Pub Date : 2024-10-09DOI: 10.1007/s00401-024-02812-z
Charlotte Gorißen, Anne Albers, Viktoria Ruf, Emil Chteinberg, Reiner Siebert, Leonille Schweizer, Lukas Kaufmann, Joachim E. Kühn, Dennis Tappe, Tanja Kuhlmann, Christian Thomas
Pub Date : 2024-10-09DOI: 10.1007/s00401-024-02811-0
Santoesha A. Ghisai, Levi van Hijfte, Wies R. Vallentgoed, C. Mircea S. Tesileanu, Iris de Heer, Johan M. Kros, Marc Sanson, Thierry Gorlia, Wolfgang Wick, Michael A. Vogelbaum, Alba A. Brandes, Enrico Franceschi, Paul M. Clement, Anna K. Nowak, Vassilis Golfinopoulos, Martin J. van den Bent, Pim J. French, Youri Hoogstrate
Accurate grading of IDH-mutant gliomas defines patient prognosis and guides the treatment path. Histological grading is challenging, and aside from CDKN2A/B homozygous deletions in IDH-mutant astrocytomas, there are no other objective molecular markers used for grading. RNA-sequencing was conducted on primary IDH-mutant astrocytomas (n = 138) included in the prospective CATNON trial, which was performed to assess the prognostic effect of adjuvant and concurrent temozolomide. We integrated the RNA-sequencing data with matched DNA-methylation and NGS data. We also used multi-omics data from IDH-mutant astrocytomas included in the TCGA dataset and validated results on matched primary and recurrent samples from the GLASS-NL study. Since discrete classes do not adequately capture grading of these tumours, we utilised DNA-methylation profiles to generate a Continuous Grading Coefficient (CGC) based on classification scores from a CNS-tumour classifier. CGC was an independent predictor of survival outperforming current WHO-CNS5 and methylation-based classification. Our RNA-sequencing analysis revealed four distinct transcription clusters that were associated with (i) upregulation of cell cycling genes; (ii) downregulation of glial differentiation genes; (iii) upregulation of embryonic development genes (e.g. HOX, PAX, and TBX) and (iv) upregulation of extracellular matrix genes. The upregulation of embryonic development genes was associated with a specific increase of CpG island methylation near these genes. Higher grade IDH-mutant astrocytomas have DNA-methylation signatures that, on the RNA level, are associated with increased cell cycling, tumour cell de-differentiation and extracellular matrix remodelling. These combined molecular signatures can serve as an objective marker for grading of IDH-mutant astrocytomas.
{"title":"Epigenetic landscape reorganisation and reactivation of embryonic development genes are associated with malignancy in IDH-mutant astrocytoma","authors":"Santoesha A. Ghisai, Levi van Hijfte, Wies R. Vallentgoed, C. Mircea S. Tesileanu, Iris de Heer, Johan M. Kros, Marc Sanson, Thierry Gorlia, Wolfgang Wick, Michael A. Vogelbaum, Alba A. Brandes, Enrico Franceschi, Paul M. Clement, Anna K. Nowak, Vassilis Golfinopoulos, Martin J. van den Bent, Pim J. French, Youri Hoogstrate","doi":"10.1007/s00401-024-02811-0","DOIUrl":"10.1007/s00401-024-02811-0","url":null,"abstract":"<div><p>Accurate grading of IDH-mutant gliomas defines patient prognosis and guides the treatment path. Histological grading is challenging, and aside from <i>CDKN2A/B</i> homozygous deletions in IDH-mutant astrocytomas, there are no other objective molecular markers used for grading. RNA-sequencing was conducted on primary IDH-mutant astrocytomas (<i>n</i> = 138) included in the prospective CATNON trial, which was performed to assess the prognostic effect of adjuvant and concurrent temozolomide. We integrated the RNA-sequencing data with matched DNA-methylation and NGS data. We also used multi-omics data from IDH-mutant astrocytomas included in the TCGA dataset and validated results on matched primary and recurrent samples from the GLASS-NL study. Since discrete classes do not adequately capture grading of these tumours, we utilised DNA-methylation profiles to generate a Continuous Grading Coefficient (CGC) based on classification scores from a CNS-tumour classifier. CGC was an independent predictor of survival outperforming current WHO-CNS5 and methylation-based classification. Our RNA-sequencing analysis revealed four distinct transcription clusters that were associated with (i) upregulation of cell cycling genes; (ii) downregulation of glial differentiation genes; (iii) upregulation of embryonic development genes (e.g. <i>HOX</i>, <i>PAX,</i> and <i>TBX</i>) and (iv) upregulation of extracellular matrix genes. The upregulation of embryonic development genes was associated with a specific increase of CpG island methylation near these genes. Higher grade IDH-mutant astrocytomas have DNA-methylation signatures that, on the RNA level, are associated with increased cell cycling, tumour cell de-differentiation and extracellular matrix remodelling. These combined molecular signatures can serve as an objective marker for grading of IDH-mutant astrocytomas.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02811-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-08DOI: 10.1007/s00401-024-02809-8
