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2. A systematic review of progranulin concentrations in biofluids in over 7,000 people—assessing the pathogenicity of GRN mutations and other influencing factors

Author

Swift, Imogen J., Rademakers, Rosa, Finch, NiCole, Baker, Matt, Ghidoni, Roberta, Benussi, Luisa, Binetti, Giuliano, Rossi, Giacomina, Synofzik, Matthis, Wilke, Carlo, Mengel, David, Graff, Caroline, Takada, Leonel T., Sánchez-Valle, Raquel, Antonell, Anna, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Arcaro, Marina, Schreiber, Stefanie, Vielhaber, Stefan, Arndt, Philipp, Santana, Isabel, Almeida, Maria Rosario, Moreno, Fermín, Barandiaran, Myriam, Gabilondo, Alazne, Stubert, Johannes, Gómez-Tortosa, Estrella, Agüero, Pablo, Sainz, M. José, Gohda, Tomohito, Murakoshi, Maki, Kamei, Nozomu, Kittel-Schneider, Sarah, Reif, Andreas, Weigl, Johannes, Jian, Jinlong, Liu, Chuanju, Serrero, Ginette, Greither, Thomas, Theil, Gerit, Lohmann, Ebba, Gazzina, Stefano, Bagnoli, Silvia, Coppola, Giovanni, Bruni, Amalia, Quante, Mirja, Kiess, Wieland, Hiemisch, Andreas, Jurkutat, Anne, Block, Matthew S., Carlson, Aaron M., Bråthen, Geir, Sando, Sigrid Botne, Grøntvedt, Gøril Rolfseng, Lauridsen, Camilla, Heslegrave, Amanda, Heller, Carolin, Abel, Emily, Gómez-Núñez, Alba, Puey, Roger, Arighi, Andrea, Rotondo, Enmanuela, Jiskoot, Lize C., Meeter, Lieke H. H., Durães, João, Lima, Marisa, Tábuas-Pereira, Miguel, Lemos, João, Boeve, Bradley, Petersen, Ronald C., Dickson, Dennis W., Graff-Radford, Neill R., LeBer, Isabelle, Sellami, Leila, Lamari, Foudil, Clot, Fabienne, Borroni, Barbara, Cantoni, Valentina, Rivolta, Jasmine, Lleó, Alberto, Fortea, Juan, Alcolea, Daniel, Illán-Gala, Ignacio, Andres-Cerezo, Lucie, Van Damme, Philip, Clarimon, Jordi, Steinacker, Petra, Feneberg, Emily, Otto, Markus, van der Ende, Emma L., van Swieten, John C., Seelaar, Harro, Zetterberg, Henrik, Sogorb-Esteve, Aitana, and Rohrer, Jonathan D.

Published
2024
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4. TDP-43 based biomarker development in amyotrophic lateral sclerosis

Author

Feneberg, Emily, Turner, Martin, Talbot, Kevin, and Gray, Elizabeth

Subjects
616.8, Proteomics, Amyotrophic lateral sclerosis, Nervous system--Degeneration, Molecular neurobiology
Abstract

Amyotrophic lateral sclerosis is a devastating neurodegenerative disease which is clinically and aetiologically heterogenous. However, TDP-43 neuropathology is a unifying hallmark found in 97% of ALS cases. Understanding the common pathological pathways downstream of TDP-43 dysregulation is essential for the development of novel drug targets, and the development of a TDP-43 based biomarker for clinical translation would have profound implications for early diagnosis and monitoring of disease progression. The work presented in the first part of this thesis addresses the need to develop TDP-43 as a unifying disease-specific biomarker. Mass spectrometry was used to detect TDP-43 from insoluble protein fractions extracted from ALS post mortem tissue with TDP-43 pathology which led to the discovery of ALS disease-specific TDP-43 peptides. These peptides were then validated in an independent targeted proteomic experiment which, for the first time, allowed the quantification of disease-relevant peptides. This enabled the measurement of an ALS-specific TDP-43 peptide signal that reflects sites of pathological truncation and an increased C-terminal TDP-43 protein ratio. This now provides a platform with which to investigate ALS biofluids with the aim to ultimately develop a disease-specific TDP-43 in vivo assay for patient stratification. In the second part of the thesis I describe the use of affinity-enrichment mass spectrometry to investigate the human wild-type and M337V mutant TDP-43 interactome in a low expression (BAC)-transgenic mouse motor neuron model. I demonstrate that the C-terminal mutation of TDP-43 disrupts specific protein-protein interactions associated with human wild-type TDP-43. In response to oxidative stress, wild-type TDP-43 interactions shift towards proteins that are relevant to cellular stress pathways, while mutant TDP-43 is bound to proteins that are independently linked to pathways known to drive ALS pathogenesis. The key interactions that were disrupted by the M337V mutation involve proteins that are important for stress granule formation and extracellular vesicle secretion. Furthermore, I was able to demonstrate correlative phenotypic abnormalities in stress granule assembly and exosome secretion in motor neurons from the human TDP-43 (BAC)-transgenic mouse model and also in human iPSC-derived motor neurons with the same TDP-43 M337V mutation. In conclusion, work in this thesis provides significant novel data to support the further development of TDP-43 as an in vivo biomarker in ALS. Analysis of the TDP-43 interactome in a physiologically relevant mouse model has defined core cellular pathways matched to relevant phenotypes which will be important for the identification of pathways relevant for drug target development.

