The prototype of transmissible neurodegenerative proteinopathies is prion diseases, characterized by aggregation of abnormally folded conformers of the native prion protein. A wealth of mechanisms ...has been proposed to explain the conformational conversion from physiological protein into misfolded, pathological form, mode of toxicity, propagation from cell‐to‐cell and regional spread. There is increasing evidence that other neurodegenerative diseases, most notably Alzheimer’s disease (Aβ and tau), Parkinson’s disease (α‐synuclein), frontotemporal dementia (TDP43, tau or FUS) and motor neurone disease (TDP43), exhibit at least some of the misfolded prion protein properties. In this review, we will discuss to what extent each of the properties of misfolded prion protein is known to occur for Aβ, tau, α‐synuclein and TDP43, with particular focus on self‐propagation through seeding, conformational strains, selective cellular and regional vulnerability, stability and resistance to inactivation, oligomers, toxicity and summarize the most recent literature on transmissibility of neurodegenerative disorders.
The aggressiveness of glioblastoma multiforme (GBM) is defined by local invasion and resistance to therapy. Within established GBM, a subpopulation of tumor-initiating cells with stem-like properties ...(GBM stem cells, GSCs) is believed to underlie resistance to therapy. The metabolic pathway autophagy has been implicated in the regulation of survival in GBM. However, the status of autophagy in GBM and its role in the cancer stem cell fraction is currently unclear. We found that a number of autophagy regulators are highly expressed in GBM tumors carrying a mesenchymal signature, which defines aggressiveness and invasion, and are associated with components of the MAPK pathway. This autophagy signature included the autophagy-associated genes DRAM1 and SQSTM1, which encode a key regulator of selective autophagy, p62. High levels of DRAM1 were associated with shorter overall survival in GBM patients. In GSCs, DRAM1 and SQSTM1 expression correlated with activation of MAPK and expression of the mesenchymal marker c-MET. DRAM1 knockdown decreased p62 localization to autophagosomes and its autophagy-mediated degradation, thus suggesting a role for DRAM1 in p62-mediated autophagy. In contrast, autophagy induced by starvation or inhibition of mTOR/PI-3K was not affected by either DRAM1 or p62 downregulation. Functionally, DRAM1 and p62 regulate cell motility and invasion in GSCs. This was associated with alterations of energy metabolism, in particular reduced ATP and lactate levels. Taken together, these findings shed new light on the role of autophagy in GBM and reveal a novel function of the autophagy regulators DRAM1 and p62 in control of migration/invasion in cancer stem cells.
Objectives
To investigate if quantitative apparent diffusion coefficient (ADC) measurements can predict genetic subtypes of non-gadolinium-enhancing gliomas, comparing whole tumour against single ...slice analysis.
Methods
Volumetric T2-derived masks of 44 gliomas were co-registered to ADC maps with ADC mean (ADC
mean
) calculated. For the slice analysis, two observers placed regions of interest in the largest tumour cross-section. The ratio (ADC
ratio
) between ADC
mean
in the tumour and normal appearing white matter was calculated for both methods.
Results
Isocitrate dehydrogenase (IDH) wild-type gliomas showed the lowest ADC values throughout (
p
< 0.001). ADC
mean
in the IDH-mutant 1p19q intact group was significantly higher than in the IDH-mutant 1p19q co-deleted group (
p
< 0.01). A volumetric ADC
mean
threshold of 1201 × 10
−6
mm
2
/s identified IDH wild-type with a sensitivity of 83% and a specificity of 86%; a volumetric ADC
ratio
cut-off value of 1.65 provided a sensitivity of 80% and a specificity of 92% (area under the curve (AUC) 0.9–0.94). A slice ADC
ratio
threshold for observer 1 (observer 2) of 1.76 (1.83) provided a sensitivity of 80% (86%), specificity of 91% (100%) and AUC of 0.95 (0.96). The intraclass correlation coefficient was excellent (0.98).
Conclusions
ADC measurements can support the distinction of glioma subtypes. Volumetric and two-dimensional measurements yielded similar results in this study.
Key Points
• Diffusion-weighted MRI aids the identification of non-gadolinium-enhancing malignant gliomas
• ADC measurements may permit non-gadolinium-enhancing glioma molecular subtyping
• IDH wild-type gliomas have lower ADC values than IDH-mutant tumours
• Single cross-section and volumetric ADC measurements yielded comparable results in this study
Studies consistently report lower ADC values in
(
) wild-type gliomas than in
mutant tumors, but their methods and thresholds vary. This research aimed to compare volumetric and regional ADC ...measurement techniques for glioma genotyping, with a focus on
status prediction.
Treatment-naïve World Health Organization grade II and III gliomas were analyzed by 3 neuroradiologist readers blinded to tissue results. ADC minimum and mean ROIs were defined in tumor and in normal-appearing white matter to calculate normalized values. T2-weighted tumor VOIs were registered to ADC maps with histogram parameters (mean, 2nd and 5th percentiles) extracted. Nonparametric testing (eta
and ANOVA) was performed to identify associations between ADC metrics and glioma genotypes. Logistic regression was used to probe the ability of VOI and ROI metrics to predict
status.
The study included 283 patients with 79
wild-type and 204
mutant gliomas. Across the study population,
status was most accurately predicted by ROI mean normalized ADC and VOI mean normalized ADC, with areas under the curve of 0.83 and 0.82, respectively
The results for ROI-based genotyping of nonenhancing and solid-patchy enhancing gliomas were comparable with volumetric parameters (area under the curve = 0.81-0.84). In rim-enhancing, centrally necrotic tumors (
= 23), only volumetric measurements were predictive (0.90).
