Academic literature on the topic 'MED/37 NEURORADIOLOGIA'

AIM The aim of the project is to evaluate the role of advanced MRI sequences (susceptibility weight imaging (SWI), diffusion tensor imaging (DTI), and arterial spin labeling (ASL) perfusion) in detecting early changes that affect preterm neonatal brain, especially in those patients without lesions at conventional MRI or with small brain injuries (i.e. low grade germinal matrix-intraventricular hemorrhage (GMHIVH)), and to correlate these subtle brain abnormalities with neurodevelopmental outcome at 24 months. METHODS Since November 2015 until June 2017, 287 preterm neonates and 108 term neonates underwent a 3T or 1.5T MRI study at term corrected age (40±1 weeks). SWI, DTI and ASL sequences were performed in all neonates. SWI sequences were evaluated using both a qualitative (SWI venography) and quantitative (Quantitative Susceptibility Map analysis (SWI-QSM)) approach. DTI data were analyzed using a Tract-Based Spatial Statistics analysis (TBSS). ASL studies were processed to estimate Cerebral Blood Flow (CBF) maps. Perinatal clinical data were collected for all neonates. Neurodevelopmental data were evaluated at 24 months in 175 neonates using 0-2 Griffiths Developmental Scales. RESULTS The analysis performed on SWI-venography revealed differences in subependymal veins morphology between preterm and term neonates with normal brain MRI, with a higher variability from the typical anatomical pattern in preterm neonates. The same analysis performed in preterm neonates with GMH-IVH revealed that the anatomical features of subependymal veins may play a potential role as predisposing factor for GMH-IVH. Moreover, the SWI-QSM analysis revealed a greater paramagnetic susceptibility in several periventricular white matter (WM) regions in preterm neonates with GMH-IVH than in healthy controls. This finding is likely related to the accumulation of hemosiderin/ferritin following the diffusion of large amounts of intraventricular blood products into the WM, and it is also supposed to trigger the cascade of lipid peroxidation and free radical formation that promote oxidative and inflammatory injury of the WM in neonatal brain after GMH-IVH. The TBSS analysis confirmed that microstructural WM injury can occur in preterm neonates with low grade GMH-IVH even in the absence of overt signal changes on conventional MRI, with different patterns of WM involvement depending on gestational age. Moreover, the distribution of these WM microstructural alterations after GMH-IVH correlates with specific neurodevelopmental impairments at 24 months of age. Finally, the analysis of brain perfusion at term-corrected age revealed lower CBF in preterms with sub-optimal neuromotor development, reinforcing the hypothesis that impaired autoregulation of CBF may contribute to the development of brain damage in preterm neonates. CONCLUSION Advanced MRI sequences can assist the standard perinatal brain imaging in the early diagnosis of preterm neonatal brain lesions and can provide new insights for predicting the neurodevelopmental trajectory. However, detailed and serial imaging of carefully chosen cohorts of neonates coupled with longer clinical follow-up are essential to ensure the clinical significance of these novel findings.

The main aim of this works is to explore the relationship between language and analogical reasoning. In fact, despite the increasing interest about the neural substrates of reasoning, at present no fMRI study systematically investigates the contribution of stimulus format/context on reasoning network. In the present work three fMRI studies are developed in order to verify how much reasoning relies on verbal language using different stimuli format and within normal and a language impaired populations. The first study focus on how different verbal context, nameable pictures versus words, may influence brain activity related to analogical reasoning in healthy adults. In a second study the same fMRI paradigm was applied to investigate brain activity during analogical reasoning in young normal readers and young dyslexics in order to understand if the reading disorder may influence the reasoning in relation to the language load requested by the stimulus format. In the third study the contribution of language and semantic system to reasoning was investigate developing a new fMRI design where analogical reasoning had to be performed either on meaningful or on abstract geometrical pictures.

The main aim of this works is to explore the relationship between language and analogical reasoning. In fact, despite the increasing interest about the neural substrates of reasoning, at present no fMRI study systematically investigates the contribution of stimulus format/context on reasoning network. In the present work three fMRI studies are developed in order to verify how much reasoning relies on verbal language using different stimuli format and within normal and a language impaired populations. The first study focus on how different verbal context, nameable pictures versus words, may influence brain activity related to analogical reasoning in healthy adults. In a second study the same fMRI paradigm was applied to investigate brain activity during analogical reasoning in young normal readers and young dyslexics in order to understand if the reading disorder may influence the reasoning in relation to the language load requested by the stimulus format. In the third study the contribution of language and semantic system to reasoning was investigate developing a new fMRI design where analogical reasoning had to be performed either on meaningful or on abstract geometrical pictures.

