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.

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.

Fractal dynamics of individual mitochondrial oscillators measure local inter-mitochondrial coupling.

Mitochondrial inner membrane potentials in cardiomyocytes may oscillate in cycles of depolarization/repolarization when the mitochondrial network is exposed to metabolic or oxidative stress. The frequencies of such oscillations are dynamically changing while clusters of weakly coupled mitochondrial oscillators adjust to a common phase and frequency. Across the cardiac myocyte, the averaged signal of the mitochondrial population follows self-similar or fractal dynamics; however, fractal properties of individual mitochondrial oscillators have not yet been examined. We show that the largest synchronously oscillating cluster exhibits a fractal dimension, D, that is indicative of self-similar behavior with D=1.27±0.11, in contrast to the remaining network mitochondria whose fractal dimension is close to that of Brownian noise, D=1.58±0.10. We further demonstrate that fractal behavior is correlated with local coupling mechanisms, whereas it is only weakly linked to measures of functional connections between mitochondria. Our findings suggest that individual mitochondrial fractal dimensions may serve as a simple measure of local mitochondrial coupling.

Navigator-based slice tracking for kidney pCASL using spin-echo EPI acquisition.

PURPOSE: To apply a navigator-based slice-tracking method to prospectively compensate respiratory motion for kidney pseudo-continuous arterial spin labeling (pCASL), using spin-echo (SE) EPI acquisition. METHODS: A single gradient-echo slice selection and projection readout at the location of the diaphragm along the inferior-superior direction was applied as a navigator. Navigator acquisition and fat suppression were inserted before each transverse imaging slice of the readouts of a 2D-SE-EPI-based pCASL sequence. Motion information was calculated after exclusion of the signal saturation in the navigator signal caused by EPI excitations. The motion information was then used to directly adjust the slice positioning in real time. RESULTS: The respiratory motion from the navigator signal was calculated, and slice positioning was changed in real time based on the motion information. We could show that motion compensation reduces kidney movement, and that the coefficients of variation across renal perfusion values were significantly reduced when motion correction was applied. The average reduction of coefficients of variation was approximately 20%, resulting in a more accurate and detailed structure of the respective perfusion maps. CONCLUSIONS: This study demonstrates the feasibility of a navigator-based slice-tracking technique in kidney imaging with a SE-EPI readout pCASL sequence to reduce kidney motion.

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.

Diabetic neuropathy is a generalized phenomenon with impact on hand functional performance and quality of life.

BACKGROUND AND PURPOSE: Diabetic sensorimotor peripheral neuropathy is usually considered to affect predominantly the lower limbs (LL-N), whereas the impact of upper limb neuropathy (UL-N) on hand functional performance and quality of life (QoL) has not been evaluated systematically. This study aims to investigate the prevalence and characteristics of UL-N and its functional and psychosocial consequences in type 2 diabetes. METHODS: Individuals with type 2 diabetes (n = 141) and an age- and sex-matched control group (n = 73) underwent comprehensive assessment of neuropathy, hand functional performance, and psychosocial status. RESULTS: The prevalence of UL-N was 30.5% in patients with diabetes and that of LL-N was 49.6%, with 25.5% exhibiting both. Patients with diabetes showed similar sensory phenotype regarding both large and small fiber functions in hands and feet. Patients with UL-N showed reduced manual dexterity, but normal hand grip force. Additionally, there was a correlation between reduced dexterity and sensory deficits. Patients with UL-N had reduced estimates of psychosocial health including health-related QoL compared to control subjects and patients without UL-N. UL-N correlated with the severity of LL-N, but not with duration of diabetes, glycemia, age, or sex. CONCLUSIONS: This study points to a substantial prevalence of UL-N in type 2 diabetes. The sensory phenotype of patients with UL-N was similar to LL-N and was characterized by loss of sensory function. Our study demonstrated an association of UL-N with impaired manual dexterity and reduced health-related QoL. Thus, upper limb sensorimotor functions should be assessed early in patients with diabetes.

