BACKGROUND: Il disturbo depressivo maggiore (MDD) è un grave disturbo psichiatrico progressivo, con episodi ricorrenti nel corso della vita. È stato riportato che le esperienze di vita stressanti, sia precoci che recenti, aumentano il rischio di sviluppare la depressione e alterano la struttura cerebrale. Recenti scoperte evidenziano un ruolo chiave dei marcatori metabolici e infiammatori nella patofisiologia del disturbo. Lo scopo dello studio è stato quello di esplorare la complessa interazione tra SLE, misure di marcatori immunitari e metabolici periferici e un profilo di neuroimaging multimodale in pazienti con MDD. METODI: Sessantuno pazienti con MDD sono stati reclutati all'interno del reparto psichiatrico di Ville Turro, Ospedale San Raffaele, e sono stati sottoposti ad acquisizione di risonanza magnetica multimodale, prelievo di sangue venoso e valutazione clinica. Trentatré controlli sani sono stati sottoposti a un prelievo di sangue. Abbiamo testato gli effetti di analiti infiammatori e metabolici (sistema Luminex) e di specifiche popolazioni di cellule immunitarie (colorazione FACS) sulle misure DTI della materia bianca (WM) e sui volumi della materia grigia (GM). Abbiamo utilizzato la tecnica della morfometria basata sui voxel per i volumi regionali di GM e la statistica spaziale basata sui tratti del cervello intero per ottenere misure DTI (anisotropia frazionaria, diffusività assiale, radiale e media) della microstruttura della WM. Inoltre, l'influenza dei marcatori infiammatori sull'associazione tra SLE e WM è stata testata con un modello di mediazione. RISULTATI: abbiamo riscontrato un aumento complessivo dei mediatori pro- e anti-infiammatori nei pazienti con MDD rispetto agli HC. Inoltre, è stato osservato un effetto del SLE sia precoce che recente sulle alterazioni della WM nel fascicolo uncinato sinistro, mediato da specifiche citochine (IL-2, IL-5, IL-6, IL-12 e VEGF). Diverse citochine, chemochine e cellule immunitarie sono risultate associate alla struttura della WM e del GM, mentre i marcatori metabolici sono stati associati alle misure DTI della microstruttura della WM. Gli effetti rilevati suggeriscono l'esistenza di processi sia tossici sia rigenerativi che agiscono in una complessa interazione. Infine, è emerso un legame tra i marcatori infiammatori e le funzioni cognitive, con un effetto di interazione tra CCL2 e IL-16 e FA sulla codifica dei simboli. CONCLUSIONE: Questi risultati supportano l'ipotesi che l'attivazione di sistemi metabolici e di risposta infiammatoria possa essere coinvolta nella fisiopatologia del MDD, interferendo con la struttura cerebrale in network cortico-limbici importanti per la regolazione dell'umore e il funzionamento neurocognitivo. Inoltre, l'esposizione al SLE sembra svolgere un ruolo centrale nell'indurre uno stato di infiammazione cronica in cui le prime esperienze di vita sembrano indurre un priming della microglia, facendo si che un secondo evento avverso in tarda adolescenza o in età adulta induca una risposta microgliale esagerata.

