Work Group Neurochemistry and Neurodegeneration (AG Otto)

 
Aims

The neurochemical differential and early diagnosis of neurodegenerative diseases represents the main focus of our interdisciplinary group. Using proteomic approaches, especially mass spectrometry, single molecule array (Simoa) and other sensitive methods, we attempt to identify new biomarker candidates in cerebrospinal fluid (CSF) and blood. These markers are characterized and further investigated with regard to their differential diagnostic and pathophysiological relevance. Finally, the aim is to implement these new biomarkers into clinical routine to improve (differential) diagnosis, convenience for patients and personalized medicine.

As a model, we first concentrated on the differential diagnosis of Creutzfeldt-Jakob disease. We now also apply these methods for the diagnosis of other neurodegenerative diseases such as Alzheimer’s disease, Parkinson´s disease and related diseases and especially frontotemporal dementia and amyotrophic lateral sclerosis (ALS) (European reference lab for the diagnosis of neurodegenerative diseases). More recently, we extended our focus to psychiatric diseases, e.g. major depressive disorder. Furthermore, we investigate multiple sclerosis patients (MS) towards the prediction of the disease course and the monitoring of disease severity and therapy efficacy based on neurochemical markers (Collaboration with AG Tumani).

A special focus of our research is put on brain-derived biomarkers indicative for neuro-axonal death such as the neuronal structure proteins neurofilament light (NfL) and phosphorylated neurofilament heavy chain (pNfH). Here, we work on the establishment of cut-off levels and investigate the potential of neurofilaments for prognosis and monitoring of different neurodegenerative diseases using highly sensitive detection methods. For the differential diagnosis of ALS we already routinely analyze NfL in serum and pNfH in CSF in our laboratories. For the diagnosis of narcolepsy our lab offers the measurement of orexin in CSF. More information can be found on the website of the CSF laboratory (https://www.uniklinik-ulm.de/neurologie/laboratorien/liquorlabor.html). We are involved in international round robin studies on neurofilament measurement (e.g. ALS Association) which are important for the implementation of neurofilaments into the diagnostic criteria of ALS.

We belong to national and international networks of specialized centers and are involved in the collection of biomaterials to build up large bio-depositories to enable research focused on the spectrum of neurodegenerative diseases which are often very rare.

Our group initiated the German Research Consortium of frontotemporal lobar degeneration to develop and evaluate parameters which help clinicians to diagnose FTLD at an early stage and follow its progression, with the overall aim to develop effective objective targets for therapeutic strategies (www.ftld.de). As this was successful, we have now started clinical trials in FTLD, investigating an active immunotherapy directed against pathologically modified tau protein that is the main constituent of pathological changes in nonfluent variant of PPA.

An important point for the implementation of fluid biomarkers into clinical routine is the standardization of sample collection, processing and storage. We are involved in several international networks with the aim to advance standardization in CSF analysis (BiomarkAPD, SOPHIA, CSF Society, KKNMS) and regularly provide workshops on basic knowledge to work with CSF.

In translational approaches we work on the elucidation of processes underlying neurodegenerative diseases or try to clarify the role that a newly identified or already established biomarker has. Widely used animal models, such as the SOD1G93A mouse, a model for ALS, as well as animals generated by our selves, such as the 14-3-3 gamma knockout mouse, are characterized within our group using a broad spectrum of techniques.

  • Mass spectrometry (Thermo QExactive Orbitrap, Sciex QTRAP6500)
  • Targeted proteomics (selected/multiple reaction monitoring, IP-MS)
  • Shotgun proteomics (label-free quantification, co-immunoprecipitation)
  • Single molecule array (Simoa) technology
  • ELISA, RIA
  • Nanoparticle tracking analysis (NanoSight)
  • Capillary electrophoresis (Beckmann PA800 Plus)
  • RT-QuIC technology
  • High throughput nanoscale CIEF immunoassay (PTM analysis)
  • Clinical proteomics (IPG-2D-PAGE, , iTRAQ)
  • 14-3-3 protein biology (deletion mutant mice)
  • Biacore binding studies
  • Neurochemical diagnosis of neurodegenerative disease (14-3-3, Tau-protein, Abeta-Peptides, S-100B, H-FABP, alpha synuclein)
  • Sample bank of CSF and Serum (Alzheimer´s disease, Parkinson´s disease, Frontotemporal dementias, Prion diseases, Amyotrophic lateral sclerosis)
Group members WG Neurochemistry and Neurodegeneration (AG Otto)
Profilbild von Univ. Prof. Dr. med. Markus Otto

