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A light microscopy-based histopathology diagnosis of human brain specimens obtained from epilepsy surgery remains the gold standard to confirm the underlying cause of a patient's focal epilepsy and further inform postsurgical patient management. The differential diagnosis of neocortical specimens in the realm of epilepsy surgery remains, however, challenging. Herein, we developed an open access, deep learning-based classifier to histopathologically assess whole slide microscopy images (WSI) and to automatically recognize various subtypes of Focal Cortical Dysplasia (FCD), according to the ILAE consensus classification update of 2022. We trained a convolutional neuronal network (CNN) with fully digitalized WSI of hematoxylin–eosin stainings obtained from 125 patients covering the spectrum of mild malformation of cortical development (mMCD), mMCD with oligodendroglial hyperplasia in epilepsy (MOGHE), FCD ILAE Type 1a, 2a and 2b using 414 formalin-fixed and paraffin-embedded archival tissue blocks. An additional series of 198 postmortem tissue blocks from 59 patients without neurological disorders served as control to train the CNN for homotypic frontal, temporal and occipital areas and heterotypic Brodmann areas 4 and 17, entorhinal cortex and dentate gyrus. Special stains and immunohistochemical reactions were used to comprehensively annotate the region of interest. We then programmed a novel tile extraction pipeline and graphical dashboard to visualize all areas on the WSI recognized by the CNN. Our deep learning-based classifier is able to compute 1000 × 1000 µm large tiles and recognizes 25 anatomical regions and FCD categories with an accuracy of 98.8% (F1 score = 0.82). Microscopic review of regions predicted by the network confirmed these results. This deep learning-based classifier will be made available as online web application to support the differential histopathology diagnosis in neocortical human brain specimens obtained from epilepsy surgery. It will also serve as blueprint to build a digital histopathology slide suite addressing all major brain diseases encountered in patients with surgically amenable focal epilepsy. [ABSTRACT FROM AUTHOR]

Purpose: Glioblastoma is associated with especially poor outcome in the elderly. It is unclear if patients aged ≥80 years benefit from tumor-specific therapy as opposed to receiving best supportive care (BSC) only. Methods: Patients with IDH-wildtype glioblastoma (WHO 2021), aged ≥80 years, and diagnosed by biopsy between 2010 and 2022 were included. Patient characteristics and clinical parameters were assessed. Uni- and multivariate analyses were performed. Results: 76 patients with a median age of 82 (range 80–89) and a median initial KPS of 80 (range 50–90) were included. Tumor-specific therapy was initiated in 52 patients (68%). 22 patients (29%) received temozolomide monotherapy, 23 patients (30%) were treated with radiotherapy (RT) alone and 7 patients (9%) received combination therapies. In 24 patients (32%), tumor-specific therapy was omitted in lieu of BSC. Overall survival (OS) was longer in patients receiving tumor-specific therapy (5.4 vs. 3.3 months, p < 0.001). Molecular stratification showed that the survival benefit was owed to patients with MGMT promoter methylation (MGMTpos) who received tumor-specific therapy as opposed to BSC (6.2 vs. 2.6 months, p < 0.001), especially to those with better clinical status and no initial polypharmacy. Patients with unmethylated MGMT promoter (MGMTneg) did not benefit from tumor-specific therapy (3.6 vs. 3.7 months, p = 0.18). In multivariate analyses, better clinical status and MGMT promoter methylation were associated with prolonged survival (p < 0.01 and p = 0.01). Conclusion: Benefit from tumor-specific treatment in patients with newly diagnosed glioblastoma aged ≥80 years might be restricted to MGMTpos patients, especially to those with good clinical status and no polypharmacy. [ABSTRACT FROM AUTHOR]

MC - methylation classes: Ganglioglioma with adverse clinical outcome (GG, PTPN11), Ganglioglioma (LGG, GG), Pleomorphic Xantoastrocytoma (LGG, PXA), (also see Fig. [Extracted from the article]

Exome-wide sequencing studies recently described PTPN11 as a novel brain somatic epilepsy gene. In contrast, germline mutations of PTPN11 are known to cause Noonan syndrome, a multisystem disorder characterized by abnormal facial features, developmental delay, and sporadically, also brain tumors. Herein, we performed a deep phenotype-genotype analysis of a comprehensive series of ganglioglioma (GG) with brain somatic alterations of the PTPN11/KRAS/NF1 genes compared to GG with common MAP-Kinase signaling pathway alterations, i.e., BRAFV600E. Seventy-two GG were submitted to whole exome sequencing and genotyping and 84 low grade epilepsy associated tumors (LEAT) to DNA-methylation analysis. In 28 tumours, both analyses were available from the same sample. Clinical data were retrieved from hospital files including disease onset, age at surgery, brain localization, and seizure outcome. A comprehensive histopathology staining panel was available in all cases. We identified eight GG with PTPN11 alterations, copy number variant (CNV) gains of chromosome 12, and the commonality of additional CNV gains in NF1, KRAS, FGFR4 and RHEB, as well as BRAFV600E alterations. Histopathology revealed an atypical glio-neuronal phenotype with subarachnoidal tumor spread and large, pleomorphic, and multinuclear cellular features. Only three out of eight patients with GG and PTPN11/KRAS/NF1 alterations were free of disabling-seizures 2 years after surgery (38% had Engel I). This was remarkably different from our series of GG with only BRAFV600E mutations (85% had Engel I). Unsupervised cluster analysis of DNA methylation arrays separated these tumours from well-established LEAT categories. Our data point to a subgroup of GG with cellular atypia in glial and neuronal cell components, adverse postsurgical outcome, and genetically characterized by complex alterations in PTPN11 and other RAS-/MAP-Kinase and/or mTOR signaling pathways. These findings need prospective validation in clinical practice as they argue for an adaptation of the WHO grading system in developmental, glio-neuronal tumors associated with early onset focal epilepsy. [ABSTRACT FROM AUTHOR]