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.

Neuron-specific biomarkers predict hypo- and hyperalgesia in individuals with diabetic peripheral neuropathy.

AIMS/HYPOTHESIS: The individual risk of progression of diabetic peripheral neuropathy is difficult to predict for each individual. Mutations in proteins that are responsible for the process of myelination are known to cause neurodegeneration and display alteration in experimental models of diabetic neuropathy. In a prospective observational human pilot study, we investigated myelin-specific circulating mRNA targets, which have been identified in vitro, for their capacity in the diagnosis and prediction of diabetic neuropathy. The most promising candidate was tested against the recently established biomarker of neural damage, neurofilament light chain protein. METHODS: Schwann cells were cultured under high-glucose conditions and mRNAs of various myelin-specific genes were screened intra- and extracellularly. Ninety-two participants with type 2 diabetes and 30 control participants were enrolled and evaluated for peripheral neuropathy using neuropathy deficit scores, neuropathy symptom scores and nerve conduction studies as well as quantitative sensory testing at baseline and after 12/24 months of a follow-up period. Magnetic resonance neurography of the sciatic nerve was performed in 37 individuals. Neurofilament light chain protein and four myelin-specific mRNA transcripts derived from in vitro screenings were measured in the serum of all participants. The results were tested for associations with specific neuropathic deficits, fractional anisotropy and the progression of neuropathic deficits at baseline and after 12 and 24 months. RESULTS: In neuronal Schwann cells and human nerve sections, myelin protein zero was identified as the strongest candidate for a biomarker study. Circulating mRNA of myelin protein zero was decreased significantly in participants with diabetic neuropathy (p < 0.001), whereas neurofilament light chain protein showed increased levels in participants with diabetic neuropathy (p < 0.05). Both variables were linked to altered electrophysiology, fractional anisotropy and quantitative sensory testing. In a receiver-operating characteristic curve analysis myelin protein zero improved the diagnostic performance significantly in combination with a standard model (diabetes duration, age, BMI, HbA1c) from an AUC of 0.681 to 0.836 for the detection of diabetic peripheral neuropathy. A follow-up study revealed that increased neurofilament light chain was associated with the development of a hyperalgesic phenotype (p < 0.05), whereas decreased myelin protein zero predicted hypoalgesia (p < 0.001) and progressive loss of nerve function 24 months in advance (HR of 6.519). CONCLUSIONS/INTERPRETATION: This study introduces a dynamic and non-invasive assessment strategy for the underlying pathogenesis of diabetic peripheral neuropathy. The diagnosis of axonal degeneration, associated with hyperalgesia, and demyelination, linked to hypoalgesia, could benefit from the usage of neurofilament light chain protein and circulating mRNA of myelin protein zero as potential biomarkers.

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.

Use of dental MRI for radiation-free guided dental implant planning: a prospective, in vivo study of accuracy and reliability.

