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Neurol Sci (2015) 36:215–220 COMT and STH polymorphisms interaction on cognitionin schizophrenia Marta Bosia • Alessandro Pigoni • Adele Pirovano • Cristina Lorenzi •Marco Spangaro • Mariachiara Buonocore • Margherita Bechi • Federica Cocchi •Carmelo Guglielmino • Placido Bramanti • Enrico Smeraldi • Roberto Cavallaro Received: 11 March 2014 / Accepted: 29 August 2014 / Published online: 5 October 2014Ó Springer-Verlag Italia 2014 Catechol-O-methyltransferase (COMT) gene, a Moreover, a significant interaction between COMT and key regulator of prefrontal cortex (PFC) dopamine (DA) STH polymorphisms was found on executive functions, availability, has been extensively studied in relation to with COMT Val/Val and STH R carriers performing cognitive domains, mainly executive functions, that are worse. Our results showed a significant interaction effect of impaired in schizophrenia, but results are still controver- COMT and STH polymorphisms on cognitive perfor- sial. Since recent studies in patients affected by neurode- mances, strengthening the involvement of STH in cognitive generative and psychiatric disorders suggested a role of saitohin (STH) gene as a concurring factor in hypofron- impaired in schizophrenia.
tality, we hypothesize that STH and COMT polymor-phisms could have an additive effect on cognition in COMT  Saitohin  Cognition  schizophrenia. Three forty three clinically stabilized Hypofrontality  Schizophrenia  Neurodegeneration patients with schizophrenia were assessed with a broadneuropsychological battery including the Brief Assessmentof Cognition in Schizophrenia, the Wisconsin Card Sorting Test and the Continuous Performance Test and were gen-otyped for COMT Val108/158Met and STH Q7R poly- Schizophrenia is a chronic mental illness affecting almost morphisms. We observed the effects of COMT on speed of 1 % of the population, characterized by cognitive and processing and executive functions, as well as a significant functional deficits leading to poor functional outcome and effect of STH on executive functions performances.
social disruption In the past decades, several studies addressed to the biological bases of cognitive impairment in schizophrenia, M. Bosia (&)  C. Lorenzi  M. Spangaro  M. Buonocore  evaluating the effects of different polymorphisms, mainly M. Bechi  F. Cocchi  C. Guglielmino  E. Smeraldi R. Cavallaro in genes involved in neurotransmission and also in neuro- Department of Clinical Neurosciences, IRCCS San Raffaele development and neurodegeneration processes [].
Scientific Institute, Milan, Italy Most consistent results have been found for a single nucleotide polymorphism in the gene coding for Catechol- O-methyltransferase (COMT), an enzyme that significantly Institute for Advanced Study IUSS, Center for Neurolinguistics contributes to the removal of dopamine (DA) from the and Theoretical Syntax (NeTS), Pavia, Italy synapse in the prefrontal cortex (PFC). The substitution ofMet for Val at codon 108/158 results in the transcription of A. Pigoni  A. Pirovano  M. Spangaro  E. Smeraldi R. Cavallaro a thermolabile variant with approximately 40 % less Universita Vita -Salute San Raffaele, Milan, Italy enzymatic activity, leading to greater availability of DA inthe PFC Numerous studies identified associations between COMT genotype and cognition in patients with IRCCS Centro Neurolesi ‘‘Bonino Pulejo'', Via Palermo 113,98121 Messina, Italy schizophrenia and their relatives, with homozygous for Neurol Sci (2015) 36:215–220 Met allele performing better than Val homozygous in test of the study, informed consent to participation was evaluating cognitive functions relying on PFC More- obtained. The protocol was approved by the local ethical over, we previously reported an association between committee and followed the principles of the Declaration COMT genotype and improvement after cognitive reme- of Helsinki.
diation [], also in relation to antipsychotic treatment However, there have also been negative findings thus pointing out the need to further explore other contributingfactors that may interact with COMT. In particular, a large All patients underwent a venous blood sample for geno- study exploring the effect of COMT Val108/158Met typic analysis. DNA was extracted from whole blood by polymorphism on executive functions, both in healthy manual extraction, using the ‘‘Illustra blood genomicPrep controls and in patients with schizophrenia, concluded that Midi Flow kit'' (GE Healthcare, Milan, Italy).
