Exploring the relationship between white and grey matter damage in primary progressive multiple sclerosis with structural magnetic resonance imaging

In the first part of this thesis, an introduction of the main characteristics of the primary-progressive form of multiple sclerosis (PPMS) (Chapter I), and of the acquisition and post-processing of the conventional and quantitative magnetic resonance imaging techniques employed in the studies presented in this thesis (Chapter II), will be presented. In the second part of this thesis, several advanced imaging techniques will be employed to answer the following two key questions on PPMS: 1) Is there is a spatial and temporal link between the pathological processes occurring in the normal appearing white matter (WM) and in the grey matter (GM) of patients with PPMS?; 2) Which regions of WM and GM abnormalities significantly contribute to clinical progression and cognitive dysfunction over time in patients with PPMS? To answer the first question, I first used tract-based spatial statistics (TBSS) and voxel-based morphometry (VBM), to explore the spatial relationship between the damage occurring in the normal-appearing WM and GM in patients with early PPMS (Chapter III). Then, I moved onto exploring the temporal relationship linking the pathological changes affecting the two compartments, employing magnetization transfer imaging (MTI) and diffusion-based tractography (Chapter IV). To answer the second question, I first looked at the prognostic role of WM lesion location in a study conducted on a large population of patients with well- established PPMS who were followed-up for ten years in five different European centres (Chapter V). Then, using a novel approach which combines MTI and TBSS, I explored the regions of short-term accrual of microstructural damage in patients with early PPMS (Chapter VI). Finally, I moved onto examining the relative contribution of WM and GM damage to long-term motor and cognitive disability in PPMS (Chapter VII). In the final Chapter, I will summarise the results of the studies presented in this thesis, provide an answer to the two key questions on PPMS, and propose future directions for research

Individualized Breakfast Programs or Glycogen Super-Compensation: Which Is the Better Performing Strategy? Insights from an Italian Soccer Referees Cohort

The role of soccer referees has grown in importance in the last decades, as has attention to their performance, which may be influenced and improved with specific and evolved training programs. Today, multiple specialists are working as a team in order to develop effective training programs. Moreover, for athletes, it is becoming more and more important to be attentive to nutrition. By considering such items, in this study, we aimed to investigate the nutritional habits of a group of referees belonging to the Italian Soccer Referees' Association (on behalf of AIA-FIGC). Our main aim was to spread a "culture of nutrition" in refereeing, starting with a survey on referees' breakfast attitudes and in order to disseminate such a "culture", we chose top-level elite referees who were younger subjects (despite the average 4 years' experience). Therefore, we enrolled 31 subjects (aged 22.74 \ub1 1.79, BMI 22.30 \ub1 1.53) and asked them about their breakfast habits. Then, for measuring their performance, we used the conventional fitness test named Yo-Yo (YYiR1), performed in three different sessions (test 1, test 2, test 3). Test 1 was carried out without any nutritional indications, test 2 was given after individualized breakfast suggestions by a designed dietician, and test 3 after an individualized glycogen super-compensation strategy. The Wilcoxon statistical analysis indicates that following an individualized breakfast strategy may enhance referees' performance (p < 0.0001), whereas no significant effects were observed with the glycogen super-compensation option. However, further studies will be necessary to better address this topic and clarify whether high-carbohydrates (high-CHO) intake may be useful in other sports

Chagas disease at the crossroad of international migration and public health policies: why a national screening might not be enough

n/

Distances on Lozenge Tilings

International audienceIn this paper, a structural property of the set of lozenge tilings of a 2n-gon is highlighted. We introduce a simple combinatorial value called Hamming-distance, which is a lower bound for the flipdistance (i.e. the number of necessary local transformations involving three lozenges) between two given tilings. It is here proven that, for n5, We show that there is some deficient pairs of tilings for which the flip connection needs more flips than the combinatorial lower bound indicates

Qualidade e características sensoriais de manga osmoticamente desidratada com xaropes de açúcar invertido e a sacarose