OBJECTIVES: To evaluate the accuracy and reliability of dental MRI for static guided implant surgery planning. MATERIALS AND METHODS: In this prospective study, a 0.4-mm isotropic, artifact-suppressed, 3T MRI protocol was used for implant planning and surgical guide production in participants in need of dental implants. Two dentists decided on treatment plan. Surgical guides were placed intraorally during a subsequent reference cone beam computed tomography (CBCT) scan. Inter-rater and inter-modality agreement were assessed by Cohen's kappa. For each participant, dental MRI and CBCT datasets were co-registered to determine three-dimensional and angular deviations between planned and surgically guided implant positions. RESULTS: Forty-five implants among 30 study participants were planned and evaluated (17 women, 13 men, mean age 56.9 ± 13.1 years). Inter-rater agreement (mean κ 0.814; range 0.704-0.927) and inter-modality agreement (mean κ 0.879; range 0.782-0.901) were both excellent for the dental MRI-based treatment plans. Mean three-dimensional deviations were 1.1 ± 0.7 (entry point) and 1.3 ± 0.7 mm (apex). Mean angular deviation was 2.4 ± 1.5°. CBCT-based adjustments of MRI plans were necessary for implant position in 29.5% and for implant axis in 6.8% of all implant sites. Changes were larger in the group with shortened dental arches compared with those for tooth gaps. Except for one implant site, all guides were suitable for clinical use. CONCLUSION: This feasibility study indicates that dental MRI is reliable and sufficiently accurate for surgical guide production. Nevertheless, more studies are needed to increase its accuracy before it can be used for implant planning outside clinical trials. KEY POINTS: • An excellent reliability for the dental MRI-based treatment plans as well as agreement between dental MRI-based and CBCT-based (reference standard) decisions were noted. • Ideal implant position was not reached in all cases by dental MRI plans. • For all but one implant site surgical guides derived from dental MRI were sufficiently accurate to perform implant placement (mean three-dimensional deviations were 1.1 ± 0.7 (entry point) and 1.3 ± 0.7 mm (apex); mean angular deviation was 2.4 ± 1.5°).

In vivo comparison of MRI- and CBCT-based 3D cephalometric analysis: beginning of a non-ionizing diagnostic era in craniomaxillofacial imaging?

OBJECTIVES: To evaluate whether magnetic resonance imaging (MRI) can serve as an alternative diagnostic tool to the "gold standard" cone-beam computed tomography (CBCT) in 3D cephalometric analysis. METHODS: In this prospective feasibility study, 12 patients (8 males, 4 females; mean age ± SD, 26.1 years ± 6.6) underwent 3D MRI and CBCT before orthognathic surgery. 3D cephalometric analysis was performed twice by two independent observers on both modalities. For each dataset, 27 cephalometric landmarks were defined from which 35 measurements (17 angles, 18 distances) were calculated. Statistical analyses included the calculation of Euclidean distances, intraclass correlation coefficients (ICCs), Bland-Altman analysis, and equivalence testing (linear mixed effects model) with a predefined equivalence margin of ± 1°/1 mm. RESULTS: Analysis of reliability for CBCT vs. MRI (intra-rater I/intra-rater II/inter-rater) revealed Euclidean distances of 0.86/0.86/0.98 mm vs. 0.93/0.99/1.10 mm for landmarks, ICCs of 0.990/0.980/0.986 vs. 0.982/0.978/0.980 for angles, and ICCs of 0.992/0.988/0.989 vs. 0.991/0.985/0.988 for distances. Bland-Altman analysis showed high levels of agreement between CBCT and MRI with bias values (95% levels of agreement) of 0.03° (- 1.49; 1.54) for angles and 0.02 mm (- 1.44; 1.47) for distances. In the linear mixed effects model, the mean values of CBCT and MRI measurements were equivalent. CONCLUSION: This feasibility study indicates that MRI enables reliable 3D cephalometric analysis with excellent agreement to corresponding measurements on CBCT. Thus, MRI could serve as a non-ionizing alternative to CBCT for treatment planning and monitoring in orthodontics as well as oral and maxillofacial surgery. KEY POINTS: • Clinically established 3D cephalometric measurements performed on MRI are highly reliable and show an excellent agreement with CBCT (gold standard). • The MRI technique applied in this study could be used as a non-ionizing diagnostic tool in orthodontics as well as oral and maxillofacial surgery. • Since most patients benefiting from 3D cephalometry are young in age, the use of MRI could substantially contribute to radiation protection and open up new possibilities for treatment monitoring.

Comparison of non-contrast-enhanced dental magnetic resonance imaging and cone-beam computed tomography in assessing the horizontal and vertical components of furcation defects in maxillary molars: An in vivo feasibility study.