Univ. Prof. Dr. med. Markus Otto

Leiter der Hochschulambulanz

apl. Prof. Dr. rer. nat. Petra Steinacker (Akademische Oberrätin)

Tel.:     +49 731-500 63112
Fax.:    +49 731-500 46111
Mail:   petra.steinacker@uni-ulm.de

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Patrick Oeckl, PhD (head proteomcis)

Tel.:     +49 731-500 63143
Fax.:    +49 731-500 46111
Mail:   patrick.oeckl@uni-ulm.de

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Dr. rer. nat. Steffen Halbgebauer

Tel.:     +49 731-500 63119
Fax.:    +49 731-500 46111
Mail:    steffen.halbgebauer@uni-ulm.de

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André Huss, PhD

Tel.:     +49 731-500 63143
Fax.:    +49 731-500 46111
Mail:    andre.huss@uni-ulm.de

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Dr. hum. biol. Sarah Anderl-Straub (neuropsychology)

Tel.:     +49 731-500 63099
Fax.:    +49 731-500 63009
Mail:    sarah.straub@uni-ulm.de

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Dr. med. Karin Graf (clinical studies)

Tel.:     +49 731-500 63099
Fax.:    +49 731-500 63009
Mail:    karin.graf@uni-ulm.de

MHD Rami Al Shweiki (MSc. Pharmaceutical Biotechnology)

Tel.:     +49 731-500 63143
Fax.:    +49 731-500 46111
Mail:   mhd.al-shweiki@uni-ulm.de

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Peggy Barschke (MSc. Biomedizin)

Tel.:     +49 731-500 63143
Fax.:    +49 731-500 46111
Mail:    peggy.barschke@uni-ulm.de

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Jolina Lombardi (MSc. Neuropsychology)

Tel.:     +49 731-500 63099
Fax.:    +49 731-500 63009
Mail:    jolina.lombardi@uni-ulm.de

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Stephen Meier

Tel.:     +49 731-500 63120
Fax.:    +49 731-500 46111
Mail:   stephen.meier@uni-ulm.de

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Dagmar Schattauer (biobank)

Tel.:     +49 731-177 5254
Fax.:    +49 731-177 1592
Mail:   neurobiobank@uni-ulm.de

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Sandra Hübsch (biobank)

Tel.:     +49 731-177 5254
Fax.:    +49 731-177 1592
Mail:    neurobiobank@uni-ulm.de

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Alice Beer (biobank)

Tel.:     +49 731-177 5254
Fax.:    +49 731-177 1592
Mail:    neurobiobank@uni-ulm.de

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Martina Hospes

Tel.:     +49 731-500 63010
Fax.:    +49 731-500 63002
Mail:    martina.hospes@uniklinik-ulm.de

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Funding selected

BMBF

Establishment of a German network for registration and diagnostic of frontotemporal lobar degeneration (www.ftld.de)

Searching for therapeutic interventions in frontotemporal dementia with C9ORF72 repeat expansions in the presymptomatic stage (Prefrontals)

Discovery, verification and validation of a biomarker profile for depression (Moodmarker)

EU

Fairpark-II - Conservative iron chelation as a disease-modifying strategy in Parkinson’s disease

MIRIADE (Multi-omics Interdisciplinary Research Integration to Address Dementia diagnosis)

Thierry Latran Foundation:

Detection of disease specific aggregates of TDP-43 in cerebrospinal fluid of ALS and FTD patients for disease specific diagnosis

ALS Association

Validation of Neurofilaments as diagnostic marker for ALS

Foundation of the state Baden Württemberg

Validation of Proteomic markers in patients with parkinsons dementia

Forschungsverbund BioCenter (BIU)

