Publications by authors named "Kathy Keyvani"

86 Publications

Report of a fulminant anti-pan-neurofascin-associated neuropathy responsive to rituximab and bortezomib.

J Peripher Nerv Syst 2021 Sep 5. Epub 2021 Sep 5.

Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.

Inflammatory neuropathies with pathogenic involvement of the nodes of Ranvier through autoantibodies have been increasingly characterized in the past years. The so-called anti-pan-NF-associated neuropathies caused by the simultaneous existence of anti-Neurofascin-186/-140 and -155-antibodies are extremely rare and cause life-threatening symptoms. Therapeutic strategies are needed as symptoms may be life-threatening and may not respond to standard first-line CIDP treatment. We report a case of a 52-year-old male with a rare anti-pan-neurofascin (NF) (-155, -186/-140)-associated neuropathy. The initial presentation was subacute with mild paresthesia leading to a fulminant "locked-in"-like syndrome requiring mechanical ventilation within the first eight weeks despite treatment with intravenous immunoglobulins. Nerve conduction studies revealed non-excitable nerves with acute spontaneous activity in electromyography. High titers of anti-Neurofascin-155, -186/-140-antibodies were detected in serum and cerebrospinal fluid. A combination of aggressive immunotherapy consisting of intravenous immunoglobulins, plasma exchange, rituximab and bortezomib resulted in clinical improvement with ambulation and non-detectable anti-neurofascin-antibodies within the following 3 months. The follow-up nerve conduction studies showed normalized amplitudes of the peripheral nerves with signs of reinnervation in electromyography. We conclude that an early aggressive immunotherapy consisting of a combination of rituximab and bortezomib could be considered as a therapeutic option for anti-pan-NF-associated neuropathies.
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http://dx.doi.org/10.1111/jns.12465DOI Listing
September 2021

Case Report: Pseudomeningeosis and Demyelinating Metastasis-Like Lesions From Checkpoint Inhibitor Therapy in Malignant Melanoma.

Front Oncol 2021 15;11:637185. Epub 2021 Apr 15.

Department of Neurology, Division of Clinical Neurooncology, University Hospital Essen, Essen, Germany.

Immune checkpoint inhibitors (ICIs) have considerably expanded the effective treatment options for malignant melanoma. ICIs revert tumor-associated immunosuppression and potentiate T-cell mediated tumor clearance. Immune-related neurologic adverse events (irNAEs) manifest in the central (CNS) or peripheral nervous system (PNS) and most frequently present as encephalitis or myasthenia gravis respectively. We report on a 47-year old male patient with metastatic melanoma who developed signs of cerebellar disease five weeks after the start of ICI treatment (ipilimumab and nivolumab). Magnetic resonance imaging (MRI) of the brain and spine revealed multiple new contrast enhancements suggestive of parenchymal and leptomeningeal metastasis. Cerebral spinal fluid (CSF) evaluation showed a lymphomononuclear pleocytosis in the absence of tumor cells. Subsequent stereotactic brain biopsy confirmed demyelinating disease. High-dose corticosteroid treatment resulted in immediate improvement of the clinical symptoms. MRI scans and CSF re-evaluation were conducted six weeks later and showed a near-complete remission. The strong resemblance to neoplastic CNS dissemination and irNAEs is a particularly difficult diagnostic challenge. Treating physicians should be aware of irNAEs as those can be effectively treated with high-dose steroids.
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http://dx.doi.org/10.3389/fonc.2021.637185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081911PMC
April 2021

Leptomeningeal disease from melanoma-Poor prognosis despite new therapeutic modalities.

Eur J Cancer 2021 05 28;148:395-404. Epub 2021 Mar 28.

Department of Dermatology, Essen University Hospital, West German Cancer Center, University of Duisburg-Essen and the German Cancer Consortium (DKTK), University of Duisburg-Essen, Essen, Germany. Electronic address:

Objective: The development of leptomeningeal disease (LMD) among melanoma patients is associated with short survival. Unspecific clinical symptoms and imprecise diagnostic criteria often delay diagnosis. Because melanoma patients with LMD have been excluded from most clinical trials, the efficacy of immune checkpoint blockade (ICB) and targeted therapies (TTs) has not been adequately investigated among these patients.

Methods: We performed a retrospective study in two tertiary-referral skin cancer centres to evaluate the clinical characteristics, diagnostics, treatments, and overall survival (OS) of melanoma patients with LMD between June 2011 and March 2019.

Results: In total, 52 patients were included. The median age at LMD diagnosis was 58 years. Most patients (n = 30, 58%) were men. The median time from the first diagnosis of unresectable disease to the first diagnosis of LMD was 8.5 months (range 0-91.5 months). Most patients (65%, n = 34) were BRAF V600 mutated. Sixteen patients (31%) presented with LMD only, whereas 36 patients (69%) presented with concomitant brain metastases at LMD diagnosis. Eleven patients (21%) showed no evidence of extracranial disease. Forty-four patients (85%) had clinical symptoms at LMD diagnosis. Forty-two patients (81%) had received at least one prior therapy. Forty patients (77%) received at least one treatment after LMD diagnosis, including TT (n = 17), ICB (n = 13), bevacizumab (n = 1), radiotherapy (n = 3), and intrathecal chemotherapy (n = 1); five patients received both TT and ICB. Twelve patients (23%) received no treatment because of rapid progression of LMD. The median OS for the entire cohort was 2.9 months (95% confidence interval [CI] 1.7-4.1). Among patients receiving systemic therapy, OS was 3.7 months (95% CI 2.4-4.9).

Conclusions: Systemic treatment with TT or ICB seems to improve OS among patients with LMD. However, despite new therapy modalities, the prognosis of LMD remains poor.
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http://dx.doi.org/10.1016/j.ejca.2021.02.016DOI Listing
May 2021

Machine learning-based differentiation between multiple sclerosis and glioma WHO II°-IV° using O-(2-[18F] fluoroethyl)-L-tyrosine positron emission tomography.

J Neurooncol 2021 Apr 27;152(2):325-332. Epub 2021 Jan 27.

Division of Clinical Neurooncology, Department of Neurology, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany.

Introduction: This study aimed to test the diagnostic significance of FET-PET imaging combined with machine learning for the differentiation between multiple sclerosis (MS) and glioma II°-IV°.

Methods: Our database was screened for patients in whom FET-PET imaging was performed for the diagnostic workup of newly diagnosed lesions evident on MRI and suggestive of glioma. Among those, we identified patients with histologically confirmed glioma II°-IV°, and those who later turned out to have MS. For each group, tumor-to-brain ratio (TBR) derived features of FET were determined. A support vector machine (SVM) based machine learning algorithm was constructed to enhance classification ability, and Receiver Operating Characteristic (ROC) analysis with area under the curve (AUC) metric served to ascertain model performance.

