Diffusion tensor imaging (DTI) reveals microstructural features of grey and white matter non-invasively. The contrast produced by DTI, however, is not fully understood and requires further validation. We used serial block-face scanning electron microscopy (SBEM) to acquire tissue metrics, i.e., anisotropy and orientation, using three-dimensional Fourier transform-based (3D-FT) analysis, to correlate with fractional anisotropy and orientation in DTI. SBEM produces high-resolution 3D data at the mesoscopic scale with good contrast of cellular membranes. We analysed selected samples from cingulum, corpus callosum, and perilesional cortex of sham-operated and traumatic brain injury (TBI) rats. Principal orientations produced by DTI and 3D-FT in all samples were in good agreement. Anisotropy values showed similar patterns of change in corresponding DTI and 3D-FT parameters in sham-operated and TBI rats. While DTI and 3D-FT anisotropy values were similar in grey matter, 3D-FT anisotropy values were consistently lower than fractional anisotropy values from DTI in white matter. We also evaluated the effect of resolution in 3D-FT analysis. Despite small angular differences in grey matter samples, lower resolution datasets provided reliable results, allowing for analysis of larger fields of view. Overall, 3D SBEM allows for more sophisticated validation studies of diffusion imaging contrast from a tissue microstructural perspective.
Preclinical imaging studies of posttraumatic epileptogenesis (PTE) have largely been proof-ofconcept studies with limited animal numbers, and thus lack the statistical power for biomarker discovery. Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) is a pioneering multicenter trial investigating preclinical imaging biomarkers of PTE. EpiBios4Rx faced the issue of harmonizing the magnetic resonance imaging (MRI) procedures and imaging data metrics prior to its execution. We present here the harmonization process between three preclinical MRI facilities at the University of Eastern Finland (UEF), the University of Melbourne (Melbourne), and the University of California, Los Angeles (UCLA), and evaluate the uniformity of the obtained MRI data. Adult, male rats underwent a lateral fluid percussion injury (FPI) and were followed by MRI 2 days, 9 days, 1 month, and 5 months post-injury. Ex vivo scans of fixed brains were conducted 7 ☆ This article is part of a Virtual Special Issue 'Discovery of diagnostic biomarkers for post-traumatic epileptogenesis-an interim analysis of procedures in a preclinical multicenter trial EpiBios4Rx'.
The primary lesion arising from the initial insult after traumatic brain injury (TBI) triggers a cascade of secondary tissue damage, which may also progress to connected brain areas in the chronic phase. The aim of this study was, therefore, to investigate variations in the susceptibility distribution related to these secondary tissue changes in a rat model after severe lateral fluid percussion injury. We compared quantitative susceptibility mapping (QSM) and R 2 * measurements with histological analyses in white and grey matter areas outside the primary lesion but connected to the lesion site. We demonstrate that susceptibility variations in white and grey matter areas could be attributed to reduction in myelin, accumulation of iron and calcium, and gliosis. QSM showed quantitative changes attributed to secondary damage in areas located rostral to the lesion site that appeared normal in R 2 * maps. However, combination of QSM and R 2 * was informative in disentangling the underlying tissue changes such as iron accumulation, demyelination, or calcifications. Therefore, combining QSM with R 2 * measurement can provide a more detailed assessment of tissue changes and may pave the way for improved diagnosis of TBI, and several other complex neurodegenerative diseases.
Posttraumatic epilepsy (PTE) is a major neurodegenerative disease accounting for 20% of symptomatic epilepsy cases. A long latent phase offers a potential window for prophylactic treatment strategies to prevent epilepsy onset, provided that the patients at risk can be identified. Some promising imaging biomarker candidates for posttraumatic epileptogenesis have been identified, but more are required to provide the specificity and sensitivity for accurate prediction. Experimental models and preclinical longitudinal, multimodal imaging studies allow follow-up of complex cascade of events initiated by traumatic brain injury, as well as monitoring of treatment effects. Preclinical imaging data from the posttraumatic brain are rich in information, yet examination of their specific relevance to epilepsy is lacking. Accumulating evidence from ongoing preclinical studies in TBI support insight into processes involved in epileptogenesis, e.g. inflammation and changes in functional and structural brain-wide connectivity. These efforts are likely to produce both new biomarkers and treatment targets for PTE.
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