Joan Liu, Lawrence Binding, Isha Puntambekar, Smriti Patodia, Yau Mun Lim, Alicja Mryzyglod, Fenglai Xiao, Shengning Pan, Remika Mito, Jane de Tisi, John S. Duncan, Sallie Baxendale, Matthias Koepp, Maria Thom
White matter microvascular alterations in temporal lobe epilepsy (TLE) may be relevant to acquired neurodegenerative processes and cognitive impairments associated with this condition. We quantified microvascular changes, myelin, axonal, glial and extracellular-matrix labelling in the gyral core and deep temporal lobe white matter regions in surgical resections from 44 TLE patients with or without hippocampal sclerosis. We compared this pathology data with in vivo pre-operative MRI diffusion measurements in co-registered regions and neuropsychological measures of cognitive impairment and decline. In resections, increased arteriolosclerosis was observed in TLE compared to non-epilepsy controls (greater sclerotic index, p < 0.001), independent of age. Microvascular changes included increased vascular densities in some regions but uniformly reduced mean vascular size (quantified with collagen-4, p < 0.05–0.0001), and increased pericyte coverage of small vessels and capillaries particularly in deep white matter (quantified with platelet-derived growth factor receptorβ and smooth muscle actin, p < 0.01) which was more marked the longer the duration of epilepsy (p < 0.05). We noted increased glial numbers (Olig2, Iba1) but reduced myelin (MAG, PLP) in TLE compared to controls, particularly prominent in deep white matter. Gene expression analysis showed a greater reduction of myelination genes in HS than non-HS cases and with age and correlation with diffusion MRI alterations. Glial densities and vascular size were increased with increased MRI diffusivity and vascular density with white matter abnormality quantified using fixel-based analysis. Increased perivascular space was associated with reduced fractional anisotropy as well as age-accelerated cognitive decline prior to surgery (p < 0.05). In summary, likely acquired microangiopathic changes in TLE, including vascular sclerosis, increased pericyte coverage and reduced small vessel size, may indicate a functional alteration in contractility of small vessels and haemodynamics that could impact on tissue perfusion. These morphological features correlate with white matter diffusion MRI alterations and might explain cognitive decline in TLE.
{"title":"Microangiopathy in temporal lobe epilepsy with diffusion MRI alterations and cognitive decline","authors":"Joan Liu, Lawrence Binding, Isha Puntambekar, Smriti Patodia, Yau Mun Lim, Alicja Mryzyglod, Fenglai Xiao, Shengning Pan, Remika Mito, Jane de Tisi, John S. Duncan, Sallie Baxendale, Matthias Koepp, Maria Thom","doi":"10.1007/s00401-024-02809-8","DOIUrl":"10.1007/s00401-024-02809-8","url":null,"abstract":"<div><p>White matter microvascular alterations in temporal lobe epilepsy (TLE) may be relevant to acquired neurodegenerative processes and cognitive impairments associated with this condition. We quantified microvascular changes, myelin, axonal, glial and extracellular-matrix labelling in the gyral core and deep temporal lobe white matter regions in surgical resections from 44 TLE patients with or without hippocampal sclerosis. We compared this pathology data with in vivo pre-operative MRI diffusion measurements in co-registered regions and neuropsychological measures of cognitive impairment and decline. In resections, increased arteriolosclerosis was observed in TLE compared to non-epilepsy controls (greater sclerotic index, <i>p</i> < 0.001), independent of age. Microvascular changes included increased vascular densities in some regions but uniformly reduced mean vascular size (quantified with collagen-4, <i>p</i> < 0.05–0.0001), and increased pericyte coverage of small vessels and capillaries particularly in deep white matter (quantified with platelet-derived growth factor receptorβ and smooth muscle actin, <i>p</i> < 0.01) which was more marked the longer the duration of epilepsy (<i>p</i> < 0.05). We noted increased glial numbers (Olig2, Iba1) but reduced myelin (MAG, PLP) in TLE compared to controls, particularly prominent in deep white matter. Gene expression analysis showed a greater reduction of myelination genes in HS than non-HS cases and with age and