Acta Neuropathologica最新文献

{"title":"Strong nuclear expression of HOXB13 is a reliable surrogate marker for DNA methylome profiling to distinguish myxopapillary ependymoma from spinal ependymoma","authors":"Suvendu Purkait,&nbsp;Sophia Praeger,&nbsp;Jörg Felsberg,&nbsp;David Pauck,&nbsp;Kerstin Kaulich,&nbsp;Marietta Wolter,&nbsp;David Koppstein,&nbsp;Guido Reifenberger","doi":"10.1007/s00401-025-02866-7","DOIUrl":"10.1007/s00401-025-02866-7","url":null,"abstract":"<div><p>Spinal ependymoma and myxopapillary ependymoma are the two most common spinal ependymal tumor types that feature distinct histological characteristics, genetic alterations and DNA methylation profiles. Their histological distinction may be difficult in individual cases and molecular diagnostic assessment, in particular DNA methylome profiling, may then be required to assign the correct diagnosis. Expression of the homeobox gene <i>HOXB13</i> at the mRNA and protein levels has been reported as a frequent finding in myxopapillary ependymoma that may serve as a diagnostic marker for these tumors. Here, we evaluated the diagnostic role of HOXB13 immunostaining in 143 spinal neoplasms, comprising 54 histologically classified myxopapillary ependymomas, 46 histologically classified spinal ependymomas, and various other tumor types. Immunohistochemical results for HOXB13 protein were compared to molecular findings obtained by bead array-based DNA methylation and DNA copy number profiling, as well as next generation gene panel sequencing-based mutational analysis. Our findings indicate strong nuclear HOXB13 expression as a reliable diagnostic marker for molecularly confirmed myxopapillary ependymoma. Moreover, we provide evidence that differential HOXB13 protein expression is related to differential <i>HOXB13</i>-associated CpG site methylation in myxopapillary vs. spinal ependymomas, which can be assessed by targeted DNA methylation analysis. Taken together, immunohistochemistry for HOXB13 protein expression and targeted DNA methylation analysis of <i>HOXB13</i> represent useful surrogate approaches that may substitute for DNA methylome profiling in routine diagnostics and facilitate precise classification of spinal ependymal tumors. In particular, strong nuclear HOXB13 immunoreactivity may serve as a novel diagnostic criterion for the classification of myxopapillary ependymoma.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02866-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698658","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}

{"title":"Chronic traumatic encephalopathy neuropathologic change in homeless","authors":"Krisztina Danics,&nbsp;Shelley L. Forrest,&nbsp;Gabor G. Kovacs","doi":"10.1007/s00401-025-02867-6","DOIUrl":"10.1007/s00401-025-02867-6","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698676","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}

{"title":"Biofluid-based staging of Alzheimer’s disease","authors":"Juan Lantero-Rodriguez,&nbsp;Laia Montoliu-Gaya,&nbsp;Nicholas J. Ashton,&nbsp;Ilaria Pola,&nbsp;Joseph Therriault,&nbsp;Nesrine Rahmouni,&nbsp;Wagner S. Brum,&nbsp;Stijn Servaes,&nbsp;Jenna Stevenson,&nbsp;Guglielmo Di Molfetta,&nbsp;Burak Arslan,&nbsp;Jesse Klostranec,&nbsp;Paolo Vitali,&nbsp;Maxime Montembeault,&nbsp;Serge Gauthier,&nbsp;Cecile Tissot,&nbsp;Arthur C. Macedo,&nbsp;Tharick A. Pascoal,&nbsp;Andreas Jeromin,&nbsp;Johan Gobom,&nbsp;Kaj Blennow,&nbsp;Henrik Zetterberg,&nbsp;Pedro Rosa-Neto,&nbsp;Andrea L. Benedet","doi":"10.1007/s00401-025-02863-w","DOIUrl":"10.1007/s00401-025-02863-w","url":null,"abstract":"<div><p>Recently, conceptual systems for the in vivo staging of Alzheimer’s disease (AD) using fluid biomarkers have been suggested. Thus, it is important to assess whether available fluid biomarkers can successfully stage AD into clinically