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Berlin Brandenburg

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  • Bendszus, Martin  (23)
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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 07 January 2014, Vol.111(1), pp.409-14
    Description: A hypoxic microenvironment induces resistance to alkylating agents by activating targets in the mammalian target of rapamycin (mTOR) pathway. The molecular mechanisms involved in this mTOR-mediated hypoxia-induced chemoresistance, however, are unclear. Here we identify the mTOR target N-myc downstream regulated gene 1 (NDRG1) as a key determinant of resistance toward alkylating chemotherapy, driven by hypoxia but also by therapeutic measures such as irradiation, corticosteroids, and chronic exposure to alkylating agents via distinct molecular routes involving hypoxia-inducible factor (HIF)-1alpha, p53, and the mTOR complex 2 (mTORC2)/serum glucocorticoid-induced protein kinase 1 (SGK1) pathway. Resistance toward alkylating chemotherapy but not radiotherapy was dependent on NDRG1 expression and activity. In posttreatment tumor tissue of patients with malignant gliomas, NDRG1 was induced and predictive of poor response to alkylating chemotherapy. On a molecular level, NDRG1 bound and stabilized methyltransferases, chiefly O(6)-methylguanine-DNA methyltransferase (MGMT), a key enzyme for resistance to alkylating agents in glioblastoma patients. In patients with glioblastoma, MGMT promoter methylation in tumor tissue was not more predictive for response to alkylating chemotherapy in patients who received concomitant corticosteroids.
    Keywords: Drug Resistance, Neoplasm ; Gene Expression Regulation, Neoplastic ; Antineoplastic Agents, Alkylating -- Pharmacology ; Brain Neoplasms -- Drug Therapy ; Cell Cycle Proteins -- Metabolism ; Glioblastoma -- Drug Therapy ; Glioma -- Drug Therapy ; Intracellular Signaling Peptides and Proteins -- Metabolism ; O(6)-Methylguanine-DNA Methyltransferase -- Pharmacology ; Tor Serine-Threonine Kinases -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    In: Neurology, 2015, Vol.84(17), pp.1782-1787
    Description: OBJECTIVES:: To investigate whether the human sciatic nerve might have a consistent somatotopic organization according to proximal fascicle input by spinal nerves. METHODS:: Twelve patients (55.3 ± 15.5 years) with confirmed lesions of either the L5 or S1 spinal nerve root underwent magnetic resonance neurography of sciatic nerve fascicles including thigh and knee levels (T2-weighted sequence with fat saturation, repetition time/echo time 7,552/52 milliseconds, voxel size 0.27 × 0.27 × 3.0 mm). Twenty healthy subjects and 12 additional patients with an established diagnosis of peripheral polyneuropathy served as 2 separate age- and sex-matched control groups. Two blinded readers assessed patients and controls for presence of distinct lesion patterns. Spatial maps of normalized T2 signal were rendered after segmentation and coregistration of sciatic nerve voxels to detect fascicle lesion patterns. RESULTS:: A clear somatotopic distribution of nerve fascicles was observed on cross-sections along the entire course of the sciatic nerve and was distinct between patients with L5 and those with S1 lesions. Fascicles emerging from L5 were ordered in anterolateral positions within sciatic nerve cross-sections, while fascicles emerging from S1 appeared posteromedially. Visual assessment discriminated these somatotopic lesions in all cases from both healthy and polyneuropathy controls. CONCLUSION:: A distinct pattern of somatotopy was identified within the sciatic nerve according to proximal fascicle input by L5 and S1 spinal nerves. Knowledge of human nerve somatotopy may have clinically useful implications in imaging-aided diagnosis of neuropathies.