Aim Imaging biomarkers in medical fields other than oncology tend to be confined to research settings. In neuroimaging, biomarkers of cerebral small vessel disease (SVD) have shown promising results for translation into the clinic but need further validation. In this work, we strove for a more clinically-oriented classification of one of the most representative of SVD biomarkers, i.e. white matter hyperintensities (WMHs), on a large cohort of community-dwelling subjects. We also used this classification to better analyse signs of SVD in a selected population of adults with congenital heart disease. Lastly, we evaluated the steps to be taken for achieving standardisation of WMH assessment. Cerebral small vessel disease in adults with tetralogy of Fallot: preliminary results In this section we describe our exploratory research on a small sample of 10 adult patients with surgically corrected tetralogy of Fallot and 10 age- and sex-matched control subjects. Cerebral microbleeds were visible in every patient and in one control subject. Also, a significant correlation between WMH volume and severity of symptoms of heart failure was observed. Even though the aetiology of the observed findings remained obscure, cerebral microbleeds and WMHs may indicate an increased susceptibility to brain microvascular damage in congenital heart disease and have been deemed worthy of further investigations. Imaging biomarkers of small vessel disease in adults with congenital heart disease: a systematic review Considering our preliminary findings, we extensively reviewed the available literature on vascular injury in adults with congenital heart disease. We found few preliminary studies on this topic, all of which carried several methodological limitations. However, all studies reported a variety of brain vascular changes in the examined patients, ranging from signs of SVD to silent stroke and cortical atrophy. The assumption that these findings differ from those visible in children with heart defects needs to be confirmed. For this purpose, neuroimaging studies in adults with congenital heart disease are needed to differentiate past global lesion burden from present chronic ongoing cerebrovascular disease. Automatic sub-classification of white matter hyperintensities: application to a large community-dwelling cohort As WMH total volume is variably associated with cognition, we developed an automatic method to classify them into four categories according to lesion location (periventricular versus deep) and lesion intensity in T1 and T2-weighted sequences. We applied this method on brain scans from 684 older adults from the Whitehall II study. We also showed that periventricular white matter hyperintensities that appear hypointense in T1-weighted images were significantly associated with poorer performance in several cognitive tests in this cohort. Interestingly, we found no association between total WMH volume and cognition. These findings suggest that sub-classifying WMHs according to both location and intensity in T1-weighted images provides added value when studying the clinical correlates of this imaging biomarker. Inconsistency in quantifying and reporting white matter hyperintensities volume: a systematic review We tried to estimate a normative range for WMH volume in healthy ageing using the highest level of evidence. We meta-analysed 2743 healthy subjects’ WMH volume reported from 17 studies. Our results showed an extremely high heterogeneity across the examined studies. We thereby proposed methodological strategies needed to overcome the current inconsistency in WMH assessment, such as harmonisation of image acquisition and standardisation of anatomical definitions. Most importantly, effective communication between researchers and clinicians is strongly warranted to translate technical know-how for imaging biomarkers assessment into clinical practice. The BACH Study In view of our preliminary results and considering the dearth of scientific evidence on the topic of brain involvement in adults with congenital heart disease, we launched the Brain Aging in Congenital Heart disease (BACH) San Donato study. This multidisciplinary study comprises an extensive brain imaging protocol to investigate signs of small vessel disease and a thorough neuropsychological battery to test patients’ cognitive performance. We found that automatically-detected white matter hyperintensities located in the deep white matter were associated with poorer performance at the frontal assessment battery. Also, this study confirmed that patients had a much larger number of cerebral microbleeds than healthy controls. Conclusions In this thesis we showed that cerebral microbleeds are over-expressed in adult patients with congenital heart disease. Longitudinal studies will aid in clarifying the role of this and other biomarkers of SVD in predicting clinical outcomes. Meanwhile, much effort must be put into reaching standardisation of WMH assessment. Optimal characterisation of brain vascular health in congenital heart disease would enable physicians to adopt prompt strategies to prevent the risk of cognitive deterioration in this category of patients. Full translation of research findings into clinical practice would then be achieved.

Arterial spin labelling (ASL) radiomics analysis to predict IDH mutation and MGMT methylation status in gliomas Fabio M. Doniselli1,2, Riccardo Pascuzzo1, Eleonora Bruno3, Domenico Aquino1, Mattia Verri, Alberto Redolfi, Valeria Cuccarini1, Marco Moscatelli1,2, Maria Grazia Bruzzone1, Luca Maria Sconfienza2,4 Abstract Objectives: To evaluate the strength and ability of radiomics features extracted from multiple tumor subregions on MR brain images to predict MGMT promoter (MGMT) methylation status and isocitrate dehydrogenase (IDH) mutation in glioma patients through a multiparametric MRI-based radiomics model, using arterial-spin labelling (ASL) perfusion imaging. Methods: Retrospective single-institution study in a cohort of 52 glioma patients. Radiomics-based models with a minimal set of relevant features and clinical parameters were built for MGMT methylation and IDH-mutation prediction from a training cohort (31 patients) and tested on an validation cohort (13 patients). Results: Feature selection methods (Boruta, RFE and LR-EL) identified age and 3 radiomics features for MGMT prediction and 3 features for IDH prediction. For IDH prediction, SVM classifier achieved average 96.8% accuracy and 0.929 AUC during the training phase, and 84.6% accuracy and 0.60 AUC on the test set. For MGMT methylation prediction, SVM classifier achieved average 67.7% accuracy and 0.765 AUC during the training phase, and 38.5% accuracy and 0.429 AUC on the test set. Conclusions: The classification model based on both demographic (age) and radiomic ASL perfusion characteristics had the best performance in predicting the IDH mutational status of gliomas. This result suggests that the proposed method has promising efficacy in predicting IDH mutational status. We have not obtained a sufficient result trying to correlate radiomics with the MGMT mutational pattern.
Assessment of quality and classification performances of MRI-based radiomics studies on MGMT methylation in gliomas: a systematic review Fabio M. Doniselli1,2*, Riccardo Pascuzzo1*, Massimiliano Agrò3, Domenico Aquino1, Federica Mazzi1, Francesco Padelli1, Marco Moscatelli1, Maria Grazia Bruzzone1, Luca M. Sconfienza2,4 Objectives To evaluate the quality of MRI-based radiomics studies predicting the O6-methylguanine-DNA methyltransferase (MGMT) methylation status in gliomas, using radiomics quality score (RQS) and Image Biomarkers Standardization Initiative (IBSI) guidelines, and examine their classification performance. Methods PubMed Medline and EMBASE were searched to identify MRI-based radiomics studies on MGMT methylation in gliomas until January 31, 2022. Included studies were scored according to RQS (16 components) and IBSI (six items) scales by two raters. Results We included 20 out of 62 identified studies. The median RQS total score was 32% of the maximum (11.5 out of 36), ranging between 8% and 44%. Eleven studies performed external validation; only three studies performed decision curve analysis to report potential clinical utility. All studies reported area under the curve (AUC) or accuracy, and 14 computed these statistics using resampling methods (e.g., cross-validation). No study performed phantom study, cost-effectiveness analysis, and prospective validation. Regarding IBSI items, 14 studies (70%) performed signal intensity normalization, while few performed N4 bias-field correction (4, 20%) and skull stripping (3, 15%). Good classification performance (AUC>0.75) was obtained by 11 (55%) studies, but only four of them performed external validation (on sets with 20-60 patients). On the contrary, seven out of the nine studies with lower classification results performed external validation (on sets with 27-126 patients). Conclusions Adherence to RQS and IBSI guidelines was generally low. MGMT methylation status appears to be correlated with radiomic features, but with great heterogeneity of results. To confirm this trend, strict implementation of RQS and IBSI criteria is needed.
