An association study between 5-HTTLPR polymorphism, COMT polymorphism, and Tourette's syndrome

Several lines of evidence suggest that a genetic component underlies Tourette's syndrome (TS). We investigated both the role of the insertion/deletion polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) and that of the Val-158-Met substitution in the catechol-O-methyl-transferase (COMT) gene in conferring susceptibility to TS. Fifty-two TS patients were recruited and compared with a control group of 63 healthy subjects. Neither a genotypic nor an allelic association was found; subdividing TS patients according to clinical variables, such as a co-diagnosis of obsessive–compulsive disorder (OCD) and a positive family history for obsessive compulsive disorder or tics, also failed to reveal a significant association. The lack of significance for 5-HTTLPR and COMT polymorphisms in conferring liability to TS does not exclude a role of different functional polymorphisms in genes coding for serotonergic or dopaminergic structures in the etiology of TS. In fact, TS is a complex disorder and these genes most likely have only a minor genetic effect in its etiology.     

Correlation between Apolipoprotein-E polymorphism and Alzheimer's disease pathology

Alzheimer's disease (AD) and small vessel disease dementia (SVDD) are common causes of dementia. The ApoE genotype has been proposed as a risk factor for AD. The frequency of the three ApoE alleles was correlated with the neuropathological changes of AD (senile plaques, neurofibrillary tangles and amyloid angiopathy) and SVDD (status lacunaris, status cribosus, leucoencephalopathy, micronecrosis and vascular fibrohyalinosis) in order to validate previous ApoE genotyping results in AD and to identify pre-clinical AD. Representative cerebral regions (cortex, gyrus cinguli, putamen, hippocampus, white matter) from 28 AD cases, 7 SVDD and 38 non-neurological controls were studied using classical histological techniques and immunohistochemistry for tau protein and amyloid-beta. The frequency of the ApoE allele 4 was significantly increased not only in AD patients but also in aged controls. However, following a detailed histopathological examination was found 62% of this group to exhibit histological changes associated with AD in limited brain areas (entorhinal region, hippocampus and adjacent temporal cortex or entorhinal region and hippocampus, or only in the entorhinal region), but 87% of these cases were found to be ApoE4 positive. The significant differences found in the distribution of ApoE allele frequencies were more marked when these cases were excluded from the control group and included as AD cases. In contrast, the frequency of the ApoE allele 2 is significantly increased in SVDD patients. Using histological techniques we confirmed the clinical diagnoses of all cases and classified the AD patients according to the severity of cortical pathology related to AD, while re-grouping from the control group those cases which had no clinical history of the disease but exhibited typical AD and SVDD histological lessions which could be considered as "pre-clinical" forms of these diseases.     

Association between tau polymorphism and male early-onset Alzheimer's disease

Neurofibrillary tangles, containing hyperphosphorylated microtubule-associated protein tau, are one of the major pathological hallmarks of Alzheimer's disease. To investigate a possible association between tau genotypes and the risk of Alzheimer's disease, we screened for polymorphisms in the tau gene and found a novel polymorphism IVS11 + 90G --> A. A case-control study (874 patients and 678 controls) showed a significant association between possession of the A allele and male Alzheimer's disease with early-onset (age of onset before 65, odds ratio = 2.65; 95% confidence interval 1.30-5.42), suggesting that age and gender modify the risk effect. However, we failed to replicate the reported association between the Saitohin gene located in the tau intron 9 and Japanese Alzheimer's disease.     

CYP19基因多态性与阿尔茨海默病遗传易感性的相关性研究

目的 探讨CYP19基因的多态性与阿尔茨海默病(AD)的关系. 方法 利用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)技术分析了102例AD患者与121名正常健康成人CYP19基因Mfe Ⅰ位点等位基因分布频率,比较基因型在AD患者与正常人之间的分布差异. 结果 (1)CYP19等位基因频率分布:AD组m1、m2分别为66.2%、33.8%,正常对照组分别为81.0%、19.0%,两组比较差异有统计学意义(X2=12.696,P<0.05).(2)CYP19基因Mfe Ⅰ位点基凶型分布频率:AD组m1/m1、m1/m2、m2/m2分布与正常对照组比较差异有统计学意义(44.1%、44.1%、11.8%:65.3%、31.4%、3.3%;X2=12.384,P<0.05). 结论 CYP19基因多态性与AD的遗传易感性有相关性.     

