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Acta Neuropathologica

Shahram Oveisgharan, Zoe Arvanitakis, Lei Yu, Jose Farfel, Julie A Schneider, David A Bennett
Alzheimer's dementia is significantly more common in women than in men. However, few pathological studies have addressed sex difference in Alzheimer's disease (AD) and other brain pathologies. We leveraged postmortem data from 1453 persons who participated in one of two longitudinal community-based studies of older adults, the Religious Orders Study and the Rush Memory and Aging Project. Postmortem examination identified AD pathologies, neocortical Lewy bodies, DNA-binding protein 43 (TDP-43), hippocampal sclerosis, gross and micro infarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy...
October 17, 2018: Acta Neuropathologica
Craig D Hughes, Minee L Choi, Mina Ryten, Lee Hopkins, Anna Drews, Juan A Botía, Maria Iljina, Margarida Rodrigues, Sarah A Gagliano, Sonia Gandhi, Clare Bryant, David Klenerman
In the original publication of this article, the author Magarida Rodrigues was written incorrectly.
October 17, 2018: Acta Neuropathologica
Qiaoli Ma, Miriam Ries, Yann Decker, Andreas Müller, Chantal Riner, Arno Bücker, Klaus Fassbender, Michael Detmar, Steven T Proulx
The relationships between cerebrospinal fluid (CSF) and brain interstitial fluid are still being elucidated. It has been proposed that CSF within the subarachnoid space will enter paravascular spaces along arteries to flush through the parenchyma of the brain. However, CSF also directly exits the subarachnoid space through the cribriform plate and other perineural routes to reach the lymphatic system. In this study, we aimed to elucidate the functional relationship between CSF efflux through lymphatics and the potential influx into the brain by assessment of the distribution of CSF-infused tracers in awake and anesthetized mice...
October 10, 2018: Acta Neuropathologica
Sarah K Kaufman, Kelly Del Tredici, Heiko Braak, Marc I Diamond
No abstract text is available yet for this article.
October 3, 2018: Acta Neuropathologica
Elaheh Ekhtiari Bidhendi, Johan Bergh, Per Zetterström, Karin Forsberg, Bente Pakkenberg, Peter M Andersen, Stefan L Marklund, Thomas Brännström
Motor neurons containing aggregates of superoxide dismutase 1 (SOD1) are hallmarks of amyotrophic lateral sclerosis (ALS) caused by mutations in the gene encoding SOD1. We have previously reported that two strains of mutant human (h) SOD1 aggregates (denoted A and B) can arise in hSOD1-transgenic models for ALS and that inoculation of such aggregates into the lumbar spinal cord of mice results in rostrally spreading, templated hSOD1 aggregation and premature fatal ALS-like disease. Here, we explored whether mutant hSOD1 aggregates with prion-like properties also exist in human ALS...
October 3, 2018: Acta Neuropathologica
Benjamin Falcon, Wenjuan Zhang, Manuel Schweighauser, Alexey G Murzin, Ruben Vidal, Holly J Garringer, Bernardino Ghetti, Sjors H W Scheres, Michel Goedert
The ordered assembly of tau protein into abnormal filaments is a defining characteristic of Alzheimer's disease (AD) and other neurodegenerative disorders. It is not known if the structures of tau filaments vary within, or between, the brains of individuals with AD. We used a combination of electron cryo-microscopy (cryo-EM) and immuno-gold negative-stain electron microscopy (immuno-EM) to determine the structures of paired helical filaments (PHFs) and straight filaments (SFs) from the frontal cortex of 17 cases of AD (15 sporadic and 2 inherited) and 2 cases of atypical AD (posterior cortical atrophy)...
