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Seppi, Dario (2016) Integration of advanced molecular analyses and magnetic resonance imaging for the identification of biomarkers of disease progression in multiple sclerosis. [Tesi di dottorato]

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Abstract (inglese)

Background. In the last 15 years, it has become increasingly accepted that cerebral grey matter (GM) damage in MS is evident since early MS stages and provides the best correlate of the rate of clinical progression since early disease stages. The lack of substantial inflammatory infiltrates, complement deposition and blood brain barrier damage in MS cortical lesions led to the initial suggestion that the mechanisms underlying GM and white matter (WM) pathology substantially differ and that activated microglia are the dominant effector cell population causing GM damage. Furthermore, in the last decade, post-mortem studies have revealed that the extent of meningeal inflammation associates positively with subpial cortical demyelination and disease progression, suggesting that chronic immune activity in the subarachnoid compartment plays a key role in mediating damage in the adjacent cerebral cortex of affected patients. Factors released by immune cells circulating in the CSF and/or colonizing the subarachnoid space may diffuse across the pial membrane, inducing a gradient of glia and neuronal pathological alterations, directly and/or indirectly through activated microglia.
Aim of the study. To combine CSF molecular and protein analyses with advanced MRI imaging techniques, able to better identify cortical grey matter demyelination, in order to identify potential early biomarkers of GM pathology and disease progression with prognostic and predictive value and to obtain information on the biological and immunological mechanisms that link the inflammatory process of the GM and the progressive neurodegeneration
Methods. Two independent cohorts of MS patients have been recruited and followed by the MS Centre of Padova. The first cohort of MS patients, composed of 35 patients and 5 controls was recruited retrospectively between February 2009 and September 2011 and followed by a detailed neurological and clinical follow-up. The second cohort of 31 patients and 13 controls was collected prospectively from January 2014 to May 2015. The patients, at their disease onset or in the very early phase of the disease, underwent a complete diagnostic work-up comprehensive of clinical evaluation, lumbar puncture and MRI evaluation inclusive of non-conventional sequences. By using the immuno-assay Bio-Plex System technique (Biorad - Bio-Plex Pro Human Chemokine panel 40-plex) we performed a protein analysis of the presence and levels of inflammatory molecules in both cohorts. In the second cohort we carried out also a gene expression analysis of the matched cellular fraction (using pre amplification real-time PCR for a panel of genes of interest).
Results. CSF protein analysis of the first cohort of MS patients reveal higher levels of proinflammatory cytokines CXCL13 (p=0,00006), CCL19 (p=0,0019), CCL1 (p=0,00018), and CCL22 (0.0009) compared to controls. Protein analysis on our second cohort pointed out an important increase of CXCL13, CXCL10, CXCL11 and CCL2 in MS population compared to controls. After stratification according to GM pathology we reported an increase of CXCL13 protein levels in the MS subgroup with higher cortical demyelination. Gene expression analysis reveals a significant increase in MS patients for CD20, CD138 and LTa compared to controls supporting the hypothesis of a key role of a B-cell response and lymphoid neogenesis in MS pathology
Conclusions. Combined CSF analysis and MRI analysis suggested that B cell immune response may play an important role in MS since the disease onset and correlates with the level of intrathecal inflammation and cortical pathology. A more detailed analysis of the CSF biomarkers suggested in the current study might provide, in addition to MRI optimization, a better indication of severity of disease process that characterized GM pathology and important tools in predicting/monitoring the evolution of the disease.

