Developing a neuroimaging-centered biomarker of Amyotrophic Lateral Sclerosis (ALS) disease progression: a multimodal and subtype-tailored approach.

• Applicants: Professor Dr. Julian Großkreutz; Privatdozent Dr. Robert Steinbach
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 583362031

Amyotrophic laterals sclerosis (ALS) is a relentlessly progressive neurodegenerative disease that is characterized by inter-individually vastly differing disease progression speed that obstructs trials and development of effective disease-modifying therapies. Therefore, this project proposes a program to develop neuroimaging-centered and subtype-specific compound biomarkers that serve as surrogates of distinct aspects of ALS disease progression. Structural Magnetic Resonance Imaging (MRI) possesses the advantage of anatomical allocation of the neurodegenerative processes and thus the important potential to serve as a disease-specific progression biomarker. In the first proposed work package preliminary results of structural MRI studies mirroring the unique disease progression aspects of i) accumulation and ii) aggressiveness shall be validated in an existing independent cohort with high-resolution structural 3 Tesla MRI. The primary goal is to develop multimodal neuroimaging biomarkers that serve as surrogates of the aforementioned clinical disease progression parameters. These disease metrics are quantified via the D50 progression model that already proofed to serve as a reliable framework to analyze heterogenous cross-sectional data of patients with ALS. In a second work-package subtype-specific progression of ALS functional decline, primarily stratified by the first region of symptom onset, will be studied. For this purpose, encompassing clinical follow-up data of two large monocentric cohorts will be analyzed with data scientific approaches. As a result, subtype-specific disease progression models shall be developed and further validated in independent multicenter datasets. In the concluding work-package the neuroimaging biomarkers developed before will be combined with signals from other sources such as blood or electrophysiological measurements in order to create compound biomarkers that will be further validated concerning their subtype-specific applicability. Ideally, there will be compound biomarkers reflecting disease accumulation that would thus represent internationally applicable and objective in-vivo markers of disease-state. Such metrics are urgently needed as they would enable patient stratification, e.g. for the usage in multi-arm/ multi-stage platform trials. In addition, disease aggressiveness biomarkers would be ideal to serve as early surrogates of treatment response for newly tested therapeutic agents and are thus currently urgently needed in the advent of precision therapy for ALS.

• DFG Programme: Research Grants