Antonis Politis

Apathy, cognitive deficits and functional impairment in schizophrenia

INTRODUCTION Apathy has been repeatedly highlighted as a core component of negative symptoms especially with regard to functional outcome of schizophrenia. The purpose of this study was to explore the relationships between apathy, cognitive deficits, and psychosocial functioning in chronic patients with schizophrenia. METHODS Thirty-six chronic patients with schizophrenia and an equal number of matched healthy participants were assessed with the clinician version of Apathy Evaluation Scale (AES-C) along with a comprehensive battery of neuropsychological measures. Functioning was assessed with the Personal and Social Performance scale (PSP) and other symptoms were measured with the Positive and Negative Syndrome Scale and the Calgary Depression Scale for Schizophrenia. RESULTS Apathy was strongly and specifically associated with poorer performance on executive tests in patient group. AES-C was significantly correlated with PSP total score as well as its subscales for social useful activities, personal and social relationships, and self-care. Multiple regression analysis revealed that apathy was the most robust predictor of current psychosocial functioning, accounting for 70% of the variance in functioning, independently of co-existent cognitive deficits. Moreover, executive dysfunction did not predict functional impairment, independently of the effect of apathy. CONCLUSION Our findings confirm that apathy has a stronger relationship to functional impairment than cognitive deficits on a cross-sectional basis in schizophrenia. Moreover, they suggest that apathy and executive dysfunction might represent different manifestations of the same syndrome, probably sharing a common neural substrate.

Induction of mania by rTMS: report of two cases

There is some evidence that repetitive transcranial magnetic stimulation (rTMS) may be effective in treating depression. Using an intensive methodology of rTMS in two drug-resistant patients, we observed a good antidepressant effect, but also, induction of manic symptoms.

Genetics of Late-Onset Alzheimer's Disease: Update from the Alzgene Database and Analysis of Shared Pathways

The genetics of late-onset Alzheimers disease (LOAD) has taken impressive steps forwards in the last few years. To date, more than six-hundred genes have been linked to the disorder. However, only a minority of them are supported by a sufficient level of evidence. This review focused on such genes and analyzed shared biological pathways. Genetic markers were selected from a web-based collection (Alzgene). For each SNP in the database, it was possible to perform a meta-analysis. The quality of studies was assessed using criteria such as size of research samples, heterogeneity across studies, and protection from publication bias. This produced a list of 15 top-rated genes: APOE, CLU, PICALM, EXOC3L2, BIN1, CR1, SORL1, TNK1, IL8, LDLR, CST3, CHRNB2, SORCS1, TNF, and CCR2. A systematic analysis of gene ontology terms associated with each marker showed that most genes were implicated in cholesterol metabolism, intracellular transport of beta-amyloid precursor, and autophagy of damaged organelles. Moreover, the impact of these genes on complement cascade and cytokine production highlights the role of inflammatory response in AD pathogenesis. Gene-gene and gene-environment interactions are prominent issues in AD genetics, but they are not specifically featured in the Alzgene database.

APOE epsilon‐4 allele and cytokine production in Alzheimer's disease

The APOE epsilon‐4 allele has consistently emerged as a susceptibility factor for Alzheimers disease (AD). Pro‐inflammatory cytokines are detectable at abnormal levels in AD, and are thought to play a pathophysiological role. Animal studies have shown dose‐dependent correlations between the number of APOE epsilon‐4 alleles and the levels of pro‐inflammatory cytokines. The aims of this study were to investigate the influence of APOE genotypes on TNF‐α, IL‐6, and IL‐1β secreted by peripheral blood mononuclear cells (PBMC) from human patients with AD and to analyze the correlation between cytokine production and AD clinical features.

Association of SORL1 Alleles with Late-Onset Alzheimer's Disease. Findings from the GIGAS_LOAD Study and Mega-Analysis

The pathophysiology of Alzheimers disease (AD) is influenced by sorting-protein related receptor (sorLa) that is less expressed in AD patients. The gene encoding sorLa (SORL1) has been investigated as a susceptibility factor for late-onset AD (LOAD) with conflicting results. Our objectives were to confirm the association between SORL1 SNPs and LOAD in two independent South-European centers and to perform a mega-analysis of published samples. We analyzed three SORL1 SNPs (intron 6: rs668387; rs689021; rs641120) from the Greece-Italy Genetic Association Study on lateonset AD (GIGAS_LOAD). Greek sample included 96 patients with LOAD (DSM-IV) and 120 unrelated controls. In Italy, a community-based sample is ongoing. 47 LOAD patients and 165 controls were recruited until study endpoint. These samples and previously published ones (Alzgene) were pooled as in a single study. A test for trend was used to analyze genotype association. In the GIGAS_LOAD sample no association was detected between SORL1 genotypes and LOAD. Conversely all SNPs were associated with LOAD in mega-analysis based on ordinal classification of genotypes (Armitages test: p < 0.001). Although our analysis of pooled samples has positive results for the association between SORL1 and AD, there is substantial heterogeneity across studies. Thus further examination into SORL1 SNPs and the population is necessary to determine the role of SORL1 in LOAD.