Published
2020

9. TDP-43 Proteinopathy Specific Biomarker Development

Author

Cordts, Isabell, Wachinger, Annika, Scialo, Carlo; https://orcid.org/0000-0003-2393-4546, Lingor, Paul, Polymenidou, Magdalini; https://orcid.org/0000-0003-1271-9445, Buratti, Emanuele, Feneberg, Emily, Cordts, Isabell, Wachinger, Annika, Scialo, Carlo; https://orcid.org/0000-0003-2393-4546, Lingor, Paul, Polymenidou, Magdalini; https://orcid.org/0000-0003-1271-9445, Buratti, Emanuele, and Feneberg, Emily

Abstract

TDP-43 is the primary or secondary pathological hallmark of neurodegenerative diseases, such as amyotrophic lateral sclerosis, half of frontotemporal dementia cases, and limbic age-related TDP-43 encephalopathy, which clinically resembles Alzheimer’s dementia. In such diseases, a biomarker that can detect TDP-43 proteinopathy in life would help to stratify patients according to their definite diagnosis of pathology, rather than in clinical subgroups of uncertain pathology. For therapies developed to target pathological proteins that cause the disease a biomarker to detect and track the underlying pathology would greatly enhance such undertakings. This article reviews the latest developments and outlooks of deriving TDP-43-specific biomarkers from the pathophysiological processes involved in the development of TDP-43 proteinopathy and studies using biosamples from clinical entities associated with TDP-43 pathology to investigate biomarker candidates.

Published
2023

10. 7 .Differentialdiagnostik

Author

Hamann, Gerhard F, primary, Dodel, Richard, additional, Otto, Markus, additional, Feneberg, Emily, additional, Anderl-Straub, Sarah, additional, Schneider, Anja, additional, and Bartels, Claudia, additional

Published
2018
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13. Poly‐GP in cerebrospinal fluid links C9orf72‐associated dipeptide repeat expression to the asymptomatic phase of ALS/FTD

Author

Lehmer, Carina, Oeckl, Patrick, Weishaupt, Jochen H, Volk, Alexander E, Diehl‐Schmid, Janine, Schroeter, Matthias L, Lauer, Martin, Kornhuber, Johannes, Levin, Johannes, Fassbender, Klaus, Landwehrmeyer, Bernhard, Schludi, Martin H, Arzberger, Thomas, Kremmer, Elisabeth, Flatley, Andrew, Feederle, Regina, Steinacker, Petra, Weydt, Patrick, Ludolph, Albert C, Edbauer, Dieter, Otto, Markus, Danek, Adrian, Feneberg, Emily, Anderl‐Straub, Sarah, von Arnim, Christine, Jahn, Holger, Schneider, Anja, Maler, Manuel, Polyakova, Maryna, Riedl, Lina, Wiltfang, Jens, and Ziegler, Georg

Published
2017
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14. Multicenter evaluation of neurofilaments in early symptom onset amyotrophic lateral sclerosis

Author

Feneberg, Emily, Oeckl, Patrick, Steinacker, Petra, Verde, Federico, Barro, Christian, Van Damme, Philip, Gray, Elizabeth, Grosskreutz, Julian, Jardel, Claude, Kuhle, Jens, Koerner, Sonja, Lamari, Foudil, Amador, Maria del Mar, Mayer, Benjamin, Morelli, Claudia, Muckova, Petra, Petri, Susanne, Poesen, Koen, Raaphorst, Joost, Salachas, François, Silani, Vincenzo, Stubendorff, Beatrice, Turner, Martin R., Verbeek, Marcel M., Weishaupt, Jochen H., Weydt, Patrick, Ludolph, Albert C., and Otto, Markus

Published
2018
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15. Advantages of routine next‐generation sequencing over standard genetic testing in the amyotrophic lateral sclerosis clinic.

Author

Scaber, Jakub, Thompson, Alexander G., Farrimond, Lucy, Feneberg, Emily, Proudfoot, Malcolm, Ossher, Lynn, Turner, Martin R., and Talbot, Kevin

Subjects
AMYOTROPHIC lateral sclerosis, GENETIC testing, NUCLEOTIDE sequencing, MOTOR neuron diseases, GENETIC epidemiology
Abstract

Background: Next‐generation sequencing has enhanced our understanding of amyotrophic lateral sclerosis (ALS) and its genetic epidemiology. Outside the research setting, testing is often restricted to those who report a family history. The aim of this study was to explore the added benefit of offering routine genetic testing to all patients in a regional ALS centre. Methods: C9ORF72 expansion testing and exome sequencing was offered to consecutive patients (150 with ALS and 12 with primary lateral sclerosis [PLS]) attending the Oxford Motor Neuron Disease Clinic within a defined time period. Results: A total of 17 (11.3%) highly penetrant pathogenic variants in C9ORF72, SOD1, TARDBP, FUS and TBK1 were detected, of which 10 were also found through standard clinical genetic testing pathways. The systematic approach resulted in five additional diagnoses of a C9ORF72 expansion (number needed to test [NNT] = 28), and two further missense variants in TARDBP and SOD1 (NNT = 69). Additionally, 3 patients were found to carry pathogenic risk variants in NEK1, and 13 patients harboured common missense variants in CFAP410 and KIF5A, also associated with an increased risk of ALS. We report two novel non‐coding loss‐of‐function splice variants in TBK1 and OPTN. No relevant variants were found in the PLS patients. Patients were offered double‐blinded participation, but >80% requested disclosure of the results. Conclusions: This study provides evidence that expanding genetic testing to all patients with a clinical diagnosis of ALS enhances the potential for recruitment to clinical trials, but will have direct resource implications for genetic counselling. [ABSTRACT FROM AUTHOR]

