Ralf Schober

Optical properties of selected native and coagulated human brain tissues in vitro in the visible and near infrared spectral range

Medical laser applications require knowledge about the optical properties of target tissue. In this study, the optical properties of selected native and coagulated human brain structures were determined in vitro in the spectral range between 360 and 1100 nm. The tissues investigated included white brain matter, grey brain matter, cerebellum and brainstem tissues (pons, thalamus). In addition, the optical properties of two human tumours (meningioma, astrocytoma WHO grade II) were determined. Diffuse reflectance, total transmittance and collimated transmittance of the samples were measured using an integrating-sphere technique. From these experimental data, the absorption coefficients, the scattering coefficients and the anisotropy factors of the samples were determined employing an inverse Monte Carlo technique. The tissues investigated differed from each other predominantly in their scattering properties. Thermal coagulation reduced the optical penetration depth substantially. The highest penetration depths for all tissues investigated were found in the wavelength range between 1000 and 1100 nm. A comparison with data from the literature revealed the importance of the employed tissue preparation technique and the impact of the theoretical model used to extract the optical coefficients from the measured quantities.

MRI-guided LASER-induced interstitial thermotherapy of cerebral neoplasms

Objective Laser-induced interstitial thermotherapy (LITT) using a neodymium:yttrium aluminum garnet (Nd: YAG) laser is a new therapeutic approach in the treatment of brain tumors. The purpose of our study was to determine the value of MRI in monitoring LITT. Materials and Methods Eight patients with intracerebral tumors were treated with LITT. The light guide was inserted via an applicator sheath that was implanted stereotaxically with CT guidance. The laser irradiation was performed within the MR unit and monitored by repetitive measurements of a T1-weighted 2D-FLASH sequence. Results During therapy in all patients, typical changes of signal intensity were seen. A gradually increasing central zone of high signal intensity was surrounded by an increasing peripheral area of reduced signal intensity. The diameter of an enhancing rim at the outer border of the peripheral area after Gd-DTPA was considered as the total lesion size. The lesion size as determined on 2D-FLASH scans during LITT accounted for 88–100% (mean 93.5%) of total lesion size on T1-weighted images after Gd-DTPA acquired immediately after therapy. On T2-weighted images the signal intensities of the two zones were vice versa. Follow-up studies showed a decrease of total lesion size (15–87%). Conclusion Our results demonstrate that MRI is feasible and effective in monitoring LITT. However, the role of LITT in the therapeutic workup of brain tumors still has to be defined in future clinical studies.

Intraoperative MRI to guide the resection of primary supratentorial glioblastoma multiforme—a quantitative radiological analysis

Patients with supratentorial high-grade glioma underwent surgery within a vertically open 0.5-T magnetic resonance (MR) system to evaluate the efficacy of intraoperative MR guidance in achieving gross-total resection. For 31 patients, preoperative clinical data and MR findings were consistent with the putative diagnosis of a high-grade glioma, in 23 cases in eloquent regions. Tumor resections were carried out within a 0.5-T MR SIGNA SP/i (GE Medical Systems, USA). The resection of the lesion was carried out using fully MR compatible neurosurgical equipment and was stopped at the point when the operation was considered complete by the surgeon viewing the operation field with the microscope. We repeated imaging to determine the residual tumor volume only visible with MRI. Areas of tissue that were abnormal on these images were localized in the bed of resection by using interactive MR guidance. The procedure of resection, imaging control and interactive image guidance was repeated where necessary. Almost all tissue with abnormal characteristics was resected, with the exception of tissue localized in eloquent brain areas. The diagnosis of glioblastoma was confirmed in all 31 cases. When comparing the tumor volume before resection and at the point where the neurosurgeon would otherwise have terminated surgery (“first control”), residual tumor tissue was detectable in 29/31 patients; the mean residual tumor volume was 30.7±24%. After repeated resections under interactive image guidance the mean residual tumor volume was 15.1%. At this step we found tumor remnants only in 20/31 patients. The perioperative morbidity (12.9%) was low. Twenty-seven patients underwent sufficient postoperative radiotherapy. We found a significant difference (logrankp=0.0037) in the mean survival times of the two groups with complete resection (n=10, median survival time 537 days) and incomplete resection (n=17, median survival time 237 days). The resection of primary glioblastoma multiforme under intraoperative MR guidance as demonstrated is a possibility to achieve a more complete removal of the tumor than with conventional techniques. In our small but homogeneous patient group we found an increase in the median survival time in patients with MRI for complete tumor resection, and the overall surgical morbidity was low.

