Analysis of the 5HT-2A T102C receptor polymorphism and psychotic symptoms in Alzheimer's disease.код для вставкиСкачать
American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 144B:126 –128 (2007) Brief Research Communication Analysis of the 5HT-2A T102C Receptor Polymorphism and Psychotic Symptoms in Alzheimer’s Disease David Craig,* Caroline Donnelly, Dominic Hart, Robyn Carson, and Peter Passmore Department of Geriatric Medicine, Division of Psychiatry and Neuroscience, Queen’s University, Belfast, Northern Ireland Although the aetiology of psychotic symptoms in Alzheimer’s disease (AD) is multi-factorial, alterations in serotonergic neurotransmission are often implicated. Polymorphisms of the serotonin receptor 5HT-2A are associated with hallucinatory symptoms and delusions in demented and non-demented cohorts. This study examined the role of the 5HT-2A T102C polymorphism in influencing psychotic symptoms in a large Northern Ireland AD population (n ¼ 406, mean MMSE 13/ 30). Forty-eight percent of patients experienced delusional symptoms and 28% experienced hallucinations during the course of their dementia. No significant association was found either in frequency of genotype or allelic variation for either set of symptoms. Furthermore, the mean delusional and hallucinatory severity scores did not differ significantly among the three genotype groups. The lack of influence of the T102C polymorphism of the 5HT-2A receptor on the emergence of psychotic symptoms in AD contrasts with previous reports in other cohorts involving smaller numbers of subjects. ß 2006 Wiley-Liss, Inc. KEY WORDS: Alzheimer’s disease; polymorphism; psychosis; serotonin; 5HT-2A Please cite this article as follows: Craig D, Donnelly C, Hart D, Carson R, Passmore P. 2007. Analysis of the 5HT2A T102C Receptor Polymorphism and Psychotic Symptoms in Alzheimer’s Disease. Am J Med Genet Part B 144B:126–128. INTRODUCTION There is increasing interest in the role of genetic factors in the causation of behavioral and psychological symptoms of dementia (BPSD) also referred to as neuropsychiatric symptoms (NPS). These symptoms are diverse and unpredictable but may originate from hitherto silent underlying inherited risks emerging in the setting of neurodegeneration [Holmes, 2000]. Symptoms of a psychotic nature are common and associated with significant carer burden [Donaldson et al., 1997, 1998]. Grant sponsor: Alzheimer’s Society Project; Grant sponsor: Ulster Garden Villages research; Grant sponsor: British Geriatric Society Start-up; Grant sponsor: NHS Research and Development Office (NI) Bursary. *Correspondence to: David Craig, Whitla Medical Building, 97 Lisburn Road, Belfast BT9 7BL, UK. E-mail: firstname.lastname@example.org Received 13 April 2006; Accepted 13 July 2006 DOI 10.1002/ajmg.b.30409 ß 2006 Wiley-Liss, Inc. The aetiology of such symptoms is multi-factorial but alterations in serotonergic neurotransmission represent a common biochemical correlate [Assal and Cummings, 2002; Ropacki and Jeste, 2005]. Serotonergic receptor genotype–phenotype interactions have been explored in non-demented populations and investigators have attempted to examine their role in Alzheimer’s disease (AD) in which a similar psychiatric phenotype may emerge. In schizophrenic cohorts, the most clearly linked serotonergic genotypic variant lies within the serotonin 2A receptor (5-HT2A, HTR2A) gene, specifically the T ! C 102 polymorphism [Williams et al., 1997; Prasad et al., 2002]. There is a general lack of clarity regarding the influence of serotonin-pathway polymorphisms in the causation of psychotic symptoms in AD. The 5-HT2A T102C polymorphism has similarly generated the most interest although reports involving other serotonin pathway polymorphisms also exist [Holmes et al., 1998; Nacmias et al., 2001; Sweet et al., 2001; Rocchi et al., 2003; Assal et al., 2004]. Holmes et al.  first reported the influence of the C variant of the 5-HT2A T ! C 102 receptor polymorphism in producing hallucinatory symptomatology in AD—a finding subsequently confirmed in a study involving a separate European cohort [Nacmias et al., 2001]. A further positive report involving the 5-HT2A 102C variant