Prognostic differences and implications on treatment strategies between butterfly glioblastoma and glioblastoma with unilateral corpus callosum infiltration

Approximately 25% of glioblastomas show at diagnosis a corpus callosum infiltration, which is associated with poor prognosis. The extent of corpus callosum involvement, however, ranges from partial unilateral to complete bilateral infiltration. The role of surgery in glioblastoma with corpus callosum involvement is controversial. In this study, we aimed to examine prognostic differences between glioblastoma with unilateral and glioblastoma with bilateral corpus callosum infiltration, and to evaluate possible treatment strategy implications. Patients with newly diagnosed glioblastoma from 2010 to 2019 were included. Corpus callosum infiltration was assessed in contrast-enhanced T1-weighted preoperative magnetic resonance imaging. Extent of resection, adjuvant treatments and overall survival were evaluated. Corpus callosum involvement was found in 96 (26.4%) out of 363 patients with newly diagnosed glioblastoma. Bilateral corpus callosum infiltration was found in 27 out of 96 patients (28%), and 69 patients had unilateral corpus callosum infiltration. Glioblastoma with corpus callosum affection had significantly lower median overall survival compared to glioblastoma without corpus callosum involvement (9 vs. 11 months, p = 0.02). A subgroup analysis of glioblastoma with unilateral corpus callosum infiltration revealed a significant difference in median overall survival dependent on extent of resection (6.5 without gross total resection vs. 11 months with gross total resection, Log-rank test p = 0.02). Our data confirms a shorter overall survival in glioblastoma subpopulation with corpus callosum involvement, especially for glioblastoma with bilateral corpus callosum infiltration. However, patients with partial corpus callosum infiltration undergoing gross total resection exhibited a significant survival benefit compared to their counterparts without gross total resection. Whenever reasonably achievable gross total resection should be considered as an integral part of the treatment strategy in glioblastoma with partial corpus callosum infiltration