Vitamin B12 Levels in Alzheimer's Disease: Association with Clinical Features and Cytokine Production

Alzheimers disease (AD) has been associated with up-regulation of pro-inflammatory cytokines (e.g., specific gene variants for TNF-alpha; IL-6; IFN-gamma) and low plasma levels of cyanocobalamin (vitamin B12). Our goal was to relate B12 levels to AD symptoms and to expression of pro-inflammatory cytokines. Clinical manifestations were investigated for a case series of fifty-five outpatients using the MMSE, Neuropsychiatric Inventory (NPI) and Cornell Scale for Depression in Dementia (CDDS). Plasma B12 levels were measured by radioligand binding assay. Basal and PMA-stimulated levels of IFN-gamma, TNF-alpha, and IL-6 were measured by ELISPOT (PBMC culture supernatant). 47 patients were genotyped for APOE. Ten patients (18%) had their B12 levels below < 250 pg/ml. They did not statistically differ from those 45 who had normal levels in most demographic and clinical features; their MMSE scores were lower (14.7 vs 19.6 p=0.03) but not after adjustment for disease duration. A greater basal production of IL-6 was reported in patients who had low B12 levels compared to normal B12 subjects (1333 pg/ml vs 976 p< 0.01); this association was confirmed after controlling for age of onset and APOE genotype. In conclusion, low B12 level is associated with greater production of IL-6 in peripheral blood mononuclear cells. Further research is warranted to elucidate whether this neuroinflammatory effect of cobalamin is implicated in the pathophysiology of AD.

Depression and Social Phobia Secondary to Alcohol Dependence

Background: According to the self-medication hypothesis, individuals with depression and anxiety disorders use alcohol to control their symptoms and subsequently become dependent. Conversely, alcohol dependence disorder (ADD) can cause or exacerbate psychiatric disorders. This study analyzed the characteristics of depression and social phobia secondary to ADD. (1) What is their functional impact? (2) Are they independent or associated conditions? (3) Do they completely remit in abstinent individuals? (4) Is the remission of one disorder associated with the remission of the other disorder? Methods: Sixty-four inpatients with ADD were evaluated with depression and anxiety disorder scales upon admission to hospital and after 5 weeks of detoxification. Results: Baseline comparisons differentiated patients with a Hamilton Rating Scale for Depression (HDRS) score >35 (n = 50; 78%) from those with an HDRS score ≤35 by higher levels of generalized anxiety and lower global functioning. Patients with generalized social phobia [Leibowitz Social Anxiety Scale (LSAS) score >60: n = 20; 31.2%] were not distinguishable from those with an LSAS score ≤60 by depressive and anxiety disorder symptoms. In postdetoxification assessment, patients who remitted from depression (HDRS score <7: n = 35; 54.6%) had a lower generalized anxiety and marginally higher levels of hypochondriasis compared to nonremitter subjects (HDRS score ≧7). Patients who remitted from social phobia (LSAS score <30: n = 32; 50%) did not significantly differ from nonremitter subjects in depressive and anxiety disorder symptoms. Generalized anxiety (Hamilton Rating Scale for Anxiety) and hypochondriasis (Whiteley Index) were the significant predictors of global functioning (Global Assessment Scale). Conclusions: Depression and social phobia secondary to ADD are independent conditions that do not completely remit after cessation of drinking. Specific treatments are needed to reduce residual depressive and anxiety symptoms in abstinent alcoholics.