correlation with diffusion MRI alterations. Glial densities and vascular size were increased with increased MRI diffusivity and vascular density with white matter abnormality quantified using fixel-based analysis. Increased perivascular space was associated with reduced fractional anisotropy as well as age-accelerated cognitive decline prior to surgery (<i>p</i> < 0.05). In summary, likely acquired microangiopathic changes in TLE, including vascular sclerosis, increased pericyte coverage and reduced small vessel size, may indicate a functional alteration in contractility of small vessels and haemodynamics that could impact on tissue perfusion. These morphological features correlate with white matter diffusion MRI alterations and might explain cognitive decline in TLE.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02809-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-05DOI: 10.1007/s00401-024-02806-x
Kohji Mori, Thomas Arzberger, Friedrich A. Grässer, Ilse Gijselinck, Stephanie May, Kristin Rentzsch, Shih‑Ming Weng, Martin H. Schludi, Julie van der Zee, Marc Cruts, Christine Van Broeckhoven, Elisabeth Kremmer, Hans A. Kretzschmar, Christian Haass, Dieter Edbauer
{"title":"Correction to: Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins","authors":"Kohji Mori, Thomas Arzberger, Friedrich A. Grässer, Ilse Gijselinck, Stephanie May, Kristin Rentzsch, Shih‑Ming Weng, Martin H. Schludi, Julie van der Zee, Marc Cruts, Christine Van Broeckhoven, Elisabeth Kremmer, Hans A. Kretzschmar, Christian Haass, Dieter Edbauer","doi":"10.1007/s00401-024-02806-x","DOIUrl":"10.1007/s00401-024-02806-x","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142377702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-24DOI: 10.1007/s00401-024-02808-9
Dietmar Rudolf Thal, Bart De Strooper
{"title":"Regulated cell death in neurodegeneration: pathways and therapeutic horizons","authors":"Dietmar Rudolf Thal, Bart De Strooper","doi":"10.1007/s00401-024-02808-9","DOIUrl":"10.1007/s00401-024-02808-9","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-24DOI: 10.1007/s00401-024-02804-z
Hoi-Khoanh Giong, Seung Jae Hyeon, Jae-Geun Lee, Hyun-Ju Cho, Uiyeol Park, Thor D. Stein, Junghee Lee, Kweon Yu, Hoon Ryu, Jeong-Soo Lee
Tauopathy, including frontotemporal lobar dementia and Alzheimer’s disease, describes a class of neurodegenerative diseases characterized by the aberrant accumulation of Tau protein due to defects in proteostasis. Upon generating and characterizing a stable transgenic zebrafish that expresses the human TAUP301L mutant in a neuron-specific manner, we found that accumulating Tau protein was efficiently cleared via an enhanced autophagy activity despite constant Tau mRNA expression; apparent tauopathy-like phenotypes were revealed only when the autophagy was genetically or chemically inhibited. We performed RNA-seq analysis, genetic knockdown, and rescue experiments with clinically relevant point mutations of valosin-containing protein (VCP), and showed that induced expression of VCP, an essential cytosolic chaperone for the protein quality system, was a key factor for Tau degradation via its facilitation of the autophagy flux. This novel function of VCP in Tau clearance was further confirmed in a tauopathy mouse model where VCP overexpression significantly decreased the level of phosphorylated and oligomeric/aggregate Tau and rescued Tau-induced cognitive behavioral phenotypes, which were reversed when the autophagy was blocked. Importantly, VCP expression in the brains of human Alzheimer’s disease patients was severely downregulated, consistent with its proposed role in Tau clearance. Taken together, these results suggest that enhancing the expression and activity of VCP in a spatiotemporal manner to facilitate the autophagy pathway is a potential therapeutic approach for treating tauopathy.
Tau病(包括额颞叶痴呆症和阿尔茨海默病)是一类神经退行性疾病,其特征是由于蛋白稳态缺陷导致的Tau蛋白异常积累。我们发现,尽管Tau mRNA的表达量保持不变,但积聚的Tau蛋白可通过增强的自噬活性被有效清除;只有当自噬受到遗传或化学抑制时,才会出现明显的类似Tau病的表型。我们对含缬氨酸蛋白(VCP)进行了RNA-seq分析、基因敲除以及与临床相关的点突变拯救实验,结果表明,VCP是蛋白质质量系统的重要细胞膜伴侣,其诱导表达是通过促进自噬通量降解Tau的关键因素。VCP在Tau清除中的这一新功能在tau病小鼠模型中得到了进一步证实,过量表达VCP可显著降低磷酸化Tau和寡聚/聚集Tau的水平,并挽救Tau诱导的认知行为表型。重要的是,VCP 在人类阿尔茨海默病患者大脑中的表达严重下调,这与它在 Tau 清除中的作用一致。综上所述,这些结果表明,以时空方式增强VCP的表达和活性以促进自噬途径是治疗牛头蛋白病的一种潜在治疗方法。
