Relationship between Cortical Thickness and Neuropsychological Performance in Normal Older Adults and Those with Mild Cognitive Impairment.

Mild cognitive impairment (MCI) has been extensively investigated in recent decades to identify groups with a high risk of dementia and to establish effective prevention methods during this period. Neuropsychological performance and cortical thickness are two important biomarkers used to predict progression from MCI to dementia. This study compares the cortical thickness and neuropsychological performance in people with MCI and cognitively healthy older adults. We further focus on the relationship between cortical thickness and neuropsychological performance in these two groups. Forty-nine participants with MCI and 40 cognitively healthy older adults were recruited. Cortical thickness was analysed with semiautomatic software, Freesurfer. The analysis reveals that the cortical thickness in the left caudal anterior cingulate (p=0.041), lateral occipital (p=0.009) and right superior temporal (p=0.047) areas were significantly thinner in the MCI group after adjustment for age and education. Almost all neuropsychological test results (with the exception of forward digit span) were significantly correlated to cortical thickness in the MCI group after adjustment for age, gender and education. In contrast, only the score on the Category Verbal Fluency Test and the forward digit span were found to have significant inverse correlations to cortical thickness in the control group of cognitively healthy older adults. The study results suggest that cortical thinning in the temporal region reflects the global change in cognition in subjects with MCI and may be useful to predict progression of MCI to Alzheimer's disease. The different pattern in the correlation of cortical thickness to the neuropsychological performance of patients with MCI from the healthy control subjects may be explained by the hypothesis of MCI as a disconnection syndrome.

A PIN1 polymorphism that prevents its suppression by AP4 associates with delayed onset of Alzheimer's disease.

Alzheimer's disease (AD), the most common form of dementia, is characterized by the presence of neurofibrillary tangles composed of tau and senile plaques of amyloid-beta peptides (Aß) derived from amyloid precursor protein (APP). Pin1 is a unique prolyl isomerase that has been shown to protect against age-dependent neurodegeneration by acting on phosphorylated tau and APP to suppress tangle formation and amyloidogenic APP processing. Here we report a functional polymorphism, rs2287839, in the Pin1 promoter that is significantly associated with a 3-year delay in the average age at onset (AAO) of late-onset AD in a Chinese population. More significantly, the Pin1 polymorphism rs2287839 is located within the consensus binding motif for the brain-selective transcription factor, AP4 (CAGCTG) and almost completely abolishes the ability of AP4 to bind and suppress the Pin1 promoter, as shown by chromatin immunoprecipitation, electrophoretic mobility shift assay, and promoter luciferase assay. Moreover, overexpression or knockdown of AP4 resulted in an 80% reduction or 2-fold increase in endogenous Pin1 levels, respectively. Thus, AP4 is a novel transcriptional repressor of Pin1 expression and the Pin1 promoter single nucleotide polymorphism (SNP) identified in this study that prevents such suppression is associated with delayed onset of AD. These results indicate that regulation of Pin1 by AP4 plays a critical role in determining age at onset of AD and might be a novel therapeutic target to delay the onset of AD.

NEDD9 gene polymorphism influences the risk of Alzheimer disease and cognitive function in Chinese older persons.

Neural precursor cell expressed, developmentally down-regulated (NEDD9) gene was a new candidate risk gene for Alzheimer disease (AD). The CC genotype of a single nucleotide polymorphism rs760678 within this gene was associated with increasing risk of AD in a large study with white population. Our study aimed to replicate the initial report in Chinese population and explore its effect on cognitive performance. A total of 262 patients with AD, 293 patients with mild cognitive impairment, and 434 cognitive intact controls were recruited in the study. The result showed that G allele had a greater risk of AD (χ for trend test=5.61, df 1, P=0.018). The effects were mainly observed among Apolipoprotein E (APOE) ε4 noncarriers (χ for trend test=4.30, df 1, P=0.038). After adjustment of sex, age, education year, and APOE ε4 status by logistic regression, significant association between NEDD9 GG genotype and AD remained [OR=2.04, 95% confidence interval (CI)=1.02-4.08, P=0.044]. The scores of Cantonese version of the Mini-mental State Examination and Alzheimer's Disease Assessment Subscale-Cognitive subscale were associated with N polymorphism after adjusting for sex, age, education year, and ApoE ε4 status (Linear regression model, P<0.05). Our study identified rs760678 within NEDD9 gene in association with the risk of AD and cognitive performance in Chinese older persons. The fact that different alleles accounted for the risk in different population might suggest that there were ethnic group specific haplotypes that were primarily responsible for the predisposition.

