to an anatomic reference atlas for quantification of 20 predefined anatomic subregions. Our pipeline also includes a segmentation and quantification approach for single myeloid cells in entire LSM datasets. This method was applied to three preclinical glioma models in male and female mice (GL261, U87MG, and S24), which exhibit different key features of the human glioma. Multiparametric MR data including T2-weighted sequences, diffusion tensor imaging, T2 and T2* relaxometry were acquired. Following tissue clearing, LSM focused on the analysis of tumor cell density, microvasculature, and innate immune cell infiltration. Correlated analysis revealed differences in quantitative MRI metrics between the tumor-bearing and the contralateral hemisphere. LSM identified tumor subregions that differed in their MRI characteristics, indicating tumor heterogeneity. Interestingly, MRI signatures, defined as unique combinations of different MRI parameters, differed greatly between the models. The direct correlation of MRI and LSM allows an in-depth characterization of preclinical glioma and can be used to decipher the structural, cellular, and, likely, molecular basis of tumoral MRI biomarkers. Our approach may be applied in other preclinical brain tumor or neurologic disease models, and the derived MRI signatures could ultimately inform image interpretation in a clinical setting.SIGNIFICANCE STATEMENT We established a histologic ground truth-based approach for MR image analyses and tested this method in three preclinical glioma models exhibiting different features of glioblastoma. Coregistration of light sheet microscopy to MRI allowed for an evaluation of quantitative MRI data in histologically distinct tumor subregions. Coregistration to a mouse brain atlas enabled a regional comparison of MRI parameters with a histologically informed interpretation of the results. Our approach is transferable to other preclinical models of brain tumors and further neurologic disorders. The method can be used to decipher the structural, cellular, and molecular basis of MRI signal characteristics. Ultimately, information derived from such analyses could strengthen the neuroradiological evaluation of glioblastoma as they enhance the interpretation of MRI data.

A diminished sciatic nerve structural integrity is associated with distinct peripheral sensory phenotypes in individuals with type 2 diabetes.

AIMS/HYPOTHESIS: Quantitative sensory testing (QST) allows the identification of individuals with rapid progression of diabetic sensorimotor polyneuropathy (DSPN) based on certain sensory phenotypes. Hence, the aim of this study was to investigate the relationship of these phenotypes with the structural integrity of the sciatic nerve among individuals with type 2 diabetes. METHODS: Seventy-six individuals with type 2 diabetes took part in this cross-sectional study and underwent QST of the right foot and high-resolution magnetic resonance neurography including diffusion tensor imaging of the right distal sciatic nerve to determine the sciatic nerve fractional anisotropy (FA) and cross-sectional area (CSA), both of which serve as markers of structural integrity of peripheral nerves. Participants were then assigned to four sensory phenotypes (participants with type 2 diabetes and healthy sensory profile [HSP], thermal hyperalgesia [TH], mechanical hyperalgesia [MH], sensory loss [SL]) by a standardised sorting algorithm based on QST. RESULTS: Objective neurological deficits showed a gradual increase across HSP, TH, MH and SL groups, being higher in MH compared with HSP and in SL compared with HSP and TH. The number of participants categorised as HSP, TH, MH and SL was 16, 24, 17 and 19, respectively. There was a gradual decrease of the sciatic nerve's FA (HSP 0.444, TH 0.437, MH 0.395, SL 0.382; p=0.005) and increase of CSA (HSP 21.7, TH 21.5, MH 25.9, SL 25.8 mm2; p=0.011) across the four phenotypes. Further, MH and SL were associated with a lower sciatic FA (MH unstandardised regression coefficient [B]=-0.048 [95% CI -0.091, -0.006], p=0.027; SL B=-0.062 [95% CI -0.103, -0.020], p=0.004) and CSA (MH ß=4.3 [95% CI 0.5, 8.0], p=0.028; SL B=4.0 [95% CI 0.4, 7.7], p=0.032) in a multivariable regression analysis. The sciatic FA correlated negatively with the sciatic CSA (r=-0.35, p=0.002) and markers of microvascular damage (high-sensitivity troponin T, urine albumin/creatinine ratio). CONCLUSIONS/INTERPRETATION: The most severe sensory phenotypes of DSPN (MH and SL) showed diminishing sciatic nerve structural integrity indexed by lower FA, likely representing progressive axonal loss, as well as increasing CSA of the sciatic nerve, which cannot be detected in individuals with TH. Individuals with type 2 diabetes may experience a predefined cascade of nerve fibre damage in the course of the disease, from healthy to TH, to MH and finally SL, while structural changes in the proximal nerve seem to precede the sensory loss of peripheral nerves and indicate potential targets for the prevention of end-stage DSPN. TRIAL REGISTRATION: ClinicalTrials.gov NCT03022721.

