Tobias Granberg

Background: Amyotrophic lateral sclerosis (ALS) is a fatal disorder with heterogeneous clinical expression. While overt morphological findings are often preceded by hypometabolism in ALS, FDG-PET is sparsely used in routine clinical practice due to costs and a somewhat uncertain diagnostic/predictive value. Meanwhile, GlucoCEST MRI is a novel radiation-free method for imaging metabolism that has yet to be applied in ALS.Aim: To evaluate the feasibility and accuracy of GlucoCEST MRI for assessing brain metabolism in ALS and study its diagnostic and predictive value.Methods: A prospective study with 120 persons with ALS and 60 matched controls will be conducted at Karolinska University Hospital using a second-generation clinical 7 Tesla MRI scanner. GlucoCEST will be processed and analyzed using advanced post-processing techniques and compared to the gold-standard, FDG-PET imaging, in patients. Patients will be longitudinally followed comprehensively over up to 4 years.Significance: GlucoCEST can integrate metabolic and structural information from a single scan to detect early neurodegeneration at a lower cost and with less patient risk and -burden than FDG-PET. As a radiation-free technique, the method is especially suitable for precision medicine approaches since it can track disease progression over time to advance our understanding of neurodegenerative disease processes and monitor the efficacy of emerging disease-modifying treatments in clinical trials.

This translational project explores mechanisms and pathophysiology, prevention and outcomes related to long-term neurocognitive decline and risk for dementia after major surgery. The ultimate goal is to provide novel prognostic and therapeutic strategies and patient-centered guidelines for safer perioperative care. We hypothesize that adverse immune response signatures to surgical trauma with impaired periphery-to-brain communication leads to unresolved systemic and neuroinflammation with risk for neurocognitive decline and dementia. Using comprehensive clinical and experimental platforms in man, animals and cells, we will in standardized surgical cohorts in Part A define a longitudinal in-depth immunological, transcriptional, and soluble atlas with a periphery-to-brain axis coupled to hard adverse brain outcomes related to neuroinflammation, neurodegeneration and risk for dementia. Key findings from this effort will in Part B be mechanistically explored in established animal models and in vitro systems to provide in-depth knowledge on targets for prognostic and possibly therapeutic strategies. Information from preclinical and clinical investigations (Part A-B) on precision-based immune signatures will be prospectively validated in broader surgical populations to search at-risk patients (part C). This knowledge will ultimately serve as base for novel perioperative guidelines and therapeutic strategies to prevent neurocognitive decline or dementia after surgery.

Dementia with Lewy bodies (DLB) is the second most common form of neurodegenerative dementia, but it is considerably under-diagnosed. The main reasons for this are the lack of a reliable biomarker for Lewy pathology, and that many DLB patients also have Alzheimer and cerebrovascular pathologies in their brains. ´Find-DLB’ is a leading international platform to tackle these problems.The purpose of ‘Find-DLB’ is to intensify DLB research in Sweden, with a strong focus on novel biomarkers and translation to precision medicine. ‘Find-DLB’ spans from 2023 to 2027, including (1) testing of a novel biomarker of Lewy pathology for immediate clinical use in hospitals across Sweden

(2) development of new imaging biomarkers to disentangle mixed pathologies and (3) elucidate what causes brain degeneration in DLB

(4) development of precision medicine risk profiles and diagnostic tools, with a strong focus on sex differences. ‘Find-DLB’ will create a prospective Swedish cohort and use unique large international data, including around 6000 participants, the largest platform of this kind.‘Find-DLB’ strives to transform the way we diagnose DLB today. It will improve management and care of our DLB patients, and will increase social awareness about the disease. Project’s findings will set the ground for precision medicine-based therapies. ‘Find-DLB’ is an unprecedented multicohort platform including collaborations among multiple centers across the world.