the relationship between COMT polymorphism and exec- For COMT Val108/158Met, polymerase chain reaction utive performances was limited to the healthy control (PCR) was performed with the following primers: 50-AC Recent studies focused on the effect of saitohin (STH) CTGACAA-30. The PCR reaction was carried out by ABI gene, located in intron 9 of the human tau gene, in several 9700 PCR thermal-cycler (Applied Biosystems, APPLE- neurodegenerative disorders, mainly dementia processes RA) in a 10 ll volume containing 150 ng of genomic [, STH gene contains a single nucleotide polymor- DNA, 5 pmol of each primer, 10 nmol of dNTPs' mix, phism (A/G), which changes glutamine residue 7 to argi- 109 HotMaster Taq Buffer and 0.5 U of HotMaster Taq nine (Q7R) ]. Interestingly, Borroni et al. [found DNA Polymerase (Eppendorf, Milan, Italy). The amplified an association between H2 haplotype, in complete linkage fragment was then purified by Multi-Screen Colum Loader disequilibrium with the STH R allele ], and both greater (MILLIPORE), filled up and packaged with Sephadex anterior brain hypoperfusion and worse clinical prognosis G-50 (Sigma–Aldrich's) to remove residual PCR reagents.
in patients affected by frontotemporal dementia (FTLD). In An aliquot of purified PCR product was then used to per- an Italian sample of patients affected by sporadic dementia, form sequencing reaction, using DYEnamic ET Dye Ter- Lorenzi et al. ] observed significant interactions minator Cycle Sequencing Kit (GE Healthcare, Milan, between STH and 5-HTTLPR, as a potential susceptibility Italy). In its turn, sequencing reaction product, was purified factor for neurodegenerative diseases. Bosia et al. [ following the above-mentioned protocol, to remove the evaluated the role of the STH polymorphism in the cog- excess of fluorescent dyes not incorporated in the DNA nitive decline in schizophrenia, reporting an association fragment. The fragment was then sequenced by MegaB- between the R allele and poorer executive performances.
ACE 500 genetic analyzer (GE Healthcare, Milan, Italy) Based on these data, it appears worth of interest to study under standard conditions.
the possible interactions between COMT and STH poly- For the STH Q7R polymorphism, a PCR was performed morphisms, both hypothesized to be concurring factors with the following primers: 50-CCCTGTAAACTCTGAC contributing to PFC functions and cognitive performances, CACAC-30 and 50-ACAGGGAAGCTACTTCCCATG-30.
especially executive functions. In this study we thus ana- The PCR reaction was carried out by ABI 9700 PCR lyzed the possible effects and interactions of STH and thermal-cycler (Applied Biosystems, APPLERA) as fol- COMT polymorphisms on cognition in a sample of patients lows: after a first step at 94 °C for 3 min, steps of 94 °C for affected by schizophrenia.
30 min, 60 °C for 30 min, 70 °C 30 min for 35 cycles.
Then, a final extension step at 70 °C for 6 min was added.
PCR product was digested using HinfI (New England Materials and methods Biolabs, England, UK) at 37 °C overnight; fragments wereseparated in 3 % Seakem agarose gel with ethidium bro- A sample of 343 Caucasian biologically unrelated out- mide. The cleaved bands were visualized by ultraviolet patients were recruited at the San Raffaele Scientific light. Depending on the presence of one or two restriction Institute of Milan (Italy). Inclusion criteria were: diag- HinfI sites, either two fragments 171?55 bp (A or Q allele) or three fragments 97?74?55 bp (G or R allele) were 18–70 years, stable antipsychotic treatment since at least 3 months and good response (defined as a reduction of30 % or more in PANSS Total Score after 3 months of treatment). Exclusion criteria were: psychiatric comor-bidities, mental retardation, substance abuse, neurological Basic clinical and demographic data were collected from disorders and brain injury. After a complete description clinical records.
Neurol Sci (2015) 36:215–220 Psychopathology was assessed by means of the Positive For analysis on antipsychotics, we stratified patients into and Negative Syndrome Scale for Schizophrenia (PANSS), three groups: first generation antipsychotics (FGA), second [administered by trained psychiatrists.
generation antipsychotics (SGA) and clozapine.