Published
2023
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17. AtypicalTDP‐43 protein expression in anALSpedigree carrying a p.Y374Xtruncation mutation inTARDBP

Author

Cooper‐Knock, Johnathan, primary, Julian, Thomas H., additional, Feneberg, Emily, additional, Highley, J. Robin, additional, Sidra, Maurice, additional, Turner, Martin R., additional, Talbot, Kevin, additional, Ansorge, Olaf, additional, Allen, Scott P., additional, Moll, Tobias, additional, Shelkovnikova, Tatyana, additional, Castelli, Lydia, additional, Hautbergue, Guillaume M., additional, Hewitt, Christopher, additional, Kirby, Janine, additional, Wharton, Stephen B., additional, Mead, Richard J., additional, and Shaw, Pamela J., additional

Published
2022
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18. Multicentre appraisal of amyotrophic lateral sclerosis biofluid biomarkers shows primacy of blood neurofilament light chain

Author

Thompson, Alexander G., primary, Gray, Elizabeth, additional, Verber, Nick, additional, Bobeva, Yoana, additional, Lombardi, Vittoria, additional, Shepheard, Stephanie R., additional, Yildiz, Ozlem, additional, Feneberg, Emily, additional, Farrimond, Lucy, additional, Dharmadasa, Thanuja, additional, Gray, Pamela, additional, Edmond, Evan C., additional, Scaber, Jakub, additional, Gagliardi, Delia, additional, Kirby, Janine, additional, Jenkins, Thomas M., additional, Fratta, Pietro, additional, McDermott, Christopher J., additional, Manohar, Sanjay G., additional, Talbot, Kevin, additional, Malaspina, Andrea, additional, Shaw, Pamela J., additional, and Turner, Martin R., additional

Published
2022
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19. Neurofilaments in the diagnosis of motoneuron diseases: a prospective study on 455 patients

Author

Steinacker, Petra, Feneberg, Emily, Weishaupt, Jochen, Brettschneider, Johannes, Tumani, Hayrettin, Andersen, Peter M, von Arnim, Christine A F, Böhm, Sarah, Kassubek, Jan, Kubisch, Christian, Lulé, Dorothée, Müller, Hans-Peter, Muche, Rainer, Pinkhardt, Elmar, Oeckl, Patrick, Rosenbohm, Angela, Anderl-Straub, Sarah, Volk, Alexander E, Weydt, Patrick, Ludolph, Albert C, and Otto, Markus

Published
2016
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20. Atypical TDP‐43 protein expression in an ALS pedigree carrying a p.Y374X truncation mutation in TARDBP.

Author

Cooper‐Knock, Johnathan, Julian, Thomas H., Feneberg, Emily, Highley, J. Robin, Sidra, Maurice, Turner, Martin R., Talbot, Kevin, Ansorge, Olaf, Allen, Scott P., Moll, Tobias, Shelkovnikova, Tatyana, Castelli, Lydia, Hautbergue, Guillaume M., Hewitt, Christopher, Kirby, Janine, Wharton, Stephen B., Mead, Richard J., and Shaw, Pamela J.

Subjects
AMYOTROPHIC lateral sclerosis, PROTEIN expression, MOTOR cortex, NONSENSE mutation, MOTOR neurons, FIBROBLASTS, GENEALOGY, MASS spectrometry
Abstract

We describe an autosomal dominant, multi‐generational, amyotrophic lateral sclerosis (ALS) pedigree in which disease co‐segregates with a heterozygous p.Y374X nonsense mutation within TDP‐43. Mislocalization of TDP‐43 and formation of insoluble TDP‐43‐positive neuronal cytoplasmic inclusions is the hallmark pathology in >95% of ALS patients. Neuropathological examination of the single case for which CNS tissue was available indicated typical TDP‐43 pathology within lower motor neurons, but classical TDP‐43‐positive inclusions were absent from motor cortex. The mutated allele is transcribed and translated in patient fibroblasts and motor cortex tissue, but overall TDP‐43 protein expression is reduced compared to wild‐type controls. Despite absence of TDP‐43‐positive inclusions we confirmed deficient TDP‐43 splicing function within motor cortex tissue. Furthermore, urea fractionation and mass spectrometry of motor cortex tissue carrying the mutation revealed atypical TDP‐43 protein species but not typical C‐terminal fragments. We conclude that the p.Y374X mutation underpins a monogenic, fully penetrant form of ALS. Reduced expression of TDP‐43 combined with atypical TDP‐43 protein species and absent C‐terminal fragments extends the molecular phenotypes associated with TDP‐43 mutations and with ALS more broadly. Future work will need to include the findings from this pedigree in dissecting the mechanisms of TDP‐43‐mediated toxicity. [ABSTRACT FROM AUTHOR]

Published
2023
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21. Detection and Quantification of Novel C?terminal TDP?43 Fragments in ALS?TDP

Author

Feneberg, Emily, Charles, Philip D., Scott, Connor, Kessler, Benedikt M., Fischer, Roman, Ansorge, Olaf, Gray, Elizabeth, Talbot, Kevin, and Turner, Martin R.