Radiomics for MGMT methylation detection in GBM using conventional pre-operative MRI Fabio M. Doniselli1,2, Riccardo Pascuzzo1, Massimiliano Agrò3, Domenico Aquino1, Elena Anghileri, Bianca Pollo, Valeria Cuccarini1, Marco Moscatelli1, Francesco DiMeco, Maria Grazia Bruzzone1, Luca M. Sconfienza2,4 Abstract Objectives: To evaluate the strength and ability of radiomics features extracted from multiple tumor subregions on MR brain images to predict MGMT promoter (MGMT) methylation status in GBM patients through a multiparametric MRI-based radiomics model. Methods: Retrospective single-institution study in a cohort of 277 GBM patients. Radiomics-based models with a minimal set of relevant features and clinical parameters were built for MGMT methylation prediction from a training cohort (196 patients) and tested on an validation cohort (81 patients). Radiomic Quality Score (RQS) was equal to 15. Results: Feature selection methods (Boruta, RFE and LR-EL) identified age and 218 radiomics features. SVM classifier achieved average 73.6% (standard deviation: 6.5%) accuracy and 0.836 (0.054) AUC during the training phase, and 59.3% (95% confidence interval: 47.8%-70.0%) accuracy and 0.553 (0.412-0.686) AUC on the test set. Conclusions: We agree on the probable presence of subtle association between imaging characteristics and MGMT methylation status. However, further verification on the strength of this association is needed, as the low diagnostic performance in the validation cohort is still not sufficiently robust to allow clinically meaningful predictions.

Un numero crescente di evidenze ha rivelato che alterazioni del sistema endosomiale-lisosomiale sono collegate ad un malfunzionamento nello smistamento di diverse proteine, portando ad una significativa alterazione della stessa omeostasi proteica. Queste alterazioni risultano particolarmente compromettenti nel campo delle malattie neurodegenerative. In questo scenario, gli esosomi, vescicole extracellulari derivate dal sistema endosomiale-lisosomiale, che riflettono le alterazioni presenti nelle cellule che le hanno prodotte, hanno attirato l'attenzione della comunità scientifica, come possibili marcatori precoci di malattia. Nel campo della malattia di Alzheimer, gli esosomi hanno dimostrato la capacità di ridurre la beta-amiloide cerebrale coinvolgendo l'assorbimento microgliale e gli effetti negativi come la diffusione della tau iperfosforilata, quindi potrebbero essere coinvolti nei meccanismi di apoptosi e, in ultima analisi, contribuire alla degenerazione dendritica. L'espressione dell'apolipoproteina E4, il fattore più rilevante nella malattia di Alzheimer ad esordio tardivo, ha un impatto negativo sulla produzione di esosomi, sia negli esosomi derivati dal cervello umano, sia nel modello murino umanizzato che esprime l'allele ApoE4. Uno dei bersagli dell'apolipoproteina E è la proteina 8 correlata al recettore delle lipoproteine a bassa densità (LRP8 o ApoER2), altamente espressa nel tessuto neuronale e attivamente coinvolta nella formazione della memoria e nella modellazione dei dendriti. Considerando che in precedenza abbiamo osservato che la localizzazione e l'elaborazione di LRP8 sono alterate nella corteccia cerebrale di pazienti affetti da Alzheimer sporadico e familiare, abbiamo deciso di analizzare il ruolo dell'LRP8 sulla produzione di esosomi. Abbiamo riscontrato che negli esosomi derivati dal cervello di pazienti affetti da Alzheimer sporadico e familiare (SAD e FAD), sono fortemente presenti frammenti C-terminali del recettore LRP8 con peso molecolare inferiore a 15 kDa, che invece non sono evidenti nei controlli; segno che il processo proteolitico di LRP8 è fortemente alterato in caso di malattia e che il contenuto delle vescicole cambia radicalmente. Anche la produzione di esosomi cambia radicalmente, essendo fortemente compromessa nel caso di FAD. Abbiamo eseguito esperimenti in vitro utilizzando cellule wild-type Neuro 2A, trasfettate stabilmente con il recettore umano LRP8 (hLRP8) (Neuro 2A DDK myc e Neuro 2A LRP8 HA) e abbiamo scoperto che l'espressione del recettore LRP8 aumenta significativamente la produzione di esosomi. Abbiamo anche espresso nelle cellule Neuro 2A wild-type, la proteina umana Amyloid Precursor Protein 695 (hAPP 695), e abbiamo osservato che i frammenti C-terminali LRP8 sono presenti sia nei lisati cellulari che negli esosomi. Abbiamo evidenziato che il trattamento con ApoE4 umano ricombinante e DAPT (un inibitore della γ-secretasi) diminuisce la produzione di esosomi in vitro e che il trattamento con ApoE4 aumenta i frammenti C-terminali di LRP8 negli esosomi. Infine, per confermare che il recettore LRP8 è coinvolto nella produzione di esosomi, abbiamo eseguito un silenziamento sul recettore LRP8 utilizzando le cellule wild-type Neuro 2A. Abbiamo osservato che silenziando l'espressione di LRP8, c'è una significativa riduzione del numero di esosomi prodotti.
