Interplay of tau and functional network connectivity in progressive supranuclear palsy: a [18F]PI-2620 PET/MRI study.

PURPOSE: Progressive supranuclear palsy (PSP) is primary 4-repeat tauopathy. Evidence spanning from imaging studies indicate aberrant connectivity in PSPs. Our goal was to assess functional connectivity network alterations in PSP patients and the potential link between regional tau-burden and network-level functional connectivity using the next-generation tau PET tracer [18F]PI-2620 and resting-state functional MRI (fMRI). MATERIAL AND METHODS: Twenty-four probable PSP patients (70.9 ± 6.9 years, 13 female), including 14 Richardson syndrome (RS) and 10 non-RS phenotypes, underwent [18F]PI-2620 PET/MRI imaging. Distribution volume ratios (DVRs) were estimated using non-invasive pharmacokinetic modeling. Resting-state fMRI was also acquired in these patients as well as in thirteen older non-AD MCI reference group (64 ± 9 years, 4 female). The functional network was constructed using 141 by 141 region-to-region functional connectivity metrics (RRC) and network-based statistic was carried out (connection threshold p < 0.001, cluster threshold pFDR < 0.05). RESULTS: In total, 9870 functional connections were analyzed. PSPs compared to aged non-AD MCI reference group expressed aberrant connectivity evidenced by the significant NBS network consisting of 89 ROIs and 118 connections among them (NBS mass 4226, pFDR < 0.05). Tau load in the right globus pallidus externus (GPe) and left dentate nucleus (DN) showed significant effects on functional network connectivity. The network linked with increased tau load in the right GPe was associated with hyperconnectivity of low-range intra-opercular connections (NBS mass 356, pFDR < 0.05), while the network linked with increased tau load in the left cerebellar DN was associated with cerebellar hyperconnectivity and cortico-cerebellar hypoconnectivity (NBS mass 517, pFDR < 0.05). CONCLUSIONS: PSP patients show altered functional connectivity. Network incorporating deep gray matter structures demonstrate hypoconnectivity, cerebellum hyperconnectivity, while cortico-cortical connections show variable changes. Tau load in the right GPe and left DN is associated with functional networks which strengthen low-scale intra-opercular and intra-cerebellar connections and weaken opercular-cerebellar connections. These findings support the concept of tau load-dependent functional network changes in PSP, by that providing evidence for downstream effects of neuropathology on brain functionality in this primary tauopathy.

[Skull base metastases with cranial nerve deficits : Clinical profile of a severe disease]. / Schädelbasismetastasen mit Hirnnervenaffektionen : Klinischer Steckbrief einer schwerwiegenden Erkrankung.

BACKGROUND AND PURPOSE: Skull base metastases are a severe complication of various malignant tumors. If cranial nerves are involved even small lesions can cause significant symptoms. Specific clinical characteristics like neurological symptoms, associated primary tumors, prognosis and optimal treatment are poorly defined and are systematically described in this article. METHODS: In a monocentric retrospective study patients with skull base metastases and cranial nerve deficits who received treatment between 2006 and 2018 were analyzed concerning clinical characteristics at initial diagnosis, treatment and course of the disease. RESULTS: In this study 45 patients with skull base metastases and cranial nerve deficits were included. The most frequent primary tumors were prostate cancer (27%), breast cancer (22%) and multiple myeloma (16%). The most involved cranial nerves were trigeminal nerve (42%), oculomomotor nerve (33%) and facial nerve (27%). Of the patients 84% had additional bone metastases outside the skull base. Dural infiltration or meningeal carcinomatosis were each observed in 13% of the patients. After radiotherapy cranial nerve deficits remained stable in 61% of all cases and in 22% symptoms improved. Median overall survival from treatment was 8 months (range 0.4-51 months). Patients with dose-escalated radiotherapy appeared to live longer (16.4 months vs. 4.7 months). This effect persisted in a multivariate analysis including the Karnofsky index, number of metastases, primary tumor and radiation dose (HR 0.37, p = 0.02). CONCLUSION: Skull base metastases with cranial nerve deficits are complex diseases with poor prognosis. Precise diagnosis and treatment are required. Further research is needed to improve treatment.

A novel technique for the measurement of CBF and CBV with robot-arm-mounted flat panel CT in a large-animal model.

BACKGROUND AND PURPOSE: Endovascular therapy is an emerging treatment option in patients with acute ischemic stroke and especially in cases presenting late after symptom onset. Information about remaining viable tissue as measured with perfusion imaging is crucial for proper patient selection. The aim of this study was to investigate whether perfusion imaging with C-arm CT in the angiography suite is feasible and provides measurements comparable with ones made by CTP. MATERIALS AND METHODS: The MCA was occluded surgically in 6 sheep. Perfusion studies were performed before surgery, immediately after, and at 3 hours after MCA occlusion by using a robotic flat panel detector C-arm angiographic system. For comparison, conventional CTP was performed at the same time points. Two different protocols with the C-arm CT were tested. Images were analyzed by 2 readers with regard to the presence and size of perfusion abnormalities. RESULTS: With C-arm CT, perfusion abnormalities were detected with a high sensitivity and specificity when vessel occlusion was confirmed by criterion standard DSA. No difference was found between lesions sizes measured with the 2 C-arm CT protocols and CTP. Growth of the CBV lesions with time was captured with C-arm CT and CTP. CONCLUSIONS: In this small study, it was feasible to qualitatively measure CBV and CBF by using a flat panel detector angiographic system.