Neurochemical approaches for diagnosis and follow-up of patients with depression

 
Selected recent publications (last 5 years)
  • Verde, F., P. Steinacker, J. H. Weishaupt, J. Kassubek, P. Oeckl, S. Halbgebauer, H. Tumani, C. A. F. von Arnim, J. Dorst, E. Feneberg, B. Mayer, H. P. Muller, M. Gorges, A. Rosenbohm, A. E. Volk, V. Silani, A. C. Ludolph and M. Otto (2019). "Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis." J Neurol Neurosurg Psychiatry 90(2): 157-164.
  • van der Ende, E. L., L. H. Meeter, J. M. Poos, J. L. Panman, L. C. Jiskoot, E. G. P. Dopper, J. M. Papma, F. J. de Jong, I. M. W. Verberk, C. Teunissen, D. Rizopoulos, C. Heller, R. S. Convery, K. M. Moore, M. Bocchetta, M. Neason, D. M. Cash, B. Borroni, D. Galimberti, R. Sanchez-Valle, R. Laforce, Jr., F. Moreno, M. Synofzik, C. Graff, M. Masellis, M. Carmela Tartaglia, J. B. Rowe, R. Vandenberghe, E. Finger, F. Tagliavini, A. de Mendonca, I. Santana, C. Butler, S. Ducharme, A. Gerhard, A. Danek, J. Levin, M. Otto, G. B. Frisoni, S. Cappa, Y. A. L. Pijnenburg, J. D. Rohrer, J. C. van Swieten and I. Genetic Frontotemporal dementia (2019). "Serum neurofilament light chain in genetic frontotemporal dementia: a longitudinal, multicentre cohort study." Lancet Neurol 18(12): 1103-1111
  • Oeckl, P., P. Weydt, D. R. Thal, J. H. Weishaupt, A. C. Ludolph and M. Otto (2019). "Proteomics in cerebrospinal fluid and spinal cord suggests UCHL1, MAP2 and GPNMB as biomarkers and underpins importance of transcriptional pathways in amyotrophic lateral sclerosis." Acta Neuropathol. Online
  • Oeckl, P., S. Halbgebauer, S. Anderl-Straub, P. Steinacker, A. M. Huss, H. Neugebauer, C. A. F. von Arnim, J. Diehl-Schmid, T. Grimmer, J. Kornhuber, P. Lewczuk, A. Danek, G. Consortium for Frontotemporal Lobar Degeneration, A. C. Ludolph and M. Otto (2019). "Glial Fibrillary Acidic Protein in Serum is Increased in Alzheimer's Disease and Correlates with Cognitive Impairment." J Alzheimers Dis 67(2): 481-488.
  • Pollak, T. A., B. R. Lennox, S. Muller, M. E. Benros, H. Pruss, L. Tebartz van Elst, H. Klein, J. Steiner, T. Frodl, B. Bogerts, L. Tian, L. Groc, A. Hasan, B. T. Baune, D. Endres, E. Haroon, R. Yolken, F. Benedetti, A. Halaris, J. H. Meyer, H. Stassen, M. Leboyer, D. Fuchs, M. Otto, D. A. Brown, A. Vincent, S. Najjar and K. Bechter (2019). "Autoimmune psychosis: an international consensus on an approach to the diagnosis and management of psychosis of suspected autoimmune origin." Lancet Psychiatry. online
  • Feneberg, E., P. Oeckl, P. Steinacker, F. Verde, C. Barro, P. Van Damme, E. Gray, J. Grosskreutz, C. Jardel, J. Kuhle, S. Koerner, F. Lamari, M. D. M. Amador, B. Mayer, C. Morelli, P. Muckova, S. Petri, K. Poesen, J. Raaphorst, F. Salachas, V. Silani, B. Stubendorff, M. R. Turner, M. M. Verbeek, J. H. Weishaupt, P. Weydt, A. C. Ludolph and M. Otto (2018). "Multicenter evaluation of neurofilaments in early symptom onset amyotrophic lateral sclerosis." Neurology 90(1): e22-e30.
  • Guo, Q., H. Bin, J. Cheng, M. Seefelder, T. Engler, G. Pfeifer, P. Oeckl, M. Otto, F. Moser, M. Maurer, A. Pautsch, W. Baumeister, R. Fernandez-Busnadiego and S. Kochanek (2018). "The cryo-electron microscopy structure of huntingtin." Nature 555(7694): 117-120.