Microstructural changes of peripheral nerves in early multiple sclerosis: A prospective magnetic resonance neurography study.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system (CNS). However, there is increasing evidence of peripheral nerve involvement. This study aims to characterize the pattern of peripheral nerve changes in patients with newly diagnosed MS using quantitative magnetic resonance (MR) neurography. METHODS: In this prospective study, 25 patients first diagnosed with MS according to the revised McDonald criteria (16 female, mean age = 32.8 ± 10.6 years) and 14 healthy controls were examined with high-resolution 3-T MR neurography of the sciatic nerve using diffusion kurtosis imaging (DKI; 20 diffusional directions, b = 0, 700, 1200 s/mm2 ) and magnetization transfer imaging (MTI). In total, 15 quantitative MR biomarkers were analyzed and correlated with clinical symptoms, intrathecal immunoglobulin synthesis, electrophysiology, and lesion load on brain and spine MR imaging. RESULTS: Patients showed decreased fractional anisotropy (mean = 0.51 ± 0.04 vs. 0.56 ± 0.03, p < 0.001), extra-axonal tortuosity (mean = 2.32 ± 0.17 vs. 2.49 ± 0.17, p = 0.008), and radial kurtosis (mean = 1.40 ± 0.23 vs. 1.62 ± 0.23, p = 0.014) and higher radial diffusivity (mean = 1.09 ∙ 10-3 mm2 /s ± 0.16 vs. 0.98 ± 0.11 ∙ 10-3 mm2 /s, p = 0.036) than controls. Groups did not differ in MTI. No significant association was found between MR neurography markers and clinical/laboratory parameters or CNS lesion load. CONCLUSIONS: This study provides further evidence of peripheral nerve involvement in MS already at initial diagnosis. The characteristic pattern of DKI parameters indicates predominant demyelination and suggests a primary coaffection of the peripheral nervous system in MS. This first human study using DKI for peripheral nerves shows its potential and clinical feasibility in providing novel biomarkers.

Magnetic resonance neurography in spinal cord injury: Imaging findings and clinical significance.

BACKGROUND AND PURPOSE: It is unknown whether changes to the peripheral nervous system following spinal cord injury (SCI) are relevant for functional recovery or the development of neuropathic pain below the level of injury. Magnetic resonance neurography (MRN) at 3 T allows detection and localization of structural and functional nerve damage. This study aimed to combine MRN and clinical assessments in individuals with chronic SCI and nondisabled controls. METHODS: Twenty participants with chronic SCI and 20 controls matched for gender, age, and body mass index underwent MRN of the L5 dorsal root ganglia (DRG) and the sciatic nerve. DRG volume, sciatic nerve mean cross-sectional area (CSA), fascicular lesion load, and fractional anisotropy (FA), a marker for functional nerve integrity, were calculated. Results were correlated with clinical assessments and nerve conduction studies. RESULTS: Sciatic nerve CSA and lesion load were higher (21.29 ± 5.82 mm2 vs. 14.08 ± 4.62 mm2 , p < 0.001; and 8.70 ± 7.47% vs. 3.60 ± 2.45%, p < 0.001) in individuals with SCI compared to controls, whereas FA was lower (0.55 ± 0.11 vs. 0.63 ± 0.08, p = 0.022). DRG volumes were larger in individuals with SCI who suffered from neuropathic pain compared to those without neuropathic pain (223.7 ± 53.08 mm3 vs. 159.7 ± 55.66 mm3 , p = 0.043). Sciatic MRN parameters correlated with electrophysiological results but did not correlate with the extent of myelopathy or clinical severity of SCI. CONCLUSIONS: Individuals with chronic SCI are subject to a decline of structural peripheral nerve integrity that may occur independently from the clinical severity of SCI. Larger volumes of DRG in SCI with neuropathic pain support existing evidence from animal studies on SCI-related neuropathic pain.

Peripheral nerve involvement in hereditary spastic paraplegia characterized by quantitative magnetic resonance neurography.

BACKGROUND AND OBJECTIVES: Hereditary spastic paraplegias (HSPs) are heterogenous genetic disorders. While peripheral nerve involvement is frequent in spastic paraplegia 7 (SPG7), the evidence of peripheral nerve involvement in SPG4 is more controversial. We aimed to characterize lower extremity peripheral nerve involvement in SPG4 and SPG7 by quantitative magnetic resonance neurography (MRN). METHODS: Twenty-six HSP patients carrying either the SPG4 or SPG7 mutation and 26 age-/sex-matched healthy controls prospectively underwent high-resolution MRN with large coverage of the sciatic and tibial nerve. Dual-echo turbo-spin-echo sequences with spectral fat-saturation were utilized for T2-relaxometry and morphometric quantification, while two gradient-echo sequences with and without an off-resonance saturation rapid frequency pulse were applied for magnetization transfer contrast (MTC) imaging. HSP patients additionally underwent detailed neurologic and electroneurographic assessments. RESULTS: All microstructural (proton spin density [ρ], T2-relaxation time, magnetization transfer ratio) and morphometric (cross-sectional area) quantitative MRN markers were decreased in SPG4 and SPG7 indicating chronic axonopathy. ρ was superior in differentiating subgroups and identifying subclinical nerve damage in SPG4 and SPG7 without neurophysiologic signs of polyneuropathy. MRN markers correlated well with clinical scores and electroneurographic results. CONCLUSIONS: MRN characterizes peripheral nerve involvement in SPG4 and SPG7 as a neuropathy with predominant axonal loss. Evidence of peripheral nerve involvement in SPG4 and SPG7, even without electroneurographically manifest polyneuropathy, and the good correlation of MRN markers with clinical measures of disease progression, challenge the traditional view of the existence of HSPs with isolated pyramidal signs and suggest MRN markers as potential progression biomarkers in HSP.