Subjects
General Neuroscience, mental disorders, Clinical Neurology, nutritional and metabolic diseases, nervous system diseases, Pathology and Forensic Medicine
Abstract

The pathological hallmark of amyotrophic lateral sclerosis (ALS) is the presence of cytoplasmic inclusions, containing C‐terminal fragments of the protein TDP‐43. Here, we tested the hypothesis that highly sensitive mass spectrometry with parallel reaction monitoring (MS‐PRM) can generate a high‐resolution map of pathological TDP‐43 peptide ratios to form the basis for quantitation of abnormal C‐terminal TDP‐43 fragment enrichment.Human cortex and spinal cord, microscopically staged for the presence of phosphoTDP‐43, p‐tau, alpha‐synuclein and beta‐amyloid pathology, were biochemically fractionated and analysed by immunoblot and MS for detection of full‐length and truncated (disease‐specific) TDP‐43 peptides. This informed synthesis of heavy isotope‐labelled peptides for absolute quantification of TDP‐43 by MS‐PRM across 16 ALS, 8 Parkinson’s and 8 Alzheimer’s disease and 8 aged control cases.We confirmed by immunoblot the previously described enrichment of pathological C‐terminal fragments in ALS‐TDP urea fractions. Subsequent MS analysis resolved specific TDP‐43 N‐ and C‐terminal peptides, including a novel N‐terminal truncation site‐specific peptide. Absolute quantification of peptides by MS‐PRM showed an increased C:N‐terminal TDP‐43 peptide ratio in ALS‐TDP brain compared to normal and disease controls. A C:N‐terminal ratio >1.5 discriminated ALS from controls with a sensitivity of 100% (CI 79.6‐100) and specificity of 100% (CI 68‐100), and from Parkinson’s and Alzheimer’s disease with a sensitivity of 93% (CI 70‐100) and specificity of 100% (CI 68‐100). N‐terminal truncation site‐specific peptides were increased in ALS in line with C‐terminal fragment enrichment, but were also found in a proportion of Alzheimer cases with normal C:N‐terminal ratio but coexistent TDP‐43 pathology.In conclusion this is a novel, sensitive and specific method to quantify the enrichment of pathological TDP‐43 fragments in human brain, which could form the basis for an antibody‐free assay. Our methodology has the potential to help clarify if specific pathological TDP‐43 peptide signatures are associated with primary or secondary TDP‐43 proteinopathies.

Published
2021

23. Comparison of CSF and serum neurofilament light and heavy chain as differential diagnostic biomarkers for ALS

Author

Halbgebauer, Steffen, primary, Steinacker, Petra, additional, Verde, Federico, additional, Weishaupt, Jochen, additional, Oeckl, Patrick, additional, von Arnim, Christine, additional, Dorst, Johannes, additional, Feneberg, Emily, additional, Mayer, Benjamin, additional, Rosenbohm, Angela, additional, Silani, Vincenzo, additional, Ludolph, Albert C, additional, and Otto, Markus, additional

Published
2021
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24. Chitotriosidase as biomarker for early stage amyotrophic lateral sclerosis: a multicenter study

Author

Steinacker, Petra, primary, Feneberg, Emily, additional, Halbgebauer, Steffen, additional, Witzel, Simon, additional, Verde, Federico, additional, Oeckl, Patrick, additional, Van Damme, Philip, additional, Gaur, Nayana, additional, Gray, Elizabeth, additional, Grosskreutz, Julian, additional, Jardel, Claude G., additional, Kachanov, Mykyta, additional, Kuhle, Jens, additional, Lamari, Foudil, additional, Maceski, Aleksandra, additional, Del Mar Amador, Maria, additional, Mayer, Benjamin, additional, Morelli, Claudia, additional, Petri, Susanne, additional, Poesen, Koen, additional, Raaphorst, Joost, additional, Salachas, François, additional, Silani, Vincenzo, additional, Turner, Martin R., additional, Verbeek, Marcel M., additional, Volk, Alexander E., additional, Weishaupt, Jochen H., additional, Weydt, Patrick, additional, Ludolph, Albert C., additional, and Otto, Markus, additional

Published
2021
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26. An ALS-linked mutation in TDP-43 disrupts normal protein interactions in the motor neuron response to oxidative stress

Author

Feneberg, Emily, primary, Gordon, David, additional, Thompson, Alexander G., additional, Finelli, Mattéa J., additional, Dafinca, Ruxandra, additional, Candalija, Ana, additional, Charles, Philip D., additional, Mäger, Imre, additional, Wood, Matthew J., additional, Fischer, Roman, additional, Kessler, Benedikt M., additional, Gray, Elizabeth, additional, Turner, Martin R., additional, and Talbot, Kevin, additional

Published
2020
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28. Comparison of CSF and serum neurofilament light and heavy chain as differential diagnostic biomarkers for ALS.

