Positron emissiontomography imaging of neuroinflammation in Multiple Sclerosis with a second generation translocator protein PET radioligand

This thesis describes a new approach for molecular imaging of neuroinflammation in Multiple Sclerosis (MS). My aim was to use the 2nd generation TSPO radioligand 18F-PBR111 to explore the potential of Positron Emission Tomography (PET) targeting the 18-kDa Translocator Protein (TSPO), as an in vivo biomarker of activated microglia in MS patients. This thesis addresses three research objectives. First, I characterised 18F-PBR111 PET signal in healthy controls’ brains and tested how it is affected by the TSPO gene polymorphism at rs6971. Second, I measured 18F-PBR111 uptake across white matter volumes segmented using structural MRI measures related to MS neuropathology. Third, I explored how 18F-PBR111 uptake in the hippocampus correlated with depressive symptoms and to the brain functional connectivity of the hippocampus. Eleven patients with relapsing-remitting MS and 22 age-matched healthy controls underwent 18F-PBR111 PET and MRI scans. Structural and functional MRI sequences were used to define conventional MS neuropathological markers and for the assessment of functional connectivity, respectively. I discovered that white matter 18F-PBR111 PET signal in healthy volunteers varied with TSPO genotype and correlated positively with age. In patients with MS, signal intensity in MRI-defined lesions was higher than that in normal-appearing white matter and correlated with the historical rate of progression of their disability. Hippocampal 18F-PBR111 uptake was higher in the MS patient group than in healthy volunteers and correlated with both depressive symptoms and functional connectivity of the hippocampus with frontal, temporal and parietal cortex. I thus discovered that this 2nd generation TSPO PET radiotracer, used in humans for the first time in our study, is sensitive to MS neuropathology consistent with recognized patterns of microglial activation and that differences between subjects can be related to disability progression. I also have discovered a novel relationship between this measure of hippocampal microglial activation and affective symptoms of MS.Open Acces

Gli istituti deflattivi del contenzioso tributario. Stato attuale e criticit\ue0

ll legislatore tributario, soprattutto a partire dal 1997, ha ritenuto di affermare in maniera sempre pi\uf9 esplicita la necessit\ue0 della collaborazione e del contraddittorio nel rapporto tra Fisco e contribuente, soprattutto in considerazione del fatto che la mancanza di un confronto tra le parti finisce per facilitare la creazione di situazioni conflittuali, che sfociano nella attivazione di posizioni di contenzioso. Sono stati cos\uec introdotti nel nostro ordinamento, gli istituti deflattivi del contenzioso tributario, in base ai quali il contribuente che, trovandosi in una situazione di lite potenziale con gli Uffici, rinuncia al contenzioso e versa l\u2019imposta, ha diritto a sanzioni ridotte nonch\ue9 ad altri vantaggi, compresa una piccola copertura verso possibili futuri accertamenti e la possibilit\ue0 di effettuare il pagamento dilazionato delle somme dovute. Sebbene oggetto di intervento nel corso degli anni, tali istituti presentano ancora numerosi profili critici e ampi margini di miglioramento

Gli istituti deflattivi del contenzioso tributario e il principio d'indisponibilit\ue0 dell'obbligazione fiscale

Il concetto d'indisponibilit\ue0 dell'obbligazione tributaria: contenuti e limiti. L'accertamento con adesione nel quadro degli strumenti deflattivi del contenzioso tributario: il discusso inquadramento teorico dell'istituto tra indisponibilit\ue0 ed accordo. Le modalit\ue0 di definizione alternativa delle controversie tributarie: l'impatto della conciliazione e della mediazione sul principio d'indisponibilit\ue0

Gli istituti deflattivi del contenzioso tributario e il principio d'indisponibilità dell'obbligazione fiscale

Il concetto d'indisponibilità dell'obbligazione tributaria: contenuti e limiti. L'accertamento con adesione nel quadro degli strumenti deflattivi del contenzioso tributario: il discusso inquadramento teorico dell'istituto tra indisponibilità ed accordo. Le modalità di definizione alternativa delle controversie tributarie: l'impatto della conciliazione e della mediazione sul principio d'indisponibilità

Carbon Dioxide Inhalation Induces Dose-Dependent and Age-Related Negative Affectivity

BACKGROUND: Carbon dioxide inhalation is known to induce an emotion similar to spontaneous panic in Panic Disorder patients. The affective response to carbon dioxide in healthy subjects was not clearly characterized yet. METHODOLOGY/PRINCIPAL FINDINGS: Sixty-four healthy subjects underwent a double inhalation of four mixtures containing respectively 0, 9, 17.5 and 35% CO(2) in compressed air, following a double blind, cross-over, randomized design. Affective responses were assessed according to DSM IV criteria for panic, using an Electronic Visual Analogue Scale and the Panic Symptom List. It was demonstrated that carbon dioxide challenges induced a dose dependent negative affect (p<0.0001). This affect was semantically identical to the DSM IV definition of panic. Older individuals were subjectively less sensitive to Carbon Dioxide (p<0.05). CONCLUSIONS/SIGNIFICANCE: CO(2) induced affectivity may lay on a continuum with pathological panic attacks. Consistent with earlier suggestions that panic is a false biological alarm, the affective response to CO(2) may be part of a protective system triggered by suffocation and acute metabolic distress

