Molecular Biomarkers for the Predictive Diagnosis of Neurodegenerative Diseases
Research Group of Prof. Dr. Jens Wiltfang
For the treatment of neurodegenerative dementia, currently only symptomatic treatment approaches are available. However, there is an urgent need for preventive treatment approaches that can forestall the threat of dementia, or at least delay the onset by several years.
The prerequisite for this is to identify high-risk patients in pre-clinical stages, with sufficiently high diagnostic certainty, in order to intervene in a timely and targeted manner. For this predictive dementia diagnosis, so-called biomarkers are required that can already indicate the dementia process in the subclinical stage (surrogate markers).
By far the most common neurodegenerative dementia is Alzheimer's disease dementia (D-AD), which alone or as a mixed dementia accounts for at least half of all dementias. More than 70 different dementias are known, some of which - like dementia in Creutzfeldt-Jakob disease - are very rare (Wiltfang et al., 2016).
Biomarker-based predictive dementia diagnostics for the identification of threat of progression to Alzheimer's dementia has now been established internationally and has already found its way into both national and international guideline recommendations. These include the S3 dementia guidelines of the two national neuropsychiatric professional associations (DGN, DGPPN), of which our research group was involved in creating (https://www.awmf.org/uploads/tx_szleitlinien/038-013l_S3-Demenzen-2016-07.pdf).
These established molecular biomarkers, i.e. dementia biomarkers in the lumbar cerebrospinal fluid (Abeta peptides, Tau proteins, light chain neurofilament) or imaging methods such as amyloid positron emission tomography (amyloid PET), are able to reliably predict the threat of D-AD as early as 15 years before patients enter the clinical stage of dementia.
Unfortunately, these procedures are either comparatively invasive (lumbar CSF puncture) or very expensive (amyloid PET) and are therefore not suitable for high-throughput identification of large groups of high-risk patients, for example in clinical private practice.
Overall objectives
The current focus of our research group is to develop minimally invasive, comparatively inexpensive and high-throughput diagnostic procedures to identify patients at high risk of impending D-AD in preclinical or prodromal stages, such as subjective cognitive deficit (SCD) or mild cognitive impairment (MCI) (Kornhuber et al., 2009).
This will enable the systematic search for promising pharmacological, but also non-pharmacological (electrophysiological neurostimulation methods, age-appropriate physical activity, diet and food supplements), preventive treatment approaches in large patient cohorts.
In this context, our research group is establishing innovative approaches for blood-based early diagnosis of Alzheimer's dementia using molecular imaging techniques (antibody-based biosensor with Fourier-transformed near-infrared spectroscopy) and attomolar-sensitive immunoassays (Nabers et al., 2019, 2016a, 2016b; Shahpasand-Kroner et al., 2018; Vogelgsang et al., 2018a, 2018b).
The latter work is based on the detection of relative concentration changes (peptide quotients) or changes in the secondary structure of so-called beta-amyloid peptides in the blood plasma of patients. However, other proteomic blood biomarkers, such as the neurofilament light chains or the astroglial biomarker GFAP (Consortium for Frontotemporal Lobar Degeneration German et al., 2019), are also relevant, especially in a longitudinal view.
Selection of current projects
- Epigenetic and micro-RNA biomarkers as early diagnostic markers for Alzheimer type dementia
Based on promising results in cerebrospinal fluid (Jain et al., 2019), our research group in close cooperation with the research groups of Prof. Fischer and Prof. Klengel also investigates the importance of epigenetic biomarkers in blood as surrogate markers for the early diagnosis of D-AD. - Biomaterial Bank
High-quality biomaterial banks are essential for the successful identification and validation of promising candidate biomarkers. In the meantime, our department has been able to establish its own CSF-supported biomaterial bank, which meets international state-of-the-art standards regarding quality and bioethical criteria. As a member of the German Center for Neurodegenerative Diseases, Göttingen (collaboration with DZNE Göttingen), we have additional access to the multicenter biomaterial banks of the DZNE, e.g. to the DELCODE cohort. Within DELCODE, one of the largest patient collectives with preclinical D-AD was recruited (Jessen et al., 2018). At the same time, there is a close cooperation with the biomarker research groups of the neurological clinic of the UMG and the newly established department of geriatrics at the UMG. - Molecular predictive markers for schizophrenic psychoses
A future focus of our research group includes the identification of molecular surrogate markers (proteomic and epigenetic biomarkers) in CSF and blood that predict an unfavorable course of preclinical schizophrenic psychosis, i.e. identify patients who develop early and pronounced so-called negative symptoms. Early detection is particularly important for preventative intervention by means of combined pharmacological and non-pharmacological approaches in order to counteract early chronification. In this area of research, we are in close cooperation with the psychiatric clinic of the Ludwig Maximilians University (LMU) in Munich.