Long-term associations between cholinesterase inhibitors and memantine use and health outcomes among patients with Alzheimer's disease

ObjectivesTo examine in an observational study (1) relationships between cholinesterase inhibitors (ChEI) and memantine use, and functional and cognitive end points and mortality in patients with Alzheimer's disease (AD); (2) relationships between other patient characteristics and these clinical end points; and (3) whether effects of the predictors change across time.MethodsThe authors conducted a multicenter, natural history study that included three university-based AD centers in the United States. A total of 201 patients diagnosed with probable AD with modified Mini-Mental State Examination (MMSE) scores ≥ 30 at study entry were monitored annually for 6 years. Discrete-time hazard analyses were used to examine relationships between ChEI and memantine use during the previous 6 months reported at each assessment, and time to cognitive (MMSE score ≤ 10) and functional (Blessed Dementia Rating Scale score ≥ 10) end points and mortality. Analyses controlled for clinical characteristics, including baseline cognition, function, and comorbid conditions, and presence of extrapyramidal signs and psychiatric symptoms at each assessment interval. Demographic characteristics included baseline age, sex, education, and living arrangement at each assessment interval.ResultsChEI use was associated with delayed time in reaching the functional end point and death. Memantine use was associated with delayed time to death. Different patient characteristics were associated with different clinical end points.ConclusionsResults suggest long-term beneficial effects of ChEI and memantine use on patient outcomes. As for all observational cohort studies, observed relationships should not be interpreted as causal effects.     

Association between tumor necrosis factor-alpha promoter polymorphism and Alzheimer's disease

Tumor necrosis factor-alpha (TNFalpha) gene polymorphisms have been reported to be associated with Alzheimer's disease (AD) in Caucasian populations. Three TNFalpha polymorphisms (-857, -863, and -1,031) were studied in a Chinese population. A high-risk TNFalpha haplotype (-1,031C-863C-857C) with an odds ratio of 2.54 (95% CI 1.37 to 4.79) for AD was identified. No interaction effect of APOE and TNFalpha genotypes was found, but both acted as important risk factors for AD.     

No association between tryptophan hydroxylase gene polymorphism and Alzheimer's disease

Serotonergic dysfunction is implicated in Alzheimer's disease (AD) on the basis of studies of serotonin and its metabolite in postmortem specimens and CSF. There were also reports on association of a tryptophan hydroxylase (TPH) intron 7 variant and CSF 5-hydroxyindoleacetic acid concentrations. These suggested TPH might be a candidate to study for possible involvement in AD. Using a case-control association approach, we studied the TPH polymorphism in 150 subjects with AD and 100 controls. There were no significant differences in genotype or allele frequencies between controls and AD patients. The negative findings suggested that this TPH polymorphism has no major effect on the development of AD. However, the genetic variation of the TPH gene related to the symptomatology of AD deserves further investigation.     

Genetic associations between cathepsin D exon 2 C-->T polymorphism and Alzheimer's disease, and pathological correlations with genotype

