Neuropathology and Applied Neurobiology最新文献

{"title":"Neuromuscular junction denervation and terminal Schwann cell loss in the hTDP-43 overexpression mouse model of amyotrophic lateral sclerosis.","authors":"Abrar Alhindi,&nbsp;Megan Shand,&nbsp;Hannah L Smith,&nbsp;Ana S Leite,&nbsp;Yu-Ting Huang,&nbsp;Dinja van der Hoorn,&nbsp;Zara Ridgway,&nbsp;Kiterie M E Faller,&nbsp;Ross A Jones,&nbsp;Thomas H Gillingwater,&nbsp;Helena Chaytow","doi":"10.1111/nan.12925","DOIUrl":"https://doi.org/10.1111/nan.12925","url":null,"abstract":"<p><strong>Aims: </strong>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with complex aetiology. Despite evidence of neuromuscular junction (NMJ) denervation and 'dying-back' pathology in models of SOD1-dependent ALS, evidence in other genetic forms of ALS is limited by a lack of suitable animal models. TDP-43, a key mediator protein in ALS, is overexpressed in neurons in Thy1-hTDP-43^WT mice. We therefore aimed to comprehensively analyse NMJ pathology in this model of ALS.</p><p><strong>Methods: </strong>Expression of TDP-43 was assessed via western blotting. Immunohistochemistry techniques, alongside NMJ-morph quantification, were used to analyse motor neuron number, NMJ denervation status and terminal Schwann cell morphology.</p><p><strong>Results: </strong>We present a time course of progressive, region-specific motor neuron pathology in Thy1-hTDP-43^WT mice. Thy1-driven hTDP-43 expression increased steadily, correlating with developing hindlimb motor weakness and associated motor neuron loss in the spinal cord with a median survival of 21 days. Pronounced NMJ denervation was observed in hindlimb muscles, mild denervation in cranial muscles but no evidence of denervation in either forelimb or trunk muscles. NMJ pathology was restricted to motor nerve terminals, with denervation following the same time course as motor neuron loss. Terminal Schwann cells were lost from NMJs in hindlimb muscles, directly correlating with denervation status.</p><p><strong>Conclusions: </strong>Thy1-hTDP-43^WT mice represent a severe model of ALS, with NMJ pathology/denervation of distal muscles and motor neuron loss, as observed in ALS patients. This model therefore provides an ideal platform to investigate mechanisms of dying-back pathology, as well as NMJ-targeting disease-modifying therapies in ALS.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 4","pages":"e12925"},"PeriodicalIF":5.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10493965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Past antihypertensive medication use is associated with lower levels of small vessel disease and lower Aβ plaque stage in the brains of older individuals.","authors":"Andrew J Affleck, Perminder S Sachdev, Glenda M Halliday","doi":"10.1111/nan.12922","DOIUrl":"10.1111/nan.12922","url":null,"abstract":"<p><strong>Aims: </strong>This study assesses the association of antihypertensive medication use on the severities of neuropathological cerebrovascular disease (CVD excluding lobar infarction) in older individuals.</p><p><strong>Methods: </strong>Clinical and neuropathological data were retrieved for 149 autopsy cases >75 years old with or without CVD or Alzheimer's disease and no other neuropathological diagnoses. Clinical data included hypertension status, hypertension diagnosis, antihypertensive medication use, antihypertensive medication dose (where available) and clinical dementia rating (CDR). Neuropathological CVD severity was evaluated for differences with anti-hypertensive medication usage.</p><p><strong>Results: </strong>Antihypertensive medication use was associated with less severe white matter small vessel disease (SVD, mainly perivascular dilatation and rarefaction), with a 5.6-14.4 times greater likelihood of less severe SVD if medicated. No significant relationship was detected between infarction (presence, type, number and size), lacunes or cerebral amyloid angiopathy and antihypertensive medication use. Only increased white matter rarefaction/oedema and not perivascular dilation was associated with Alzheimer's pathology, with a 4.3 times greater likelihood of reduced Aβ progression through the brain if white matter rarefaction severity was none or mild. Antihypertensive medication use was associated with reduced Aβ progression but only in those with moderate to severe white matter SVD.