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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]

Background: Human encephalitis can originate from a variety of different aetiologies, of which infection is the most common one. The diagnostic work-up is specifically challenging in patients with travel history since a broader spectrum of unfamiliar additional infectious agents, e. g. tropical disease pathogens, needs to be considered. Here we present a case of encephalitis of unclear aetiology in a female traveller returning from Africa, who in addition developed an atypical herpes simplex virus (HSV) encephalitis in close temporal relation with high-dose steroid treatment.Case Presentation: A previously healthy 48-year-old female presented with confusion syndrome and impaired vigilance which had developed during a six-day trip to The Gambia. The condition rapidly worsened to a comatose state. Extensive search for infectious agents including a variety of tropical disease pathogens was unsuccessful. As encephalitic signs persisted despite of calculated antimicrobial and antiviral therapy, high-dose corticosteroids were applied intravenously based on the working diagnosis of an autoimmune encephalitis. The treatment did, however, not improve the patient's condition. Four days later, bihemispheric signal amplification in the insular and frontobasal cortex was observed on magnetic resonance imaging (MRI). The intracranial pressure rapidly increased and could not be controlled by conservative treatment. The patient died due to tonsillar herniation 21 days after onset of symptoms. Histological examination of postmortem brain tissue demonstrated a generalized lymphocytic meningoencephalitis. Immunohistochemical reactions against HSV-1/2 indicated an atypical manifestation of herpesviral encephalitis in brain tissue. Moreover, HSV-1 DNA was detected by a next-generation sequencing (NGS) metagenomics approach. Retrospective analysis of cerebrospinal fluid (CSF) and serum samples revealed HSV-1 DNA only in specimens one day ante mortem.Conclusions: This case shows that standard high-dose steroid therapy can contribute to or possibly even trigger fulminant cerebral HSV reactivation in a critically ill patient. Thus, even if extensive laboratory diagnostics including wide-ranging search for infectious pathogens has been performed before and remained without results, continuous re-evaluation of potential differential diagnoses especially regarding opportunistic infections or reactivation of latent infections is of utmost importance, particularly if new symptoms occur. [ABSTRACT FROM AUTHOR]

After many years of controversy, there is now recent and solid evidence that classical Borna disease virus 1 (BoDV-1) can infect humans. On the basis of six brain autopsies, we provide the first systematic overview on BoDV-1 tissue distribution and the lesion pattern in fatal BoDV-1-induced encephalitis. All brains revealed a non-purulent, lymphocytic sclerosing panencephalomyelitis with detection of BoDV-1-typical eosinophilic, spherical intranuclear Joest–Degen inclusion bodies. While the composition of histopathological changes was constant, the inflammatory distribution pattern varied interindividually, affecting predominantly the basal nuclei in two patients, hippocampus in one patient, whereas two patients showed a more diffuse distribution. By immunohistochemistry and RNA in situ hybridization, BoDV-1 was detected in all examined brain tissue samples. Furthermore, infection of the peripheral nervous system was observed. This study aims at raising awareness to human bornavirus encephalitis as differential diagnosis in lymphocytic sclerosing panencephalomyelitis. A higher attention to human BoDV-1 infection by health professionals may likely increase the detection of more cases and foster a clearer picture of the disease. [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]

Both tumors underwent 450K-methylation analysis that identified posterior fossa ependymomas, group A (EPN PFA) (0.67 (1) and 0.99 (2), respectively), which have aggressive behavior and bad outcomes. Therefore, the 450K-methylation profiling strongly suggests that the initial manifestation represented like the second one an anaplastic ependymoma and not a medulloblastoma, thus prompting to consider methylation profiling for all pediatric small blue round cell tumors. Still, this case emphasizes the relevance and importance of molecular analyses of pediatric brain tumors as (1) histological assessment only can be misleading, particularly in small blue round cell tumors and (2) different tumor entities in the same patient can be clearly distinguished. [Extracted from the article]

Background: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease.Objective: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases.Methods: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898).Results: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10-6 , all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4).Interpretation: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

