Veronica Marinelli

Increased M1/decreased M2 signature and signs of Th1/Th2 shift in chronic patients with bipolar disorder, but not in those with schizophrenia

We here present data on immune gene expression of chemokines, chemokine receptors, cytokines and regulatory T-cell (T-reg) markers in chronic patients suffering from either schizophrenia (SCZ, N=20) or bipolar disorder (BD=20) compared with healthy controls (HCs, N=20). We extracted RNA from peripheral blood mononuclear cells and performed real-time (RT)-PCR to measure mRNA levels of chemokines, chemokine receptors, cytokines and T-reg markers. All the analyses were Bonferroni-corrected. The classical monocyte activation (M1) markers il6, ccl3 were significantly increased in BD as compared with both HC and SCZ patients (P=0.03 and P=0.002; P=0.024 and P=0.021, respectively), whereas markers of alternative (M2) monocyte activation ccl1, ccl22 and il10 were coherently decreased (controls: P=0.01, P=0.001 and P=0.09; SCZ subjects: P=0.02, P=0.05 and P=0.011, respectively). Concerning T-cell markers, BD patients had compared with HC downregulated ccr5 (P=0.02) and upregulated il4 (P=0.04) and compared with both healthy and SCZ individuals downregulated ccl2 (P=0.006 and P=0.003) and tgfβ (P=0.004 and P=0.007, respectively). No significant associations were found between any immune gene expression and clinical variables (prior hospitalizations, Brief Psychiatric Rating Scale, medications’ dosages and lifetime administration). Although some markers are expressed by different immune cell types, these findings suggest a coherent increased M1/decrease M2 signature in the peripheral blood of BD patients with potential Th1/Th2 shift. In contrast, all the explored immune marker levels were preserved in SCZ. Further larger studies are needed to investigate the relevance of inflammatory response in BD, trying to correlate it to psychopathology, treatment and outcome measures and, possibly, to brain connectivity.

Shared impairment in associative learning in schizophrenia and bipolar disorder

BACKGROUND Schizophrenia (SCZ) and bipolar disorder (BD) share some cognitive commonalities. However, the role of associative learning, which is a cornerstone of human cognition mainly relying on hippocampus, has been under-investigated. We assessed behavioral performance during associative learning in a group of SCZ, BD and healthy controls (HC). METHODS Nineteen patients with SCZ (36 ± 8.1 years; 13 males, 6 females; all Caucasians), 14 patients with BD (41 ± 9.6 years; 5 males, 9 females; all Caucasians) and 45 HC (27.7 ± 6.9 years; 18 males, 27 females; all Caucasians) were studied. Learning was assessed using an established object-location paired-associative learning paradigm. Subjects learned associations between nine equi-familiar common objects and locations in a nine-location grid. Performance data were analyzed in a repeated measures analysis of variance with time (repeated) and group as factors. RESULTS Learning curves (performance = (1-e(-k x time)) fitted to average performance data in the three groups revealed lower learning rates in SCZ and BD (k = 0.17 and k = 0.34) than HC (k = 0.78). Significant effects of group (F = 11.05, p < 0.001) and time (F = 122.06, p < 0.001) on learning performance were observed. CONCLUSIONS Our study showed that associative learning is impaired in both SCZ and BD, being potentially not affected by medication. Future studies should investigate the neural substrates of learning deficits in SCZ and BD, particularly focusing on hippocampus function and glutamatergic transmission.

Linguistic production and syntactic comprehension in schizophrenia and bipolar disorder

Perlini C, Marini A, Garzitto M, Isola M, Cerruti S, Marinelli V, Rambaldelli G, Ferro A, Tomelleri L, Dusi N, Bellani M, Tansella M, Fabbro F, Brambilla P. Linguistic production and syntactic comprehension in schizophrenia and bipolar disorder.

Laterality effects in schizophrenia and bipolar disorder

There are numerous reports in the literature of lateralised structural cerebral abnormalities and alterations of the corpus callosum in the major psychoses. In the light of these findings the purpose of this study was to directly compare hemispheric differences and callosal interhemispheric transmission (IT) in schizophrenia and bipolar disorder. To do that we tested schizophrenic (SCZ), bipolar disorder (BD) patients and controls in a simple manual reaction time (RT) task with lateralised visual stimuli (Poffenberger paradigm) which enables one to test both laterality effects and IT time. We found an overall slowing of responses with the right hand in schizophrenics but not in bipolar patients, who, like controls, showed no hand differences. This selective slowing down of the right hand is likely to be related to abnormalities of intrahemispheric cortico-cortical connections in the left hemisphere. In contrast, IT time was similar in SCZ and BD patients and did not differ with respect to controls. Two are the novel findings of the present study: first both SZC and BD share a normal IT of visuomotor information despite the presence of callosal abnormalities. Second, an impairment of intrahemispheric left hemispheric processing is present only in SCZ patients. This represents a potentially important clue to a further understanding of the pathogenetic differences between the two major psychoses.

