Magnetic Resocance Imaging Methods in the Follow-up of Multiple Sclerosis and in Farby Disease

Multiple sclerosis (MS) is a chronic immune-mediated inflammatory disorder of the central nervous system. MS is the most common disabling central nervous system (CNS) disease of young adults in the Western world. In Finland, the prevalence of MS ranges between 1/1000 and 2/1000 in different areas. Fabry disease (FD) is a rare hereditary metabolic disease due to mutation in a single gene coding α-galactosidase A (alpha-gal A) enzyme. It leads to multi-organ pathology, including cerebrovascular disease. Currently there are 44 patients with diagnosed FD in Finland. Magnetic resonance imaging (MRI) is commonly used in the diagnostics and follow-up of these diseases. The disease activity can be demonstrated by occurrence of new or Gadolinium (Gd)-enhancing lesions in routine studies. Diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI) are advanced MR sequences which can reveal pathologies in brain regions which appear normal on conventional MR images in several CNS diseases. The main focus in this study was to reveal whether whole brain apparent diffusion coefficient (ADC) analysis can be used to demonstrate MS disease activity. MS patients were investigated before and after delivery and before and after initiation of diseasemodifying treatment (DMT). In FD, DTI was used to reveal possible microstructural alterations at early timepoints when excessive signs of cerebrovascular disease are not yet visible in conventional MR sequences. Our clinical and MRI findings at 1.5T indicated that post-partum activation of the disease is an early and common phenomenon amongst mothers with MS. MRI seems to be a more sensitive method for assessing MS disease activity than the recording of relapses. However, whole brain ADC histogram analysis is of limited value in the follow-up of inflammatory conditions in a pregnancy-related setting because the pregnancy-related physiological effects on ADC overwhelm the alterations in ADC associated with MS pathology in brain tissue areas which appear normal on conventional MRI sequences. DTI reveals signs of microstructural damage in brain white matter of FD patients before excessive white matter lesion load can be observed on conventional MR scans. DTI could offer a valuable tool for monitoring the possible effects of enzyme replacement therapy in FD.Siirretty Doriast

Stratifying Ischaemic Stroke Patients Across 3 Treatment Windows Using T2 Relaxation Times, Ordinal Regression and Cumulative Probabilities

Unknown onset time is a common contraindication for anti-thrombolytic treatment of ischaemic stroke. T2 relaxation-based signal changes within the lesion can identify patients within or beyond the 4.5-hour intravenous thrombolysis treatment-window. However, now that intra-arterial thrombolysis is recommended between 4.5 and 6 hours from symptom onset and mechanical thrombectomy is considered safe between 6 and 24 hours, there are three treatment-windows to consider. Here we show a cumulative ordinal regression model, incorporating the T2 relaxation time, predicts the probabilities of a patient being within one of the three treatment-windows and is more accurate than signal intensity changes from T2 weighted images

Predictors of training-related improvement in visuomotor performance in patients with multiple sclerosis: A behavioural and MRI study

Background: The development of tailored recovery-oriented strategies in multiple sclerosis requires early identification of an individual’s potential for functional recovery. Objective: To identify predictors of visuomotor performance improvements, a proxy of functional recovery, using a predictive statistical model that combines demographic, clinical and magnetic resonance imaging (MRI) data. Methods: Right-handed multiple sclerosis patients underwent baseline disability assessment and MRI of the brain structure, function and vascular health. They subsequently undertook 4 weeks of right upper limb visuomotor practice. Changes in performance with practice were our outcome measure. We identified predictors of improvement in a training set of patients using lasso regression; we calculated the best performing model in a validation set and applied this model to a test set. Results: Patients improved their visuomotor performance with practice. Younger age, better visuomotor abilities, less severe disease burden and concurrent use of preventive treatments predicted improvements. Neuroimaging localised outcome-relevant sensory motor regions, the microstructure and activity of which correlated with performance improvements. Conclusion: Initial characteristics, including age, disease duration, visuo-spatial abilities, hand dexterity, self-evaluated disease impact and the presence of disease-modifying treatments, can predict functional recovery in individual patients, potentially improving their clinical management and stratification in clinical trials. MRI is a correlate of outcome, potentially supporting individual prognosis

Imaging of neuroinflammation in multiple sclerosis brain : a positron emission tomography and diffusion tensor imaging study