The Borna disease virus 1 (BoDV-1) causes severe and often fatal encephalitis in humans. The virus is endemic in parts of Germany, Liechtenstein, Switzerland and Austria. As an increasing number of human BoDV-1 encephalitis cases is being diagnosed, the chance for healthcare professionals to come into contact with infected tissues and bodily fluids from patients with known acute bornavirus encephalitis is also increasing. Therefore, risk assessments are needed. Based on three different incidences of possible exposure to BoDV-1 including an autopsy knife injury, a needlestick injury, and a spill accident with cerebrospinal fluid from patients with acute BoDV-1 encephalitis, we perform risk assessments and review published data. BoDV-1 infection status of the index patient's tissues and bodily fluids to which contact had occurred should be determined. There is only scarce evidence for possible postexposure prophylaxis, serology, and imaging in healthcare professionals who possibly came into contact with the virus. Despite decade-long laboratory work with BoDV-1, not a single clinically apparent laboratory infection has been published. Given the increasing number of severe or fatal BoDV-1 encephalitis cases, there is a growing need for efficacy-tested, potent antiviral therapeutics against BoDV-1 in humans, both in clinically ill patients and possibly as postexposure prophylaxis in healthcare professionals. [ABSTRACT FROM AUTHOR]

TSPO is a promising novel tracer target for positron-emission tomography (PET) imaging of brain tumors. However, due to the heterogeneity of cell populations that contribute to the TSPO-PET signal, imaging interpretation may be challenging. We therefore evaluated TSPO enrichment/expression in connection with its underlying histopathological and molecular features in gliomas. We analyzed TSPO expression and its regulatory mechanisms in large in silico datasets and by performing direct bisulfite sequencing of the TSPO promotor. In glioblastoma tissue samples of our TSPO-PET imaging study cohort, we dissected the association of TSPO tracer enrichment and protein labeling with the expression of cell lineage markers by immunohistochemistry and fluorescence multiplex stains. Furthermore, we identified relevant TSPO-associated signaling pathways by RNA sequencing. We found that TSPO expression is associated with prognostically unfavorable glioma phenotypes and that TSPO promotor hypermethylation is linked to IDH mutation. Careful histological analysis revealed that TSPO immunohistochemistry correlates with the TSPO-PET signal and that TSPO is expressed by diverse cell populations. While tumor core areas are the major contributor to the overall TSPO signal, TSPO signals in the tumor rim are mainly driven by CD68-positive microglia/macrophages. Molecularly, high TSPO expression marks prognostically unfavorable glioblastoma cell subpopulations characterized by an enrichment of mesenchymal gene sets and higher amounts of tumor-associated macrophages. In conclusion, our study improves the understanding of TSPO as an imaging marker in gliomas by unveiling IDH-dependent differences in TSPO expression/regulation, regional heterogeneity of the TSPO PET signal and functional implications of TSPO in terms of tumor immune cell interactions. [ABSTRACT FROM AUTHOR]

The MAPT gene, encoding the microtubule-associated protein tau on chromosome 17q21.31, is result of an inversion polymorphism, leading to two allelic variants (H1 and H2). Homozygosity for the more common haplotype H1 is associated with an increased risk for several tauopathies, but also for the synucleinopathy Parkinson's disease (PD). In the present study, we aimed to clarify whether the MAPT haplotype influences expression of MAPT and SNCA, encoding the protein α-synuclein (α-syn), on mRNA and protein levels in postmortem brains of PD patients and controls. We also investigated mRNA expression of several other MAPT haplotype-encoded genes. Postmortem tissues from cortex of fusiform gyrus (ctx-fg) and of the cerebellar hemisphere (ctx-cbl) of neuropathologically confirmed PD patients (n = 95) and age- and sex-matched controls (n = 81) were MAPT haplotype genotyped to identify cases homozygous for either H1 or H2. Relative expression of genes was quantified using real-time qPCR; soluble and insoluble protein levels of tau and α-syn were determined by Western blotting. Homozygosity for H1 versus H2 was associated with increased total MAPT mRNA expression in ctx-fg regardless of disease state. Inversely, H2 homozygosity was associated with markedly increased expression of the corresponding antisense MAPT-AS1 in ctx-cbl. PD patients had higher levels of insoluble 0N3R and 1N4R tau isoforms regardless of the MAPT genotype. The increased presence of insoluble α-syn in PD patients in ctx-fg validated the selected postmortem brain tissue. Our findings in this small, but well controlled cohort of PD and controls support a putative biological relevance of tau in PD. However, we did not identify any link between the disease-predisposing H1/H1 associated overexpression of MAPT with PD status. Further studies are required to gain a deeper understanding of the potential regulatory role of MAPT-AS1 and its association to the disease-protective H2/H2 condition in the context of PD. [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]