and biologically relevant categories. In the TRIAD cohort, we explored whether p-tau217, p-tau205 and NTA-tau (biomarkers of early, intermediate and late AD pathology, respectively) have potential for biofluid-based staging in cerebrospinal fluid (CSF; <i>n</i> = 219) and plasma (<i>n</i> = 150), and compared them in a paired CSF and plasma subset (<i>n</i> = 76). Our findings suggest a good concordance between biofluid staging and underlying pathology when classifying amyloid-positivity into three categories based on neurofibrillary pathology: minimal/non-existent (p-tau217 positive), early-to-intermediate (p-tau217 and p-tau205 positivity), and advanced tau tangle deposition (p-tau217, p-tau205 and NTA-tau positive), as indexed by tau-PET. Discordant cases accounted for 4.6% and 13.3% of all CSF and plasma measurements respectively (9.2% and 11.8% in paired samples). Notably, CSF- and plasma-based staging matched one another in 61.7% of the cases, while approximately 32% of the remaining participants were one to three biofluid stages higher in CSF as compared to plasma. Overall, these exploratory results suggest that biofluid staging of AD holds potential for offering valuable insights into underlying AD hallmarks and disease severity. However, its applicability beyond molecular characterization at research settings has yet to be demonstrated.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02863-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143632568","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}

{"title":"Constitutional variants in PTEN: a frequent finding in patients with papillary tumors of the pineal region subtype B (PTPR-B) associated with isolated loss of chromosome 10","authors":"Steffen Hirsch,&nbsp;Ramin Rahmanzade,&nbsp;Kerstin Grund,&nbsp;Christian Sutter,&nbsp;Kathrin Schramm,&nbsp;Florian Selt,&nbsp;Jonas Ecker,&nbsp;Barbara C. Jones,&nbsp;Daniel Schrimpf,&nbsp;Martin Demmert,&nbsp;Ana S. Guerreiro Stücklin,&nbsp;Pablo Hernaiz Driever,&nbsp;Markus Mezger,&nbsp;Ines Brecht,&nbsp;Sasan D. Adib,&nbsp;Bastian Brummel,&nbsp;Dominik Sturm,&nbsp;Nicola Dikow,&nbsp;Maja Hempel,&nbsp;Till Milde,&nbsp;Kristian Pajtler,&nbsp;David T. W. Jones,&nbsp;Stefan M. Pfister,&nbsp;Andreas von Deimling,&nbsp;Felix Sahm,&nbsp;Christian P. Schaaf","doi":"10.1007/s00401-025-02865-8","DOIUrl":"10.1007/s00401-025-02865-8","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02865-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143612298","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}

{"title":"High resolution autoradiography of [18F]MK-6240 and [18F]Flortaucipir shows similar neurofibrillary tangle binding patterns preferentially recognizing middling neurofibrillary tangle maturity","authors":"Sujala Ghatamaneni,&nbsp;Courtney Hruska,&nbsp;Ian Shin,&nbsp;Tyler Bruinsma,&nbsp;Nancy Scott,&nbsp;Jeyeon Lee,&nbsp;Ping Fang,&nbsp;Hoon-Ki Min,&nbsp;Christina M. Moloney,&nbsp;Ashley C. Wood,&nbsp;Eleni Constantopoulos,&nbsp;Ross R. Reichard,&nbsp;Christopher G. Schwarz,&nbsp;David T. Jones,&nbsp;Jonathan Graff-Radford,&nbsp;David S. Knopman,&nbsp;Clifford R. Jack Jr.,&nbsp;Ronald C. Petersen,&nbsp;Dennis W. Dickson,&nbsp;Melissa E. Murray,&nbsp;Val J. Lowe","doi":"10.1007/s00401-025-02864-9","DOIUrl":"10.1007/s00401-025-02864-9","url":null,"abstract":"<div><p>Recent developments in tau positron emission tomography (PET) radiotracers have enhanced the visualization of tau aggregates in Alzheimer’s disease (AD). The maturity level of neurofibrillary tangles can affect its recognition by biomarkers. Early detection of tau aggregates regarding tangle pathology is of interest in early diagnosis and comparison of tau radiotracers in this aspect is important. This study focused on head to head pathologic comparison of [¹⁸F]MK-6240 and [¹⁸F]Flortaucipir