[Comparison of four digital and one conventional radiographic image systems for the chest in a patient study with subsequent system optimization]. / Vergleich von vier digitalen und einem konventionellen Röntgenaufnahmesystem für den Thorax mittels einer Patientenstudie mit nachfolgender Systemoptimierung.

PURPOSE: Using a patient study to prove the clinical relevance of a comparison of five different radiographic systems for the chest conducted with an anthropomorphic chest phantom. Depending on the results, it was tested whether the performance of a modern digital system with a transparent imaging plate can be improved by changing the post-processing of the image. METHOD: Chest radiographs of patients were taken with a CsI/aSi-flat panel detector (FDR), transparent imaging plate (tDLR), selenium drum detector (DSR), conventional storage phosphor plate (DLR) and asymmetrical screen-film-system (aFFS), and compared using image criteria scoring (ICS) and visual grading analysis (VGA) for anatomical structures (modified criterions of the EUR 16 260 EN guidelines). After optimizing the post processing, the images of the tDLR-system were evaluated once more in a phantom ROC study and patient VGA study. RESULTS: The flat panel detector-system proved to meet best the anatomical image quality criteria, followed by DSR, tDLR, aFFS and DLR. The modified post processing of the tDLR-images resulted in a significantly better detection of simulated pathological lung-structures, but improved the perceptibility of anatomical structures only slightly. CONCLUSIONS: The results of the patient VGA study and the phantom ROC study are similar and considered valid. The new digital imaging systems with flat panel detector and transparent imaging plate provide the best image quality of the tested radiographic devices for chest imaging, assuming that all system components are attuned and optimized for the type of structure to be detected. Image processing is of primary importance for system optimization.

Pineal epidermoid coinciding with pineocytoma.

Tumours of the pineal region are uncommon. We report on a 62-year-old male presenting with Parinaud's syndrome and aqueduct stenosis caused by a cystic tumour in the pineal region. During surgery, adjacent to the cystic tumour, a second smaller tumour was identified, which was clearly separate from the first tumour and from the pineal gland. Histological examination disclosed the cystic tumour as an epidermoid cyst, whereas the second tumour demonstrated histological and immunohistochemical features of a pineocytoma. The unique finding of two different types of tumours in the pineal region is evaluated with regard to the histogenesis of epidermoid cysts and pineocytomas.

Mitochondrial DNA as a clonal tumor cell marker: gliomatosis cerebri.

The aim of this study was a clonal analysis of gliomatosis cerebri (GC), a rare disease characterized by diffuse, extensively infiltrating glial tumors of the central nervous system. Two females of the series were not informative in assays for X-chromosomal inactivation, and a polycytosine tract of the mitochondrial DNA (mtDNA) was tested as a clonal marker. Following fluorescent PCR, a fraction of human individuals shows several electrophoretic bands in normal tissues, some of which can be lost in corresponding glial tumors. Two male patients of our series fulfilled this prerequisite and were thus informative. In patient 1, four tumor samples from the left temporal and occipital cortex, histologically corresponding to WHO grades III and IV, showed an identical loss of bands, which was not observed in tumor-free brain and in tumors from the left cerebellum, from fornix and corpus callosum, and from the right occipital cortex, corresponding to WHO grades III and IV. Since this patient exhibited a TP53 mutation in exon 7, we sequenced this exon in all tissue samples of this individual. The mutation was found selectively in the tumor samples with a loss of mtDNA bands. In patient 2, all tumors (histologically corresponding to WHO grade II) from putamen, thalamus, midbrain and right parietal cortex exhibited an identical loss of bands in the mtDNA analysis. Taken together, these results support that even distant tumors in a patient with GC can share a common clonal origin. They demonstrate the extraordinary mobility and infiltrative power of these tumor cells.

[Chest radiography: ROC phantom study of four different digital systems and one conventional radiographic system]. / Thoraxübersichtsaufnahme: ROC-Phantomstudie an vier verschiedenen digitalen und einemkonventionellen Röntgenaufnahmesystem.