References
- Consortium for Frontotemporal Lobar Degeneration German, Oeckl, P., Halbgebauer, S., Anderl-Straub, S., Steinacker, P., Huss, A.M., Neugebauer, H., von Arnim, C.A.F., Diehl-Schmid, J., Grimmer, T., Kornhuber, J., Lewczuk, P., Danek, A., Ludolph, A.C., Otto, M., 2019. Glial Fibrillary Acidic Protein in Serum is Increased in Alzheimer’s Disease and Correlates with Cognitive Impairment. J. Alzheimers Dis. 67, 481–488. https://doi.org/10.3233/JAD-180325
- Jain, G., Stuendl, A., Rao, P., Berulava, T., Pena Centeno, T., Kaurani, L., Burkhardt, S., Delalle, I., Kornhuber, J., Hüll, M., Maier, W., Peters, O., Esselmann, H., Schulte, C., Deuschle, C., Synofzik, M., Wiltfang, J., Mollenhauer, B., Maetzler, W., Schneider, A., Fischer, A., 2019. A combined miRNA-piRNA signature to detect Alzheimer’s disease. Transl. Psychiatry 9, 250. https://doi.org/10.1038/s41398-019-0579-2
- Jessen, F., Spottke, A., Boecker, H., Brosseron, F., Buerger, K., Catak, C., Fliessbach, K., Franke, C., Fuentes, M., Heneka, M.T., Janowitz, D., Kilimann, I., Laske, C., Menne, F., Nestor, P., Peters, O., Priller, J., Pross, V., Ramirez, A., Schneider, A., Speck, O., Spruth, E.J., Teipel, S., Vukovich, R., Westerteicher, C., Wiltfang, J., Wolfsgruber, S., Wagner, M., Düzel, E., 2018. Design and first baseline data of the DZNE multicenter observational study on predementia Alzheimer’s disease (DELCODE). Alzheimers Res. Ther. 10. https://doi.org/10.1186/s13195-017-0314-2
- Kornhuber, J., Schmidtke, K., Frölich, L., Perneczky, R., Wolf, S., Hampel, H., Jessen, F., Heuser, I., Peters, O., Weih, M., Jahn, H., Luckhaus, C., Hüll, M., Gertz, H.-J., Schröder, J., Pantel, J., Rienhoff, O., Seuchter, S.A., Rüther, E., Henn, F., Maier, W., Wiltfang, J., 2009. Early and Differential Diagnosis of Dementia and Mild Cognitive Impairment. Dement. Geriatr. Cogn. Disord. 27, 404–417. https://doi.org/10.1159/000210388
- Nabers, A., Hafermann, H., Wiltfang, J., Gerwert, K., 2019. Aβ and tau structure-based biomarkers for a blood- and CSF-based two-step recruitment strategy to identify patients with dementia due to Alzheimer’s disease. Alzheimers Dement. Diagn. Assess. Dis. Monit. 11, 257–263. https://doi.org/10.1016/j.dadm.2019.01.008
- Nabers, A., Ollesch, J., Schartner, J., Kötting, C., Genius, J., Hafermann, H., Klafki, H., Gerwert, K., Wiltfang, J., 2016a. Amyloid-β-Secondary Structure Distribution in Cerebrospinal Fluid and Blood Measured by an Immuno-Infrared-Sensor: A Biomarker Candidate for Alzheimer’s Disease. Anal. Chem. 88, 2755–2762. https://doi.org/10.1021/acs.analchem.5b04286
- Nabers, A., Ollesch, J., Schartner, J., Kötting, C., Genius, J., Haußmann, U., Klafki, H., Wiltfang, J., Gerwert, K., 2016b. An infrared sensor analysing label-free the secondary structure of the Abeta peptide in presence of complex fluids. J. Biophotonics 9, 224–234. https://doi.org/10.1002/jbio.201400145
- Shahpasand-Kroner, H., Klafki, H.-W., Bauer, C., Schuchhardt, J., Hüttenrauch, M., Stazi, M., Bouter, C., Wirths, O., Vogelgsang, J., Wiltfang, J., 2018. A two-step immunoassay for the simultaneous assessment of Aβ38, Aβ40 and Aβ42 in human blood plasma supports the Aβ42/Aβ40 ratio as a promising biomarker candidate of Alzheimer’s disease. Alzheimers Res. Ther. 10. https://doi.org/10.1186/s13195-018-0448-x
- Vogelgsang, J., Shahpasand-Kroner, H., Vogelgsang, R., Streit, F., Vukovich, R., Wiltfang, J., 2018a. Multiplex immunoassay measurement of amyloid-β42 to amyloid-β40 ratio in plasma discriminates between dementia due to Alzheimer’s disease and dementia not due to Alzheimer’s disease. Exp. Brain Res. 236, 1241–1250. https://doi.org/10.1007/s00221-018-5210-x
- Vogelgsang, J., Wiltfang, J., Klafki, H.W., 2018b. Validation of a Chemiluminescence Immunoassay for Measuring Amyloid-β in Human Blood Plasma. Methods Mol. Biol. Clifton NJ 1750, 111–124. https://doi.org/10.1007/978-1-4939-7704-8_7
- Wiltfang, J., Trost, S., Hampel, H.-J., 2016. Demenz, in: Möller, H.-J., Laux, G., Kapfhammer, H.-P. (Eds.), Psychiatrie, Psychosomatik, Psychotherapie. Springer Berlin Heidelberg, Berlin, Heidelberg, pp. 1–89. https://doi.org/10.1007/978-3-642-45028-0_59-1
Ph.D. students
- Leandra Baumbach
- Miriam Berens
- Katja Gull
- Julia Hasenkamp
- Viktoria Kluge
- Judith Leweke
- Max Ludwig
- Nicole Marek
- Lara Rohdenburg
- Sophie Schaper
- Kristina Schwan
- Marlena Walter
- Konrad Waschkies
- Tamara Wild
- Anna Wunderlich
Contact
Research group leader
Prof. Dr. Jens Wiltfang
Tel.: +49 551 3960601
Fax.: +49 551 3960604
psychiatrie.sekretariat(at)med.uni-goettingen.de