ABSTRACT Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, where the immune system attacks the protective myelin sheet surrounding the nerve cell axons, causing neuroinflammation and neurodegeneration. In this thesis, molecular and microstructural brain changes were evaluated in MS patients using diffusion tensor imaging (DTI) and positron emission tomography (PET) with translocator protein (TSPO) binding radioligand. In MS, TSPO is expressed mainly in activated microglia and therefore TSPO is considered as a marker of inflammation. The aim of this thesis was to evaluate the association between TSPO PET radioligand uptake and DTI macroparameters, as well as their association to clinical disability, in normal appearing white matter (NAWM). Moreover, the aim was to study if the individual physiological properties including age, body mass index (BMI) and sex have influence on the observed variability, which has been reported in previous clinical PET studies. The results showed that increased TSPO uptake in NAWM was associated with altered NAWM DTI macroparameters, their regional correspondence was consistent, and they both were associated with advanced clinical disability. Increased age was associated with higher TSPO uptake in NAWM and in thalamus of MS patients, whereas in healthy control subjects, higher age was associated with higher cortical TSPO uptake. However, a multicenter data analysis of healthy volunteers revealed that higher age was associated with higher cortical and subcortical TSPO uptake only in male subjects. Additionally, higher TSPO uptake was associated with lower BMI, and females showed higher TSPO uptake compared to males. The results demonstrate that PET and DTI can be used as complementary imaging modalities in clinical MS studies. TSPO levels may be associated with age, BMI and sex suggesting that they can be confounding factors in clinical designs. Subtle microglial activation may be initially related to normal ageing but is accentuated following neuroinflammation. ’ KEYWORDS: [11C](R)-PK11195, [11C]PBR28, ageing, body mass index, BMI, DTI, microglia, multiple sclerosis, PET, sex, TSPOTIIVISTELMÄ Multippeliskleroosi (MS-tauti) on keskushermoston autoimmuunisairaus, jossa immuunijärjestelmä hyökkää hermosoluja suojaavaa myeliiniä vastaan aiheuttaen tulehdusreaktiota ja hermosolujen rappeutumista. Tässä tutkimuksessa tarkasteltiin MS-tautiin liittyviä aivojen molekulaarisia ja rakenteellisia muutoksia käyttämällä diffuusiotensorikuvantamista (DTI) ja positroniemissiotomografiaa (PET) translokaattoriproteiiniin (TSPO) sitoutuvalla merkkiaineella. MS-taudissa TSPO esiintyy pääosin aktivoituneissa mikroglia-soluissa ja siksi sitä pidetään tulehdusreaktion markkerina. Tämän tutkimuksen tarkoituksena oli arvioida TSPO-sitoutumisen yhteyttä DTI-kuvantamisen makroparametreihin ja kummankin yhteyttä kliinisiin mittaustuloksiin. Koska aiemmissa kliinisissä tutkimuksissa on havaittu runsaasti yksilöllistä vaihtelua TSPO-sitoutumisessa, oli tavoitteena tarkastella yksilöllisten fysiologisten tekijöiden, kuten iän, painoindeksin ja sukupuolen yhteyttä TSPO-sitoutumiseen. Tulosten mukaan kohonnut TSPO-sitoutuminen terveessä valkeassa aineessa (NAWM) oli yhteydessä muuttuneisiin DTI-makroparametreihin, alueellinen vastaavuus oli yhtenevää ja kummankin menetelmän tulokset olivat yhteydessä kliinisiin mittaustuloksiin. Ikääntyminen oli yhteydessä kohonneeseen TSPO-sitou-tumiseen NAWM:ssa ja talamuksissa MS-potilailla, kun taas terveillä koehenkilöillä ikääntyminen oli yhteydessä korkeampaan kortikaaliseen TSPO-sitoutumiseen. Laajempi monikeskustutkimus osoitti kuitenkin, että ikääntyminen oli yhteydessä korkeampaan kortikaaliseen ja subkortikaaliseen TSPO-sitoutumiseen vain miehillä. Lisäksi korkeampi TSPO-sitoutuminen oli yhteydessä matalampaan painoindeksiin ja naisilla TSPO-sitoutuminen oli korkeampaa miehiin verrattuna. Tulokset osoittavat, että PET- ja DTI-kuvantaminen ovat toisiaan täydentäviä menetelmiä MS-taudin kuvantamisessa. Ikä, painoindeksi ja sukupuoli voivat olla sekoittavia tekijöitä kliinisissä TSPO-tutkimuksissa. TSPO-sitoutuminen liittyy normaaliin ikääntymiseen, mutta se korostuu tulehdusreaktion yhteydessä. AVAINSANAT: [11C](R)-PK11195, [11C]PBR28, DTI, ikääntyminen, mikroglia, MS-tauti, PET, painoindeksi, sukupuoli, TSP

The sequence of structural, functional and cognitive changes in multiple sclerosis