and psychotic symptoms [Rocchi et al., 2003] was followed by the finding of a significant under representation of 5-HT2A 102C homozygotes in a Chinese population of AD patients exhibiting delusions [Lam et al., 2004]. Similarly, the 102T genotype of the 5-HT2A receptor was weakly but significantly associated with delusions in a recent report by Assal et al. . The 5HT2A receptor is a site of action for atypical antipsychotic agents and there is some tentative evidence, in a small cohort, that the T102C polymorphism negatively influences the efficacy of antipsychotic treatment in patients with probable AD with BPSD who carry the C allele [Engelborghs et al., 2004]. In AD, both the T and the C allele at position 102 have therefore been linked to psychotic symptoms and the C allele to antipsychotic treatment response. Neither base change alters the amino acid sequence of the 5HT-2A receptor as both produce a serine amino acid at codon 34 [Warren et al., 1993]. The change may, however, have functional consequences both in terms of unconfirmed reports of lower reported cortical receptor density in C allele schizophrenic patients identified post-mortem [Polesskaya and Sokolov, 2002; Bray et al., 2004] and higher recorded N100 amplitudes in CC homozygotes after clozapine treatment [Yu et al., 2001]. This may reflect the influence of a separate gene existing in linkage disequilibrium. The uncertain of role of the T102C 5-HT2A polymorphism in influencing psychotic symptoms in AD encouraged us to examine its carriage in a large, well characterized cohort which exists within the genetically homogeneous Northern Ireland population. METHODS Following ethical approval from the Research Ethics Committee, The Queen’s University of Belfast, informed 5HT-2A Polymorphism and Psychosis in AD written consent was obtained from next-of-kin and patients where possible. Patients, fulfilling the criteria for probable AD [McKhann et al., 1984], were identified from out-patient memory clinic records based at three centers (Belfast City Hospital Trust, Mater Infirmorum, and Holywell Hospital). Patients were included who had a carer with contact at least 3 days a week for at least 3 years to ensure reliability of data. A validated neuropsychological assessment tool, the Neuropsychiatric Inventory with Caregiver Distress (NPI-D) [Kaufer et al., 1998] was employed to record delusional and hallucinatory symptomatology and carers were asked regarding known prior psychiatric history affecting the subjects. Carers are permitted in the NPI-D to provide overall symptom score according to the composite of frequency x severity. DNA extracted from peripheral blood leukocytes was analyzed for the 5HT-2A T102C polymorphism as previously reported [Holmes et al., 1998]. Chi-squared analysis was used to compare genotype and allele frequencies and to test whether the genotype frequencies deviated from expected Hardy– Weinberg equilibrium. Age and MMSE were compared using the Mann–Whitney test and a one-way analysis of variance (ANOVA) was employed for psychotic symptom score. The level of statistical significance was set at less than 5%. Data were analyzed using the SPSS computer software program [Chicago Ill, 2000]. RESULTS Genotyping was performed in 406 patients. The mean MMSE was 13/30. Thirty-one percent were male. The average age of the cohort was 78. There was no difference in age or MMSE scores between patients in the three genotype groups CC, TC, and TT. Alleles did not differ significantly from that predicted by the Hardy–Weinberg equilibrium. Table I provides frequency data for the 5HT-2A T102C polymorphism in those with and without delusional symptoms. Approximately half (48%) of subjects experienced this symptom during the course of their dementia. A chi-square analysis failed to show any significant alteration in the distribution of CC, TC, TT genotypes between groups. Allelic carriage was similarly non-significant (T allele: delusions absent 45.9%, delusions present 40.8%, ChiSquare ¼ 2.110, df ¼ 1, P ¼ 0.146). ANOVA analysis of severity data in 188 delusional patients failed to reveal any significant relationship between symptom severity score and genotype (P ¼ 