Investigation of Experimental Endovascular Air Embolisms Using a New Model for the Generation and Detection of Highly Calibrated Micro Air Bubbles.

BACKGROUND: Air embolism (AE), especially when affecting the brain, is an underrated and potentially life-threatening complication in various endovascular interventions. This study aims to investigate experimental AEs using a new model to generate micro air bubbles (MAB), to assess the impact of a catheter on these MAB, and to demonstrate the applicability of this model in vivo. MATERIALS AND METHODS: Micro air bubbles were created using a system based on microfluidic channels. The MAB were detected and analyzed automatically. Micro air bubbles, with a target size of 85 µm, were generated and injected through a microcatheter. The MAB diameters proximal and distal to the catheter were assessed and compared. In a subsequent in vivo application, 2000 MAB were injected into the aorta (at the aortic valve) and into the common carotid artery (CCA) of a rat, respectively, using a microcatheter, resembling AE occurring during cardiovascular interventions. RESULTS: Micro air bubbles with a highly calibrated size could be successfully generated (median: 85.5 µm, SD 1.9 µm). After passage of the microcatheter, the MAB were similar in diameter (median: 86.6 µm) but at a lower number (60.1% of the injected MAB) and a substantially higher scattering of diameters (SD 29.6 µm). In vivo injection of MAB into the aorta resulted in cerebral microinfarctions in both hemispheres, whereas injection into the CCA caused exclusively ipsilateral microinfarctions. CONCLUSION: Using this new AE model, MAB can be generated precisely and reproducibly, resulting in cerebral microinfarctions. This model is feasible for further studies on the pathophysiology and prevention of AE in cardiovascular procedures.

Diagnostic compatibility of various fixed orthodontic retainers for head/neck MRI and dental MRI.

OBJECTIVES: To evaluate the diagnostic MRI compatibility of different fixed orthodontic retainers using a high-resolution 3D-sequence optimized for artifact reduction. MATERIALS AND METHODS: Maxillary and mandibular retainers made of five different materials were scanned in vitro and in vivo at 3 T MRI using an MSVAT-SPACE sequence. In vitro, artifact volumes were determined for all maxillary and mandibular retainers (AVmax; AVmand). In vivo, two independent observers quantified the extent of artifacts based on the visibility of 124 dental and non-dental landmarks using a five-point rating scale (1 = excellent, 2 = good, 3 = acceptable, 4 = poor, 5 = not visible). RESULTS: Rectangular-steel retainers caused the largest artifacts (AVmax/AVmand: 18,060/15,879 mm3) and considerable diagnostic impairment in vivo (mean landmark visibility score ± SD inside/outside the retainer areas: 4.8 ± 0.8/2.9 ± 1.6). Smaller, but diagnostically relevant artifacts were observed for twistflex steel retainers (437/6317 mm3, 3.1 ± 1.7/1.3 ± 0.7). All retainers made of precious-alloy materials produced only very small artifact volumes (titanium grade 1: 70/46 mm3, titanium grade 5: 47/35 mm3, gold: 23/21 mm3) without any impact on image quality in vivo (each retainer: visibility scores of 1.0 ± 0.0 for all landmarks inside and outside the retainer areas). CONCLUSIONS: In contrast to steel retainers, titanium and gold retainers are fully compatible for both head/neck and dental MRI when using MSVAT-SPACE. CLINICAL RELEVANCE: This study demonstrates that titanium and gold retainers do not impair the diagnostic quality of head/neck and dental MRI when applying an appropriate artifact-reduction technique. Steel retainers, however, are not suitable for dental MRI and can severely impair image quality in head/neck MRI of the oral cavity.

Diffusion MRI in Peripheral Nerves: Optimized b Values and the Role of Non-Gaussian Diffusion.

