Amyotrophic lateral sclerosis (ALS) and half of cases of frontotemporal lobe degeneration (FTLD) belong to the TDP-43 proteinopathies. It is now well established that ALS is a multisystemic disease that affects not only the motor system but also prefrontal and temporal cortical networks that are associated with specific behavioral and cognitive functions.

The Rostock research group "Cognition in ALS" has set itself the goal of improving the understanding of ALS as a systemic disease of the brain beyond the motor system and providing biomarkers as a model with which hypotheses on the disease pathogenesis can be tested in vivo. The key question for our research is why most ALS patients are not cognitively impaired (55%), many are cognitively impaired (35%), and some are demented (FTD, 5-10%). Understanding risk or resilience mechanisms in the extramotor cortical networks in ALS patients would help identify treatment options for dementia. Our main activities therefore concern clinical characterization, neuropsychology, neuroimaging, genetics and autopsy studies focusing on the relationship between structural and functional changes. Thus, we correlated a significant association of pathological TDP-43 expression in extramotor regions with the degree of cognitive decline (Prudlo 2016).

Our key long-term goals as a result of follow-up visits every three to six months are:

     1. Evaluation of the cognitive and behavioral status of ALS patients
     2. The evaluation of the longitudinal data as part of our ongoing imaging study (to determine the dynamic changes in structural and functional connectivity)
     3. The correlation of the imaging data with the cognitive status of the ALS patients
     4. Participation in the development of a neuropathological molecular research program with autopsy material from ALS patients with and without FTD (in cooperation with Prof. Manuela Neumann, DZNE Tübingen)
     5. The identification of known mutations, unclassified variants and potentially new ALS-causing genes (it is crucial to validate these unclassified variants in known genes and potentially new genes using functional assays. We do this e.g. in     collaboration with Prof. A. Hermann, Rostock, or Prof. Dieter Edbauer, DZNE Munich)
     6. Collecting skin fibroblasts from patients with defined genetic variations to screen in vitro phenotypes associated with ALS and FTD (in collaboration with Andreas Hermann, albrecht-kossel-institut.med.uni-rostock.de )

Future research projects will address three main topics:

1.) Language in ALS

In collaboration with the German Research Center for Artificial Intelligence (DFKI; Dr. Alexandersson and colleagues) in Saarbrücken, we started to analyze the language abilities of 160 non-demented ALS patients compared to 80 healthy controls using a computer-aided speech recognition program. The aim of this study is to confirm and characterize the prevalence of language impairments.

2.) 18F-FDG-PET and cognition in ALS

We are conducting a study to correlate the signature of glucose metabolism (using 18F-2-fluoro-2-deoxy-D-glucose PET) with various cognitive states in ALS patients. This investigation is carried out in cooperation with the Clinic for Nuclear Medicine of the University Medical Center Rostock (Prof. Bernd Joachim Krause and colleagues). Our goal is to compare and contrast the FDG-PET as an in vivo measurement with structural MRI and autopsy data.

3.) BrainBank activities in Rostock

We have one of the largest brain autopsy programs in northern Germany with the aim of a molecular research program aimed at correlating clinical and molecular pathological findings. All autopsies were carried out by the Institute for Forensic Medicine at the Rostock University Medical Center (Prof. Büttner and colleagues) in close cooperation with Prof. Manuela Neumann from the DZNE in Tübingen.

Schlüsselpublikationen

Temp AGM, Dyrba M, Büttner C, Kasper E, Machts J, Kaufmann J, Vielhaber S, Teipel S, Prudlo J Cognitive Profiles of Amyotrophic Lateral Sclerosis Differ in Resting-State Functional Connectivity: An fMRI Study. Front Neurosci. 2021 Jun 23;15:682100. doi: 10.3389/fnins.2021.682100. eCollection 2021.

Temp AGM, Prudlo J, Vielhaber S, Machts J, Hermann A, Teipel SJ, Kasper E. Cognitive reserve and regional brain volume in amyotrophic lateral sclerosis.´Cortex. 2021 Jun;139:240-248.