postmortem binding as seen on high resolution autoradiography as compared to CP-13 (early tangle maturity) and PHF-1 (middling tangle maturity) immunohistochemistry (IHC) to evaluate the tangle maturity pathology specificity of binding for tau aggregates in AD, atypical AD and non-AD tauopathies. Analyses were performed on serial 5 μm formalin-fixed paraffin-embedded human brain sections acquired from the Mayo Clinic brain bank. Visual assessment of colocalization with IHC as well as quantitative analyses were used. Evaluation of the tracers’ off-target binding profiles were performed. Both tracers had similar binding properties for tau aggregates with preference to middling tangle maturity as shown by comparison to immunohistochemical distributions. Both the tracers showed strong binding to AD tau aggregates and no or minimal binding to non-AD tauopathies which corroborates with other studies.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02864-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143618392","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}

{"title":"Characterizing white matter and vascular pathologies in brain donors exposed to repetitive head impacts","authors":"Sheina Emrani,&nbsp;Anne Koutures,&nbsp;Yorghos Tripodis,&nbsp;Madeline Uretsky,&nbsp;Bobak Abdolmohammadi,&nbsp;Christopher Nowinski,&nbsp;Daniel H. Daneshvar,&nbsp;Brigid Dwyer,&nbsp;Douglas I. Katz,&nbsp;Lee E. Goldstein,&nbsp;Robert C. Cantu,&nbsp;Brett M. Martin,&nbsp;Joseph N. Palmisano,&nbsp;Kristen Dams-O’Connor,&nbsp;John F. Crary,&nbsp;Robert A. Stern,&nbsp;Jesse Mez,&nbsp;Victor E. Alvarez,&nbsp;Bertrand R. Huber,&nbsp;Ann C. McKee,&nbsp;Thor D. Stein,&nbsp;Michael L. Alosco","doi":"10.1007/s00401-025-02860-z","DOIUrl":"10.1007/s00401-025-02860-z","url":null,"abstract":"<div><p>Chronic traumatic encephalopathy (CTE) is a progressive brain disease linked to repetitive head impacts (RHI), often incurred from contact sports, and can lead to dementia. Here, we investigated the association between RHI and white matter/vascular neuropathologies and their relative contribution to dementia status in deceased men 50 + years old with and without exposure to RHI from various types of contact and collision sports. Our sample included two RHI groups from the UNITE brain bank: (1) American Football players (RHI-AF, <i>n</i> = 79), and (2) non-AF contact and collision sport athletes (e.g., boxing, rugby; RHI-CCS, <i>n</i> = 49). Controls included similarly aged (± 5 years) male brain donors without RHI. A modified ischemic injury scale (mIIS) served as a global measure of white matter and vascular neuropathologies, encompassing nine subcomponents. Dementia was determined through diagnostic consensus conference based on interviews with families. Using linear regression models controlling for age at death, mIIS was different in RHI-AF versus non-RHI only (<i>p</i> = 0.036). Subsequent logistic regression of each mIIS subcomponent, controlling for age at death, demonstrated that worse white matter rarefaction (RHI-AF; Beta = 1.42, [95% CI 2.03–8.43]; RHI-CCS; Beta = 1.93, [95% CI 2.35–20.17]) and hippocampal sclerosis (RHI-AF; Beta = 2.01, [95% CI 2.69–20.81]; RHI-CCS; Beta = 2.19, [95% CI 2.49–32.10]) was more common in RHI groups from their controls. Further, logistic regressions found that higher global mIIS correlated with increased odds of dementia in only the RHI-AF group (<i>p</i> = 0.02), driven by white matter rarefaction (<i>β</i> = 0.94, [95% CI 1.66–4.00]) and hippocampal sclerosis (<i>β</i> = 1.08, [95% CI 1.35–6.42]). There were similar findings in RHI-CCS group for odds of dementia (<i>p</i> = 0.048), including white matter rarefaction (<i>β</i> = 0.68, [95% CI 1.22–3.21], <i>p</i> = 0.05). Overall, these results demonstrate that white matter  rarefaction and hippocampal sclerosis are linked to RHI exposure across all types of contact sports. Further, these pathologies contribute to dementia independent of p-tau pathology in American football players.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02860-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143553829","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}

