Caratterizzazione dei sintomi neurovegetativi e neuropsicologici nella malattia di Parkinson associata a mutazioni del gene glucocerebrosidasi

Pochi studi hanno indagato il profilo dei sintomi non-motori nella malattia di Parkinson associata al gene glucocerebrosidasi (GBA). Questo studio è mirato alla caratterizzazione dei sintomi non-motori, con particolare attenzione alla valutazione delle funzioni neurovegetativa, cognitiva e comportamentale, nel parkinsonismo associato a mutazione del gene GBA con la finalità di verificare se tali sintomi non-motori siano parte dello spettro clinico di questi pazienti. E’ stato condotto su una coorte di pazienti affetti da malattia di Parkinson che erano stati tutti sottoposti ad una analisi genetica per la ricerca di mutazioni in uno dei geni finora associati alla malattia di Parkinson. All’interno di questa coorte omogenea sono stati identificati due gruppi diversi in relazione al genotipo (pazienti portatori della mutazione GBA e pazienti non portatori di nessuna mutazione) e le caratteristiche non-motorie sono state confrontate nei due gruppi. Sono state pertanto indagati il sistema nervoso autonomo, mediante studio dei riflessi cardiovascolari e analisi dei sintomi disautonomici, e le funzioni cognitivo-comportamentali in pazienti affetti da malattia di Parkinson associata a mutazione del gene GBA. I risultati sono stati messi a confronto con il gruppo di controllo. Lo studio ha mostrato che i pazienti affetti da malattia di Parkinson associata a mutazione del gene GBA presentavano maggiore frequenza di disfunzioni ortosimpatiche, depressione, ansia, apatia, impulsività, oltre che di disturbi del controllo degli impulsi rispetto ai pazienti non portatori. In conclusione, i pazienti GBA positivi possono esprimere una sintomatologia non-motoria multidominio con sintomi autonomici, cognitivi e comportamentali in primo piano. Pertanto l’impostazione terapeutica in questi pazienti dovrebbe includere una accurata valutazione dei sintomi non-motori e un loro monitoraggio nel follow up clinico, allo scopo di ottimizzare i risultati e ridurre i rischi di complicazioni.

Essays in Economic Geography and Long-Term Development

This dissertation has two main themes: first, the economic impact of tourism on cities and, secondly, the determinants of European long-run development, with a focus on the pre-Industrial era. The common thread is the attempt to develop economic geography models that incorporate spatial frictions and are liable to be given empirical content. Chapter 1, written in conjunction with G. Alfredo Minerva, provides an empirical analysis of the relationship between tourism and economic activity across Italian municipalities, and lays down the basic elements of an urban theory of tourism in an a-spatial setting. Chapter 2 extends these ideas to a quantitative urban framework to study the economic impact and the welfare consequences of tourism into the city of Venice. The model is given empirical content thanks to a large collection of data at the Census tract level for the Municipality of Venice, and then used to perform counterfactual policty analysis. In chapter 3, with Matteo Santacesaria, we consider a setting where agents are continuously distributed over a two-dimensional heterogeneous geography, and are allowed to do business at a finite set of markets. We study the equilibrium partition of the economic space into a collection of mutually-exclusive market areas, and provide condition for this equilibrium partition to exist and to be unique. Finally, chapter 4 "The rise of (urban) Europe: a Quantitative-Spatial analysis", co-authored with Matteo Cervellati and Alex Lehner, sets up a quantitative economic geography model to understand the roots of the Industrial Revolution, in an attempt to match the evolution of the European urban network, and the corresponding city-size distribution, over the period A.D. 1000-1850. It highlights the importance of agricultural trade across cities for the emergence of large manufacturing hubs.

SPHERA, a new Italian convection-permitting regional reanalysis: improving heavy-rainfall representation and describing hail-prone environments

Extreme weather events related to deep convection are high-impact critical phenomena whose reliable numerical simulation is still challenging. High-resolution (convection-permitting) modeling setups allow to switch off physical parameterizations accountable for substantial errors in convection representation. A new convection-permitting reanalysis over Italy (SPHERA) has been produced at ARPAE to enhance the representation and understanding of extreme weather situations. SPHERA is obtained through a dynamical downscaling of the global reanalysis ERA5 using the non-hydrostatic model COSMO at 2.2 km grid spacing over 1995-2020. This thesis aims to verify the expectations placed on SPHERA by analyzing two weather phenomena that are particularly challenging to simulate: heavy rainfall and hail. A quantitative statistical analysis over Italy during 2003-2017 for daily and hourly precipitation is presented to compare the performance of SPHERA with its driver ERA5 considering the national network of rain gauges as reference. Furthermore, two extreme precipitation events are deeply investigated. SPHERA shows a quantitative added skill over ERA5 for moderate to severe and rapid accumulations in terms of adherence to the observations, higher detailing of the spatial fields, and more precise temporal matching. These results prompted the use of SPHERA for the investigation of hailstorms, for which the combination of multiple information is crucial to reduce the substantial uncertainties permeating their understanding. A proxy for hail is developed by combining hail-favoring environmental numerical predictors with observations of ESWD hail reports and satellite overshooting top detections. The procedure is applied to the extended summer season (April-October) of 2016-2018 over the whole SPHERA spatial domain. The results indicate maximum hail likelihood over pre-Alpine regions and the northern Adriatic sea around 15 UTC in June-July, in agreement with recent European hail climatologies. The method demonstrates enhanced performance in case of severe hail occurrences and the ability to separate between ambient signatures depending on hail severity.

Liquid biopsy for prostate cancer molecular characterization: homologous recombination system and genomic profile

Pathogenic aberrations in homologous recombination DNA repair (HRR) genes occur in approximately 1 to 4 men with advanced prostate cancer (PCa). Treatment with PARP inhibitors (PARPi) has recently been introduced for metastatic castration-resistant PCa patients, increasing clinicians' interest in the molecular characterization of all PCa patients. The limitations of using old, low-quality tumor tissue for genetic analysis, which is very common for PCa, can be overcome by using liquid biopsy as an alternative biomarker source. In this study, we aimed to evaluate the detection of molecular alterations in HRR genes on liquid biopsy compared with tumor tissue from PCa patients. Secondarily, we explored the genomic instability score (GIS), and a broader range of gene alterations for in-depth characterization of the PCa cohort. Plasma samples were collected from 63 patients with PCa. Sophia Homologous Recombination Solution (targeting 16 HRR genes) and shallow whole genome sequencing (sWGS) were used for genomic analysis of tissue DNA and circulating tumor DNA (ct). A total of 33 alterations (mainly on TP53, ATM, CHEK2, CDK12, and BRCA1/2) were identified in 28,5% of PCa plasma patients. By integrating the mutational and sWGS data, the HRR status of PCa patients was determined and a concordance agreement of 85,7% was identified with tumor tissue. A median GIS of 15 was obtained, reaching a score of 63 in 2 samples with double alterations, BRCA1 and TP53. We explored the PCa mutation landscape, and the most significant enriched pathways identified were the sphingosine 1-phosphate (S1P) receptor signaling and the PI3K-AKT-mTOR pathway. HRR analysis on FFPE and liquid biopsy samples show high concordance, demonstrating that the noninvasive ctDNA-enriched plasma can be an optimal alternative source for molecular SNV and CNV analysis. In addition, the evaluation of GIS and pathway interaction should be considered for more comprehensive molecular characterization in PCa patients.