Heng-Liang Yeh

Complexity of spontaneous BOLD activity in default mode network is correlated with cognitive function in normal male elderly: a multiscale entropy analysis

The nonlinear properties of spontaneous fluctuations in blood oxygen level-dependent (BOLD) signals remain unexplored. We test the hypothesis that complexity of BOLD activity is reduced with aging and is correlated with cognitive performance in the elderly. A total of 99 normal older and 56 younger male subjects were included. Cognitive function was assessed using Cognitive Abilities Screening Instrument and Wechsler Digit Span Task. We employed a complexity measure, multiscale entropy (MSE) analysis, and investigated appropriate parameters for MSE calculation from relatively short BOLD signals. We then compared the complexity of BOLD signals between the younger and older groups, and examined the correlation between cognitive test scores and complexity of BOLD signals in various brain regions. Compared with the younger group, older subjects had the most significant reductions in MSE of BOLD signals in posterior cingulate gyrus and hippocampal cortex. For older subjects, MSE of BOLD signals from default mode network areas, including hippocampal cortex, cingulate cortex, superior and middle frontal gyrus, and middle temporal gyrus, were found to be positively correlated with major cognitive functions, such as attention, orientation, short-term memory, mental manipulation, and language. MSE from subcortical regions, such as amygdala and putamen, were found to be positively correlated with abstract thinking and list-generating fluency, respectively. Our findings confirmed the hypothesis that complexity of BOLD activity was correlated with aging and cognitive performance based on MSE analysis, and may provide insights on how dynamics of spontaneous brain activity relates to aging and cognitive function in specific brain regions.

Association of CHRNA4 polymorphism with depression and loneliness in elderly males

The cholinergic receptor, nicotinic, alpha 4 (CHRNA4) gene encodes the neuronal nicotinic acetylcholine receptor alpha‐4 subunit. Recent research has shown that a variation in CHRNA4 (rs1044396) affects attention and negative emotionality in normal adults. To determine the link between CHRNA4 variation and cognitive function/depressed mood, this study conducted a genotype–phenotype correlation analysis between the common CHRNA4:rs1044396 variant and several baseline parameters of cognition and depressed mood in 192 elderly male subjects without major psychiatric disorders or dementia. Study findings identified a significant link between the CHRNA4:rs1044396 polymorphism and depression and loneliness in the aged. Compared to carriers of at least one T‐allele, carriers of the homozygous C/C genotype described themselves as more depressed and lonely. This is the first evidence which may implicate CHRNA4 in depressed emotions in the elderly.

Heterozygote advantage of the MTHFR C677T polymorphism on specific cognitive performance in elderly Chinese males without dementia.

Aims: Aging is associated with cognitive deterioration, and genetic factors are implicated in individual cognitive differences in the aged. The C677T mutation in the 5,10-methylenetetrahydrofolate reductase gene (MTHFR) yields a common thermolabile variant (T) with reduced enzyme activity and consequent elevation of serum homocysteine concentrations. We designed the present study to investigate whether this functional polymorphism may affect global and specific cognitive functions in older Chinese males without dementia. Methods: The subjects included 356 elderly males without major psychiatric disorders or dementia, who were assessed by the Cognitive Abilities Screening Instruments (CASI) and the Wechsler Digit Span Task tests. Results: A significant association was found between the MTHFR C677T polymorphism and total CASI scores (p = 0.012), particularly in short-term memory (p = 0.002) and concentration/mental manipulation (p = 0.007). Post hoc tests indicated that the C/T heterozygotes achieved better cognitive function test results than C/C or T/T carriers. No association was found between the MTHFR genotype and the Wechsler Digit Span Task tests. Conclusion: These results suggest that a heterozygote advantage exists for the MTHFR C677T polymorphism in specific cognitive functions in elderly Chinese males without dementia.

Functional Connectivity Density Mapping of Depressive Symptoms and Loneliness in Non-Demented Elderly Male

Background: Depression and loneliness are prevalent and highly correlated phenomena among the elderly and influence both physical and mental health. Brain functional connectivity changes associated with depressive symptoms and loneliness are not fully understood. Methods: A cross-sectional functional MRI study was conducted among 85 non-demented male elders. Geriatric depression scale-short form (GDS) and loneliness scale were used to evaluate the severity of depressive symptoms and loneliness, respectively. Whole brain voxel-wise resting-state functional connectivity density (FCD) mapping was performed to delineate short-range FCD (SFCD) and long-range FCD (LFCD). Regional correlations between depressive symptoms or loneliness and SFCD or LFCD were examined using general linear model (GLM), with age incorporated as a covariate and depressive symptoms and loneliness as predictors. Results: Positive correlations between depressive symptoms and LFCD were observed in left rectal gyrus, left superior frontal gyrus, right supraorbital gyrus, and left inferior temporal gyrus. Positive correlations between depressive symptoms and SFCD were observed in left middle frontal gyrus, left superior frontal gyrus, bilateral superior medial frontal gyrus, left inferior temporal gyrus, and left middle occipital region. Positive correlations between SFCD and loneliness were centered over bilateral lingual gyrus. Conclusion: Depressive symptoms are associated with FCD changes over frontal and temporal regions, which may involve the cognitive control, affective regulation, and default mode networks. Loneliness is associated with FCD changes in bilateral lingual gyri that are known to be important in social cognition. Depressive symptoms and loneliness may be associated with different brain regions in non-demented elderly male.