Background Diffusion-weighted imaging (DWI) provides specific in vivo information about tissue microstructure, which is increasingly recognized for various applications outside the central nervous system. However, standard sequence parameters are commonly adopted from optimized central nervous system protocols, thus potentially neglecting differences in tissue-specific diffusional behavior. Purpose To characterize the optimal tissue-specific diffusion imaging weighting scheme over the b domain in peripheral nerves under physiologic and pathologic conditions. Materials and Methods In this prospective cross-sectional study, 3-T MR neurography of the sciatic nerve was performed in healthy volunteers (n = 16) and participants with type 2 diabetes (n = 12). For DWI, 16 b values in the range of 0-1500 sec/mm2 were acquired in axial and radial diffusion directions of the nerve. With a region of interest-based approach, diffusion-weighted signal behavior as a function of b was estimated using standard monoexponential, biexponential, and kurtosis fitting. Goodness of fit was assessed to determine the optimal b value for two-point DWI/diffusion tensor imaging (DTI). Results Non-Gaussian diffusional behavior was observed beyond b values of 600 sec/mm2 in the axial and 800 sec/mm2 in the radial diffusion direction in both participants with diabetes and healthy volunteers. Accordingly, the biexponential and kurtosis models achieved a better curve fit compared with the standard monoexponential model (Akaike information criterion >99.9% in all models), but the kurtosis model was preferred in the majority of cases. Significant differences between healthy volunteers and participants with diabetes were found in the kurtosis-derived parameters Dk and K. The results suggest an upper bound b value of approximately 700 sec/mm2 for optimal standard DWI/DTI in peripheral nerve applications. Conclusion In MR neurography, an ideal standard diffusion-weighted imaging/diffusion tensor imaging protocol with b = 700 sec/mm2 is suggested. This is substantially lower than in the central nervous system due to early-occurring non-Gaussian diffusion behavior and emphasizes the need for tissue-specific b value optimization. Including higher b values, kurtosis-derived parameters may represent promising novel imaging markers of peripheral nerve disease. ©RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Jang and Du in this issue.

Brain tumor classification of virtual NMR voxels based on realistic blood vessel-induced spin dephasing using support vector machines.

Remodeling of tissue microvasculature commonly promotes neoplastic growth; however, there is no imaging modality in oncology yet that noninvasively quantifies microvascular changes in clinical routine. Although blood capillaries cannot be resolved in typical magnetic resonance imaging (MRI) measurements, their geometry and distribution influence the integral nuclear magnetic resonance (NMR) signal from each macroscopic MRI voxel. We have numerically simulated the expected transverse relaxation in NMR voxels with different dimensions based on the realistic microvasculature in healthy and tumor-bearing mouse brains (U87 and GL261 glioblastoma). The 3D capillary structure in entire, undissected brains was acquired using light sheet fluorescence microscopy to produce large datasets of the highly resolved cerebrovasculature. Using this data, we trained support vector machines to classify virtual NMR voxels with different dimensions based on the simulated spin dephasing accountable to field inhomogeneities caused by the underlying vasculature. In prediction tests with previously blinded virtual voxels from healthy brain tissue and GL261 tumors, stable classification accuracies above 95% were reached. Our results indicate that high classification accuracies can be stably attained with achievable training set sizes and that larger MRI voxels facilitated increasingly successful classifications, even with small training datasets. We were able to prove that, theoretically, the transverse relaxation process can be harnessed to learn endogenous contrasts for single voxel tissue type classifications on tailored MRI acquisitions. If translatable to experimental MRI, this may augment diagnostic imaging in oncology with automated voxel-by-voxel signal interpretation to detect vascular pathologies.

Quantitative magnetic resonance neurographic characterization of peripheral nerve involvement in manifest and pre-ataxic spinocerebellar ataxia type 3.

BACKGROUND AND PURPOSE: Knowledge about the exact underlying pathophysiological changes involved in the genesis and progression of spinocerebellar ataxia type 3 (SCA3) is limited. Lower extremity peripheral nerve lesions in clinically, genetically and electrophysiologically classified ataxic and pre-ataxic SCA3 mutation carriers were characterized and quantified by magnetic resonance neurography (MRN). METHODS: Eighteen SCA3 mutation carriers and 20 age-/sex-matched healthy controls were prospectively enrolled. All SCA3 mutation carriers underwent detailed neurological and electrophysiological examinations. 3 T MRN covered the lumbosacral plexus and proximal thigh to the tibiotalar joint by using T2-weighted inversion recovery sequences, dual-echo relaxometry sequences with spectral fat saturation, and two gradient-echo sequences with and without an off-resonance saturation rapid frequency pulse. Detailed quantification of nerve lesions by morphometric and microstructural MRN markers, including T2 relaxometry and magnetization transfer contrast imaging, was conducted in all study participants. RESULTS: MRN detected peripheral nerve damage in ataxic and pre-ataxic SCA3. The quantitative markers proton spin density (ρ), T2 relaxation time, magnetization transfer ratio and cross-sectional area were decreased in SCA3, indicating chronic axonopathy. MTR and ρ identified early, subclinical nerve damage in pre-ataxic SCA3 and in SCA3 mutation carriers without polyneuropathy and were superior in differentiating between all subgroups. Additionally, microstructural markers correlated well with clinical symptom scores and electrophysiological results. CONCLUSIONS: Our data provide a comprehensive characterization of peripheral nerve damage in SCA3 and assist in understanding the mechanisms of the multisystemic disease evolution. Evidence of peripheral nerve involvement prior to the onset of clinically overt ataxia might have important implications for designing early intervention studies.

Characterization and quantification of alcohol-related polyneuropathy by magnetic resonance neurography.