Genetic variations represent major risk factors for Alzheimer's disease (AD). While familial early onset AD is associated with mutations in the amyloid precursor protein and presenilin genes, only the e4 allele of the apolipoprotein E (APOE) gene has so far been established as a genetic risk factor for late onset familial and sporadic AD. It has been suggested that the C-->T (224Ala-->Val) transition within exon 2 of the cathepsin D gene (CTSD) might represent a risk factor for late onset AD. The objective of this study was to investigate whether possession of the CTSD exon 2 T allele increases the risk of developing AD, and to determine whether this modulates the amyloid pathology of the disease in conjunction with, or independent of, the APOE e4 allele. Blood samples were obtained from 412 patients with possible or probable AD and brain tissues from a further 148 patients with AD confirmed by postmortem examination. CTSD and APOE genotyping were performed by PCR on DNA extracted from blood, or from frontal cortex or cerebellum in the postmortem cases. Pathological measures of amyloid beta protein (Abeta), as plaque Abeta40 and Abeta42(3) load and degree of cerebral amyloid angiopathy were made by image analysis or semiquantitative rating, respectively. CTSD genotype frequencies in AD were not significantly different from those in control subjects, nor did these differ between cases of early or late onset AD or between younger and older controls. There was no gene interaction between the CTSD T and APOE e4 alleles. The amount of plaque Abeta40 was greater in patients carrying the CTSD T allele than in non-carriers, and in patients bearing APOE e4 allele compared with non-carriers. Possession of both these alleles acted synergistically to increase levels of plaque Abeta40, especially in those individuals who were homozygous for the APOE e4 allele. Possession of the CTSD T allele had no effect on plaque Abeta42(3) load or degree of CAA. Possession of the CTSD T allele does not increase the risk of developing AD per se, but has a modulating effect on the pathogenesis of the disorder by increasing, in concert with the APOE e4 allele, the amount of Abeta deposited as senile plaques in the brain in the form of Abeta40.     

Influence of 5-HTTLPR polymorphism on resting state perfusion in patients with major depression

Neuroimaging studies in major depressive disorder (MDD) have indicated dysregulation in a network involving prefrontal cortex, subgenual cingulate and the amygdalae, which is known to be modulated by serotonin. The serotonergic system is the principal target for pharmacological treatment in MDD and the functional variable serotonin promoter polymorphism (5-HTTLPR) influences susceptibility, course and treatment response of MDD. Using data from a previously published sample of 89 MDD-patients, we examined post hoc the effect of 5-HTTLPR status on resting state perfusion, as measured with ^99mTc-HMPAO-SPECT. MDD patients were stratified according to receptor polymorphism, both using a bi-allelic (group A: L/L vs. group B: S/S and S/L genotype) and a tri-allelic approach (Group A′: LA/LA vs. Group B′: non-LA/LA genotype). There were no significant differences between both subgroups regarding age, gender, severity of depression, medication, or treatment response (p > 0.1). Using the bi-allelic approach, Group B, compared to group A, revealed a significantly higher resting state perfusion in medial prefrontal cortex (p_voxel (FWE) < 0.05). Additional ROI analyses showed relative overactivity of the amygdalae in group B (p_voxel (FWE) < 0.05). Similar effects were observed in the tri-allelic approach. The opposite contrasts (Group A > Group B) revealed no significant effects. We demonstrate that in patients with MDD, 5-HTTLPR gene polymorphism modulates resting state perfusion in key structures of mood processing. While the clinical impact of these findings will need to be further investigated in larger cohort studies, the necessity to monitor and to account for individual 5-HTTLPR-status in future MDD imaging studies is highly recommended.     

Relation of apolipoprotein E polymorphism to clinically diagnosed Alzheimer's disease in the Korean population

The gene for human apolipoprotein E (APOE) is found on the long arm of chromosome 19 (19q13.2) and exists in three common allelic forms, epsilon2, epsilon3, and epsilon4. The APOE epsilon4 allele is overrepresented in Alzheimer's disease (AD) and is accepted as a genetic risk factor. Some studies reported a protective effect of the APOE epsilon2 allele for AD. However, there are some ethnic variations in the proportion of different APOE alleles and their relationship to AD. We examine the distribution of APOE alleles from 30 AD patients and 158 controls in Korea. The control subjects were all cognitively intact unrelated Koreans. The frequencies of APOE alleles in AD patients were 18.3% (epsilon2), 58.3% (epsilon3), and 23.3% (epsilon4). The corresponding frequencies in controls were 13.3% (epsilon2), 72.5% (epsilon3), and 14.2% (epsilon4). The frequency of the APOE epsilon2 allele in AD patients was not significantly different from that in controls. When statistical analysis was conducted after the exclusion of the APOE epsilon2 allele, the frequency of the APOE epsilon4 allele in AD patients was significantly higher than that in controls (P < 0.05). These results support that the APOE epsilon4 allele plays a role as a risk factor for AD in Koreans and suggest that the APOE epsilon2 allele may not play a protective role in the development of AD in Koreans.     