AIM: To compare non-contrast-enhanced dental magnetic resonance imaging (NCE-dMRI) and cone-beam computed tomography (CBCT) in assessing horizontal and vertical furcation defects in maxillary molars in vivo. MATERIALS AND METHODS: (NCE-dMRI) and CBCT were performed in 23 patients with severe periodontitis. Sixty-five first/second maxillary molars (195 furcation entrances) were analysed by two independent observers on both modalities to assess the horizontal and vertical components of furcation defects. Reliability of defect classification was evaluated using weighted kappa (κ) statistics. Agreement between NCE-dMRI and CBCT was determined by the Bland-Altman analysis. Sensitivity and specificity of NCE-dMRI were calculated using CBCT as the reference. RESULTS: Inter-radicular bone loss was observed in 94 furcation entrances. Intra- and inter-rater κ-values were ≥0.9 for both NCE-dMRI and CBCT. The Bland-Altman analysis showed mean differences (95% limits of agreement) of 0.12 mm (-0.67 to 0.90) for horizontal and 0.12 mm (-1.27 to 1.50) for vertical measurements. For the detection of furcation defects, sensitivity/specificity of NCE-dMRI was 98%/100% for horizontal and 99%/99% for vertical components. For defect classification, sensitivity values of NCE-dMRI were 88%/89%/100% (horizontal degree I/II/III) and 95%/91%/80% (vertical subclass A/B/C), respectively. CONCLUSIONS: Non-contrast-enhanced dental magnetic resonance imaging demonstrated high reliability and high agreement with CBCT for the assessment of furcation defects in maxillary molars.

In vivo accuracy of dental magnetic resonance imaging in assessing maxillary molar furcation involvement: A feasibility study in humans.

AIM: To investigate the accuracy and reliability of dental magnetic resonance imaging (dMRI) in assessing maxillary molar furcation involvement (FI). MATERIAL AND METHODS: In this prospective study, 22 patients with severe periodontitis underwent cone-beam computed tomography (CBCT) and dMRI. For 192 furcation entrances, the degree of horizontal FI was assessed by two independent observers on both modalities. Results of dMRI were compared with CBCT (reference modality) to assess the accuracy of dMRI. Cohen's kappa (κ), sensitivity and specificity were calculated for FI classification. Bland-Altman analysis and the Kruskal-Wallis test were used to evaluate measurement accuracy of dMRI. RESULTS: Based on CBCT findings, 93 furcation entrances revealed FI (degree I/II/III: 35/19/39). Intra- and inter-reader agreement was excellent for both modalities (κ-range: 0.884 to 0.933). dMRI measurements showed high agreement with CBCT (bias: 0.17 mm; 95% limits of agreement: -1.05 to 1.38 mm), and measurement accuracy did not differ among different degrees of FI (p = .67). For FI detection, sensitivity and specificity of dMRI were 98% and 99%. For FI classification, sensitivity values of dMRI were 89%/84%/100% for degree I/II/III. CONCLUSIONS: Compared to CBCT (non-invasive gold standard), dMRI demonstrates high accuracy and reliability in evaluating the degree of FI in maxillary molars.

In vivo reliability of 3D cephalometric landmark determination on magnetic resonance imaging: a feasibility study.