Results: A total of 41 patients met selection criteria, including seven patients with MS and 34 patients with glioma. TBR values were significantly higher in the glioma group (TBRmax glioma vs. MS: p = 0.002; TBRmean glioma vs. MS: p = 0.014). In a subgroup analysis, TBR values significantly differentiated between MS and glioblastoma (TBRmax glioblastoma vs. MS: p = 0.0003, TBRmean glioblastoma vs. MS: p = 0.0003) and between MS and oligodendroglioma (ODG) (TBRmax ODG vs. MS: p = 0.003; TBRmean ODG vs. MS: p = 0.01). The ability to differentiate between MS and glioma II°-IV° increased from 0.79 using standard TBR analysis to 0.94 using a SVM based machine learning algorithm.

Conclusions: FET-PET imaging may help differentiate MS from glioma II°-IV° and SVM based machine learning approaches can enhance classification performance.
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http://dx.doi.org/10.1007/s11060-021-03701-1DOI Listing
April 2021

Genetic knockdown of Klk8 has sex-specific multi-targeted therapeutic effects on Alzheimer's pathology in mice.

Neuropathol Appl Neurobiol 2021 08 27;47(5):611-624. Epub 2021 Jan 27.

Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany.

Aims: Previous work in our lab has identified the protease kallikrein-8 (KLK8) as a potential upstream mover in the pathogenesis of Alzheimer's disease (AD). We showed pathologically elevated levels of KLK8 in the cerebrospinal fluid and blood of patients with mild cognitive impairment or dementia due to AD, and in brains of patients and transgenic CRND8 (TgCRND8) mice in incipient stages of the disease. Furthermore, short-term antibody-mediated KLK8 inhibition in moderate stage disease alleviated AD pathology in female mice. However, it remains to be shown whether long-term reversal of KLK8 overexpression can also counteract AD. Therefore, the effects of genetic Klk8-knockdown were determined in TgCRND8 mice.

Methods: The effects of heterozygous ablation of murine Klk8 (mKlk8) gene on AD pathology of both sexes were examined by crossbreeding TgCRND8 [hAPP+/-] with mKlk8-knockdown [mKlk8+/-] mice resulting in animals with or without AD pathology which revealed pathologically elevated or normal KLK8 levels.

Results: mKlk8-knockdown had negligible effects on wildtype animals but led to significant decline of amyloid beta (Aβ) and tau pathology as well as an improvement of structural neuroplasticity in a sex-specific manner in transgenics. These changes were mediated by a shift to non-amyloidogenic cleavage of the human amyloid precursor protein (APP), recovery of the neurovascular unit and maintaining microglial metabolic fitness. Mechanistically, Klk8-knockdown improved Aβ phagocytosis in primary glia and Aβ resistance in primary neurons. Most importantly, transgenic mice revealed less anxiety and a better memory performance.

Conclusions: These results reinforce the potential of KLK8 as a therapeutic target in AD.
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http://dx.doi.org/10.1111/nan.12687DOI Listing
August 2021

The interaction of insoluble Amyloid-β with soluble Amyloid-β dimers decreases Amyloid-β plaque numbers.

Neuropathol Appl Neurobiol 2021 08 7;47(5):603-610. Epub 2021 Jan 7.

Department of Neuropathology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Objectives: The heterogeneity of Amyloid-beta (Aβ) plaque load in patients with Alzheimer's disease (AD) has puzzled neuropathology. Since brain Aβ plaque load does not correlate with cognitive decline, neurotoxic soluble Aβ oligomers have been championed as disease-causing agents in early AD. So far, investigating molecular interactions between soluble oligomeric Aβ and insoluble Aβ in vivo has been difficult because of the abundance of Aβ oligomer species and the kinetic equilibrium in which they coexist. Here, we investigated whether Aβ plaque heterogeneity relates to interactions of different Aβ conformers.

Materials And Methods: We took advantage of transgenic mice that generate exclusively Aβ dimers (tgDimer mice) but do not develop Aβ plaques or neuroinflammation during their lifetime, crossed them to the transgenic CRND8 mice that develop plaques after 90 days and measured Aβ plaque load using immunohistochemical and biochemical assays. Furthermore, we performed in vitro thioflavin T (ThT) aggregation assays titrating synthetic Aβ -S8C dimers into fibril-forming synthetic Aβ .

Results: We observed a lower number of Aβ plaques in the brain of double transgenic mice compared to tgCRND8 mice alone while the average plaque size remained unaltered. Corroborating these in vivo findings, synthetic Aβ-S8C dimers inhibited fibril formation of wild-type Aβ also in vitro, seen by an increased half-time in the ThT assay.

Conclusions: Our study indicates that Aβ dimers directly interfere with Aβ fibril formation in vivo and in vitro. The variable interaction of Aβ dimers with insoluble Aβ seeds could thus contribute to the heterogeneity of Aβ plaque load in AD patients.
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http://dx.doi.org/10.1111/nan.12685DOI Listing
August 2021

Neurobehavioral effects in rats with experimentally induced glioblastoma after treatment with the mTOR-inhibitor rapamycin.

Neuropharmacology 2021 02 5;184:108424. Epub 2020 Dec 5.

Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, 45122, Essen, Germany. Electronic address:

Psychiatric symptoms as seen in affective and anxiety disorders frequently appear during glioblastoma (GBM) treatment and disease progression, additionally deteriorate patient's daily life routine. These central comorbidities are difficult to recognize and the causes for these effects are unknown. Since overactivation of mechanistic target of rapamycin (mTOR)- signaling is one key driver in GBM growth, the present study aimed at examining in rats with experimentally induced GBM, neurobehavioral consequences during disease progression and therapy. Male Fisher 344 rats were implanted with syngeneic RG2 tumor cells in the right striatum and treated with the mTOR inhibitor rapamycin (3 mg/kg; once daily, for eight days) before behavioral performance, brain protein expression, and blood samples were analyzed. We could show that treatment with rapamycin diminished GBM tumor growth, confirming mTOR-signaling as one key driver for tumor growth. Importantly, in GBM animals' anxiety-like behavior was observed but only after treatment with rapamycin. These behavioral alterations were moreover accompanied by aberrant glucocorticoid receptor, phosphorylated p70 ribosomal S6 kinase alpha (p-p70s6k), and brain derived neurotrophic factor protein expression in the hippocampus and amygdala in the non-tumor-infiltrated hemisphere of the brain. Despite the beneficial effects on GBM tumor growth, our findings indicate that therapy with rapamycin impaired neurobehavioral functioning. This experimental approach has a high translational value. For one, it emphasizes aberrant mTOR functioning as a central feature mechanistically linking complex brain diseases and behavioral disturbances. For another, it highlights the importance of elaborating the cause of unwanted central effects of immunosuppressive and antiproliferative drugs used in transplantation medicine, immunotherapy, and oncology.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108424DOI Listing
February 2021

The genetic landscape of choroid plexus tumors in children and adults.

Neuro Oncol 2021 04;23(4):650-660

Institute of Neuropathology, University Hospital Münster, Münster, Germany.