{"title":"Tau accumulation is cleared by the induced expression of VCP via autophagy","authors":"Hoi-Khoanh Giong, Seung Jae Hyeon, Jae-Geun Lee, Hyun-Ju Cho, Uiyeol Park, Thor D. Stein, Junghee Lee, Kweon Yu, Hoon Ryu, Jeong-Soo Lee","doi":"10.1007/s00401-024-02804-z","DOIUrl":"10.1007/s00401-024-02804-z","url":null,"abstract":"<div><p>Tauopathy, including frontotemporal lobar dementia and Alzheimer’s disease, describes a class of neurodegenerative diseases characterized by the aberrant accumulation of Tau protein due to defects in proteostasis. Upon generating and characterizing a stable transgenic zebrafish that expresses the human <i>TAU</i><sup>P301L</sup> mutant in a neuron-specific manner, we found that accumulating Tau protein was efficiently cleared via an enhanced autophagy activity despite constant Tau mRNA expression; apparent tauopathy-like phenotypes were revealed only when the autophagy was genetically or chemically inhibited. We performed RNA-seq analysis, genetic knockdown, and rescue experiments with clinically relevant point mutations of valosin-containing protein (VCP), and showed that induced expression of VCP, an essential cytosolic chaperone for the protein quality system, was a key factor for Tau degradation via its facilitation of the autophagy flux. This novel function of VCP in Tau clearance was further confirmed in a tauopathy mouse model where <i>VCP</i> overexpression significantly decreased the level of phosphorylated and oligomeric/aggregate Tau and rescued Tau-induced cognitive behavioral phenotypes, which were reversed when the autophagy was blocked. Importantly, VCP expression in the brains of human Alzheimer’s disease patients was severely downregulated, consistent with its proposed role in Tau clearance. Taken together, these results suggest that enhancing the expression and activity of VCP in a spatiotemporal manner to facilitate the autophagy pathway is a potential therapeutic approach for treating tauopathy.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11422276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142306917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-21DOI: 10.1007/s00401-024-02780-4
Pascual Torres, Santiago Rico-Rios, Miriam Ceron-Codorniu, Marta Santacreu-Vilaseca, David Seoane-Miraz, Yahya Jad, Victòria Ayala, Guillermo Mariño, Maria Beltran, Maria P. Miralles, Pol Andrés-Benito, Joaquin Fernandez-Irigoyen, Enrique Santamaria, Carlos López-Otín, Rosa M. Soler, Monica Povedano, Isidro Ferrer, Reinald Pamplona, Matthew J. A. Wood, Miguel A. Varela, Manuel Portero-Otin
Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease with a mean survival time of three years. The 97% of the cases have TDP-43 nuclear depletion and cytoplasmic aggregation in motor neurons. TDP-43 prevents non-conserved cryptic exon splicing in certain genes, maintaining transcript stability, including ATG4B, which is crucial for autophagosome maturation and Microtubule-associated proteins 1A/1B light chain 3B (LC3B) homeostasis. In ALS mice (G93A), Atg4b depletion worsens survival rates and autophagy function. For the first time, we observed an elevation of LC3ylation in the CNS of both ALS patients and atg4b−/− mouse spinal cords. Furthermore, LC3ylation modulates the distribution of ATG3 across membrane compartments. Antisense oligonucleotides (ASOs) targeting cryptic exon restore ATG4B mRNA in TARDBP knockdown cells. We further developed multi-target ASOs targeting TDP-43 binding sequences for a broader effect. Importantly, our ASO based in peptide-PMO conjugates show brain distribution post-IV administration, offering a non-invasive ASO-based treatment avenue for neurodegenerative diseases.
{"title":"TDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibition","authors":"Pascual Torres, Santiago Rico-Rios, Miriam Ceron-Codorniu, Marta Santacreu-Vilaseca, David Seoane-Miraz, Yahya Jad, Victòria Ayala, Guillermo Mariño, Maria Beltran, Maria P. Miralles, Pol Andrés-Benito, Joaquin Fernandez-Irigoyen, Enrique Santamaria, Carlos López-Otín, Rosa M. Soler, Monica Povedano, Isidro Ferrer, Reinald Pamplona, Matthew J. A. Wood, Miguel A. Varela, Manuel Portero-Otin","doi":"10.1007/s00401-024-02780-4","DOIUrl":"10.1007/s00401-024-02780-4","url":null,"abstract":"<div><p>Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease with a mean survival time of three years. The 97% of the cases have TDP-43 nuclear depletion and cytoplasmic aggregation in motor neurons. TDP-43 prevents non-conserved cryptic exon splicing in certain genes, maintaining transcript stability, including <i>ATG4B</i>, which is crucial for autophagosome maturation and Microtubule-associated proteins 1A/1B light chain 3B (LC3B) homeostasis. In ALS mice (G93A), <i>Atg4b</i> depletion worsens survival rates and autophagy function. For the first time, we observed an elevation of LC3ylation in the CNS of both ALS patients and <i>atg4b</i><sup><i>−/−</i></sup> mouse spinal cords. Furthermore, LC3ylation modulates the distribution of ATG3 across membrane compartments. Antisense oligonucleotides (ASOs) targeting cryptic exon restore <i>ATG4B</i> mRNA in <i>TARDBP</i> knockdown cells. We further developed multi-target ASOs targeting TDP-43 binding sequences for a broader effect. Importantly, our ASO based in peptide-PMO conjugates show brain distribution post-IV administration, offering a non-invasive ASO-based treatment avenue for neurodegenerative diseases.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02780-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142275595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-19DOI: 10.1007/s00401-024-02801-2