Abstract (italiano)

Presupposti dello studio. Studi istopatologici e neuroradiologici hanno dimostrato, soprattutto negli ultimi 15 anni come la sclerosi multipla, considerata classicamente una patologia elettiva della sostanza bianca, sia una patologia caratterizzata da un coinvolgimento, fin dalle prime fasi di malattia, anche della sostanza grigia corticale e profonda che ben correla con il quadro di disabilità fisica e cognitiva ampiamente descritto. Dal punto di vista istopatologico tale coinvolgimento è caratterizzato dalla presenza di lesioni corticali che si distinguono per una minor componente infiammatoria, per un’assenza di danno a carico della barriera ematoencefalica e per un minor deposito di fattori del complemento. Alla luce di tale descrizione sembra che i meccanismi che sottendono il danno a carico della sostanza grigia differiscano almeno in parte da quelli osservati a carico della sostanza bianca. In particolare è stata osservata un’associazione tra lesioni corticali e la presenza di infiltrati infiammatori meningei correlata ad una maggiore disabilità clinica. È stato quindi evidenziato come molecole pro-infiammatorie rilasciate dalle cellule infiammatorie residenti nelle meningi diffondano attraverso lo spazio subaracnoideo e agiscono, direttamente o indirettamente attivando la componente microgliale, sulla adiacente corteccia cerebrale determinando un gradiente di danno corticale.
Obiettivi. L’obiettivo di questo studio è stato quello di verificare la presenza di possibili potenziali biomarcatori di danno corticale mediante l’applicazione combinata di: a) tecniche avanzate di analisi proteica e analisi molecolare applicate allo studio del liquido cerebro spianale; b) tecniche non convenzionali di risonanza magnetica, in grado di caratterizzare il danno a carico della sostanza grigia sia focale che diffuso.
Materiali e metodi. Sono state arruolate due coorti di pazienti: la prima studiata retrospettivamente era composta da 35 pazienti e 5 controlli; la seconda arruolata nello studio con un approccio di tipo longitudinale era composta da 31 pazienti e 13 controlli. Tutti i pazienti erano caratterizzati da un esordio relativamente recente e la precedente somministrazione di terapie immunomodulanti rappresentava un criterio di esclusione. Tutti i pazienti si sono sottoposti ad un iter diagnostico completo comprensivo di valutazione clinica, esami di laboratorio, esame del liquido cerebrospinale e risonanza magnetica comprensiva di sequenze non convenzionali per verificare la presenza di lesioni della sostanza grigia. Lo studio del liquido cerebrospinale prevedeva inoltre uno studio di analisti proteica mediante immuno-assay (Bio-Plex System technique Biorad - Bio-Plex Pro Human Chemokine panel 40-plex) per lo studio di 40 citochine/chemochine e uno studio di analisi di gene expression.
Risultati. L’analisi proteica del liquor nella prima coorte ha evidenziato la presenza di elevati valori di CXCL13 (p=0,00006), CCL19 (p=0,0019), CCL1 (p=0,00018), e CCL22 (0.0009) rispetto alla popolazione di controllo. L’analisi proteica della seconda coorte ha evidenziato, sempre rispetto alla popolazione di controllo, un aumento delle seguenti citochine: CXCL13, CXCL10, CXCL11 e CCL2. Dopo stratificazione in base al carico corticale abbiamo evidenziato nei pazienti con un maggior coinvolgimento della sostanza grigia un aumento dei livelli proteici di CXCL13 e una maggior espressione di CD20, CD138, CXCL13 and LTa a supporto di un ruolo della risposta infiammatoria mediata dai linfociti B.
Conclusioni. L’analisi combinata di liquor e risonanza magnetica suggerisce che la risposta immunologica mediata dai linfociti B gioca un ruolo importante nella patogenesi della sclerosi multipla e che il livello di infiammazione intratecale ben correla con la patologia corticale. I risultati del nostro studio suggeriscono quindi che l’uso di biomarker liquorali potrebbero essere di supporto nella caratterizzazione della patologia corticale nella sclerosi multipla.

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Tipo di EPrint:Tesi di dottorato
Relatore:Pegoraro, Elena
Dottorato (corsi e scuole):Ciclo 28 > Scuole 28 > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > NEUROSCIENZE
Data di deposito della tesi:01 Febbraio 2016
Anno di Pubblicazione:31 Gennaio 2016
Parole chiave (italiano / inglese):Multiple Sclerosis MRI Neuroimmunology B cells
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/26 Neurologia
Struttura di riferimento:Dipartimenti > Dipartimento di Neuroscienze
Codice ID:9510
Depositato il:06 Ott 2016 17:02
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