    Keywords: Repetition ; Spinal Nerves ; Sciatic Nerve ; Segmentation ; Image Processing ; N.M.R. ; Maps ; Knee ; Polyneuropathy ; Neuropathy ; Neurology & Neuropathology;
    ISSN: 0028-3878
    E-ISSN: 1526632X
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  • 3
    Language: English
    In: 2012, Vol.7(11), p.e49742
    Description: Patients with ulnar neuropathy of unclear etiology occasionally present with lesion extension from elbow to upper arm level on MRI. This study investigated whether MRI thereby distinguishes multifocal neuropathy from focal-compressive neuropathy at the elbow. ; This prospective study was approved by the institutional ethics committee and written informed consent was obtained from all participants. 122 patients with ulnar mononeuropathy of undetermined localization and etiology by clinical and electrophysiological examination were assessed by MRI at upper arm and elbow level using T2-weighted fat-saturated sequences at 3T. Twenty-one patients were identified with proximal ulnar nerve lesions and evaluated for findings suggestive of disseminated neuropathy (i) subclinical lesions in other nerves, (ii) unfavorable outcome after previous decompressive elbow surgery, and (iii) subsequent diagnosis of inflammatory or other disseminated neuropathy. Two groups served as controls for quantitative analysis of nerve-to-muscle signal intensity ratios: 20 subjects with typical focal ulnar neuropathy at the elbow and 20 healthy subjects. ; In the group of 21 patients with proximal ulnar nerve lesion extension, T2-w ulnar nerve signal was significantly (p〈0.001) higher at upper arm level than in both control groups. A cut-off value of 1.92 for maximum nerve-to-muscle signal intensity ratio was found to be sensitive (86%) and specific (100%) to discriminate this group. Ten patients (48%) exhibited additional T2-w lesions in the median and/or radial nerve. Another ten (48%) had previously undergone elbow surgery without satisfying outcome. Clinical follow-up was available in 15 (71%) and revealed definitive diagnoses of multifocal neuropathy of various etiologies in four patients. In another eight, diagnoses could not yet be considered definitive but were consistent with multifocal neuropathy. ; Proximal ulnar nerve T2 lesions at upper arm level are detected by MRI and indicate the presence of a non-focal disseminated neuropathy instead of a focal compressive neuropathy.
    Keywords: Research Article ; Biology ; Medicine ; Immunology ; Physiology ; Neurological Disorders ; Radiology And Medical Imaging
    E-ISSN: 1932-6203
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  • 4
    In: Neurology, 2016, Vol.87(18), pp.1884-1891
    Description: OBJECTIVE:: To investigate the spatial pattern of lesion dispersion in posterior interosseous neuropathy syndrome (PINS) by high-resolution magnetic resonance neurography. METHODS:: This prospective study was approved by the local ethics committee and written informed consent was obtained from all patients. In 19 patients with PINS and 20 healthy controls, a standardized magnetic resonance neurography protocol at 3-tesla was performed with coverage of the upper arm and elbow (T2-weighted fat-saturated: echo time/repetition time 52/7,020 milliseconds, in-plane resolution 0.27 × 0.27 mm). Lesion classification of the radial nerve trunk and its deep branch (which becomes the posterior interosseous nerve) was performed by visual rating and additional quantitative analysis of normalized T2 signal of radial nerve voxels. RESULTS:: Of 19 patients with PINS, only 3 (16%) had a focal neuropathy at the entry of the radial nerve deep branch into the supinator muscle at elbow/forearm level. The other 16 (84%) had proximal radial nerve lesions at the upper arm level with a predominant lesion focus 8.3 ± 4.6 cm proximal to the humeroradial joint. Most of these lesions (75%) followed a specific somatotopic pattern, involving only those fascicles that would form the posterior interosseous nerve more distally. CONCLUSIONS:: PINS is not necessarily caused by focal compression at the supinator muscle but is instead frequently a consequence of partial fascicular lesions of the radial nerve trunk at the upper arm level. Neuroimaging should be considered as a complementary diagnostic method in PINS.
    Keywords: 120 ; 181 ; Article;
    ISSN: 0028-3878
    E-ISSN: 1526632X
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  • 5
    In: Neurology, 2014, Vol.82(7), pp.598-606
    Description: OBJECTIVE:: We sought to determine lesion sites and spatial lesion patterns in spontaneous anterior interosseous nerve syndrome (AINS) with high-resolution magnetic resonance neurography (MRN). METHODS:: In 20 patients with AINS and 20 age- and sex-matched controls, MRN of median nerve fascicles was performed at 3T with large longitudinal anatomical coverage (upper arm/elbow/forearm): 135 contiguous axial slices (T2-weighted: echo time/repetition time 52/7,020 ms, time of acquisition: 15 minutes 48 seconds, in-plane resolution: 0.25 × 0.25 mm). Lesion classification was performed by visual inspection and by quantitative analysis of normalized T2 signal after segmentation of median nerve voxels. RESULTS:: In all patients and no controls, T2 lesions of individual fascicles were observed within upper arm median nerve trunk and strictly followed a somatotopic/internal topography: affected were those motor fascicles that will form the anterior interosseous nerve further distally while other fascicles were spared. Predominant lesion focus was at a mean distance of 14.6 ± 5.4 cm proximal to the humeroradial joint. Discriminative power of quantitative T2 signal analysis and of qualitative lesion rating was high, with 100% sensitivity and 100% specificity (p 〈 0.0001). Fascicular T2 lesion patterns were rated as multifocal (n = 17), monofocal (n = 2), or indeterminate (n = 1) by 2 independent observers with strong agreement (kappa = 0.83). CONCLUSION:: It has been difficult to prove the existence of fascicular/partial nerve lesions in spontaneous neuropathies using clinical and electrophysiologic findings. With MRN, fascicular lesions with strict somatotopic organization were observed in upper arm median nerve trunks of patients with AINS. Our data strongly support that AINS in the majority of cases is not a surgically treatable entrapment neuropathy but a multifocal mononeuropathy selectively involving, within the main trunk of the median nerve, the motor fascicles that continue distally to form the anterior interosseous nerve.
