Abstract: Frontotemporal lobar degeneration (FTLD) includes different heterogeneous conditions, mainly characterised by personality changes, along with cognitive deficits in language and executive functions. Movement disorders are variably represented. Behavioural disturbances constitute the core feature of FTLD, and eating disorders represent one of the most distinguishing symptoms between FTLD and Alzheimer's disease (AD). The biochemical correlates of such dysfunctions remain to be defined. The adipocyte derived hormone leptin is known to play a foundamental role in food intake and energy balance. To understand whether leptin could be involved in FTLD eating abnormalities, we measured serum leptin levels in 59 patients with FTLD compared with 25 with AD. Serum leptin levels in patients with FTLD were comparable with those in patients with AD. Nevertheless, females with FTLD showed significantly higher leptin levels compared with females with AD. No difference was found between FTDL and AD males or within the spectrum of patients with FTLD. Hyperphagic FTLD females showed higher circulating leptin levels in comparison with those without eating abnormalities; no differences were found between males with FTLD with respect to serum leptin and food intake disturbances. The present study showed a selective gender difference in leptin levels between females with FTLD and AD, which may suggest specific cognitive and behavioural networks need to be investigated.
Abstract: Recent evidence indicates that the vascular endothelial growth factor (VEGF) may be involved in the neuronal mechanisms underlying both the depression aetiology and the response to pharmacological and non pharmacological antidepressant treatments. To investigate whether VEGF peripheral levels are altered in depression and are modulated by antidepressant therapies, we analyzed the serum VEGF concentrations in 25 subjects affected by major depression (MD) before (T0) and after 8 (T8) and 12 (T12) weeks of escitalopram treatment. No significant alterations in VEGF serum levels were found at T0, even considering possible effects of confounders such as gender and smoking habit (r(2)=0.227 p=0.74). No changes appeared during the treatment (F(1.83, 43.86)=0.962; p=0.383) and there was no correlation between percentage VEGF variations at T12 and symptoms improvements (p=0.823). The present work represents the first report on the evaluation of serum VEGF levels in MD patients. However, before discarding serum VEGF as a biochemical marker in the diagnosis and treatment of depression, our negative results need to be confirmed in larger patient samples stratified for clinical characteristics, co-morbidities, cardiovascular diseases and confounding factors.
Abstract: The frequent polymorphism XbaI (A351G) in the estrogen receptor alpha (ERalpha) gene has been associated with some postmenopausal pathologies' risk such as Alzheimer's disease (AD) or cognitive decline. In the present study, we explored whether the XbaI polymorphism leads to different gray matter volumes using voxel-based morphometry (VBM) on 20 magnetic resonance images of healthy postmenopausal women. Subjects carrying the less common XbaI/X allele were contrasted to non-carriers in groups well balanced by relevant confounding variables. The XbaI/X allele carriers displayed clusters ranging from 9 to 28% of tissue reductions in the cerebellar (cluster size, z, stereotactic coordinates: 16 mm(3); 3.17; 14, -94, -38) and cerebral cortex, in particular in the occipital lobe (272 mm(3); 3.76; -38,-68,-16), in the middle frontal gyrus (192 mm(3); 3.71; 38, 12, 38) and in the middle temporal gyrus, while the opposite comparison was negative. The XbaI/X allele in ERalpha gene is associated to smaller gray matter volumes of the cerebral and cerebellar cortex. This allele might increase the susceptibility for senile neurodegenerative conditions, being associated to smaller cerebral reserve.
Abstract: Repetitive transcranial magnetic stimulation (rTMS) is a painless and safe brain stimulation technique that has been found to be effective in treating depression symptoms. The potential usefulness of rTMS, in particular to treat drug resistant patients, might be increased by identifying genetic predictors of efficacy. According to this rationale, we investigated the role of two functional polymorphisms in the genes coding for the serotonin transporter (5-HTTLPR) and the brain-derived neurotrophic factor (BDNF Val66Met), and rTMS response in a group of 36 drug resistant patients affected by mood disorders. rTMS treatment significantly improved depression symptomatology (p<0.0001) and the response was significantly greater in 5-HTTLPR LL homozygotes compared to S allele carriers (p=0.007) and in BDNF Val/Val homozygotes compared to Met allele carriers (p=0.024). These findings provide evidences about the involvement of both polymorphisms in rTMS antidepressant response. Further investigations in larger samples are needed to clarify the usefulness of 5-HTTLPR and BDNF Val66Met genotyping in the optimization of non-pharmacological treatments in mood disorders.
