Quantitative imaging of astrogliosis and neuroinflammation

National Institute On Aging

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Abstract

As indicated in the Goals and Objectives section, the main goals of this research initiative are to discover diagnostic imaging biomarkers for astrogliosis and neuroinflammation by investigating the relationships between advanced multidimensional MRI signal signatures and increased glial fibrillary acidic protein (GFAP) deposition. Below, milestones from this project are summarized: 1. We investigated ex vivo cerebral cortical tissue specimens derived from seven subjects who sustained blast induced injuries, which resulted in scar-border forming astrogliosis without being accompanied by other types of neuropathologic abnormality, and from seven control brain donors. By performing a combined postmortem radiology and histopathology correlation study we found that astrogliosis induces microstructural and chemical changes that are robustly detected with multidimensional MRI, and which can be attributed to astrogliosis because no axonal damage, demyelination, or tauopathy were histologically observed in any of the cases in the study. Importantly, we showed that no one-dimensional T1, T2, or diffusion MRI measurement can disentangle the microscopic alterations caused by this neuropathology. 2. Based on these finding, we developed a within-subject anomaly detection procedure that generates MRI-based astrogliosis biomarker maps ex vivo, which were significantly and strongly correlated with co-registered histological images of increased GFAP deposition. Our findings elucidate the underpinning of MRI signal response from astrogliosis, and the demonstrated high spatial sensitivity and specificity in detecting reactive astrocytes at the individual level, and if reproduced in vivo, will significantly impact neuroimaging studies of injury, disease, repair, and aging, in which astrogliosis has so far been an invisible process radiologically. 3. Individuals with intact cognition and Abeta and tau neuropathology are referred to as asymptomatic AD (AsymAD), which shows that although Abeta deposits appear early in the pathogenesis of AD, they cannot account for cognitive decline. In the Baltimore Longitudinal Study of Aging (BLSA) autopsy series, AsymAD subjects represent approximately 50% of individuals with preserved cognition beyond 75 years of age, and could hold the key to understating resistance to the toxic effects of AD pathology. Postmortem examination of the association between reactive astrocytes and cognitive decline revealed a significant increase in definite AD cases compared to AsymAD. This finding suggests that astrogliosis predominantly contributes to the late-stage of the disease and holds promise as a potential predictor of cognitive state, distinguishing asymptomatic and definite AD cases. We have been investigating BLSA autopsy tissue samples obtained from individuals with definite AD, AsymAD, as well as age-matched control subjects, using the novel multidimensional MRI methods described above. Results from this study would elucidate the role of neuroinflammation in AD, and its potential in serving as a disease biomarker.