Background: Choroid plexus tumors (CPTs) are intraventricular brain tumors predominantly arising in children but also affecting adults. In most cases, driver mutations have not been identified, although there are reports of frequent chromosome-wide copy-number alterations and TP53 mutations, especially in choroid plexus carcinomas (CPCs).

Methods: DNA methylation profiling and RNA-sequencing was performed in a series of 47 CPTs. Samples comprised 35 choroid plexus papillomas (CPPs), 6 atypical choroid plexus papillomas (aCPPs) and 6 CPCs plus three recurrences thereof. Targeted TP53 and TERT promotor sequencing was performed in all samples. Whole exome sequencing (WES) and linked-read whole genome sequencing (WGS) was performed in 25 and 4 samples, respectively.

Results: Tumors comprised the molecular subgroups "pediatric A" (N=11), "pediatric B" (N=12) and "adult" (N=27). Copy-number alterations mainly represented whole-chromosomal alterations with subgroup-specific enrichments (gains of Chr1, 2 and 21q in "pediatric B" and gains of Chr5 and 9 and loss of Chr21q in "adult"). RNA sequencing yielded a novel CCDC47-PRKCA fusion transcript in one adult choroid plexus papilloma patient with aggressive clinical course; an underlying Chr17 inversion was demonstrated by linked-read WGS. WES and targeted sequencing showed TP53 mutations in 7/47 CPTs (15%), five of which were children. On the contrary, TERT promoter mutations were encountered in 7/28 adult patients (25%) and associated with shorter progression-free survival (log-rank test, p=0.015).

Conclusion: Pediatric CPTs lack recurrent driver alterations except for TP53, whereas CPTs in adults show TERT promoter mutations or a novel CCDC47-PRKCA gene fusion, being associated with a more unfavorable clinical course.
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http://dx.doi.org/10.1093/neuonc/noaa267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041331PMC
April 2021

PDCD10-Deficiency Promotes Malignant Behaviors and Tumor Growth via Triggering EphB4 Kinase Activity in Glioblastoma.

Front Oncol 2020 7;10:1377. Epub 2020 Aug 7.

Department of Neurosurgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

We previously reported an angiogenic and tumor-suppressor-like function of programmed cell death 10 (PDCD10) in glioblastoma (GBM). However, the underlying mechanism remains to be elucidated. We hypothesized that loss of PDCD10 activates GBM cells and tumor progression via EphB4. To this end, PDCD10 was knocked down in U87 and T98g by lentiviral mediated shRNA transduction (shPDCD10). GBM cell phenotype and tumor growth in a mouse xenograft model were investigated in presence or absence of the treatment with a specific EphB4 kinase inhibitor NVP-BHG712 (NVP). We demonstrated that knockdown of PDCD10 in GBM cells significantly upregulated the mRNA and protein expression of EphB4 accompanied by the activation of Erk1/2. EphB4 kinase activity, reflected by phospho-EphB4, significantly increased in shPDCD10 GBM cells, and in tumors derived from shPDCD10 GBM xenografts, which was abolished by the treatment with NVP. Furthermore, NVP treatment significantly suppressed PDCD10-knockdown mediated aggressive GBM cell phenotype and extensive tumor cell proliferation, the tumor neo-angiogenesis, and a quick progression of tumor formation . In summary, loss of PDCD10 activates GBM cells and promotes tumor growth via triggering EphB4. Targeting EphB4 might be an effective strategy particularly for the personalized therapy in GBM patients with PDCD10-deficiency.
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http://dx.doi.org/10.3389/fonc.2020.01377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427606PMC
August 2020

The predominant expression of cancer stem cell marker ALDH1A3 in tumor infiltrative area is associated with shorter overall survival of human glioblastoma.

BMC Cancer 2020 Jul 17;20(1):672. Epub 2020 Jul 17.

Department of Neurosurgery and Spine Surgery, University hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany.

Background: ALDH1A3 is a cancer stem cell marker in neoplasms including glioblastoma (GBM). However, the comprehensive role of ALDH1A3 in GBM remains unclear. This study attempted to investigate the expression of ALDH1A3 in human GBM tissues and its association with clinical parameters.

Methods: Thirty primary GBM and 9 control were enrolled in this study. ALDH1A3 mRNA and protein expression levels were detected by RT-PCR and western blot, respectively. Immunohistochemistry and immunofluorescence staining were performed to evaluate the regional and cellular expression manner of ALDH1A3. The association of ALDH1A3 expression with multiple clinical parameters was analyzed.

Results: ALDH1A3 protein level, but not mRNA level, in a subgroup of GBM was significantly higher than that in the control group. ALDH1A3 immunoreactivity was detected heterogeneously in individual GBMs. Fifteen of 30 cases showed a positive of ALDH1A3 immunoreactivity which was predominantly observed in the tumor infiltrative area (TI). Double immunofluorescence staining revealed a co-localization of ALDH1A3 with GFAP in glial-shaped cells and in tumor cells. ALDH1A3 immunoreactivity was often merged with CD44, but not with CD68. Moreover, ALDH1A3 expression was positively associated with the tumor edema grade and inversely with overall survival (OS) (median OS: 16 months vs 10 months), but with neither MGMT promoter methylation status nor Ki67 index in GBM. An upregulation of ALDH1A3 was accompanied by a reduced expression of STAT3β and p-STAT3β.

Conclusions: Inter- and intra-tumoral heterogeneous expression of ALDH1A3 was exhibited in GBMs. A high immunoreactivity of ALDH1A3 in tumor infiltrative area was associated with shorter OS, especially in patients with MGMT promoter methylation. Our findings propose ALDH1A3 not only as a predictive biomarker but also as a potential target for personalized therapy of GBM.
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http://dx.doi.org/10.1186/s12885-020-07153-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368792PMC
July 2020

Compromised Hippocampal Neuroplasticity in the Interferon-α and Toll-like Receptor-3 Activation-Induced Mouse Depression Model.

Mol Neurobiol 2020 Jul 5;57(7):3171-3182. Epub 2020 Jun 5.

Department of Neurology, University Hospital Essen, Hufelandstr. 55, D-45122, Essen, Germany.

Disrupted neuronal plasticity due to subtle inflammation is considered to play a fundamental role in the pathogenesis of major depressive disorder. Interferon-α (IFN-α) potentiates immune responses against viral pathogens that induce toll-like receptor-3 (TLR3) activation but evokes severe major depressive disorder in humans by mechanisms that remain insufficiently described. By using a previously established mouse model of depression induced by combined delivery of IFN-α and polyinosinic:polycytidylic acid (poly(I:C)), a TLR3 agonist, we provide evidence that IFN-α and poly(I:C) reduce apical dendritic spine density in the hippocampal CA1 area ex vivo via mechanisms involving decreased TrkB signaling. In vitro, IFN-α and poly(I:C) treatments required neuronal activity to reduce dendritic spine density and TrkB signaling. The levels of presynaptic protein vesicular glutamate transporter (VGLUT)-1 and postsynaptic protein postsynaptic density-95 (PSD95) were specifically decreased, whereas the expression of both synaptic and extrasynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor 1 (AMPAR1) was increased by IFN-α and poly(I:C) delivery. Patch clamp recordings in primary hippocampal neurons revealed that morphological changes at the synapse induced by IFN-α and poly(I:C) costimulation were accompanied by an increased action potential threshold and action potential frequency, indicative of impaired neuronal excitability. Taken together, IFN-α and poly(I:C) delivery leads to structural and functional alterations at the synapse indicating that compromised neuroplasticity may play an integral role in the pathogenesis of immune response-induced depression.
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http://dx.doi.org/10.1007/s12035-020-01927-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320059PMC
July 2020

Macrophages/Microglia Represent the Major Source of Indolamine 2,3-Dioxygenase Expression in Melanoma Metastases of the Brain.

