Search

Genetic background has been considered one of the important contributors to the rate of cognitive decline among patients with Alzheimer's disease (AD). We conducted a 4-year longitudinal follow-up study, recruited 255 AD and 44 mild cognitive impairment (MCI) patients, and used a data-driven trajectory analysis to examine the influence of selected AD risk genes on the age for and the rate of cognitive decline in Han Chinese population. Genotyping of selected single-nucleotide polymorphisms in the APOE, ABCA7, SORL1, BIN1, GAB2, and CD33 genes was conducted, and a Bayesian hierarchical model was fitted to analyze the trajectories of cognitive decline among different genotypes. After adjusting for sex and education years, the APOE e4 allele was associated with an earlier mean change of -2.39 years in the age at midpoint of cognitive decline, the G allele in ABCA7 rs3764650 was associated with an earlier mean change of -1.75 years, and the T allele in SORL1 rs3737529 was associated with a later mean change of 2.6 years. Additionally, the rate of cognitive decline was associated with the APOE e4 allele and SORL1 rs3737529. In summary, APOE and SORL1 might be the most important genetic factors related to cognitive decline in Han Chinese population.

Background Frail older adults are predisposed to multiple comorbidities and adverse events. Recent interventional studies have shown that frailty can be improved and managed. In this study, effective individualized home-based exercise and nutrition interventions were developed for reducing frailty in older adults. Methods This study was a four-arm, single-blind, randomized controlled trial conducted between October 2015 and June 2017 at Miaoli General Hospital in Taiwan. Overall, 319 pre-frail or frail older adults were randomly assigned into one of the four study groups (control, exercise, nutrition, and exercise plus nutrition [combination]) and followed up during a 3-month intervention period and 3-month self-maintenance period. Improvement in frailty scores was the primary outcome. Secondary outcomes included improvements in physical performance and mental health. The measurements were performed at baseline, 1 month, 3 months, and 6 months. Results At the 6-month measurement, the exercise (difference in frailty score change from baseline: − 0.23; 95% confidence interval [CI]: − 0.41, − 0.05; p = 0.012), nutrition (− 0.28; 95% CI: − 0.46, − 0.11; p = 0.002), and combination (− 0.34; 95% CI: − 0.52, − 0.16; p Conclusions The designated home-based exercise and nutrition interventions can help pre-frail or frail older adults to improve their frailty score and physical performance. Trial registration Retrospectively registered at ClinicalTrials.gov (identifier: NCT03477097); registration date: March 26, 2018.

Aim Behavioral and psychological symptoms of dementia (BPSD) are important predictors for institutional placement, caregiver distress and depression for patients with dementia. We aim to investigate BPSD in institutional residents with dementia in Taiwan. Methods We conducted a nationwide study surveying institutional residents in Taiwan. Institutional residents from 22 counties and cities in Taiwan were recruited and analyzed in our study. We recorded demographic data, severity of dementia and disability, presence of BPSD, and past medical history of institutional residents in Taiwan. We recorded the characteristics of BPSD and analyzed the possible risks of BPSD in residents with dementia. Results A total of 4722 institutional residents were recruited and analyzed in our study. The prevalence of dementia was 87.2% (4119 residents). Among residents with dementia, 1546 (37.5%) had presented BPSD in the past 3 months. The most frequent three types of BPSD were nighttime behavior (17.9%), resistance against care (13.4%) and depression (12.9%). Old age, female gender, and lower MMSE (Mini-Mental State Examination) scores were associated with BPSD. Moderate dementia (OR = 1.73, 95% CI = 1.30-2.31) and mild activities of daily living (ADL) dependence (OR = 2.13, 95% CI = 1.06-4.27) increased the risks of BPSD. Reviews of past medical history showed that orthopedic disease, eye disease, genitourinary disease, dementia, psychiatric disorder and intellectual disability were associated with increasing risks of BPSD. Conclusions We concluded that moderate dementia and mild ADL dependence increased the risks of BPSD in institutional residents with dementia. Geriatr Gerontol Int 2021; ••: ••-••.

Background Frail older adults are predisposed to multiple comorbidities and adverse events. Recent interventional studies have shown that frailty can be improved and managed. In this study, effective individualized home-based exercise and nutrition interventions were developed for reducing frailty in older adults. Methods This study was a four-arm, single-blind, randomized controlled trial conducted between October 2015 and June 2017 at Miaoli General Hospital in Taiwan. Overall, 319 pre-frail or frail older adults were randomly assigned into one of the four study groups (control, exercise, nutrition, and exercise plus nutrition [combination]) and followed up during a 3-month intervention period and 3-month self-maintenance period. Improvement in frailty scores was the primary outcome. Secondary outcomes included improvements in physical performance and mental health. The measurements were performed at baseline, 1 month, 3 months, and 6 months. Results At the 6-month measurement, the exercise (difference in frailty score change from baseline: − 0.23; 95% confidence interval [CI]: − 0.41, − 0.05; p = 0.012), nutrition (− 0.28; 95% CI: − 0.46, − 0.11; p = 0.002), and combination (− 0.34; 95% CI: − 0.52, − 0.16; p