Abstract: Research on -G308A functional polymorphism in the tumor necrosis factor alpha (TNFalpha) gene as a susceptibility factor for schizophrenia has provided contrasting results in different populations. Therefore we conducted a meta-analysis of the published case-control association studies and a replication study in a large sample. Meta-analyses (total sample: 2512 cases versus 3223 controls) showed that the AA genotype was weakly associated with schizophrenia susceptibility in Caucasoids (Odd Ratio OR=1.65, 95% CI=1.00-2.71 Z=1.98 p=0.05). The replication case-control association study (323 DSM-IV-TR schizophrenia patients and 346 controls) showed that the A allele conferred an increased susceptibility for schizophrenia only in males (OR=1.73, 95% CI=1.07-2.79, p=0.025), and the association became more specific when only patients of the paranoid subtype were compared to the controls (relative risk ratio=3.09, 95% CI=1.28-7.47, p=0.012). The presence of the A allele was also associated with a later age at onset of schizophrenia in the whole sample (F(1,291)=7.094, p=0.008). Our results confirm that TNFalpha A allele could have an effect on vulnerability to schizophrenia but further studies revaluating the role of gender and diagnostic subtypes are necessary to confirm these findings.
Abstract: Serotonin (5-HT) receptors 2A are expressed in brain regions involved in memory and learning processes. Recently, a functional single nucleotide polymorphism in the 5-HT2A receptor gene leading to an amino-acid substitution at residue 452 (His452Tyr) has been involved in memory performance, persons with the rare 452Tyr allele showing poorer memory performance compared to His452His subjects. To investigate a putative structural effect of this polymorphism on temporal areas typically involved in memory processes, we performed voxel-based morphometry (VBM) and region-of-interest (ROI) volumetric analysis on high-resolution magnetic resonance images in 15 carriers and 61 noncarriers of the 452Tyr allele. ROI volumetric analysis showed a significant reduction of the fractional volume of the temporal white matter in 452Tyr carriers (0.67+/-0.07 vs 0.73+/-0.08; P=0.007). VBM confirmed this finding and in addition showed reduced grey matter in the left hippocampus, left inferior temporal gyrus, and bilaterally in the middle and superior temporal gyrus. A possible effect on synaptic plasticity or neurodevelopment might explain the influence of the His452Tyr polymorphism on temporal brain structures, and this might be the basis for poorer memory performance in 452Tyr carriers. These findings should be considered preliminary and future replication is needed.
Abstract: Several findings have suggested that the neurotrophin BDNF could contribute to clinical efficacy of antidepressant treatments. The purpose of this study was to analyse if ECT operates a modulation of serum BDNF levels in a sample of drug resistant depressed patients. The results obtained show significantly higher serum levels of BDNF following ECT. More specifically, while no change occurred in the whole sample between T0 (baseline) and T1 (after ECT) (p=0.543) a significant increase has been identified at T2, one month after the end of ECT (p=0.002). However, the BDNF augmentation was evident even between T0 and T1 in a subgroup of patients who has low baseline BDNF levels. Although future researches are needed, the results herein presented show for the first time that ECT is associated with changes in serum BDNF and further support the possible involvement of BDNF in antidepressant therapies.
Abstract: BACKGROUND: Depression has been associated with low brain-derived neurotrophic factor (BDNF) serum levels, while antidepressant drugs appear to mend this alteration. The purpose of this study was to assess BDNF serum levels in drug resistant depressed patients before and after repetitive Transcranial Magnetic Stimulation (rTMS) antidepressant treatment. METHODS: BDNF levels were measured in serum of 16 resistant depressed patients using the ELISA technique. RESULTS: BDNF baseline levels showed a negative correlation with illness severity measured by HDRS scores (R = -0.517, p = 0.04) and a significant increase of serum BDNF was found after rTMS treatment (t = -2.549, df = 15, p = 0.022). CONCLUSIONS: Our findings support the relationship between decreased serum BDNF and depression symptomatology and suggest a normalizing effect of rTMS antidepressant treatment. Further replications in larger samples will help to clarify the relevance of this preliminary data in the rTMS mechanism of action.