Alzheimer-related τ-pathology in the perforant path target zone and in the hippocampal stratum oriens and radiatum correlates with onset and degree of dementia

Abnormal phosphorylation of the tau-protein is regarded as a crucial step in the formation of neurofibrillary tangles in the neuronal cell body and neuropil threads in dendrites. We studied the effects of tau-pathology on the clinical expression of dementia in 106 autopsy cases in the entorhinal region, the hippocampal stratum oriens, the stratum radiatum, and the perforant path target zone. The first cytoskeletal lesions were located in the perikarya and dendrites of the pre-alpha cells of the transentorhinal and entorhinal region. Next, abnormally phosphorylated tau-protein (PHF-tau) was found in the neuropil of the CA1-subiculum region. Thereafter, the stratum radiatum and stratum oriens began to be involved in PHF-tau pathology in Braak stage II. In the Braak stages IV and V, the stratum radiatum was completely involved, the stratum oriens increasingly so. Beginning in Braak stage III, we noted cases having PHF-tau pathology in the perforant path target zone of the outer molecular layer of the dentate gyrus. The increase of this pathology with ever greater involvement on the part of the entorhinohippocampal circuit correlated significantly not only with the Braak stages and with the neurochemically determined hippocampal content of PHF-tau but also with the degree of dementia as defined by the clinical dementia rating (CDR) scale. The affection of the stratum oriens in combination with PHF-tau pathology in the stratum radiatum and in the outer molecular layer of the dentate gyrus was encountered almost exclusively in demented individuals (CDR 1-3). These results indicate that axonal PHF-tau pathology in hippocampal pathways presumably is critical for the clinical expression of dementia and may constitute an anatomical substrate of clinically verifiable memory dysfunction in Alzheimers disease.

In vivo detection limits of magnetically labeled embryonic stem cells in the rat brain using high-field (17.6 T) magnetic resonance imaging.

Stem cell transplantation is a promising therapeutic approach for several neurological disorders. However, it has yet to fulfill its high expectations, partially due to the lack of a reliable noninvasive method for monitoring the biodistribution of the grafted stem cells in vivo. We have used high-resolution magnetic resonance imaging (MRI) at 17.6 T, combined with efficient magnetic labeling of the stem cells with iron oxide nanoparticles, in order to assess the in vivo detection limit in small animal models. Injection of different concentrations of magnetically labeled stem cells in gel phantoms led to significant reductions in image intensity from small cellular clusters of less than 10 cells. To determine the detection limit in vivo, various numbers of both labeled and unlabeled cells were injected stereotactically into the striatum of rats. Significant hypointense signal changes were observed for 100 labeled cells. After injection of approximately 20 labeled cells, signal reduction at the injection site was observed but could not be assigned unambiguously to the cells. Our results show that high-field MRI allows tracking of a minimal number of cells in vivo, well below the number used in previous studies, opening the possibility of gaining new insights into cell migration and differentiation.

Minor Tumour Shrinkage in Nonfunctioning Pituitary Adenomas by Long-Term Treatment with the Dopamine Agonist Cabergoline

AbstractObjective: The purpose of this study was to define safety and efficacy of medical therapy in the treatment of nonfunctioning pituitary tumours. Design: We studied thirteen patients with a clinically nonfunctioning pituitary macroadenoma for response to cabergoline treatment for 1 year. Twelve/13 patients were already operated and had residual or recurrent tumours. Methods: We determined the outcome of treatment by visual perimetry, computed tumour size measurement in MRI and hormonal response (changes in pituitary function, reduction of α-subunit). Results: Seven/13 patients on cabergoline had a tumour shrinkage above 10% of the initial tumour volume. In 4 patients, this tumour shrinkage was correlated to an increasing distance of the tumour to the optic chiasm. Only 2/9 patients with visual field defects before therapy showed improvements in visual acuity under cabergoline. No significant side effects of the therapeutical regimens were observed. Neither LH and/or FSH expression in the tumour cells nor the reduction of the α-subunit serum levels by medical therapy was correlated to tumour shrinkage. Conclusion: Given that these patients had advanced disease which makes it difficult to find significant therapeutic effects, medical therapy with potent dopamine agonists such as cabergoline may evolve as a novel therapeutic option in a subgroup of patients with clinically nonfunctioning tumours declining operation and radiotherapy.