OBJECTIVE: 3D cephalometric analysis performed on cone-beam or multi-slice computed tomography (CBCT, MSCT) has superior diagnostic value compared to 2D cephalometry based on radiographs. However, this comes at the expense of increased radiation risks for the predominantly young patients. Magnetic resonance imaging (MRI) has the potential to overcome this diagnostic dilemma but has not been established for 3D cephalometry so far. Since landmark reliability forms the basis for 3D cephalometry, we evaluated the in vivo reliability of established 3D landmarks using MRI. MATERIALS AND METHODS: Sixteen orthodontic patients underwent MRI at 3 Tesla using a 0.5 mm 3D sequence. On each MRI scan, 44 cephalometric landmarks were determined. Image analysis was performed twice by two independent observers. Intra- and inter-rater agreement was assessed by mean measurement errors and intraclass correlation coefficients (ICCs). Measurement errors were calculated as Euclidean distances and distances for x-, y-, and z-coordinates. RESULTS: Overall, MRI-based 3D cephalometric landmarks revealed a high reliability comparable to prior in vivo studies using CBCT/MSCT. Intra- and inter-rater ICCs were consistently higher than 0.9. Intra-rater comparisons showed mean measurement differences (ranges) of 0.87 mm (0.41-1.63) for rater I and 0.94 mm (0.49-1.28) for rater II. Average inter-rater difference was 1.10 mm (0.52-2.29). Distinct differences in reliability between the various landmarks were observed, corresponding well with the landmarks' specific shapes. CONCLUSIONS: The present study demonstrates that MRI enables reliable determination of 3D cephalometric landmarks in vivo. CLINICAL RELEVANCE: This study emphasizes the potential of MRI to perform treatment planning and monitoring in orthodontics as well as oral and maxillofacial surgery without radiation exposure.

Diabetic neuropathy differs between type 1 and type 2 diabetes: Insights from magnetic resonance neurography.

OBJECTIVE: To visualize and quantify differences of microstructural nerve damage in distal symmetric diabetic neuropathy (DPN) between type 1 diabetes (T1D) and type 2 diabetes (T2D), and to detect correlations between neuropathic symptoms and serological risk factors. METHODS: Three-tesla magnetic resonance neurography of the sciatic nerve was performed in 120 patients (T1D, n = 35; T2D, n = 85) with either DPN (n = 84) or no DPN (n = 36). Results were subsequently correlated with clinical, serological, and electrophysiological patient data. RESULTS: T2-weighted (T2w)-hyperintense lesions correlated negatively with tibial compound motor action potential (r = -0.58, p < 0.0001) and peroneal nerve conduction (r = 0.51, p = 0.0002), and positively with neuropathy disability score (NDS; r = -0.54, p < 0.0001), neuropathy symptom score (NSS; r = 0.52, p < 0.0001), and HbA1c level (r = 0.23, p = 0.014). T2w-hypointense lesions correlated positively with NDS (r = 0.28, p = 0.002), NSS (r = 0.36, p < 0.0001), and serum triglycerides (r = 0.34, p = 0.0003), and negatively with serum high-density lipoprotein (HDL; r = -0.48, p < 0.0001). For DPN in T1D, elevated values of T2w-hyperintense lesions (19.67 ± 4.13% vs 12.49 ± 1.23%, p = 0.027) and HbA1c (8.74 ± 0.29% vs 7.11 ± 0.16%, p < 0.0001) were found when compared to T2D. For DPN in T2D, elevated T2w-hypointense lesions (23.41 ± 2.69mm3 vs 11.43 ± 1.74mm3 , p = 0.046) and triglycerides (220.70 ± 23.70mg/dl vs 106.60 ± 14.51mg/dl, p < 0.0001), and lower serum HDL (51.29 ± 3.02mg/dl vs 70.79 ± 4.65mg/dl, p < 0.0001) were found when compared to T1D. INTERPRETATION: The predominant type of nerve lesion in DPN differs between T1D and T2D. Correlations found between lesion type and serological parameters indicate that predominant nerve lesions in T1D are associated with poor glycemic control and loss of nerve conduction, whereas predominant lesions in T2D are associated with changes in lipid metabolism. These findings may be helpful for future studies on the underlying pathophysiological pathways and possible treatments for DPN in T1D and T2D. Ann Neurol 2018;83:588-598.

Peripheral nerve involvement in multiple sclerosis: Demonstration by magnetic resonance neurography.