</p><p><strong>Conclusions: </strong>This histopathological study provides further evidence that antihypertensive medication use in older individuals is associated with white matter SVD and not with other CVD pathologies. This is mainly due to a reduction in white matter perivascular dilation and rarefaction/oedema. Even in those with moderate to severe white matter SVD, antihypertensive medication use reduced rarefaction and Aβ propagation through the brain.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 4","pages":"e12922"},"PeriodicalIF":5.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10947144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10140257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond vacuolar pathology: Multiomic profiling of Danon disease reveals dysfunctional mitochondrial homeostasis.","authors":"Felix Kleefeld, Andreas Hentschel, Arpad von Moers, Katrin Hahn, Rita Horvath, Hans-Hilmar Goebel, Corinna Preusse, Jens Schallner, Markus Schuelke, Andreas Roos, Werner Stenzel","doi":"10.1111/nan.12920","DOIUrl":"10.1111/nan.12920","url":null,"abstract":"","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 4","pages":"e12920"},"PeriodicalIF":5.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10195250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover Image, Volume 49, Issue 4","authors":"Abrar Alhindi, Megan Shand, Hannah L. Smith, Ana S. Leite, Yu-Ting Huang, Dinja van der Hoorn, Zara Ridgway, K. Faller, Ross A. Jones, T. Gillingwater, Helena Chaytow","doi":"10.1111/nan.12930","DOIUrl":"https://doi.org/10.1111/nan.12930","url":null,"abstract":"","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"1 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45471548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First report of medulloblastoma in a patient with MUTYH-associated polyposis.","authors":"Marie-Charlotte Villy,&nbsp;Mathilde Warcoin,&nbsp;Mathilde Filser,&nbsp;Bruno Buecher,&nbsp;Lisa Golmard,&nbsp;Voreak Suybeng,&nbsp;Mathias Schwartz,&nbsp;Ivan Bieche,&nbsp;Sophie Vacher,&nbsp;Valérie Laurence,&nbsp;Franck Bourdeaut,&nbsp;Michèle Bernier,&nbsp;Tom Gutman,&nbsp;Dominique Stoppa-Lyonnet,&nbsp;Julien Masliah-Planchon,&nbsp;Chrystelle Colas","doi":"10.1111/nan.12929","DOIUrl":"https://doi.org/10.1111/nan.12929","url":null,"abstract":"<p><strong>Aims: </strong>The mutY DNA glycosylase encoded by the MUTYH gene prevents G:C → T:A transversions through the base excision repair DNA repair system. Germline biallelic pathogenic variants in MUTYH cause an adenomatous polyposis called MUTYH-associated polyposis (MAP), an autosomal recessive disease (OMIM: 608456), with an increased risk of colorectal cancer. Digestive lesions in this context show an excess of G:C → T:A transversions, individualising a specific mutational signature associated with MUTYH deficiency called signature SBS36. Predisposition to other tumours in patients with germline biallelic pathogenic variants in MUTYH is suspected but remains unclear. We report the first case of medulloblastoma in a patient with MAP, carrying the homozygous pathogenic variant c.1227_1228dup, p.(Glu410Glyfs*43) in MUTYH.</p><p><strong>Methods: </strong>Whole exome sequencing was performed on the medulloblastoma to enlighten single nucleotide variants of interest, microsatellite status and mutational signature. The objective was to determine the involvement of MUTYH deficiency in the oncogenesis of this medulloblastoma.</p><p><strong>Results: </strong>The medulloblastoma has the mutational signature SBS36 and driver pathogenic variants in CTNNB1, PTCH1 and KDM6A corresponding to G:C → T:A transversions, suggesting a role of MUTYH deficiency in oncogenesis.</p><p><strong>Conclusions: </strong>Therefore, medulloblastoma could be a rare manifestation associated with germline biallelic pathogenic variants in MUTYH.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 4","pages":"e12929"},"PeriodicalIF":5.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10137368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanoscale reorganisation of synaptic proteins in Alzheimer's disease.","authors":"","doi":"10.1111/nan.12932","DOIUrl":"https://doi.org/10.1111/nan.12932","url":null,"abstract":"","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 4","pages":"e12932"},"PeriodicalIF":5.