An increasing number of evidences has revealed that alterations of endosomal–lysosomal system are connected to alterated sorting and trafficking of different proteins, leading to a significant alteration of protein homeostasis itself. These alterations result particularly compromising in the field of neurodegenerative diseases. In this scenario, exosomes, extracellular vesicles derived from endosomal– lysosomal system, reflecting the alterations present in the cells that produced them, have attracted the attention of the scientific community, as possible early markers of disease. In the field of Alzheimer Disease, exosomes have been shown the capacity to reduce brain Amyloid-beta involving microglial uptake, and negative effects as spreading hyperphosphorylated tau, therefore they could be involved in the mechanisms of apoptosis and, ultimately, contribute to dendritic degeneration. Apolipoprotein E4 expression, the most relevant factor in Late Onset Alzheimer Disease, has a negative impact on exosomes production, both in human brain derived exosomes, and in humanized mouse model expressing ApoE4 allele. One of the target of Apolipoprotein E is Low-density lipoprotein Receptor-related Protein 8 (LRP8 or ApoER2), highly expressed in neuronal tissue and actively involved in memory formation and spines dendridic modeling. Considering that we previously observed that LRP8 localization and processing are alterated in the cerebral cortex of sporadic and familial Alzheimer’s Disease patients, we decided to analyze the role LRP8 on exosomes production. We found that in exosomes derived from brain of patients affected by sporadic and familial Alzheimer (SAD and FAD), C-terminal fragments of the LRP8 receptor with molecular weight less than 15 kDa are strongly present, which instead are not evident in controls; a sign that the proteolytic processing of LRP8 is strongly altered in case of disease and that the contents of the vesicles change radically. The production of exosomes also changes radically, being strongly compromised in the case of FAD. We performed in-vitro experiments using Neuro 2A wild-type cells, stably transfected with human LRP8 (hLRP8) receptor (Neuro 2A DDK myc and Neuro 2A LRP8 HA), and we found that LRP8 receptor expression significantly increases exosomes production. We also expressed in Neuro 2A wild-type cells, the human protein Amyloid Precursor Protein 695 (hAPP 695), and we observed that LRP8 C-terminal fragments are present both in the cell lysates and in the exosomes. We also reported that recombinant human ApoE4 and DAPT (a γ-Secretase inihibitor) treatment, decrease exosomes production in-vitro, and that ApoE4 treatment increase LRP8 C-terminal fragments in exosomes. Finally, to confirm that LRP8 receptor is involved in exosomes production, we performed a silencing on the LRP8 receptor using the Neuro 2A wild- type cells. We observed that silencing the expression of LRP8, there is a significant reduction in the number of exosomes produced.

BACKGROUND: schizophrenic and bipolar disorders are complex and disabling psychiatric diseases whose classical nosography and classification are still under challenging debate aiming to overcome the traditional “Kraepelinian Dichotomy”. For the past hundred years most clinical work and research in psychiatry has proceeded under the assumption that schizophrenia and bipolar disorderaredistinctentities with separate underlying disease processes and treatments. In more recent years there has been increasing evidence for phenomenological, biological and genetic overlap between the two disorders (Potash and Bienvenu 2009). Nowadays, the categorical approach to psychiatric nosography is in contrast with the recent neurobiological, neuropsychological and genetic findings in affective and schizophrenic disorders. Further, symptoms and signs constituting bipolar and schizophrenic disorders are continuously, not dichotomously, distributed; there may be no point of “real cleavage” (Phelps et al. 2008). This recognition has led some clinicians and researchers to call for a diagnostic model that, moving to a “dimensional perspective”, formally recognizes a continuous spectrum from schizophrenic to bipolar (and recurrent depressive) disorders. Kelsoe argued that the existing data coming from various fields of research in bipolar and schizophrenic disorders may best fit a model in which different set of genes predispose to overlapping phenotypes in a continuum. Given the apparent overlap of regions of the genome implicated in bipolar disorder with those for schizophrenia (Kelsoe 1999; Berrettini 2000), the data suggest the possibility that a common polygenic background predisposes to both bipolar disorder and schizophrenia, according to the so-called “multiple threshold model” (Kelsoe 2003). As highlighted by Craddock and Owen, the recent findings are compatible with a model of functional psychosis in which susceptibility to a spectrum of clinical phenotypes is under the influence of overlapping sets of genes, which, together with environmental and epigenetic factors, determine an individual’s expression of illness (Craddock and Owen 2005). A lot of interest is focusing on brain structural abnormalities in patients suffering from schizophrenia and bipolar disorder. A huge amount of neuroimaging studies has been published so far, however the literature is heterogeneous and there is still some degree of uncertainty concerning what key regions are involved in the pathogenesis of such disorders. Schizophrenia and Bipolar Disorder have a number of overlapping symptoms and risk factors, but it is not yet clear if the disorders are characterized by similar deviations in brain morphometry or whether any such deviations reflect the impact of shared susceptibility genes on brain structure. To date there is no consensus about whether, and to what extent, gray matter loss in Schizophrenia is mirrored in Bipolar Disorder and what is the effect of medication or other confounding factors. Studies in family members of patients, who share the risk of the disease but not the confounding factors, may help elucidate whether abnormalities in brain structures are shared by both illnesses. AIM OF THE STUDY: to investigate hippocampal gray matter volume differences in a group of patients with bipolar-schizophrenic spectrum disorders, a group of their unaffected first-degree relatives, and a group of healthy control subjects. METHODS: a total of 104 subjects - 36 schizophrenic or schizoaffective (SZ), 27 bipolar (BP), 2 major depression, 8 unaffected relatives (UR), and 31 healthy controls (HC) - underwent 1,5 T MRI scanning, with volumetric T1 3D acquisition protocol, at the Neuroradiology Unit of Conegliano Hospital. We calculate bilateral hippocampal gray matter volume (HV) and total cerebral volume (TCV) in a sample of 31 SZ, 27 BP, 8 UR and 26 HC, with a stereological method using ANALYZE 10.0 software. RESULTS: we found statistically significant reductions in bilateral HV in the BP-SZ patients compared to HC; the direct comparison between patient groups identified statistically significant reduction in the right HV of SZ, but no significant differences for left HV or TCV (however statistical significance was lost after normalization); statistically significant reduction in the left HV and a trend towards statistical significance for right HV in the UR compared to HC (a trend towards statistically significant reduction in bilateral HV persisted after normalization). CONCLUSION: it might be speculated that the alterations of the gray matter volume in the hippocampus highlighted in our study could be interpreted as a possible structural “biological marker” in the schizophrenic-bipolar spectrum.