Purpose: Glioma patients, especially recurrent glioma, suffer from a poor prognosis. While advances to classify glioma on a molecular level improved prognostication at initial diagnosis, markers to prognosticate survival in the recurrent situation are still needed. As 18 kDa translocator protein (TSPO) was previously reported to be associated with aggressive histopathological glioma features, we correlated the TSPO positron emission tomography (PET) signal using [18F]GE180 in a large cohort of recurrent glioma patients with their clinical outcome. Methods: In patients with [18F]GE180 PET at glioma recurrence, [18F]GE180 PET parameters (e.g., SUVmax) as well as other imaging features (e.g., MRI volume, [18F]FET PET parameters when available) were evaluated together with patient characteristics (age, sex, Karnofsky-Performance score) and neuropathological features (e.g. WHO 2021 grade, IDH-mutation status). Uni- and multivariate Cox regression and Kaplan–Meier survival analyses were performed to identify prognostic factors for post-recurrence survival (PRS) and time to treatment failure (TTF). Results: Eighty-eight consecutive patients were evaluated. TSPO tracer uptake correlated with tumor grade at recurrence (p < 0.05), with no significant differences in IDH-wild-type versus IDH-mutant tumors. Within the subgroup of IDH-mutant glioma (n = 46), patients with low SUVmax (median split, ≤ 1.60) had a significantly longer PRS (median 41.6 vs. 25.3 months, p = 0.031) and TTF (32.2 vs 8.7 months, p = 0.001). Also among IDH-wild-type glioblastoma (n = 42), patients with low SUVmax (≤ 1.89) had a significantly longer PRS (median not reached vs 8.2 months, p = 0.002). SUVmax remained an independent prognostic factor for PRS in the multivariate analysis including CNS WHO 2021 grade, IDH status, and age. Tumor volume defined by [18F]FET PET or contrast-enhanced MRI correlated weakly with TSPO tracer uptake. Treatment regimen did not differ among the median split subgroups. Conclusion: Our data suggest that TSPO PET using [18F]GE180 can help to prognosticate recurrent glioma patients even among homogeneous molecular subgroups and may therefore serve as valuable non-invasive biomarker for individualized patient management. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to build and evaluate a prediction model which incorporates clinical parameters and radiomic features extracted from static as well as dynamic [18F]FET PET for the survival stratification in patients with newly diagnosed IDH-wildtype glioblastoma. Methods: A total of 141 patients with newly diagnosed IDH-wildtype glioblastoma and dynamic [18F]FET PET prior to surgical intervention were included. Patients with a survival time ≤ 12 months were classified as short-term survivors. First order, shape, and texture radiomic features were extracted from pre-treatment static (tumor-to-background ratio; TBR) and dynamic (time-to-peak; TTP) images, respectively, and randomly divided into a training (n = 99) and a testing cohort (n = 42). After feature normalization, recursive feature elimination was applied for feature selection using 5-fold cross-validation on the training cohort, and a machine learning model was constructed to compare radiomic models and combined clinical-radiomic models with selected radiomic features and clinical parameters. The area under the ROC curve (AUC), accuracy, sensitivity, specificity, and positive and negative predictive values were calculated to assess the predictive performance for identifying short-term survivors in both the training and testing cohort. Results: A combined clinical-radiomic model comprising six clinical parameters and six selected dynamic radiomic features achieved highest predictability of short-term survival with an AUC of 0.74 (95% confidence interval, 0.60–0.88) in the independent testing cohort. Conclusions: This study successfully built and evaluated prediction models using [18F]FET PET-based radiomic features and clinical parameters for the individualized assessment of short-term survival in patients with a newly diagnosed IDH-wildtype glioblastoma. The combination of both clinical parameters and dynamic [18F]FET PET–based radiomic features reached highest accuracy in identifying patients at risk. Although the achieved accuracy level remained moderate, our data shows that the integration of dynamic [18F]FET PET radiomic data into clinical prediction models may improve patient stratification beyond established prognostic markers. [ABSTRACT FROM AUTHOR]

Parkinson´s disease (PD) pathology progresses throughout the nervous system. Whereas motor symptoms are always present, there is a high variability in the prevalence of non-motor symptoms. It has been postulated that the progression of the pathology is based on a prion-like disease mechanism partly due to the seeding effect of endocytosed-alpha-synuclein (ASYN) on the endogenous ASYN. Here, we analyzed the role of endogenous ASYN in the progression of PD-like pathology in vivo and in vitro and compared the effect of endocytosed-ASYN as well as paraquat and rotenone on primary enteric, dopaminergic and cortical neurons from wild-type and ASYN-KO mice. Our results show that, in vivo, pathology progression did not occur in the absence of endogenous ASYN. Remarkably, the damage caused by endocytosed-ASYN, rotenone or paraquat was independent from endogenous ASYN and related to the alteration of the host´s mitochondrial membrane potential. Dopaminergic neurons were very sensitive to these noxae compared to other neuronal subtypes. These results suggest that ASYN-mitochondrial interactions play a major role in initiating the pathological process in the host neuron and endogenous ASYN is essential for the transsynaptical transmission of the pathology. Our results also suggest that protecting mitochondrial function is a valid primary therapeutic target. [ABSTRACT FROM AUTHOR]

Tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) exhibit characteristic neuronal and glial inclusions of hyperphosphorylated Tau (pTau). Although the astrocytic pTau phenotype upon neuropathological examination is the most guiding feature in distinguishing both diseases, regulatory mechanisms controlling their transitions into disease-specific states are poorly understood to date. Here, we provide accessible chromatin data of more than 45,000 single nuclei isolated from the frontal cortex of PSP, CBD, and control individuals. We found a strong association of disease-relevant molecular changes with astrocytes and demonstrate that tauopathy-relevant genetic risk variants are tightly linked to astrocytic chromatin accessibility profiles in the brains of PSP and CBD patients. Unlike the established pathogenesis in the secondary tauopathy Alzheimer disease, microglial alterations were relatively sparse. Transcription factor (TF) motif enrichments in pseudotime as well as modeling of the astrocytic TF interplay suggested a common pTau signature for CBD and PSP that is reminiscent of an inflammatory immediate-early response. Nonetheless, machine learning models also predicted discriminatory features, and we observed marked differences in molecular entities related to protein homeostasis between both diseases. Predicted TF involvement was supported by immunofluorescence analyses in postmortem brain tissue for their highly correlated target genes. Collectively, our data expand the current knowledge on risk gene involvement (e.g., MAPT, MAPK8, and NFE2L2) and molecular pathways leading to the phenotypic changes associated with CBD and PSP. [ABSTRACT FROM AUTHOR]

Progressive respiratory failure and hyperinflammatory response is the primary cause of death in the coronavirus disease 2019 (COVID-19) pandemic. Despite mounting evidence of disruption of the hypothalamus-pituitary-adrenal axis in COVID-19, relatively little is known about the tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to adrenal glands and associated changes. Here we demonstrate adrenal viral tropism and replication in COVID-19 patients. Adrenal glands showed inflammation accompanied by inflammatory cell death. Histopathologic analysis revealed widespread microthrombosis and severe adrenal injury. In addition, activation of the glycerophospholipid metabolism and reduction of cortisone intensities were characteristic for COVID-19 specimens. In conclusion, our autopsy series suggests that SARS-CoV-2 facilitates the induction of adrenalitis. Given the central role of adrenal glands in immunoregulation and taking into account the significant adrenal injury observed, monitoring of developing adrenal insufficiency might be essential in acute SARS-CoV-2 infection and during recovery. Progressive respiratory failure is the primary cause of death in patients with COVID-19, but pathologies in other tissues may also occur. Here the authors report that adrenal tropism of SARS-CoV-2 is associated with adrenalitis, reduced adrenal cortisol levels and severe adrenal damage in a post-mortem case series of patients with severe fatal COVID-19. [ABSTRACT FROM AUTHOR]