Tove Freiburghaus, Daria Pawlik, Kevin Oliveira Hauer, Rik Ossenkoppele, Olof Strandberg, Antoine Leuzy, Jonathan Rittmo, Cécilia Tremblay, Geidy E. Serrano, Michael J. Pontecorvo, Thomas G. Beach, Ruben Smith, Oskar Hansson
[18F]Flortaucipir is an FDA-approved tau-PET tracer that is increasingly utilized in clinical settings for the diagnosis of Alzheimer’s disease. Still, a large-scale comparison of the in vivo PET uptake to quantitative post-mortem tau pathology and to other co-pathologies is lacking. Here, we examined the correlation between in vivo [18F]flortaucipir PET uptake and quantitative post-mortem tau pathology in corresponding brain regions from the AVID A16 end-of-life study (n = 63). All participants underwent [18F]flortaucipir PET scans prior to death, followed by a detailed post-mortem neuropathological examination using AT8 (tau) immunohistochemistry. Correlations between [18F]flortaucipir standardized uptake value ratios (SUVRs) and AT8 immunohistochemistry were assessed across 18 regions-of-interest (ROIs). To assess [18F]flortaucipir specificity and level of detection for tau pathology, correlations between [18F]flortaucipir SUVR and neuritic plaque score and TDP-43 stage were also computed and retention was further assessed in individuals with possible primary age-related tauopathy (PART), defined as Thal phase ≤ 2 and Braak stage I–IV. We found modest-to-strong correlations between in vivo [18F]flortaucipir SUVR and post-mortem tau pathology density in corresponding brain regions in all neocortical regions analyzed (rho-range = 0.61–0.79, p < 0.0001 for all). The detection threshold of [18F]flortaucipir PET was determined to be 0.85% of surface area affected by tau pathology in a temporal meta-ROI, and 0.15% in a larger cortical meta-ROI. No significant associations were found between [18F]flortaucipir SUVRs and post-mortem tau pathology in individuals with possible PART. Further, there was no correlation observed between [18F]flortaucipir and level of amyloid-β neuritic plaque load (rho-range = – 0.16–0.12; p = 0.48–0.61) or TDP-43 stage (rho-range = – 0.10 to – 0.30; p = 0.18–0.65). In conclusion, our in vivo vs post-mortem study shows that the in vivo [18F]flortaucipir PET signal primarily reflects tau pathology, also at relatively low densities of tau proteinopathy, and does not bind substantially to tau neurites in neuritic plaques or in individuals with PART.
[18F]Flortaucipir是一种经FDA批准的tau-PET示踪剂,越来越多地被用于阿尔茨海默病的临床诊断。然而,目前还缺乏将体内 PET 摄取与死后 tau 病理定量及其他合并病理进行大规模比较的研究。在这里,我们研究了 AVID A16 生命末期研究(n = 63)中相应脑区的体内 [18F]flortaucipir PET 摄取与死后 tau 病理定量之间的相关性。所有参与者在死前都接受了[18F]氟替瑞匹PET扫描,随后使用AT8(tau)免疫组化技术进行了详细的死后神经病理学检查。评估了18个感兴趣区(ROI)的[18F]氟替瑞匹标准化摄取值比(SUVRs)与AT8免疫组化之间的相关性。为了评估[18F]flortaucipir对tau病理学的特异性和检测水平,我们还计算了[18F]flortaucipir SUVR与神经斑块评分和TDP-43分期之间的相关性,并进一步评估了可能患有原发性年龄相关tau病(PART)(Thal分期≤2和Braak分期I-IV)的个体的保留率。我们发现,在分析的所有新皮质区域中,体内[18F]氟陶西哌 SUVR 与相应脑区的死后 tau 病理学密度之间存在中度到高度的相关性(rho-range = 0.61-0.79, p < 0.0001)。在颞叶元ROI中,[18F]flortaucipir PET的检测阈值被确定为受tau病理学影响的表面积的0.85%,而在更大的皮层元ROI中,[18F]flortaucipir PET的检测阈值为0.15%。在可能患有PART的患者中,[18F]flortaucipir SUVR与死后tau病理学之间没有发现明显的关联。此外,在[18F]flortaucipir和淀粉样β神经斑块负荷水平(rho-范围=-0.16-0.12;p=0.48-0.61)或TDP-43阶段(rho-范围=-0.10至-0.30;p=0.18-0.65)之间也没有观察到相关性。总之,我们的活体与尸检研究表明,活体[18F]氟陶西哌 PET 信号主要反映 tau 病理学,在 tau 蛋白病变的密度相对较低时也是如此,并且不会与神经里质斑块中的 tau 神经元或 PART 患者的 tau 神经元发生实质性结合。
{"title":"Association of in vivo retention of [18f] flortaucipir pet with tau neuropathology in corresponding brain regions","authors":"Tove Freiburghaus, Daria Pawlik, Kevin Oliveira Hauer, Rik Ossenkoppele, Olof Strandberg, Antoine Leuzy, Jonathan Rittmo, Cécilia Tremblay, Geidy E. Serrano, Michael J. Pontecorvo, Thomas G. Beach, Ruben Smith, Oskar Hansson","doi":"10.1007/s00401-024-02801-2","DOIUrl":"10.1007/s00401-024-02801-2","url":null,"abstract":"<div><p>[<sup>18</sup>F]Flortaucipir is an FDA-approved tau-PET tracer that is increasingly utilized in clinical settings for the diagnosis of Alzheimer’s disease. Still, a large-scale comparison of the in vivo PET uptake to quantitative <i>post-mortem</i> tau pathology and to other co-pathologies is lacking. Here, we