    Keywords: Data Processing ; Median Nerve ; Image Processing ; Joints ; Repetition ; Classification ; Segmentation ; Peripheral Nervous System ; N.M.R. ; Elbow ; Forearm ; Neuropathy ; Topography ; Neuroanatomy, Histology & Cytology;
    ISSN: 0028-3878
    E-ISSN: 1526632X
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  • 6
    Language: English
    In: Radiology, October 2014, Vol.273(1), pp.185-93
    Description: To investigate the ability of diffusion-tensor imaging (DTI) and T2 to help detect the mildest nerve lesion conceivable, that is, subclinical ulnar neuropathy at the elbow. This prospective study was approved by the institutional ethics board. Written informed consent was obtained from all participants. Magnetic resonance neurography was performed at 3.0 T by using proton density- and T2-weighted relaxometry and DTI on elbows in 30 healthy subjects without clinical evidence of neuropathy. Quantitative analysis of ulnar nerve T2 and fractional anisotropy (FA) was performed, and T2 and FA values were correlated to electrical nerve conduction velocities (NCVs) with Pearson correlation analysis. Additional qualitative assessment of T2-weighted and FA images was performed by two readers, and sensitivity and specificity were calculated. Ten of the 30 subjects (33%) had NCV slowing across the elbow segment. Compared with subjects without NCV slowing, subjects with slowing had decreased FA values (0.51 ± 0.09 vs 0.41 ± 0.07, respectively; P = .006) and increased T2 values (64.2 msec ± 10.9 vs 76.2 msec ± 13.7, respectively; P = .01) in the proximal ulnar sulcus. FA values showed a significant correlation (P = .01) with NCV slowing over the sulcus as an electrophysiologic indicator of myelin sheath damage. Qualitative assessment of FA maps and T2-weighted images helped identify subjects with conduction slowing with a sensitivity of 80% and 55%, respectively, and a specificity of 83% and 63%. FA maps can accurately depict even mild peripheral neuropathy and perform better than the current standard of reference, T2-weighted images. DTI may therefore add diagnostic value as a highly sensitive technique for the detection of peripheral neuropathy.
    Keywords: Diffusion Tensor Imaging -- Methods ; Peripheral Nervous System Diseases -- Diagnosis
    ISSN: 00338419
    E-ISSN: 1527-1315
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  • 7
    In: Neurology, 2018, Vol.91(7), pp.e625-e634
    Description: OBJECTIVE: To detect, localize, and quantify peripheral nerve lesions in amyloid light chain (AL) amyloidosis by magnetic resonance neurography (MRN) in correlation with clinical and electrophysiologic findings. METHODS: We prospectively examined 20 patients with AL-polyneuropathy (PNP) and 25 age- and sex-matched healthy volunteers. After detailed neurologic and electrophysiologic testing, the patient group was subdivided into mild and moderate PNP. MRN in a 3.0 tesla scanner with anatomical coverage from the lumbosacral plexus and proximal thigh down to the tibiotalar joint was performed by using T2-weighted and dual-echo 2-dimensional sequences with spectral fat saturation and a 3-dimensional, T2-weighted inversion recovery sequence. Besides evaluation of nerve T2-weighted signal, detailed quantification of nerve injury by morphometric (nerve caliber) and microstructural MRN markers (proton spin density, T2 relaxation time) was conducted. RESULTS: Nerve T2-weighted signal increase correlated with disease severity: moderate (420.2 ± 60.1) vs mild AL-PNP (307.2 ± 17.9; p = 0.0003) vs controls (207.0 ± 6.4; p 〈 0.0001). Proton spin density was also higher in moderate (tibial: 525.5 ± 53.0; peroneal: 553.6 ± 64.5; sural: 492.0 ± 56.6) and mild AL-PNP (tibial: 431.6 ± 22.0; peroneal: 457.6 ± 21.7; sural: 404.8 ± 25.2) vs controls (tibial: 310.5 ± 14.1; peroneal: 313.6 ± 11.6; sural: 261.7 ± 11.0; p 〈 0.0001 for all nerves). T2 relaxation time was elevated in moderate AL-PNP only (tibial: p = 0.0106; peroneal: p = 0.0070; sural: p = 0.0190). Tibial nerve caliber was higher in moderate (58.0 ± 8.8 mm) vs mild AL-PNP (46.5 ± 2.5 mm; p = 0.008) vs controls (39.1 ± 1.2 mm; p 〈 0.0001). CONCLUSIONS: MRN detects and quantifies peripheral nerve injury in AL-PNP in vivo with high sensitivity and in close correlation with the clinical stage. Quantitative parameters are feasible new imaging biomarkers for the detection of early AL-PNP and might help to monitor microstructural nerve tissue changes under treatment.