BACKGROUND: We characterized and quantified peripheral nerve damage in alcohol-dependent patients (ADP) by magnetic resonance neurography (MRN) in correlation with clinical and electrophysiologic findings. METHODS: Thirty-one adult patients with a history of excessive alcohol consumption and age-/sex-matched healthy controls were prospectively examined. After detailed neurologic and electrophysiologic testing, the patient group was subdivided into ADP with alcohol-related polyneuropathy (ALN) and without ALN (Non-ALN). 3T MRN with anatomical coverage from the proximal thigh down to the tibiotalar joint was performed using dual-echo 2-dimensional relaxometry sequences with spectral fat saturation. Detailed quantification of nerve injury by morphometric (cross-sectional area [CSA]) and microstructural MRN markers (proton spin density [ρ], apparent T2-relaxation-time [T2app ]) was conducted in all study participants. RESULTS: MRN detected nerve damage in ADP with and without ALN. A proximal-to-distal gradient was identified for nerve T2-weighted (T2w)-signal and T2app in ADP, indicating a proximal predominance of nerve lesions. While all MRN markers differentiated significantly between ADP and controls, microstructural markers were able to additionally differentiate between subgroups: tibial nerve ρ at thigh level was increased in ALN (p < 0.0001) and in Non-ALN (p = 0.0052) versus controls, and T2app was higher in ALN versus controls (p < 0.0001) and also in ALN versus Non-ALN (p = 0.0214). T2w-signal and CSA were only higher in ALN versus controls. CONCLUSIONS: MRN detects and quantifies peripheral nerve damage in ADP in vivo even in the absence of clinically overt ALN. Microstructural markers (T2app , ρ) are most suitable for differentiating between ADP with and without manifest ALN, and may help to elucidate the underlying pathomechanism in ALN.

Quantitative assessment of contrast-enhancement patterns of the healthy dental pulp by magnetic resonance imaging: A prospective in vivo study.

AIM: This prospective in vivo study aimed to optimize the assessment of pulpal contrast-enhancement (PCE) on dental magnetic resonance imaging (dMRI) and investigate physiological PCE patterns. METHODOLOGY: In 70 study participants, 1585 healthy teeth were examined using 3-Tesla dMRI before and after contrast agent administration. For all teeth, the quotient of post- and pre-contrast pulp signal intensity (Q-PSI) was calculated to quantify PCE. First, pulp chambers were analysed in 10 participants to compare the coefficient of variation of mean versus maximum Q-PSI values (Q-PSImean versus Q-PSImax ). Second, dynamic PCE was evaluated in 10 subjects to optimize the time interval between contrast agent application and image acquisition. Finally, 50 participants (age groups: 20-29, 30-39, 40-49, 50-59 and 60-69 years) were examined to analyse age, gender, tooth types and maxilla versus mandible as independent factors of PCE. Statistical analysis was performed using Wilcoxon signed rank test and linear mixed models. RESULTS: PCE assessment based on Q-PSImax was associated with a significantly smaller coefficient of variation compared with Q-PSImean , with median values of 0.17 versus 0.21 (p = .002). Analysis of dynamic PCE revealed an optimal timing interval for image acquisition 4 min after contrast media application. No significant differences in PCE were observed by comparing age groups, female versus male participants and maxillary versus mandibular teeth (p > .05). Differences between tooth types were small (median Q-PSImax values of 2.52/2.32/2.30/2.20 for molars/premolars/canines/incisors) but significant (p < .05), except for the comparison of canines versus premolars (p = .80). CONCLUSIONS: PCE in dMRI was a stable intra-individual marker with only minor differences between different tooth types, thus forming an important basis for intra-individual controls when assessing teeth with suspected endodontic pathosis. Furthermore, it was demonstrated that PCE is independent of age, gender and jaw type. These findings indicate that dMRI-based PCE analysis could be a valuable diagnostic tool for the identification of various pulp diseases in future patient studies.

Endodontic working length measurements of premolars and molars in high-resolution dental MRI: a clinical pilot study for assessment of reliability and accuracy.

OBJECTIVES: To prospectively assess the reliability and accuracy of high-resolution, dental MRI (dMRI) for endodontic working length (WL) measurements of premolars and molars under clinical conditions. MATERIALS AND METHODS: Three-Tesla dMRI was performed in 9 subjects who also had undergone cone-beam computed tomography (CBCT) (mean age: 47 ± 13.5 years). A total of 34 root canals from 12 molars (4/8, upper/lower jaw; 22 root canals) and 11 premolars (2/9 upper/lower jaw; 12 root canals) were included. CBCT and dMRI datasets were reconstructed to visualize the root canal in one single slice. Subsequently, two radiologists measured the root canal lengths in both modalities twice in blinded fashion. Reliability and accuracy for both modalities were assessed using intraclass correlation coefficients (ICCs) and Bland-Altman analysis, respectively. RESULTS: Reliability (intra-rater I/II; inter-rater) of dental MRI measurements was excellent and comparable to CBCT for premolars (0.993/0.900; 0.958 vs. 0.993/0.956; 0.951) and for molars (0.978/0.995; 0.986 vs. 0.992/0.996; 0.989). Bland-Altman analysis revealed a mean underestimation/bias (95% confidence interval) of dMRI measurements of 0.8 (- 1.44/3.05) mm for premolars and 0.4 (- 1.55/2.39) mm for molars. In up to 59% of the cases, the accuracy of dMRI for WL measurements was within the underestimation margin of 0 to 2 mm short of the apical foramen AF. CONCLUSIONS: In vivo demonstration and measurement of WL are feasible using dMRI. The reliability of measurements is high and equivalent to CBCT. Nonetheless, due to lower spatial resolution and longer acquisition time, the accuracy of dMRI is inferior to CBCT, impeding its current use for clinical treatment planning. CLINICAL RELEVANCE: dMRI is a promising radiation-free imaging technique. Its reliability for endodontic working length measurements is high, but its accuracy is not satisfactory enough yet.