Author

Halbgebauer, Steffen, Steinacker, Petra, Verde, Federico, Weishaupt, Jochen, Oeckl, Patrick, von Arnim, Christine, Dorst, Johannes, Feneberg, Emily, Mayer, Benjamin, Rosenbohm, Angela, Silani, Vincenzo, Ludolph, Albert C., and Otto, Markus

Subjects
ALZHEIMER'S disease diagnosis, RESEARCH, NERVE tissue proteins, RESEARCH methodology, DIFFERENTIAL diagnosis, MEDICAL cooperation, EVALUATION research, COMPARATIVE studies, AMYOTROPHIC lateral sclerosis, RECEIVER operating characteristic curves, LONGITUDINAL method, FRONTOTEMPORAL dementia, CYTOPLASM
Abstract

Objective: Elevated levels of neurofilament light (NfL) and heavy (NfH) chain in amyotrophic lateral sclerosis (ALS) cerebrospinal fluid (CSF) and serum reflect neuro-axonal degeneration and are used as diagnostic biomarkers. However, studies comparing the differential diagnostic potential for ALS of all four parameters are missing. Here, we measured serum NfL/NfH and CSF NfL/NfH in a large cohort of ALS and other neurological disorders and analysed the differential diagnostic potential.Methods: In total CSF and serum of 294 patients were analysed. The diagnostic groups comprised: ALS (n=75), frontotemporal lobar degeneration (FTLD) (n=33), Alzheimer's disease (n=20), Parkinson's disease (dementia) (n=18), Creutzfeldt-Jakob disease (n=11), non-neurodegenerative controls (n=77) (Con) and 60 patients who were seen under the direct differential diagnosis of a patient with ALS (Con.DD).Results: CSF and serum NfL and NfH showed significantly increased levels in ALS (p<0.0001) compared with Con and Con.DD. The difference between ALS and FTLD was markedly stronger for NfH than for NfL. CSF and serum NfL demonstrated a stronger correlation (r=0.84 (95% CI 0.80 to 0.87), p<0.001) than CSF and serum NfH (r=0.68 (95% CI 0.61 to 0.75), p<0.0001). Comparing ALS and Con.DD, receiver operating characteristic analysis revealed the best area under the curve (AUC) value for CSF NfL (AUC=0.94, 95% CI 0.91 to 0.98), followed by CSF NfH (0.93, 95% CI 0.88 to 0.98), serum NfL (0.93, 95% CI 0.89 to 0.97) and serum NfH (0.88, 95% CI 0.82 to 0.94).Conclusion: Our results demonstrate that CSF NfL and NfH as well as serum NfL are equally suited for the differential diagnosis of ALS, whereas serum NfH appears to be slightly less potent. [ABSTRACT FROM AUTHOR]

Published
2022
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29. Chitotriosidase (CHIT1) is increased in microglia and macrophages in spinal cord of amyotrophic lateral sclerosis and cerebrospinal fluid levels correlate with disease severity and progression

Author

Steinacker, Petra, Verde, Federico, Fliessbach, Klaus, Foerstl, Hans, Giese, Armin, Jahn, Holger, Kassubek, Jan, Kornhuber, Johannes, Landwehrmeyer, G Bernhard, Lauer, Martin, Pinkhardt, Elmar Hans, Prudlo, Johannes, Fang, Lubin, Rosenbohm, Angela, Schneider, Anja, Schroeter, Matthias L, Tumani, Hayrettin, von Arnim, Christine A F, Weishaupt, Jochen, Weydt, Patrick, Ludolph, Albert C, Yilmazer Hanke, Deniz, Otto, Markus, Feneberg, Emily, group, FTLDc study, Ackl, Nibal, Arlt, Sönke, Albrecht, Franziska, Bisenius, Sandrine, Gehlhaar, Svenja, Gleiss, Jakob, Halder, Theresa, Lehmbeck, Jan, Lampe, Leonie, Oeckl, Patrick, Levin, Johannes, Maler, Manuel, Oberhauser, Felix, Oberstein, Timo, Prix, Catharina, Raiser, Theresa, Richter-Schmiedinger, Tanja, Saur, Dorothee, Schachner, Lisa, Schönecker, Sonja, Roeber, Sigrun, Schuemberg, Katharina, Stenglein-Krapf, Gisela, Wlasich, Elisabeth, Anderl-Straub, Sarah, Danek, Adrian, Diehl-Schmid, Janine, and Fassbender, Klaus