Front Immunol 2020 5;11:120. Epub 2020 Feb 5.

Skin Cancer Unit of the Dermatology Department, Medical Faculty, West German Cancer Center, University Duisburg-Essen, Essen, Germany.

The manifestation of brain metastases in patients with advanced melanoma is a common event that limits patient's survival and quality of life. The immunosuppressive properties of the brain parenchyma are very different compared to the rest of the body, making it plausible that the current success of cancer immunotherapies is specifically limited here. In melanoma brain metastases, the reciprocal interplay between immunosuppressive mediators such as indoleamine 2, 3-dioxygenase (IDO) or programmed cell death-ligand 1 (PD-L1) in the context of neoplastic transformation are far from being understood. Therefore, we analyzed the immunoreactive infiltrate (CD45, CD3, CD8, Forkhead box P3 [FoxP3], CD11c, CD23, CD123, CD68, Allograft Inflammatory factor 1[AIF-1]) and PD-L1 with respect to IDO expression and localization in melanoma brain metastases but also in matched metastases at extracranial sites to correlate intra- and interpatient data with therapy response and survival. Comparative tissue analysis identified macrophages/microglia as the major source of IDO expression in melanoma brain metastases. In contrast to the tumor infiltrating lymphocytes, melanoma cells exhibited low IDO expression levels paralleled by cell surface presentation of PD-L1 in intracranial metastases. Absolute numbers and pattern of IDO-expressing cells in metastases of the brain correlated with recruitment and localization of CD8 T cells, implicating dynamic impact on the regulation of T cell function in the brain parenchyma. However, paired analysis of matched intra- and extracranial metastases identified significantly lower fractions of cytotoxic CD8 T cells in intracranial metastases while all other immune cell populations remain unchanged. In line with the already established clinical benefit for PD-L1 expression in extracranial melanoma metastases, Kaplan-Meier analyses correlated PD-L1 expression in brain metastases with favorable outcome in advanced melanoma patients undergoing immune checkpoint therapy. In summary, our data provide new insights into the landscape of immunosuppressive factors in melanoma brain metastases that may be useful in the implication of novel therapeutic strategies for patients undergoing cancer immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2020.00120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013086PMC
March 2021

Tumour Treating Fields (TTFields) in combination with lomustine and temozolomide in patients with newly diagnosed glioblastoma.

J Cancer Res Clin Oncol 2020 Mar 11;146(3):787-792. Epub 2019 Dec 11.

Division of Clinical Neurooncology, Department of Neurology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.

Purpose: In the EF-14 trial for newly diagnosed glioblastoma (ndGBM) patients addition of Tumour Treating Fields (TTFields) to temozolomide treatment resulted in a significantly improved overall survival (OS). In the NOA-09/CeTeG trial, combination of lomustine and temozolomide was superior to temozolomide monotherapy in patients with O6-methylguanine DNA methyltransferase (MGMT) promoter methylated (MGMTm) ndGBM. We evaluated combination of these two treatment modalities in patients with MGMTm ndGBM. There have been so far no data on the combination of these two efficient regimens.

Methods: This bicentric retrospective analysis investigated 16 patients. Parameters evaluated included safety outcome as measured by Common Toxicity Criteria for Adverse Events (CTCAE), clinical outcomes, and compliance to treatment.

Results: Hematologic adverse events CTCAE ≥ 3 were observed in seven, hepatotoxic adverse events of CTCAE ≥ 3 in four patients. Mild to moderate skin toxicity was detected in six patients. At data cutoff, patients demonstrated a median progression-free survival (PFS) of 20 months. The usage rate of TTFields showed a high median adherence (83%) to the therapy.

Conclusions: This analysis provides first indication that the combination of TTFields/lomustine/temozolomide is safe and feasible. The observed survival outcomes might suggest potential beneficial effects.
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http://dx.doi.org/10.1007/s00432-019-03106-8DOI Listing
March 2020

Non-invasive tumor decoding and phenotyping of cerebral gliomas utilizing multiparametric F-FET PET-MRI and MR Fingerprinting.

Eur J Nucl Med Mol Imaging 2020 06 6;47(6):1435-1445. Epub 2019 Dec 6.

Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, Hufelandstraße 55, 45147, Essen, Germany.

Objectives: The introduction of the 2016 WHO classification of CNS tumors has made the combined molecular and histopathological characterization of tumors a pivotal part of glioma patient management. Recent publications on radiogenomics-based prediction of the mutational status have demonstrated the predictive potential of imaging-based, non-invasive tissue characterization algorithms. Hence, the aim of this study was to assess the potential of multiparametric F-FET PET-MRI including MR fingerprinting accelerated with machine learning and radiomic algorithms to predict tumor grading and mutational status of patients with cerebral gliomas.

Materials And Methods: 42 patients with suspected primary brain tumor without prior surgical or systemic treatment or biopsy underwent an F-FET PET-MRI examination. To differentiate the mutational status and the WHO grade of the cerebral tumors, support vector machine and random forest were trained with the radiomics signature of the multiparametric PET-MRI data including MR fingerprinting. Surgical sampling served as a gold standard for histopathological reference and assessment of mutational status.

Results: The 5-fold cross-validated area under the curve in predicting the ATRX mutation was 85.1%, MGMT mutation was 75.7%, IDH1 was 88.7%, and 1p19q was 97.8%. The area under the curve of differentiating low-grade glioma vs. high-grade glioma was 85.2%.

Conclusion: F-FET PET-MRI and MR fingerprinting enable high-quality imaging-based tumor decoding and phenotyping for differentiation of low-grade vs. high-grade gliomas and for prediction of the mutational status of ATRX, IDH1, and 1p19q. These initial results underline the potential of F-FET PET-MRI to serve as an alternative to invasive tissue characterization.
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http://dx.doi.org/10.1007/s00259-019-04602-2DOI Listing
June 2020

Inhibition of excessive kallikrein-8 improves neuroplasticity in Alzheimer's disease mouse model.

Exp Neurol 2020 02 14;324:113115. Epub 2019 Nov 14.