Reliability and reproducibility of sciatic nerve magnetization transfer imaging and T2 relaxometry.

OBJECTIVES: To assess the interreader and test-retest reliability of magnetization transfer imaging (MTI) and T2 relaxometry in sciatic nerve MR neurography (MRN). MATERIALS AND METHODS: In this prospective study, 21 healthy volunteers were examined three times on separate days by a standardized MRN protocol at 3 Tesla, consisting of an MTI sequence, a multi-echo T2 relaxometry sequence, and a high-resolution T2-weighted sequence. Magnetization transfer ratio (MTR), T2 relaxation time, and proton spin density (PSD) of the sciatic nerve were assessed by two independent observers, and both interreader and test-retest reliability for all readout parameters were reported by intraclass correlation coefficients (ICCs) and standard error of measurement (SEM). RESULTS: For the sciatic nerve, overall mean ± standard deviation MTR was 26.75 ± 3.5%, T2 was 64.54 ± 8.2 ms, and PSD was 340.93 ± 78.8. ICCs ranged between 0.81 (MTR) and 0.94 (PSD) for interreader reliability and between 0.75 (MTR) and 0.94 (PSD) for test-retest reliability. SEM for interreader reliability was 1.7% for MTR, 2.67 ms for T2, and 21.3 for PSD. SEM for test-retest reliability was 1.7% for MTR, 2.66 ms for T2, and 20.1 for PSD. CONCLUSIONS: MTI and T2 relaxometry of the sciatic nerve are reliable and reproducible. The values of measurement imprecision reported here may serve as a guide for correct interpretation of quantitative MRN biomarkers in future studies. KEY POINTS: • Magnetization transfer imaging (MTI) and T2 relaxometry of the sciatic nerve are reliable and reproducible. • The imprecision that is unavoidably associated with different scans or different readers can be estimated by the here presented SEM values for the biomarkers T2, PSD, and MTR. • These values may serve as a guide for correct interpretation of quantitative MRN biomarkers in future studies and possible clinical applications.

Brain tumour cells interconnect to a functional and resistant network.

Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease.

Three-dimensional accuracy of partially guided implant surgery based on dental magnetic resonance imaging.

OBJECTIVES: To measure in vivo 3D accuracy of backward-planned partially guided implant surgery (PGIS) based on dental magnetic resonance imaging (dMRI). MATERIAL AND METHODS: Thirty-four patients underwent dMRI examinations. Tooth-supported templates were backward planned using standard dental software, 3D-printed, and placed intraorally during a cone beam computed tomography (CBCT) scan. Treatment plans were verified for surgical viability in CBCT, and implants were placed with guiding of the pilot drill. High-precision impressions were taken after healing. The 3D accuracy of 41 implants was evaluated by comparing the virtually planned and definitive implant positions with respect to implant entry point, apex, and axis. Deviations from the dMRI-based implant plans were compared with the maximum deviations calculated for a typical single implant. RESULTS: Twenty-eight implants were placed as planned in dMRI. Evaluation of 3D accuracy revealed mean deviations (99% confidence intervals) of 1.7 ± 0.9mm (1.2-2.1mm) / 2.3 ± 1.1mm (1.8-2.9 mm) / 7.1 ± 4.8° (4.6-9.6°) for entry point / apex / axis. The maximum deviations calculated for the typical single implant surpassed the upper bounds of the 99% CIs for the apex and axis, but not for the entry point. In the 13 other implants, dMRI-based implant plans were optimized after CBCT. Here, deviations between the initial dMRI plan and definitive implant position were only in part higher than in the unaltered group (1.9 ± 1.7 mm [0.5-3.4 mm] / 2.5 ± 1.5 mm [1.2-3.8 mm] / 6.8 ± 3.8° [3.6-10.1°] for entry point / apex / axis). CONCLUSIONS: The 3D accuracy of dMRI-based PGIS was lower than that previously reported for CBCT-based PGIS. Nonetheless, the values seem promising to facilitate backward planning without ionizing radiation.

Evaluation of magnetic resonance imaging artifacts caused by fixed orthodontic CAD/CAM retainers-an in vitro study.

