MRI investigation of a model of chronic inflammation in the CNS

Thesis

Magnetic resonance imaging (MRI) is an established clinical tool for diagnosing Multiple Sclerosis (MS), the archetypal CNS neuroinflammatory disease. The aim of this work was to develop and characterise a chronic demyelinating inflammatory lesion, like those in MS, using MRI, histology and immunocytochemistry, to identify MR-markers of disease activity and to correlate these with developing histopathology. The second aim of this work was to investigate the effect of a peripheral infection on a quiescent CNS lesion, since infections have been hypothesised to be important in the exacerbation of MS.

Prior to MRI, the DTK lesion was charcaterised histologically. An increase in macrophage and astrocyte numbers was the earliest histological event. Conventional MRI techniques, such as T₁- and T₂-weighted imaging were then used to characterise the lesion. The lesion was hypointense on T₁- and T₂-weighted images, and later, a hyperintense region was found to surround the hypointense core.

Contrast enhancement, diffusion and magnetisation transfer characteristics of the lesion were then investigated. Contrast enhancement occurred at the same time as T₂ hyperintensities. Increased ADC corresponded to areas of contrast enhancement and T₂ hyperintensity. Reactive astrocytes spatially mapped to these regions. Decreased ADC regions corresponded to regions of T₁ and T₂ hypointensity. The hypercellular lesion core, composed of T cells, macrophages and MHC class II expressing cells spatially mapped to the hypointense core on T₁- and T₂-weighted images and ADC maps. The MTR was reduced in the absence of demyelination and significant oedema.

Blood volume changes were also investigated, and focal increases in rCBV were found, and were associated with dilation of blood vessels and Laminin upregulation.

The final objective of this thesis was to investigate the effect of peripheral infection on the DTK lesion. The immune response was reactivated, and was observed by an increase in rCBV, T₁ relaxation time, and re-opening of the BBB six hours post-infectious challenge.

This work has successfully demonstrated that pathophysiological changes can be followed non-invasively with MRI throughout the evolution of the untreated DTK lesion.

Authors: Broom, K

• Peer review status: Peer reviewed
• DOI: 10.5287/ora-yxjadrmjj
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford