Jakob Matschke

Allelic Losses at 1p, 9q, 10q, 14q, and 22q in the Progression of Aggressive Meningiomas and Undifferentiated Meningeal Sarcomas

Meningiomas are usually benign tumors; however, they can recur after surgical resection and occasionally show histological progression to a higher malignancy grade. Five such rare cases of aggressively recurring meningiomas were present in our departmental cohort of 923 primary meningeal neoplasms operated over a 17-year period. Four other aggressively recurring meningeal tumors with a very similar clinical and histomorphological appearance (three undifferentiated meningeal sarcomas, one hemangiopericytoma) was also included in this study. We investigated whether disease progression can be traced by genetic alterations and whether a pattern of genetic alterations is specific for meningiomas. A total of 40 specimens from primary tumors and multiple recurrences of the nine patients were analyzed with 26 polymorphic allelic markers for deletions on 1p, 1q, 9q, 10q, 14q, and 22q. Loss of heterozygosity (LOH) at 22q was observed in all meningiomas cases at the earliest time point analyzed. Allelic loss at 1p was seen in the original tumor in two cases and upon meningioma recurrence in two others. Deletion on 10q occurred during tumor progression in two cases, and on 9q and 14q in one case. While allelic loss at 22q appears to be an early event in aggressive meningioma disease, there is a clear correlation of further deletions on chromosome arms 1p, 9q, 10q, and 14q with histopathological and clinical progression, as shown in these intraindividual trackings. None of these genetic findings were present in the non-meningiomatous meningeal tumors, indicating that meningothelial cells have their own lineage-specific genetic pathways towards clinical malignancy.

Hematogenous dissemination of glioblastoma multiforme

Hematogenous spread of glioblastoma multiforme (GBM) might be responsible for reported extracranial metastases and transmission of GBM by organ transplantation. Circulating Brain Tumor Cells Glioblastoma multiforme is an aggressive brain tumor that is most common in adults. It was generally thought that glioblastoma could not metastasize outside the central nervous system, and patients were even allowed to serve as organ donors. However, some reports of glioblastoma transmission through transplanted organs prompted researchers to reconsider this idea. Now, Müller et al. report that about 20% of glioblastoma patients have circulating tumor cells in their blood, suggesting that these patients should not serve as organ donors and offering new insights into the biology of this generally incurable disease. Glioblastoma multiforme (GBM) is the most frequent and aggressive brain tumor in adults. The dogma that GBM spread is restricted to the brain was challenged by reports on extracranial metastases after organ transplantation from GBM donors. We identified circulating tumor cells (CTCs) in peripheral blood (PB) from 29 of 141 (20.6%) GBM patients by immunostaining of enriched mononuclear cells with antibodies directed against glial fibrillary acidic protein (GFAP). Tumor cell spread was not significantly enhanced by surgical intervention. The tumor nature of GFAP-positive cells was supported by the absence of those cells in healthy volunteers and the presence of tumor-specific aberrations such as EGFR gene amplification and gains and losses in genomic regions of chromosomes 7 and 10. Release of CTCs was associated with EGFR gene amplification, suggesting a growth potential of these cells. We demonstrate that hematogenous GBM spread is an intrinsic feature of GBM biology.

Autoantibodies against β-Amyloid Are Common in Alzheimer's Disease and Help Control Plaque Burden

Active or passive immunization of Alzheimers disease (AD) patients leads to targeting of β‐amyloid plaques by immunoglobulins (IgG) and their subsequent removal by microglia. Here, we investigate whether naturally occurring autoantibodies to β‐amyloid contribute to β‐amyloid plaque removal in nonimmunized AD patients.

High molecular mass assemblies of amyloid-β oligomers bind prion protein in patients with Alzheimer’s disease