Introduction: The cIMPACT-NOW update 6 first introduced glioblastoma diagnosis based on the combination of IDH-wildtype (IDHwt) status and TERT promotor mutation (pTERTmut). In glioblastoma as defined by histopathology according to the WHO 2016 classification, MGMT promotor status is associated with outcome. Whether this is also true in glioblastoma defined by molecular markers is yet unclear. Methods: We searched the institutional database for patients with: (1) glioblastoma defined by histopathology; and (2) IDHwt astrocytoma with pTERTmut. MGMT promotor methylation was analysed using methylation-specific PCR and Sanger sequencing of CpG sites within the MGMT promotor region. Results: We identified 224 patients with glioblastoma diagnosed based on histopathology, and 54 patients with IDHwt astrocytoma with pTERTmut (19 astrocytomas WHO grade II and 38 astrocytomas WHO grade III). There was no difference in the number of MGMT methylated tumors between the two cohorts as determined per PCR, and also neither the number nor the pattern of methylated CpG sites differed as determined per Sanger sequencing. Progression-free (PFS) and overall survival (OS) was similar between the two cohorts when treated with radio- or chemotherapy. In both cohorts, higher numbers of methylated CpG sites were associated with favourable outcome. Conclusions: Extent and pattern of methylated CpG sites are similar in glioblastoma and IDHwt astrocytoma with pTERTmut. In both tumor entities, higher numbers of methylated CpG sites appear associated with more favourable outcome. Evaluation in larger prospective cohorts is warranted. [ABSTRACT FROM AUTHOR]

Background: O-(2-[18F]-fluoroethyl)-L-tyrosine (18F-FET) is a highly sensitive PET tracer for glioma imaging, and its uptake is suggested to be driven by an overexpression of the L-type amino-acid transporter 1 (LAT1). However, 30% of low- and 5% of high-grade gliomas do not present enhanced 18F-FET uptake at primary diagnosis ("18F-FET-negative gliomas") and the pathophysiologic basis for this phenomenon remains unclear. The aim of this study was to determine the expression of LAT1 in a homogeneous group of newly diagnosed 18F-FET-negative gliomas and to compare them to a matched group of 18F-FET-positive gliomas. Forty newly diagnosed IDH-mutant astrocytomas without 1p/19q codeletion were evaluated (n = 20 18F-FET-negative (tumour-to-background ratio (TBR) < 1.6), n = 20 18F-FET-positive gliomas (TBR > 1.6)). LAT1 immunohistochemistry (IHC) was performed using SLC7A5/LAT1 antibody. The percentage of LAT1-positive tumour cells (%) and the staining intensity (range 0–2) were multiplied to an overall score (H-score; range 0–200) and correlated to PET findings as well as progression-free survival (PFS). Results: IHC staining of LAT1 expression was positive in both, 18F-FET-positive as well as 18F-FET-negative gliomas. No differences were found between the 18F-FET-negative and 18F-FET-positive group with regard to percentage of LAT1-positive tumour cells, staining intensity or H-score. Interestingly, the LAT1 expression showed a significant negative correlation with the PFS (p = 0.031), whereas no significant correlation was found for TBRmax, neither in the overall group nor in the 18F-FET-positive group only (p = 0.651 and p = 0.140). Conclusion: Although LAT1 is reported to mediate the uptake of 18F-FET into tumour cells, the levels of LAT1 expression do not correlate with the levels of 18F-FET uptake in IDH-mutant astrocytomas. In particular, the lack of tracer uptake in 18F-FET-negative gliomas cannot be explained by a reduced LAT1 expression. A higher LAT1 expression in IDH-mutant astrocytomas seems to be associated with a short PFS. Further studies regarding mechanisms influencing the uptake of 18F-FET are necessary. [ABSTRACT FROM AUTHOR]

Purpose: Pituitary adenoma (PA) constitutes the third most common intracranial neoplasm. The mostly benign endocrine lesions express no hormone (null cell PA) or the pituitary hormone(s) of the cell lineage of origin. In 0.5–1.5% of surgical specimens and in up to 10% of autopsy cases, two or three seemingly separate PA may coincide. These multiple adenomas may express different hormones, but whether or not expression of lineage-restricted transcription factors and molecular features are distinct within multiple lesions remains unknown. Methods: Searching the data bank of the German Pituitary Tumor Registry 12 double pituitary adenomas with diverse lineage were identified among 3654 adenomas and 6 hypophyseal carcinomas diagnosed between 2012 and 2020. The double adenomas were investigated immunohistochemically for expression of hormones and lineage markers. In addition, chromosomal gains and losses as well as global DNA methylation profiles were assessed, whenever sufficient material was available (n = 8 PA). Results: In accordance with the literature, combinations of GH/prolactin/TSH–FSH/LH adenoma (4/12), GH/prolactin/TSH–ACTH adenoma (3/12), and ACTH–FSH/LH adenoma (3/12) were observed. Further, two out of 12 cases showed a combination of a GH/prolactin/TSH adenoma with a null-cell adenoma. Different expression pattern of hormones were confirmed by different expression of transcription factors in 11/12 patients. Finally, multiple lesions that were molecularly analysed in 4 patients displayed distinct copy number changes and global methylation pattern. Conclusion: Our data confirm and extend the knowledge on multiple PA and suggest that such lesions may origin from distinct cell types. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate radiomic features extracted from standard static images (20–40 min p.i.), early summation images (5–15 min p.i.), and dynamic [18F]FET PET images for the prediction of TERTp-mutation status in patients with IDH-wildtype high-grade glioma. Methods: A total of 159 patients (median age 60.2 years, range 19–82 years) with newly diagnosed IDH-wildtype diffuse astrocytic glioma (WHO grade III or IV) and dynamic [18F]FET PET prior to surgical intervention were enrolled and divided into a training (n = 112) and a testing cohort (n = 47) randomly. First-order, shape, and texture radiomic features were extracted from standard static (20–40 min summation images; TBR20–40), early static (5–15 min summation images; TBR5–15), and dynamic (time-to-peak; TTP) images, respectively. Recursive feature elimination was used for feature selection by 10-fold cross-validation in the training cohort after normalization, and logistic regression models were generated using the radiomic features extracted from each image to differentiate TERTp-mutation status. The areas under the ROC curve (AUC), accuracy, sensitivity, specificity, and positive and negative predictive value were calculated to illustrate diagnostic power in both the training and testing cohort. Results: The TTP model comprised nine selected features and achieved highest predictability of TERTp-mutation with an AUC of 0.82 (95% confidence interval 0.71–0.92) and sensitivity of 92.1% in the independent testing cohort. Weak predictive capability was obtained in the TBR5–15 model, with an AUC of 0.61 (95% CI 0.42–0.80) in the testing cohort, while no predictive power was observed in the TBR20–40 model. Conclusions: Radiomics based on TTP images extracted from dynamic [18F]FET PET can predict the TERTp-mutation status of IDH-wildtype diffuse astrocytic high-grade gliomas with high accuracy preoperatively. [ABSTRACT FROM AUTHOR]