examined the correlation between in vivo [<sup>18</sup>F]flortaucipir PET uptake and quantitative <i>post-mortem</i> tau pathology in corresponding brain regions from the AVID A16 end-of-life study (<i>n</i> = 63). All participants underwent [<sup>18</sup>F]flortaucipir PET scans prior to death, followed by a detailed <i>post-mortem</i> neuropathological examination using AT8 (tau) immunohistochemistry. Correlations between [<sup>18</sup>F]flortaucipir standardized uptake value ratios (SUVRs) and AT8 immunohistochemistry were assessed across 18 regions-of-interest (ROIs). To assess [<sup>18</sup>F]flortaucipir specificity and level of detection for tau pathology, correlations between [<sup>18</sup>F]flortaucipir SUVR and neuritic plaque score and TDP-43 stage were also computed and retention was further assessed in individuals with possible primary age-related tauopathy (PART), defined as Thal phase ≤ 2 and Braak stage I–IV. We found modest-to-strong correlations between in vivo [<sup>18</sup>F]flortaucipir SUVR and <i>post-mortem</i> tau pathology density in corresponding brain regions in all neocortical regions analyzed (rho-range = 0.61–0.79, p < 0.0001 for all). The detection threshold of [<sup>18</sup>F]flortaucipir PET was determined to be 0.85% of surface area affected by tau pathology in a temporal meta-ROI, and 0.15% in a larger cortical meta-ROI. No significant associations were found between [<sup>18</sup>F]flortaucipir SUVRs and <i>post-mortem</i> tau pathology in individuals with possible PART. Further, there was no correlation observed between [<sup>18</sup>F]flortaucipir and level of amyloid-β neuritic plaque load (rho-range = – 0.16–0.12; <i>p</i> = 0.48–0.61) or TDP-43 stage (rho-range = – 0.10 to – 0.30; <i>p</i> = 0.18–0.65). In conclusion, our in vivo vs <i>post-mortem</i> study shows that the in vivo [<sup>18</sup>F]flortaucipir PET signal primarily reflects tau pathology, also at relatively low densities of tau proteinopathy, and does not bind substantially to tau neurites in neuritic plaques or in individuals with PART.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02801-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-16DOI: 10.1007/s00401-024-02794-y
Mónica Zufiría, Oihane Pikatza-Menoio, Maddi Garciandia-Arcelus, Xabier Bengoetxea, Andrés Jiménez, Amaia Elicegui, María Levchuk, Olatz Arnold-García, Jon Ondaro, Pablo Iruzubieta, Laura Rodríguez-Gómez, Uxoa Fernández-Pelayo, Mikel Muñoz-Oreja, Ana Aiastui, José Manuel García-Verdugo, Vicente Herranz-Pérez, Miren Zulaica, Juan José Poza, Rebeca Ruiz-Onandi, Roberto Fernández-Torrón, Juan Bautista Espinal, Mario Bonilla, Ana Lersundi, Gorka Fernández-Eulate, Javier Riancho, Ainara Vallejo-Illarramendi, Ian James Holt, Amets Sáenz, Edoardo Malfatti, Stéphanie Duguez, Lorea Blázquez, Adolfo López de Munain, Gorka Gerenu, Francisco Gil-Bea, Sonia Alonso-Martín
Amyotrophic Lateral Sclerosis (ALS) is a multisystemic neurodegenerative disorder, with accumulating evidence indicating metabolic disruptions in the skeletal muscle preceding disease symptoms, rather than them manifesting as a secondary consequence of motor neuron (MN) degeneration. Hence, energy homeostasis is deeply implicated in the complex physiopathology of ALS and skeletal muscle has emerged as a key therapeutic target. Here, we describe intrinsic abnormalities in ALS skeletal muscle, both in patient-derived muscle cells and in muscle cell lines with genetic knockdown of genes related to familial ALS, such as TARDBP (TDP-43) and FUS. We found a functional impairment of myogenesis that parallels defects of glucose oxidation in ALS muscle cells. We identified FOXO1 transcription factor as a key mediator of these metabolic and functional features in ALS muscle, via gene expression profiling and biochemical surveys in TDP-43 and FUS-silenced muscle progenitors. Strikingly, inhibition of FOXO1 mitigated the impaired myogenesis in both the genetically modified and the primary ALS myoblasts. In addition, specific in vivo conditional knockdown of TDP-43 or FUS orthologs (TBPH or caz) in Drosophila muscle precursor cells resulted in decreased innervation and profound dysfunction of motor nerve terminals and neuromuscular synapses, accompanied by motor abnormalities and reduced lifespan. Remarkably, these phenotypes were partially corrected by foxo inhibition, bolstering the potential pharmacological management of muscle intrinsic abnormalities associated with ALS. The findings demonstrate an intrinsic muscle dysfunction in ALS, which can be modulated by targeting FOXO factors, paving the way for novel therapeutic approaches that focus on the skeletal muscle as complementary target tissue.