Institute of Neuropathology, University of Duisburg-Essen, Hufelandstr, 55, 45122 Essen, Germany. Electronic address:

We recently identified excessive cerebral kallikrein-8 (KLK8) mRNA and protein levels at incipient stages of Alzheimer's disease (AD) in AD patients and TgCRND8 mice. Additionally, we showed that antibody-mediated KLK8 inhibition exerts therapeutic effects on AD along with enhancing neuroplasticity, resulting in improved spatial memory in mice. Mounting evidence further substantiates an important role of the protease KLK8 in neuroplasticity. In the present study we sought to gain new mechanistic insights in the interplay between KLK8, neuroplasticity and tau phosphorylation in the context of AD. We here demonstrate that KLK8 inhibition increased the number of hippocampal Ki-67 and doublecortin positive, proliferative neuronal progenitor cells in transgenic mice, whereas the same action in wildtypes had no effect. In line with these results, KLK8 inhibition reduced the levels of its pro-proliferative interaction partners KLK6 and protease-activated receptor 2 only in wildtypes, while the levels of its proliferation-supporting substrate neuregulin-1 and the non-complexed form of its complexing-partner phosphatidylethanolamine binding protein 1 were enhanced in both genotypes. Concomitant incubation of beta-amyloid (Aβ)-producing primary neurons with KLK8 and its inhibitory antibody increased neurite complexity and soma size. KLK8 inhibition in SH-SY5Y cells or in primary neurons increased levels of the neuroplasticity-supporting KLK8 substrate ephrin receptor B2 (EPHB2) and total tau while decreasing the relative amount of phospho-tau in relation to total tau. KLK8 blockade further enhanced cell proliferation in SH-SY5Y cells. Additional co-incubation with an inhibitory anti-EPHB2 antibody decreased total tau levels and neurite complexity and increased the ratio of phospho-tau/total tau, underlining the key role of EPHB2 on this plastic change. In a reverse in vitro approach, KLK8 induction reduced EPHB2 and total tau and increased the ratio of phospho-tau/total tau, leading to impaired proliferation and neuronal differentiation. These results underline the therapeutic potential of KLK8 inhibition by counteracting plasticity deficits in AD-affected brain.
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http://dx.doi.org/10.1016/j.expneurol.2019.113115DOI Listing
February 2020

Desmoplastic myxoid tumor, SMARCB1-mutant: clinical, histopathological and molecular characterization of a pineal region tumor encountered in adolescents and adults.

Acta Neuropathol 2020 02 16;139(2):277-286. Epub 2019 Nov 16.

Institute of Neuropathology, University Hospital Münster, Pottkamp 2, Münster, Germany.

Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly occurring in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. SMARCB1-mutant tumors in adolescents and adults are rare and may show uncommon histopathological and clinical features. Here we report seven SMARCB1-deficient intracranial tumors sharing distinct clinical, histopathological and molecular features. Median age of the four females and three males was 40 years (range 15-61 years). All tumors were located in the pineal region. Histopathologically, these tumors displayed spindled and epithelioid cells embedded in a desmoplastic stroma alternating with a variable extent of a loose myxoid matrix. All cases showed loss of nuclear SMARCB1/INI1 protein expression, expression of EMA and CD34 was frequent and the Ki67/MIB1 proliferation index was low in the majority of cases (median 3%). Three cases displayed heterozygous SMARCB1 deletions and two cases a homozygous SMARCB1 deletion. On sequencing, one tumor showed a 2 bp deletion in exon 4 (c.369_370del) and one a short duplication in exon 3 (c.237_276dup) both resulting in frameshift mutations. Most DNA methylation profiles were not classifiable using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-SNE analysis and hierarchical clustering analysis, however, all tumors grouped closely together and showed similarities with ATRT-MYC. After a median observation period of 48 months, three patients were alive with stable disease, whereas one patient experienced tumor progression and three patients had succumbed to disease. In conclusion, our series represents an entity with distinct clinical, histopathological and molecular features showing epigenetic similarities with ATRT-MYC. We propose the designation desmoplastic myxoid tumor (DMT), SMARCB1-mutant, for these tumors.
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http://dx.doi.org/10.1007/s00401-019-02094-wDOI Listing
February 2020

Simultaneous primary cancer occurrence of melanoma and pulmonary adenocarcinoma in leptomeningeal metastases: a case report.

BMC Cancer 2019 Oct 23;19(1):995. Epub 2019 Oct 23.

Division of Clinical Neurooncology, Department of Neurology, University Hospital Essen, University Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany.

Background: Leptomeningeal metastasis (LM) is a predominantly late stage, devastating complication of a variety of malignant solid tumors. Diagnosis relies predominantly on neurological, radiographic, and cerebrospinal fluid (CSF) assessments. Recently, liquid biopsy tests derived from CSF has shown to be a feasible, noninvasive promising approach to tumor molecular profiling for proper brain cancer diagnostic treatment, thereby providing an opportunity for CSF-based personalized medicine. However, LM is typically misleadingly assumed to originate from only one primary tumor type.

Case Presentation: In this case report, we provide first evidence of the co-occurrence of LM originating from more than one primary tumor types.

Discussion And Conclusions: Based on this patient case profile, the co-occurrence of LM from two or more primary tumor types should be accounted for when deriving diagnostic conclusions from liquid biopsy tests.
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http://dx.doi.org/10.1186/s12885-019-6183-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813083PMC
October 2019

CSF and blood Kallikrein-8: a promising early biomarker for Alzheimer's disease.

J Neurol Neurosurg Psychiatry 2020 01 1;91(1):40-48. Epub 2019 Aug 1.

Institute of Neuropathology, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany

Objective: There is still an urgent need for supportive minimally invasive and cost-effective biomarkers for early diagnosis of Alzheimer's disease (AD). Previous work in our lab has identified Kallikrein-8 (KLK8) as a potential candidate since it shows an excessive increase in human brain in preclinical disease stages. The aim of this study was to evaluate the diagnostic performance of cerebrospinal fluid (CSF) and blood KLK8 for AD and mild cognitive impairment (MCI) due to AD.

Methods: In this multi-centre trans-sectional study, clinical and laboratory data as well as CSF and/or blood serum samples of 237 participants, including 98 patients with mild AD, 21 with MCI due to AD and 118 controls were collected. CSF and/or serum KLK8 levels were analysed by ELISA. The diagnostic accuracy of KLK8 in CSF and blood was determined using receiver operating characteristic (ROC) analyses and compared with that of CSF core biomarkers Aβ42, P-tau and T-tau.

Results: The diagnostic accuracy of CSF KLK8 was as good as that of core CSF biomarkers for AD (area under the curve (AUC)=0.89) and in case of MCI (AUC=0.97) even superior to CSF Aβ42. Blood KLK8 was a similarly strong discriminator for MCI (AUC=0.94) but slightly weaker for AD (AUC=0.83).

Conclusions: This is the first study to demonstrate the potential clinical utility of blood and CSF KLK8 as a biomarker for incipient AD. Future prospective validation studies are warranted.
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http://dx.doi.org/10.1136/jnnp-2019-321073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952834PMC
January 2020

Histopathology of Moyamoya angiopathy in a European patient.

