Translating from Macro-scale to Micro-scale in Multiple Sclerosis: Histological underpinnings of macroscopic structural and functional alterations in MS

Concluding remarks 1. What are the cellular substrates of DTI measured diffusivity alterations in normal appearing and lesioned cortex in MS? - Chapter 2.1 showed that axonal orientation may be an important driver of diffusivity measures, such as FA, not only in white matter but also in grey matter in MS and in control cortex. - Chapter 2.1 showed that the typical diffusivity pattern of MRI measured low FA in NAGM compared to controls and increased FA in grey matter lesions compared to NAGM in MS is associated with cortical axonal degeneration. 2. What are the cellular substrates of DTI based network measures of integration and segregation in MS? - Chapter 2.2 showed that cortical regions with segregative properties are characterized by small neurons and a low axonal density, while regions with integrative properties contain large neurons and high axonal densities. - Chapter 2.2 showed that MS patients with a higher whole brain WM lesion volume showed higher more pronounced segregative properties and less integrative properties and correspondingly also smaller neurons and a lower axonal densities on average. 3. To what extent do remote white matter and local grey matter pathology explain cortical neuroaxonal degeneration in MS? - Chapter 3 showed that both white matter damage and cortical demyelination contribute to cortical axonal loss. Variance in cortical axonal density in NAGM is explained for 22.6% by remote axonal diffusivity in WML and for 12.6% by axonal diffusivity in NAWM. Furthermore, local cortical demyelination was associated with additional axonal loss in lesioned cortex and explained 34.4% of variance in axonal loss, while microglia showed no association. 4. What are possible histological substrates of altered brain function in MS? - Chapter 4 showed that GAD67 immuno-reactivity is increased in WM astrocytes, inhibitory interneurons and synapses in inflamed and demyelinated hippocampi of MS patients. This is possibly related to cognitive functioning according to the medical history of the donors. - Preliminary data showed that inhibitory synaptic and excitatory synaptic densities are reduced in layer 6 of the cortex. This may reflect ongoing processes such as synaptic displacement, synaptic stripping and neurodegeneration