肌萎缩侧索硬化症(ALS)是一种多系统神经退行性疾病,越来越多的证据表明,骨骼肌的代谢紊乱先于疾病症状出现,而不是运动神经元(MN)变性的继发后果。因此,能量平衡与渐冻症复杂的生理病理有密切关系,而骨骼肌已成为关键的治疗靶点。在这里,我们描述了 ALS 骨骼肌的内在异常,既包括源自患者的肌肉细胞,也包括基因敲除与家族性 ALS 相关基因(如 TARDBP (TDP-43) 和 FUS)的肌肉细胞系。我们发现在 ALS 肌肉细胞中存在与葡萄糖氧化缺陷相似的肌生成功能障碍。通过对 TDP-43 和 FUS 沉默的肌肉祖细胞进行基因表达谱分析和生化调查,我们发现 FOXO1 转录因子是 ALS 肌肉中这些代谢和功能特征的关键介导因子。令人震惊的是,抑制 FOXO1 可减轻转基因和原发性 ALS 肌母细胞受损的肌生成。此外,在果蝇肌肉前体细胞中特异性地在体内条件性敲除TDP-43或FUS同源物(TBPH或caz)会导致运动神经末梢和神经肌肉突触的神经支配减少和功能严重失调,并伴有运动异常和寿命缩短。值得注意的是,这些表型可通过抑制 foxo 得到部分纠正,从而增强了对与渐冻症相关的肌肉内在异常进行药物治疗的潜力。这些发现证明了渐冻症的内在肌肉功能障碍可以通过靶向 FOXO 因子来调节,从而为以骨骼肌为补充靶组织的新型治疗方法铺平了道路。
{"title":"Dysregulated FOXO1 activity drives skeletal muscle intrinsic dysfunction in amyotrophic lateral sclerosis","authors":"Mónica Zufiría, Oihane Pikatza-Menoio, Maddi Garciandia-Arcelus, Xabier Bengoetxea, Andrés Jiménez, Amaia Elicegui, María Levchuk, Olatz Arnold-García, Jon Ondaro, Pablo Iruzubieta, Laura Rodríguez-Gómez, Uxoa Fernández-Pelayo, Mikel Muñoz-Oreja, Ana Aiastui, José Manuel García-Verdugo, Vicente Herranz-Pérez, Miren Zulaica, Juan José Poza, Rebeca Ruiz-Onandi, Roberto Fernández-Torrón, Juan Bautista Espinal, Mario Bonilla, Ana Lersundi, Gorka Fernández-Eulate, Javier Riancho, Ainara Vallejo-Illarramendi, Ian James Holt, Amets Sáenz, Edoardo Malfatti, Stéphanie Duguez, Lorea Blázquez, Adolfo López de Munain, Gorka Gerenu, Francisco Gil-Bea, Sonia Alonso-Martín","doi":"10.1007/s00401-024-02794-y","DOIUrl":"10.1007/s00401-024-02794-y","url":null,"abstract":"<div><p>Amyotrophic Lateral Sclerosis (ALS) is a multisystemic neurodegenerative disorder, with accumulating evidence indicating metabolic disruptions in the skeletal muscle preceding disease symptoms, rather than them manifesting as a secondary consequence of motor neuron (MN) degeneration. Hence, energy homeostasis is deeply implicated in the complex physiopathology of ALS and skeletal muscle has emerged as a key therapeutic target. Here, we describe intrinsic abnormalities in ALS skeletal muscle, both in patient-derived muscle cells and in muscle cell lines with genetic knockdown of genes related to familial ALS, such as <i>TARDBP</i> (TDP-43) and <i>FUS</i>. We found a functional impairment of myogenesis that parallels defects of glucose oxidation in ALS muscle cells. We identified FOXO1 transcription factor as a key mediator of these metabolic and functional features in ALS muscle, via gene expression profiling and biochemical surveys in TDP-43 and FUS-silenced muscle progenitors. Strikingly, inhibition of FOXO1 mitigated the impaired myogenesis in both the genetically modified and the primary ALS myoblasts. In addition, specific in vivo conditional knockdown of TDP-43 or FUS orthologs (<i>TBPH</i> or <i>caz</i>) in <i>Drosophila</i> muscle precursor cells resulted in decreased innervation and profound dysfunction of motor nerve terminals and neuromuscular synapses, accompanied by motor abnormalities and reduced lifespan. Remarkably, these phenotypes were partially corrected by <i>foxo</i> inhibition, bolstering the potential pharmacological management of muscle intrinsic abnormalities associated with ALS. The findings demonstrate an intrinsic muscle dysfunction in ALS, which can be modulated by targeting FOXO factors, paving the way for novel therapeutic approaches that focus on the skeletal muscle as complementary target tissue.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02794-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-11DOI: 10.1007/s00401-024-02802-1
Nicholas Nuechterlein, Sadie Cimino, Allison Shelbourn, Vinny Ha, Sonali Arora, Sharika Rajan, Linda G. Shapiro, Eric C. Holland, Kenneth Aldape, Tresa McGranahan, Mark R. Gilbert, Patrick J. Cimino