Is Neuregulin 1 Involved in Determining Cerebral Volumes in Schizophrenia? Preliminary Results Showing a Decrease in Superior Temporal Gyrus Volume

Background/Aims: Reduced left superior temporal gyrus (STG) volume is one of the most replicated imaging findings in schizophrenia. However, it remains unclear whether genes play any role in our understanding of such structural alteration. It has been proposed that Neuregulin 1 (NRG1) might be a promising gene involved in schizophrenia, because of its role in neurodevelopment and neuroplasticity. In this study, the association between NRG1 and STG anatomy in patients with schizophrenia was explored for the first time. Methods: We investigated a 1-year treated prevalence cohort of patients with schizophrenia in contact with the South Verona Community-Based Mental Health Service. A blood sample was collected for DNA extraction and brain structure was assessed with an MRI scan. A total of 27 subjects with schizophrenia underwent both assessments and were included in the study. Results: We investigated the association between the polymorphism SNP8NRG222662 (rs4623364) of NRG1 and volume of the STG. We found that patients homozygous for the C allele had reduced left STG gray and white matter volumes in comparison to those homozygous for the G allele (p < 0.01 and p < 0.001, respectively). Conclusions: This exploratory study suggests that NRG1 may be involved in determining STG size in schizophrenia, and may play a role in the neurogenetic basis of the language disturbances seen in this disorder. However, due to our small sample size, the results should be regarded as preliminary and replicated in a larger sample.

Chronological age and its impact on associative learning proficiency and brain structure in middle adulthood.

INTRODUCTION The rate of biological change in middle-adulthood is relatively under-studied. Here, we used behavioral testing in conjunction with structural magnetic resonance imaging to examine the effects of chronological age on associative learning proficiency and on brain regions that previous functional MRI studies have closely related to the domain of associative learning. METHODS Participants (n=66) completed a previously established associative learning paradigm, and consented to be scanned using structural magnetic resonance imaging. Age-related effects were investigated both across sub-groups in the sample (younger vs. older) and across the entire sample (using regression approaches). RESULTS Chronological age had substantial effects on learning proficiency (independent of IQ and Education Level), with older adults showing a decrement compared to younger adults. In addition, decreases in estimated gray matter volume were observed in multiple brain regions including the hippocampus and the dorsal prefrontal cortex, both of which are strongly implicated in associative learning. CONCLUSION The results suggest that middle adulthood may be a more dynamic period of life-span change than previously believed. The conjunctive application of narrowly focused tasks, with conjointly acquired structural MRI data may allow us to enrich the search for, and the interpretation of, age-related changes in cross-sectional samples.

Increased gyrification in schizophrenia and non affective first episode of psychosis

BACKGROUND Prefrontal cortex gyrification has been suggested to be altered in patients with schizophrenia and first episode psychosis. Therefore, it may represent a possible trait marker for these illnesses and an indirect evidence of a disrupted underlying connectivity. The aim of this study was to add further evidence to the existing literature on the role of prefrontal gyrification in psychosis by carrying out a study on a sizeable sample of chronic patients with schizophrenia and non-affective first-episode psychosis (FEP-NA) patients. METHODS Seventy-two patients with schizophrenia, 51 FEP-NA patients (12 who later develop schizophrenia) and 95 healthy controls (HC) underwent magnetic resonance imaging (MRI). Cortical folding was quantified using the automated gyrification index (GI). GI values were compared among groups and related to clinical variables. RESULTS Both FEP-NA and patients with schizophrenia showed a higher mean prefrontal GI compared to HC (all p<0.05). Interestingly, no differences have been observed between the two patients groups as well as between FEP-NA patients who did and did not develop schizophrenia. CONCLUSIONS Our results suggest the presence of a shared aberrant prefrontal GI in subjects with both schizophrenia and first-episode psychosis. These findings support the hypothesis that altered GI represents a neurodevelopmental trait marker for psychosis, which may be involved in the associated neurocognitive deficits.