The current classification of sporadic Creutzfeldt–Jakob disease (sCJD) includes six major clinicopathological subtypes defined by the physicochemical properties of the protease-resistant core of the pathologic prion protein (PrPSc), defining two major PrPSc types (i.e., 1 and 2), and the methionine (M)/valine (V) polymorphic codon 129 of the prion protein gene (PRNP). How these sCJD subtypes relate to the well-documented phenotypic heterogeneity of genetic CJD (gCJD) is not fully understood. We analyzed molecular and phenotypic features in 208 individuals affected by gCJD, carrying 17 different mutations, and compared them with those of a large series of sCJD cases. We identified six major groups of gCJD based on the combination PrPSc type and codon 129 genotype on PRNP mutated allele, each showing distinctive histopathological characteristics, irrespectively of the PRNP associated mutation. Five gCJD groups, named M1, M2C, M2T, V1, and V2, largely reproduced those previously described in sCJD subtypes. The sixth group shared phenotypic traits with the V2 group and was only detected in patients carrying the E200K-129M haplotype in association with a PrPSc type of intermediate size ("i") between type 1 and type 2. Additional mutation-specific effects involved the pattern of PrP deposition (e.g., a "thickened" synaptic pattern in E200K carriers, cerebellar "stripe-like linear granular deposits" in those with insertion mutations, and intraneuronal globular dots in E200K-V2 or -M"i"). A few isolated cases linked to rare PRNP haplotypes (e.g., T183A-129M), showed atypical phenotypic features, which prevented their classification into the six major groups. The phenotypic variability of gCJD is mostly consistent with that previously found in sCJD. As in sCJD, the codon 129 genotype and physicochemical properties of PrPSc significantly correlated with the phenotypic variability of gCJD. The most common mutations linked to CJD appear to have a variable and overall less significant effect on the disease phenotype, but they significantly influence disease susceptibility often in a strain-specific manner. The criteria currently used for sCJD subtypes can be expanded and adapted to gCJD to provide an updated classification of the disease with a molecular basis. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the most common neurodegenerative movement disorder and is characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and the gradual appearance of α-synuclein (α-syn)-containing neuronal protein aggregates. Although the exact mechanism of α-syn-mediated cell death remains elusive, recent research suggests that α-syn-induced alterations in neuronal excitability contribute to cell death in PD. Because the fragile X mental retardation protein (FMRP) controls the expression and function of numerous neuronal genes related to neuronal excitability and synaptic function, we here investigated the role of FMRP in α-syn-associated pathological changes in cell culture and mouse models of PD as well as in post-mortem human brain tissue from PD patients. We found FMRP to be decreased in cultured DA neurons and in the mouse brain in response to α-syn overexpression. FMRP was, furthermore, lost in the SNc of PD patients and in patients with early stages of incidental Lewy body disease (iLBD). Unlike fragile X syndrome (FXS), FMR1 expression in response to α-syn was regulated by a mechanism involving Protein Kinase C (PKC) and cAMP response element-binding protein (CREB). Reminiscent of FXS neurons, α-syn-overexpressing cells exhibited an increase in membrane N-type calcium channels, increased phosphorylation of ERK1/2, eIF4E and S6, increased overall protein synthesis, and increased expression of Matrix Metalloproteinase 9 (MMP9). FMRP affected neuronal function in a PD animal model, because FMRP-KO mice were resistant to the effect of α-syn on striatal dopamine release. In summary, our results thus reveal a new role of FMRP in PD and support the examination of FMRP-regulated genes in PD disease progression. [ABSTRACT FROM AUTHOR]

Cognitive decline and dementia in neurodegenerative diseases are associated with synapse dysfunction and loss, which may precede neuron loss by several years. While misfolded and aggregated α-synuclein is recognized in the disease progression of synucleinopathies, the nature of glutamatergic synapse dysfunction and loss remains incompletely understood. Using fluorescence-activated synaptosome sorting (FASS), we enriched excitatory glutamatergic synaptosomes from mice overexpressing human alpha-synuclein (h-αS) and wild-type littermates to unprecedented purity. Subsequent label-free proteomic quantification revealed a set of proteins differentially expressed upon human alpha-synuclein overexpression. These include overrepresented proteins involved in the synaptic vesicle cycle, ER–Golgi trafficking, metabolism and cytoskeleton. Unexpectedly, we found and validated a steep reduction of eukaryotic translation elongation factor 1 alpha (eEF1A1) levels in excitatory synapses at early stages of h-αS mouse model pathology. While eEF1A1 reduction correlated with the loss of postsynapses, its immunoreactivity was found on both sides of excitatory synapses. Moreover, we observed a reduction in eEF1A1 immunoreactivity in the cingulate gyrus neuropil of patients with Lewy body disease along with a reduction in PSD95 levels. Altogether, our results suggest a link between structural impairments underlying cognitive decline in neurodegenerative disorders and local synaptic defects. eEF1A1 may therefore represent a limiting factor to synapse maintenance. [ABSTRACT FROM AUTHOR]

Purpose: According to the updated WHO classification of gliomas with its emphasis on molecular parameters, tumours with an IDH-wildtype status have a dismal prognosis. To ensure timely adjustment of treatment, demand for non-invasive prediction methods is high. 18F-FET PET has been shown to be an important diagnostic tool for glioma management. The aim of this study was to assess the value of dynamic 18F-FET PET for the non-invasive prediction of the IDH-mutation status. Methods: Newly diagnosed WHO grade II–IV glioma patients with MRI and dynamic 18F-FET PET were included. The 18F-FET PET parameters mean and maximal tumour-to-background ratio (TBRmean, TBRmax) and minimal time-to-peak (TTPmin) were evaluated. The diagnostic power for the prediction of the IDH genotype (positive/negative predictive value) was tested in the overall study group and in the subgroup of non-contrast enhancing gliomas. Results: Three hundred forty-one patients were evaluated. Molecular analyses revealed 178 IDH-mutant and 163 IDH-wildtype tumours. Overall, 270/341 gliomas were classified as 18F-FET-positive (TBRmax > 1.6), 90.2% of the IDH-wildtype and 69.1% of IDH-mutant gliomas. Median TBRmax was significantly higher in IDH-wildtype compared with IDH-mutant gliomas (2.9 vs. 2.3, p < 0.001); however, ROC-analyses revealed no reliable cutoff due to a high overlap (range 1.0–7.1 vs. 1.1–7.9). Dynamic analysis revealed a significantly shorter TTPmin in IDH-wildtype gliomas; using TTPmin ≤ 12.5 min as indicator for IDH-wildtype gliomas, a positive predictive value of 87% was reached (negative predictive value 72%, AUC = 0.796, p ≤ 0.001). A total of 161/341 gliomas did not show contrast enhancement on MRI; even within this subgroup, TTPmin ≤ 12.5 min remained a good predictor of IDH-wildtype glioma (positive predictive value 83%, negative predictive value 90%; AUC = 0.868, p < 0.001). Conclusion: A short TTPmin in dynamic 18F-FET PET serves as good predictor of highly aggressive IDH-wildtype status in gliomas. In particular, a high diagnostic power was observed in the subgroup of non-contrast enhancing gliomas, which helps to identify patients with worse prognosis. [ABSTRACT FROM AUTHOR]