0.10; mean score CC-6/12, TC-7/12, and TT-5/12). Table II shows the proportions of patients experiencing hallucinations according to T102C genotype. Hallucinations were present in 28% of those surveyed. No significant relationship was seen either in frequency of genotype (above) or a separate analysis of allelic variation (T allele: hallucinations absent 43.7%, hallucinations present 41.0% Chi-Square ¼ 0.200, df ¼ 1, P ¼ 0.654). Mean hallucination severity scores in 108 patients according to genotype were as follows: CC-5/12, TC-4/12, and TT-4/12. These differences were not significantly different (ANOVA, P ¼ 0.45). After subjects with a positive prior psychiatric history were removed from the genotypic analysis, the values of chi-square remained statistically insignificant (delusions, Pearson ChiTABLE I. Analysis of Delusions According to Genotype of 5HT-2A T102C Polymorphism CC TC 127 TABLE II. Analysis of Hallucinations According to Genotype of 5HT-2A T102C Polymorphism Hallucinations Absent Present CC TC TT 98 (33.3%) 33 (29.5%) 135 (45.9%) 64 (57.1%) 61 (20.7%) 15 (13.4%) Pearson Chi-Square ¼ 4.805, df ¼ 2, P ¼ 0.090. Square ¼ 1.673, df ¼ 2, P ¼ 0.433; hallucinations, Pearson ChiSquare ¼ 4.975, df ¼ 2, P ¼ 0.083). DISCUSSION As previously reported, delusional symptoms were seen to affect around half of subjects and in over a quarter of patients hallucinations were experienced [Craig et al., 2005]. Genotyping indicated that the T102C polymorphism of the serotonin 2A receptor exerts no influence on the emergence of delusional/ hallucinatory symptoms in AD. There is some indication of a trend effect involving hallucinations and the T allele which appears to be underrepresented in those with this symptom but this was not confirmed in a separate analysis of allele carriage. The site of the receptor, 13q14-q21, has not been, as far as we are aware, identified in linkage studies as one of potential interest in the search for loci relevant to psychotic change in AD [Bacanu et al., 2002]. Differences in populations under study and their size and methodologies employed may account for the differences in reported results. The previous findings of a positive association between T102C and psychosis in AD utilizing the NPI have been based on studies involving smaller cohorts [Assal et al., 2004; Lam et al., 2004]. The population presented herein is of a sufficiently advanced phase of illness (mean MMSE 13/30) that adequate time has passed to allow the phenotype to emerge— psychotic phenomenon typically appear in the early phase of disease [Devanand et al., 1997; Haupt et al., 2000]. The work is limited by its cross-sectional nature and dependent on the recall of a carer (albeit one with an intimate knowledge of the patient’s activities). Psychosis in the context of dementia is a complex syndrome in which many different genetic and environmental factors operate—the lack of clear data supporting a consistent contribution by the 5HT-2A receptor polymorphism suggests its influence is minor overall while questions remain regarding the functional significance of this particular SNP and the effect of allelic variation on, for example, the expression of transcribed mRNA sequence in brain post-morten studies [Polesskaya and Sokolov, 2002; Bray et al., 2004]. Future studies may seek to examine longitudinally the appearance and disappearance of these symptoms as well as the pharmacogenomic aspects of 5HT-2A variation and its influence of drug efficacy particularly with regard to antipsychotic response in AD. ACKNOWLEDGMENTS This work was supported by an Alzheimer’s Society Project Grant, an Ulster Garden Villages research grant and a British Geriatric Society Start-up grant. CD is supported by a NHS Research and Development Office (NI) Bursary. TT REFERENCES Delusions Absent Present 62 (29.7%) 69 (35.2%) 104 (49.8%) 94 (48.0%) Pearson Chi-Square ¼ 1.779, df ¼ 2, P ¼ 0.411. 