{"title":"Human brain tissue with MOGHE carrying somatic SLC35A2 variants reveal aberrant protein expression and protein loss in the white matter","authors":"Erica Cecchini,&nbsp;Simon Geffers,&nbsp;Roland Coras,&nbsp;Dorothea Schultheis,&nbsp;Christian Holtzhausen,&nbsp;Kristina Karandasheva,&nbsp;Harald Herrmann,&nbsp;Friedrich Paulsen,&nbsp;Christine Stadelmann,&nbsp;Katja Kobow,&nbsp;Till Hartlieb,&nbsp;Christian G. Bien,&nbsp;Dennis Lal,&nbsp;Ingmar Blumcke,&nbsp;Lucas Hoffmann","doi":"10.1007/s00401-025-02858-7","DOIUrl":"10.1007/s00401-025-02858-7","url":null,"abstract":"<div><p>Mild Malformation of Cortical Development with Oligodendroglial Hyperplasia in Epilepsy (MOGHE) is a recently described disease entity primarily affecting young children with drug-resistant epilepsy, mainly affecting the frontal lobe. The condition is histopathologically defined by focal lesions with patchy areas of increased oligodendroglial cell density at the grey-white matter boundary and heterotopic neurons in the white matter. Approximately half of the individuals with MOGHE carry brain somatic variants in the <i>SLC35A2</i> gene, which affects the UDP-galactose transporter and thus sphingolipid glycosylation. To investigate the impact of <i>SLC35A2</i> variants on protein expression, we analysed MOGHE brain tissue with and without <i>SLC35A2</i> mosaicism, distinguishing missense from nonsense variants. We developed an antibody targeting the N-terminus of the SLC35A2 galactose transporter and applied it for immunofluorescence (IF) analyses in a MOGHE cohort comprising 59 genetically tested individuals selected from three centres in Germany. The cohort included 13 individuals with <i>SLC35A2</i> missense variants and 15 with <i>SLC35A2</i> nonsense variants. Our findings confirm the localisation of the SLC35A2 protein in the Golgi apparatus of all neuroepithelial cell types as well as within Golgi outposts along oligodendroglial processes. The protein distribution was altered in MOGHE samples dependent on the <i>SLC35A2</i> variant and its allelic frequency. Western blot and IF analyses revealed a significant SLC35A2 reduction in MOGHE tissues carrying nonsense variants. Ultrastructural analyses from three MOGHE samples demonstrated hypomyelination in regions with increased oligodendroglial cell densities, regardless of the harbouring of <i>SLC35A2</i> variants. Notably, this hypomyelination pattern decreased with age. These results suggested a role for the SLC35A2 protein in the pathogenesis of MOGHE and indicated the presence of additional myelin-associated pathomechanisms in those individuals who do not carry a pathogenic <i>SLC35A2</i> variant.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02858-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546549","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}

{"title":"Parkinson-like wild-type superoxide dismutase 1 pathology induces nigral dopamine neuron degeneration in a novel murine model","authors":"Amr H. Abdeen,&nbsp;Benjamin G. Trist,&nbsp;Sara Nikseresht,&nbsp;Richard Harwood,&nbsp;Stéphane Roudeau,&nbsp;Benjamin D. Rowlands,&nbsp;Fabian Kreilaus,&nbsp;Veronica Cottam,&nbsp;David Mor,&nbsp;Miriam Richardson,&nbsp;Joel Siciliano,&nbsp;Julia Forkgen,&nbsp;Greta Schaffer,&nbsp;Sian Genoud,&nbsp;Anne A. Li,&nbsp;Nicholas Proschogo,&nbsp;Bernadeth Antonio,&nbsp;Gerald Falkenberg,&nbsp;Dennis Brueckner,&nbsp;Kai Kysenius,&nbsp;Jeffrey R. Liddell,&nbsp;Sandrine Chan Moi