Abstract: BACKGROUND AND AIMS: Substantial evidence supports the hypothesis that impairment of mitochondrial function and increased oxidative damage are involved in the pathogenesis of several neurodegenerative disorders including Alzheimer's disease (AD). Manganese superoxide dismutase (MnSOD) plays a major role in protecting the mitochondrion from oxidative damage due to superoxide radicals and other excited oxygen species. Recent studies have indicated that MnSOD mRNA levels are significantly increased in the lymphocytes of AD patients, supporting the role of oxidative alterations in the pathogenetic mechanism underlying this neurodegeneration. A potentially functional amino acid polymorphism (Ala-9Val) has been described in the signal sequence of enzymes associated with decreased defense capacity against oxidative stress. The object of this study was to investigate the association between this polymorphism of the MnSOD gene and AD in the Italian population. METHODS: The Ala-9Val polymorphism was genotyped by PCR amplification and SSCP analysis in 227 AD patients and 198 healthy controls. RESULTS: No significant differences in genotype or allele frequencies between cases and controls, even after stratification for APOE carrier status, were observed. CONCLUSIONS: Our data suggest that the Ala-9Val polymorphism in the MnSOD gene is not associated with genetic susceptibility in AD patients.
Abstract: Glycogen synthase kinase-3 (GSK-3) is a downstream component of the Wnt pathway and recent studies have reported abnormal levels of GSK-3beta in schizophrenia. In a sample of 147 schizophrenic patients and 212 healthy individuals, we analyzed two common SNPs at position -1727 A/T and -50 C/T and a (CAA)(n) repeat polymorphism localized in intron 1 of the gene. The results showed that the allele, genotype and haplotype distributions for the three polymorphisms investigated do not differ between schizophrenic patients in general and control subjects. However, in the subtype of paranoid schizophrenic patients, we found that the (CAA)(3)/(CAA)(5) heterozygotes were more often represented. Although taken from a small sample, our results support the reports that GSK-3beta appears to be involved in a subtype of schizophrenic patients, but not in schizophrenia in general. In conclusion, we would speculate that this gene may be linked to some features of psychotic disorders rather than to schizophrenia itself.
Abstract: Clinical and immunopathological evidence support a potential role of the pro- and anti-inflammatory cytokine network in neurodegeneration of Alzheimer's disease (AD). Moreover, association studies suggest a possible involvement of cytokine-related genes in the susceptibility to sporadic AD. Since conflicting results are associated with the pro-inflammatory pathway, we investigated a putative effect of the anti-inflammatory counterpart focusing on the interleukin-10 (IL-10) gene. The 5' flanking region contains numerous polymorphisms; in particular, three single nucleotide polymorphisms (-1082 G/A, -819 T/C, -592 C/A) are in linkage disequilibrium resulting in three haplotypes GCC, ACC and ATA. We analyzed the IL-10 haplotype distributions in 215 Italian sporadic AD patients and 153 controls in an association case-control study. Haplotype frequencies did not reveal differences between the two samples, however the genotype GCC/ACC was more represented in AD patients (OR 1.91, 95% CI: 1.18-3.07). This putative risk factor could be independent of the presence of the ApoE epsilon 4 allele. Our results provide new insights on a possible involvement of the IL-10 gene in susceptibility to sporadic AD even though further functional and genetic investigations are necessary to clarify its role in AD.
Abstract: It has been established that cytokines play a critical role in the regulation of the CNS and recent studies have suggested that dysfunctions of both pro-inflammatory (IL-1beta, IL-6, and TNF-alpha) and anti-inflammatory (IL-1RA and IL-10) cytokines could be involved in the pathophysiology of schizophrenia. Previous studies have reported that functional polymorphisms in some cytokines genes may have important regulatory effects on such system. Therefore, the aim of the present study was to explore the possible role of the IL-1beta -511C/T and IL-1RA (86bp)(n) repeats polymorphisms in schizophrenia. A case control association study comparing genotype and allele frequencies in 346 northen Italian subjects (169 schizophrenic patients and 177 unrelated healthy volunteers) was performed. The frequencies of IL-1beta -511C and IL-1RA allele 1 (86bp)(4) are significantly higher in schizophrenic patients compared to controls (IL-1beta -511 P=0.047; IL-1RA (86bp)(n) P=0.002). Moreover our data show a protective effect of the IL-1RA allele 2 (86bp)(2) against schizophrenia (OR=0.59 95%CI:0.388-0.910; P=0.016) and this effect is enhanced by the concomitant presence of IL-1beta -511T (OR=0.48 95%CI:0.30-0.76; P=0.002). Our findings support the hypothesis that genetically determined changes in IL-1 metabolism regulation may contribute to the pathogenesis of schizophrenia confirming a role of IL-1 gene cluster in disease susceptibility.