Subjects
0301 basic medicine, cytology [Pyramidal Tracts], Male, Pathology, metabolism [White Matter], Intermediate Filaments, Pyramidal Tracts, metabolism [Microglia], Severity of Illness Index, Creutzfeldt-Jakob Syndrome, 0302 clinical medicine, Cerebrospinal fluid, chitotriosidase, cerebrospinal fluid [Parkinson Disease], metabolism [Creutzfeldt-Jakob Syndrome], Amyotrophic lateral sclerosis, Microglia, metabolism [Hexosaminidases], Parkinson Disease, Frontotemporal lobar degeneration, cerebrospinal fluid [Creutzfeldt-Jakob Syndrome], Middle Aged, White Matter, cerebrospinal fluid [Alzheimer Disease], Survival Rate, Psychiatry and Mental health, medicine.anatomical_structure, Hexosaminidases, Spinal Cord, Disease Progression, cerebrospinal fluid [Amyotrophic Lateral Sclerosis], Female, metabolism [Alzheimer Disease], medicine.medical_specialty, metabolism [Spinal Cord], cerebrospinal fluid [Frontotemporal Lobar Degeneration], metabolism [Parkinson Disease], White matter, 03 medical and health sciences, Alzheimer Disease, medicine, Humans, ddc:610, metabolism [Intermediate Filaments], Aged, business.industry, metabolism [Amyotrophic Lateral Sclerosis], cytology [Spinal Cord], Macrophages, Amyotrophic Lateral Sclerosis, Case-control study, Spinal cord, medicine.disease, metabolism [Frontotemporal Lobar Degeneration], 030104 developmental biology, metabolism [Pyramidal Tracts], Case-Control Studies, Immunology, metabolism [Macrophages], Surgery, Neurology (clinical), Differential diagnosis, Frontotemporal Lobar Degeneration, business, 030217 neurology & neurosurgery
Abstract

ObjectivesNeurochemical markers of amyotrophic lateral sclerosis (ALS) that reflect underlying disease mechanisms might help in diagnosis, staging and prediction of outcome. We aimed at determining the origin and differential diagnostic and prognostic potential of the putative marker of microglial activation chitotriosidase (CHIT1).MethodsAltogether 316 patients were included, comprising patients with sporadic ALS, ALS mimics (disease controls (DCo)), frontotemporal lobar degeneration (FTLD), Creutzfeldt-Jakob disease (CJD), Alzheimer’s disease (AD), Parkinson’s disease (PD) and healthy controls (Con). CHIT1 and neurofilament levels were determined in cerebrospinal fluid (CSF) and blood and analysed with regard to diagnostic sensitivity and specificity and prognostic performance. Additionally, postmortem tissue was analysed for CHIT1 expression.ResultsIn ALS, CHIT1 CSF levels were higher compared with Con (pConclusionsCHIT1 concentrations in the CSF of patients with ALS may reflect the extent of microglia/macrophage activation in the white matter of the spinal cord. CHIT1 could be a potentially useful marker for differential diagnosis and prediction of disease progression in ALS and, therefore, seems suitable as a supplemental marker for patient stratification in therapeutic trials.

Published
2018
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30. A language-based sum score for the course and therapeutic intervention in primary progressive aphasia

Author

Semler, Elisa, Anderl-Straub, Sarah, Kornhuber, Johannes, Landwehrmeyer, Bernhard, Lauer, Martin, Muche, Rainer, Prudlo, Johannes, Schneider, Anja, Schroeter, Matthias L, Ludolph, Albert C, Otto, Markus, consortium, FTLD, Uttner, Ingo, Bisenius, Sandrine, Feneberg, Emily, Faber, Jennifer, Hammer, Anke, Haefner, Sibylle, Kasper, Elisabeth, Kurzwelly, Delia, Levin, Johannes, Lornsen, Finn, Luley, Maxine, Diehl-Schmid, Janine, Maler, Manuel, Müller, Hans-Peter, Oberstein, Timo, Pellkofer, Hannah, Prix, Catharina, Riederer, Isabelle, Roßmeier, Carola, Schomburg, Robert, Roeske, Sandra, Schönecker, Sonja, Danek, Adrian, Spitzer, Philipp, Spottke, Annika, Stuke, Katharina, Teipel, Stefan, von Arnim, Christine, Wilken, Petra, Wiltfang, Jens, Einsiedler, Beate, Fassbender, Klaus, Fließbach, Klaus, Huppertz, Hans-Jürgen, Jahn, Holger, and FTLD consortium

Subjects
Male, therapy [Aphasia, Primary Progressive], cerebrospinal fluid [Amyloid beta-Peptides], Audiology, Neuropsychological Tests, lcsh:RC346-429, Primary progressive aphasia, 0302 clinical medicine, pathology [Brain], Assessment of cognitive disorders/dementia, Medizinische Fakultät, Memory span, Cognitive decline, Language, pathology [Atrophy], Volumetric MRI, 05 social sciences, Neuropsychology, Brain, Cognition, Middle Aged, amyloid beta-protein (1-42), Magnetic Resonance Imaging, 3. Good health, Cognitive test, Boston Naming Test, Neurology, therapy [Cognition Disorders], Disease Progression, Female, medicine.symptom, Frontotemporal dementia, medicine.medical_specialty, Cognitive Neuroscience, diagnostic imaging [Aphasia, Primary Progressive], tau Proteins, 050105 experimental psychology, Statistics, Nonparametric, lcsh:RC321-571, 03 medical and health sciences, Aphasia, medicine, Humans, 0501 psychology and cognitive sciences, cerebrospinal fluid [Peptide Fragments], Cognitive neuropsychology in dementia, ddc:610, cerebrospinal fluid [Aphasia, Primary Progressive], lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, lcsh:Neurology. Diseases of the nervous system, etiology [Atrophy], Aged, Amyloid beta-Peptides, business.industry, Research, complications [Aphasia, Primary Progressive], etiology [Cognition Disorders], medicine.disease, Peptide Fragments, Aphasia, Primary Progressive, cerebrospinal fluid [tau Proteins], Neurology (clinical), Atrophy, business, Cognition Disorders, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract

Background With upcoming therapeutic interventions for patients with primary progressive aphasia (PPA), instruments for the follow-up of patients are needed to describe disease progression and to evaluate potential therapeutic effects. So far, volumetric brain changes have been proposed as clinical endpoints in the literature, but cognitive scores are still lacking. This study followed disease progression predominantly in language-based performance within 1 year and defined a PPA sum score which can be used in therapeutic interventions. Methods We assessed 28 patients with nonfluent variant PPA, 17 with semantic variant PPA, 13 with logopenic variant PPA, and 28 healthy controls in detail for 1 year. The most informative neuropsychological assessments were combined to a sum score, and associations between brain atrophy were investigated followed by a sample size calculation for clinical trials. Results Significant absolute changes up to 20% in cognitive tests were found after 1 year. Semantic and phonemic word fluency, Boston Naming Test, Digit Span, Token Test, AAT Written language, and Cookie Test were identified as the best markers for disease progression. These tasks provide the basis of a new PPA sum score. Assuming a therapeutic effect of 50% reduction in cognitive decline for sample size calculations, a number of 56 cases is needed to find a significant treatment effect. Correlations between cognitive decline and atrophy showed a correlation up to r = 0.7 between the sum score and frontal structures, namely the superior and inferior frontal gyrus, as well as with left-sided subcortical structures. Conclusion Our findings support the high performance of the proposed sum score in the follow-up of PPA and recommend it as an outcome measure in intervention studies.

Published
2018

32. Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis

Author

Verde, Federico, primary, Steinacker, Petra, additional, Weishaupt, Jochen H, additional, Kassubek, Jan, additional, Oeckl, Patrick, additional, Halbgebauer, Steffen, additional, Tumani, Hayrettin, additional, von Arnim, Christine A F, additional, Dorst, Johannes, additional, Feneberg, Emily, additional, Mayer, Benjamin, additional, Müller, Hans-Peter, additional, Gorges, Martin, additional, Rosenbohm, Angela, additional, Volk, Alexander E, additional, Silani, Vincenzo, additional, Ludolph, Albert C, additional, and Otto, Markus, additional

Published
2018
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34. Initial Identification of a Blood-Based Chromosome Conformation Signature for Aiding in the Diagnosis of Amyotrophic Lateral Sclerosis

Author

Salter, Matthew, primary, Corfield, Emily, additional, Ramadass, Aroul, additional, Grand, Francis, additional, Green, Jayne, additional, Westra, Jurjen, additional, Lim, Chun Ren, additional, Farrimond, Lucy, additional, Feneberg, Emily, additional, Scaber, Jakub, additional, Thompson, Alexander, additional, Ossher, Lynn, additional, Turner, Martin, additional, Talbot, Kevin, additional, Cudkowicz, Merit, additional, Berry, James, additional, Hunter, Ewan, additional, and Akoulitchev, Alexandre, additional

Published
2018
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36. Multicenter evaluation of neurofilaments in early symptom onset amyotrophic lateral sclerosis

Author

Feneberg, Emily, primary, Oeckl, Patrick, additional, Steinacker, Petra, additional, Verde, Federico, additional, Barro, Christian, additional, Van Damme, Philip, additional, Gray, Elizabeth, additional, Grosskreutz, Julian, additional, Jardel, Claude, additional, Kuhle, Jens, additional, Koerner, Sonja, additional, Lamari, Foudil, additional, Amador, Maria del Mar, additional, Mayer, Benjamin, additional, Morelli, Claudia, additional, Muckova, Petra, additional, Petri, Susanne, additional, Poesen, Koen, additional, Raaphorst, Joost, additional, Salachas, François, additional, Silani, Vincenzo, additional, Stubendorff, Beatrice, additional, Turner, Martin R., additional, Verbeek, Marcel M., additional, Weishaupt, Jochen H., additional, Weydt, Patrick, additional, Ludolph, Albert C., additional, and Otto, Markus, additional

Published
2017
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37. Recent biomarker approaches in the diagnosis of frontotemporal lobar degeneration/Neurochemische Ansätze in der Diagnose der Frontotemporalen Lobärdegeneration

Author

Feneberg, Emily, Steinacker, Petra, Lehnert, Stefan, Neumann, Manuela, Otto, Markus, Feneberg, Emily, Steinacker, Petra, Lehnert, Stefan, Neumann, Manuela, and Otto, Markus

Abstract

Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of syndromes with different symptoms. Frontotemporal lobar degeneration is mostly used as a clinical umbrella term for different diseases. In some clinical subtypes of the FTLD spectrum, a close correlation with underlying pathology can be found. Neuroimaging techniques, such as magnetic resonance imaging and position emission tomography help to detect neuroanatomical lesions and therefore obtain relevance for in vivo prediction of neurodegeneration. However, there is still a lack of neurochemical biomarkers helping to differentiate between underlying histopathologies. The following review gives an overview about present neurochemical biomarker studies and perspective approaches in the diagnosis of FTLD