  • Huss, A., A. Abdelhak, S. Halbgebauer, B. Mayer, M. Senel, M. Otto and H. Tumani (2018). "Intrathecal immunoglobulin M production: A promising high-risk marker in clinically isolated syndrome patients." Ann Neurol 83(5): 1032-1036
  • Semler, E., S. Anderl-Straub, I. Uttner, J. Diehl-Schmid, A. Danek, B. Einsiedler, K. Fassbender, K. Fliessbach, H. J. Huppertz, H. Jahn, J. Kornhuber, B. Landwehrmeyer, M. Lauer, R. Muche, J. Prudlo, A. Schneider, M. L. Schroeter, A. C. Ludolph, M. Otto and F. consortium (2018). "A language-based sum score for the course and therapeutic intervention in primary progressive aphasia." Alzheimers Res Ther 10(1): 41.
  • Steinacker, P., S. Anderl-Straub, J. Diehl-Schmid, E. Semler, I. Uttner, C. A. F. von Arnim, H. Barthel, A. Danek, K. Fassbender, K. Fliessbach, H. Foerstl, T. Grimmer, H. J. Huppertz, H. Jahn, J. Kassubek, J. Kornhuber, B. Landwehrmeyer, M. Lauer, J. M. Maler, B. Mayer, P. Oeckl, J. Prudlo, A. Schneider, A. E. Volk, J. Wiltfang, M. L. Schroeter, A. C. Ludolph, M. Otto and F. T. s. group (2018). "Serum neurofilament light chain in behavioral variant frontotemporal dementia." Neurology 91(15): e1390-e1401.
  • Lehmer, C., P. Oeckl, J. H. Weishaupt, A. E. Volk, J. Diehl-Schmid, M. L. Schroeter, M. Lauer, J. Kornhuber, J. Levin, K. Fassbender, B. Landwehrmeyer, D. German Consortium for Frontotemporal Lobar, M. H. Schludi, T. Arzberger, E. Kremmer, A. Flatley, R. Feederle, P. Steinacker, P. Weydt, A. C. Ludolph, D. Edbauer and M. Otto (2017). "Poly-GP in cerebrospinal fluid links C9orf72-associated dipeptide repeat expression to the asymptomatic phase of ALS/FTD." EMBO Mol Med 9(7): 859-868.
  • Steinacker, P., E. Semler, S. Anderl-Straub, J. Diehl-Schmid, M. L. Schroeter, I. Uttner, H. Foerstl, B. Landwehrmeyer, C. A. von Arnim, J. Kassubek, P. Oeckl, H. J. Huppertz, K. Fassbender, K. Fliessbach, J. Prudlo, C. Rossmeier, J. Kornhuber, A. Schneider, A. E. Volk, M. Lauer, A. Danek, A. C. Ludolph, M. Otto and F. T. S. Group (2017). "Neurofilament as a blood marker for diagnosis and monitoring of primary progressive aphasias." Neurology 88(10): 961-969.
  • Weydt, P., P. Oeckl, A. Huss, K. Muller, A. E. Volk, J. Kuhle, A. Knehr, P. M. Andersen, J. Prudlo, P. Steinacker, J. H. Weishaupt, A. C. Ludolph and M. Otto (2016). "Neurofilament levels as biomarkers in asymptomatic and symptomatic familial amyotrophic lateral sclerosis." Ann Neurol 79(1): 152-158.
  • Oeckl, P., F. Metzger, M. Nagl, C. A. von Arnim, S. Halbgebauer, P. Steinacker, A. C. Ludolph and M. Otto (2016). "Alpha-, Beta-, and Gamma-synuclein Quantification in Cerebrospinal Fluid by Multiple Reaction Monitoring Reveals Increased Concentrations in Alzheimer's and Creutzfeldt-Jakob Disease but No Alteration in Synucleinopathies." Mol Cell Proteomics 15(10): 3126-3138.
  • Halbgebauer, S., M. Nagl, H. Klafki, U. Haussmann, P. Steinacker, P. Oeckl, J. Kassubek, E. Pinkhardt, A. C. Ludolph, H. Soininen, S. K. Herukka, J. Wiltfang and M. Otto (2016). "Modified serpinA1 as risk marker for Parkinson's disease dementia: Analysis of baseline data." Sci Rep 6: 26145.