October 1, 2018: Acta Neuropathologica
Ke Xu, Liang Ding, Ti-Cheng Chang, Ying Shao, Jason Chiang, Heather Mulder, Shuoguo Wang, Tim I Shaw, Ji Wen, Laura Hover, Clay McLeod, Yong-Dong Wang, John Easton, Michael Rusch, James Dalton, James R Downing, David W Ellison, Jinghui Zhang, Suzanne J Baker, Gang Wu
Double minute chromosomes are extrachromosomal circular DNA fragments frequently found in brain tumors. To understand their evolution, we characterized the double minutes in paired diagnosis and relapse tumors from a pediatric high-grade glioma and four adult glioblastoma patients. We determined the full structures of the major double minutes using a novel approach combining multiple types of supporting genomic evidence. Among the double minutes identified in the pediatric patient, only one carrying EGFR was maintained at high abundance in both samples, whereas two others were present in only trace amounts at diagnosis but abundant at relapse, and the rest were found either in the relapse sample only or in the diagnosis sample only...
September 28, 2018: Acta Neuropathologica
Daniel J Brat, Kenneth Aldape, Howard Colman, Eric C Holland, David N Louis, Robert B Jenkins, B K Kleinschmidt-DeMasters, Arie Perry, Guido Reifenberger, Roger Stupp, Andreas von Deimling, Michael Weller
No abstract text is available yet for this article.
September 26, 2018: Acta Neuropathologica
Hlin Kvartsberg, Tammaryn Lashley, Christina E Murray, Gunnar Brinkmalm, Nicholas C Cullen, Kina Höglund, Henrik Zetterberg, Kaj Blennow, Erik Portelius
Synaptic degeneration and neuronal loss are early events in Alzheimer's disease (AD), occurring long before symptom onset, thus making synaptic biomarkers relevant for enabling early diagnosis. The postsynaptic protein neurogranin (Ng) is a cerebrospinal fluid (CSF) biomarker for AD, also in the prodromal phase. Here we tested the hypothesis that during AD neurodegeneration, processing of full-length Ng into endogenous peptides in the brain is increased. We characterized Ng in post-mortem brain tissue and investigated the levels of endogenous Ng peptides in relation to full-length protein in brain tissue of patients with sporadic (sAD) and familial Alzheimer's disease (fAD), healthy controls and individuals who were cognitively unaffected but amyloid-positive (CU-AP) in two different brain regions...
September 22, 2018: Acta Neuropathologica
Jean-Philippe Courade, Rachel Angers, Georges Mairet-Coello, Nathalie Pacico, Kerry Tyson, Daniel Lightwood, Rebecca Munro, David McMillan, Robert Griffin, Terry Baker, Dale Starkie, Ruodan Nan, Marta Westwood, Marie-Laetitia Mushikiwabo, Sophie Jung, Geofrey Odede, Berni Sweeney, Andrew Popplewell, Gillian Burgess, Patrick Downey, Martin Citron
In Alzheimer's disease (AD) and other tauopathies, the cytosolic protein Tau misfolds and forms intracellular aggregates which accumulate within the brain leading to neurodegeneration. Clinical progression is tightly linked to the progressive spread of Tau pathology throughout the brain, and several lines of evidence suggest that Tau aggregates or "seeds" may propagate pathology by spreading from cell to cell in a "prion like" manner. Accordingly, blocking the spread of extracellular seeds with an antibody could be a viable therapeutic approach...
September 20, 2018: Acta Neuropathologica
Craig D Hughes, Minee L Choi, Mina Ryten, Lee Hopkins, Anna Drews, Juan A Botía, Maria Iljina, Magarida Rodrigues, Sarah A Gagliano, Sonia Gandhi, Clare Bryant, David Klenerman
Despite the wealth of genomic and transcriptomic data in Parkinson's disease (PD), the initial molecular events are unknown. Using LD score regression analysis, we show significant enrichment in PD heritability within regulatory sites for LPS-activated monocytes and that TLR4 expression is highest within human substantia nigra, the most affected brain region, suggesting a role for TLR4 inflammatory responses. We then performed extended incubation of cells with physiological concentrations of small alpha-synuclein oligomers observing the development of a TLR4-dependent sensitized inflammatory response with time, including TNF-α production...