BACKGROUND: Major Depressive Disorder (MDD) is a severe progressive psychiatric disorder, with lifetime-recurrent episodes. Both early and recent stressful life experiences (SLEs) have been reported to rise the risk of developing depression and to alter the brain structure. Recent findings point out a key role of both metabolic and inflammatory markers in the pathophysiology of the disorder. The aim of the study was to explore the complex interplay between SLEs, measures of peripheral immune and metabolic markers, and a multimodal neuroimaging profile in MDD patients. METHODS: Sixty-one MDD patients were recruited within the psychiatric ward of Ville Turro, San Raffaele Hospital, and underwent multimodal MRI acquisition, venous blood sampling and clinical evaluation. Thirty-three healthy controls underwent a blood sampling. We tested the effects of inflammatory and metabolic analytes (Luminex system) and specific immune cells populations (FACS staining) on DTI measures of white matter (WM) microstructure and on gray matter (GM) volumes. We used voxel based morphometry technique for regional GM volumes and whole brain tract-based spatial statistics to obtain DTI measures (fractional anisotropy, axial, radial, and mean diffusivity) of WM microstructure. Furthermore, the influence of inflammatory markers on the association between SLEs and WM was tested with mediation effect models. RESULTS: We found an overall increase of both pro- and anti- inflammatory mediators in MDD patients compared to HC. Moreover, an effect of both early and recent SLEs on WM alterations in the left uncinate fasciculus was observed and was mediated by specific cytokines (IL-2, IL-5, IL-6, IL-12 and VEGF). Several cytokines, chemokines and immune cells resulted to be associated with both WM and GM structure, while metabolic markers associated with DTI measures of WM microstructure. The detected effects suggests the existence of both toxic and regenerative processes which act in a complex interplay. Finally, a link between inflammatory markers and cognitive domain emerged, with an interaction effect of CCL2 and IL-16 and FA on symbol coding. CONCLUSION: These findings support the hypothesis that activated metabolic and inflammatory response systems might be involved in MDD pathophysiology, interfering with brain structure in crucial cortico-limbic networks important for mood regulation and neurocognitive functioning. Moreover, exposure to SLEs seems to play a pivotal role in inducing a state of chronic inflammation in which early life experiences seems to prime microglia, so that a second hit in late adolescent or adulthood induced an exaggerated microglial response.

Role of inflammation and metabolism in structural brain integrity in Major Depressive disorder / Elena Beatrice Mazza - : . , 2022 Oct 04. ((34. ciclo, Anno Accademico 2020/2021.

Role of inflammation and metabolism in structural brain integrity in Major Depressive disorder

MAZZA, ELENA BEATRICE
2022

Abstract

BACKGROUND: Major Depressive Disorder (MDD) is a severe progressive psychiatric disorder, with lifetime-recurrent episodes. Both early and recent stressful life experiences (SLEs) have been reported to rise the risk of developing depression and to alter the brain structure. Recent findings point out a key role of both metabolic and inflammatory markers in the pathophysiology of the disorder. The aim of the study was to explore the complex interplay between SLEs, measures of peripheral immune and metabolic markers, and a multimodal neuroimaging profile in MDD patients. METHODS: Sixty-one MDD patients were recruited within the psychiatric ward of Ville Turro, San Raffaele Hospital, and underwent multimodal MRI acquisition, venous blood sampling and clinical evaluation. Thirty-three healthy controls underwent a blood sampling. We tested the effects of inflammatory and metabolic analytes (Luminex system) and specific immune cells populations (FACS staining) on DTI measures of white matter (WM) microstructure and on gray matter (GM) volumes. We used voxel based morphometry technique for regional GM volumes and whole brain tract-based spatial statistics to obtain DTI measures (fractional anisotropy, axial, radial, and mean diffusivity) of WM microstructure. Furthermore, the influence of inflammatory markers on the association between SLEs and WM was tested with mediation effect models. RESULTS: We found an overall increase of both pro- and anti- inflammatory mediators in MDD patients compared to HC. Moreover, an effect of both early and recent SLEs on WM alterations in the left uncinate fasciculus was observed and was mediated by specific cytokines (IL-2, IL-5, IL-6, IL-12 and VEGF). Several cytokines, chemokines and immune cells resulted to be associated with both WM and GM structure, while metabolic markers associated with DTI measures of WM microstructure. The detected effects suggests the existence of both toxic and regenerative processes which act in a complex interplay. Finally, a link between inflammatory markers and cognitive domain emerged, with an interaction effect of CCL2 and IL-16 and FA on symbol coding. CONCLUSION: These findings support the hypothesis that activated metabolic and inflammatory response systems might be involved in MDD pathophysiology, interfering with brain structure in crucial cortico-limbic networks important for mood regulation and neurocognitive functioning. Moreover, exposure to SLEs seems to play a pivotal role in inducing a state of chronic inflammation in which early life experiences seems to prime microglia, so that a second hit in late adolescent or adulthood induced an exaggerated microglial response.
BENEDETTI, FRANCESCO
Role of inflammation and metabolism in structural brain integrity in Major Depressive disorder / Elena Beatrice Mazza - : . , 2022 Oct 04. ((34. ciclo, Anno Accademico 2020/2021.
Doctoral Thesis
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/132511
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