Background and purpose: Knowledge about the seizure prevalence in the whole symptomatic course, from disease onset to death, in neurodegenerative diseases (ND) is lacking. Therefore, the aim was to investigate seizure prevalence and associated clinical implications in neuropathologically diagnosed ND. Methods: Clinical records of cases from the Neurobiobank Munich, Germany, were analyzed. Neuropathological diagnoses of the assessed cases included Alzheimer disease (AD), corticobasal degeneration (CBD), frontotemporal lobar degeneration (FTLD), Lewy body disease (LBD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Seizure prevalence during the whole symptomatic disease phase was assessed and compared amongst ND. Associations between first clinical symptom and seizure prevalence and between seizures and disease duration were examined. Results: In all, 454 patients with neuropathologically diagnosed ND and with available and meaningful clinical records were investigated (AD, n = 144; LBD, n = 103; PSP, n = 93; FTLD, n = 53; MSA, n = 36; CBD, n = 25). Seizure prevalence was 31.3% for AD, 20.0% for CBD, 12.6% for LBD, 11.3% for FTLD, 8.3% for MSA and 7.5% for PSP. Seizure prevalence was significantly higher in AD compared to FTLD (p = 0.005), LBD (p = 0.001), MSA (p = 0.005) and PSP (p < 0.001). No other significant differences regarding seizure prevalence were found between the studied ND. Cognitive first symptoms in ND were associated with an increased seizure prevalence (21.1% vs. 11.0% in patients without cognitive first symptoms) and motor first symptoms with a decreased seizure prevalence (10.3% vs. 20.5% in patients without motor first symptoms). Seizures were associated with a longer disease duration in MSA (12.3 vs. 7.0 years in patients without seizures; p = 0.017). Conclusions: Seizures are a clinically relevant comorbidity in ND, particularly in AD. Knowledge of the first clinical symptom in ND may allow for estimation of seizure risk. [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: 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]

Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients. [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]

Simple Summary: IDH-wildtype (IDHwt) gliomas represent a tumor entity with poor overall survival. Only rare cases have an overall survival over several years. Dynamic and static 18F-FET PET is recommended as valuable complementary tool for glioma imaging in gliomas. This study shows that, besides molecular genetic prognosticators, long survival (≥36 months survival) in IDHwt gliomas is associated with a longer time-to-peak and smaller volume on 18F-FET PET at initial diagnosis compared to glioma patients with a short-term survival (≤15 months survival). 18F-FET uptake intensity and MRI-derived tumor size do not differ in patients with long-term survival compared to patient with a short-term survival. Background: IDHwt diffuse gliomas represent the tumor entity with one of the worst clinical outcomes. Only rare cases present with a long-term survival of several years. Here we aimed at comparing the uptake characteristics on dynamic 18F-FET PET, clinical and molecular genetic parameters of long-term survivors (LTS) versus short-term survivors (STS): Methods: Patients with de-novo IDHwt glioma (WHO grade III/IV) and 18F-FET PET prior to any therapy were stratified into LTS (≥36 months survival) and STS (≤15 months survival). Static and dynamic 18F-FET PET parameters (mean/maximal tumor-to-background ratio (TBRmean/max), biological tumor volume (BTV), minimal time-to-peak (TTPmin)), diameter and volume of contrast-enhancement on MRI, clinical parameters (age, sex, Karnofksy-performance-score), mode of surgery; initial treatment and molecular genetics were assessed and compared between LTS and STS. Results: Overall, 75 IDHwt glioma patients were included (26 LTS, 49 STS). LTS were significantly younger (p < 0.001), had a higher rate of WHO grade III glioma (p = 0.032), of O(6)-Methylguanine-DNA methyltransferase (MGMT) promoter methylation (p < 0.001) and missing Telomerase reverse transcriptase promoter (TERTp) mutations (p = 0.004) compared to STS. On imaging, LTS showed a smaller median BTV (p = 0.017) and a significantly longer TTPmin (p = 0.008) on 18F-FET PET than STS, while uptake intensity (TBRmean/max) did not differ. In contrast to the tumor-volume on PET, MRI-derived parameters such as tumor size as well as all other above-mentioned parameters did not differ between LTS and STS (p > 0.05 each). Conclusion: Besides molecular genetic prognosticators, a long survival time in IDHwt glioma patients is associated with a longer TTPmin as well as a smaller BTV on 18F-FET PET at initial diagnosis. 18F-FET uptake intensity as well as the MRI-derived tumor size (volume and maximal diameter) do not differ in patients with long-term survival. [ABSTRACT FROM AUTHOR]