OBJECTIVES: Magnetic resonance imaging (MRI) image quality can be severely impaired by artifacts caused by fixed orthodontic retainers. In clinical practice, there is a trend towards using computer-aided design/computer-aided manufacturing (CAD/CAM) retainers. This study aimed to quantify MRI artifacts produced by these novel CAD/CAM retainers. MATERIAL AND METHODS: Three CAD/CAM retainers and a stainless-steel retainer ("Twistflex"; clinical reference standard) were scanned in vitro at 3-T MRI using a high-resolution 3D sequence. The artifact diameters and three-dimensional artifact volumes (AV) were determined for all mandibular (AVmand) and maxillary (AVmax) retainers. Moreover, the corresponding ratio of artifact volume to retainer volume (AV/RVmand, AV/RVmax) was calculated. RESULTS: Twistflex caused large artifact volumes (AVmand: 13530 mm3; AVmax: 15642 mm3; AV/RVmand: 2602; AV/RVmax: 2235). By contrast, artifact volumes for CAD/CAM retainers were substantially smaller: whereas artifact volumes for cobalt-chromium retainers were moderate (381 mm3; 394 mm3; 39; 31), grade-5 titanium (110 mm3; 126 mm3; 12; 12) and nickel-titanium (54 mm3; 78 mm3; 12; 14) both produced very small artifact volumes. CONCLUSION: All CAD/CAM retainers caused substantially smaller volumes of MRI artifacts compared to Twistflex. Grade-5 titanium and nickel-titanium CAD/CAM retainers showed the smallest artifact volumes. CLINICAL RELEVANCE: CAD/CAM retainers made from titanium or nickel-titanium may not relevantly impair image quality in head/neck and dental MRI. Artifacts caused by cobalt-chromium CAD/CAM retainers may mask nearby dental/periodontal structures. In contrast, the large artifacts caused by Twistflex are likely to severely impair diagnosis of oral and adjacent pathologies.

Multimodal Predictive Modeling of Endovascular Treatment Outcome for Acute Ischemic Stroke Using Machine-Learning.

BACKGROUND AND PURPOSE: This study assessed the predictive performance and relative importance of clinical, multimodal imaging, and angiographic characteristics for predicting the clinical outcome of endovascular treatment for acute ischemic stroke. METHODS: A consecutive series of 246 patients with acute ischemic stroke and large vessel occlusion in the anterior circulation who underwent endovascular treatment between April 2014 and January 2018 was analyzed. Clinical, conventional imaging (electronic Alberta Stroke Program Early CT Score, acute ischemic volume, site of vessel occlusion, and collateral score), and advanced imaging characteristics (CT-perfusion with quantification of ischemic penumbra and infarct core volumes) before treatment as well as angiographic (interval groin puncture-recanalization, modified Thrombolysis in Cerebral Infarction score) and postinterventional clinical (National Institutes of Health Stroke Scale score after 24 hours) and imaging characteristics (electronic Alberta Stroke Program Early CT Score, final infarction volume after 18-36 hours) were assessed. The modified Rankin Scale (mRS) score at 90 days (mRS-90) was used to measure patient outcome (favorable outcome: mRS-90 ≤2 versus unfavorable outcome: mRS-90 >2). Machine-learning with gradient boosting classifiers was used to assess the performance and relative importance of the extracted characteristics for predicting mRS-90. RESULTS: Baseline clinical and conventional imaging characteristics predicted mRS-90 with an area under the receiver operating characteristics curve of 0.740 (95% CI, 0.733-0.747) and an accuracy of 0.711 (95% CI, 0.705-0.717). Advanced imaging with CT-perfusion did not improved the predictive performance (area under the receiver operating characteristics curve, 0.747 [95% CI, 0.740-0.755]; accuracy, 0.720 [95% CI, 0.714-0.727]; P=0.150). Further inclusion of angiographic and postinterventional characteristics significantly improved the predictive performance (area under the receiver operating characteristics curve, 0.856 [95% CI, 0.850-0.861]; accuracy, 0.804 [95% CI, 0.799-0.810]; P<0.001). The most important parameters for predicting mRS 90 were National Institutes of Health Stroke Scale score after 24 hours (importance =100%), premorbid mRS score (importance =44%) and final infarction volume on postinterventional CT after 18 to 36 hours (importance =32%). CONCLUSIONS: Integrative assessment of clinical, multimodal imaging, and angiographic characteristics with machine-learning allowed to accurately predict the clinical outcome following endovascular treatment for acute ischemic stroke. Thereby, premorbid mRS was the most important clinical predictor for mRS-90, and the final infarction volume was the most important imaging predictor, while the extent of hemodynamic impairment on CT-perfusion before treatment had limited importance.

Structural Nerve Remodeling at 3-T MR Neurography Differs between Painful and Painless Diabetic Polyneuropathy in Type 1 or 2 Diabetes.