INTRODUZIONE: schizofrenia e disturbo bipolare sono malattie psichiatriche complesse e invalidanti, il cui inquadramento nosografico è oggetto di continuo dibattito nel superamento della classica “dicotomia Kraepeliniana” tra Dementia Praecox e Malattia Maniaco-Depressiva. Negli ultimi cento anni, buona parte della pratica clinica e della ricerca in psichiatria sono state basate sull’assunto che schizofrenia e disturbo bipolare fossero entità categorialmente distinte, separate da distinti meccanismi patologici e trattamenti. In anni più recenti invece, si sono accumulate numerose evidenze a supporto di una parziale sovrapposizione fenomenologica, biologica e genetica tra questi disturbi (Potash e Bienvenu 2009). Attualmente, l’approccio nosografico “categoriale” nei disturbi affettivi e schizofrenici è in contrasto con le più recenti scoperte in ambito neurobiologico, neuropsicologico e genetico. Inoltre è stato evidenziato come, nemmeno dal punto di vista clinico vi sia un reale punto di “separazione” tra i due disturbi, che presentano segni e sintomi comuni e sovrapponibili (Phelps et al. 2008). Tale consapevolezza ha portato clinici e ricercatori a orientarsi verso un modello diagnostico che, spostandosi in una prospettiva “dimensionale”, formalmente riconosce l’esistenza di uno spettro tra disturbi schizofrenici e bipolari. Kelsoe afferma che i dati provenienti dai vari filoni di ricerca nei disturbi bipolari e schizofrenici potrebbero essere meglio spiegati da un modello in cui differenti set di geni predispongono a fenotipi clinici che si sovrappongono in un continuum. Data la documentata sovrapposizione fra regioni genomiche implicate nel disturbo bipolare con quelle della schizofrenia (Kelsoe 1999; Berrettini 2000), le evidenze suggeriscono la possibilità che un substrato poligenico comune possa conferire una predisposizione a entrambi i disturbi, secondo il cosiddetto modello delle “soglie multiple” (Kelsoe 2003). Come sottolineato da Craddock e Owen, le più recenti scoperte in tale ambito sono compatibili con un modello di psicosi funzionale, nel quale la suscettibilità ad uno spettro di fenotipi clinici è sotto l’influenza di un set di geni condivisi, che, insieme a fattori ambientali ed epigenetici, determina l’espressione di malattia in ciascun individuo (Craddock e Owen 2005). Notevole interesse si sta inoltre focalizzando sulle alterazioni strutturali cerebrali in pazienti affetti da schizofrenia e disturbo bipolare. Nonostante l’ingente mole di studi di neuroimaging finora pubblicati, la letteratura sull’argomento è molto eterogenea ed esiste ancora notevole incertezza su quali siano le specifiche regioni cerebrali coinvolte nella patogenesi di tali disturbi. Schizofrenia e Disturbo Bipolare condividono una serie di sintomi e fattori di rischio, ma non è ancora stato chiarito se questi disturbi siano caratterizzati da comuni modificazioni morfometriche cerebrali e se tali alterazioni riflettano l’impatto di geni comuni di suscettibilità sulla morfologia del cervello. Ad oggi, non è stato definitivamente chiarito se, e fino a che punto, la documentata perdita di sostanza grigia nella Schizofrenia si rifletta anche nel Disturbo Bipolare e su quali siano gli effetti della farmacoterapia o di altri fattori di confondimento. Gli studi sui membri non affetti di pazienti schizofrenici e bipolari, che condividono la predisposizione genetica ai disturbi, ma non i fattori di confondimento, posso rivelarsi utili nel verificare se le varie anomalie cerebrali siano condivise nelle due patologie. SCOPO DELLO STUDIO: analizzare eventuali differenze volumetriche nella sostanza grigia ippocampale in un gruppo di pazienti dello spettro bipolare-schizofrenico, un gruppo di familiari di primo grado non affetti e un gruppo di soggetti sani di controllo. MATERIALI E METODI: un totale di 104 sogetti - 36 pazienti con disturbo schizofrenico o schizoaffettivo (SZ), 27 pazienti con disturbo bipolare (BP), 2 pazienti affetti da depressione maggiore ricorrente, 8 familiari di primo grado non affetti (UR) e 31 controlli sani (HC) sono stati sottoposti ad una procedura di Risonanza Magnetica cerebrale ad 1,5 Tesla, secondo un protocollo di acquisizione di sequenze T1 3D volumetriche, presso l’Unità Operativa di Neuroradiologia del Presidio Ospedaliero di Conegliano. Mediante l’utilizzo del Software ANALYZE 10.0, sono stati calcolati, con un metodo stereologico, i volumi bilaterali della sostanza grigia ippocampale (HV) ed il volume cerebrale totale (TCV) in un campione di 31 SZ, 27 BP, 8 UR e 26 HC. RISULTATI: sono state riscontrate riduzioni volumetriche statisticamente significative della sostanza grigia di ippocampo destro e sinistro tra i gruppi di pazienti dello spettro bipolare-schizofrenico rispetto ai controlli; nel confronto diretto tra il gruppo di pazienti schizofrenici e quello dei bipolari è stata identificata una riduzione statisticamente significativa del volume della sostanza grigia dell’ippocampo destro (tale significatività non persiste in seguito a normalizzazione) e nessuna significativa differenza nei volumi della sostanza grigia dell’ippocampo sinistro o nel volume cerebrale totale; nel confronto tra il gruppo di familiari di primo grado non affetti rispetto al gruppo di soggetti sani di controllo è stata evidenziata una significativa riduzione volumetrica della sostanza grigia dell’ippocampo sinistro e un trend verso la significatività statistica per l’ippocampo destro (tali riduzioni volumetriche della grigia ippocampale mantenevano bilateralmente tale trend verso la significatività statistica anche dopo la normalizzazione). CONCLUSIONE: la alterazione volumetrica della sostanza grigia ippocampale evidenziata nel nostro studio potrebbe essere interpretata come un possibile “marker biologico” strutturale nei disturbi dello spettro schizofrenico-bipolare.