Progression of neurofibrillary changes and PHF-τ in end-stage Alzheimer’s disease is different from plaque and cortical microglial pathology

In terminal Alzheimers disease (AD) the frequency of plaques was found to be reduced in single cases. To test this finding in a larger sample, and in order to determine whether the number of plaques labeled with different markers and the distribution of neurofibrillary tangles are correlated positively to each other and to the degree of dementia, a sample of 134 autopsy brains with and 15 without AD-related pathology has been examined. All of the cases were staged according to Braak and Braak. Both the frequency of plaques immunopositive for beta-amyloid, amyloid precursor protein, and apolipoprotein E and that of microglial cells in the cortex and in the white matter were determined semiquantitatively. The content and distribution of PHF-tau was ascertained by ELISA and immunohistochemistry. Both the clinical dementia rating and the global deterioration scale were used as clinical parameters retrospectively. Correlation coefficients were calculated for all parameters and differences were evaluated statistically. With progressive distribution of neurofibrillary tangles and increasing content of PHF-tau the plaque stages and the degree of cortical microglia reaction increased up to the Braak-stages IV and V, thereafter showing a slightly decreasing tendency in the investigated regions. In end-stage AD resorption of beta-amyloid seems to surpass its deposition. The microglial reaction in the white matter correlated neither with the Braak-stage nor with the accumulation of amyloid. With regard to the degree of dementia, both scales correlated well with the pathological changes. Our data show that neuronal cytoskeletal alterations progressively increase with progressive dementia until the end stage of AD in contrast to the frequencies of plaques and cortical microglial cells, and are therefore preferable for staging purposes.

Laser-induced thermotherapy of neoplastic lesions in the brain – underlying tissue alterations, MRI-monitoring and clinical applicability

SummaryLaser-induced thermotherapy (LITT) is a minimally invasive neurosurgical approach to the stereotactic treatment of brain tumors in poorly accessible regions. Its clinical applicability has been shown in several experimental and clinical studies under on-line monitoring by magnetic resonance imaging (MRI). This review characterizes LITT as an alternative neurosurgical approach with specific focus on the typical histological alterations and ultrastructural cellular changes following laser irradiation in the central nervous system. The spatial and temporal pattern of these changes is discussed in their relevance to the neurosurgical treatment of neoplastic lesions using LITT.

The subunits of α2-macroglobulin receptor/low density lipoprotein receptor-related protein, native and transformed α2-macroglobulin and interleukin 6 in Alzheimer's disease

Abstract To explore the role of α2-macroglobulin receptor/low density lipoprotein receptor-related protein (α2M-R/LRP) and its ligands in the pathogenesis of Alzheimers disease (AD), antibodies were raised against its α- and β-subunits and their expression pattern in the CNS in AD and control cases was correlated with that of native and transformed α2-macroglobulin (α2M) and interleukin 6 (IL-6). The transmembranous β-subunit of α2M-R/LRP and transformed α2M were found in plaque cores in AD. Extramembranous α-subunit and native α2M immunoreactivities were localized in activated plaque-associated astrocytes and extracellulary in plaques. IL-6 immunostaining was associated with neurofibrillary changes, and was also found extracellularly in the center of plaques and in microglial cells. Our finding that plaque cores contain a second transmembranous protein fragment, the β-subunit of α2M-R/LRP, suggests ongoing membrane-protein degradation. By altering clearance and scavenger-like functions, fragmentation and breakdown of α2M-R/LRP may have an important role in extracellular amyloid deposition and the formation of neurofibrillary tangles in AD.

Advanced approach for intraoperative MRI guidance and potential benefit for neurosurgical applications.

To present an advanced approach for intraoperative image guidance in an open 0.5 T MRI and to evaluate its effectiveness for neurosurgical interventions by comparison with a dynamic scan‐guided localization technique.