Background The pathophysiologic mechanisms underlying painful symptoms in diabetic polyneuropathy (DPN) are poorly understood. They may be associated with MRI characteristics, which have not yet been investigated. Purpose To investigate correlations between nerve structure, load and spatial distribution of nerve lesions, and pain in patients with DPN. Materials and Methods In this prospective single-center cross-sectional study, participants with type 1 or 2 diabetes volunteered between June 2015 and March 2018. Participants underwent 3-T MR neurography of the sciatic nerve with a T2-weighed fat-suppressed sequence, which was preceded by clinical and electrophysiologic tests. For group comparisons, analysis of variance or the Kruskal-Wallis test was performed depending on Gaussian or non-Gaussian distribution of data. Spearman correlation coefficients were calculated for correlation analysis. Results A total of 131 participants (mean age, 62 years ± 11 [standard deviation]; 82 men) with either type 1 (n = 45) or type 2 (n = 86) diabetes were evaluated with painful (n = 64), painless (n = 37), or no (n = 30) DPN. Participants who had painful diabetic neuropathy had a higher percentage of nerve lesions in the full nerve volume (15.2% ± 1.6) than did participants with nonpainful DPN (10.4% ± 1.7, P = .03) or no DPN (8.3% ± 1.7; P < .001). The amount and extension of T2-weighted hyperintense nerve lesions correlated positively with the neuropathy disability score (r = 0.37; 95% confidence interval [CI]: 0.21, 0.52; r = 0.37; 95% CI: 0.20, 0.52, respectively) and the neuropathy symptom score (r = 0.41; 95% CI: 0.25, 0.55; r = 0.34; 95% CI: 0.17, 0.49, respectively). Negative correlations were found for the tibial nerve conduction velocity (r = -0.23; 95% CI: -0.44, -0.01; r = -0.37; 95% CI: -0.55, -0.15, respectively). The cross-sectional area of the nerve was positively correlated with the neuropathy disability score (r = 0.23; 95% CI: 0.03, 0.36). Negative correlations were found for the tibial nerve conduction velocity (r = -0.24; 95% CI: -0.45, -0.01). Conclusion The amount and extension of T2-weighted hyperintense fascicular nerve lesions were greater in patients with painful diabetic neuropathy than in those with painless diabetic neuropathy. These results suggest that proximal fascicular damage is associated with the evolution of painful sensory symptoms in diabetic polyneuropathy. © RSNA, 2019 Online supplemental material is available for this article.

Noninvasive Characterization of Tumor Angiogenesis and Oxygenation in Bevacizumab-treated Recurrent Glioblastoma by Using Dynamic Susceptibility MRI: Secondary Analysis of the European Organization for Research and Treatment of Cancer 26101 Trial.

Background Relevance of antiangiogenic treatment with bevacizumab in patients with glioblastoma is controversial because progression-free survival benefit did not translate into an overall survival (OS) benefit in randomized phase III trials. Purpose To perform longitudinal characterization of intratumoral angiogenesis and oxygenation by using dynamic susceptibility contrast agent-enhanced (DSC) MRI and evaluate its potential for predicting outcome from administration of bevacizumab. Materials and Methods In this secondary analysis of the prospective randomized phase II/III European Organization for Research and Treatment of Cancer 26101 trial conducted between October 2011 and December 2015 in 596 patients with first recurrence of glioblastoma, the subset of patients with availability of anatomic MRI and DSC MRI at baseline and first follow-up was analyzed. Patients were allocated into those administered bevacizumab (hereafter, the BEV group; either bevacizumab monotherapy or bevacizumab with lomustine) and those not administered bevacizumab (hereafter, the non-BEV group with lomustine monotherapy). Contrast-enhanced tumor volume, noncontrast-enhanced T2 fluid-attenuated inversion recovery (FLAIR) signal abnormality volume, Gaussian-normalized relative cerebral blood volume (nrCBV), Gaussian-normalized relative blood flow (nrCBF), and tumor metabolic rate of oxygen (nTMRO2) was quantified. The predictive ability of these imaging parameters was assessed with multivariable Cox regression and formal interaction testing. Results A total of 254 of 596 patients were evaluated (mean age, 57 years ± 11; 155 men; 161 in the BEV group and 93 in non-BEV group). Progression-free survival was longer in the BEV group (3.7 months; 95% confidence interval [CI]: 3.0, 4.2) compared with the non-BEV group (2.5 months; 95% CI: 1.5, 2.9; P = .01), whereas OS was not different (P = .15). The nrCBV decreased for the BEV group (-16.3%; interquartile range [IQR], -39.5% to 12.0%; P = .01), but not for the non-BEV group (1.2%; IQR, -17.9% to 23.3%; P = .19) between baseline and first follow-up. An identical pattern was observed for both nrCBF and nTMRO2 values. Contrast-enhanced tumor and noncontrast-enhanced T2 FLAIR signal abnormality volumes decreased for the BEV group (-66% [IQR, -83% to -35%] and -33% [IQR, -71% to -5%], respectively; P < .001 for both), whereas they increased for the non-BEV group (30% [IQR, -17% to 98%], P = .001; and 10% [IQR, -13% to 82%], P = .02, respectively) between baseline and first follow-up. None of the assessed MRI parameters were predictive for OS in the BEV group. Conclusion Bevacizumab treatment decreased tumor volumes, angiogenesis, and oxygenation, thereby reflecting its effectiveness for extending progression-free survival; however, these parameters were not predictive of overall survival (OS), which highlighted the challenges of identifying patients that derive an OS benefit from bevacizumab. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Dillon in this issue.