Abstract: Infective agents (e.g., viruses) together with functional alterations of the immune system have been hypothesized to be implicated in the multifactorial pathogenesis of schizophrenia. The viral hypothesis of schizophrenia has been supported by the observation of birth peaks in winter seasons, prenatal exposure to virus epidemics and specific geographic patterns. On the other hand, not all the data published have shown consistent results supporting the immune hypothesis. Thus, it is likely that immune response factors may play a role in the pathogenesis of the disease only in specific subgroups of patients. The aim of the study was to investigate for the presence of differences of IL-6, IL-6R, gp130 and CC16 among four groups of chronic schizophrenic patients categorized according to the season of birth. We hypothesized that patients born in winter and spring would have had increased values of these cytokines. No significant differences were found among the four groups in any of the measures considered. These preliminary results appear to exclude a major role of the season of birth in determining reported interleukins system alterations in chronic schizophrenia.
Abstract: BACKGROUND: Schizophrenia is one of the most severe psychiatric disorders, with a worldwide incidence of 1%. Several reports show abnormal cytokine levels in psychotic patients and indicate a possible role of the immune response system in the pathogenesis of schizophrenia. Increased concentrations of interleukin 10 (IL-10) have been found in plasma of schizophrenic patients, suggesting its potential role as a candidate gene for susceptibility to schizophrenia. IL-10 gene maps on chromosome 1 (q31-q32), a locus associated with genetic susceptibility to schizophrenia. Three functional haplotypes of the gene (GCC, ACC, ATA) have been described, derived from different combinations of three "single nucleotide polymorphisms" and directly related to the expression levels of the protein. METHODS: We analyzed allele, genotype, and haplotype distributions in an association case-control study involving 106 schizophrenic patients and 143 unrelated healthy volunteers using polymerase chain reaction (PCR)-Single Strand Conformation Polymorphism and PCR Restriction Fragment Length Polymorphism methods. RESULTS: Our results show a significant increase of GCC homozygotes (the high IL-10-producing haplotype) in schizophrenic patients compared to control subjects (chi(2) = 13, p =.023; odds ratio = 3.03; 95% confidence interval, 1.274-7.355). CONCLUSIONS: These data could partly explain the abnormal secretion of IL-10 occurring in schizophrenic patients in response to infections or different stressors and suggest a potential role of IL-10 as a candidate gene for susceptibility to schizophrenia.
Abstract: There is now evidence that schizophrenia may be accompanied by an activation of the monocytic and T-helper-2 (Th-2) arms of cell-mediated immunity (CMI) and by various alterations in the Th-1 arm of CMI. There is also evidence that repeated administration of typical and atypical antipsychotics may result in negative immunomodulatory effects. This study was carried out to examine (1) the serum concentrations of interleukin-8 (IL-8), IL-10, the soluble CD8 (sCD8) and the leukemia inhibitory factor receptor (LIF-R) in nonresponders to treatment with typical neuroleptics as compared with normal volunteers and responders to treatment; and (2) the effects of atypical antipsychotics on the above immune variables. The latter were determined in 17 nonresponders to treatment with neuroleptics and in seven normal volunteers and 14 schizophrenic patients who had a good response to treatment with antipsychotic agents. The nonresponders had repeated measurements of the immune variables before, and 2 and 4 months after treatment with clozapine or risperidone. Serum IL-8 and IL-10 were significantly higher in schizophrenic patients than in normal controls. The serum concentrations of the sCD8 were significantly increased 2 months, but not 4 months, after starting treatment with atypical antipsychotics. Serum LIF-R concentrations were significantly increased 2 and 4 months after starting treatment with atypical antipsychotics. It is concluded that: (1) schizophrenia is characterized by an activation of both pro-inflammatory and anti-inflammatory aspects of cell-mediated immunity; (2) prolonged treatment with atypical antipsychotics may increase the anti-inflammatory capacity of the serum in schizophrenic patients by increasing serum LIF-R concentrations; and (3) short-term treatment with clozapine may induce signs of immune activation which disappear upon prolonged treatment.
