Genetically Determined Measures of Striatal D2 Signaling Predict Prefrontal Activity during Working Memory Performance

Background: Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known. Methods: Thirty-seven healthy subjects were genotyped for rs1076560 (G>T) and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors) and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors), as well as BOLD fMRI during N-Back working memory. Results: Subjects carrying the T allele (previously associated with reduced D2S expression) had striatal reductions of [ 123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers) and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT. Conclusions: Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic- cortical pathwa

DRD2 genotype predicts prefrontal activity during working memory after stimulation of D2 receptors with bromocriptine

Rationale: Pharmacological stimulation of D2 receptors modulates prefrontal neural activity associated with working memory (WM) processing. The T allele of a functional single-nucleotide polymorphism (SNP) within DRD2 (rs1076560 G > T) predicts reduced relative expression of the D2S receptor isoform and less efficient neural cortical responses during WM tasks. Objective: We used functional MRI to test the hypothesis that DRD2 rs1076560 genotype interacts with pharmacological stimulation of D2 receptors with bromocriptine on prefrontal responses during different loads of a spatial WM task (N-Back). Methods: Fifty-three healthy subjects (38 GG and 15 GT) underwent two 3-T functional MRI scans while performing the 1-, 2- and 3-Back versions of the N-Back WM task. Before the imaging sessions, either bromocriptine or placebo was administered to all subjects in a counterbalanced order. A factorial repeated-measures ANOVA within SPM8 (p < 0.05, family-wise error corrected) was used. Results: On bromocriptine, GG subjects had reduced prefrontal activity at 3-Back together with a significant decrement in performance, compared with placebo. On the other hand, GT subjects had lower activity for the same level of performance at 1-Back but a trend for reduced behavioral performance in the face of unchanged activity at 2-Back. Conclusions: These results indicate that bromocriptine stimulation modulates prefrontal activity in terms of disengagement or of efficiency depending on DRD2 genotype and working memory load

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Associazione della variazione genetica in RTN4R con espressione di Nogor, volume di sostamza bianca ed elaborazione cognitiva prefrontale. Uno studio post-mortem ed uno in soggetti sani

Il gene RTN4R è localizzato sulla regione 22q11 e codifica per un recettore assonale (Nogo-R) implicato nei meccanismi di crescita assonale. Studi precedenti hanno dimostrato un’associazione fra il gene RTN4R e specifici fenotipi associati a schizofrenia. In questo lavoro, sono stati studiati i potenziali correlati molecolari, di imaging cerebrale e comportamentali associati a varianti genetiche di RTN4R. Nello specifico sono stati valutati l’espressione di mRNA in corteccia prefrontale, il volume di sostanza bianca, l’attività corticale durante working memory e le abilità cognitive attentive-esecutive. In un campione di tessuto di corteccia prefrontale post-mortem di 268 soggetti sani, è stato trovato che il polimorfismo rs696884 del gene RTN4R era associato a livelli differenti di espressione di Nogo-R, in particolare i soggetti AA erano associati ad un decremento dei livelli di mRNA in confronto a soggetti GG. Inoltre, lo studio in vivo su 282 soggetti sani ha mostrato che il genotipo AA era associato anche ad una riduzione di volume della sostanza bianca nella corteccia prefrontale, ad un incremento dell’attività prefrontale di working memory, durante una sessione di risonanza magnetica funzionale, ed a punteggi inferiori a test di valutazione delle funzioni attinenti il dominio cognitivo attentivo-esecutivo. Complessivamente, tali risultati suggeriscono che variazioni genetiche di RTN4R modulano le funzioni prefrontali. Ulteriori studi sono necessari per analizzare la relazione fra RTN4R e schizofrenia

Il contributo della psicodiagnostica alla perizia psichiatrica nell’anziano

È un dato ormai acquisito che la popolazione anziana sta aumentando nel nostro paese. Ciò comporta nuove problematiche medico-legali, criminologiche, psichiatriche e psicologiche per le discipline forensi, che si dovranno sempre più confrontare con le delicate questioni che questa fascia d’età solleva in ambito valutativo e peritale. Gli autori, nel loro lavoro, si soffermano in particolar modo sul ruolo ed il contributo, le potenzialità ed i limiti che la psicodiagnostica forense può fornire a tali delicate questioni valutative, che ormai non appartengono più al futuro, ma al presente di chi opera in questo ambito

The assessment of the level and of the intellectual qualities at the expert level. The contribution of two psychodiagnostic tools: the Wechsler scales and the Raven matrices