TPH2 gene variants and anxiety during alcohol detoxification outcome

Clinical outcome of alcoholism may be partly under genetic control. The serotonergic system is involved in alcohol intake, and it has been widely investigated in alcohol dependence. Recently, attention has been focused on the neuronal tryptophan hydroxylase 2 gene (TPH2). TPH2 variants have been consistently associated with anxiety-related traits; since anxiety is critical for alcohol dependence treatment, in the present paper we investigated 9 SNPs within the THP2 gene in anxiety symptoms during the detoxification procedure. The sample comprised 68 alcohol-dependent patients who where evaluated with the Hamilton Rating Scale for Anxiety, before and after the detoxification procedure. Other psychopathological indicators of outcome, such as depression and anxiety sub-features were also investigated. We did not observe a role for TPH2 variants in the efficacy of treatment in relieving anxiety and other psychopathological symptoms. However, a haplotype that included the promoter rs4570625 polymorphism (associated with anxiety-related traits in previous studies) showed an association with the severity of anxiety symptoms on admission. This preliminary finding, although obtained on a small sample, may provide further support for a role of the TPH2 gene in emotional behaviors. Furthermore, the present study suggests the possible functional significance of the promoter rs4570625 polymorphism. The present preliminary results are of interest in alcoholism, given that comorbidity with anxiety represents a critical problem in treatment settings and response to detoxification.

Epistasis between IL1A, IL1B, TNF, HTR2A, 5-HTTLPR and TPH2 variations does not impact alcohol dependence disorder features.

We assessed a set of biological (HDL, LDL, SGOT, SGPT, GGT, HTc, Hb and T levels) and psychometric variables (investigated through HAM-D, HAM-A, GAS, Liebowitz Social Anxiety Scale, Mark & Mathews Scale, Leyton scale, and Pilowski scale) in a sample of 64 alcohol dependent patients, at baseline and after a detoxification treatment. Moreover, we recruited 47 non-consanguineous relatives who did not suffer alcohol related disorders and underwent the same tests. In both groups we genotyped 11 genetic variations (rs1800587; rs3087258; rs1799724; 5-HTTLPR; rs1386493; rs1386494; rs1487275; rs1843809; rs4570625; rs2129575; rs6313) located in genes whose impact on alcohol related behaviors and disorders has been hypothesized (IL1A, IL1B, TNF, 5-HTTLPR, TPH2 and HTR2A). We analyzed the epistasis of these genetic variations upon the biological and psychological dimensions in the cases and their relatives. Further on, we analyzed the effects of the combined genetic variations on the short – term detoxification treatment efficacy. Finally, being the only not yet investigated variation within this sample, we analyzed the impact of the rs6313 alone on baseline assessment and treatment efficacy. We detected the following results: the couple rs6313 + rs2129575 affected the Leyton -Trait at admission (p = 0.01) (obsessive-compulsive trait), whilst rs1800587 + 5-HTTLPR impacted the Pilowski test at admission (p = 0.01) (hypochondriac symptoms). These results did not survive Bonferroni correction (p ≤ 0.004). This lack of association may depend on the incomplete gene coverage or on the small sample size which limited the power of the study. On the other hand, it may reflect a substantial absence of relevance of the genotype variants toward the alcohol related investigated dimensions. Nonetheless, the marginal significance we detected could witness an informative correlation worth investigating in larger samples.

Age and education adjusted normative data and discriminative validity for Rey’s Auditory Verbal Learning Test in the elderly Greek population

ABSTRACT Rey’s Auditory Verbal Learning Test (RAVLT) is a widely used neuropsychological test to assess episodic memory. In the present study we sought to establish normative and discriminative validity data for the RAVLT in the elderly population using previously adapted learning lists for the Greek adult population. We administered the test to 258 cognitively healthy elderly participants, aged 60–89 years, and two patient groups (192 with amnestic mild cognitive impairment, aMCI, and 65 with Alzheimer’s disease, AD). From the statistical analyses, we found that age and education contributed significantly to most trials of the RAVLT, whereas the influence of gender was not significant. Younger elderly participants with higher education outperformed the older elderly with lower education levels. Moreover, both clinical groups performed significantly worse on most RAVLT trials and composite measures than matched cognitively healthy controls. Furthermore, the AD group performed more poorly than the aMCI group on most RAVLT variables. Receiver operating characteristic (ROC) analysis was used to examine the utility of the RAVLT trials to discriminate cognitively healthy controls from aMCI and AD patients. Area under the curve (AUC), an index of effect size, showed that most of the RAVLT measures (individual and composite) included in this study adequately differentiated between the performance of healthy elders and aMCI/AD patients. We also provide cutoff scores in discriminating cognitively healthy controls from aMCI and AD patients, based on the sensitivity and specificity of the prescribed scores. Moreover, we present age- and education-specific normative data for individual and composite scores for the Greek adapted RAVLT in elderly subjects aged between 60 and 89 years for use in clinical and research settings.