Abstract: Experimental and clinical studies suggest an involvement of the opioid neuropeptide system in schizophrenia. In particular, the prodynorphin (PDYN), the precursor of the dynorphin opioid peptides, has been shown to play an important role in several aspects of human mental diseases. Recently, a functional polymorphism in the promoter of PDYN gene has been described. We studied the possible relationship between this polymorphism and schizophrenia and we found no significant difference in allelic and genotype distributions between schizophrenic patients and control subjects. However, we observed a significant interactive effect with the receptor 3 of dopamine gene (DRD3); in particular, the frequency of subjects carrying PDYN allele 3 being also homozygotes for DRD3 Gly allele (of Ser9Gly polymorphism) was significantly greater in patients than controls. We conclude that PDYN gene polymorphism alone does not alter the risk for schizophrenia but, by an epistatic interaction with the Gly allele of DRD3 gene, may contribute to the susceptibility to this disorder.
Abstract: Recently, it was shown that schizophrenia is accompanied by an activation of the inflammatory response system with signs of an acute phase response, such as increased plasma haptoglobin (Hp) concentrations. Hp is characterized by a molecular variation with three known phenotypes, i.e. Hp 1-1, Hp 2-1 and Hp 2-2. The aim of the present study was to examine Hp phenotypic and genotypic frequencies in schizophrenic patients. Hp phenotyping was carried out in 98 Northwestern Italian schizophrenic patients and the phenotypic and genotypic distributions were compared with the distributions established in the Northwestern Italian population. Plasma Hp concentrations were determined by means of a laser nephelometric method. The allele frequency of the Hp phenotypes in schizophrenia, i.e. Hp 1-1 (9.2%), Hp 2-1 (38.8%) and Hp 2-2 (52.0%), was significantly different from that in the Northwestern Italian population, i.e. Hp 1-1 (17.0%), Hp 2-1 (51.3%) and Hp 2-2 (38.5%). The frequency of the Hp-2 gene was significantly higher in schizophrenic patients (71.7%) as compared with the observed frequency in the Northwestern Italian population (62.5%). The alterations in Hp phenotypic and genotypic distribution were more pronounced in the schizo-affective, disorganized, undifferentiated and residual schizophrenic patients than in paranoid schizophrenic patients. More than a third (35.7%) of the schizophrenic patients showed plasma Hp concentrations which were higher than the upper limits of normality. Schizophrenia is accompanied by an altered distribution of the Hp phenotypes and genotypes, suggesting that genetic variation on chromosome 16 may be associated with schizophrenia.
Abstract: There is now some evidence that schizophrenia may be accompanied by an activation of the inflammatory response system (IRS) and that typical antipsychotics may suppress some signs of IRS activation in that illness. This study was carried out to examine (i) the serum concentrations of interleukin-6 (IL-6), IL-6 receptor (IL-6R), IL-1R antagonist (IL-1RA) and Clara Cell protein (CC16), an endogenous anticytokine, in nonresponders to treatment with typical neuroleptics and (ii) the effects of atypical antipsychotics on the above IRS variables. The above parameters were determined in 17 patients with treatment-resistant schizophrenia (TRS) to treatment with neuroleptics and in seven normal volunteers and 14 schizophrenic patients who had a good response to treatment with antipsychotic agents. Patients with TRS had repeated measurements of the IRS variables before and 2 and 4 months after treatment with atypical antipsychotics. Serum IL-6 was significantly higher in schizophrenic patients, irrespective of their response to typical antipsychotics, than in normal controls. Serum IL-1RA was significantly higher in the TRS patients than in controls, whereas responders took up an intermediate position. The serum concentrations of CC16 were significantly lower after treatment with atypical antipsychotics during 4 months than before treatment. It is concluded that (i) schizophrenia and, in particular, TRS is characterized by an activation of the monocytic arm of cell-mediated immunity and (ii) atypical antipsychotics may decrease the anti-inflammatory capacity of the serum in TRS patients.
Abstract: Abnormalities in the cAMP-dependent protein kinase (PKA), a central component of cAMP signaling, have been reported in several psychiatric disorders. Previous studies showed cAMP signaling alterations in schizophrenic patients but less is known about the involvement of PKA in such disorder. Therefore, we investigated the PKA subunits by Western blot analysis in platelets from 12 patients with schizophrenia and 13 controls. The results showed that the immunolabeling of the PKA regulatory subunits type I (RI) and type II (RII) was significantly reduced in patients compared with controls whereas no differences were observed in the catalytic (C) subunit of the enzyme. These preliminary data suggest that schizophrenic patients have altered PKA levels, thus supporting that dysfunctions in the components of cAMP signaling may contribute to the pathophysiology of schizophrenia.