Background and purpose: Clinical diagnostic criteria for neurodegenerative diseases have been framed based on clinical phenomenology. However, systematic knowledge about the first reported clinical symptoms in neurodegenerative diseases is lacking. Therefore, the aim was to determine the prevalence and clinical implications of the first clinical symptom (FS) as assessed by medical history in neuropathologically proven neurodegenerative diseases. Methods: Neuropathological diagnoses from the Neurobiobank Munich, Germany, were matched with clinical records for analyses of the diagnostic and prognostic values of FSs. Results: In all, 301 patients with the neuropathological diagnoses Alzheimer disease (AD), progressive supranuclear palsy (PSP), frontotemporal lobar degeneration (FTLD), Lewy body disease (LBD) including the neuropathologically indistinguishable clinical phenotypes Parkinson disease and dementia with Lewy bodies, multiple system atrophy (MSA) and corticobasal degeneration (CBD) were studied. Memory disturbance was the most common FS in AD (34%), FTLD (19%) and LBD (26%), gait disturbance in PSP (35%) and MSA (27%) and aphasia and personality changes in CBD (20%, respectively). In a model adjusting for prevalence in the general population, AD was predicted by memory disturbance in 79.0%, aphasia in 97.2%, personality changes in 96.0% and by cognitive disturbance in 99.0%. Gait disturbance and tremor predicted LBD in 54.6% and 97.3%, coordination disturbance MSA in 59.4% and dysarthria FTLD in 73.0%. Cognitive FSs were associated with longer survival in AD (12.0 vs. 5.3 years; p < 0.001) and FTLD (8.2 vs. 4.1 years; p = 0.005) and motor FSs with shorter survival in PSP (7.2 vs. 9.7; p = 0.048). Conclusions: Assessing FSs in neurodegenerative diseases may be beneficial for accuracy of diagnosis and prognosis and thereby may improve clinical care and precision of study recruitment. [ABSTRACT FROM AUTHOR]

Background and Purpose: For diagnosis of medulloblastoma, the updated World Health Organization classification now demands for genetic typing, defining more precisely the tumor biology, therapy, and prognosis. We investigated potential associations between magnetic resonance imaging (MRI) parameters including apparent diffusion coefficient (ADC) and neuropathologic features of medulloblastoma, focusing on genetic subtypes.Methods: This study was a retrospective single-center analysis of 32 patients (eight females, median age = 9 years [range, 1-57], mean 12.6 ± 11.3) from 2012 to 2019. Genetic subtypes (wingless [WNT]; sonic hedgehog [SHH]; non-WNT/non-SHH), histopathology, immunohistochemistry (p53, Ki67), and the following MRI parameters were correlated: tumor volume, location (midline, pontocerebellar, and cerebellar hemisphere), edema, hydrocephalus, metastatic disease (presence/absence and each), contrast-enhancement (minor, moderate, and distinct), cysts (none, small, and large), hemorrhage (none, minor, and major), and ADCmean . The ADCmean was calculated using manually set regions of interest within the solid tumor. Statistics comprised univariate and multivariate testing.Results: Out of 32 tumors, three tumors were WNT activated (9.4%), 13 (40.6%) SHH activated, and 16 (50.0%) non-WNT/non-SHH. Hemispherical location (n = 7/8, P = .003) and presence of edema (8/8; P < .001, specificity 100%, positive predictive value 100%) were significantly associated with SHH activation. The combined parameter "no edema + no metastatic disease + cysts" significantly discriminated WNT-activated from SHH-activated medulloblastoma (P = .036). ADCmean (10-6 mm2 /s) was 484 for WNT-activated, 566 for SHH-activated, and 624 for non-WNT/non-SHH subtypes (P = .080). A significant negative correlation was found between ADCmean and Ki67 (r = -.364, P = .040).Conclusion: MRI analysis enabled noninvasive differentiation of SHH-activated medulloblastoma. ADC alone was not reliable for genetic characterization, but associated with tumor proliferation rate. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the diagnostic accuracy and safety of extended stereotactic brain biopsy (ESBB) in a single center cohort with suspected primary angiitis of the central nervous system (PACNS). Methods: A standardized stereotactic biopsy targeting MRI-positive lesions and collecting samples from the meninges and the cortex as well as from the white matter was performed in 23 patients with clinically suspected PACNS between 2010 and 2017. The relationship between biopsy yield and clinical characteristics, cerebrospinal fluid parameters, MR-imaging, time point of biopsy and exact localization of biopsy as well as number of tissue samples were examined. Results: PACNS was confirmed in 7 of 23 patients (30.4%). Alternative diagnoses were identified in 7 patients (30%). A shorter time period between the onset or worsening of symptoms (p = 0.018) and ESBB significantly increased the diagnostic yield. We observed only minor and transient postoperative complications in 3 patients (13.0%). ESBB led to a direct change of the therapeutic regime in 13 of 23 patients (56.5%). Careful neuropathological analysis furthermore revealed that cortical samples were crucial in obtaining a diagnosis. Conclusion: ESBB is a safe approach with good feasibility, even in critically ill patients, and high diagnostic accuracy in patients with suspected PACNS changing future therapies in 13 of 23 patients (56.5%). Early biopsy after symptom onset/worsening is crucial and (sub)acute MRI-lesions should be targeted with a particular need for biopsy samples from the cortical layer. [ABSTRACT FROM AUTHOR]