Messenger RNA (mRNA) translation is the terminal step in protein synthesis, providing a crucial regulatory checkpoint for this process. Translational control allows specific cell types to respond to rapid changes in the microenvironment or to serve specific functions. For example, neurons use mRNA transport to achieve local protein synthesis at significant distances from the nucleus, the site of RNA transcription. Altered expression or functions of the various components of the translational machinery have been linked to several pathologies in the central nervous system. In this review, we provide a brief overview of the basic principles of mRNA translation, and discuss alterations of this process relevant to CNS disease conditions, with a focus on brain tumors and chronic neurological conditions. Finally, synthesizing this knowledge, we discuss the opportunities to exploit the biology of altered mRNA translation for novel therapies in brain disorders, as well as how studying these alterations can shed new light on disease mechanisms. [ABSTRACT FROM AUTHOR]

Diffuse midline glioma (DMG), H3 K27M mutant (WHO grade IV) is listed as a separate CNS tumor entity since 2016 [[5]], after large sequencing efforts had discovered H3 K27M mutations frequently appearing in gliomas located in midline structures [[11]]. So, the parallel occurrence of H3 and I FGFR1/BRAF i mutations within a single tumor may complicate the diagnostic decision towards a low grade or a high grade glioma. [Extracted from the article]

BACE1 is the rate-limiting protease in the production of synaptotoxic β-amyloid (Aβ) species and hence one of the prime drug targets for potential therapy of Alzheimer’s disease (AD). However, so far pharmacological BACE1 inhibition failed to rescue the cognitive decline in mild-to-moderate AD patients, which indicates that treatment at the symptomatic stage might be too late. In the current study, chronic in vivo two-photon microscopy was performed in a transgenic AD model to monitor the impact of pharmacological BACE1 inhibition on early β-amyloid pathology. The longitudinal approach allowed to assess the kinetics of individual plaques and associated presynaptic pathology, before and throughout treatment. BACE1 inhibition could not halt but slow down progressive β-amyloid deposition and associated synaptic pathology. Notably, the data revealed that the initial process of plaque formation, rather than the subsequent phase of gradual plaque growth, is most sensitive to BACE1 inhibition. This finding of particular susceptibility of plaque formation has profound implications to achieve optimal therapeutic efficacy for the prospective treatment of AD. [ABSTRACT FROM AUTHOR]

To successfully treat Alzheimer's disease (AD), pathophysiological events in preclinical stages need to be identified. Preclinical AD refers to the stages that exhibit amyloid deposition in the brain but have normal cognitive function, which are replicated in young adult APPswe/PS1deltaE9 (deltaE9) mice. By long-term in vivo two-photon microscopy, we demonstrate impaired adaptive spine plasticity in these transgenic mice illustrated by their failure to increase dendritic spine density and form novel neural connections when housed in enriched environment (EE). Decrease of amyloid plaques by reducing BACE1 activity restores the gain of spine density upon EE in deltaE9 mice, but not the remodeling of neural networks. On the other hand, anti-inflammatory treatment with pioglitazone or interleukin 1 receptor antagonist in deltaE9 mice successfully rescues the impairments in increasing spine density and remodeling of neural networks during EE. Our data suggest that neuroinflammation disrupts experience-dependent structural plasticity of dendritic spines in preclinical stages of AD. [ABSTRACT FROM AUTHOR]

Synaptic failure is an immediate cause of cognitive decline and memory dysfunction in Alzheimer's disease. Dendritic spines are specialized structures on neuronal processes, on which excitatory synaptic contacts take place and the loss of dendritic spines directly correlates with the loss of synaptic function. Dendritic spines are readily accessible for both in vitro and in vivo experiments and have, therefore, been studied in great detail in Alzheimer's disease mouse models. To date, a large number of different mechanisms have been proposed to cause dendritic spine dysfunction and loss in Alzheimer's disease. For instance, amyloid beta fibrils, diffusible oligomers or the intracellular accumulation of amyloid beta have been found to alter the function and structure of dendritic spines by distinct mechanisms. Furthermore, tau hyperphosphorylation and microglia activation, which are thought to be consequences of amyloidosis in Alzheimer's disease, may also contribute to spine loss. Lastly, genetic and therapeutic interventions employed to model the disease and elucidate its pathogenetic mechanisms in experimental animals may cause alterations of dendritic spines on their own. However, to date none of these mechanisms have been translated into successful therapeutic approaches for the human disease. Here, we critically review the most intensely studied mechanisms of spine loss in Alzheimer's disease as well as the possible pitfalls inherent in the animal models of such a complex neurodegenerative disorder. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is thought to be caused by accumulation of amyloid-β protein (Aβ), which is a cleavage product of amyloid precursor protein (APP). Transgenic mice overexpressing APP have been used to recapitulate amyloid-β pathology. Among them, APP23 and APPswe/PS1deltaE9 (deltaE9) mice are extensively studied. APP23 mice express APP with Swedish mutation and develop amyloid plaques late in their life, while cognitive deficits are observed in young age. In contrast, deltaE9 mice with mutant APP and mutant presenilin-1 develop amyloid plaques early but show typical cognitive deficits in old age. To unveil the reasons for different progressions of cognitive decline in these commonly used mouse models, we analyzed the number and turnover of dendritic spines as important structural correlates for learning and memory. Chronic in vivo two-photon imaging in apical tufts of layer V pyramidal neurons revealed a decreased spine density in 4-5-month-old APP23 mice. In age-matched deltaE9 mice, in contrast, spine loss was only observed on cortical dendrites that were in close proximity to amyloid plaques. In both cases, the reduced spine density was caused by decreased spine formation. Interestingly, the patterns of alterations in spine morphology differed between these two transgenic mouse models. Moreover, in APP23 mice, APP was found to accumulate intracellularly and its content was inversely correlated with the absolute spine density and the relative number of mushroom spines. Collectively, our results suggest that different pathological mechanisms, namely an intracellular accumulation of APP or extracellular amyloid plaques, may lead to spine abnormalities in young adult APP23 and deltaE9 mice, respectively. These distinct features, which may represent very different mechanisms of synaptic failure in AD, have to be taken into consideration when translating results from animal studies to the human disease. [ABSTRACT FROM AUTHOR]