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10139481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A threshold for mitotic activity and post-surgical residual volume defines distinct prognostic groups for astrocytoma IDH-mutant.","authors":"Suzanne Tran,&nbsp;Alice Thomas,&nbsp;Ilyes Aliouat,&nbsp;Carine Karachi,&nbsp;Fernando Lozano,&nbsp;Karima Mokhtari,&nbsp;Caroline Dehais,&nbsp;Loïc Feuvret,&nbsp;Catherine Carpentier,&nbsp;Marine Giry,&nbsp;Habiba Doukani,&nbsp;Julie Lerond,&nbsp;Yannick Marie,&nbsp;Marc Sanson,&nbsp;Ahmed Idbaih,&nbsp;Alexandre Carpentier,&nbsp;Khê Hoang-Xuan,&nbsp;Mehdi Touat,&nbsp;Laurent Capelle,&nbsp;Franck Bielle","doi":"10.1111/nan.12928","DOIUrl":"https://doi.org/10.1111/nan.12928","url":null,"abstract":"<p><strong>Aims: </strong>The distinction between CNS WHO grade 2 and grade 3 is instrumental in choosing between observational follow-up and adjuvant treatment for resected astrocytomas IDH-mutant. However, the criteria of CNS WHO grade 2 vs 3 have not been updated since the pre-IDH era.</p><p><strong>Methods: </strong>Maximal mitotic activity in consecutive high-power fields corresponding to 3 mm² was examined for 118 lower-grade astrocytomas IDH-mutant. The prognostic value for time-to-treatment (TTT) and overall survival (OS) of mitotic activity and other putative prognostic factors (including age, performance status, pre-surgical tumour volume, multilobar involvement, post-surgical residual tumour volume and midline involvement) was assessed for tumours with ATRX loss and the absence of CDKN2A homozygous deletion or CDK4 amplification, contrast enhancement, histological necrosis and microvascular proliferation.</p><p><strong>Results: </strong>Seventy-one per cent of the samples had <6 mitoses per 3 mm² . Mitotic activity, residual volume and multilobar involvement were independent prognostic factors of TTT. The threshold of ≥6 mitoses per 3 mm² identified patients with a shorter TTT (median 18.5 months). A residual volume ≥1 cm³ also identified patients with a shorter TTT (median 24.5 months). The group defined by <6 mitoses per 3 mm² and a residual volume <1 cm³ had the longest TTT (median 73 months) and OS (100% survival at 7 years). These findings were confirmed in a validation cohort of 52 tumours.</p><p><strong>Conclusions: </strong>Mitotic activity and post-surgical residual volume can be combined to evaluate the prognosis for patients with resected astrocytomas IDH-mutant. Patients with <6 mitoses per 3 mm² and a residual volume <1 cm³ were the best candidates for observational follow-up.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 4","pages":"e12928"},"PeriodicalIF":5.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10493980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ectopic expression of neuronal adenosine kinase, a biomarker in mesial temporal lobe epilepsy without hippocampal sclerosis.","authors":"Mengyi Guo, Jing Wang, Zhonghua Xiong, Xiongfei Wang, Yujiao Yang, Yifan Zhang, Chongyang Tang, Jing Zhang, Yuguang Guan, Fan Chen, Kun Yao, Pengfei Teng, Jian Zhou, Feng Zhai, Detlev Boison, Guoming Luan, Tianfu Li","doi":"10.1111/nan.12926","DOIUrl":"10.1111/nan.12926","url":null,"abstract":"<p><strong>Aims: </strong>Mesial temporal lobe epilepsy without hippocampal sclerosis (no-HS MTLE) refers to those MTLE patients who have neither magnetic resonance imaging (MRI) lesions nor definite pathological evidence of hippocampal sclerosis. They usually have resistance to antiepileptic drugs, difficulties in precise seizure location and poor surgical outcomes. Adenosine is a neuroprotective neuromodulator that acts as a seizure terminator in the brain. The role of adenosine in no-HS MTLE is still unclear. Further research to explore the aetiology and pathogenesis of no-HS MTLE may help to find new therapeutic targets.</p><p><strong>Methods: </strong>In surgically resected hippocampal specimens, we examined the maladaptive changes of the adenosine system of patients with no-HS MTLE. In order to better understand the dysregulation of the adenosine pathway in no-HS MTLE, we developed a rat model based on the induction of focal cortical lesions through a prenatal freeze injury.</p><p><strong>Results: </strong>We first examined the adenosine system in no-HS MTLE patients who lack hippocampal neuronal loss and found ectopic expression of the astrocytic adenosine metabolising enzyme adenosine kinase (ADK) in hippocampal pyramidal neurons, as well as downregulation of neuronal A₁ receptors (A₁ Rs) in the hippocampus. In the no-HS MTLE model rats, the transition of ADK from neuronal expression to an adult pattern of glial expression in the hippocampus was significantly delayed.</p><p><strong>Conclusions: </strong>Ectopic expression of neuronal ADK might be a pathological hallmark of no-HS MTLE. Maladaptive changes in adenosine metabolism might be a novel target for therapeutic intervention in no-HS MTLE.