The elderly population is increasing rapidly worldwide, and frailty is a common geriatric syndrome. Comprehensive dietary management strategies may have beneficial effects on frailty prevention and reversal. This 3-month single-blind, paralleled, randomized controlled trial compared the effects of micronutrients and/or protein supplements, and a personalised diet on frailty status in elderly individuals.Between 2014 and 2015, 40 prefrail or frail subjects aged=65 years were recruited at Miaoli General Hospital, Taiwan. Of these, 37 completed the study, and 36 were included in the analysis. Participants were randomly assigned to one of four treatment groups: (1) the control (2) multiple micronutrient supplements, (3) multiple micronutrients plus isolated soy protein supplement, and (4) individualised nutrition education with customised dishware and food supplements (mixed nuts and skimmed milk powder). Dietary intake, protein biomarkers, frailty score, and geriatric depression score were assessed.Individualised nutrition education with customised dishware and food supplements significantly increased the participants' intake of vegetables, dairy, and nuts, in addition to increasing the concentration of urinary urea nitrogen. It yielded a significant reduction in frailty score (p0.05) and a borderline reduction (p=0.063) in geriatric depression score. No significant beneficial changes were observed for the other two intervention groups.Our study indicated that a dietary approach with easy-to-comprehend dishware and food supplements to optimize the distribution of the consumption of six food groups improved frailty status and, potentially, psychological well-being in elderly people.

Alzheimer's disease (AD), an irreversible neurodegenerative disease, is the most common type of dementia in elderly people. This present study incorporated multiple structural and functional connectivity metrics into a graph theoretical analysis framework and investigated alterations in brain network topology in patients with mild cognitive impairment (MCI) and AD. By using this multiparametric analysis, we expected different connectivity metrics may reflect additional or complementary information regarding the topological changes in brain networks in MCI or AD. In our study, a total of 73 subjects participated in this study and underwent the magnetic resonance imaging scans. For the structural network, we compared commonly used connectivity metrics, including fractional anisotropy and normalized streamline count, with multiple diffusivity-based metrics. We compared Pearson correlation and covariance by investigating their sensitivities to functional network topology. Significant disruption of structural network topology in MCI and AD was found predominantly in regions within the limbic system, prefrontal and occipital regions, in addition to widespread alterations of local efficiency. At a global scale, our results showed that the disruption of the structural network was consistent across different edge definitions and global network metrics from the MCI to AD stages. Significant changes in connectivity and tract-specific diffusivity were also found in several limbic connections. Our findings suggest that tract-specific metrics (e.g., fractional anisotropy and diffusivity) provide more sensitive and interpretable measurements than does metrics based on streamline count. Besides, the use of inversed radial diffusivity provided additional information for understanding alterations in network topology caused by AD progression and its possible origins. Use of this proposed multiparametric network analysis framework may facilitate early MCI diagnosis and AD prevention., Highlights • Alzheimer's disease alters structural network mainly in limbic and superior frontal regions. • Altered global network topology may occur in earlier stage during mild cognitive impairment. • The capability of proposed multiparametric network analysis has been demonstrated. • The potential of inversed radial diffusivity on network analysis has been shown.

Summary For characterizing the genetic mechanisms of complex diseases familial data with multiple correlated quantitative traits are usually collected in genetic studies. To analyze such data, various multivariate tests have been proposed to investigate the association between the underlying disease genes and the multiple traits. Although these multivariate association tests may have better power performance than the univariate association tests, they suffer from loss of testing power when the genetic models of the putative genes are misspecified. To address the problem, in this paper we aim to develop a family-based robust multivariate association test. We will first establish the optimal multivariate score tests for the recessive, additive, and dominant genetic models. Based on these optimal tests, a maximum-type robust multivariate association test is then obtained. Simulations are conducted to compare the power of our method with that of other existing multivariate methods. The results show that the robust multivariate test does manifest the robustness in power over all plausible genetic models. A practical data set is applied to demonstrate the applicability of our approach. The results suggest that the robust multivariate test is more powerful than the robust univariate test when dealing with multiple quantitative traits.