Association between 5-HT(2A) receptor polymorphism and psychotic symptoms in Alzheimer's disease.

BACKGROUND: The aim of this study is to analyze the segregation of the 102T/C polymorphism in the serotonin 2A receptor gene in patients affected by sporadic and familial Alzheimer's disease (FAD) with and without psychotic symptoms. METHODS: The polymorphism was analyzed in 275 subjects. A semistructured interview was used to obtain information about delusions, hallucinations, and other specific behavioral signs occurring during the disease. RESULTS: Fifty-two percent of AD patients with psychotic symptoms were homozygous for the C102 allele, as compared with 6.9% of AD patients without psychosis. Similarly, the C102/C102 genotype was significantly more frequent in FAD patients with psychosis than in FAD patients without (46.5% vs. 7.8%). CONCLUSIONS: Our data strongly confirm and extend to FAD previous studies suggesting that the genetic variation at this locus is associated with prominent psychotic features in AD and that the 102C allele could play an important role in late-onset AD.     

5-羟色胺2A受体基因多态性与阿尔茨海默病的关联分析

目的 探讨中国汉族人群中５－羟色胺（５－ＨＴ）２Ａ（５－ＨＴ２Ａ）受体基因多态性与阿尔茨海默病（ＡＤ）的相互关系,方法 应用聚合酶链式反应（ＰＣＲ）－限制片段长度多态性（ＲＦＬＰ）方法,在８２例ＡＤ患者和９７名正常人中观察了５－ＨＴ２Ａ受体基因和载脂蛋白Ｅ（ＡｐｏＥ）基因多态性的分布,结果 （１）５－ＨＴ２Ａ受体基因多态性与ＡＤ是不存在任何关联（Ｐ〉０．０５）;（２）在进行ＡｐｏＥ基因分型后,Ａｐ     

Repeated suicidal behaviour: Stressful life events and 5-HTTLPR genetic polymorphism

Stressful life events and dysregulated mono-aminergic neurotransmission have been associated with suicidal behaviour. The aim of this investigation was to analyze suicidal behaviour in multiple attempters in relation to the stressful life events, and to the polymorphism of the serotonin transporter (SERT) gene. Multiple suicide attempters, admitted to the University Psychiatric Clinic, were interviewed for the number of previous suicide attempts and for the occurrence of stressful life events, recorded in a Life History Calendar. The patients were further genotyped for 5-HTTLPR polymorphism of SERT. The number of suicide attempts was found to be significantly correlated with the number of negative life events experienced during the 6 months preceding each suicide attempt. The L/L genotype was associated with a reduced number of multiple suicide attempts. These results should prompt future study with a larger number of subjects to further investigate the interaction of genetic and environmental factors in repeated suicidal behaviour.     

Brain structure and allelic associations in Alzheimer's disease

Background

Alzheimer's disease (AD), the most prevalent form of dementia, affects 6.5 million Americans and over 50 million people globally. Clinical, genetic, and phenotypic studies of dementia provide some insights of the observed progressive neurodegenerative processes, however, the mechanisms underlying AD onset remain enigmatic.

Aims

This paper examines late-onset dementia-related cognitive impairment utilizing neuroimaging-genetics biomarker associations.

Materials and Methods

The participants, ages 65–85, included 266 healthy controls (HC), 572 volunteers with mild cognitive impairment (MCI), and 188 Alzheimer's disease (AD) patients. Genotype dosage data for AD-associated single nucleotide polymorphisms (SNPs) were extracted from the imputed ADNI genetics archive using sample-major additive coding. Such 29 SNPs were selected, representing a subset of independent SNPs reported to be highly associated with AD in a recent AD meta-GWAS study by Jansen and colleagues.