Examining the association between late-life leisure activity participation and global cognitive decline in community-dwelling elderly Chinese in Hong Kong.

OBJECTIVE: This study examines the association between late-life leisure activity participation and global cognitive decline in community-dwelling elderly Chinese in Hong Kong. METHODS: Five hundred and five participants, not clinically demented at the baseline, were analysed in the follow-up study of a population-based community survey among Hong Kong Chinese aged 60 and over. Information regarding leisure activity participation, global cognitive function and important sociodemographic variables was collected. Late life leisure activity profiles were classified into intellectual, social, physical and recreational categories, and were measured by total hours per week, total frequency and total number of subtypes. Multivariate logistic regression analyses were used to evaluate the association between leisure activity participation at the baseline and the incidence of global cognitive decline at the 22-month follow-up. The incidence of global cognitive decline was defined as a one-point drop in z-score of the Cantonese version of the mini-mental state examination (CMMSE). RESULTS: At the follow-up, a higher level of participation in intellectual activities was significantly associated with a lower incidence of global cognitive decline as measured by both the total hours per week (multivariate-adjusted OR 0.97 (95% CI 0.94-0.99, p=0.003)), and the total number of subtypes (multivariate-adjusted OR 0.74 (95% CI 0.58-0.95, p=0.018)). CONCLUSIONS: A higher level of late-life intellectual activity participation was associated with less global cognitive decline among community-dwelling elderly Chinese in Hong Kong.

Prevalence of neuropsychiatric symptoms in chinese older persons with mild cognitive impairment-a population-based study.

OBJECTIVES: To estimate the point prevalence and correlates of neuropsychiatric (NP) symptoms among older adults with mild cognitive impairment (MCI) and normal cognition (NC) in a Chinese community. DESIGN: Cross-sectional study derived from a population-based prevalence study of MCI and dementia. SETTING AND PARTICIPANTS: This survey was conducted in Hong Kong from 2005 to 2006. Seven hundred eighty-eight community-dwelling older adults (450 NC and 338 MCI) were recruited. Cognitive and NP data were obtained. RESULTS: The point prevalence of at least one NP symptom in NC and MCI were 29% and 36.7%, respectively (logistic regression controlled for age and education, odds ratio = 1.38, 95% confidence interval [CI]: 1.01-1.89, Wald χ = 4.10, df = 1, p = 0.04). Agitation (1.8% versus 5.1%), apathy (7.6% versus 15.2%), and irritability (4.2% versus 8%) were more prevalent in subjects with MCI (p <0.05). Logistic regression analyses showed that apathy score was a significant factor associated with the status of NC or MCI (logistic regression, apathy, p = 0.031, Exp(B) = 1.23, 95% CI: 1.02-1.47; Hosmer and Lemeshow test, χ = 8.6, df = 8, p = 0.38, R = 0.23). CONCLUSIONS: The authors reported the findings of one of the first population-based studies estimating the point prevalence of NP symptoms in Asian older adults with MCI. Taking into account of its prevalence and magnitude of effects, apathy is a clinically significant symptom in MCI. Its predictive value for conversion to dementia warrants further evaluation.

Cholesterol 24-hydroxylase (CYP46A1) polymorphisms are associated with faster cognitive deterioration in Chinese older persons: a two-year follow up study.