A desidratação osmótica tem se tornado uma tecnologia cada vez mais usual no processamento de alimentos desidratados, por apresentar vantagens como a redução nas perdas de cor e sabor durante o tratamento térmico, inibição do escurecimento enzimático, prescindindo da adição de agentes sulfitantes, e principalmente economia no consumo de energia. Este trabalho avaliou o efeito da utilização de xaropes de açúcar invertido e sacarose como agentes osmóticos na desidratação de manga. As condições utilizadas no processo de desidratação foram: relação xarope/fruto de 3:1(v/p); temperatura de 45ºC e agitação constante. Os frutos in natura e osmo-desidratados foram avaliados quanto ao pH, umidade, atividade de água (a a) e sólidos solúveis (ºBrix). Determinou-se a incorporação de sólidos e a perda de massa após o processo de desidratação. A aceitação sensorial dos frutos in natura e osmo-desidratados foi avaliada através de um teste com escala hedônica, para os atributos aroma, sabor, textura e aceitação global. A desidratação osmótica resultou na redução da umidade e da a a, no aumento do Brix e na manutenção do pH da manga. Os tratamentos com xarope de açúcar invertido ocasionaram mais alterações na umidade, na a a, no Brix, na incorporação de sólidos e na perda de massa comparado ao tratamento com xarope de sacarose. As mangas osmo-desidratadas com o xarope de açúcar invertido (55,3% de taxa de inversão) obtiveram uma aceitação semelhante às mangas in natura, tendo sido considerado o tratamento mais adequado para esse fim.Osmotic dehydration is becoming more popular as a complementary treatment in the processing of dehydrated foods, since it presents some advantages such as minimising heat damage to the colour and flavour, inhibiting enzymatic browning and thus dispensing the addition of sulphite and, mainly, reducing energy costs. The objective of the present study was to evaluate the effect of using inverted sugar and sucrose syrups as osmotic agents in the dehydration of mango. The conditions used in the dehydration process were: syrup/fruit ratio of 3:1 (v/w); temperature of 45ºC and constant stirring. The in natura and osmo-dehydrated fruits were evaluated in relation to pH, moisture content, water activity (a w) and soluble solids (ºBrix). Solids incorporation and loss in mass after the dehydration process were also determined. The sensory acceptance of the in natura and osmo-dehydrated fruits was determined for the attributes of aroma, flavour, texture and overall acceptance using a hedonic scale. Osmotic dehydration resulted in a reduction in moisture content and water activity, an increase in Brix and maintenance of the pH. The treatment with inverted sugar syrup resulted in more significant alterations in moisture content, a w, Brix, solids incorporation and loss in mass than the treatment with sucrose syrup. Mangos osmo-dehydrated with inverted sugar (55.3% inversion rate) syrup obtained acceptance similar to in natura mangos, this treatment being considered the most adequate for dehydration purposes

A novel approach with "skeletonised MTR" measures tract-specific microstructural changes in early primary-progressive MS

We combined tract‐based spatial statistics (TBSS) and magnetization transfer (MT) imaging to assess white matter (WM) tract‐specific short‐term changes in early primary‐progressive multiple sclerosis (PPMS) and their relationships with clinical progression. Twenty‐one PPMS patients within 5 years from onset underwent MT and diffusion tensor imaging (DTI) at baseline and after 12 months. Patients' disability was assessed. DTI data were processed to compute fractional anisotropy (FA) and to generate a common WM “skeleton,” which represents the tracts that are “common” to all subjects using TBSS. The MT ratio (MTR) was computed from MT data and co‐registered with the DTI. The skeletonization procedure derived for FA was applied to each subject's MTR image to obtain a “skeletonised” MTR map for every subject. Permutation tests were used to assess (i) changes in FA, principal diffusivities, and MTR over the follow‐up, and (ii) associations between changes in imaging parameters and changes in disability. Patients showed significant decreases in MTR over one year in the corpus callosum (CC), bilateral corticospinal tract (CST), thalamic radiations, and superior and inferior longitudinal fasciculi. These changes were located both within lesions and the normal‐appearing WM. No significant longitudinal change in skeletonised FA was found, but radial diffusivity (RD) significantly increased in several regions, including the CST bilaterally and the right inferior longitudinal fasciculus. MTR decreases, RD increases, and axial diffusivity decreases in the CC and CST correlated with a deterioration in the upper limb function. We detected tract‐specific multimodal imaging changes that reflect the accrual of microstructural damage and possibly contribute to clinical impairment in PPMS. We propose a novel methodology that can be extended to other diseases to map cross‐subject and tract‐specific changes in MTR

T2 lesion location really matters: a 10 year follow-up study in primary progressive multiple sclerosis

Objectives: Prediction of long term clinical outcome in patients with primary progressive multiple sclerosis (PPMS) using imaging has important clinical implications, but remains challenging. We aimed to determine whether spatial location of T2 and T1 brain lesions predicts clinical progression during a 10-year follow-up in PPMS. Methods: Lesion probability maps of the T2 and T1 brain lesions were generated using the baseline scans of 80 patients with PPMS who were clinically assessed at baseline and then after 1, 2, 5 and 10 years. For each patient, the time (in years) taken before bilateral support was required to walk (time to event (TTE)) was used as a measure of progression rate. The probability of each voxel being ‘lesional’ was correlated with TTE, adjusting for age, gender, disease duration, centre and spinal cord cross sectional area, using a multiple linear regression model. To identify the best, independent predictor of progression, a Cox regression model was used. Results: A significant correlation between a shorter TTE and a higher probability of a voxel being lesional on T2 scans was found in the bilateral corticospinal tract and superior longitudinal fasciculus, and in the right inferior fronto-occipital fasciculus (p<0.05). The best predictor of progression rate was the T2 lesion load measured along the right inferior fronto-occipital fasciculus (p=0.016, hazard ratio 1.00652, 95% CI 1.00121 to 1.01186). Conclusion: Our results suggest that the location of T2 brain lesions in the motor and associative tracts is an important contributor to the progression of disability in PPMS, and is independent of spinal cord involvement

