The mechanical network of the brain is a major contributor to neural health and has been recognized by in vivo magnetic resonance elastography (MRE) to be highly responsive to diseases. However, until now only brain softening was observed and no mechanism was known that reverses the common decrement of neural elasticity during aging or disease. We used MRE in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) mouse model for dopaminergic neurodegeneration as observed in Parkinson’s disease (PD) to study the mechanical response of the brain on adult hippocampal neurogenesis as a robust correlate of neuronal plasticity in healthy and injured brain. We observed a steep transient rise in elasticity within the hippocampal region of up to over 50% six days after MPTP treatment correlating with increased neuronal density in the dentate gyrus, which could not be detected in healthy controls. Our results provide the first indication that new neurons reactively generated following neurodegeneration substantially contribute to the mechanical scaffold of the brain. Diagnostic neuroimaging may thus target on regions of the brain displaying symptomatically elevated elasticity values for the detection of neuronal plasticity following neurodegeneration.
Background DNA methylation‐based classification of cancer provides a comprehensive molecular approach to diagnose tumours. In fact, DNA methylation profiling of human brain tumours already profoundly impacts clinical neuro‐oncology. However, current implementation using hybridisation microarrays is time consuming and costly. We recently reported on shallow nanopore whole‐genome sequencing for rapid and cost‐effective generation of genome‐wide 5‐methylcytosine profiles as input to supervised classification. Here, we demonstrate that this approach allows us to discriminate a wide spectrum of primary brain tumours. Results Using public reference data of 82 distinct tumour entities, we performed nanopore genome sequencing on 382 tissue samples covering 46 brain tumour (sub)types. Using bootstrap sampling in a cohort of 55 cases, we found that a minimum set of 1000 random CpG features is sufficient for high‐confidence classification by ad hoc random forests. We implemented score recalibration as a confidence measure for interpretation in a clinical context and empirically determined a platform‐specific threshold in a randomly sampled discovery cohort (N = 185). Applying this cut‐off to an independent validation series (n = 184) yielded 148 classifiable cases (sensitivity 80.4%) and demonstrated 100% specificity. Cross‐lab validation demonstrated robustness with concordant results across four laboratories in 10/11 (90.9%) cases. In a prospective benchmarking (N = 15), the median time to results was 21.1 h. Conclusions In conclusion, nanopore sequencing allows robust and rapid methylation‐based classification across the full spectrum of brain tumours. Platform‐specific confidence scores facilitate clinical implementation for which prospective evaluation is warranted and ongoing.
The biomechanical properties of brain tissue are altered by histopathological changes due to neurodegenerative diseases like Parkinson's disease (PD). Such alterations can be measured by magnetic resonance elastography (MRE) as a non-invasive technique to determine viscoelastic parameters of the brain. Until now, the correlation between histopathological mechanisms and observed alterations in tissue viscoelasticity in neurodegenerative diseases is still not completely understood. Thus, the objective of this study was to evaluate (1) the validity of MRE to detect viscoelastic changes in small and specific brain regions: the substantia nigra (SN), midbrain and hippocampus in a mouse model of PD, and (2) if the induced dopaminergic neurodegeneration and inflammation in the SN is reflected by local changes in viscoelasticity. Therefore, MRE measurements of the SN, midbrain and hippocampus were performed in adult female mice before and at five time points after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin hydrochloride (MPTP) treatment specifically lesioning dopaminergic neurons in the SN. At each time point, additional mice were utilized for histological analysis of the SN. After treatment cessation, we observed opposed viscoelastic changes in the midbrain, hippocampus and SN with the midbrain showing a gradual rise and the hippocampus a distinct transient increase of viscous and elastic parameters, while viscosity and–to a lesser extent—elasticity in the SN decreased over time. The decrease in viscosity and elasticity in the SN was paralleled by a reduced number of neurons due to the MPTP-induced neurodegeneration. In conclusion, MRE is highly sensitive to detect local viscoelastic changes in specific and even small brain regions. Moreover, we confirmed that neuronal cells likely constitute the backbone of the adult brain mainly accounting for its viscoelasticity. Therefore, MRE could be established as a new potential instrument for clinical evaluation and diagnostics of neurodegenerative diseases.
BackgroundParkinson’s disease (PD) is characterized by dopaminergic cell loss and inflammation in the substantia nigra (SN) leading to motor deficits but also to hippocampus-associated non-motor symptoms such as spatial learning and memory deficits. The cognitive decline is correlated with impaired adult hippocampal neurogenesis resulting from dopamine deficit and inflammation, represented in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) mouse model of PD. In the inflammatory tissue, cyclooxygenase (COX) is upregulated leading to an ongoing inflammatory process such as prostaglandin-mediated increased cytokine levels. Therefore, inhibition of COX by indomethacin may prevent the inflammatory response and the impairment of adult hippocampal neurogenesis.MethodsWildtype C57Bl/6 and transgenic Nestin-GFP mice were treated with MPTP followed by short-term or long-term indomethacin treatment. Then, aspects of inflammation and neurogenesis were evaluated by cell counts using immunofluorescence and immunohistochemical stainings in the SN and dentate gyrus (DG). Furthermore, hippocampal mRNA expression of neurogenesis-related genes of the Notch, Wnt, and sonic hedgehog signaling pathways and neurogenic factors were assessed, and protein levels of serum cytokines were measured.ResultsIndomethacin restored the reduction of the survival rate of new mature neurons and reduced the amount of amoeboid CD68+ cells in the DG after MPTP treatment. Indomethacin downregulated genes of the Wnt and Notch signaling pathways and increased neuroD6 expression. In the SN, indomethacin reduced the pro-inflammatory cellular response without reversing dopaminergic cell loss.ConclusionIndomethacin has a pro-neurogenic and thereby restorative effect and an anti-inflammatory effect on the cellular level in the DG following MPTP treatment. Therefore, COX inhibitors such as indomethacin may represent a therapeutic option to restore adult neurogenesis in PD.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1179-4) contains supplementary material, which is available to authorized users.
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