Pituitary gland shrinkage in bipolar disorder: The role of gender

BACKGROUND Hyperactivity of the Hypothalamic-Pituitary-Adrenal Axis (HPAA) has been consistently reported in mood disorders. However, only few studies investigated the Pituitary gland (PG) in Bipolar Disorder (BD) and the results are so far contrasting. Therefore, the aim of this study is to explore the integrity of the PG as well as the role of gender and the impact of clinical measurements on this structure in a sample of BD patients compared to healthy controls (HC). METHODS 34 BD patients and 41 HC underwent a 1.5 T MRI scan. PG volumes were manually traced for all subjects. Psychiatric symptoms were assessed by means of the Brief Psychiatry Rating Scale, the Hamilton Depression Rating Scale and the Bech Rafaelsen Mania Rating Scale. RESULTS We found decreased PG volumes in BD patients compared to HC (F = 24.9, p < 0.001). Interestingly, after dividing the sample by gender, a significant PG volume decrease was detected only in female BD patients compared to female HC (F = 9.1, p < 0.001), but not in male BD compared to male HC (F = -0.12, p = 0.074). No significant correlations were observed between PG volumes and clinical variables. CONCLUSIONS Our findings suggest that BD patients have decreased PG volumes, probably due to the long-term hyperactivity of the HPAA and to the consequent strengthening of the negative feedback control towards the PG volume itself. This alteration was particularly evident in females, suggesting a role of gender in affecting PG volumes in BD. Finally, the absence of significant correlations between PG volumes and clinical variables further supports that PG disruption is a trait feature of BD, being independent of symptoms severity and duration of treatment.

Brain Perfusion Characterizes First Episode of Psychosis Patients in Respect to Healthy Controls.

Introduction Vascular changes in the brain are relevant in schizophrenia [e.g. 1] and in bipolar disorder [2]. The study of first episode psychosis (FEP) allows the analysis of brain morphology and function without confounds due to chronicity. Objectives To characterize brain perfusion in FEP. Aims To see if FEP exhibit modified perfusion in respect to healthy controls (HC), and identify the most affected brain areas. Methods We acquired T1 and DSC images of 35 FEP patients (45 +/- 10 years old) and 35 HC (42 +/- 8), using Gadolinium (0.1 mmol/Kg). We computed cerebral blood volume (CBV), cerebral blood flow (CBF) and mean transit time (MTT) [3] in the whole brain and in left and right frontal, parietal, temporal and occipital lobes, insula, caudate and cerebellum Results Mean values of all quantities resulted lower in patients, up to 12% for CBV in right frontal lobe, 11% for CBF in left cerebellum and 16% for MTT in right frontal lobe. We used a support vector machine (SVM) to classify subjects on the basis of the histogram of perfusion values. We found that the classification reached accuracies over 80%, especially in the frontal brain areas. Conclusions FEP show altered perfusion parameters, which allow automatic classification with good accuracy, showing that brain vascular characteristics can be considered as marker of psychosis. [1] Peruzzo et al (2011). J Neural Transm, 118, 4:563-70. [2] Agarwal et al (2008). J Affect Disord, 110, 1-2:106-14. [3] Ostergaard et al (1996). Magn Reson Med, 36, 5:715-25.

Patterns of Pragmatic Verbal Abilities in Subjects with First Episode Psychosis and Matched Healthy Controls

Introduction Pragmatic abilities play a crucial role in daily functioning and have been suggested to be impaired in schizophrenia. Nevertheless, patterns of such deficits at the onset of the illness still needs to be elucidated. Objectives To outline pragmatic abilities in the first episode of psychosis (FEP). Aims To evaluate pragmatic verbal performance and its relationship with pre-frontal abilities in FEP subjects recruited in a large randomized multi-center controlled study (GET UP). Methods 58 FEP (mean age±SD:34±9 years; 46% males) and 58 1:1 matched healthy controls (HC) were assessed on the metaphor and idiom comprehension subtask of the MEC Protocol and with WCST. A PAF Analysis with Promax rotation of open (=spontaneous explanations) and closed (=multiple choice) metaphors/idioms and WCST variables was conducted. Results A 3-factor latent structure emerged in both groups but partially different patterns emerged. As for FEP, open metaphor/idiom explanations loaded into Factor 1 (Self-generated inferences); Factor 2 (Feedback-generated inferences) was loaded by WCST perseverative errors and by closed metaphor explanations. Finally, closed metaphors/idioms loaded into Factor 3 (Inhibition). As for HC, Factor 1 was similarly loaded but explained less variance; Factor 2 was qualitatively different (Reasoning, self+feedback-generated inferences), being loaded by the WCST number of categories and by open metaphors/idioms. Factor 3 was loaded by closed metaphors. Conclusions Findings suggest a shared underlying cognitive construct in self-generating perceptual inferences both for verbal pragmatics and pre-frontal skills in HC and patients, while a failure to integrate different sources of perceptual evidence is found only in FEP.