J Neurol 2019 Sep 4;266(9):2258-2262. Epub 2019 Jun 4.

Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany.

Background And Purpose: Moyamoya angiopathy (MMA) is rare outside Asia. Little is known about pathophysiology in European patients. This study aims to elucidate the histopathology of non-Asian MMA and its similarities and differences to those cases from Asia.

Methods: Here, we present a 57-year-old European woman with MMA and describe the post-mortem examination results of the brain and cerebral arteries.

Results: Histopathological findings in cerebral blood vessels were identical to those found in Asians. This included thickening and undulation of the internal elastic lamina as well as fibrocellular thickening and proliferation of smooth muscle cells of the intima in the distal segments of the internal carotid arteries and in proximal and middle segments of the anterior and middle cerebral arteries. Collateral vessels showed fragmented internal elastic lamina and thinning of the media with isolated microaneurysms.

Conclusions: Histopathological changes found in this European patient are identical with those described in Asians. Despite suspected different genetic triggers and unknown pathophysiological cascades, MMA in Europeans seems to result in a common final pathway compared with the disease in Asians.
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http://dx.doi.org/10.1007/s00415-019-09406-wDOI Listing
September 2019

Comparison of L-Methyl-11C-Methionine PET With Magnetic Resonance Spectroscopy in Detecting Newly Diagnosed Glioma.

Clin Nucl Med 2019 Jun;44(6):e375-e381

Nuclear Medicine Unit, Department of Imaging and Clinical Pathology, Rovigo, Italy.

Aims: Amino acid PET and magnetic resonance spectroscopy (MRS) are at the forefront of noninvasive imaging techniques used for detection and subtyping of glioma-suspicious lesions. In this pilot study, we compare L-methyl-C-methionine PET and MRS for their ability to predict glioma subtypes.

Methods: Nineteen patients with histologically, confirmed newly diagnosed glioma underwent preoperative L-methyl-C-methionine PET and MRS in 1 diagnostic session. According to the molecular portfolio and histopathologic diagnosis, patients were subdivided in isocitrate dehydrogenase (IDH) wild-type glioblastoma, IDH wild-type grade II/III glioma, IDH-mutant grade II/III glioma without 1p/19q codeletion, and with 1p/19q codeletion subgroups. Maximum tumor-to-brain ratio (TBRmax), creatine, choline, and N-acetyl aspartate peaks were correlated with postoperative histopathologic tumor diagnoses.

Results: Maximum tumor-to-brain ratio was highest in glioblastoma patients (4.18) followed by patients with IDH wild-type grade II and III glioma (3.41). The latter TBRmax values were higher compared with those in patients with IDH-mutant grade II/III glioma without 1p/19q codeletion (1.95) and in patients with IDH-mutant 1p/19q codeleted grade II and III glioma (2.79). Magnetic resonance spectroscopy marker distribution showed no clear trend. Receiver operating characteristic analysis revealed TBRmax to be the best performing parameter in identifying IDH status (area under the curve, 0.67) and all spectroscopy markers combined in identifying glioma subgroups (area under the curve, 0.68), respectively.

Conclusions: L-Methyl-C-methionine PET and MRS bear limited potential in glioma subgrouping. L-Methyl-C-methionine PET appears to be superior in differentiating IDH status, whereas MRS is more helpful in glioma subgrouping.
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http://dx.doi.org/10.1097/RLU.0000000000002577DOI Listing
June 2019

Regorafenib in patients with recurrent high-grade astrocytoma.

J Cancer Res Clin Oncol 2019 Apr 28;145(4):1037-1042. Epub 2019 Feb 28.

Division of Clinical Neurooncology, Department of Neurology, University Hospital Essen, University Duisburg-Essen, 45147, Essen, Germany.

Purpose: Antiangiogenic treatment approaches have failed to improve outcome in randomized trials of high-grade astrocytoma. One key mechanism of resistance to antiangiogenic treatment may concern the upregulation of alternative pro-angiogenic pathways. Regorafenib is a potent multikinase inhibitor that may alter some of those pathways. In this retrospective study, we investigated efficacy and radiographic tumor growth patterns of regorafenib in recurrent high-grade astrocytoma.

Methods: We screened for patients with high-grade astrocytoma in whom regorafenib was administered for at least 4 weeks. We assessed treatment efficacy in terms of progression-free survival (PFS), overall survival, and adverse events defined by Common Toxicity Criteria (CTC). In addition, radiographic tumor growth patterns were determined at baseline and recurrence.

Results: A total of 6 patients met eligibility criteria. The number of recurrences prior to regorafenib varied between 2 and 6. Patients were on regorafenib treatment for at least 4 weeks and maximally 14 weeks. Median PFS was 3.5 months and ranged from 2.0 to 4.0 months. Radiographic response was progressive disease in all patients with an objective response rate of 0%. CTC°3 adverse events were observed in all but one patient. The most common radiographic growth pattern was local with no change in growth pattern at recurrence. An infiltrative tumor growth was not induced in any patient.

Conclusions: This retrospective study indicates a very poor performance of regorafenib in recurrent high-grade astrocytoma with a fairly high number of CTC°3 adverse events. In addition, regorafenib does not seem to bear a potential for infiltrative tumor growth promotion.
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http://dx.doi.org/10.1007/s00432-019-02868-5DOI Listing
April 2019

Hybrid 11C-MET PET/MRI Combined With "Machine Learning" in Glioma Diagnosis According to the Revised Glioma WHO Classification 2016.

Clin Nucl Med 2019 Mar;44(3):214-220

Department of Nuclear Medicine, Radiology, NeuroRadiology, Clinical Pathology, S. Maria della Misericordia Hospital, Rovigo, Italy.

Purpose: With the advent of the revised WHO classification from 2016, molecular features, including isocitrate dehydrogenase (IDH) mutation have become important in glioma subtyping. This pilot trial analyzed the potential for C-methionine (MET) PET/MRI in classifying glioma according to the revised WHO classification using a machine learning model.

Methods: Patients with newly diagnosed WHO grade II-IV glioma underwent preoperative MET-PET/MRI imaging. Patients were retrospectively divided into four groups: IDH wild-type glioblastoma (GBM), IDH wild-type grade II/III glioma (GII/III-IDHwt), IDH mutant grade II/III glioma with codeletion of 1p19q (GII/III-IDHmut1p19qcod) or without 1p19q-codeletion (GII/III-IDHmut1p19qnc). Within each group, the maximum tumor-to-brain-ratio (TBRmax) of MET-uptake was calculated. To gain generalizable implications from our data, we made use of a machine learning algorithm based on a development and validation subcohort. A support vector machine model was fit to the development subcohort and evaluated on the validation subcohort. Receiver operating characteristic (ROC) analysis served as metric to assess model performance.

