Imaging Neuroinflammation in Progressive Multiple Sclerosis

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system CNS), where inflammation and neurodegeneration lead to irreversible neuronal damage. In MS, a dysfunctional immune system causes auto‐reactive lymphocytes to migrate into CNS where they initiate an inflammatory cascade leading to focal demyelination, axonal degeneration and neuronal loss. One of the hallmarks of neuronal injury and neuroinflammation is the activation of microglia. Activated microglia are found not only in the focal inflammatory lesions, but also diffusely in the normal‐appearing white matter (NAWM), especially in progressive MS. The purine base, adenosine is a ubiquitous neuromodulator in the CNS and also participates in the regulation of inflammation. The effect of adenosine mediated via adenosine A2A receptors has been linked to microglial activation, whereas modulating A2A receptors may exert neuroprotective effects. In the majority of patients, MS presents with a relapsing disease course, later advancing to a progressive phase characterised by a worsening, irreversible disability. Disease modifying treatments can reduce the severity and progression in relapsing MS, but no efficient treatment exists for progressive MS. The aim of this research was to investigate the prevalence of adenosine A2A receptors and activated microglia in progressive MS by using in vivo positron emission tomography (PET) imaging and [11C]TMSX and [11C](R)‐PK11195 radioligands. Magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI) was performed to evaluate structural brain damage. Non‐invasive input function methods were also developed for the analyses of [11C]TMSX PET data. Finally, histopathological correlates of [11C](R)‐PK11195 radioligand binding related to chronic MS lesions were investigated in post‐mortem samples of progressive MS brain using autoradiography and immunohistochemistry. [11C]TMSX binding to A2A receptors was increased in NAWM of secondary progressive MS (SPMS) patients when compared to healthy controls, and this correlated to more severe atrophy in MRI and white matter disintegration (reduced fractional anisotropy, FA) in DTI. The non‐invasive input function methods appeared as feasible options for brain [11C]TMSX images obviating arterial blood sampling. [11C](R)‐PK11195 uptake was increased in the NAWM of SPMS patients when compared to patients with relapsing MS and healthy controls. Higher [11C](R)‐PK11195 binding in NAWM and total perilesional area of T1 hypointense lesions was associated with more severe clinical disability, increased brain atrophy, higher lesion load and reduced FA in NAWM in the MS patients. In autoradiography, increased perilesional [11C](R)‐PK11195 uptake was associated with increased microglial activation identified using immunohistochemistry. In conclusion, brain [11C]TMSX PET imaging holds promise in the evaluation of diffuse neuroinflammation in progressive MS. Being a marker of microglial activation, [11C](R)‐ PK11195 PET imaging could possibly be used as a surrogate biomarker in the evaluation of the neuroinflammatory burden and clinical disease severity in progressive MS.

Philosophiam theoreticam in practicam influentem sistens 1

Invokaatio: Deus benedicat.

Theses (1827-02-03)

Painovuosi nimekkeestä.

Disquisitiones practicae 5

Nimekettä edeltää hepreankielinen invokaatio.

De parabolis

Dedikaatio: Johannes Gezelius, Georgius Biugg, Israel Alftanus, Martinus Gallus, Samuel Backman, Martinus Rivelius, Bartholdus Vaehl, Ericus Wallenius, Jacobus Hildeen, Michael Gavelius, Johannes Gabrielis.

Vindicias Providentiae divinae contra exceptiones deistarum, continens

Invokaatio: D.D.

De gratia Dei 8

Variantti A.

De anthropomorphismo

Dedikaatio: Daniel Backman.

De denario Beati Petri 1

Invokaatio: Q.B.V.

De bibliothecariis Academiae Aboënsis 15

Arkit: 1 arkintunnukseton lehti, T4.

De principiis primis

Variantti B.

De terrae motu

Invokaatio: Theû synergûntos.

De monarchia Dei universali

Invokaatio: I.N.J.S.

Roadmap for Service Charging Development

Corporate support functions are increasingly being concentrated into service centers. Service Management principles guide companies in the transition. Service Financial Management is an integral part in supporting the strategic positioning of the service center. The main goal of this thesis is to create a step-by-step plan to improve and automate the service charging processes for the finance service function of the case company. Automating the service transaction data collection for reporting is expected to improve efficiency, reliability and transparency. Interviews with finance service managers are held to define current processes and areas for improvement. These create the basis for the creation of a development roadmap that takes place in two phases. The first phase is to create an environment where automation is possible, and the second phase is the automation of each finance service. Benchmarking interviews are held with the service centers in three other companies to discover best practices. The service charging processes between the studied companies are found incompatible, and suggestions for process automation cannot be inferred. Some implications of Service Financial Management decisions to the strategy of the service center are identified. The bundling of services and charging them inside or outside of the goal-setting frame of the business unit can be used to support the strategic choice and customer acceptance of the service center.