Moving beyond the tensor: Advanced characterisation of white matter microstructure in Huntington’s Disease using translational neuroimaging

Huntington’s disease (HD) is a genetic neurodegenerative disorder leading to devastating cognitive, psychiatric and motor symptoms. Currently, this disease cannot be cured, and a research priority is to increase the understanding of its pathogenesis and to provide biomarkers for evaluating the efficacy of targeted therapies. Subtle and progressive white matter (WM) alterations have been observed early in HD progression, before clinical onset of the disease. However the aetiology of WM degeneration and its role in disease pathogenesis remain unclear. The assessment of early WM microstructural changes in the HD brain is therefore of fundamental importance, as this might prove useful for the identification of disease-related biomarkers and for measuring responsiveness to pharmaceutical and other therapeutic approaches. The primary aim of this work was to exploit both ultra-strong gradients (300 mT/m) and ultra-high field (7 Tesla, 9.4 Tesla) to assess WM microstructure in HD, using a variety of MRI techniques in premanifest and manifest patients, as well as in a mouse model of the disease. Specifically, this Thesis moved beyond the diffusion tensor framework, with the application of advanced WM microstructural imaging. Using these advanced MR techniques I was able to provide a comprehensive and detailed characterisation of WM microstructural alterations in the HD brain, and to better tease apart changes in apparent myelin from alterations in axon microstructure. Assessing both human patients and a mouse model of HD allowed for direct cross-species comparisons and bi-directional translation of results. Additionally, I was able to exploit the improved compartmental specificity obtained by complementing standard DTI metrics with advanced MRI measurements, to study the effects of two months of a novel drumming training on WM plasticity in patients with manifest HD

The effect of ERAS management in gastric cancer: assessment from the IMIGASTRIC study

Background:Establish protocols to enhance the surgical management (ERAS) can improve outcomes, shortening hospital stay and save resources. Several studies have carried out for colorectal surgery, while a lack of evidence for gastrectomy remains.This study aims to evaluate the impact of ERAS strategies in a large series of patients underwent gastric cancer surgery.Methods:This is a propensity score-matched case-control study, comparing an ERAS group with a control group. Data were recorded through a tailored and protected web-based system. Primary outcomes: hospital stay, complications rate. Among the secondary outcomes, there are: POD of mobilization, POD of starting liquid diet and soft solid diet.Results:Patients in the ERAS and control groups were 1:1 matched by the closest propensity score on the logit scale and with a Caliber = 0.2. The successful matching resulted in a total sample of 440 patients. The two groups showed no differences in all baseline patients characteristics, type of surgery (P=0.31) and stage of the disease (P=0.61). A benefit in favor of the ERAS management was found in the length of hospital stay (P=0.0004) and complications rate (P=0.001).Conclusion:An ERAS program can safely be established in referral centers for gastric cancer, enabling to significantly improve the main clinical outcomes

A critical review of white matter changes in Huntington’s disease

Huntington’s disease is a genetic neurodegenerative disorder. White matter alterations have recently been identified as a relevant pathophysiological feature of Huntington’s disease, but their etiology and role in disease pathogenesis and progression remain unclear. Increasing evidence suggests that white matter changes in this disorder are due to alterations in myelin-associated biological processes. This review first discusses evidence from neurochemical studies lending support to the ‘De-myelination hypothesis’ of Huntington’s disease, and demonstrating aberrant myelination and changes in oligodendrocytes in the Huntington’s brain. Next, evidence from neuroimaging studies is reviewed, the limitations of the described methodologies are discussed, and suggested interpretations of findings from published studies are challenged. Although our understanding of Huntington’s associated pathological changes in the brain will increasingly rely on neuroimaging techniques, the shortcomings of these methodologies must not be forgotten. Advances in MRI techniques and tissue modeling will enable a better in vivo, longitudinal characterization of the biological properties of white matter microstructure. This, in turn, will facilitate identification of disease-related biomarkers and the specification of outcome measures in clinical trials

Radioguided Parathyroidectomy with Portable Mini Gamma-Camera for the Treatment of Primary Hyperparathyroidism

Background. A proper localisation of pathological parathyroid glands is essential for a minimally invasive approach in the surgical treatment of primary hyperparathyroidism (PHP). The recent introduction of portable mini gamma-cameras (pMGCs) enabled intraoperative scintigraphic scanning. The aim of our study is to evaluate the efficacy of this new method and compare it with the preoperative localisation surveys. Methods. 20 patients were studied; they were evaluated preoperatively by neck ultrasound and Tc-sestaMIBI-scintigraphy and intraoperatively with the pMGC IP Guardian 2. The results obtained from the three evaluations were compared. Results. The pMGC presented a sensitivity of 95%, a specificity of 98.89%, and a diagnostic accuracy of 98.18%, which were higher than those of preoperative ultrasound (sensitivity 55%; specificity 95%; diagnostic accuracy 87%) and scintigraphy with Tc-sestaMIBI (sensitivity 73.68%; specificity 96.05%; diagnostic accuracy 91.58%). Conclusions. The pMGC can be used effectively as an intraoperative method to find the correct location of the pathological parathyroid glands. The pMGC is more reliable than the currently used preoperative and intraoperative localisation techniques