Aim: We aimed to identify the effect of SNPs in the α-subunits of GABAA receptors on epilepsy treatment outcomes by using a gene-wide tagging method. Materials & methods: There were 720 epileptic patients included in the present study. A total of 136 tagging SNPs in GABRA1, GABRA2, GABRA3, GABRA4, GABRA5 and GABRA6 were genotyped by Illumina®GoldenGate® Genotyping platform. Clinical information, such as prescribed antiepileptic drugs, height, weight, epilepsy syndrome classification, etiology, number of attacks, renal function and liver function were collected. The associations between SNPs and epilepsy treatment outcomes were analyzed using SAS® version 9.1.3. Both multivariate logistic regression and multifactor dimensionality reduction analyses were performed. Results: The results of single gene effects did not remain significant after Bonferroni’s corrections. Further multivariate logistic regression and multifactor dimensionality reduction analyses of interactions between these genes showed that under adjustment of clinical factors, the epilepsy treatment outcomes were significantly associated with the genotype combinations of GABRA1 rs6883877, GABRA2 rs511310 and GABRA3 rs4828696 (p < 0.0001; adjusted r2 = 0.149). Conclusion: Our results indicated that genetic variants in the α subunits of GABAA receptors may interactively affect the treatment responses of antiepileptic drugs. Further replication using an independent sample collection would be essential to confirm our findings. Original submitted 13 June 2013; Revision submitted 12 August 2013

Aim: The present study explored the integrative effect of genes encoding methadone pharmacokinetic and pharmacodynamic pathways on methadone maintenance doses in Han Chinese Patients. Materials & methods: Genomic DNA was extracted from 321 opioid-dependent patients and 202 healthy controls, and realtime-PCR and PCR-RFLP were conducted to determine the genotypes. Results: Pair-wise comparisons revealed that carriers of the variants ABCB1 3435C>T or CYP2B6 516G>T alleles were more likely to require a higher methadone dose than noncarriers (both p < 0.0001). On the other hand, carriers of the variant DRD2 -214A>G or 939C>T allele had a twofold chance of requiring a lower methadone dose than noncarriers (p = 0.001). Proportional odds regression with adjustment of cofactors demonstrated that ABCB1, CYP2B6, OPRM1, ANKK1 and DRD2 genetic variants were jointly correlated with optimal methadone dose (adjusted r2 = 53%). Conclusions: These findings provide new insight to the fact that the interindividual variability of methadone dosage requirement is polygenetic and cannot be explained by a single-gene effect. Original submitted 4 May 2011; Revision submitted 8 July 2011

Aims: Valproic acid (VPA) is one of the most widely used antiepileptic drugs. The aim of the study was to investigate whether polymorphisms in genes related to pharmacokinetic and pharmacodynamic pathways of VPA were associated with the large interindividual variability in dosages and concentrations. Methods & results: Genetic polymorphisms in six candidate genes were detected in 162 epileptic patients under maintenance with VPA monotherapy and stable seizure control by real-time PCR and PCR-RFLP. Results of statistical analysis demonstrated that carriers of the variant UGT1A6 19T>G, 541A>G and 552A>C allele tended to require higher VPA dosages and lower ln(concentration-to-dose ratios [CDRs]) than noncarriers (p < 0.0001) and the homozygous carriers also seemed to require higher VPA dosages and lower lnCDRs (p < 0.0001). On the other hand, carriers of the variant GRIN2B -200T>G allele were more likely to require lower VPA dosages than noncarriers (p < 0.0001) and the homozygous carriers also tended to require lower dosages and higher lnCDRs (p < 0.0001). In addition, the regression model of CDR of VPA also revealed that genetic variants in UGT1A6, GRIN2B and UGT2B7 genes interactively affect CDRs of VPA (adjusted r2 = 47%). Conclusion: Although there was a limited sample size, the study identified genetic factors associated with VPA therapy optimization that has not been revealed, and provided useful information for individualized VPA therapy in epileptic patients. Original submitted 9 February 2011; Revision submitted 20 April 2011

Aim: Carbamazepine (CBZ) is one of the most widely used antiepileptic drugs. The aim of the present study is to investigate the impacts of polymorphisms in genes related to pharmacokinetic and pharmacodynamic pathways of CBZ on the large interindividual variability in dosages and concentrations. Methods & results: Genetic polymorphisms in the candidate genes were detected in 234 epileptic patients under maintenance CBZ monotherapy by real-time PCR and PCR-RFLP. Results of statistical analysis demonstrated that carriers of the variant SCN1A IVS5–91G>A and EPHX1 c.337T>C allele tended to require higher CBZ dosages and lower ln(concentration–dose ratios) than noncarriers (p < 0.0001) and the homozygous carriers also seemed to require higher CBZ dosages and lower ln(concentration–dose ratios) (p < 0.0001). In addition, the multiple regression model of concentration–dose ratio of CBZ also revealed that genetic variants in SCN1A, EPHX1 and UGT2B7 genes interactively affect the concentration–dose ratio of CBZ (adjusted r2 = 55%). Conclusion: The present study identified genetic factors associated with CBZ therapy optimization and provided useful information for individualized CBZ therapy in epileptic patients. Further studies in larger populations are needed to confirm our results. Original submitted: 22 July 2011; Revision submitted: 27 September 2011