OBJECTIVES: We previously found that the polymorphisms of cholesterol 24-hydroxylase (CYP46A1) gene were associated with the risk of Alzheimer's disease (AD) in Chinese. However, its effect in predicting progression of cognitive decline remains unknown. METHODS: Two hundred and eighty-one Chinese subjects (121 cognitively intact, 101 with mild cognitive impairment and 59 with mildly dementia) were followed-up with a mean (SD) duration of 25.22(5.74) months. Association between the CYP46A1 gene polymorphisms and 2-year cognitive deterioration were evaluated. RESULTS: At follow-up, 225(80.0%) subjects were reassessed. Sixty-three subjects were diagnosed as AD, 68 were MCI and 94 were cognitively intact. Among them, 158 had improved or remained stable while 67 deteriorated. The 'deteriorated' group was older than 'improved or stable' group (t-test, t = -2.87, p < 0.001). IVS2-150 polymorphism was associated with a higher risk of cognitive deterioration. Subjects with T allele were more likely to deteriorate compared with those without T allele (Pearson chi(2) = 8.98, df 2, p = 0.011). IVS3-128 CC genotype was higher in 'improved or stable' group (Likelihood Ratio = 6.55, df 2, p = 0.038), suggesting a protective role for this allele. The two other polymorphisms, IVS1-192 and IVS4-122, did not show any significant association with cognitive function. CONCLUSION: CYP46A1 gene may act to modulate the course of cognitive deterioration in late life.

Association between HLA-A alleles and Alzheimer's disease in a southern Chinese community.

BACKGROUND/AIM: HLA-A is a locus of the major histocompatibility complex situated on chromosome 6p21.3. Several genome-wide linkage analyses suggested that a putative locus predisposition for Alzheimer's disease (AD) is found on chromosome 6p21. In this study, we investigated the association between HLA-A alleles and AD in a Chinese community. METHODS: Fine genotyping of 160 Chinese AD and 167 age-matched nondemented subjects was performed for the first time by sequence-based typing of the HLA-A locus. RESULTS: We found that HLA-A2 carriers (including prevalent alleles, 0201, 0203 and 0207) were more prevalent in the AD group; the frequency of HLA-A2 was increased in AD patients versus controls, but the difference was not significant after Bonferroni correction for the number of alleles tested (p = 0.075). A gene-gene interaction was observed between ApoE and HLA-A, the presence of HLA-A24 (particularly the prevalent allele 2402) might act as another independent risk factor of developing AD for subjects not carrying the ApoE epsilon4 allele (relative risk = 2.98, 95% CI = 1.14-8.24). Carriers of HLA-A2 had an earlier onset of AD by 2.4 years (p = 0.030) and HLA-A2 interacted with ApoE epsilon4 in modulating the age at onset in AD. CONCLUSIONS: This study suggested that HLA-A may be involved in the pathogenesis of AD.

Association of prostaglandin-endoperoxide synthase 2 (PTGS2) polymorphisms and Alzheimer's disease in Chinese.

Cyclooxygenase-2 (COX-2, encoded by the gene prostaglandin-endoperoxide synthase 2, PTGS2) is a key enzyme in the conversion of arachidonic acid to prostaglandins. The prostaglandins produced by COX-2 are involved in inflammation and pain response in different tissues in the body. Enhanced COX-2 expression had been found in regions of brains from patients with Alzheimer's disease (AD). Here, we proceeded to test the hypothesis that polymorphisms of the PTGS2 gene predispose to AD. IVS5-275 T>G and Ex10+837 T>C in addition to three tagging SNPs from HapMap database, which provided a comprehensive coverage of genetic variations in the PTGS2 gene in Chinese were genotyped among 257 AD patients and 244 age-matched healthy Chinese subjects. Genetic associations were analyzed by chi(2)-test and haplotypes analysis. Although the previously reported protective polymorphism (rs20417, -765 G/C) for AD in PTGS2 gene was not polymorphic in the Chinese population, SNPs in both the promoter (-2319 G>T) and 3' region (Ex10+837 T>C) of PTGS2 were associated with the risk of AD (p=0.01 and 0.03, respectively). Carriers of Ex10+837 T allele had a 1.5-fold increase in the risk of AD. This study suggested that PTGS2 gene was a predisposition gene and arachidonic acid metabolism might be involved in the pathogenesis of AD. It provided further evidence to support a role of inflammation in the development and progression of AD.

Characteristic profiles of instrumental activities of daily living in Chinese older persons with mild cognitive impairment.