PURPOSE: To compare the diagnostic quality of five different radiographic systems used in chest radiography for visualization of differently configured, clinically relevant pathologic pulmonary structures. MATERIALS AND METHODS: Four digital detector systems using as detection unit a CsI/aSi-based flat panel detector, a transparent imaging plate, a selenium detector and a conventional storage phosphor plate were analyzed for this study, as well as an asymmetrical film-screen system. The analyzed imaging material consisted of radiographs of an anthropomorphic chest-phantom with superimposed simulated pulmonary structures. The images were evaluated for different pathologic structures by a newly developed multiple structure ROC (ms-ROC). RESULTS: The performance of each system was found to have a strong structure-related variability. The flat panel detector system had the best overall performance. The theoretical advantage of the 4k-matrix of the transparent imaging plate over the 3k-matrix of the flat panel detector was only confirmed for reticular structures. CONCLUSIONS: In addition to comparing the image quality of the different systems, this study shows that the performance of a radiographic system depends on the structure to be analyzed. The modified ROC (ms-ROC) provides valid results with less effort.

[Optimized image processing with modified preprocessing of image data sets of a transparent imaging plate by way of the lateral view of the cervical spine]. / Optimierte Bildverarbeitung durch ein modifiziertes Pre-Processing von Bilddatensätzen eines transparenten Speicherfoliensystems am Beispiel der seitlichen HWS-Aufnahme.

PURPOSE: To improve the diagnostic quality of lateral radiographs of the cervical spine by pre-processing the image data sets produced by a transparent imaging plate with both-side reading and to evaluate any possible impact on minimizing the number of additional radiographs and supplementary investigations. MATERIAL AND METHODS: One hundred lateral digital radiographs of the cervical spine were processed with two different methods: processing of each data set using the system-imminent parameters and using the manual mode. The difference between the two types of processing is the level of the latitude value. Hard copies of the processed images were judged by five radiologists and three neurosurgeons. The evaluation applied the image criteria score (ICS) without conventional reference images. RESULTS: In 99 % of the lateral radiographs of the cervical spine, all vertebral bodies could be completed delineated using the manual mode, but only 76 % oft the images processed by the system-imminent parameters showed all vertebral bodies. Thus, the manual mode enabled the evaluation of up to two additional more caudal vertebral bodies. The manual mode processing was significantly better concerning object size and processing artifacts. This optimized image processing and the resultant minimization of supplementary investigations was calculated to correspond to a theoretical dose reduction of about 50 %. CONCLUSION: The introduction of optimized organ programs for the upper and lower cervical spine based on the 12-bit data of the images should improve the evaluation of the lateral radiograph of the cervical spine without reducing the latitude value.

Gliomatosis cerebri: post-mortem molecular and immunohistochemical analyses in a case treated with thalidomide.

Gliomatosis cerebri (GC) is a rare tumor of the central nervous system (CNS) characterized by widespread diffuse infiltration of the brain and spinal cord by neoplastic glial cells. We report the case of a 17-year-old boy with a bioptically diagnosed fibrillary astrocytoma. The administration of thalidomide, which was suggested to be beneficial in the treatment of human cancers, had no substantial clinical effect on our patient. Autopsy studies revealed a diffuse infiltration of the frontal and temporal lobes of the right hemisphere, brainstem, and the leptomeninges covering the whole spinal cord by an astrocytic tumor, which showed features both of low-grade astrocytoma and glioblastoma multiforme. No mutations in the p53 and PTEN tumor suppressor genes were found; immunoreactivities for p53, PTEN, and EGFR could not be detected.

MGMT- and P450 3A-inhibitors do not sensitize glioblastoma cell cultures against nitrosoureas.

UNLABELLED: AIM, MATERIAL AND METHODS: Using RT-PCR and immunohistochemistry the expression of cytochrome P450 was evaluated in a series of 22 glioblastomas and 4 anaplastic astrocytomas (WHO grade III). Since rat liver P450 can catalyze the denitrosation of the nitrosourea compound BCNU in vitro, cell culture experiments were performed to test a possible sensitizing effect of P450 3A inhibitors (tiamulin and ketoconazole) in BCNU treatment of glial tumor cells. O6-benzylguanine (BG), an inhibitor of the DNA repair enzyme O6-methylguanine-DNA-methyltransferase (MGMT), was used in parallel experiments, since MGMT is discussed as a main mechanism in nitrosourea resistance. RESULTS: RT-PCR reactions with primers designed according to the sequences for CYP1A1 and CYP2E1 were always positive, while those for CYP1A2 and CYP2D6 were negative. The strongest PCR products were detected with CYP3A primers, but CYP3A expression was heterogeneous within the tumor samples. Antibodies to human liver CYP3A4 stained a subfraction of tumor cells (18% of the cells in glioblastomas and 14% in grade III astrocytomas) and to some extend neurons in normal brain areas, while astrocytes were negative. For cell culture experiments with P450 3A and MGMT inhibitors, early passages of 3 glioblastomas, a late passage of an immortalized cell line derived from a reoccurring glioblastoma, and the human glioblastoma line LN405 were used. The sensitivity of the tumor cells for both nitrosourea compounds was very low, when low concentrations were applied (comparable to the achievable blood concentrations in glioma patients). Strong effects did only occur when the concentrations were raised 9-fold or 27-fold. CONCLUSION: In no case could a significant sensitizing effect of P450 3A- and MGMT inhibitors be demonstrated.