Results

We identified the significant correlations between the 29 genomic markers (GMs) and the 200 neuroimaging markers (NIMs). The odds ratios and relative risks for AD and MCI (relative to HC) were predicted using multinomial linear models.

Discussion

In the HC and MCI cohorts, mainly cortical thickness measures were associated with GMs, whereas the AD cohort exhibited different GM-NIM relations. Network patterns within the HC and AD groups were distinct in cortical thickness, volume, and proportion of White to Gray Matter (pct), but not in the MCI cohort. Multinomial linear models of clinical diagnosis showed precisely the specific NIMs and GMs that were most impactful in discriminating between AD and HC, and between MCI and HC.

Conclusion

This study suggests that advanced analytics provide mechanisms for exploring the interrelations between morphometric indicators and GMs. The findings may facilitate further clinical investigations of phenotypic associations that support deep systematic understanding of AD pathogenesis.     

Alpha2-macroglobulin gene polymorphism in patients with Alzheimer's disease

Recent studies suggest that alpha 2-macroglobulin (alpha 2 m) may play a role in the pathogenesis of Alzheimer's Disease (AD). The presence of alpha 2-macroglobulin G/G genotype is thought to increase the risk of AD. The aim of the study was to analyse alpha 2 m polymorphism in two groups: AD patients (n = 60, F = 41, M. = 19, mean age 73.3 +/- 6.3) and non-demented control group (n = 58, F = 36, M. = 22, mean age 73.1 +/- 8.3, mean MMSE score 27). Frequencies of genotypes A/A, A/G, G/G in AD group were: 0.46: 0.42: 0.12. In control group those frequencies were: 0.40: 0.48: 0.12. The lack of statistically significant difference between G/G frequencies in both groups of patients may suggest that alpha 2-macroglobulin G/G genotype is not a risk factor for AD.     

Interactions between life stressors and susceptibility genes (5-HTTLPR and BDNF) on depression in Korean elders.

BACKGROUND: It has been reported that the functional polymorphism in the serotonin transporter gene linked promoter region (5-HTTLPR) modifies the association between stressful life events (SLEs) and depression in child, adolescent, and adult populations. We sought to replicate this finding in elders and, additionally, to test modifying effects of the brain-derived neurotrophic factor (BDNF) val66met polymorphism. METHODS: In 732 Korean community residents ages 65+, diagnosis of depression (Geriatric Mental State Schedule), information on SLEs, and genotypes for 5-HTTLPR and BDNF val66met were ascertained. Of those without depression at baseline, 521 (88%) were followed up 2.5 years later. Interactions between SLEs and the two genotypes were investigated for both prevalent depression at baseline and incident depression at follow-up. RESULTS: Significant interactions of SLEs with both 5-HTTLPR and BDNF genotypes were observed on risk of depression after adjustment for age, gender, education, and disability. A significant three-way interaction between 5-HTTLPR, BDNF, and SLEs was also found. The same findings were observed for predictors of incident depression in the prospective analysis. CONCLUSIONS: These findings suggest that environmental risk of depression is modified by at least two genes and that gene-environment interactions are found even into old age.     

Association between Alzheimer's disease and a functional polymorphism in the Myeloperoxidase gene

A polymorphism in the Myeloperoxidase gene (MPO) has previously been demonstrated to be associated with gender-specific risk in an Alzheimer's Disease (AD) autopsy sample. We have investigated this polymorphism in our own samples of 226 Caucasian cases and 166 controls and 59 Hispanic cases and 75 controls. In Caucasians we find a significant association between MPO genotype and AD (P = 0.03), although we do not observe any effects of gender or any interaction with the APOE gene. Specifically, the MPO GG genotype contributes a 1.57-fold increased risk for AD. In Hispanics there was no effect of MPO genotype, or of MPO genotype in interaction with age or gender, on diagnosis of AD.