Astrocyte and oligodendrocyte dynamics in central pontine myelinolysis

Introduction: Astrocytopathy is known to be an early feature of different neuroinflammatory diseases. However, the impact of astrocyte loss and repopulation on the development and progression of demyelinating lesions in complex etiologies, such as multiple sclerosis, is difficult to determine. To more easily analyse astrocyte- oligodendrocyte-interactions during lesion formation and progression in the human brain, diseases like Central pontine myelinolysis (CPM) can be used as a less complex model of demyelinating disorders. CPM is a rare neurological condition characterized by damage to the myelin sheath of pontine nerves after osmotic shifts in serum. Astrocytopathy is regarded to be the first event in the pathogenesis of CPM lesions. Methods: Histological investigation of autopsy tissue from human CPM patients was performed. Lesions were staged considering the myelination and the appearance of different astrocyte subtypes, which was used to judge behaviour of the astrocytic compartment. Further, dynamics of oligodendrocyte loss and repopulation were analysed and compared to the astrocytic repopulation. Results: Early-staged lesions were largely demyelinated and showed an overall reduction of astrocyte densities. The few astrocytes present showed a bipolar morphology and were APQ4-negative, indicating an immature state. Intermediate- stage lesions were still largely demyelinated, but had increased overall densities of astrocytes, which did not yet reflect densities observed in the perilesion. Astrocytes appeared mostly ramified and AQP4-positive, indicating maturity. Nevertheless, bipolar astrocytes were still observable, indicating that repopulation was not yet finalized. Late-stage CPM-lesions were at least partially remyelinated. Astrocytes were detectable in overall densities comparable to the perilesion and showed a ramified (or even reactive morphology), as well as regular expression of AQP4. Investigating the oligodendrocytes, intralesional densities were reduced in early- and intermediate-stage lesions when compared to the perilesion. Re-increase in oligodendrocyte densities was first observable in late-stage lesions, but did not reach perilesional levels. Conclusion: The study at hand indicates that the recovery of demyelinated osmolyte- induced pontine lesions follows a distinct time-course. Repopulation of the lesion with oligodendrocytes is not carried out until lesions are completely repopulated with functional resident astrocytes, as indicated by the ramified morphology and the expression of AQP4. Further studies will be needed to determine, whether the appearance of immature astrocytes, indicating an ongoing repopulation of lesions with astrocytes, correlates with an inefficient repair of demyelinated lesions.:List of Abbreviations.................................................................................................................6 1 Introduction................................................................................................................7 1.1 Osmotic Demyelinating Syndrome......................................................................... 7 1.2 Clinical manifestation............................................................................................. 9 1.3 Diagnosis and Management of CPM.....................................................................11 1.4 Aetiology of Central Pontine Myelinolysis.................................. ......................... 14 1.5 The brain, its adaptation to hyponatraemia and response to correction – pathophysiology of CPM............................................................................................16 1.6 Pathology of myelin............................................................................................. 19 1.6.1 Astrocytopathy and oligodendrocytopathy.................................................................................................20 1.7 Aims of the study................................................................................................. 23 2 Material und Methods............................................................................................. 24 2.1 Patient tissue........................................................................................................ 24 2.2 Histology and immunohistochemistry................................................................................................24 2.2.1 Basic concepts........................................................................................... ......24 2.2.2 Hematoxylin and Eosin (HE)............................................................................. 26 2.2.3 Luxol Fast Blue/ Periodic Acid Schiff stain........................................................27 2.2.4 Immunohistochemistry. Application and Protocol.............................................28 2.3 Implementation.................................................................................................... 31 2.4 Estimation of demyelination................................................................................. 32 2.5 Analysis of cell density and proliferation.............................................................. 32 2.6 Data plotting and statistical analysis.................................................................... 32 3 Results..................................................................................................................... 33 3.1 Patient cohort....................................................................................................... 33 3.2 Characteristics of demyelination.......................................................................... 35 3.3 CPM lesion and disease staging.......................................................................... 37 3.4 Astrocytes within human CPM lesions................................................................. 42 3.4.1 Astrocyte densities are decreased in early CPM lesions....................................42 3.4.2 Astrocytes in CPM– morphological distinctions.................................................45 3.5 Oligodendrocyte densities within human CPM lesions.........................................48 3.6 Macrophages and activated microglia.................................................................. 54 3.6.1 KiM1P – a marker for infiltrating macrophages and activated microglia............54 3.6.2 Proliferating Iba1+ cells are observed in all lesion stages..................................58 4 Discussion................................................................................................................ 61 4.1 Lesion Staging...................................................................................................... 61 4.2 Astrocytes in the pathogenesis of CPM............................................................... 65 4.3 Oligodendrocyte pathology in CPM..................................................................... 69 4.4 Mechanisms of regeneration in human CPM lesions............................................72 4.5 Summary, interpretation and limitations of our study............................................78 5 Conclusion and Outlook.......................................................................................... 80 6 Bibliography............................................................................................................. 82 7 List of Tables.............................................................................................................91 8 List of Figures.......................................................................................................... 92 9 Appendix.................................................................................................................. 94 9.1 Declaration of Authenticity.....................................................................................94 9.2 Acknowledgements...............................................................................................9

Lack of astrocytes hinders parenchymal oligodendrocyte precursor cells from reaching a myelinating state in osmolyte-induced demyelination

Demyelinated lesions in human pons observed after osmotic shifts in serum have been referred to as central pontine myelinolysis (CPM). Astrocytic damage, which is prominent in neuroinflammatory diseases like neuromyelitis optica (NMO) and multiple sclerosis (MS), is considered the primary event during formation of CPM lesions. Although more data on the effects of astrocyte-derived factors on oligodendrocyte precursor cells (OPCs) and remyelination are emerging, still little is known about remyelination of lesions with primary astrocytic loss. In autopsy tissue from patients with CPM as well as in an experimental model, we were able to characterize OPC activation and differentiation. Injections of the thymidine-analogue BrdU traced the maturation of OPCs activated in early astrocyte-depleted lesions. We observed rapid activation of the parenchymal NG