Oligodendroglioma, IDH-mutant and 1p/19q-codeleted has highly variable outcomes that are strongly influenced by patient age. The distribution of oligodendroglioma age is non-Gaussian and reportedly bimodal, which motivated our investigation of age-associated molecular alterations that may drive poorer outcomes. We found that elevated HOXD12 expression was associated with both older patient age and shorter survival in the TCGA (FDR < 0.01, FDR = 1e−5) and the CGGA (p = 0.03, p < 1e−3). HOXD12 gene body hypermethylation was associated with older age, higher WHO grade, and shorter survival in the TCGA (p < 1e−6, p < 0.001, p < 1e−3) and with older age and higher WHO grade in Capper et al. (p < 0.002, p = 0.014). In the TCGA, HOXD12 gene body hypermethylation and elevated expression were independently prognostic of NOTCH1 and PIK3CA mutations, loss of 15q, MYC activation, and standard histopathological features. Single-nucleus RNA and ATAC sequencing data showed that HOXD12 activity was elevated in neoplastic tissue, particularly within cycling and OPC-like cells, and was associated with a stem-like phenotype. A pan-HOX DNA methylation analysis revealed an age and survival-associated HOX-high signature that was tightly associated with HOXD12 gene body methylation. Overall, HOXD12 expression and gene body hypermethylation were associated with an older, atypically aggressive subtype of oligodendroglioma.
{"title":"HOXD12 defines an age-related aggressive subtype of oligodendroglioma","authors":"Nicholas Nuechterlein, Sadie Cimino, Allison Shelbourn, Vinny Ha, Sonali Arora, Sharika Rajan, Linda G. Shapiro, Eric C. Holland, Kenneth Aldape, Tresa McGranahan, Mark R. Gilbert, Patrick J. Cimino","doi":"10.1007/s00401-024-02802-1","DOIUrl":"10.1007/s00401-024-02802-1","url":null,"abstract":"<div><p>Oligodendroglioma, IDH-mutant and 1p/19q-codeleted has highly variable outcomes that are strongly influenced by patient age. The distribution of oligodendroglioma age is non-Gaussian and reportedly bimodal, which motivated our investigation of age-associated molecular alterations that may drive poorer outcomes. We found that elevated HOXD12 expression was associated with both older patient age and shorter survival in the TCGA (FDR < 0.01, FDR = 1e−5) and the CGGA (<i>p</i> = 0.03, <i>p</i> < 1e−3). <i>HOXD12</i> gene body hypermethylation was associated with older age, higher WHO grade, and shorter survival in the TCGA (<i>p</i> < 1e−6, <i>p</i> < 0.001, <i>p</i> < 1e−3) and with older age and higher WHO grade in Capper et al. (<i>p</i> < 0.002, <i>p</i> = 0.014). In the TCGA, <i>HOXD12</i> gene body hypermethylation and elevated expression were independently prognostic of <i>NOTCH1</i> and <i>PIK3CA</i> mutations, loss of 15q, MYC activation, and standard histopathological features. Single-nucleus RNA and ATAC sequencing data showed that HOXD12 activity was elevated in neoplastic tissue, particularly within cycling and OPC-like cells, and was associated with a stem-like phenotype. A pan-HOX DNA methylation analysis revealed an age and survival-associated HOX-high signature that was tightly associated with <i>HOXD12</i> gene body methylation. Overall, HOXD12 expression and gene body hypermethylation were associated with an older, atypically aggressive subtype of oligodendroglioma.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02802-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142166235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}