MRI signature in a novel mouse model of genetically induced adult oligodendrocyte cell death

Abstract

Two general pathological processes contribute to multiple sclerosis (MS): acute inflammation and degeneration. While magnetic resonance imaging (MRI) is highly sensitive in detecting abnormalities related to acute inflammation both clinically and in animal models of experimental autoimmune encephalomyelitis (EAE), the correlation of these readouts with acute and future disabilities has been found rather weak. This illustrates the need for imaging techniques addressing neurodegenerative processes associated with MS. In the present work we evaluated the sensitivity of different MRI techniques (T(2) mapping, macrophage tracking based on labeling cells in vivo by ultrasmall particles of iron oxide (USPIO), diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI)) to detect histopathological changes in a novel animal model making use of intrinsic, temporally and spatially controlled triggering of oligodendrocyte cell death. This mouse model allows studying the MRI signature associated to neurodegenerative processes of MS in the absence of adaptive inflammatory components that appear to be foremost in the EAE models. Our results revealed pronounced T(2) hyperintensities in brain stem and cerebellar structures, which we attribute to structural alteration of white matter by pronounced vacuolation. Brain areas were found devoid of significant macrophage infiltration in line with the absence of a peripheral inflammatory response. The significant decrease in diffusion anisotropy derived from DTI measures in these structures is mainly caused by a pronounced decrease in diffusivity parallel to the fiber indicative of axonal damage. Triggering of oligodendrocyte ablation did not translate into a significant increase in radial diffusivity. Only minor decreases in MT ratio have been observed, which is attributed to inefficient removal of myelin debris AbstractTwo general pathological processes contribute to multiple sclerosis (MS): acute inflammation and degeneration. While magnetic resonance imaging (MRI) is highly sensitive in detecting abnormalities related to acute inflammation both clinically and in animal models of experimental autoimmune encephalomyelitis (EAE), the correlation of these readouts with acute and future disabilities has been found rather weak. This illustrates the need for imaging techniques addressing neurodegenerative processes associated with MS.In the present work we evaluated the sensitivity of different MRI techniques (T2 mapping, macrophage tracking based on labeling cells in vivo by ultrasmall particles of iron oxide (USPIO), diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI)) to detect histopathological changes in a novel animal model making use of intrinsic, temporally and spatially controlled triggering of oligodendrocyte cell death. This mouse model allows studying the MRI signature associated to neurodegenerative processes of MS in the absence of adaptive inflammatory components that appear to be foremost in the EAE models. Our results revealed pro...

Advancing Cardiovascular, Neurovascular, and Renal Magnetic Resonance Imaging in Small Rodents Using Cryogenic Radiofrequency Coil Technology

“…MTR correlates significantly with the degree of myelination as shown in postmortem tissue of MS patients (Schmierer et al, 2004 ). The decline in MTR that was observed in the oligodendrogliopathy model with the aid of the CryoProbe (Figure 6B ) could be corroborated with evidence of white matter pathology upon histological analysis (Figure 6C ; Mueggler et al, 2012 ).…”

“…For instance transgenic models involving suicide genes that induce oligodendrogliopathy are powerful tools for studying non-inflammatory demyelination and remyelination (Traka et al, 2010 ; Pohl et al, 2011 ). Using a cryogenically-cooled RF coil, pronounced T 2 hyperintensities were revealed in brain stem and cerebellar structures of this model (Figure 6A ); these changes were accompanied with a decreased magnetization transfer ratio (MTR; Figure 6B ; Mueggler et al, 2012 ). MTR reflects the exchange of magnetization between pools of differently mobilized protons (Wolff and Balaban, 1989 ), commonly a rather freely mobile pool and a rather immobile pool associated with macromolecules, such as in axonal membranes or myelin (Alonso-Ortiz et al, 2015 ).…”

Increased Body Mass Index Is Associated With a Global and Distributed Decrease in White Matter Microstructural Integrity

“…For example, a small functional MRI study showed that obesity was associated with reductions in brain activity during the performance of a demanding working memory task and that the strongest predictor of reduced activation was not higher BMI but lower insulin sensitivity (18). In addition, inflammatory pathways have been implicated in white matter atrophy in both humans (40) and animal models (41) and also increase with obesity. Neuropsychological studies have suggested that some cognitive domains supported by these same brain areas are compromised in obesity (e.g., planning and mental flexibility, problem solving, memory, psychomotor speed (42–45)).…”

Magnetization transfer ratio does not correlate to myelin content in the brain in the MOG-EAE mouse model

“…The stronger decrease is thought to be due to axonal swelling, cellular infiltration and edema (Boretius et al, 2012). In mice with EAE induced by proteolipid protein, a decrease in MTR was seen in brainstem, cerebellum and frontal cortex, but not olfactory bulb (Mueggler et al, 2012). In a study of the effect of glatiramer acetate (GA) on EAE mice, the untreated EAE mice are shown to have lower MTR values than the GA treated (Aharoni et al, 2013).…”