Alzheimers disease is the most common form of dementia and the generation of oligomeric species of amyloid-β is causal to the initiation and progression of it. Amyloid-β oligomers bind to the N-terminus of plasma membrane-bound cellular prion protein (PrP(C)) initiating a series of events leading to synaptic degeneration. Composition of bound amyloid-β oligomers, binding regions within PrP(C), binding affinities and modifiers of this interaction have been almost exclusively studied in cell culture or murine models of Alzheimers disease and our knowledge on PrP(C)-amyloid-β interaction in patients with Alzheimers disease is limited regarding occurrence, binding regions in PrP(C), and size of bound amyloid-β oligomers. Here we employed a PrP(C)-amyloid-β binding assay and size exclusion chromatography on neuropathologically characterized Alzheimers disease and non-demented control brains (n = 15, seven female, eight male, average age: 79.2 years for Alzheimers disease and n = 10, three female, seven male, average age: 66.4 years for controls) to investigate amyloid-β-PrP(C) interaction. PrP(C)-amyloid-β binding always occurred in Alzheimers disease brains and was never detected in non-demented controls. Neither expression level of PrP(C) nor known genetic modifiers of Alzheimers disease, such as the PrP(C) codon 129 polymorphism, influenced this interaction. In Alzheimers disease brains, binding of amyloid-β to PrP(C) occurred via the PrP(C) N-terminus. For synthetic amyloid-β42, small oligomeric species showed prominent binding to PrP(C), whereas in Alzheimers disease brains larger protein assemblies containing amyloid-β42 bound efficiently to PrP(C). These data confirm Alzheimers disease specificity of binding of amyloid-β to PrP(C) via its N-terminus in a large cohort of Alzheimers disease/control brains. Differences in sizes of separated protein fractions between synthetic and brain-derived amyloid-β binding to PrP(C) suggest that larger assemblies of amyloid-β or additional non-amyloid-β components may play a role in binding of amyloid-β42 to PrP(C) in Alzheimers disease.

Molecular characterization of long-term survivors of glioblastoma using genome-and transcriptome-wide profiling

The prognosis of glioblastoma, the most malignant type of glioma, is still poor, with only a minority of patients showing long‐term survival of more than three years after diagnosis. To elucidate the molecular aberrations in glioblastomas of long‐term survivors, we performed genome‐ and/or transcriptome‐wide molecular profiling of glioblastoma samples from 94 patients, including 28 long‐term survivors with >36 months overall survival (OS), 20 short‐term survivors with <12 months OS and 46 patients with intermediate OS. Integrative bioinformatic analyses were used to characterize molecular aberrations in the distinct survival groups considering established molecular markers such as isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations, and O6‐methylguanine DNA methyltransferase (MGMT) promoter methylation. Patients with long‐term survival were younger and more often had IDH1/2‐mutant and MGMT‐methylated tumors. Gene expression profiling revealed over‐representation of a distinct (proneural‐like) expression signature in long‐term survivors that was linked to IDH1/2 mutation. However, IDH1/2‐wildtype glioblastomas from long‐term survivors did not show distinct gene expression profiles and included proneural, classical and mesenchymal glioblastoma subtypes. Genomic imbalances also differed between IDH1/2‐mutant and IDH1/2‐wildtype tumors, but not between survival groups of IDH1/2‐wildtype patients. Thus, our data support an important role for MGMT promoter methylation and IDH1/2 mutation in glioblastoma long‐term survival and corroborate the association of IDH1/2 mutation with distinct genomic and transcriptional profiles. Importantly, however, IDH1/2‐wildtype glioblastomas in our cohort of long‐term survivors lacked distinctive DNA copy number changes and gene expression signatures, indicating that other factors might have been responsible for long survival in this particular subgroup of patients.© 2014 UICC

Deposition of hyperphosphorylated tau in cerebellum of PS1 E280A Alzheimer's disease.

Early‐onset familial Alzheimers disease (AD) caused by presenilin‐1 mutation E280A (PS1‐E280A) presents wide clinical and neuropathological variabilities. We characterized clinically and neuropathologically PS1‐E280A focusing in cerebellar involvement and compared it with early‐onset sporadic Alzheimers disease (EOSAD). Twelve E280A brains and 12 matched EOSAD brains were analyzed for beta‐amyloid and hyperphosphorylated tau (pTau) morphology, beta‐amyloid subspecies 1–40, 1–42 levels, pTau levels, and expression of stress kinases in frontal cortex and cerebellum. The data were correlated to clinical and genetic findings. We observed higher beta‐amyloid load, beta‐amyloid 1–42 and pTau concentrations in frontal cortex of PS1‐E280A compared with EOSAD. High beta‐amyloid load was found in the cerebellum of PS1‐E280A and EOSAD patients. In PS1‐E280A, beta‐amyloid localized to the molecular and Purkinje cell layers, whereas EOSAD showed them in Purkinje and granular cell layers. Surprisingly, 11 out of 12 PS1‐E280A patients showed deposition of pTau in the cerebellum. Also, seven out of 12 PS1‐E280A patients presented cerebellar ataxia. We conclude that deposition of beta‐amyloid in the cerebellum is prominent in early‐onset AD irrespective of genetic or sporadic origin. The presence of pTau in cerebellum in PS1‐E280A underscores the relevance of cerebellar involvement in AD and might be correlated to clinical phenotype.

Hypoxia and oxygenation induce a metabolic switch between pentose phosphate pathway and glycolysis in glioma stem-like cells

Fluctuations in oxygen tension during tissue remodeling impose a major metabolic challenge in human tumors. Stem-like tumor cells in glioblastoma, the most common malignant brain tumor, possess extraordinary metabolic flexibility, enabling them to initiate growth even under non-permissive conditions. We identified a reciprocal metabolic switch between the pentose phosphate pathway (PPP) and glycolysis in glioblastoma stem-like (GS) cells. Expression of PPP enzymes is upregulated by acute oxygenation but downregulated by hypoxia, whereas glycolysis enzymes, particularly those of the preparatory phase, are regulated inversely. Glucose flux through the PPP is reduced under hypoxia in favor of flux through glycolysis. PPP enzyme expression is elevated in human glioblastomas compared to normal brain, especially in highly proliferative tumor regions, whereas expression of parallel preparatory phase glycolysis enzymes is reduced in glioblastomas, except for strong upregulation in severely hypoxic regions. Hypoxia stimulates GS cell migration but reduces proliferation, whereas oxygenation has opposite effects, linking the metabolic switch to the “go or grow” potential of the cells. Our findings extend Warburg’s observation that tumor cells predominantly utilize glycolysis for energy production, by suggesting that PPP activity is elevated in rapidly proliferating tumor cells but suppressed by acute severe hypoxic stress, favoring glycolysis and migration to protect cells against hypoxic cell damage.

Ocular pathology in shaken baby syndrome and other forms of infantile non-accidental head injury

Retinal and optic nerve sheath hemorrhages are an essential part of the various forms of inflicted neurotrauma in infants, especially in its most common variant, the shaken baby syndrome (SBS). Clinically, ophthalmologists play an important part for the diagnosis and further management of patients with SBS. For the forensic pathologist, a thorough understanding of the basic principles behind the morphological phenomena commonly encountered in the orbita is required. This review summarizes the present knowledge of ocular pathology in inflicted infantile neurotrauma, focusing strongly on SBS. Furthermore, a review of the most recent literature on the subject is given.

Association between Deposition of Beta-Amyloid and Pathological Prion Protein in Sporadic Creutzfeldt-Jakob Disease

Background: Alzheimer’s disease (AD) and prion diseases such as sporadic Creutzfeldt-Jakob disease (sCJD) share common features concerning their molecular pathogenesis and neuropathological presentation and the coexistence of AD and CJD in patients suggest an association between the deposition of the proteolytically processed form of the amyloid precursor protein, β-amyloid (Aβ), which deposits in AD, and the abnormal form of the prion protein, PrPSc, which deposits in sCJD. Methods: We have characterized sCJD patients (n = 14), AD patients (n = 5) and nondemented controls (n = 5) with respect to the deposition of PrPSc and Aβ morphologically, biochemically and genetically and correlated these findings to clinical data. Results: sCJD-diseased individuals with abundant deposits of Aβ present with a specific clinicopathological profile, defined by higher age at disease onset, long disease duration, a genetic profile and only minimal amounts of PrPSc in the cerebellum. Conclusion: The co-occurrence of pathological changes typical for sCJD and AD in combination with the inverse association between accumulation of Aβ and PrPSc in a subgroup of sCJD patients is indicative of common pathways involved in the generation or clearance of Aβ and PrPSc in a subgroup of sCJD patients.

Shaken baby syndrome: a common variant of non-accidental head injury in infants

BACKGROUND Recent cases of child abuse reported in the media have underlined the importance of unambiguous diagnosis and appropriate action. Failure to recognize abuse may have severe consequences. Abuse of infants often leaves few external signs of injury and therefore merits special diligence, especially in the case of non-accidental head injury, which has high morbidity and mortality. METHODS Selective literature review including an overview over national and international recommendations. RESULTS Shaken baby syndrome is a common manifestation of non-accidental head injury in infancy. In Germany, there are an estimated 100 to 200 cases annually. The characteristic findings are diffuse encephalopathy and subdural and retinal hemorrhage in the absence of an adequate explanation. The mortality can be as high as 30%, and up to 70% of survivors suffer long-term impairment. Assessment of suspected child abuse requires meticulous documentation in order to preserve evidence as well as radiological, ophthalmological, laboratory, and forensic investigations. CONCLUSIONS The correct diagnosis of shaken baby syndrome requires understanding of the underlying pathophysiology. Assessment of suspected child abuse necessitates painstaking clinical examination with careful documentation of the findings. A multidisciplinary approach is indicated. Continuation, expansion, and evaluation of existing preventive measures in Germany is required.