Published
2017

38. Chitotriosidase (CHIT1) is increased in microglia and macrophages in spinal cord of amyotrophic lateral sclerosis and cerebrospinal fluid levels correlate with disease severity and progression

Author

Steinacker, Petra, primary, Verde, Federico, additional, Fang, Lubin, additional, Feneberg, Emily, additional, Oeckl, Patrick, additional, Roeber, Sigrun, additional, Anderl-Straub, Sarah, additional, Danek, Adrian, additional, Diehl-Schmid, Janine, additional, Fassbender, Klaus, additional, Fliessbach, Klaus, additional, Foerstl, Hans, additional, Giese, Armin, additional, Jahn, Holger, additional, Kassubek, Jan, additional, Kornhuber, Johannes, additional, Landwehrmeyer, G Bernhard, additional, Lauer, Martin, additional, Pinkhardt, Elmar Hans, additional, Prudlo, Johannes, additional, Rosenbohm, Angela, additional, Schneider, Anja, additional, Schroeter, Matthias L, additional, Tumani, Hayrettin, additional, von Arnim, Christine A F, additional, Weishaupt, Jochen, additional, Weydt, Patrick, additional, Ludolph, Albert C, additional, Yilmazer Hanke, Deniz, additional, and Otto, Markus, additional

Published
2017
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39. Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis.

Author

Verde, Federico, Steinacker, Petra, Weishaupt, Jochen H., Kassubek, Jan, Oeckl, Patrick, Halbgebauer, Steffen, Tumani, Hayrettin, von Arnim, Christine A. F., Dorst, Johannes, Feneberg, Emily, Mayer, Benjamin, Müller, Hans-Peter, Gorges, Martin, Rosenbohm, Angela, Volk, Alexander E., Silani, Vincenzo, Ludolph, Albert C., and Otto, Markus

Subjects
SERODIAGNOSIS, AMYOTROPHIC lateral sclerosis, FRONTOTEMPORAL lobar degeneration, FRONTOTEMPORAL dementia, CREUTZFELDT-Jakob disease, CYTOPLASMIC filaments
Abstract

Objective: To determine the diagnostic and prognostic performance of serum neurofilament light chain (NFL) in amyotrophic lateral sclerosis (ALS).Methods: This single-centre, prospective, longitudinal study included the following patients: 124 patients with ALS; 50 patients without neurodegenerative diseases; 44 patients with conditions included in the differential diagnosis of ALS (disease controls); 65 patients with other neurodegenerative diseases (20 with frontotemporal dementia, 20 with Alzheimer's disease, 19 with Parkinson's disease, 6 with Creutzfeldt-Jakob disease (CJD)). Serum NFL levels were measured using the ultrasensitive single molecule array (Simoa) technology.Results: Serum NFL levels were higher in ALS in comparison to all other categories except for CJD. A cut-off level of 62 pg/mL discriminated between ALS and all other conditions with 85.5% sensitivity (95% CI 78% to 91.2%) and 81.8% specificity (95% CI 74.9% to 87.4%). Among patients with ALS, serum NFL correlated positively with disease progression rate (rs=0.336, 95% CI 0.14 to 0.506, p=0.0008), and higher levels were associated with shorter survival (p=0.0054). Serum NFL did not differ among patients in different ALS pathological stages as evaluated by diffusion-tensor imaging, and in single patients NFL levels were stable over time.Conclusions: Serum NFL is increased in ALS in comparison to other conditions and can serve as diagnostic and prognostic biomarker. We established a cut-off level for the diagnosis of ALS. [ABSTRACT FROM AUTHOR]

Published
2019
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46. Neurofilaments in the diagnosis of motoneuron diseases: a prospective study on 455 patients

Author

Steinacker, Petra, primary, Feneberg, Emily, additional, Weishaupt, Jochen, additional, Brettschneider, Johannes, additional, Tumani, Hayrettin, additional, Andersen, Peter M, additional, von Arnim, Christine A F, additional, Böhm, Sarah, additional, Kassubek, Jan, additional, Kubisch, Christian, additional, Lulé, Dorothée, additional, Müller, Hans-Peter, additional, Muche, Rainer, additional, Pinkhardt, Elmar, additional, Oeckl, Patrick, additional, Rosenbohm, Angela, additional, Anderl-Straub, Sarah, additional, Volk, Alexander E, additional, Weydt, Patrick, additional, Ludolph, Albert C, additional, and Otto, Markus, additional

Published
2015
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49. Intact Protein Analysis of Ubiquitin in Cerebrospinal Fluid by Multiple Reaction Monitoring Reveals Differences in Alzheimer’s Disease and Frontotemporal Lobar Degeneration

Author

Oeckl, Patrick, primary, Steinacker, Petra, additional, von Arnim, Christine A. F., additional, Straub, Sarah, additional, Nagl, Magdalena, additional, Feneberg, Emily, additional, Weishaupt, Jochen H., additional, Ludolph, Albert C., additional, and Otto, Markus, additional

Published
2014
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