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Hsu W.-C.,Chang Gung University | Hsu W.-C.,Dementia Center | Chu Y.-C.,Chang Gung University | Chu Y.-C.,Dementia Center | And 9 more authors.
Medicine (United States) | Year: 2016

Mounting evidence shows that hyperhomocysteinemia is a risk factor for cognitive decline. This study enrolled subjects with normal serum levels of B12 and folate and performed thorough neuropsychological assessments to illuminate the independent role of homocysteine on cognitive functions. Participants between ages 50 and 85 were enrolled with Modified Hachinski ischemic score of <4, adequate visual and auditory acuity to allow neuropsychological testing, and good general health. Subjects with cognitive impairment resulting from secondary causes were excluded. Each of the participants completed evaluations of general intellectual function, including the Mini-Mental State Examination, Cognitive Abilities Screening Instrument, Clinical Dementia Rating, and a battery of neuropsychological assessments. This study enrolled 225 subjects (90 subjects younger than 65 years and 135 subjects aged 65 years or older). The sex proportion was similar between the 2 age groups. Years of education were significantly fewer in the elderly (7.49±5.40 years) than in the young (9.76±4.39 years, P=0.001). There was no significant difference in body mass index or levels of vitamin B12 and folate between the 2 age groups. Homocysteine levels were significantly higher in the elderly group compared to the younger group (10.8±2.7 vs. 9.5± 2.5mmol/L, respectively, P=0.0006). After adjusting for age, sex, and education, only the Digit Symbol Substitution (DSS) score was significantly lower in subjects with hyperhomocysteinemia (homocysteine >12mmol/L) than those with homocysteine 12mmol/L in the elderly group (DSS score: 7.1±2.7 and 9.0±3.0, respectively, beta=1.6, 95% confidence interval [CI]=2.8?0.5, P= 0.001) and borderline significance was noted in the combined age group (beta=1.1, 95% CI=2.1?0.1, P=0.04). We did not find an association between hyperhomocysteinemia and other neuropsychological assessments. This is the first study to demonstrate a significant association between hyperhomocysteinemia (>12mmol/L) and low DSS score, suggesting that DSS score may be an independent marker of cognitive impairment in response to hyperhomocysteinemia, especially in the elderly. Further replication studies with larger cohorts are needed to confirm our results. Copyright © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All.

Kim J.H.,Dementia Center | Go S.M.,Dr. Hwangs Neurology Clinic | Seo S.W.,Samsung | Seo S.W.,Sungkyunkwan University | And 8 more authors.
Dementia and Geriatric Cognitive Disorders | Year: 2015

Background: Subcortical vascular dementia (SVaD) is one of the most common dementias, after Alzheimer's disease (AD) dementia. Few survival analyses in SVaD patients have been reported. Methods: The dates and causes of death of 146 SVaD and 725 AD patients were included. We used the Cox proportional hazards model to compare survival between SVaD and AD patients and to explore possible factors related to survival of SVaD patients. Results: The median survival time after the onset of SVaD (109 months) was shorter than that recorded for AD (152 months). The most common cause of death in SVaD was stroke (47.1%). Factors associated with shorter survival in SVaD were late onset, male sex, worse baseline cognition, absence of hypertension and a family history of stroke. Conclusions: Stroke prevention may be important in SVaD treatment because 47.1% of SVaD patients died of stroke. A family history of stroke and absence of hypertension were associated with a shorter survival in SVaD, suggesting the existence of genetic or unknown risk factors. © 2015 S. Karger AG, Basel.

Kim J.H.,Dementia Center | Song P.,Inje University | Lim H.,Ilsan Hospital | Lee J.-H.,Kyung Hee University | And 2 more authors.
PLoS ONE | Year: 2014

Alzheimer's disease (AD) has a strong propensity to run in families. However, the known risk genes excluding APOE are not clinically useful. In various complex diseases, gene studies have targeted rare alleles for unsolved heritability. Our study aims to elucidate previously unknown risk genes for AD by targeting rare alleles. We used data from five publicly available genetic studies from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the database of Genotypes and Phenotypes (dbGaP). A total of 4,171 cases and 9,358 controls were included. The genotype information of rare alleles was imputed using 1,000 genomes. We performed gene-based analysis of rare alleles (minor allele frequency≤3%). The genome-wide significance level was defined as meta P<1.8×10-6 (0.05/number of genes in human genome = 0.05/28,517). ZNF628, which is located at chromosome 19q13.42, showed a genome-wide significant association with AD. The association of ZNF628 with AD was not dependent on APOE ε4. APOE and TREM2 were also significantly associated with AD, although not at genome-wide significance levels. Other genes identified by targeting common alleles could not be replicated in our gene-based rare allele analysis. We identified that rare variants in ZNF628 are associated with AD. The protein encoded by ZNF628 is known as a transcription factor. Furthermore, the associations of APOE and TREM2 with AD were highly significant, even in gene-based rare allele analysis, which implies that further deep sequencing of these genes is required in AD heritability studies. Copyright: © 2014 Kim et al.

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