Increasing evidence suggests that performance of the instrumental activities of daily living (IADL) can be impaired at the mild cognitive impairment (MCI) stage. Our study aimed at investigating the profiles of functional impairment in Chinese subjects with MCI. Subjects with MCI were categorized into single-domain amnestic MCI (a-MCI) (n=54) and multiple-domain amnestic MCI (md-MCI) (n=93) groups. Their functional scores of Disability Assessment of Dementia (DAD) were compared with those of cognitively normal elderly controls (NC) (n=78) and those with mild Alzheimer's disease (AD) (n=85). Subjects with md-MCI had intermediate performance in IADL between the NC and those with mild AD. Subjects with a-MCI had functional scores similar to those of normal controls. Age, education, and global cognitive test scores were not associated with functional scores in MCI subjects. Our results demonstrated that Chinese older persons with md-MCI had impairment in IADL, as compared to NC and subjects with a-MCI. This finding suggests that assessment of IADL should be incorporated in the clinical evaluation of MCI.

Subjective complaints and self-evaluation of memory test performance in Questionable dementia.

BACKGROUND: The clinical significance of subjective memory complaints in elderly subjects has been an area of active research. In this study, we evaluated subjective complaints and self-evaluation of memory test performance in subjects with Questionable dementia (QD) and mild Alzheimer's disease (AD). METHODS: Ninety-two subjects (35 cognitively intact normal controls NC, 33 QD, and 24 mild AD) were assessed. Subjective memory complaints were evaluated using a memory inventory for the Chinese (MIC); objective assessment of awareness was assessed by the self-evaluation of own memory test performance. Cognitive function was assessed with the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), Category Verbal Fluency Test (CVFT) and Executive Interview (EXIT-25). Depressive symptoms were evaluated with the Cornell Scale for Depression in Dementia (CSDD). RESULTS: The total number of subjective memory complaints (MI-tol) were significantly different between different subject groups (Kruskal Wallis test, chi2 = 13.19, p = 0.001). Significant correlations between scores of the MI-tol and CSDD (r = 0.33, p < 0.001), CMMSE (r = -0.33, p < 0.001), CDR (r = 0.36, p < 0.001) were found. In self-evaluation of memory test performance, the NC group tended to under-estimate while the AD subjects tended to over-estimate their performance. Group differences in the discrepancies of self-evaluation of memory performance were significant for both the immediate (Kruskal Wallis test, chi2 = 9.86, p = 0.007) and delayed recall (Kruskal Wallis test, chi2 = 10.55, p < 0.001) trials. CONCLUSIONS: Subjects with QD and mild AD showed higher frequency of subjective memory complaints, reflecting that the subjects still retain some ability to appreciate own memory function. However, the trend for over-estimation of performance in AD subjects suggests that the precision of estimation may be suboptimal. Moreover, depressive symptoms may affect the presentation of memory complaints and this factor should be carefully considered in future prospective studies.

Reduced semantic fluency as an additional screening tool for subjects with questionable dementia.

BACKGROUND: Subjective memory complaints in subjects with mild cognitive impairment may represent a genuine decline in episodic memory. This paper evaluates the neuropsychological correlates of the semantic fluency test in subjects with questionable dementia (QD). METHODS: A total of 331 Chinese subjects (118 normal controls, NC, 150 with QD and 63 with mild Alzheimer's disease, AD) were assessed with the Category Verbal Fluency Test (CVFT), the AD Assessment Scale-cognitive subscale (ADAS-Cog), and digit and verbal span tests. CVFT performance was evaluated in each Clinical Dementia Rating (CDR) group. The total number of exemplars, the subcategory and the category size generated were evaluated. Neuropsychological correlates of CVFT scores were computed. RESULTS: Significant differences in CVFT performance were found between the different CDR groups. The subjects with QD had intermediate scores compared to the NC and AD subjects (1-way ANOVA, p < 0.001, post-hoc Bonferroni comparisons). In NC the CVFT scores were significantly associated with ADAS-Cog total, and immediate and delayed recall scores (partial correlations controlled for age and education, p < 0.005). In the QD group the CVFT scores were correlated with ADAS-Cog total, and immediate recall and object naming scores (partial correlation controlled for age and education, p < 0.005). Regression analysis revealed that age and delayed recall were significant predictors of CVFT performance in NCs. In the QD group, age, ADAS-Cog immediate recall and object naming scores predicted the CVFT performance. CONCLUSIONS: The CVFT was impaired in the subjects with QD. Apart from episodic memory, semantic memory deficits also occur early in AD. The different cognitive predictors of CVFT scores in the NC and QD groups suggest that the test is associated with specific psychological functions at different stages of cognitive impairment.