Drumming motor sequence training induces apparent myelin remodelling in Huntington’s disease: a longitudinal diffusion MRI and quantitative magnetization transfer study

Background:Impaired myelination may contribute to Huntington’s disease (HD) pathogenesis. Objective:This study assessed differences in white matter (WM) microstructure between HD patients and controls, and tested whether drumming training stimulates WM remodelling in HD. Furthermore, it examined whether training-induced microstructural changes are related to improvements in motor and cognitive function. Methods:Participants undertook two months of drumming exercises. Working memory and executive function were assessed before and post-training. Changes in WM microstructure were investigated with diffusion tensor magnetic resonance imaging (DT-MRI)-based metrics, the restricted diffusion signal fraction (Fr) from the composite hindered and restricted model of diffusion (CHARMED) and the macromolecular proton fraction (MPF) from quantitative magnetization transfer (qMT) imaging. WM pathways linking putamen and supplementary motor areas (SMA-Putamen), and three segments of the corpus callosum (CCI, CCII, CCIII) were studied using deterministic tractography. Baseline MPF differences between patients and controls were assessed with tract-based spatial statistics. Results:MPF was reduced in the mid-section of the CC in HD subjects at baseline, while a significantly greater change in MPF was detected in HD patients relative to controls in the CCII, CCIII, and the right SMA-putamen post-training. Further, although patients improved their drumming and executive function performance, such improvements did not correlate with microstructural changes. Increased MPF suggests training-induced myelin changes in HD. Conclusion:Though only preliminary and based on a small sample size, these results suggest that tailored behavioural stimulation may lead to neural benefits in early HD, that could be exploited for delaying disease progression

proNGF Measurement in Cerebrospinal Fluid Samples of a Large Cohort of Living Patients With Alzheimer's Disease by a New Automated Immunoassay

The discovery of new biomarkers for Alzheimer's disease (AD) is essential for an accurate diagnosis, to conceive new strategies of treatments, and for monitoring the efficacy of potential disease-modifying therapies in clinical trials. proNGF levels in the cerebrospinal fluid (CSF) represent a promising diagnostic biomarker for AD, but its validation was hampered by the absence of a reliable immunoassay. In the literature, proNGF is currently measured in postmortem brain tissue by semiquantitative immunoblot. Here we describe the development and validation of a new method to measure proNGF in the CSF of living patients. This method, based on molecular size separation by capillary electrophoresis, is automated and shows a 40-fold increase in sensitivity with respect to the proNGF immunoblot, largely used in literature, and is robust, specific, and scalable to high-throughput. We have measured proNGF in the cerebrospinal fluid of 84 living patients with AD, 13 controls, and 15 subjective memory complaints (SMC) subjects. By comparing the proNGF levels in the three groups, we found a very significant difference between proNGF levels in AD samples compared with both controls and SMC subjects, while no significant difference was found between SMC and controls. Because of the development of this new immunoassay, we are ready to explore the potentiality of proNGF as a new biomarker for AD or subgroups thereof, as well as for other neurodegenerative diseases

IL-27, but not IL-35, inhibits neuroinflammation through modulating GM-CSF expression

IL-27 and IL-35 are heterodimeric cytokines, members of the IL-12 family and considered to have immunomodulatory properties. Their role during neuroinflammation had been investigated using mutant mice devoid of either one of their subunits or lacking components of their receptors, yielding conflicting results. We sought to understand the therapeutic potential of IL-27 and IL-35 delivered by gene therapy in neuroinflammation. We constructed lentiviral vectors expressing IL-27 and IL-35 from a single polypeptide chain, and we validated in vitro their biological activity. We injected IL-27 and IL-35-expressing lentiviral vectors into the cerebrospinal fluid (CSF) of mice affected by experimental neuroinflammation (EAE), and performed clinical, neuropathological and immunological analyses. Both cytokines interfere with neuroinflammation, but only IL-27 significantly modulates disease development, both clinically and neuropathologically. IL-27 protects from autoimmune inflammation by inhibiting granulocyte macrophages colony-stimulating factor (GM-CSF) expression in CD4+ T cells and by inducing program death-ligand 1 (PD-L1) expression in both CNS-resident and CNS-infiltrating myeloid cells. We demonstrate here that IL-27 holds therapeutic potential during neuroinflammation and that IL-27 inhibits GM-CSF and induces pd-l1 mRNA in vivo