Impaired olfaction is an early symptom in Parkinson disease (PD), although the exact cause is as yet unknown. Here, we investigated the link between PD-related mutant α-Synuclein (α-SYN) pathology and olfactory deficit, by examining the integration of adult-born neurons in the olfactory bulb (OB) of A30P α-SYN overexpressing mice. To this end, we chose to label one well-known vulnerable subpopulation of adult-born cells, the dopaminergic neurons. Using in vivo two-photon imaging, we followed the dynamic process of neuronal turnover in transgenic A30P α-SYN and wild-type mice over a period of 2.5 months. Our results reveal no difference in the number of cells that reach and possibly integrate into, the glomerular layer in the OB. However, in mutant transgenic mice these new neurons have a significantly shortened survival, resulting in an overall reduction in the addition of neurons to the glomerular layer over time. We therefore propose unstable integration and impaired homeostasis of functional new neurons as a likely contributor to odour discrimination deficits in mutant α-SYN mice. [ABSTRACT FROM AUTHOR]

A fascinating yet perhaps overlooked trait of the p75 neurotrophin receptor (p75) is its ability to bind ligands with no obvious neurotrophic function. Using cultured basal forebrain (BF) neurons, this study demonstrates selective internalization of amyloid β (Aβ) 1-42 in conjunction with p75 (labelled with IgG192-Cy3) by cholinergic cells. Active under resting conditions, this process was enhanced by high K stimulation and was insensitive to inhibitors of regulated synaptic activity-tetrodotoxin or botulinum neurotoxins (BoNT type/A and/B). Blockade of sarco-endoplasmic reticulum (SERCA) Ca ATPase with thapsigargin and CPA or chelation of Ca with EGTA-AM strongly suppressed the endocytosis of p75, implicating the role of ER released Ca. The uptake of IgG192-Cy3 was also reduced by T-type Ca channel blocker mibefradil but not Cd, an indiscriminate blocker of high voltage-activated Ca currents. A strong co-localization of IgG192-Cy3 with late endosome (Rab7) or lysosome (Lamp1) qualifier proteins suggest these compartments as the primary destination for internalized IgG192 and Aβ. Selective uptake and labeling of BF cholinergic cells with IgG192-Cy3 injected into the prefrontal cortex was verified also in vivo. The significance of these findings in relation to Aβ clearance in the cerebral cortex and pathophysiology of Alzheimer's disease is discussed. [ABSTRACT FROM AUTHOR]

Background: In gliomas molecular biomarkers are increasingly gaining diagnostic, prognostic and predictive significance. Determination of biomarker status after biopsy is important as not all patients are eligible for open tumor resection. We developed and validated prospectively (6/10-12/11) a protocol allowing for both reliable determination of multiple biomarkers and representative histological diagnoses from small-sized biopsies. Methods: All molecular stereotactic biopsies were performed according to a detailed workflow. The selection of specimens best suited for molecular analyses was intra-operatively guided by the attending neuropathologist. Postoperative screening was done by methylation specific PCR using two distinct cryopreserved specimens to test for reproducibility of the findings and to rule out contamination. The DNA of a single best-suited specimen (1 mm) was subjected to detailed molecular analysis ( MGMT promoter methylation, IDH1/2 mutational status, LOH 1p and/or 19q). Results: 159 consecutively enrolled untreated gliomas were analyzed (94 glioblastomas, 2 gliosarcomas, 24 anaplastic astrocytomas, 10 oligo-tumors grade II/III, 20 grade II astrocytomas and 9 pilocytic astrocytomas). Transient morbidity was 2 %. Overall, the drop-out rate due to tissue contamination was 0.4 %. Median time from biopsy to histological and molecular genetic analyses was 3 and 5 days, respectively. Distributions of the respective biomarker status for tumor subgroups were consistent with the literature. The final histological diagnosis was changed/modified in 5/159 patients according to molecular findings. Treatment after molecular biopsy was highly personalized. Conclusions: Molecular stereotactic biopsy is feasible and safe, can be implemented in daily clinical practice, improves diagnostic precision and enables personalized treatment. [ABSTRACT FROM AUTHOR]

Genetic analysis revealed the hexanucleotide repeat expansion GGGGCC within the regulatory region of the gene C9orf72 as the most common cause of familial amyotrophic lateral sclerosis and the second most common cause of frontotemporal lobar degeneration. Since repeat expansions might cause RNA toxicity via sequestration of RNA-binding proteins, we searched for proteins capable of binding to GGGGCC repeats. In vitro-transcribed biotinylated RNA containing hexanucleotide GGGGCC or, as control, AAAACC repeats were incubated with nuclear protein extracts. Using stringent filtering protocols 20 RNA-binding proteins with a variety of different functions in RNA metabolism, translation and transport were identified. A subset of these proteins was further investigated by immunohistochemistry in human autopsy brains. This revealed that hnRNP A3 formed neuronal cytoplasmic and intranuclear inclusions in the hippocampus of patients with C9orf72 repeat extensions. Confocal microcopy showed that these inclusions belong to the group of the so far enigmatic p62-positive/TDP-43 negative inclusions characteristically seen in autopsy cases of diseased C9orf72 repeat expansion carriers. Thus, we have identified one protein component of these pathognomonic inclusions. [ABSTRACT FROM AUTHOR]

Amyloid-beta plaque deposition represents a major neuropathological hallmark of Alzheimer's disease. While numerous studies have described dendritic spine loss in proximity to plaques, much less is known about the kinetics of these processes. In particular, the question as to whether synapse loss precedes or follows plaque formation remains unanswered. To address this question, and to learn more about the underlying kinetics, we simultaneously imaged amyloid plaque deposition and dendritic spine loss by applying two-photon in vivo microscopy through a cranial window in double transgenic APPPS1 mice. As a result, we first observed that the rate of dendritic spine loss in proximity to plaques is the same in both young and aged animals. However, plaque size only increased significantly in the young cohort, indicating that spine loss persists even many months after initial plaque appearance. Tracking the fate of individual spines revealed that net spine loss is caused by increased spine elimination, with the rate of spine formation remaining constant. Imaging of dendritic spines before and during plaque formation demonstrated that spine loss around plaques commences at least 4 weeks after initial plaque formation. In conclusion, spine loss occurs, shortly but with a significant time delay, after the birth of new plaques, and persists in the vicinity of amyloid plaques over many months. These findings hence give further hope to the possibility that there is a therapeutic window between initial amyloid plaque deposition and the onset of structural damage at spines. [ABSTRACT FROM AUTHOR]