Fat,&nbsp;Sharlynn Wu,&nbsp;Jennifer Fifita,&nbsp;Thomas E. Lockwood,&nbsp;David P. Bishop,&nbsp;Ian Blair,&nbsp;Richard Ortega,&nbsp;Peter J. Crouch,&nbsp;Kay L. Double","doi":"10.1007/s00401-025-02859-6","DOIUrl":"10.1007/s00401-025-02859-6","url":null,"abstract":"<div><p>Atypical wild-type superoxide dismutase 1 (SOD1) protein misfolding and deposition occurs specifically within the degenerating substantia nigra pars compacta (SNc) in Parkinson disease. Mechanisms driving the formation of this pathology and relationship with SNc dopamine neuron health are yet to be fully understood. We applied proteomic mass spectrometry and synchrotron-based biometal quantification to post-mortem brain tissues from the SNc of Parkinson disease patients and age-matched controls to uncover key factors underlying the formation of wild-type SOD1 pathology in this disorder. We also engineered two of these factors - brain copper deficiency and upregulated SOD1 protein levels - into a novel mouse strain, termed the SOCK mouse, to verify their involvement in the development of Parkinson-like wild-type SOD1 pathology and their impact on dopamine neuron health. Soluble SOD1 protein in the degenerating Parkinson disease SNc exhibited altered post-translational modifications, which may underlie changes to the enzymatic activity and aggregation of the protein in this region. These include decreased copper binding, dysregulation of physiological glycosylation, and atypical oxidation and glycation of key SOD1 amino acid residues. We demonstrated that the biochemical profile introduced in SOCK mice promotes the same post-translational modifications and the development of Parkinson-like wild-type SOD1 pathology in the midbrain and cortex. This pathology accumulates progressively with age and is accompanied by nigrostriatal degeneration and dysfunction, which occur in the absence of α-synuclein deposition. These mice do not exhibit weight loss nor spinal cord motor neuron degeneration, distinguishing them from transgenic mutant SOD1 mouse models. This study provides the first in vivo evidence that mismetallation and altered post-translational modifications precipitates wild-type SOD1 misfolding, dysfunction, and deposition in the Parkinson disease brain, which may contribute to SNc dopamine neuron degeneration. Our data position this pathology as a novel drug target for this disorder, with a particular focus on therapies capable of correcting alterations to SOD1 post-translational modifications.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02859-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143546548","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}

{"title":"Evidence of COMT dysfunction in the olfactory bulb in Parkinson’s disease","authors":"Leah C. Beauchamp,&nbsp;Laura J. Ellett,&nbsp;Sydney M. A. Juan,&nbsp;Xiang M. Liu,&nbsp;Cameron P. J. Hunt,&nbsp;Clare L. Parish,&nbsp;Laura H. Jacobson,&nbsp;Claire E. Shepherd,&nbsp;Glenda M. Halliday,&nbsp;Ashley I. Bush,&nbsp;Laura J. Vella,&nbsp;David I. Finkelstein,&nbsp;Kevin J. Barnham","doi":"10.1007/s00401-025-02861-y","DOIUrl":"10.1007/s00401-025-02861-y","url":null,"abstract":"<div><p>Hyposmia is one of the most prevalent non-motor symptoms of Parkinson’s disease and antecedes motor dysfunction by up to a decade. However, the underlying pathophysiology remains poorly understood. In this study, we investigated the mechanisms of dopamine metabolism in post-mortem olfactory bulbs from ten Parkinson’s disease and ten neurologic control subjects. In contrast to the loss of dopaminergic neurons in the midbrain, we observed an increase in tyrosine hydroxylase-positive neurons in the Parkinson’s disease olfactory bulb, suggesting a potential role for dopamine in the hyposmia associated with the condition. Using immunohistochemistry, high-performance