Regional normalized mean ADC measurements are noninferior to volumetric segmentation for defining solid glioma
status. Partially necrotic, rim-enhancing tumors are unsuitable for ROI assessment and may benefit from volumetric ADC quantification.
The largest kindred with inherited prion disease P102L, historically Gerstmann-Sträussler-Scheinker syndrome, originates from central England, with émigrés now resident in various parts of the ...English-speaking world. We have collected data from 84 patients in the large UK kindred and numerous small unrelated pedigrees to investigate phenotypic heterogeneity and modifying factors. This collection represents by far the largest series of P102L patients so far reported. Microsatellite and genealogical analyses of eight separate European kindreds support multiple distinct mutational events at a cytosine-phosphate diester-guanidine dinucleotide mutation hot spot. All of the smaller P102L kindreds were linked to polymorphic human prion protein gene codon 129M and were not connected by genealogy or microsatellite haplotype background to the large kindred or each other. While many present with classical Gerstmann-Sträussler-Scheinker syndrome, a slowly progressive cerebellar ataxia with later onset cognitive impairment, there is remarkable heterogeneity. A subset of patients present with prominent cognitive and psychiatric features and some have met diagnostic criteria for sporadic Creutzfeldt-Jakob disease. We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P = 0.02). Unexpectedly, apolipoprotein E4 carriers have a delayed age of onset by 10 years (P = 0.02). We found a preponderance of female patients compared with males (54 females versus 30 males, P = 0.01), which probably relates to ascertainment bias. However, these modifiers had no impact on a semi-quantitative pathological phenotype in 10 autopsied patients. These data allow an appreciation of the range of clinical phenotype, modern imaging and molecular investigation and should inform genetic counselling of at-risk individuals, with the identification of two genetic modifiers.
Objective
Adjustable differential pressure (DP) valves in combination with fixed anti-siphon devices are currently a popular combination in counteracting the effects of cerebrospinal fluid ...overdrainage following implantation of a ventriculoperitoneal shunt system. The study examined the flow performance of three DP valves in successive combination with an anti-siphon device in an in vitro shunt laboratory with and without vertical motion.
Methods
We analyzed three DP valves (Codman Hakim Medos programmable valve HM, Codman CertasPlus CP, and Miethke proGAV PG, in combination with either Codman SiphonGuard SG or Miethke ShuntAssistant SA), resulting in the evaluation of six different valve combinations. Defined DP conditions between 4 and 40 cm H
2
O within a simulated shunt system were generated and the specific flow characteristics were measured. In addition, combinations with SA, which is a gravity-dependent valve, were measured in defined spatial positions (90°, 60°). All device combinations were tested during vertical motion with movement frequencies of 2, 3, and 4 Hz.
Results
All valve combinations effectively counteracted the siphon effect in relation to the chosen DP. Angulation-related flow changes were similar in the three combinations of DP valve and SA in the 60° and 90° position. In CP-SA and PG-SA, repeated vertical movement at 2, 3, and 4 Hz led to significant increase in flow, whereas in HM-SA, constant increase was seen at 4 Hz only (flow change at 4Hz, DP 40 cm H
2
O: PG (opening pressure 4 cm H
2
O) 90°: 0.95 ml/min, 60°: 0.71 ml/min; HM (opening pressure 4 cm H
2
O) 90°: 0.66 ml/min, 60°: 0.41 ml/min; CP (PL 2) 90°: 0.94 ml/min, 60°: 0.79 ml/min;
p
< 0.01); however, HM-SA showed relevant motion-induced flow already at low DPs (0.85 ml/min, DP 4 cm H
2
O). In combinations of DP valve with SG, increase of flow was far less pronounced and even led to significant reduction of flow in certain constellations. Maximum overall flow increase was 0.46 ± 0.04 ml/min with a HM (opening pressure 12 cm H
2
O) at 2 Hz and a DP of 10 cm H
2
O, whereas maximum flow decrease was 1.12 ± 0.08 with a PG (opening pressure 4 cm H
2
O) at 3 Hz and a DP of 10 cmH
2
O.
Conclusion
In an experimental setup, all valve combinations effectively counteracted the siphon effect in the vertical position according to their added resistance. Motion-induced increased flow was consistently demonstrated in combinations of DP valve and SA. The combination of HM and SA especially showed relevant motion-induced flow already at low DPs. In combinations of DP and SG, the pattern of the motion induced flow was more inconsistent and motion even led to significant flow reduction, predominantly at DPs of 10 and 20 cmH
2
O.
Mutations in receptor tyrosine kinase (RTK) growth factor receptors (epidermal growth factor receptor, platelet-derived growth factor receptor, MET and ERBB2), which result in downstream activation ...of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathway and PI(3)K/Akt pathway, are found in almost all high-grade gliomas and MAPK signaling is necessary for continued glioma maintenance. In addition, BRAF is mutated in the majority of low-grade gliomas and its expression and activity is significantly increased in the majority of high-grade gliomas. Although the importance of RTKs and RAS signaling in glioma development has been shown, the role of BRAF has yet to be characterized. We evaluated the effect of activated BRAF in glioma formation using the retroviral replication-competent avian leukosis virus long terminal repeat, splice acceptor (RCAS)/TVA system to transfer genes encoding activated forms of BRAF, KRas, Akt and Cre to nestin-expressing neural progenitor cells in Ink4a/Arf(lox/lox) mice in vivo. Although expression of activated BRAF alone is not sufficient for tumorigenesis, the combination of activated BRAF and Akt or BRAF with Ink4a/Arf loss is transforming. Interestingly, activated BRAF generates gliomas with characteristics similar to activated KRas in the context of Akt but not Ink4a/Arf loss. Our studies show a role for BRAF activation and signaling in glioma development and as potential target for glioma therapy.
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