The amyloid precursor protein (APP) is transported in high amounts to the presynaptic endings where its function is still unknown. Several studies indicate that lack of APP or its overexpression affects the number of dendritic spines, the postsynaptic compartment of excitatory synapses. Since synapse loss has been identified as one of the most important structural correlates of cognitive decline in Alzheimer's diseases (AD), the physiological function of APP at synapses, specifically at dendritic spines, has come into focus in AD research. This review intends to give an overview of the very controversial results on APP expression on dendritic spine number in the mouse brain. [ABSTRACT FROM AUTHOR]

The kinetics of amyloid plaque formation and growth as one of the characteristic hallmarks of Alzheimer's disease (AD) are fundamental issues in AD research. Especially the question how fast amyloid plaques grow to their final size after they are born remains controversial. By long-term two-photon in vivo imaging we monitored individual methoxy-X04-stained amyloid plaques over 6 weeks in 12 and 18 months old Tg2576 mice. We found that in 12 months old mice, newly appearing amyloid plaques were initially small in volume and subsequently grew over time. The growth rate of plaques was inversely proportional to their volume; thus amyloid plaques that were already present at the first imaging time point grew over time but slower compared to new plaques. Additionally, we analyzed 18 months old Tg2576 mice in which we neither found newly appearing plaques nor a significant growth of pre-existing plaques over 6 weeks of imaging. In conclusion, newly appearing amyloid plaques are initially small in size but grow over time until plaque growth can not be detected anymore in aged mice. These results suggest that drugs that target plaque formation should be most effective early in the disease, when plaques are growing. [ABSTRACT FROM AUTHOR]

Brain metastasis frequently occurs in individuals with cancer and is often fatal. We used multiphoton laser scanning microscopy to image the single steps of metastasis formation in real time. Thus, it was possible to track the fate of individual metastasizing cancer cells in vivo in relation to blood vessels deep in the mouse brain over minutes to months. The essential steps in this model were arrest at vascular branch points, early extravasation, persistent close contacts to microvessels and perivascular growth by vessel cooption (melanoma) or early angiogenesis (lung cancer). Inefficient steps differed between the tumor types. Long-term dormancy was only observed for single perivascular cancer cells, some of which moved continuously. Vascular endothelial growth factor-A (VEGF-A) inhibition induced long-term dormancy of lung cancer micrometastases by preventing angiogenic growth to macrometastases. The ability to image the establishment of brain metastases in vivo provides new insights into their evolution and response to therapies. [ABSTRACT FROM AUTHOR]

Treatment and prognosis of gliomas depend on their histological tumour grade. The aim of the study was to evaluate the potential of [18F]fluoroethyltyrosine (FET) PET for non-invasive tumour grading in untreated patients. Dynamic FET PET studies were performed in 54 patients who, based on MRI, were estimated to have low grade (LG; n = 20), intermediate (WHO II–III; n = 4) or high grade (HG; n = 30) tumours. For standard evaluation, tumour SUVmax and the ratio to background (SUVmax/BG) were calculated (sum image: 20–40 min). For dynamic evaluation, mean SUV values within a 90% isocontour ROI (SUV90) and the SUV90/BG ratios were determined for each time frame to evaluate the course of FET uptake. Results were correlated with histopathological findings from PET-guided stereotactic biopsies. Histology revealed gliomas in all patients. Using the standard method a statistically significant difference ( p = 0.001) was found between LG ( n = 20; SUVmax/BG: 2.16 ± 0.98) and HG ( n = 34; SUVmax/BG: 3.29 ± 1.06) gliomas (opt. threshold 2.58: SN71%/SP85%/area under ROC curve [AUC]:0.798), however, with a marked overlap between WHO II to IV tumours. Time activity curves showed slight increase in LG, whereas HG tumours presented with an early peak (10–20 min) followed by a decrease. Dynamic evaluation successfully separated LG from HG gliomas with higher diagnostic accuracy (SN94%/SP100%/AUC:0.967). Based on the ratio-based method, a statistically significant difference was found between LG and HG gliomas. Due to the interindividual variability, however, no reliable individual grading was possible. In contrast, dynamic evaluation allowed LG and HG gliomas to be differentiated with high diagnostic power and, thus, should supplement the conventional method. [ABSTRACT FROM AUTHOR]

The prion protein (PrPC) is a copper-binding, cell-surface protein that plays an essential role in the etiology of transmissible spongiform encephalopathies. Atomic absorption spectroscopy studies have established that synaptosomal copper content is reduced in PrPC-deficient mice as compared with wild-type (WT) or PrP-overexpressing mice. To address the question of whether this is the result of a loss of function of PrPC in copper transport across the plasma membrane at the synapse, we have used synaptosomes incubated with 67Cu as a model system to characterize the mechanism of copper accumulation in nerve terminals. Our results demonstrate that mouse brain synaptosomes accumulate copper efficiently by at least two distinct mechanisms. In the presence of 1 m M EDTA, copper was taken up via a saturable high-affinity process that was moderately susceptible to competition by high concentrations of NiCl2. Uptake characteristics were clearly different in the presence of 400 µ M histidine, with the most noticeable dissimilarities being considerably elevated uptake rates and moderate competition by ZnCl2 rather than NiCl2. No significant differences in copper uptake capability between WT and PrPC-knockout synaptosomes were observed under any of the experimental conditions tested in this study. Furthermore, preincubation of synaptosomes with an antibody binding to the copper-binding repeat region of the prion protein had no effect on copper uptake either. Taken together, our data indicate that synaptosomal copper uptake is independent of PrPC. [ABSTRACT FROM AUTHOR]

Unlabelled: Malignant ectomesenchymoma is a rare tumour that contains both ectodermal and mesenchymal elements. Only three patients with a manifestation in the cerebrum and clinicopathological data have been reported until now. We present a patient with an intracerebral ectomesenchymoma, review the literature and discuss currently available therapeutic options. In a 10-year-old girl, a left suprasellar temporo-parieto-occipitally localised tumour was diagnosed. The tumour was completely excised macroscopically in two surgical sessions. For the mesenchymal part of the tumour she subsequently underwent multidrug chemotherapy followed by radiation therapy. Considering the neuroectodermal element of the tumour, radiotherapy was applied to the craniospinal axis with a local boost. Therapy was tolerated well without any severe side effects. Six years from diagnosis, the patient is alive without a tumour relapse.Conclusion: Due to the sparcity of reported cases with malignant ectomesenchymoma, the role of adjuvant therapy is unclear. Multimodal therapy may be able to improve outcome. [ABSTRACT FROM AUTHOR]