The measurement and evaluation of that set of cognitive functions that go under the name of intelligence, as well as the study and collection of data on human performance, in order to reach conclusions about the functioning of subjects suspected of presenting neurological disorders or psychiatrists, they pose different and complex problems when they are carried out in the psychological and psychiatric forensic field.The centrality of the clinical-forensic investigations must be placed on the functioning of the subject and not so much on the nosographic and classification aspects. Much will also depend on the constructs and concepts of intelligence and intellectual functioning to be referred to.The mental efficiency reagents of the Wechsler scales and of the Raven test, if well used, in the forensic context, represent different and excellent psychodiagnostic tools, which contribute to measure differently intelligence of a subject, minor or adult and also any damage or limitations from which it is characterized. In the present work it comes in terms of limits and potential

La valutazione del livello e delle qualità intellettive a livello peritale. Il contributo di due strumenti psicodiagnostici: le scale Wechsler e le matrici di Raven

The measurement and evaluation of that set of cognitive functions that go under the name of intelligence, as well as thestudy and collection of data on human performance, in order to reach conclusions about the functioning of subjects suspectedof presenting neurological disorders or psychiatrists, they pose different and complex problems when they are carried outin the psychological and psychiatric forensic field. The centrality of the clinical-forensic investigations must be placed onthe functioning of the subject and not so much on the nosographic and classification aspects. Much will also depend on theconstructs and concepts of intelligence and intellectual functioning to be referred to. The mental efficiency reagents of theWechsler scales and of the Raven test, if well used, in the forensic context, represent different and excellent psychodiagnostictools, which contribute to measure differently intelligence of a subject, minor or adult and also any damage or limitationsfrom which it is characterized. In the present work it comes in terms of limits and potential.La misurazione e la valutazione di quell’insieme di funzioni cognitive che vanno sotto il nome di intelligenza, così come lostudio e la raccolta di dati sulle prestazioni umane, al fine di giungere a conclusioni circa il funzionamento di soggetti che sisospetta presentino disturbi neurologici o psichiatrici, pongono diversi e complessi problemi quando sono svolti in ambitopsicologico e psichiatrico forense. La centralità delle indagini clinico-forensi dovrà essere posta sul funzionamento del soggettoe non tanto sugli aspetti nosografici e classificatori. Molto dipenderà anche dai costrutti e dai concetti di intelligenza e funzionamentointellettivo a cui fare riferimento. I reattivi di efficienza mentale delle scale Wechsler e del test di Raven, se benusati, nel contesto forense, rappresentano differenti ed utili strumenti psicodiagnostici, che contribuiscono a misurare evalutare in modo diverso e con metodo, l’intelligenza di un soggetto, minore o adulto, mettendo in luce anche eventualidanni o limitazioni da cui è caratterizzato. Nel presente lavoro se ne tratta in termini di limiti e potenzialità

D2 receptor genotype and striatal dopamine signaling predict motor cortical activity and behavior in humans

Objective: Pre-synaptic D2 receptors regulate striatal dopamine release and DAT activity, key factors for modulation of motor pathways. A functional SNP of DRD2 (rs1076560 GNT) is associated with alternative splicing such that the relative expression of D2S (mainly pre-synaptic) vs. D2L (mainly post-synaptic) receptor isoforms is decreased in subjects with the T allele with a putative increase of striatal dopamine levels. To evaluate how DRD2 genotype and striatal dopamine signaling predict motor cortical activity and behavior in humans, we have investigated the association of rs1076560 with BOLD fMRI activity during a motor task. To further evaluate the relationship of this circuitry with dopamine signaling, we also explored the correlation between genotype based differences in motor brain activity and pre-synaptic striatal DAT binding measured with [123I] FP-CIT SPECT. Methods: Fifty healthy subjects, genotyped for DRD2 rs1076560 were studied with BOLD-fMRI at 3 T while performing a visually paced motor task with their right hand; eleven of these subjects also underwent [123I] FP-CIT SPECT. SPM5 random-effects models were used for statistical analyses. Results: Subjects carrying the T allele had greater BOLD responses in left basal ganglia, thalamus, supplementary motor area, and primary motor cortex, whose activity was also negatively correlated with reaction time at the task. Moreover, left striatal DAT binding and activity of left supplementary motor area were negatively correlated. Interpretation: The present results suggest that DRD2 genetic variation was associated with focusing of responses in the whole motor network, in which activity of predictable nodes was correlated with reaction time and with striatal pre-synaptic dopamine signaling. Our results in humans may help shed light on genetic risk for neurobiological mechanisms involved in the pathophysiology of disorders with dysregulation of striatal dopamine like Parkinson's disease