liquid chromatography, western blot, and enzyme-linked immunosorbent assays, we demonstrate a reduction in catechol-<i>O</i>-methyltransferase catabolism of dopamine to homovanillic acid, potentially due to a depletion of the methyl donor substrate <i>S</i>-adenosyl methionine. We hypothesized that reduction in catechol-<i>O</i>-methyltransferase activity would result in increased dopamine occupation of the D₂ receptor, and consequent inhibition of olfactory processing. Next, we conducted pharmacological interventions to modify dopamine dynamics in hyposmic tau knockout mice, which exhibit altered dopamine metabolism. Our hypothesis was supported by the observation that the D₂ receptor antagonist haloperidol temporarily alleviated olfactory deficits in these tau knockout mice. This study implicates a potential role of catechol-<i>O</i>-methyltransferase-mediated dopamine metabolism in the early olfactory impairments associated with Parkinson’s disease.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02861-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143521672","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}

{"title":"A quantitative Lewy-fold-specific alpha-synuclein seed amplification assay as a progression marker for Parkinson’s disease","authors":"Alexander M. Bernhardt,&nbsp;Sebastian Longen,&nbsp;Svenja V. Trossbach,&nbsp;Marcello Rossi,&nbsp;Daniel Weckbecker,&nbsp;Felix Schmidt,&nbsp;Alexander Jäck,&nbsp;Sabrina Katzdobler,&nbsp;Urban M. Fietzek,&nbsp;Endy Weidinger,&nbsp;Carla Palleis,&nbsp;Viktoria Ruf,&nbsp;Simone Baiardi,&nbsp;Piero Parchi,&nbsp;Günter U. Höglinger,&nbsp;Torsten Matthias,&nbsp;Johannes Levin,&nbsp;Armin Giese","doi":"10.1007/s00401-025-02853-y","DOIUrl":"10.1007/s00401-025-02853-y","url":null,"abstract":"<div><p>Misfolded α-synuclein (αSyn) is the hallmark of α-synucleinopathies such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). While seed amplification assays (SAA) have demonstrated ultrasensitive detection of misfolded αSyn, they have been primarily used reliably to provide binary (positive/negative) results for diagnostic purposes. We developed an SAA with enhanced specificity for Lewy-fold α-synucleinopathies and introduced a quantifiable measure correlating with clinical severity. Cerebrospinal fluid (CSF) of 170 patients with neurodegenerative diseases and controls was analyzed. Blinded measurements demonstrated 97.8% sensitivity and 100% specificity for Lewy-fold α-synucleinopathies, correctly identifying PD and DLB while excluding MSA. In addition, we validated the strain specificity of the assay by testing brain homogenates from 30 neuropathologically confirmed cases. A novel Lewy-fold pathology (LFP) score based on positive signals in a dilution series provided a quantitative measure of αSyn seeds. The LFP score significantly correlated with motor and cognitive impairment presented by Hoehn and Yahr stage, MDS-UPDRS III, and MoCA. Longitudinal tracking in seven PD cases showed progressive LFP score increases corresponding with clinical deterioration, highlighting the assay’s potential for monitoring disease progression at an individual level. Our Lewy-fold-specific SAA enhances ante-mortem diagnosis and differentiates Lewy-fold α-synucleinopathies from MSA. Unlike previous assays, the LFP score offers a quantitative assessment, showing promise as a progression marker and pharmacodynamic biomarker for αSyn-targeting therapies. This represents an important step toward developing an αSyn SAA that could help to track disease progression quantitatively, with potential applications in both clinical diagnostics and therapeutic trials.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02853-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143446431","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}