Long-term MRI alterations and spatial navigation deficits in anti-NMDA receptor encephalitis

• Applicant: Professor Dr. Carsten Finke
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 431553520

Anti-NMDA receptor (NMDAR) encephalitis is a severe, potentially lethal autoimmune encephalitis that was discovered only a decade ago. The typically young patients present with psychosis, hallucinations, movement disorders, seizures and cognitive impairment. Despite this severe disease course, clinical routine MRI remains mostly unremarkable. Given this clinico-radiological paradox, routine MRI can provide only limited diagnostic and prognostic value and cannot elucidate the pathophysiological mechanisms of the disease. Using advanced MRI analyses, we have previously identified characteristic structural and functional imaging correlates of NMDAR encephalitis. However, longitudinal advanced imaging studies are still missing, the microstructural changes underlying tissue damage remain elusive and routine MRI biomarkers are not available. In addition, current cognitive assessments lack ecological validity and suitable parallel versions for reliable longitudinal testing.Work package (WP) 1 of this proposal will therefore investigate the longitudinal development of structural brain damage and functional connectivity alterations in NMDAR encephalitis. Trajectories of grey and white matter damage, reversibility of whole brain volumes loss and dynamics of functional network changes will be assessed. Predictors of these imaging changes will be identified and the impact of imaging alterations on long-term clinical and cognitive outcome will be evaluated. WP2 will apply three novel structural MRI analyses, i.e. myelin imaging, multi-parameter mapping (in-vivo histology MRI) and fractal analysis. These analyses will identify microstructural changes (e.g., demyelination, iron content) and spatial patterns of structural damage, establish novel sensitive imaging biomarkers and provide proof-of-concept for future multi-center quantitative MRI studies. WP3 will assess spatial navigation using four complementary virtual reality (VR) paradigms and will evaluate their potential as sensitive and ecologically valid measures of hippocampal dysfunction. VR paradigms will test different navigation subfunctions, provide a wide range of outcome measures and facilitate comparison with existing data sets. In addition, a VR/active motion paradigm will allow for a direct comparison with real-world navigation performance.The results of the proposed project will inform and update current pathophysiological concepts of NMDAR encephalitis and will have a direct impact on patient management, e.g. by the prevention of risk factors for structural damage. The findings will furthermore help to reduce the clinico-radiological paradox, characterize pathophysiological mechanisms of tissue damage and facilitate the development of sensitive imaging biomarkers. Finally, the project will yield a detailed characterization of navigation deficits and establish a basis for a sensitive and longitudinally implementable assessment of hippocampal dysfunction in NMDAR encephalitis.

• DFG Programme: Research Grants