    Keywords: Adult–Pathology ; Aged–Complications ; Analysis of Variance–Diagnostic Imaging ; Case-Control Studies–Etiology ; Evoked Potentials, Motor–Etiology ; Female–Etiology ; Ganglia, Spinal–Etiology ; Humans–Etiology ; Imaging, Three-Dimensional–Etiology ; Immunoglobulin Light-Chain Amyloidosis–Etiology ; Magnetic Resonance Imaging–Etiology ; Male–Etiology ; Middle Aged–Etiology ; Polyneuropathies–Etiology ; Protons–Etiology ; Severity of Illness Index–Etiology ; Protons;
    ISSN: 0028-3878
    E-ISSN: 1526632X
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  • 8
    In: Annals of Neurology, December 2015, Vol.78(6), pp.939-948
    Description: Objective The aim of this work was to localize and quantify alterations of nerve microstructure in diabetic polyneuropathy (DPN) by magnetic resonance (MR) neurography with large anatomical coverage. Methods Patients (N=25) with mild-to-moderate (Neuropathy-Symptom-Score [NSS]/Neuropathy Deficit Score [NDS] 3.8 plus or minus 0.3/2.6 plus or minus 0.5) and patients (n=10) with severe DPN (6.2 plus or minus 0.6/7.4 plus or minus 0.5) were compared to patients (n=15) with diabetes but no DPN and to age-/sex-matched nondiabetic controls (n=25). All subjects underwent MR neurography with large spatial coverage and high resolution from spinal nerve to ankle level: four slabs per leg, each with 35 axial slices (T2- and proton-density-weighted two dimensional turbo-spin-echo sequences; voxel size: 0.40.33.5mm super(3)) and a three-dimensional T2-weighted sequence to cover spinal nerves and plexus. Nerve segmentation was performed on a total of 280 slices per subject. Nerve lesion voxels were determined independently from operator input by statistical classification against the nondiabetic cohort. At the site with highest lesion-voxel burden, signal quantification was performed by calculating nerve proton spin density and T2 relaxation time. Results Total burden of nerve lesion voxels was significantly increased in DPN (p=0.003) with strong spatial predominance at thigh level, where average lesion voxel load was significantly higher in severe (57 plus or minus 18.4; p=0.0022) and in mild-to-moderate DPN (35 plus or minus 4.0; p〈0.001) than in controls (18 plus or minus 3.6). Signal quantification at the site of predominant lesion burden (thigh) revealed a significant increase of nerve proton spin density in severe (360 plus or minus 22.9; p=0.043) and in mild-to-moderate DPN (365 plus or minus 15.2; p=0.001) versus controls (288 plus or minus 13.4), but not of T2 relaxation time (p=0.49). Nerve proton spin density predicted severity of DPN with an odds ratio of 2.9 (95% confidence interval: 2.4-3.5; p〈0.001) per 100 proton spins. Interpretation In DPN, the predominant site of microstructural nerve alteration is at the thigh level with a strong proximal-to-distal gradient. Nerve proton spin density at the thigh level is a novel quantitative imaging biomarker of early DPN and increases with neuropathy severity. Ann Neurol 2015; 78:939-948
    Keywords: Statistics ; Protons ; Image Processing ; Biomarkers ; Diabetes Mellitus ; Leg ; Spinal Nerves ; Classification ; Segmentation ; Ankle ; N.M.R. ; Brain Slice Preparation ; Polyneuropathy ; Neuropathy ; Neurology & Neuropathology;
    ISSN: 0364-5134
    E-ISSN: 1531-8249
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  • 9
    Language: English
    In: PLoS ONE, 01 January 2017, Vol.12(8), p.e0183845
    Description: To investigate in vivo morphological and functional correlates of oxaliplatin-induced peripheral neuropathy (OXA-PNP) by magnetic resonance neurography (MRN).Twenty patients (7 female, 13 male, 58.9±10.0 years) with mild to moderate OXA-PNP and 20 matched controls (8 female, 12 male, 55.7±15.6 years) were prospectively enrolled. All patients underwent a detailed neurophysiological examination prior to neuroimaging. A standardized imaging protocol at 3.0 Tesla included the lumbosacral plexus and both sciatic nerves and their branches using T2-weighted fat-saturated sequences and diffusion