September 17, 2018: Acta Neuropathologica
Michael S Pollanen, Sylvester Onzivua, Janice Robertson, Paul M McKeever, Francis Olawa, David L Kitara, Amanda Fong
Nodding syndrome is an epidemic neurologic disorder of unknown cause that affects children in the subsistence-farming communities of East Africa. We report the neuropathologic findings in five fatal cases (13-18 years of age at death) of nodding syndrome from the Acholi people in northern Uganda. Neuropathologic examination revealed tau-immunoreactive neuronal neurofibrillary tangles, pre-tangles, neuropil threads, and dot-like lesions involving the cerebral cortex, subcortical nuclei and brainstem. There was preferential involvement of the frontal and temporal lobes in a patchy distribution, mostly involving the crests of gyri and the superficial cortical lamina...
September 15, 2018: Acta Neuropathologica
Amanda M Liesinger, Neill R Graff-Radford, Ranjan Duara, Rickey E Carter, Fadi S Hanna Al-Shaikh, Shunsuke Koga, Kelly M Hinkle, Sarah K DiLello, McKenna F Johnson, Adel Aziz, Nilufer Ertekin-Taner, Owen A Ross, Dennis W Dickson, Melissa E Murray
Women reportedly make up two-thirds of Alzheimer's disease (AD) dementia sufferers. Many estimates regarding AD, however, are based on clinical series lacking autopsy confirmation. The Florida Autopsied Multi-Ethnic (FLAME) cohort was queried for AD cases with a total of 1625 identified ranging in age from 53 to 102 years at death. Standard neuropathologic procedures were employed and clinical information was retrospectively collected. Clinicopathologic and genetic data (MAPT and APOE) were stratified by sex...
September 15, 2018: Acta Neuropathologica
Giselle Y López, Jessica Van Ziffle, Courtney Onodera, James P Grenert, Iwei Yeh, Boris C Bastian, Jennifer Clarke, Nancy Ann Oberheim Bush, Jennie Taylor, Susan Chang, Nicholas Butowski, Anuradha Banerjee, Sabine Mueller, Cassie Kline, Joseph Torkildson, David Samuel, Aleli Siongco, Corey Raffel, Nalin Gupta, Sandeep Kunwar, Praveen Mummaneni, Manish Aghi, Philip Theodosopoulos, Mitchel Berger, Joanna J Phillips, Melike Pekmezci, Tarik Tihan, Andrew W Bollen, Arie Perry, David A Solomon
Radiotherapy improves survival for common childhood cancers such as medulloblastoma, leukemia, and germ cell tumors. Unfortunately, long-term survivors suffer sequelae that can include secondary neoplasia. Gliomas are common secondary neoplasms after cranial or craniospinal radiation, most often manifesting as high-grade astrocytomas with poor clinical outcomes. Here, we performed genetic profiling on a cohort of 12 gliomas arising after therapeutic radiation to determine their molecular pathogenesis and assess for differences in genomic signature compared to their spontaneous counterparts...
September 8, 2018: Acta Neuropathologica
Eric T Hsu, Mihika Gangolli, Shiran Su, Laurena Holleran, Thor D Stein, Victor E Alvarez, Ann C McKee, Robert E Schmidt, David L Brody
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repeated head traumas. Using immunohistochemistry for glial fibrillary acidic protein as a marker, plus automated quantitative analysis, we examined the characteristics and extent of astrogliosis present in stage III and IV CTE, along with Alzheimer's disease (AD), and frontotemporal dementia (FTD) cases. Astrogliosis in CTE patients was more diffuse compared to that of AD and FTD patients, which was concentrated in the sulcal depths...
September 7, 2018: Acta Neuropathologica
Basilis Zikopoulos, Xuefeng Liu, Justin Tepe, Iris Trutzer, Yohan J John, Helen Barbas
Autism has been linked with the changes in brain connectivity that disrupt neural communication, especially involving frontal networks. Pathological changes in white matter are evident in adults with autism, particularly affecting axons below the anterior cingulate cortices (ACC). It is still unknown whether axon pathology appears early or late in development and whether it changes or not from childhood through adulthood. To address these questions, we examined typical and pathological development of about 1 million axons in post-mortem brains of children, adolescents, and adults with and without autism (ages 3-67 years)...