SCOPO Confrontare la performance diagnostica della valutazione qualitativa e quella automatica quantitativa delle immagini TC-perfusione nell’identificazione di core ischemico e penombra ischemica in pazienti con stroke ischemico acuto del circolo posteriore. MATERIALI E METODI Sono stati consecutivamente inclusi nello studio pazienti colpiti da ictus ischemico acuto in territorio di circolo posteriore sottoposti in regime di urgenza a protocollo multimodale TC (GE “Lightspeed” a 64 strati) includendo lo studio di perfusione, dal mese di gennaio 2016 al mese di dicembre 2018. Secondo necessità clinica, alcuni pazienti sono stati studiati al tempo 0 anche con RM (Philips “Intera” 3,0T o “Ingenia” 1,5T) mediante sequenze DWI e FLAIR, mentre altri sono stati sottoposti ad esame RM in un secondo momento. Per determinare l’estensione della lesione ischemica è stato utilizzato il punteggio Posterior circulation - Acute Stroke Prognosis Early CT Score (pc-ASPECT score) applicato nella la valutazione semiquantitativa delle immagini TC basali e nelle mappe perfusionali mediante software CTP-4 (tempo di transito medio, MTT; volume ematico cerebrale, CBV; flusso ematico cerebrale, CBF) al tempo 0, delle sequenze DWI delle RM eseguite al tempo 0 o al controllo, e delle TC basali eseguite di controllo. Le acquisizioni TC perfusionali sono state, inoltre, rielaborate anche mediante il software RAPID (iSchemia View) ottenendo in modo automatico mappe perfusionali colorimetriche e quantitative, includendo anche il parametro tempo al picco massimo (Tmax). RISULTATI Sono stati inclusi 50 pazienti (34 maschi e 16 femmine) con età media di 71,9 anni, tutti sottoposti a protocollo TC multimodale (TC basale + angio-TC + TC perfusione) in acuto (< 24 ore dall’esordio dei sintomi); di questi, 28 pazienti sono stati anche sottoposti a studio RM, entro 8 ore dall’esordio nella metà dei casi. Dei 50 pazienti inclusi, 6 non hanno mostrato core ischemico al follow-up né alterazione di almeno due parametri di perfusione e sono stati considerati come controlli negativi. La valutazione qualitativa dei parametri MTT-CTP4D e Tmax-RAPID nelle mappe colorimetriche ha mostrato la più alta sensibilità (SE) (MTT: 88,6%, p<0,05; Tmax: 90,9%, p<0,05) con sovrapponibile accuratezza (ACC) (88%> 84%, p>0,05) tra i due software. La valutazione qualitativa della TC basale e quella del parametro CBF nella mappa di mismatch RAPID hanno presentato i più bassi valori di SE (29,6% e 6,8% p<0,05) e ACC (38% e 18% p<0,05). La valutazione automatica quantitativa del parametro CBF nelle mappe di mismatch RAPID si è rivelata inferiore in termini di SE (6,8%) rispetto a quella qualitativa delle mappe ottenute con i software CTP4 e RAPID (81,8% e 61,4%), entrambe con equiparabile SE (81,8% > 61,4%, p>0,05). La valutazione automatica quantitativa del parametro Tmax nelle mappe di mismatch RAPID ha presentato ridotte SE e ACC (90,9%>65,9% e 88%>70%) rispetto a quella qualitativa delle mappe colorimetriche RAPID. Non è stata riscontrata significativa differenza tra i punteggi pc-ASPECT assegnati mediante valutazione delle mappe colorimetriche MTT e Tmax né tra quelli attribuiti nelle mappe CBV CTP4D and CBF-RAPID. CONCLUSIONE Indipendentemente dal software utilizzato, la valutazione qualitativa delle mappe colorimetriche ha mostrato maggiore SE rispetto all’analisi automatica quantitativa ed i parametri perfusionali MTT e Tmax sono risultati i più sensibili. Le mappe di mismatch elaborate automaticamente da RAPID non hanno identificato o hanno sottostimato il danno ischemico nella maggior parte dei pazienti, specialmente a carico del talamo e del tronco encefalico. L’attribuzione dei punteggi pc-ASPECT nelle mappe colorimetriche ha mostrato sostanziale equivalenza dei modelli di mismatch MTT-CBV and Tmax-CBF.