Simple Summary: The translocator protein (TSPO) has been under extensive investigation as a specific marker in positron emission tomography (PET) to visualize brain lesions following injury or disease. In recent years, TSPO is increasingly appreciated as a potential novel therapeutic target in cancer. In Glioblastoma (GBM), the most malignant primary brain tumor, TSPO expression levels are strongly elevated and scientific evidence accumulates, hinting at a pivotal role of TSPO in tumorigenesis and glioma progression. The aim of this review is to summarize the current literature on TSPO with respect to its role both in diagnostics and especially with regard to the critical hallmarks of cancer postulated by Hanahan and Weinberg. Overall, our review contributes to a better understanding of the functional significance of TSPO in Glioblastoma and draws attention to TSPO as a potential modulator of treatment response and thus an important factor that may influence the clinical outcome of GBM. Glioblastoma (GBM) is the most fatal primary brain cancer in adults. Despite extensive treatment, tumors inevitably recur, leading to an average survival time shorter than 1.5 years. The 18 kDa translocator protein (TSPO) is abundantly expressed throughout the body including the central nervous system. The expression of TSPO increases in states of inflammation and brain injury due to microglia activation. Not least due to its location in the outer mitochondrial membrane, TSPO has been implicated with a broad spectrum of functions. These include the regulation of proliferation, apoptosis, migration, as well as mitochondrial functions such as mitochondrial respiration and oxidative stress regulation. TSPO is frequently overexpressed in GBM. Its expression level has been positively correlated to WHO grade, glioma cell proliferation, and poor prognosis of patients. Several lines of evidence indicate that TSPO plays a functional part in glioma hallmark features such as resistance to apoptosis, invasiveness, and proliferation. This review provides a critical overview of how TSPO could regulate several aspects of tumorigenesis in GBM, particularly in the context of the hallmarks of cancer proposed by Hanahan and Weinberg in 2011. [ABSTRACT FROM AUTHOR]

Objective: The number of diagnosed fatal encephalitis cases in humans caused by the classical Borna disease virus (BoDV‐1) has been increasing, ever since it was proved that BoDV‐1 can cause human infections. However, awareness of this entity is low, and a specific imaging pattern has not yet been identified. We therefore provide the first comprehensive description of the morphology of human BoDV‐1 encephalitis, with histopathological verification of imaging abnormalities. Methods: In an institutional review board‐approved multicenter study, we carried out a retrospective analysis of 55 magnetic resonance imaging (MRI) examinations of 19 patients with confirmed BoDV‐1 encephalitis. Fifty brain regions were analyzed systematically (T1w, T2w, T2*w, T1w + Gd, and DWI), in order to discern a specific pattern of inflammation. Histopathological analysis of 25 locations in one patient served as correlation for MRI abnormalities. Results: Baseline imaging, acquired at a mean of 11 ± 10 days after symptom onset, in addition to follow‐up scans of 16 patients, revealed characteristic T2 hyperintensities with a predilection for the head of the caudate nucleus, insula, and cortical spread to the limbic system, whereas the occipital lobes and cerebellar hemispheres were unaffected. This gradient was confirmed by histology. Nine patients (47.4%) developed T1 hyperintensities of the basal ganglia, corresponding to accumulated lipid phagocytes on histology and typical for late‐stage necrosis. Interpretation: BoDV‐1 encephalitis shows a distinct pattern of inflammation in both the early and late stages of the disease. Its appearance can mimic sporadic Creutzfeldt–Jakob disease on MRI and should be considered a differential diagnosis in the case of atypical clinical presentation. ANN NEUROL 2020;88:723–735 [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]