Metabolic Signature of Arrhythmogenic Cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM) is a genetic-based cardiac disease accompanied by severe ventricular arrhythmias and a progressive substitution of the myocardium with fibro-fatty tissue. ACM is often associated with sudden cardiac death. Due to the reduced penetrance and variable expressivity, the presence of a genetic defect is not conclusive, thus complicating the diagnosis of ACM. Recent studies on human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) obtained from ACM individuals showed a dysregulated metabolic status, leading to the hypothesis that ACM pathology is characterized by an impairment in the energy metabolism. However, despite efforts having been made for the identification of ACM specific biomarkers, there is still a substantial lack of information regarding the whole metabolomic profile of ACM patients. The aim of the present study was to investigate the metabolic profiles of ACM patients compared to healthy controls (CTRLs). The targeted Biocrates AbsoluteIDQ® p180 assay was used on plasma samples. Our analysis showed that ACM patients have a different metabolome compared to CTRLs, and that the pathways mainly affected include tryptophan metabolism, arginine and proline metabolism and beta oxidation of fatty acids. Altogether, our data indicated that the plasma metabolomes of arrhythmogenic cardiomyopathy patients show signs of endothelium damage and impaired nitric oxide (NO), fat, and energy metabolism

Mutation-related magnetization-transfer, not axon density, drives white matter differences in premanifest Huntington disease:Evidence from in vivo ultra-strong gradient MRI

White matter (WM) alterations have been observed in Huntington disease (HD) but their role in the disease-pathophysiology remains unknown. We assessed WM changes in premanifest HD by exploiting ultra-strong-gradient magnetic resonance imaging (MRI). This allowed to separately quantify magnetization transfer ratio (MTR) and hindered and restricted diffusion-weighted signal fractions, and assess how they drove WM microstructure differences between patients and controls. We used tractometry to investigate region-specific alterations across callosal segments with well-characterized early- and late-myelinating axon populations, while brain-wise differences were explored with tract-based cluster analysis (TBCA). Behavioral measures were included to explore disease-associated brain-function relationships. We detected lower MTR in patients' callosal rostrum (tractometry: p = .03; TBCA: p = .03), but higher MTR in their splenium (tractometry: p = .02). Importantly, patients' mutation-size and MTR were positively correlated (all p-values < .01), indicating that MTR alterations may directly result from the mutation. Further, MTR was higher in younger, but lower in older patients relative to controls (p = .003), suggesting that MTR increases are detrimental later in the disease. Finally, patients showed higher restricted diffusion signal fraction (FR) from the composite hindered and restricted model of diffusion (CHARMED) in the cortico-spinal tract (p = .03), which correlated positively with MTR in the posterior callosum (p = .033), potentially reflecting compensatory mechanisms. In summary, this first comprehensive, ultra-strong gradient MRI study in HD provides novel evidence of mutation-driven MTR alterations at the premanifest disease stage which may reflect neurodevelopmental changes in iron, myelin, or a combination of these

Fifteen years trends of cardiogenic shock and mortality in patients with diabetes and acute coronary syndromes

PURPOSE: Our study was intended to examine time trends of management and mortality of acute coronary syndrome patients with associated diabetes mellitus. METHODS: We analyzed data from 5 nationwide registries established between 2001 and 2014, including consecutive acute coronary syndrome patients admitted to the Italian Intensive Cardiac Care Units. RESULTS: Of 28,225 participants, 8521 (30.2%) had diabetes: as compared with patients without diabetes, they were older and had significantly higher rates of prior myocardial infarction and comorbidities (all P &lt; .0001). Prevalence of diabetes and comorbidities increased over time (P for trend &lt; .0001). Cardiogenic shock rates were higher in patients with diabetes, as compared with those without diabetes (7.8% vs 2.8%, P &lt; .0001), and decreased significantly over time only in patients without diabetes (P = .007). Revascularization rates increased over time in patients both with and without diabetes (both P for trend &lt; .0001), although with persistingly lower rates in patients with diabetes. All-cause in-hospital mortality was higher in patients with diabetes (5.4 vs 2.5%, respectively, P &lt; .0001) and decreased more consistently in patients without diabetes (P for trend = .007 and &lt; .0001, respectively). At multivariable analysis, diabetes remains an independent predictor of both cardiogenic shock (odds ratio 2.03; 95% confidence interval, 1.77-2.32; P &lt; .0001) and mortality (odds ratio 1.95; 95% confidence interval, 1.69-2.26; P &lt; .0001). CONCLUSIONS: Despite significant mortality reductions observed over 15 years in acute coronary syndromes, patients with diabetes continue to show threefold higher rates of cardiogenic shock and lower revascularization rates as compared with patients without diabetes. These findings may explain the persistingly higher mortality of patients with diabetes and acute coronary syndromes