OBJECTIVE: To detect and quantify peripheral nerve lesions in multiple sclerosis (MS) by magnetic resonance neurography (MRN). METHODS: Thirty-six patients diagnosed with MS based on the 2010 McDonald criteria (34 with the relapsing-remitting form, 2 with clinically isolated syndrome) with and without disease-modifying treatment were compared to 35 healthy age-/sex-matched volunteers. All patients underwent detailed neurological and electrophysiological examinations. Three Tesla MRN with large anatomical coverage of both legs and the lumbosacral plexus was performed by using 2-dimensional (2D) fat-saturated, T2-weighted (T2w) and dual echo turbo spin echo sequences as well as a 3D T2-weighted, fat-saturated SPACE sequence. Besides qualitative visual nerve assessment, a T2w signal quantification was performed by calculation of proton spin density and T2 relaxation time. Nerve diameter was measured as a morphometric criterion. RESULTS: T2w hyperintense nerve lesions were detectable in all MS patients, with a mean lesion number at thigh level of 151.5 ± 5.7 versus 19.1 ± 2.4 in controls (p < 0.0001). Nerve proton spin density was higher in MS (tibial/peroneal: 371.8 ± 7.7/368.9 ± 8.2) versus controls (tibial/peroneal: 266.0 ± 11.0/276.8 ± 9.7, p < 0.0001). In contrast, T2 relaxation time was significantly higher in controls (tibial/peroneal: 82.0 ± 2.1/78.3 ± 1.7) versus MS (tibial/peroneal: 64.3 ± 1.0/61.2 ± 0.9, p < 0.0001). Proximal tibial and peroneal nerve caliber was higher in MS (tibial: 52.4 ± 2.1mm2 , peroneal: 25.4 ± 1.3mm2 ) versus controls (tibial: 45.2 ± 1.4mm2 , p < 0.0015; peroneal: 21.3 ± 0.7mm2 , p = 0.0049). INTERPRETATION: Peripheral nerve lesions could be visualized and quantified in MS in vivo by high-resolution MRN. Lesions are defined by an increase of proton spin density and a decrease of T2 relaxation time, indicating changes in the microstructural organization of the extracellular matrix in peripheral nerve tissue in MS. By showing involvement of the peripheral nervous system in MS, this proof-of-concept study may offer new insights into the pathophysiology and treatment of MS. Ann Neurol 2017;82:676-685.

Association of Small Fiber Function with Microvascular Perfusion of Peripheral Nerves in Patients with Type 2 Diabetes : Study using Quantitative Sensory Testing and Magnetic Resonance Neurography.

INTRODUCTION/AIMS: Diabetic small fiber neuropathy (SFN) is caused by damage to thinly myelinated A­fibers (δ) and unmyelinated C­fibers. This study aimed to assess associations between quantitative sensory testing (QST) and parameters of peripheral nerve perfusion obtained from dynamic contrast enhanced (DCE) magnetic resonance neurography (MRN) in type 2 diabetes patients with and without SFN. METHODS: A total of 18 patients with type 2 diabetes (T2D, 8 with SFN, 10 without SFN) and 10 healthy controls (HC) took part in this cross-sectional single-center study and underwent QST of the right leg and DCE-MRN of the right thigh with subsequent calculation of the sciatic nerve constant of capillary permeability (Ktrans), extravascular extracellular volume fraction (Ve), and plasma volume fraction (Vp). RESULTS: The Ktrans (HC 0.031 min-1 ± 0.009, T2D 0.043 min-1 ± 0.015; p = 0.033) and Ve (HC 1.2% ± 1.5, T2D: 4.1% ± 5.1; p = 0.027) were lower in T2D patients compared to controls. In T2D patients, compound z­scores of thermal and mechanical detection correlated with Ktrans (r = 0.73; p = 0.001, and r = 0.57; p = 0.018, respectively) and Ve (r = 0.67; p = 0.002, and r = 0.69; p = 0.003, respectively). Compound z­scores of thermal pain and Vp (r = -0.57; p = 0.015) correlated negatively. DISCUSSION: The findings suggest that parameters of peripheral nerve microcirculation are related to different symptoms in SFN: A reduced capillary permeability may result in a loss of function related to insufficient nutritional supply, whereas increased capillary permeability may be accompanied by painful symptoms related to a gain of function.