Neuropsychological performances were assessed with Differences between COMT and STH genotypes and the following tests, administered by trained psychologists.
demographic and clinical characteristics were analyzed The Brief Assessment of Cognition in Schizophrenia with one-way analysis of variance (ANOVA) for quanti- (BACS), a brief evaluation of the main cognitive functions tative measures, or v2 test for dichotomic variables (gender that are usually impaired in schizophrenic patients and treatment class).
includes the following tasks: verbal memory and learning Effects of COMT and STH genotypes and their inter- (list of words), working memory (sequence of numbers), action on cognitive performances were analyzed by means motor function (token motor task), speed of processing of General Linear Model (GLM), with scores of BACS, (symbol coding), verbal fluency (semantic categories), WCST and CPT as dependent variables and COMT and letter fluency, executive function, subcomponent of plan- STH genotypes as categorical factors. To be more con- ning (Tower of London).
servative, given the unbalanced groups sizes, we used HSD The Wisconsin Card Sorting Test (WCST) ] evalu- Test for Unequal numbers to determine significant differ- ates visuospatial skills and the ability to classify, keep the ences between genotypes groups.
set, switch the attentive focus, and inhibit interferinganswers. The score results from the number of categoriescompleted by the patient, a measure of abstract reasoning and the number of perseverative errors, evaluating morespecifically cognitive flexibility.
DNA analysis showed reliable results for COMT genotype The Continuous Performance Test (CPT) [a com- in 339 subjects and for STH genotype in 342 subjects.
puterized test, presenting a sequence of stimuli to be rec- Genotypes were distributed as follows: 68 Met/Met, 174 ognized ignoring distractors, evaluates sustained and Met/Val and 97 Val/Val for COMT gene; 214 Q/Q, 113 Q/R and 15 R/R for STH gene. Allelic distributions fol-lowed Hardy–Weinberg equilibrium.
Demographic and clinical characteristics stratified by COMT and STH genotypes are reported in Table No STATISTICA Software for Windows, version 8 (StatSoft significant differences were observed between genotype Inc., Tulsa, OK, USA) was used to perform statistical All patients were taking antipsychotic treatments: 129 As in previous works, for analysis on COMT genotype subjects were on clozapine, 112 on risperidone, 80 on we grouped patients as Val/Val and Met carriers [], while haloperidol, 13 on olanzapine, 5 on aripiprazole, 3 on for STH genotype we grouped patients in Q/Q homozygous paliperidone and 1 on quetiapine. The v2 test showed no and R carriers [given the low frequency of the G/G significant differences in genotypes distribution (COMT and STH both separately and in interaction) among Table 1 Demographic and clinical features of the sample, stratified by COMT and STH genotypes Education (years) PANSS negative (score) PANSS positive (score) PANSS general (score) PANSS total (score) years years, SD standard deviation, NS not significant Neurol Sci (2015) 36:215–220 Table 2 Antipsychotic F = 3.67, p = 0.056), a significant main effect of STH COMT*STH genotypes genotype (g2p = 0.021, F = 6.34, p = 0.01) and a signifi- cant COMT*STH interaction (g2 p = 0.002). Post-hoc HSD for Unequal numbers showed that subjects carrying COMT Val/Val genotype and STH R allele performed worse than both COMT Val/Val and STH Q/Q carriers (p = 0.019) and COMT Met allele and STH R carriers (p = 0.046).
Mean scores of neuropsychological performances strat- ified by COMT and STH genotypes are reported inTable Significant effects of COMT*STH interaction on FGA first generation antipsychotics, SGA second generation anti-psychotics, SD standard deviation, NS not significant WCST number of categories are displayed in Fig. treatment groups (FGA, SGA and clozapine) as shown inTable .
The GLM Analysis with COMT and STH genotypes as categorical predictors and the score of cognitive tests as To our knowledge this is the first study evaluating inter- dependent variables showed significant effects only for actions between COMT and STH polymorphisms on cog- Symbol Coding BACS' subtest and WCST number of nitive functions in a sample of patients with schizophrenia.
Our results confirm previous literature reporting an Symbol Coding BACS' subtest evaluates selective effect of COMT genotype on several cognitive measures.
attention and working memory, representing a global In detail, we observed a significant effect of COMT on measure of speed of processing. The analysis on symbol Symbol Coding BACS subtest, with better performances coding revealed a significant overall model (R2 = 0.036, among Met carriers and a similar trend on WCST ‘‘number F = 3.79, p = 0.01), with significant main effect of of categories''.
COMT genotype (g2p = 0.02, F = 4.93, p = 0.027) and a Results also revealed a significant main effect of STH trend of COMT*STH interaction (g2p = 0.011, F = 3.32, genotype on WCST ‘‘number of categories'', showing the p = 0.069). Post-hoc HSD for Unequal numbers on COMT patients carrying the STH R allele performed worse than main effect showed a significant difference between Q/Q homozygous, supporting previous findings ].