The neurometabolic basis of mood instability: the parvalbumin interneuron link — a systematic review and meta-analysis

The neurobiological bases of mood instability are poorly understood. Neuronal network alterations and neurometabolic abnormalities have been implicated in the pathophysiology of mood and anxiety conditions associated with mood instability and hence are candidate mechanisms underlying its neurobiology. Fast-spiking parvalbumin GABAergic interneurons modulate the activity of principal excitatory neurons through their inhibitory action determining precise neuronal excitation balance. These interneurons are directly involved in generating neuronal networks activities responsible for sustaining higher cerebral functions and are especially vulnerable to metabolic stress associated with deficiency of energy substrates or mitochondrial dysfunction. Parvalbumin interneurons are therefore candidate key players involved in mechanisms underlying the pathogenesis of brain disorders associated with both neuronal networks’ dysfunction and brain metabolism dysregulation. To provide empirical support to this hypothesis, we hereby report meta-analytical evidence of parvalbumin interneurons loss or dysfunction in the brain of patients with Bipolar Affective Disorder (BPAD), a condition primarily characterized by mood instability for which the pathophysiological role of mitochondrial dysfunction has recently emerged as critically important. We then present a comprehensive review of evidence from the literature illustrating the bidirectional relationship between deficiency in mitochondrial-dependent energy production and parvalbumin interneuron abnormalities. We propose a mechanistic explanation of how alterations in neuronal excitability, resulting from parvalbumin interneurons loss or dysfunction, might manifest clinically as mood instability, a poorly understood clinical phenotype typical of the most severe forms of affective disorders. The evidence we report provides insights on the broader therapeutic potential of pharmacologically targeting parvalbumin interneurons in psychiatric and neurological conditions characterized by both neurometabolic and neuroexcitability abnormalities

Symptom Dimensions as Predictors of Clinical Outcome, Duration of Hospitalization, and Aggressive Behaviours in Acutely Hospitalized Patients with Psychotic Exacerbation

In the present study we extract clusters of symptoms in acute hospitalized psychotic patients during a re-exacerbation phase, using factor analysis of BPRS-E. We aim to investigate the relative contribution of each symptom dimension in predicting the severity of symptoms at discharge, the length of acute hospitalization, and the occurrence of aggressive behaviours during acute hospitalization. The data are drawn from a prospective, naturalistic, observational study of 183 patients with Psychotic Disorders consecutively admitted to a psychiatric ward, during a re-exacerbation phase. General symptomatology has been measured through BPRS-E at admission and at discharge. Statistical analyses include principal component analysis and multiple linear regression

Online information on medical cannabis is not always aligned with scientific evidence and may raise unrealistic expectations

There is a growing literature on the potential medical uses of Cannabis sativa and cannabinoid compounds. Although these have only been approved by regulatory agencies for a few indications, there is a hype about their possible benefits in a variety of conditions and a large market in the wellness industry. As in many cases patients search for information on cannabis products online, we have analyzed the information on medical cannabis available on the Internet. Therefore, this study aims at assessing the quality of the information available online on medical cannabis

Parasuicide and drug self-poisoning: analysis of the epidemiological and clinical variables of the patients admitted to the Poisoning Treatment Centre (CAV), Niguarda General Hospital, Milan

Epidemiological knowledge of parasuicides and drug self-poisoning is still limited by a lack of data. A number of preliminary studies, which require further analysis, evidenced that parasuicidal acts occur more often among females, that the peak rate is generally recorded between the ages of 15 and 34 years and psychotropic medications seems to be the most frequently used. The aim of this study was to describe the demographic and clinical variables of a sample of subjects admitted to the Posisoning Treatment Centre (CAV), Niguarda General Hospital, Milan, following drug self-poisoning. Furthermore, this study is aimed to identify the risk factors associated to parasuicidal gestures, with special care for the used drugs, the presence of psychiatric or organic disorders, alcoholism and drug addiction. The study included the 201 patients attending the CAV in 1999 and 2000 who satisfied the criteria of self-poisoning attempts: 106 cases in 1999 and 95 in 2000. The sample had a prevalence of females (64%). The peak rates of parasuicides from drug self-poisoning were reached between 21 and 30 years among the females, and 31 and 40 years among the males. 81.6% of the patients used one or more psychoactive drugs, the most frequent being the benzodiazepines (58.7%), classic neuroleptics (16.9%) and new-generation antidepressants (SSRIs, SNRIs, NARIs) (12.9%). The prevalence of mood disorders was higher among females (64% vs 42%), whereas schizophrenia was more frequently diagnosed in males (22% vs 10%). 61% (33%) had a history of previous attempted suicides. The presence of clinically relevant organic diseases was observed in 24.9% of the sample