43 (20.6%) 33 (16.8%) Assal F, Cummings JL. 2002. Neuropsychiatric symptoms in the dementias. Curr Opin Neurol 15:445–450. Assal F, Alarcon M, Solomon EC, Masterman D, Geschwind DH, Cummings JL. 2004. Association of the serotonin transporter and receptor gene 128 Craig et al. polymorphisms in neuropsychiatric symptoms in Alzheimer disease. Arch Neurol 61:1249–1253. Bacanu SA, Devlin B, Chowdari KV, DeKosky ST, Nimgaonkar VL, Sweet RA. 2002. Linkage analysis of Alzheimer disease with psychosis. Neurology 59:118–120. Bray NJ, Buckland PR, Hall H, Owen MJ, O’Donovan MC. 2004. The serotonin-2A receptor gene locus does not contain common polymorphism affecting mRNA levels in adult brain. Mol Psychiatry 9:109–114. Chicago, Ill. 2000. Statistical product and service solutions. Version 10.0. Chicago, Ill: SPSS Inc. Craig D, Mirakhur A, Hart DJ, McIlroy SP, Passmore AP. 2005. A crosssectional study of neuropsychiatric symptoms in 435 patients with Alzheimer’s disease. Am J Geriatr Psychiatry 13:460–468. Devanand DP, Jacobs DM, Tang MX, et al. 1997. The course of psychopathologic features in mild to moderate Alzheimer disease. Arch Gen Psychiatry 54:257–263. Donaldson C, Tarrier N, Burns A. 1997. The impact of the symptoms of dementia on caregivers. Br J Psychiatry 170:62–68. Donaldson C, Tarrier N, Burns A. 1998. Determinants of carer stress in Alzheimer’s disease. Int J Geriatr Psychiatry 13:248–256. Engelborghs S, Holmes C, McCulley M, De Deyn PP. 2004. 5-HT2A receptor polymorphism may modulate antipsychotic treatment response in Alzheimer’s disease. Int J Geriatr Psychiatry 19:1108–1109. Haupt M, Kurz A, Janner M. 2000. A 2-year follow-up of behavioural and psychological symptoms in Alzheimer’s Disease. Dement Geriatr Cogn Disord 11:147–152. Holmes C. 2000. Contribution of gentics to the understanding of behavioural and psychological symptoms of dementia. Int Psychogeriatr 12(Suppl 1): 83–88. Lam LC, Tang NL, Ma SL, Zhang W, Chiu HF. 2004. 5-HT2A T102C receptor polymorphism and neuropsychiatric symptoms in Alzheimer’s disease. Int J Geriatr Psychiatry 19:523–526. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. 1984. Clinical diagnosis of Alzheimer’s disease: Report of the NINCDSADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology 34:939– 944. Nacmias B, Tedde A, Forleo P, et al. 2001. Association between 5-HT(2A) receptor polymorphism and psychotic symptoms in Alzheimer’s disease. Biol Psychiatry 50:472–475. Polesskaya OO, Sokolov BP. 2002. Differential expression of the ‘‘C’’ and ‘‘T’’ alleles of the 5-HT2A receptor gene in the temporal cortex of normal individuals and schizophrenics. J Neurosci Res 67:812–822. Prasad S, Semwal P, Deshpande S, Bhatia T, Nimgaonkar VL, Thelma BK. 2002. Molecular genetics of schizophrenia: Past, present and future. J Biosci 27:35–52. Rocchi A, Micheli D, Ceravolo R, Manca ML, Tognoni G, Siciliano G, Murri L. 2003. Serotoninergic polymorphisms (5-HTTLPR and 5-HT2A): Association studies with psychosis in Alzheimer disease. Genet Test 7:309–314. Ropacki SA, Jeste DV. 2005. Epidemiology of and risk factors for psychosis of Alzheimer’s disease: A review of 55 studies published from 1990 to 2003. Am J Psychiatry 162:2022–2030. Sweet RA, Pollock BG, Sukonick DL, et al. 2001. The 5-HTTPR polymorphism confers liability to a combined phenotype of psychotic and aggressive behavior in Alzheimer disease. Int Psychogeriatr 13:401–409. Warren JT Jr, Peacock ML, Rodriguez LC, Fink JK. 1993. An MspI polymorphism in the hyman serotonin receptor gene (HTR2): Detection by DGGE and RFLP analysis. Hum Mol Genet 2:338. Holmes C, Arranz MJ, Powell JF, Collier DA, Lovestone S. 1998. 5-HT2A and 5-HT2C receptor polymorphisms and psychopathology in late onset Alzheimer’s disease. Hum Mol Genet 7:1507–1509. Williams J, McGuffin P, Nothen M, Owen MJ. 1997. Meta-analysis of association between the 5-HT2a receptor T102C polymorphism and schizophrenia. EMASS Collaborative Group. European Multicentre Association Study of Schizophrenia. Lancet 349:1221–1226. Kaufer DI, Cummings JL, Christine D, et al. 1998. Assessing the impact of neuropsychiatric symptoms in Alzheimer’s disease: The Neuropsychiatric Inventory Caregiver Distress Scale. J Am Geriatr Soc 46:210–215. Yu YW, Tsai SJ, Yang KH, Lin CH, Chen MC, Hong CJ. 2001. Evidence for an association between polymorphism in the serotonin-2A receptor variant (102T/C) and increment of N100 amplitude in schizophrenics treated with clozapine. Neuropsychobiology 43:79–82.