Louise van der Weerd, Marjolein Bulk
Post-mortem brain imaging helps us to interpreting findings from conventional (ante mortem) MRI and enables us to directly compare and correlate MRI parameters to histo(patho)logical substrates. Correlative post-mortem studies have an important bridging function: they have the ultimate potential to translate the pathological process to the clinical diagnosis using MRI, thereby integrating findings from bench to bedside.
Within our research group we developed MRI protocols for post-mortem imaging and histopathology of brain tissue. Optimized protocols exist for scanning entire brains, intact hemispheres and single brainslabs at the 7T Philips scanner. To acquire ultra-high resolution 7T MRI scans, small tissueblocks are scanned at a pre-clinal 7T MRI (Bruker Pharmascan). In order to determine the underlying neuropathological substrate of the imaging findings on MRI, post-mortem MRI and neuropathological findings are correlated using established image registration and processing pipelines.
- Determine the histopathological correlates of 7T MRI contrasts;
- Correlate MRI and histopathological findings with clinical phenotypes and outcomes;
- Validate iron accumulation as an imaging biomarker for disease progression in neurodegenerative diseases.
Iron accumulation in neurodegenerative diseases
7T MRI provides unique image contrast compared to conventional 3T MRI, particularly for susceptibility-weighted contrast (T2*, SWI, or QSM). Therefore, post-mortem brain imaging is used to investigate the role of iron and myelin on MRI contrast.
Post-mortem MRI followed by histopathology is used to differentiate between sub-types of AD. By correlating the clinical phenotype with the neuropathological and radiological patterns results from this study may lead to a better insight in pathological processes and new diagnostic and therapeutic strategies. Recently, we showed that the MRI contrast changes observed in Alzheimer’s disease are best explained by increased iron accumulation and changes in cortical myelin, whereas amyloid and tau showed less spatial correspondence with T2*-weighted MRI. Neuropathologically, subtypes of Alzheimer’s disease showed different patterns of iron accumulation and cortical myelin changes independent of amyloid and tau that may be detected by high-field susceptibility-based MRI. Moreover, as changes in iron are shown to be correlated with the severity of Alzheimer’s disease, post-mortem MRI will help the interpretation of high resolution in vivo MRI and suggest the potential of using changes in iron-based MRI contrast to indirectly determine the degree of AD pathology in patients.
Using susceptibility-weighted MRI, several groups including our Huntington’s disease research group at LUMC reported an increase of iron signal in the striatum of Huntington patients. Although these studies did show the use of iron-sensitive MRI scans to detect iron accumulation in patients and its potential as a biomarker for disease progression, the underlying pathological substrates have never been investigated. Findings from this study will contribute to the interpretation of in vivo imaging studies on the association between iron dysregulation, neuroinflammation and clinical outcome.
Well-characterized, high-quality brain tissue of patients with neurodegenerative diseases and of non-neurological control subjects is a prerequisite to study the brain, and are extremely important for the study of neurological disorders. We collaborate with the Netherlands Brain Bank (NBB) and The Normal Aging Brain Collection Amsterdam (NABCA) to provide a comprehensive collection of post-mortem (ultra-)high-field MRI (3Tesla and 7Tesla) and neuropathological datasets of patients and non-neurological controls. By providing MRI within the pipeline, these brain banks uniquely stimulate translational neurosciences; from molecular and morphometric tissue studies to the clinical setting. Post-mortem 7T MRI of hemispheres included in these collections are scanned at the Gorter Center for High Field MRI. Tissues and MRI scans are made available to researchers around the world. (websites: https://www.brainbank.nl/ and http://nabca.eu/)
Figure 1. Existing protocol for post-mortem imaging and histopathology of brain tissue. In Alzheimer’s Disease susceptibility-weighted MRI scans show a high correlation with cortical iron deposits in AD.
Louise van der Weerd, PhD
C.J. Gorter Center for High Field MRI
Department of Radiology - C3Q
Leiden University Medical Center
2333 ZA Leiden
Phone: +31 71 526 64760