tensor imaging. Quantitative assessment included volumetry of the dorsal root ganglia (DRG), sciatic nerve normalized T2 (nT2) signal and caliber, and fractional anisotropy (FA), mean diffusivity (MD), axial (AD) and radial diffusivity (RD). Additional qualitative evaluation of sciatic, peroneal, and tibial nerves evaluated the presence, degree, and distribution of nerve lesions.DRG hypertrophy in OXA-PNP patients (207.3±47.7mm3 vs. 153.0±47.1mm3 in controls, p = 0.001) was found as significant morphological correlate of the sensory neuronopathy. In contrast, peripheral nerves only exhibited minor morphological alterations qualitatively. Quantitatively, sciatic nerve caliber (27.3±6.7mm2 vs. 27.4±7.4mm2, p = 0.80) and nT2 signal were not significantly changed in patients (1.32±0.22 vs. 1.22±0.26, p = 0.16). AD, RD, and MD showed a non-significant decrease in patients, while FA was unchanged.OXA-PNP manifests with morphological and functional correlates that can be detected in vivo by MRN. We report hypertrophy of the DRG that stands in contrast to experimental and postmortem studies. DRG volume should be further investigated as a biomarker in other sensory peripheral neuropathies and ganglionopathies.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 10
    In: Journal of Neurochemistry, October 2014, Vol.131(2), pp.251-264
    Description: Human glioblastomas may be hierarchically organized. Within this hierarchy, glioblastoma‐initiating cells have been proposed to be more resistant to radiochemotherapy and responsible for recurrence. Here, established stem cell markers and stem cell attributed characteristics such as self‐renewal capacity and tumorigenicity have been profiled in primary glioblastoma cultures to predict radiosensitivity. Furthermore, the sensitivity to radiotherapy of different subpopulations within a single primary glioblastoma culture was analyzed by a flow cytometric approach using Nestin, SRY (sex‐determining region Y)‐box 2 (SOX2) and glial fibrillary acidic protein. The protein expression of Nestin and SOX2 as well as the mRNA levels of Musashi1, L1 cell adhesion molecule, CD133, Nestin, and pleiomorphic adenoma gene‐like 2 inversely correlated with radioresistance in regard to the clonogenic potential. Only CD44 protein expression correlated positively with radioresistance. In terms of proliferation, Nestin protein expression and Musashi1, pleiomorphic adenoma gene‐like 2, and CD133 mRNA levels are inversely correlated with radioresistance. Higher expression of stem cell markers does not correlate with resistance to radiochemotherapy in the cancer genome atlas glioblastoma collective. SOX2 expressing subpopulations exist within single primary glioblastoma cultures. These subpopulations predominantly form the proliferative pool of the primary cultures and are sensitive to irradiation. Thus, profiling of established stem cell markers revealed a surprising result. Except CD44, the tested stem cell markers showed an inverse correlation between expression and radioresistance. Markers used to define glioma‐initiating cells (GIC) are generally not defining a more resistant, but rather a more sensitive group of glioma cells. An exemption is CD44 expression. Also proliferation of the GIC culture itself was not systematically associated with radiosensitivity or – resistance, but a SOX‐2 positive, proliferative subgroup within a GIC culture is showing the highest radiosensitivity. Markers used to define glioma‐initiating cells (GIC) are generally not defining a more resistant, but rather a more sensitive group of glioma cells. An exemption is CD44 expression. Also proliferation of the GIC culture itself was not systematically associated with radiosensitivity or – resistance, but a SOX‐2 positive, proliferative subgroup within a GIC culture is showing the highest radiosensitivity.
    Keywords: Cd133 ; Glioma‐Initiating Cells ; Profiling ; Radiotherapy Sensitivity ; Sox2 ; Stem Cell Markers
    ISSN: 0022-3042
    E-ISSN: 1471-4159
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