Interaction between catechol-O-methyltransferase (COMT) Val 158Met genotype and genetic vulnerability to schizophrenia during explicit processing of aversive facial stimuli

Background. Emotion dysregulation is a key feature of schizophrenia, a brain disorder strongly associated with genetic risk and aberrant dopamine signalling. Dopamine is inactivated by catechol-O-methyltransferase (COMT), whose gene contains a functional polymorphism (COMT Val158Met) associated with differential activity of the enzyme and with brain physiology of emotion processing. The aim of the present study was to investigate whether genetic risk for schizophrenia and COMT Val158Met genotype interact on brain activity during implicit and explicit emotion processing. Method. A total of 25 patients with schizophrenia, 23 healthy siblings of patients and 24 comparison subjects genotyped for COMT Val158Met underwent functional magnetic resonance imaging during implicit and explicit processing of facial stimuli with negative emotional valence. Results. We found a main effect of diagnosis in the right amygdala, with decreased activity in patients and siblings compared with control subjects. Furthermore, a genotyperdiagnosis interaction was found in the left middle frontal gyrus, such that the effect of genetic risk for schizophrenia was evident in the context of the Val/Val genotype only, i.e. the phenotype of reduced activity was present especially in Val/Val patients and siblings. Finally, a complete inversion of the COMT effect between patients and healthy subjects was found in the left striatum during explicit processing. Conclusions. Overall, these results suggest complex interactions between genetically determined dopamine signalling and risk for schizophrenia on brain activity in the prefrontal cortex during emotion processing. On the other hand, the effects in the striatum may represent state-related epiphenomena of the disorder itself

COGNITIVE DEFICITS AS INTERMEDIATE PHENOTYPE IN SCHIZOPHRENIA

Background: Cognitive deficits have been demonstrated both in patients with schizophrenia and in their unaffected first-degree relatives, suggesting that it might be considered as a familial vulnerability marker. Substantial impairment have been described for short term memory, attention, working memory, executive function. Therefore cognitive impairment has been suggested as a endophenotype We used the neuropsychological battery for estimate the principals schizophrenia cognitive disfunctions order to determine which components are impaired in both patients and their siblings, possibly reflecting shared genetic effects. Methods: We studied 184 subjects. 60 patients with schizophrenia: 36 males; mean \ub1 SD; age = 33.6 \ub1 9.5 years; TIB (Intelligence Short Test, premorbid IQ) = 106.31 \ub1 9.56; parental socioeconomic status (Hollingshead Scale) = 30.1 \ub1 16.1; handedness (Edinburgh Scale) = 0.7 \ub1 0.4. 54 unaffected siblings: 30 males; mean + SD; age = 35.8 \ub1 9 years; TIB (Intelligence Short Test, premorbid IQ) = 107.7 \ub1 9.1; parental socioeconomic status (Hollingshead Scale) = 28.3 \ub1 16.2; handedness (Edinburgh Scale) = 0.7 \ub1 0.4. 70 normal controls: 31 males; mean + SD; age = 32.9 \ub1 7.2 years; TIB (Intelligence Short Test, premorbid IQ) = 113.7 \ub1 6; parental socioeconomic status (Hollingshead Scale) = 33.3 \ub1 13.4; handedness (Edinburgh Scale) = 0.7 \ub1 0.4. Subjects underwent a set of neuropsychological tests assessing WM (N-back), sustained attention (Continuous Performance Test, CPT), executive function (Wisconsin Card Sorting Test, WCST), cognitive flexibility (Trail Making Test A-B) and we calculated a Z score for all subjects. Results: There was no significant differences between diagnostic groups in any socio-demographic variables. Consistent with previous reports healthy siblings had an average performance at the composite score which was in between that of healthy controls and that of patients with schizophrenia. Moreover our results demonstrate a diagnosis effect on working memory performance and TMT score where siblings had an intermediate performance between that of schizophrenic patients and controls. Discussion: These results demonstrate a significant evidence of potential susceptibility of siblings to cognitive impairments suggesting an association with genetic predisposition to schizophrenia. Moreover this study suggests the opportunity of using WM and cognitive flexibility as a neurocognitive endophenotype for investigation in schizophrenia research