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 4","pages":"e12926"},"PeriodicalIF":4.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11000230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10130269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Psychotic symptoms in frontotemporal dementia with TDP-43 tend to be associated with type B pathology.","authors":"Veronica Hirsch-Reinshagen, Christa Hercher, Fidel Vila-Rodriguez, Manuela Neumann, Rosa Rademakers, William G Honer, Ging-Yuek R Hsiung, Ian R Mackenzie","doi":"10.1111/nan.12921","DOIUrl":"10.1111/nan.12921","url":null,"abstract":"<p><strong>Aims: </strong>Psychotic symptoms are increasingly recognized as a distinguishing clinical feature in patients with dementia due to frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Within this group, carriers of the C9orf72 repeat expansion are particularly prone to develop delusions and hallucinations.</p><p><strong>Methods: </strong>The present retrospective study sought to provide novel details about the relationship between FTLD-TDP pathology and the presence of psychotic symptoms during life.</p><p><strong>Results: </strong>We found that FTLD-TDP subtype B was more frequent in patients with psychotic symptoms than in those without. This relationship was present even when corrected for the presence of C9orf72 mutation, suggesting that pathophysiological processes leading to the development of subtype B pathology may increase the risk of psychotic symptoms. Within the group of FTLD-TDP cases with subtype B pathology, psychotic symptoms tended to be associated with a greater burden of TDP-43 pathology in the white matter and a lower burden in lower motor neurons. When present, pathological involvement of motor neurons was more likely to be asymptomatic in patients with psychosis.</p><p><strong>Conclusions: </strong>This work suggests that psychotic symptoms in patients with FTLD-TDP tend to be associated with subtype B pathology. This relationship is not completely explained by the effects of the C9orf72 mutation and raises the possibility of a direct link between psychotic symptoms and this particular pattern of TDP-43 pathology.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 4","pages":"e12921"},"PeriodicalIF":4.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10527970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10493475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is islet amyloid polypeptide indeed expressed in the human brain?","authors":"Sylwia Libard,&nbsp;Irina Alafuzoff","doi":"10.1111/nan.12917","DOIUrl":"https://doi.org/10.1111/nan.12917","url":null,"abstract":"<p><strong>Aims: </strong>This study aims to study the association between pancreatic islet amyloid polypeptide (IAPP) and Alzheimer's disease neuropathological change (ADNC) in brain biopsies obtained from subjects with idiopathic normal pressure hydrocephalus (iNPH) and in post-mortem (PM) brain samples obtained from aged individuals.</p><p><strong>Methods: </strong>For the immunohistochemical (IHC) analyses, two IAPP antibodies (Abs), monoclonal and polyclonal, and Abs directed towards ADNC were applied.</p><p><strong>Results: </strong>The iNPH cohort included 113 subjects. Amyloid-β (Aβ) was detected in 50% and hyperphosphorylated τ (HPτ) in 47% of the cases. Concomitant pathology was seen in 32%. The PM cohort included 77 subjects. Aβ was detected in 69% and HPτ in 91% of the cases. Combined Aβ/HPτ pathology was seen in 62%. Reactivity for the monoclonal IAPP was not detected in the brain tissue in either of the cohorts. Reactivity for the polyclonal IAPP was observed in all 77 PM brain samples.</p><p><strong>Conclusions: </strong>There was no specific expression of IAPP in human brain tissue; hence, an association between IAPP and ADNC is not assessable. Of note, the observed reactivity of the polyclonal IAPP Ab was not reproduced with a specific monoclonal Ab; thus, we considered the observed staining with the polyclonal Ab to be unreliable. When using IHC, several pitfalls, especially the choice of an Ab, always need to be considered. Polyclonal Abs cross-react with other epitopes and proteins, thus leading to false-positive results. This seems to be the case for the polyclonal IAPP Abs in the human brain.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"49 4","pages":"e12917"},"PeriodicalIF":5.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10512549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}