Prudlo J, König J, Schuster C, Kasper E, Buettner A, Teipel S, Neumann M. TDP-43 pathology and cognition in ALS: A prospective clinicopathologic correlation study. Neurology. 2016; 87(10):1019-23. doi: 10.1212/WNL.0000000000003062

Dorst J, Schuster J, Dreyhaupt J, Witzel S, Weishaupt JH, Kassubek J, Weiland U, Petri S, Meyer T, Grehl T, Hermann A, Jordan B, Grosskreutz J, Zeller D, Boentert M, Schrank B, Prudlo J, Winkler AS, Gorbulev S, Roselli F, Dupuis L, Otto M, Ludolph AC. Effect of high-caloric nutrition on serum neurofilament light chain levels in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2020 Sep;91(9):1007-1009

Barschke P, Oeckl P, Steinacker P, Al Shweiki MR, Weishaupt JH, Landwehrmeyer GB, Anderl-Straub S, Weydt P, Diehl-Schmid J, Danek A, Kornhuber J, Schroeter ML, Prudlo J, Jahn H, Fassbender K, Lauer M, van der Ende EL, van Swieten JC, Volk AE, Ludolph AC, Otto M; German FTLD consortium. Different CSF protein profiles in amyotrophic lateral sclerosis and frontotemporal dementia with C9orf72 hexanucleotide repeat expansion. J Neurol Neurosurg Psychiatry. 2020 May;91(5):503-511.

Diehl-Schmid J, Licata A, Goldhardt O, Förstl H, Yakushew I, Otto M, Anderl-Straub S, Beer A, Ludolph AC, Landwehrmeyer GB, Levin J, Danek A, Fliessbach K, Spottke A, Fassbender K, Lyros E, Prudlo J, Krause BJ, Volk A, Edbauer D, Schroeter ML, Drzezga A, Kornhuber J, Lauer M; FTLDc Study Group, Grimmer T. FDG-PET underscores the key role of the thalamus in frontotemporal lobar degeneration caused by C9ORF72 mutations. Transl Psychiatry. 2019 Jan 31;9(1):54.

Albrecht F, Mueller K, Ballarini T, Lampe L, Diehl-Schmid J, Fassbender K, Fliessbach K, Jahn H, Jech R, Kassubek J, Kornhuber J, Landwehrmeyer B, Lauer M, Ludolph AC, Lyros E, Prudlo J, Schneider A, Synofzik M, Wiltfang J, Danek A, Otto M; FTLD-Consortium, Schroeter ML. Unraveling corticobasal syndrome and alien limb syndrome with structural brain imaging. Cortex. 2019 Aug;117:33-40.

Ludolph AC, Dorst J, Dreyhaupt J, Weishaupt JH, Kassubek J, Weiland U, Meyer T, Petri S, Hermann A, Emmer A, Grosskreutz J, Grehl T, Zeller D, Boentert M, Schrank B, Prudlo J, Winkler AS, Gorbulev S, Roselli F, Schuster J, Dupuis L; LIPCAL-ALS Study Group. Effect of High-Caloric Nutrition on Survival in Amyotrophic Lateral Sclerosis. Ann Neurol. 2020 Feb;87(2):206-216.

Ludolph AC, Schuster J, Dorst J, Dupuis L, Dreyhaupt J, Weishaupt JH, Kassubek J, Weiland U, Petri S, Meyer T, Grosskreutz J, Schrank B, Boentert M, Emmer A, Hermann A, Zeller D, Prudlo J, Winkler AS, Grehl T, Heneka MT, Wollebæk Johannesen S, Göricke B; RAS-ALS Study Group. Safety and efficacy of rasagiline as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomised, double-blind, parallel-group, placebo-controlled, phase 2 trial. Lancet Neurol. 2018 Aug;17(8):681-688. doi: 10.1016/S1474-4422(18)30176-5

Steinacker P, Anderl-Straub S, Diehl-Schmid J, Semler E, Uttner I, von Arnim CAF, Barthel H, Danek A, Fassbender K, Fliessbach K, Foerstl H, Grimmer T, Huppertz HJ, Jahn H, Kassubek J, Kornhuber J, Landwehrmeyer B, Lauer M, Maler JM, Mayer B, Oeckl P, Prudlo J, Schneider A, Volk AE, Wiltfang J, Schroeter ML, Ludolph AC, Otto M; FTLDc study group. Serum neurofilament light chain in behavioral variant frontotemporal dementia. Neurology. 2018 Oct 9;91(15):e1390-e1401.