September 6, 2018: Acta Neuropathologica
Eleanor K Pickett, Jamie Rose, Caoimhe McCrory, Chris-Anne McKenzie, Declan King, Colin Smith, Thomas H Gillingwater, Christopher M Henstridge, Tara L Spires-Jones
Of all of the neuropathological changes observed in Alzheimer's disease (AD), the loss of synapses correlates most strongly with cognitive decline. The precise mechanisms of synapse degeneration in AD remain unclear, although strong evidence indicates that pathological forms of both amyloid beta and tau contribute to synaptic dysfunction and loss. Synaptic mitochondria play a potentially important role in synapse degeneration in AD. Many studies in model systems indicate that amyloid beta and tau both impair mitochondrial function and impair transport of mitochondria to synapses...
September 6, 2018: Acta Neuropathologica
Damian Stichel, Azadeh Ebrahimi, David Reuss, Daniel Schrimpf, Takahiro Ono, Mitsuaki Shirahata, Guido Reifenberger, Michael Weller, Daniel Hänggi, Wolfgang Wick, Christel Herold-Mende, Manfred Westphal, Sebastian Brandner, Stefan M Pfister, David Capper, Felix Sahm, Andreas von Deimling
EGFR amplification (EGFRamp), the combination of gain of chromosome 7 and loss of chromosome 10 (7+/10-), and TERT promoter mutation (pTERTmut) are alterations frequently observed in adult IDH-wild-type (IDHwt) glioblastoma (GBM). In the absence of endothelial proliferation and/or necrosis, these alterations currently are considered to serve as a surrogate for upgrading IDHwt diffuse or anaplastic astrocytoma to GBM. Here, we set out to determine the distribution of EGFRamp, 7+/10-, and pTERTmut by analyzing high-resolution copy-number profiles and next-generation sequencing data of primary brain tumors...
September 5, 2018: Acta Neuropathologica
Michael C Pace, Guilian Xu, Susan Fromholt, John Howard, Keith Crosby, Benoit I Giasson, Jada Lewis, David R Borchelt
The deposition of pathologic misfolded proteins in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, frontotemporal dementia and amyotrophic lateral sclerosis is hypothesized to burden protein homeostatic (proteostatic) machinery, potentially leading to insufficient capacity to maintain the proteome. This hypothesis has been supported by previous work in our laboratory, as evidenced by the perturbation of cytosolic protein solubility in response to amyloid plaques in a mouse model of Alzheimer's amyloidosis...
August 23, 2018: Acta Neuropathologica
Mariet Allen, Xue Wang, Daniel J Serie, Samantha L Strickland, Jeremy D Burgess, Shunsuke Koga, Curtis S Younkin, Thuy T Nguyen, Kimberly G Malphrus, Sarah J Lincoln, Melissa Alamprese, Kuixi Zhu, Rui Chang, Minerva M Carrasquillo, Naomi Kouri, Melissa E Murray, Joseph S Reddy, Cory Funk, Nathan D Price, Todd E Golde, Steven G Younkin, Yan W Asmann, Julia E Crook, Dennis W Dickson, Nilüfer Ertekin-Taner
Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder characterized by tau pathology in neurons and glial cells. Transcriptional regulation has been implicated as a potential mechanism in conferring disease risk and neuropathology for some PSP genetic risk variants. However, the role of transcriptional changes as potential drivers of distinct cell-specific tau lesions has not been explored. In this study, we integrated brain gene expression measurements, quantitative neuropathology traits and genome-wide genotypes from 268 autopsy-confirmed PSP patients to identify transcriptional associations with unique cell-specific tau pathologies...
August 22, 2018: Acta Neuropathologica
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