Do grade II ankle sprains have chronic effects on the functional ability of ballet dancers performing single-leg flat-foot stance? An observational cross-sectional study

Ballet dancers have a higher risk than the general population of ankle sprains. Ankle proprioception is of the utmost importance for executing static and dynamic positions typical of ballet dancing. Ankle sprains can create changes in functional ability that may affect ballet performance. The aim of this cross-sectional observational study is to evaluate if non-professional ballet dancers that were previously injured with a grade II ankle sprain carry a long-term stability deficit in ballet specific positions (pass\ue9, arabesque) and in single-leg flat-foot stance, thereby affecting ballet performance. We enrolled 22 amateur female ballet dancers, 11 who previously had a grade II ankle injury and 11 who had no history of ankle injury. Stabilometric data (Center of Pressure Speed and Elipse Area) were assessed with the postural electronic multisensory baropodometer in normal, arabesque, and pass\ue8 positions with both open and closed eyes. Using an unpaired t-test, we compared healthy and pathological feet of the ankle injury group for a standard monopodalic position and two ballet-specific positions. No difference between pathological and healthy feet of non-professional ballet dancers who suffered grade II ankle injury was detected. According to the parameters considered in this study, grade II ankle sprains seem to have a favorable prognosis in the sample that we evaluated

Individual mapping of innate immune cell activation is a candidate marker of patient-specific trajectories of disability worsening in Multiple Sclerosis

Objective: To develop a novel approach to generate individual maps of white matter (WM) innate immune cell activation using 18F-DPA-714 translocator protein (TSPO) positron emission tomography (PET), and to explore the relationship between these maps and individual trajectories of disability worsening in patients with multiple sclerosis (MS). Methods: Patients with MS (n = 37), whose trajectories of disability worsening over the 2 years preceding study entry were calculated, and healthy controls (n = 19) underwent magnetic resonance magnetic and 18F-DPA-714 PET. A threshold of significant activation of 18F-DPA-714 binding was calculated with a voxel-wise randomized permutation-based comparison between patients and controls, and used to classify each WM voxel in patients as characterized by a significant activation of innate immune cells (DPA+) or not. Individual maps of innate immune cell activation in the WM were employed to calculate the extent of activation in WM regions-of-interests and to classify each WM lesion as "DPA-active", "DPA-inactive" or "unclassified". Results: Compared with the WM of healthy controls, patients with MS had a significantly higher percentage of DPA+ voxels in the normal-appearing WM, (NAWM in patients=24.9±9.7%; WM in controls=14.0±7.8%, p<0.001). In patients with MS, the percentage of DPA+ voxels showed a significant increase from NAWM, to perilesional areas, T2 hyperintense lesions and T1 hypointense lesions (38.1±13.5%, 45.0±17.9%, and 51.9±22.9%, respectively, p<0.001). Among the 1379 T2 lesions identified, 512 were defined as DPA-active and 258 as DPA-inactive. A higher number of lesions classified as DPA-active (OR=1.13, P = 0.009), a higher percentage of DPA+ voxels in the NAWM (OR=1.16, P = 0.009) and in T1-spin-echo lesions (OR=1.06, P = 0.036), were significantly associated with a retrospective more severe clinical trajectory in patients with MS. Conclusion: A more severe trajectory of disability worsening in MS is associated with an innate immune cells activation inside and around WM lesions. 18F-DPA-714 PET may provide a promising biomarker to identify patients at risk of severe clinical trajectory

Dynamic imaging of individual remyelination profiles in multiple sclerosis

Background Quantitative in vivo imaging of myelin loss and repair in patients with multiple sclerosis (MS) is essential to understand the pathogenesis of the disease and to evaluate promyelinating therapies. Selectively binding myelin in the central nervous system white matter, Pittsburgh compound B ([11C]PiB) can be used as a positron emission tomography (PET) tracer to explore myelin dynamics in MS. Methods Patients with active relapsing-remitting MS (n = 20) and healthy controls (n = 8) were included in a longitudinal trial combining PET with [11C]PiB and magnetic resonance imaging. Voxel-wise maps of [11C]PiB distribution volume ratio, reflecting myelin content, were derived. Three dynamic indices were calculated for each patient: the global index of myelin content change; the index of demyelination; and the index of remyelination. Results At baseline, there was a progressive reduction in [11C]PiB binding from the normal-appearing white matter to MS lesions, reflecting a decline in myelin content. White matter lesions were characterized by a centripetal decrease in the tracer binding at the voxel level. During follow-up, high between-patient variability was found for all indices of myelin content change. Dynamic remyelination was inversely correlated with clinical disability (p = 0.006 and beta-coefficient = -0.67 with the Expanded Disability Status Scale; p = 0.003 and beta-coefficient = -0.68 with the MS Severity Scale), whereas no significant clinical correlation was found for the demyelination index. Interpretation [11C]PiB PET allows quantification of myelin dynamics in MS and enables stratification of patients depending on their individual remyelination potential, which significantly correlates with clinical disability. This technique should be considered to assess novel promyelinating drugs. Ann Neurol 2016;79:726-73