Neuropathology and Applied Neurobiology最新文献

Aims: DNA methylation profiling, recently endorsed by the World Health Organisation (WHO) as a pivotal diagnostic tool for brain tumours, most commonly relies on bead arrays. Despite its widespread use, limited data exist on the technical reproducibility and potential cross-institutional differences. The LOGGIC Core BioClinical Data Bank registry conducted a prospective laboratory comparison trial with 12 international laboratories to enhance diagnostic accuracy for paediatric low-grade gliomas, focusing on technical aspects of DNA methylation data generation and profile interpretation under clinical real-time conditions.

Methods: Four representative low-grade gliomas of distinct histologies were centrally selected, and DNA extraction was performed. Participating laboratories received a DNA aliquot and performed the DNA methylation-based classification and result interpretation without knowledge of tumour histology. Additionally, participants were required to interpret the copy number profile derived from DNA methylation data and conduct DNA sequencing of the BRAF hotspot p.V600 due to its relevance for low-grade gliomas. Results had to be returned within 30 days.

Results: High technical reproducibility was observed, with a median pairwise correlation of 0.99 (range 0.94-0.99) between coordinating laboratory and participants. DNA methylation-based tumour classification and copy number profile interpretation were consistent across all centres, and BRAF mutation status was accurately reported for all cases. Eleven out of 12 centres successfully reported their analysis within the 30-day timeframe.

Conclusion: Our study demonstrates remarkable concordance in DNA methylation profiling and profile interpretation across 12 international centres. These findings underscore the potential contribution of DNA methylation analysis to the harmonisation of brain tumour diagnostics.

Aims: Recent advances in artificial intelligence, particularly with large language models like GPT-4Vision (GPT-4V)-a derivative feature of ChatGPT-have expanded the potential for medical image interpretation. This study evaluates the accuracy of GPT-4V in image classification tasks of histopathological images and compares its performance with a traditional convolutional neural network (CNN).

Methods: We utilised 1520 images, including haematoxylin and eosin staining and tau immunohistochemistry, from patients with various neurodegenerative diseases, such as Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). We assessed GPT-4V's performance using multi-step prompts to determine how textual context influences image interpretation. We also employed few-shot learning to enhance improvements in GPT-4V's diagnostic performance in classifying three specific tau lesions-astrocytic plaques, neuritic plaques and tufted astrocytes-and compared the outcomes with the CNN model YOLOv8.

Results: GPT-4V accurately recognised staining techniques and tissue origin but struggled with specific lesion identification. The interpretation of images was notably influenced by the provided textual context, which sometimes led to diagnostic inaccuracies. For instance, when presented with images of the motor cortex, the diagnosis shifted inappropriately from AD to CBD or PSP. However, few-shot learning markedly improved GPT-4V's diagnostic capabilities, enhancing accuracy from 40% in zero-shot learning to 90% with 20-shot learning, matching the performance of YOLOv8, which required 100-shot learning to achieve the same accuracy.

Conclusions: Although GPT-4V faces challenges in independently interpreting histopathological images, few-shot learning significantly improves its performance. This approach is especially promising for neuropathology, where acquiring extensive labelled datasets is often challenging.

Immunoglobulin Mu-binding protein 2 (IGHMBP2) pathogenic variants result in the fatal, neurodegenerative disease spinal muscular atrophy with respiratory distress type 1 (SMARD1) and the milder, Charcot-Marie-Tooth (CMT) type 2S (CMT2S) neuropathy. More than 20 years after the link between IGHMBP2 and SMARD1 was revealed, and 10 years after the discovery of the association between IGHMBP2 and CMT2S, the pathogenic mechanism of these diseases is still not well defined. The discovery that IGHMBP2 functions as an RNA/DNA helicase was an important step, but it did not reveal the pathogenic mechanism. Helicases are enzymes that use ATP hydrolysis to catalyse the separation of nucleic acid strands. They are involved in numerous cellular processes, including DNA repair and transcription; RNA splicing, transport, editing and degradation; ribosome biogenesis; translation; telomere maintenance; and homologous recombination. IGHMBP2 appears to be a multifunctional factor involved in several cellular processes that regulate gene expression. It is difficult to determine which processes, when dysregulated, lead to pathology. Here, we summarise our current knowledge of the clinical presentation of IGHMBP2-related diseases. We also overview the available models, including yeast, mice and cells, which are used to study the function of IGHMBP2 and the pathogenesis of the related diseases. Further, we discuss the structure of the IGHMBP2 protein and its postulated roles in cellular functioning. Finally, we present potential anomalies that may result in the neurodegeneration observed in IGHMBP2-related disease and highlight the most prominent ones.

Aims: Astrocytic tau pathology is a major feature of tauopathies and ageing-related tau astrogliopathy (ARTAG). The substantia nigra (SN) is one of the important degenerative areas in tauopathies with parkinsonism. Nigral tau pathology is usually reported as neuronal predominant with less prominent astrocytic involvement. We aimed to identify cases with prominent astrocytic tau pathology in the SN.