• Toxicity of reRT plus BEV was compared to reRT only for recurrent glioma patients. • Radionecrosis and symptomatic oedema (RN/SE) were less frequent in reRT plus BEV. • RN/SE rate was 21.8% (27/124) for reRT plus BEV and 37.8% (14/37) for reRT only. • No BEV was the only significant risk factor for RN/SE on multivariate analysis. The role of bevacizumab (BEV) in the setting of reirradiation (reRT) of malignant glioma recurrences is poorly defined. At our institution, reRT plus BEV was routinely used until its disapproval for glioma treatment by the European Medical Agency. Accordingly, reRT was applied without the addition of BEV since 2017. Here we present for the first time outcome and toxicity profiles of reRT plus BEV and reRT alone for malignant glioma recurrences. All adult patients consecutively undergoing reRT of a recurrent malignant glioma (37 anaplastic astrocytoma, WHO III; 124 glioblastoma, WHO IV) between 2007 and 2017 were included. In one group of patients, BEV (10 mg/kg bodyweight) was applied concomitantly on days 1 and 15 of reRT. Radiation toxicity referred to clinically significant toxicities of proven symptomatic radionecrosis (RN) and symptomatic oedema (SE) requiring steroid treatment for more than six weeks after reRT. Post-recurrence survival (PRS) and freedom from RN/SE were estimated with the Kaplan–Meier method. Prognostic factors were obtained from proportional hazards models. BEV plus reRT was applied in 124 and reRT alone in 37 patients. Both groups were comparable in terms of their patient-, tumour-, and RT/reRT-related variables. PRS was independent from the applied reRT protocols. RN/SE was less frequently seen after reRT plus BEV absolutely (27/124 (21.8%) vs. 14/37 (37.8%) patients; p = 0.025) and over time (1-year RN/SE rate: 23.9% vs. 54.1%; p = 0.013). The unadjusted and adjusted hazard ratio for RN/SE was doubled in case of reRT alone. Absence of BEV remained the only risk factor for RN/SE in multivariate models (p = 0.026). Concomitant BEV effectively reduces treatment toxicity of reRT and should be reconsidered in future reRT protocols. [ABSTRACT FROM AUTHOR]

Rosette-forming glioneuronal tumor (RGNT) is a rare brain neoplasm that primarily affects young adults. Although alterations affecting the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathway have been associated with this low-grade entity, comprehensive molecular investigations of RGNT in larger series have not been performed to date, and an integrated view of their genetic and epigenetic profiles is still lacking. Here we describe a genome-wide DNA methylation and targeted sequencing-based characterization of a molecularly distinct class of tumors (n = 30), initially identified through genome-wide DNA methylation screening among a cohort of > 30,000 tumors, of which most were diagnosed histologically as RGNT. FGFR1 hotspot mutations were observed in all tumors analyzed, with co-occurrence of PIK3CA mutations in about two-thirds of the cases (63%). Additional loss-of-function mutations in the tumor suppressor gene NF1 were detected in a subset of cases (33%). Notably, in contrast to most other low-grade gliomas, these tumors often displayed co-occurrence of two or even all three of these mutations. Our data highlight that molecularly defined RGNTs are characterized by highly recurrent combined genetic alterations affecting both MAPK and PI3K signaling pathways. Thus, these two pathways appear to synergistically interact in the formation of RGNT, and offer potential therapeutic targets for this disease. [ABSTRACT FROM AUTHOR]