Results: Of a total of 259 patients, 39 patients met the inclusion criteria. TBRmax was highest in the GBM cohort (TBRmax 3.83 ± 1.30) and significantly higher (P = 0.004) compared to GII/III-IDHmut1p19qnc group, where TBRmax was lowest (TBRmax 2.05 ± 0.94). ROC analysis showed poor AUC for glioma subtyping (AUC 0.62) and high AUC of 0.79 for predicting IDH status. In the GII/III-IDHmut1p19qcod group, TBR values were slightly higher than in the IDHmut1p19qnc group.

Conclusions: MET-PET/MRI imaging in pre-operatively classifying glioma entities appears useful for the assessment of IDH status. However, a larger trial is needed prior to translation into the clinical routine.
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http://dx.doi.org/10.1097/RLU.0000000000002398DOI Listing
March 2019

Loss of programmed cell death 10 activates tumor cells and leads to temozolomide-resistance in glioblastoma.

J Neurooncol 2019 Jan 3;141(1):31-41. Epub 2018 Nov 3.

Department of Neurosurgery, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany.

Purpose: Glioblastoma (GBM) is one of the most aggressive and incurable primary brain tumors. Identification of novel therapeutic targets is an urgent priority. Programmed cell death 10 (PDCD10), a ubiquitously expressed apoptotic protein, has shown a dual function in different types of cancers and in chemo-resistance. Recently, we reported that PDCD10 was downregulated in human GBM. The aim of this study was to explore the function of PDCD10 in GBM cells.

Methods: PDCD10 was knocked down in three GBM cell lines (U87, T98g and LN229) by lentiviral-mediated shRNA transduction. U87 and T98g transduced cells were used for phenotype study and LN229 and T98g cells were used for apoptosis study. The role of PDCD10 in apoptosis and chemo-resistance was investigated after treatment with staurosporine and temozolomide. A GBM xenograft mouse model was used to confirm the function of PDCD10 in vivo. A protein array was performed in PDCD10-knockdown and control GBM cells.

Results: Knockdown of PDCD10 in GBM cells promoted cell proliferation, adhesion, migration, invasion, and inhibited apoptosis and caspase-3 activation. PDCD10-knockdown accelerated tumor growth and increased tumor mass by 2.1-fold and led to a chemo-resistance of mice treated with temozolomide. Immunostaining revealed extensive Ki67-positive cells and less activation of caspase-3 in PDCD10-knockdown tumors. The protein array demonstrated an increased release of multiple growth factors from PDCD10-knockdown GBM cells.

Conclusions: Loss of programmed cell death 10 activates tumor cells and leads to temozolomide-resistance in GBM, suggesting PDCD10 as a potential target for GBM therapy.
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http://dx.doi.org/10.1007/s11060-018-03017-7DOI Listing
January 2019

FGFR1:TACC1 fusion is a frequent event in molecularly defined extraventricular neurocytoma.

Acta Neuropathol 2018 08 5;136(2):293-302. Epub 2018 Jul 5.

Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.

Extraventricular neurocytoma (EVN) is a rare primary brain tumor occurring in brain parenchyma outside the ventricular system. Histopathological characteristics resemble those of central neurocytoma but exhibit a wider morphologic spectrum. Accurate diagnosis of these histologically heterogeneous tumors is often challenging because of the overlapping morphological features and the lack of defining molecular markers. Here, we explored the molecular landscape of 40 tumors diagnosed histologically as EVN by investigating copy number profiles and DNA methylation array data. DNA methylation profiles were compared with those of relevant differential diagnoses of EVN and with a broader spectrum of diverse brain tumor entities. Based on this, our tumor cohort segregated into different groups. While a large fraction (n = 22) formed a separate epigenetic group clearly distinct from established DNA methylation profiles of other entities, a subset (n = 14) of histologically diagnosed EVN grouped with clusters of other defined entities. Three cases formed a small group close to but separated from the epigenetically distinct EVN cases, and one sample clustered with non-neoplastic brain tissue. Four additional samples originally diagnosed otherwise were found to molecularly resemble EVN. Thus, our results highlight a distinct DNA methylation pattern for the majority of tumors diagnosed as EVN, but also indicate that approximately one third of morphological diagnoses of EVN epigenetically correspond to other brain tumor entities. Copy number analysis and confirmation through RNA sequencing revealed FGFR1-TACC1 fusion as a distinctive, recurrent feature within the EVN methylation group (60%), in addition to a small number of other FGFR rearrangements (13%). In conclusion, our data demonstrate a specific epigenetic signature of EVN suitable for characterization of these tumors as a molecularly distinct entity, and reveal a high frequency of potentially druggable FGFR pathway activation in this tumor group.
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http://dx.doi.org/10.1007/s00401-018-1882-3DOI Listing
August 2018

Aβ dimers induce behavioral and neurochemical deficits of relevance to early Alzheimer's disease.

Neurobiol Aging 2018 09 17;69:1-9. Epub 2018 Apr 17.

Center for Behavioral Neuroscience, Institute of Experimental Psychology, University of Düsseldorf, Düsseldorf, Germany.

We examined behaviors and neurotransmitter levels in the tgDimer mouse, a model for early Alzheimer's disease, that expresses exclusively soluble amyloid beta (Aβ) dimers and is devoid of Aβ plaques, astrogliosis, and neuroinflammation. Seven-month-old mice were subjected to tests of motor activity, attention, anxiety, habituation learning, working memory, and depression-related behaviors. They were impaired in nonselective attention and motor learning and showed anxiety- and despair-related behaviors. In 7- and 12-month-old mice, levels of acetylcholine, dopamine, and serotonin were measured in neostriatum, ventral striatum, prefrontal cortex, hippocampus, amygdala, and entorhinal cortex by high-performance liquid chromatography. The tgDimer mice had lower serotonin turnover rates in hippocampus, ventral striatum, and amygdala relative to wild type controls. The aged tgDimer mice had less hippocampal acetylcholine than adult tgDimers. Stress-test results, based on corticosterone levels, indicated an intact hypothalamus-pituitary-adrenal axis in 12-month-old mice. Since neither Aβ plaques nor astrogliosis or neuroinflammation was responsible for these phenotypes, we conclude that Aβ dimers contribute to neurotransmitter dysfunction and behavioral impairments, characteristic for the early stages of Alzheimer's disease.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.04.005DOI Listing
September 2018

Higher levels of kallikrein-8 in female brain may increase the risk for Alzheimer's disease.

Brain Pathol 2018 11 10;28(6):947-964. Epub 2018 Apr 10.

Institute of Neuropathology, University of Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany.