Methods: We use the term nigral tau-astrogliopathy (NITAG) to describe cases showing an unusually high density of ARTAG with less neuronal tau pathology in the SN. We collected clinical information and studied the distribution of tau pathology, morphological features and immunostaining profiles in three cases.

Results: Three cases, all males with parkinsonism, were identified with the following clinicopathological diagnoses: (i) atypical parkinsonism with tau pathology reminiscent to that in postencephalitic parkinsonism (69-year-old); (ii) multiple system atrophy (73-year-old); (iii) traumatic encephalopathy syndrome/chronic traumatic encephalopathy (84-year-old). Double-labelling immunofluorescence confirmed co-localization of GFAP and phosphorylated tau in affected astrocytes. Staining profiles of NITAG revealed immunopositivity for various phosphorylated tau antibodies. Some astrocytic tau lesions were also seen in other brainstem regions and cerebral grey matter.

Conclusions: We propose NITAG is a rare neuropathological feature, and not a distinct disease entity, in the frame of multiple system ARTAG, represented by abundant tau-positive astrocytes in various brain regions but having the highest density in the SN. The concept of NITAG allows the stratification of cases with various background pathologies to understand its relevance and contribution to neuronal dysfunction.

Previous reports have shown that IL-6 and IFN-⍺ induce distinct transcriptomic and morphological changes in microglia. Here, we demonstrate that IL-6 increases tissue surveillance, migration and phagocytosis in primary murine microglia, whereas IFN-⍺ inhibits these functions. Our results provide a crucial link between transcriptome and function. It holds the potential to serve as the foundation for future studies aimed at identifying therapeutic targets for cytokine-mediated neuroinflammatory diseases.

Aims: Endoplasmic reticulum stress followed by the unfolded protein response is one of the cellular mechanisms contributing to the progression of α-synuclein pathology in Parkinson's disease and other Lewy body diseases. We aimed to investigate the activation of endoplasmic reticulum stress and its correlation with α-synuclein pathology in human post-mortem brain tissue.

Methods: We analysed brain tissue from 45 subjects-14 symptomatic patients with Lewy body disease, 19 subjects with incidental Lewy body disease, and 12 healthy controls. The analysed brain regions included the medulla, pons, midbrain, striatum, amygdala and entorhinal, temporal, frontal and occipital cortex. We analysed activation of endoplasmic reticulum stress via levels of the unfolded protein response-related proteins (Grp78, eIF2α) and endoplasmic reticulum stress-regulating neurotrophic factors (MANF, CDNF).

Results: We showed that regional levels of two endoplasmic reticulum-localised neurotrophic factors, MANF and CDNF, did not change in response to accumulating α-synuclein pathology. The concentration of MANF negatively correlated with age in specific regions. eIF2α was upregulated in the striatum of Lewy body disease patients and correlated with increased α-synuclein levels. We found the upregulation of chaperone Grp78 in the amygdala and nigral dopaminergic neurons of Lewy body disease patients. Grp78 levels in the amygdala strongly correlated with soluble α-synuclein levels.

Conclusions: Our data suggest a strong but regionally specific change in Grp78 and eIF2α levels, which positively correlates with soluble α-synuclein levels. Additionally, MANF levels decreased in dopaminergic neurons in the substantia nigra. Our research suggests that endoplasmic reticulum stress activation is not associated with Lewy pathology but rather with soluble α-synuclein concentration and disease progression.

Aims: Mutations in the MAPT gene encoding tau protein can cause autosomal dominant neurodegenerative tauopathies including frontotemporal dementia (often with Parkinsonism). In Alzheimer's disease, the most common tauopathy, synapse loss is the strongest pathological correlate of cognitive decline. Recently, Positron Emission Tomography (PET) imaging with synaptic tracers revealed clinically relevant loss of synapses in primary tauopathies; however, the molecular mechanisms leading to synapse degeneration in primary tauopathies remain largely unknown. In this study, we examined post-mortem brain tissue from people who died with frontotemporal dementia with tau pathology (FTDtau) caused by the MAPT intronic exon 10 + 16 mutation, which increases splice variants containing exon 10 resulting in higher levels of tau with four microtubule-binding domains.

Methods: We used RNA sequencing and histopathology to examine temporal cortex and visual cortex, to look for molecular phenotypes compared to age, sex and RNA integrity matched participants who died without neurological disease (n = 12 FTDtau10 + 16 and 13 controls).

Results: Bulk tissue RNA sequencing reveals substantial downregulation of gene expression associated with synaptic function. Upregulated biological pathways in human MAPT 10 + 16 brain included those involved in transcriptional regulation, DNA damage response and neuroinflammation. Histopathology confirmed increased pathological tau accumulation in FTDtau10 + 16 cortex as well as a loss of presynaptic protein staining and region-specific increased colocalization of phospho-tau with synapses in temporal cortex.

Conclusions: Our data indicate that synaptic pathology likely contributes to pathogenesis in FTDtau10 + 16 caused by the MAPT 10 + 16 mutation.