Aggregation of alpha-synuclein (α-SN) is a key pathogenic event in Parkinson’s disease (PD) leading to dopaminergic degeneration. The identification of natural compounds inhibiting α-SN aggregation may have a major role in treating PD. Different Scutellaria species are known as valuable medicinal plants, primarily due to their high flavonoid levels. Scutellaria pinnatifida (S. pinnatifida) is endemic to Iran; however, the knowledge of its pharmaceutical properties is limited. Here we report that S. pinnatifida extracts have an anti-fibrillation effect on α-SN aggregation and neuroprotective properties on PC12 and primary dopaminergic neurons. Treatment during α-SN fibril formation with S. pinnatifida extracts showed that the extractions performed with dichloromethane (DCMEx) and n-butanol (BuOHEx) strongly inhibited α-SN fibrillation. TLC-based analysis revealed that S. pinnatifida contains a great amount of flavonoids with high antioxidant properties as shown using a radical scavenging assay. Further analysis using HPLC and Mass spectroscopy on the DCMEx revealed the presence of baicalein in this extract. We then selected the more efficient extracts based on cell viability and ROS scavenging on PC12 cells and tested their neuroprotective properties on primary dopaminergic neurons. Our results showed the extracts strongly protected against α-SN oligomers. Surprisingly, they also neutralized the severe toxicity of paraquat. Therefore, S. pinnatifida may be a potential valuable medicinal herb for further studies related to the treatment of PD. [ABSTRACT FROM AUTHOR]

Background Special diphenyl-pyrazole compounds and in particular anle138b were found to reduce the progression of prion and Parkinson's disease in animal models. The therapeutic impact of these compounds was attributed to the modulation of α-synuclein and prion-protein aggregation related to these diseases. Methods Photophysical and photochemical properties of the diphenyl-pyrazole compounds anle138b, anle186b and sery313b and their interaction with monomeric and aggregated α-synuclein were studied by fluorescence techniques. Results The fluorescence emission of diphenyl-pyrazole is strongly increased upon incubation with α-synuclein fibrils, while no change in fluorescence emission is found when brought in contact with monomeric α-synuclein. This points to a distinct interaction between diphenyl-pyrazole and the fibrillar structure with a high binding affinity ( K d = 190 ± 120 nM) for anle138b. Several α-synuclein proteins form a hydrophobic binding pocket for the diphenyl-pyrazole compound. A UV-induced dehalogenation reaction was observed for anle138b which is modulated by the hydrophobic environment of the fibrils. Conclusion Fluorescence of the investigated diphenyl-pyrazole compounds strongly increases upon binding to fibrillar α-synuclein structures. Binding at high affinity occurs to hydrophobic pockets in the fibrils. General significance The observed particular fluorescence properties of the diphenyl-pyrazole molecules open new possibilities for the investigation of the mode of action of these compounds in neurodegenerative diseases. The high binding affinity to aggregates and the strong increase in fluorescence upon binding make the compounds promising fluorescence markers for the analysis of aggregation-dependent epitopes. [ABSTRACT FROM AUTHOR]

Simple Summary: Radiotracers targeting the translocator protein (TSPO) have recently gained substantial interest, since TSPO is overexpressed in malignant gliomas, where it correlates inversely with patient's survival. The high-affinity TSPO PET ligand [18F]GE180 was found to depict tumor areas with a remarkably high contrast and has been shown to provide non-invasive information on histological tumor grades. Yet, its significance was questioned with the argument, that the high contrast may solely arise from nonspecific accumulation in tissue supplied by leaky vessels. This study aimed to address this question by providing a detailed evaluation of spatial associations between TSPO and amino acid PET with relative contrast enhancement in T1-weighted MRI. The results show that [18F]GE180 contrast does not reflect a disrupted blood–brain barrier (BBB) only and that multi-modal imaging generates complementary information, which may better depict spatial heterogeneity of tumor biology and may be used to individualize the therapy for each patient. In this study, dual PET and contrast enhanced MRI were combined to investigate their correlation per voxel in patients at initial diagnosis with suspected glioblastoma. Correlation with contrast enhancement (CE) as an indicator of BBB leakage was further used to evaluate whether PET signal is likely caused by BBB disruption alone, or rather attributable to specific binding after BBB passage. PET images with [18F]GE180 and the amino acid [18F]FET were acquired and normalized to healthy background (tumor-to-background ratio, TBR). Contrast enhanced images were normalized voxel by voxel with the pre-contrast T1-weighted MRI to generate relative CE values (rCE). Voxel-wise analysis revealed a high PET signal even within the sub-volumes without detectable CE. No to moderate correlation of rCE with TBR voxel-values and a small overlap as well as a larger distance of the hotspots delineated in rCE and TBR-PET images were detected. In contrast, voxel-wise correlation between both PET modalities was strong for most patients and hotspots showed a moderate overlap and distance. The high PET signal in tumor sub-volumes without CE observed in voxel-wise analysis as well as the discordant hotspots emphasize the specificity of the PET signals and the relevance of combined differential information from dual PET and MRI images. [ABSTRACT FROM AUTHOR]