COMT Met carriers and COMT Val/Val (p = 0.02), the Moreover, analyses suggest an additive effect of COMT latter showing worse performances.
and STH polymorphisms. A significant interaction was The analysis on WCST number of categories completed, found on WCST number of categories with subjects car- a measure of abstract thinking, showed a significant overall rying COMT Val/Val genotype and STH R allele per- model (R2 = 0.040, F = 4.14, p = 0.007), with a slightly forming significantly worse than both COMT Val/Val and significant main effect of COMT genotype (g2p = 0.012, STH Q/Q carriers and COMT Met allele and STH R Table 3 Mean scores of neuropsychological tests, stratified by COMT and STH genotypes Val/Val (mean ± SD) Met carriers (mean ± SD) R carriers (mean ± SD) Correct sequences WCST cat.comp.
Neurol Sci (2015) 36:215–220 healthy controls and in a group of controls affected byFTLD may be helpful to understand physiologic mecha-nisms underlying cognitive processes. Second, focusing onsingle polymorphisms may be restrictive and we cannotexclude that our results may depend on interaction withdifferent polymorphism or on other unexplored factors,such a downstream effect in the pathway where COMT andSTH are normally involved.
Although explanation of our results is far from clear and the effect that we observed may depend on a set of inter-acting neurobiological factors, the role of STH genotype oncognitive functions appears to be worthy of further inves-tigation, that might help understanding its neurophysio-logic value.
Fig. 1 Number of categories completed in the Wisconsin CardSorting Test (WCST), stratified by COMT and STH groupedgenotypes. General Linear Model: F = 10.03; p = 0.002 carriers. A trend of interaction between COMT and STH 1. Keefe RS, Harvey PD (2012) Cognitive impairment in schizo- was also observed on Symbol Coding.
phrenia. Handb Exp Pharmacol 213:11–37 Our results thus suggest an interaction of COMT and 2. Bilder RM, Howe A, Novak N, Sabb FW, Parker DS (2011) The STH polymorphisms on cognition, strengthening the genetics of cognitive impairment in schizophrenia: a phenomic involvement of STH in cognitive impairments, especially perspective. Trends Cogn Sci 15(9):428–435 3. Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, in domains commonly impaired in schizophrenia. Symbol Weinshilboum RM (1996) Human catechol-O-methyltransferase Coding subtest represents a general measure of process- pharmacogenetics: description of a functional polymorphism and ing speed, a domain sensible to neurodevelopment insults its potential application to neuropsychiatric disorders. Pharma- and neurodegeneration processes, often used as an indi- 4. Ira E, Zanoni M, Ruggeri M, Dazzan P, Tosato S (2013) COMT, cator of severity in schizophrenia []. Number of cate- neuropsychological function and brain structure in schizophrenia: gories subtest, on the other hand, is a global measure of a systematic review and neurobiological interpretation. J Psychi- executive functioning, in particular abstract thinking, atry Neurosci 38(6):366–380 domains commonly impaired in patients with schizo- 5. Bosia M, Bechi M, Marino E, Anselmetti S, Poletti S, Cocchi F, Smeraldi E, Cavallaro R (2007) Influence of catechol-O-meth- yltransferase Val158Met polymorphism on neuropsychological Interestingly, patients carrying STH R allele and COMT and functional outcomes of classical rehabilitation and cognitive Val/Val performed significantly worse than the others.
remediation in schizophrenia. Neurosci Lett 417(3):271 Although the specific effect of STH polymorphism is still 6. Bosia M, Zanoletti A, Spangaro M, Buonocore M, Bechi M, Cocchi F, Pirovano A, Lorenzi C, Bramanti P, Smeraldi E, unclear, some speculations are possible. Previous findings Cavallaro R (2014) Factors affecting cognitive remediation in patients affected by FTLD, sporadic dementia and response in schizophrenia: The role of COMT gene and anti- schizophrenia pointed out R allele as a possible factor psychotic treatment. Psy Res 217(1–2):9–14 contributing to worse prognosis –suggesting that 7. Szo¨ke A, Schu¨rhoff F, Me´ary A, Mathieu F, Chevalier F, Trandafir A, Alter C, Roy I, Bellivier F, Leboyer M (2006) Lack the STH genotype may be involved in disorders with a of influence of COMT and NET genes variants on executive neurodegenerative component. The interaction observed functions in schizophrenic and bipolar patients, their first-degree between COMT and STH genotypes suggests an additive relatives and controls. Am J Med Genet B Neuropsychiatr Genet effect that may be explained hypothesizing that COMT 8. Barnett JH, Jones PB, Robbins TW, Mu¨ller U (2007) Effects of functional effect on DA levels may be more critical in STH the catechol-O-methyltransferase Val158Met polymorphism on R carriers which could have an higher susceptibility to an executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls. Mol Psychiatry A number of limitations should be taken into account.
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