A 10-year-old girl presented with a cerebral malignant ectomesenchymoma (MEM), a very unusual tumour with undifferentiated mesenchymal as well as ectodermal elements. Somatostatin receptor scintigraphy (SRS) was performed during the diagnostic workup. The recurrent residual tumour mass was exactly visualized with SRS, and was negative after successful treatment of the patient. The potential application of SRS in initial staging, follow-up and therapy planning in MEM is discussed. This is the first application of SRS in MEM. [ABSTRACT FROM AUTHOR]

In the original publication, electronic supplementary files are incorrectly processed and published online. [ABSTRACT FROM AUTHOR]

Presents research which shows that the amino-terminal domain of prion protein exhibits five to six sites that bind copper (Cu(II)) presented as a glycine chelate. The binding that occurs at neutral Ph; How the findings indicate that prion protein can exist in a copper-metalloprotein form in vivo; Research method; Results.

Synapsin Ia, Ib, IIa, and IIb are neuronal phosphoproteins, which are supposed to play a role in the short-term regulation of neurotransmitter release. Besides a high degree of homology among the four synapsin subtypes, there are structural differences in the 3′end of their coding region. Here we present the first extensive study of the expression of their gene transcripts by using in situ hybridization and northern blot analysis. Our results show regionally and temporally distinct expression patterns of synapsin Ia, Ib, IIa, and IIb, which suggests different functional properties of the four synapsin subtypes. There was no specific messenger RNA (mRNA) expression of synapsin IIb in most brain regions apart from the cerebellum, suggesting a minor functional role of this synapsin subtype. Synapsin Ia, Ib, and IIa mRNA were expressed earlier in ontogenetically older brain regions such as the piriform cortex, the thalamus, and the hippocampus and later in ontogenetically younger areas such as the neocortex and the cerebellum. Owing to the distinct expression pattern of the synapsin subtypes, we suppose that the synapsins might be essential for the underlying molecular mechanism of pattern formation and plasticity in distinct brain regions during different states of rat brain development. [ABSTRACT FROM AUTHOR]

Synapsin I is a synaptic phosphoprotein that is involved in the short-term regulation of neurotransmitter release. In this report we present the first extensive study of the developmental expression of its corresponding messenger ribonucleic acid (mRNA) by in situ hybridization and northern blot analysis in rat brain. Synapsin I mRNA showed pronounced differences in expression in different brain regions during postnatal development. The early expression of synapsin I mRNA in ontogenetically older regions such as the thalamus, the piriform cortex and the hippocampus coincides with the earlier maturation of these regions, in contrast to its later expression in ontogenetically younger areas such as the cerebellum and the neocortex. An intriguing expression pattern was found in the hippocampus. In all hippocampal subregions synapsin I mRNA expression increased from postnatal day (PND) 1 to 17. After PND 17, however, there was a marked dissociation between persisting high expression levels in CA3 and the dentate gyrus and a strong decline in synapsin I mRNA expression in CA1. The persistence of synapsin I in some adult rat brain regions indicates that it plays a part in synapse formation during plastic adaption in neuronal connectivities. [ABSTRACT FROM AUTHOR]

MGMT promotor methylation is associated with favourable outcome in high-grade glioma. In glioma WHO grade II, it is unclear whether the extent of MGMT promotor methylation and its prognostic role is independent from other molecular markers. We performed a retrospective analysis of 155 patients with glioma WHO grade II. First, all 155 patients were assigned to three molecular groups according to the 2016 WHO classification system: (1) oligodendroglioma, IDH-mutant and 1p19q co-deleted (n = 81); (2) astrocytoma, IDH-mutant and 1p19q non-codeleted (n = 54); (3) astrocytoma, IDH-wildtype (n = 20). MGMT promotor methylation was quantified using Sanger sequencing of the CpG sites 74–98 within the MGMT promotor region. Highest numbers of methylated CpG sites were found for oligodendroglioma, IDH-mutant and 1p19q co-deleted. When 1p19q co-deletion was absent, numbers of methylated CpG sites were higher in the presence of IDH-mutation. Accordingly, lowest numbers were seen in the IDH-wildtype subpopulation. In the entire cohort, larger numbers of methylated CpG sites were associated with favourable outcome. When analysed separately for the three WHO subgroups, a similar association was only retained in astrocytoma, IDH-wildtype. Collectively, extent of MGMT promotor methylation was strongly associated with other molecular markers and added prognostic information in astrocytoma, IDH-wildtype. Evaluation in prospective cohorts is warranted. [ABSTRACT FROM AUTHOR]

The article discusses a study by N. Rudinskiy and colleagues concerning the use of Arc::dVenus mouse to illuminate the pathophysiology of Alzheimer's disease. Researchers have studied the effects of the deposition of extracellular β-amyloid in visual cortex. Study reveals that the functional disruption in neuronal network is being associated with the visual activity in the animal model of Alzheimer's disease. Study also shows the presence of strong aberrant activity near amyloid plaques.

Microglia, the immune cells of the brain, can have a beneficial effect in Alzheimer's disease by phagocytosing amyloid-β. Two-photon in vivo imaging of neuron loss in the intact brain of living Alzheimer's disease mice revealed an involvement of microglia in neuron elimination, indicated by locally increased number and migration velocity of microglia around lost neurons. Knockout of the microglial chemokine receptor Cx3cr1, which is critical in neuron-microglia communication, prevented neuron loss. [ABSTRACT FROM AUTHOR]

Dopamine (DA) release in striatum is functionally segregated across a dorsolateral/ventromedial axis. Interestingly, nigrostriatal DA signaling disruption in Parkinson's disease (PD) preferentially affects the dorsolateral striatum. The relationship between afferent presynaptic calcium transients (PreCaTs) in DA terminals and DA release in dorsolateral (Caudato-Putamen, DLS) and ventromedial (Nucleus Accumbens Shell, VS) striatal subregions was examined by ex vivo real-time dual-recording in conditional transgenic mice expressing the calcium indicator protein GCaMP3. In DLS, minimal increases in cytosolic calcium trigger steep DA release while PreCaTs and DA release in VS both were proportional to the number of pulses in burst stimulation. Co-expressing α-synuclein with the Parkinson's disease (PD)-associated A53T mutation and GCaMP3 in midbrain DA neurons revealed augmented cytosolic steady state and activity-dependent intra-terminal calcium levels preferentially in DLS, as well as hyperactivation and enhanced expression of N-type calcium channels. Thus, unbalanced calcium channel activity is a presynaptic mechanism to consider in the multifaceted pathogenic pathways of progressive neurodegeneration. [ABSTRACT FROM AUTHOR]