AIM To examine and compare the diagnostic performance in the detection of acute posterior circulation strokes between qualitative evaluation of software-generated colour maps and automatic assessment of CT perfusion (CTP) parameters by RAPID. METHODS AND MATERIALS Imaging data were retrospectively collected from a prospective database of consecutive patients undergone to multimodal CT scan dataset (GE “Lightspeed” a 64 slices) including CTP performed on admission (<24h after symptom onset) between January 2016 and December 2018. Follow-up imaging consisted in non-contrast CT (NCCT). If clinically indicated, MRI (Philips Intera 3.0 T or Philips Achieva Ingenia 1.5T) was performed either soon after the CTP at the admission or later as follow-up control including DWI and FLAIR sequences. The Posterior circulation - Acute Stroke Prognosis Early CT Score (pc-ASPECT score) was used for quantifying the extent of ischaemic areas on initial NCCT and color-coded maps generated by CTP4 software ( cerebral blood flow, CBF; cerebral blood volume, CBV; mean transit time, MTT). Final pc-ASPECTS was calculated on follow-up NCCT and/or on MRI if performed. Afterwards, CTP data were also processed by RAPID software (iSchemia View) obtaining color-coded maps, including time-to maximum (Tmax), and automatic quantitative mismatch maps. RESULTS A total of 50 patients met the inclusion criteria. 6 out of the 50 patients did not show ischemic core at follow-up imaging neither alteration of at least two perfusion parameters in the same location and were grouped as negative controls. All patients underwent to follow-up NCCT and 28 of them also underwent DWI-MRI. Out of the 28 patients undergone MRI, 14 patients (50%) underwent DWI study within 8 hours after multimodal CT study at admission. The sensitivity (SE) of qualitative evaluation of color-coded MTT-CTP4D map and color-coded Tmax-RAPID map resulted significantly higher than the other ones (MTT: 88.6%, p<0.05; Tmax: 90.9%, p<0.05) with comparable diagnostic accuracy (ACC) (88%> 84%, p>0.05). NCCT at baseline and CBF provided by RAPID quantitative perfusion mismatch maps had the lowest SE (29.6% and 6.8% p<0.05, respectively) and ACC (38% and 18% p<0.05, respectively). CBF assessment provided by quantitative RAPID perfusion mismatch maps showed significant lowest SE (6.8%) in comparison to qualitative evaluations of both color-coded CBF-CTP4D and CBF-RAPID maps (81.8% and 61.4% respectively); no significant SE difference was found between qualitative evaluations of color-coded CBF-CTP4D and CBF-RAPID maps (81.8% > 61.4%, p>0.05).Qualitative evaluation of color-coded Tmax -RAPID maps showed significant higher SE and ACC than quantitative assessment of Tmax automatically provided by RAPID perfusion mismatch maps (90.9%>65.9% and 88%>70%, respectively). No significant differences were found between the pc-ASPECT scores assessed on color-coded MTT and Tmax maps neither between the scores assessed on color-coded CBV-CTP4D and CBF-RAPID maps. CONCLUSION Independently to the software employed, qualitative analysis of color-coded maps resulted more sensitive in the detection of ischemic changes than automatic quantitative analysis. The most sensitive perfusion parameters were MTT and Tmax. RAPID software generated mismatch maps overlooked and underestimated the extent of the ischemic core in the major part of the patients as compared with the qualitative analysis. The limits of identification of the lesions by automatic quantitative mismatch maps mainly lied in the thalamus and brainstem. Visual assessment of CTP pc-ASPECTS on color-coded perfusion maps revealed equivalence of both mismatch models (MTT-CBV and Tmax-CBF) commonly applied in acute setting with implications for treatment decision-making.

Introduction. Plenty of literature focused on the topography of multiple sclerosis (MS) injury localization within brain. Various theories were proposed to explain this pattern, calling into question two main hypothesis: 1- preexistent tissue-intrinsic microstructural susceptibility factors 2- cerebrospinal-fluid (CSF)-borne soluble inflammatory factors diffusing through the brain surfaces (inner-ependymal-ventricular and outer-pial-cortical), thence affecting the parenchyma with a decreasing distribution along a distance-from-CSF gradient. However, despite more than one hundred years of efforts, the etio-physio-pathological basis of the onset and development of the MS plaque has not been completely unveiled yet. Recent technological advances in magnetic resonance imaging (MRI) and data post-processing, enabling an in-vivo definition of the local microstructure of the white matter (WM), give new perspectives for untangling the secrets of this complex disease. Materials & Methods. With a novel algorithm to analyze diffusion weighted MRI images, “NODDI”, we created detailed atlases of the microstructural characteristics of the normal WM in a healthy population; parallelly, we defined the topography of the lesions for a MS-affected population. By superposition of the patients lesion maps onto the healthy atlas, we could then test if any of the microstructural NODDI parameters is predictive of development of a T1-visible lesion. We then tested at which deepness of the gradient of distance from CSF, the a-priori microstructural susceptibility factor was more responsible of the T1-visible lesion development. Finally, we computed the mean distance from the CSF of the T1-lesioned tissue, compared to the T1-spared one. Results. In the corresponding areas where the patients developed T1-visible lesions, we found significant higher values of Neurite Density (ND) on the healthy population atlas, if compared to the areas where no lesion was visible on T1 imaging. The a-priori tissue property of high ND was found to have its greatest influence on T1-visible lesion formation especially in the deep WM layer (the furthest from the pial and ventricular surfaces). The NODDI microstructural parameter Orientation Dispersion Index (ODI) showed to have no influence at any level on the tissue proneness to develop a T1-visible lesion. The average distance of the T1-lesioned tissue from the ventricles was higher than the one of the T1-spared tissue. Conclusion. Our results suggest that an higher density of neurites seem to play a role on the probability of development of a T1-visible WM lesion in MS, while the orientation dispersion of the axons does not appear to have any impact on these pathological events. An higher coherence and compactness of structure in the myelin-rich WM areas could constitute a facilitating factor for the auto-inflammatory immune process against myelin antigens. It is interesting to see that this effect, which appears already significant when considered the whole brain, looks to be even more prominent in the “deep WM layer”, which is the furthest-from-CSF part of WM. Conversely, the lesion-promoting effect of high ND seems to be attenuated or neutralized in the WM layers neighboring the CSF: this fact brings to speculate the existence of some underlying interaction between inflammatory soluble factors and tissue structure, at different WM deepness levels.