Background: As disease progression remains poorly understood in multiple sclerosis (MS), we aim to investigate the sequence in which different disease milestones occur using a novel data-driven approach. Methods: We analysed a cohort of 295 relapse-onset MS patients and 96 healthy controls, and considered 28 features, capturing information on T2-lesion load, regional brain and spinal cord volumes, resting-state functional centrality (“hubness”), microstructural tissue integrity of major white matter (WM) tracts and performance on multiple cognitive tests. We used a discriminative event-based model to estimate the sequence of biomarker abnormality in MS progression in general, as well as specific models for worsening physical disability and cognitive impairment. Results: We demonstrated that grey matter (GM) atrophy of the cerebellum, thalamus, and changes in corticospinal tracts are early events in MS pathology, whereas other WM tracts as well as the cognitive domains of working memory, attention, and executive function are consistently late events. The models for disability and cognition show early functional changes of the default-mode network and earlier changes in spinal cord volume compared to the general MS population. Overall, GM atrophy seems crucial due to its early involvement in the disease course, whereas WM tract integrity appears to be affected relatively late despite the early onset of WM lesions. Conclusion: Data-driven modelling revealed the relative occurrence of both imaging and non-imaging events as MS progresses, providing insights into disease propagation mechanisms, and allowing fine-grained staging of patients for monitoring purpose

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.Siirretty Doriast

Brain imaging biomarkers in Multiple Sclerosis

Background: Iron rim lesions (IRLs), white matter lesions (WMLs) accumulation and linear brain atrophy measurements have been suggested to be important imaging biomarkers in multiple sclerosis (MS). The extent to which these markers are related to MS diagnosis and predict disease prognosis remains unclear. Furthermore, research Magnetic Resonance Imaging (MRI) findings need validation in clinical settings before they can be incorporated into clinical practice. Methods: I conducted two reviews one was a mapping review on IRLs and the other was a meta-analysis on WMLs in MS. I then tested the diagnostic and prognostic usefulness of the IRL in two studies: (1) a large, cross-sectional, multi-centre study of patients with MS and mimicking disorders using 3T MRI, (2) a retrospective single-centre study of patients with first presentation of a clinically isolated syndrome (CIS) or at the early stage of the disease using 7T MRI. I also explored the utility of routine, non-standardised MRI scans measuring WMLs number, volume and linear measures of atrophy at the early stage of the disease and examined their role in predicting long-term disability. Results: The IRLs achieved high specificity (up to 99%) in diagnosing MS compared to MS-mimics but low sensitivity of 24%. All patients with IRLs showing a central vein sign (CVS) had MS or CIS, giving a diagnostic specificity of 100% but equally low sensitivity of 21%. Moreover, the presence of IRLs was also a predictor of long-term disability, especially in patients with ≥4 IRLs. IRLs had a greater impact on disability compared to the WMLs number and volume. Linear brain atrophy of Inter-Caudate Distance (ICD) and Third Ventricle Width (TVW) had a significant impact in predicting disability after 10 years. Conclusions: The perilesional IRLs may reduce diagnostic uncertainty in MS by being a highly specific imaging diagnostic biomarker, especially when used in conjunction with the CVS. Also, the presence and number of IRLs hold prognostic value for long-term physical disability in MS. Simple and reliable assessment of brain atrophy remains challenging in clinical practice

Investigating metabolic, vascular and structural neuroplasticity in healthy and diseased brain using advanced neuroimaging techniques

The brain’s lifelong capacity for reorganization is termed ‘plasticity’. It relies on molecular signalling translated into long lasting modifications. MRI has been widely used to assess neuroplasticity in vivo, showing brain’s ability to undergo functional and structural reorganization. However, there is a lack of understanding of the physiological events supporting neuroplasticity and advanced MRI techniques could help in the investigation of the biological meaning of these events and their alterations during neuroinflammation. This thesis has two main aims. Neuroscientifically, it aims to better understand mechanisms supporting neuroplasticity in the healthy and diseased brain. Methodologically, it aims to explore new MRI approaches to the study of neuroplasticity. The early experiments investigate the mechanisms underlying long-term neuroplasticity in MS. The studies then aim to elucidate the changes in brain energetics underlying adaptation in healthy and MS brain using calibrated fMRI. I explored new approaches to analyse the relative oxygen consumption during task adaptation in the same population. A new task to study short-term neuroplasticity was validated and used to demonstrate changes in resting blood flow after task execution. The same task was used to investigate the relationship between GM myelination and functional activity during task execution. Overall, we show the feasibility of using quantitative methods to study neuroplasticity, encouraging their application to improve biological interpretation in imaging studies. Our results highlight the importance of studying the brain as a network and the advantages of integrating different MRI modalities. We also show that our methods are applicable to MS populations, despite the observed metabolic impairment with neuroinflammation. Our methods may, in future, contribute to the study of disease progression and to the development of targeted interventions to limit the damage of inflammation