Simple Summary: This study aims at using a multi-technique approach to detect and analyze the effects of high dose rate spatially fractionated radiation therapies and to compare them to seamless broad beam irradiation targeting healthy and glioblastoma-bearing rat brains and delivering three different doses per each irradiation geometry. Brains were analyzed post mortem by multi-scale X-ray phase contrast imaging–computed tomography, histology, immunohistochemistry, X-ray fluorescence, and small- and wide-angle X-ray scattering to achieve detailed visualization, characterization and classification in 3D of the radio-induced effects on brain tissues. The original results bring new insights to the understanding of the response of cerebral tissue and tumors treated with high dose rate spatially fractioned radiotherapies and put the basis for channeling studies of in-vivo applications for monitoring RT effects. The purpose of this study is to use a multi-technique approach to detect the effects of spatially fractionated X-ray Microbeam (MRT) and Minibeam Radiation Therapy (MB) and to compare them to seamless Broad Beam (BB) irradiation. Healthy- and Glioblastoma (GBM)-bearing male Fischer rats were irradiated in-vivo on the right brain hemisphere with MRT, MB and BB delivering three different doses for each irradiation geometry. Brains were analyzed post mortem by multi-scale X-ray Phase Contrast Imaging–Computed Tomography (XPCI-CT), histology, immunohistochemistry, X-ray Fluorescence (XRF), Small- and Wide-Angle X-ray Scattering (SAXS/WAXS). XPCI-CT discriminates with high sensitivity the effects of MRT, MB and BB irradiations on both healthy and GBM-bearing brains producing a first-time 3D visualization and morphological analysis of the radio-induced lesions, MRT and MB induced tissue ablations, the presence of hyperdense deposits within specific areas of the brain and tumor evolution or regression with respect to the evaluation made few days post-irradiation with an in-vivo magnetic resonance imaging session. Histology, immunohistochemistry, SAXS/WAXS and XRF allowed identification and classification of these deposits as hydroxyapatite crystals with the coexistence of Ca, P and Fe mineralization, and the multi-technique approach enabled the realization, for the first time, of the map of the differential radiosensitivity of the different brain areas treated with MRT and MB. 3D XPCI-CT datasets enabled also the quantification of tumor volumes and Ca/Fe deposits and their full-organ visualization. The multi-scale and multi-technique approach enabled a detailed visualization and classification in 3D of the radio-induced effects on brain tissues bringing new essential information towards the clinical implementation of the MRT and MB radiation therapy techniques. [ABSTRACT FROM AUTHOR]

While cerebrospinal fluid (CSF) biomarkers for Creutzfeldt-Jakob disease (CJD) are established and partly included in the diagnostic criteria, no blood biomarkers are available. Here, we assessed the utility of serum neurofilament light chain (NF-L) and tau protein in comparison to CSF markers (NF-L and phosphorylated NF heavy chain (pNF-H), tau, S100B, 14-3-3) and prion conversion assay (real-time quaking induced conversion (RT-QuIC)) for sporadic and genetic CJD. Importantly, a Gerstmann-Sträussler-Scheinker mutation carrier in the asymptomatic phase and at disease onset was included as well. Both NF-L and tau were markedly increased in CJD serum, reaching similar or even better performance as in CSF (sensitivity and specificity for serum NF-L 100% and 85.5%, and for serum tau 84.6% and 96.2%, respectively). Serum S100B showed high sensitivity as well (84.2%), but lower specificity (63%). CSF neurofilaments were increased before symptom onset, while prion seeding assay was negative. Just before a clinical diagnosis could be made, all CSF markers and NF-L in the serum were increased and CSF prion conversion assay was positive. The data suggest that neurofilaments are sensitive and specific blood markers for the diagnosis of genetic and sporadic CJD and might represent promising tools to predict disease onset. [ABSTRACT FROM AUTHOR]