Women seem to have a higher vulnerability to Alzheimer's disease (AD), but the underlying mechanisms of this sex dichotomy are not well understood. Here, we first determined the influence of sex on various aspects of Alzheimer's pathology in transgenic CRND8 mice. We demonstrate that beta-amyloid (Aβ) plaque burden starts to be more severe around P180 (moderate disease stage) in female transgenics when compared to males and that aging aggravates this sex-specific difference. Furthermore, we show that female transgenics suffer from higher levels of neurovascular dysfunction around P180, resulting in impaired Aβ peptide clearance across the blood-brain-barrier at P360. Female transgenics show also higher levels of diffuse microgliosis and inflammation, but the density of microglial cells surrounding Aβ plaques is less in females. In line with this finding, testosterone compared to estradiol was able to improve microglial viability and Aβ clearance in vitro. The spatial memory of transgenics was in general poorer than in wildtypes and at P360 worse in females irrespective of their genotype. This difference was accompanied by a slightly diminished dendritic complexity in females. While all the above-named sex-differences emerged after the onset of Aβ pathology, kallikrein-8 (KLK8) protease levels were, as an exception, higher in female than in male brains very early when virtually no plaques were detectable. In a second step, we quantified cerebral KLK8 levels in AD patients and healthy controls, and could ascertain, similar to mice, higher KLK8 levels not only in AD-affected but also in healthy brains of women. Accordingly, we could demonstrate that estradiol but not testosterone induces KLK8 synthesis in neuronal and microglial cells. In conclusion, multiple features of AD are more pronounced in females. Here, we show for the first time that this sex-specific difference may be meditated by estrogen-induced KLK8 overproduction long before AD pathology emerges.
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http://dx.doi.org/10.1111/bpa.12599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028555PMC
November 2018

Repeated Systemic Treatment with Rapamycin Affects Behavior and Amygdala Protein Expression in Rats.

Int J Neuropsychopharmacol 2018 06;21(6):592-602

Institute of Medical Psychology and Behavioral Immunobiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Background: Clinical data indicate that therapy with small-molecule immunosuppressive drugs is frequently accompanied by an incidence rate of neuropsychiatric symptoms. In the current approach, we investigated in rats whether repeated administration of rapamycin, reflecting clinical conditions of patients undergoing therapy with this mammalian target of rapamycin inhibitor, precipitates changes in neurobehavioral functioning.

Methods: Male adult Dark Agouti rats were daily treated with i.p. injections of rapamycin (1, 3 mg/kg) or vehicle for 8 days. On days 6 and 7, respectively, behavioral performance in the Elevated Plus-Maze and the Open-Field Test was evaluated. One day later, amygdala tissue and blood samples were taken to analyze protein expression ex vivo.

Results: The results show that animals treated with rapamycin displayed alterations in Elevated Plus-Maze performance with more pronounced effects in the higher dose group. Besides, an increase in glucocorticoid receptor density in the amygdala was seen in both treatment groups even though p-p70 ribosomal S6 kinase alpha, a marker for mammalian target of rapamycin functioning, was not affected. Protein level of the neuronal activity marker c-Fos was again only elevated in the higher dose group. Importantly, effects occurred in the absence of acute peripheral neuroendocrine changes.

Conclusions: Our findings indicate that anxiety-related behavior following rapamycin treatment was not directly attributed to mTOR-dependent mechanisms or stress but rather due to hyperexcitability of the amygdala together with glucocorticoid receptor-regulated mechanism(s) in this brain region. Together, the present results support the contention that subchronic treatment with rapamycin may induce neurobehavioral alterations in healthy, naive subjects. We here provide novel insights in central effects of systemic rapamycin in otherwise healthy subjects but also raise the question whether therapy with this drug may have detrimental effects on patients' neuropsychological functioning during immune therapy.
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http://dx.doi.org/10.1093/ijnp/pyy017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6007742PMC
June 2018

Association of primary central nervous system vasculitis with the presence of specific human leucocyte antigen gene variant.

Clin Neurol Neurosurg 2017 Sep 23;160:137-141. Epub 2017 Jun 23.

Department of Neurology, Alfried-Krupp-von Bohlen und Halbach Hospital, Alfried-Krupp-Straße 21, 45130 Essen, Germany.

Objectives: The etiology and genetic susceptibility of primary central nervous system vasculitis (PCNSV) are still unclear.

Patients And Methods: We analyzed the DNA of 25 Caucasian patients with PCNSV for human leucocyte antigen genes HLA-A, HLA-B, HLA-DRB1, and HLA-DQB1, respectively. HLA-frequencies of the 25 patients with PCNSV were compared with HLA-frequencies of matched Caucasian controls.

Results: No statistically significant associations were found for HLA-B, HLA-DR1 and HLA-DQB1 variant. In the PCNSV group, only the HLA-A*69 variant was found more often than expected statistically.

Conclusion: The results of this study indicate a potential association of HLA marker with PCNSV in Caucasian patients. Further studies are needed to elucidate the role of genes within the human major histocompatibility complex in the pathogenesis of this angiopathy.
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http://dx.doi.org/10.1016/j.clineuro.2017.06.009DOI Listing
September 2017

Response letter.

Authors:
Kathy Keyvani

Alzheimers Dement 2017 09 8;13(9):1070-1071. Epub 2017 Jul 8.

Institute of Neuropathology, University of Duisburg-Essen, Essen, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jalz.2017.06.003DOI Listing
September 2017

EphB4 forward signalling mediates angiogenesis caused by CCM3/PDCD10-ablation.

J Cell Mol Med 2017 09 1;21(9):1848-1858. Epub 2017 Apr 1.

Department of Neurosurgery, University of Duisburg-Essen, Essen, Germany.

CCM3, also named as PDCD10, is a ubiquitous protein expressed in nearly all tissues and in various types of cells. It is essential for vascular development and post-natal vessel maturation. Loss-of-function mutation of CCM3 predisposes for the familial form of cerebral cavernous malformation (CCM). We have previously shown that knock-down of CCM3 stimulated endothelial angiogenesis via impairing DLL4-Notch signalling; moreover, loss of endothelial CCM3 stimulated tumour angiogenesis and promoted tumour growth. The present study was designed to further elucidate the inside signalling pathway involved in CCM3-ablation-mediated angiogenesis. Here we report for the first time that silencing endothelial CCM3 led to a significant up-regulation of EphB4 mRNA and protein expression and to an increased kinase activity of EphB4, concomitantly accompanied by an activation of Erk1/2, which was reversed by treatment with the specific EphB4 kinase inhibitor NVP-BHG712 (NVP), indicating that silencing CCM3 activates EphB4 kinase forward signalling. Furthermore, treatment with NVP rescued the hyper-angiogenic phenotype induced by knock-down of endothelial CCM3 in vitro and in vivo. Additional study demonstrated that the activation of EphB4 forward signalling in endothelial cells under basal condition and after CCM3-silence was modulated by DLL4/Notch signalling, relying EphB4 at downstream of DLL4/Notch signalling. We conclude that angiogenesis induced by CCM3-silence is mediated by the activation of EphB4 forward signalling. The identified endothelial signalling pathway of CCM3-DLL4/Notch-EphB4-Erk1/2 may provide an insight into mechanism of CCM3-ablation-mediated angiogenesis and could potentially contribute to novel therapeutic concepts for disrupting aberrant angiogenesis in CCM and in hyper-vascularized tumours.
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http://dx.doi.org/10.1111/jcmm.13105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571521PMC
September 2017
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