INTRODUCTION A mood characterised by alternating mania and depression have been matter of curiosity and attention since ancient times. According to T.J. Crow’s theory on psychosis, Schizophrenia is strictly linked to the development of the faculty of language (begun in hominids from 6 to 4.2 million years ago) which depends by (anatomical and functional) asymmetry observable between the two cerebral hemispheres (Crow 2004). Several data in the recent (and older) (Griesinger 1845) scientific literature support the hypothesis that schizophrenia and bipolar disorder are similar due to a large number of partially common features: symptomatology, genetics, cognitive features, neurobiology, connectivity alteration, etc.. A brief historical account about how often the classification of this disease changed across the last two centuries may suggest how the knowledge underling this diagnostic category is still fragile. AIM OF THE RESEARCH The goal of this paper is to study Functional Connectivity (FC) among bipolar patients and to test the compatibility of Crow’s paradigm with Bipolar Disorder, verifying the potential presence of hemispheric asymmetry alteration (left dominance deficit) through fMRI analysis. MATERIALS AND METHODS 18 outpatients of the Mood Disorders Unit at the Psychiatric Clinic of the University of Padua have been recruited. All subjects had a diagnosis of Bipolar Disorder type I or type II, according to the criteria of the DSM-IV-TR). 16 healthy individuals were chosen matched for age, sex and education. Clinical and psychological conditions at the time of the experiment were investigated through some psychometric scales widely used for the evaluation of mood, anxiety and other psychopathologic aspects. All subjects underwent a MRI scan both in resting state and while they were attending two tasks: a phonemic (verbal fluency) exercise and a visuo-spatial test (mental rotations). RESULTS From the neuropsychological point of view the phonemic task revealed no significant (p<0.05) differences between groups; on the contrary patients group showed decreased performance at the visuo-spatial task. MRI FC was analysed using two different techniques. Independent Component Analysis (ICA) showed mainly a volume within the Dorsal Attention Network located in left Precuneus (Brodmann Area 7) where patient group presented a reduction of FC compared to controls. Graph analysis brought to light a number of inter-hemispheric and left intra-hemispheric connections revealed to be significantly less active in patients compared to controls, on the contrary substantial conservation of indices at the Network Level was observed.
INTRODUZIONE Un tono timico caratterizzato da un’alternanza di mania e depressione è stato oggetto di interesse e attenzione fin dai tempi antichi. Secondo La teoria di T.J. Crow sulla psicosi, la schizofrenia è strettamente legata allo sviluppo della facoltà del linguaggio (che ha avuto origine negli ominidi da 6 a 4,2 milioni di anni fa) che dipende dall'asimmetria (anatomica e funzionale) osservabile tra i due emisferi cerebrali (Crow 2004). Diversi dati nella letteratura scientifica recente (e più antica – Griesinger 1845) supportano l'ipotesi che la schizofrenia e il disturbo bipolare siano simili per un gran numero di caratteristiche parzialmente comuni: sintomatologia, genetica, cognitività, neurobiologia, alterazione della connettività, ecc. Un breve resoconto storico di quanto spesso la classificazione di questa malattia sia cambiata negli ultimi due secoli può suggerire come la conoscenza sottesa a questa categoria diagnostica sia ancora fragile. SCOPO DELLA RICERCA L'obiettivo di questo studio è quello di studiare la connettività funzionale (FC) tra i pazienti bipolari e testare la compatibilità del paradigma di Crow con il disturbo bipolare, verificando la potenziale presenza di alterazioni dell'asimmetria emisferica (deficit di dominanza sinistra) attraverso l'analisi fMRI (risonanza magnetica funzionale). MATERIALI E METODI Sono stati reclutati 18 pazienti ambulatoriali dell'Unità di Disturbi dell'Umore presso la Clinica Psichiatrica dell'Università di Padova. Tutti i soggetti avevano una diagnosi di disturbo bipolare di tipo I o di tipo II, secondo i criteri del DSM-IV-TR). Sono stati scelti 16 individui sani abbinati per età, sesso e istruzione. Le condizioni cliniche e psicologiche al momento dell'esperimento sono state studiate attraverso alcune scale psicometriche ampiamente utilizzate per la valutazione dell'umore, dell'ansia e di altri aspetti psicopatologici. Tutti i soggetti sono stati sottoposti a una risonanza magnetica sia in stato di riposo che durante l’esecuzione di due compiti: un esercizio fonemico (fluenza verbale) e un test visuo-spaziale (rotazioni mentali). RISULTATI Dal punto di vista neuropsicologico, il compito fonemico non ha rivelato differenze significative (p<0.05) tra i gruppi; al contrario, il gruppo di pazienti ha mostrato una riduzione delle prestazioni nel compito visuo-spaziale. I dati fMRI sono stati analizzati utilizzando due tecniche diverse. L'Independent Component Analysis (ICA) ha mostrato principalmente un volume all'interno della Dorsal Attention Network situato nel precuneo sinistro (area 7 di Brodmann) dove il gruppo di pazienti presentava una riduzione significativa della FC rispetto ai controlli. L'analisi dei grafi ha portato alla luce un numero di connessioni intra-emisferiche e intra-emisferiche di sinistra rivelate significativamente meno attive nei pazienti rispetto ai controlli, al contrario è stata osservata una sostanziale conservazione degli indici a livello di rete.