Effect of Bcl-2 rs956572 Polymorphism on Age-Related Gray Matter Volume Changes

The anti-apoptotic protein B-cell CLL/lymphoma 2 (Bcl-2) gene is a major regulator of neural plasticity and cellular resilience. Recently, the Bcl-2 rs956572 single nucleotide polymorphism was proposed to be a functional allelic variant that modulates cellular vulnerability to apoptosis. Our cross-sectional study investigated the genetic effect of this Bcl-2 polymorphism on age-related decreases in gray matter (GM) volume across the adult lifespan. Our sample comprised 330 healthy volunteers (191 male, 139 female) with a mean age of 56.2±22.0 years (range: 21–92). Magnetic resonance imaging and genotyping of the Bcl-2 rs956572 were performed for each participant. The differences in regional GM volumes between G homozygotes and A-allele carriers were tested using optimized voxel-based morphometry. The association between the Bcl-2 rs956572 polymorphism and age was a predictor of regional GM volumes in the right cerebellum, bilateral lingual gyrus, right middle temporal gyrus, and right parahippocampal gyrus. We found that the volume of these five regions decreased with increasing age (all P<.001). Moreover, the downward slope was steeper among the Bcl-2 rs956572 A-allele carriers than in the G-homozygous participants. Our data provide convergent evidence for the genetic effect of the Bcl-2 functional allelic variant in brain aging. The rs956572 G-allele, which is associated with significantly higher Bcl-2 protein expression and diminished cellular sensitivity to stress-induced apoptosis, conferred a protective effect against age-related changes in brain GM volume, particularly in the cerebellum.

ASSOCIATION BETWEEN RENAL FUNCTION AND COGNITIVE PERFORMANCE IN ELDERLY COMMUNITY-DWELLING MEN WITHOUT DEMENTIA

Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: Dr. Vázquez-Valdez developed the conceptualization and design of the study, performed the analyses, and interpreted the data. He wrote the manuscript under the supervision of Drs. Aguilar-Navarro and Ávila-Funes. The coauthors certify that they have participated substantially in the conceptualization and design of this work, the analysis of the data, and the writing of the manuscript. They have reviewed the final version of the manuscript and approved it for publication. Sponsor’s Role: None.

Catechol-O-Methyltransferase Val158Met Polymorphism on the Relationship between White Matter Hyperintensity and Cognition in Healthy People

Background White matter lesions can be easily observed on T2-weighted MR images, and are termed white matter hyperintensities (WMH). Their presence may be correlated with cognitive impairment; however, the relationship between regional WMH volume and catechol-O-methyltransferase (COMT) Val158Met polymorphism in healthy populations remains unclear. Methods We recruited 315 ethnic Chinese adults with a mean age of 54.9±21.8 years (range: 21–89 y) to examine the genetic effect of COMT on regional WMH and the manner in which they interact to affect cognitive function in a healthy adult population. Cognitive tests, structural MRI scans, and genotyping of COMT were conducted for each participant. Results Negative correlations between the Digit Span Forward (DSF) score and frontal WMH volumes (r = −.123, P = .032, uncorrected) were noted. For the genetic effect of COMT, no significant difference in cognitive performance was observed among 3 genotypic groups. However, differences in WMH volumes over the subcortical region (P = .016, uncorrected), whole brain (P = .047, uncorrected), and a trend over the frontal region (P = .050, uncorrected) were observed among 3 COMT genotypic groups. Met homozygotes and Met/Val heterozygotes exhibited larger WMH volumes in these brain regions than the Val homozygotes. Furthermore, a correlation between the DSF and regional WMH volume was observed only in Met homozygotes. The effect size (cohen’s f) revealed a small effect. Conclusions The results indicate that COMT might modulate WMH volumes and the effects of WMH on cognition.

Association of MTHFR C677T polymorphism with loneliness but not depression in cognitively normal elderly males

Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism is involved in folate and homocysteine metabolism, and has been associated with geriatric disorders, including dementia and late-life depression. The present work aimed to investigate the effect of MTHFR C677T polymorphism on the presence of depression and loneliness in cognitively normal male subjects. A total of 323 cognitively normal male subjects were included in this study (mean age=80.6; SD=5.3). Depression was assessed by the Geriatric Depression Scale-Short Form (GDS-SF) and loneliness by UCLA loneliness scales. Analysis of variance (ANOVA) was used to test the between MTHFR genotype difference in depression and loneliness. Multiple regression was used to test the effect of MTHFR polymorphism on the loneliness, controlling for age, education, cognitive function, and depression. ANOVA showed a significant between-genotype difference in loneliness scores (P=0.015), and post hoc comparisons showed that subjects with C/C genotype had significantly higher loneliness ratings, compared to those with C/T or T/T genotype. Regression analysis indicated that the effect of MTHFR polymorphism on loneliness was independent of age, education, cognitive function, and depression. Our findings suggest that MTHFR C677T polymorphism may be linked more to loneliness than depression in the cognitively normal elderly males, and may be implicated in the pathophysiology of late-life depression in relation to MTHFR genes.

Association of depression and loneliness with specific cognitive performance in non-demented elderly males.

Background Loneliness and depression are very common in the aged population. Both have negative impacts on cognition in the elderly. The present study aimed to investigate the effect of loneliness and depression on total as well as specific cognitive domains in cognitively normal male subjects. Material/Methods A total of 189 cognitively normal male subjects were recruited and underwent Cognitive Abilities Screening Instrument (CASI) and Wechsler Digit Span Task tests. Depression was assessed by the Geriatric Depression Scale-Short Form (GDS-SF) and loneliness by UCLA loneliness scales. Partial correlation test was used to explore the correlation between loneliness/depression and total as well as specific cognition function, with the controlled factors of age and education. Results Both depression and loneliness are negatively correlated with global cognitive function as evaluated with CASI (r=−0.227, p=0.002; r=−0.214, p=0.003, respectively). The domains of Attention, Orientation, Abstraction and judgment, and List-generating fluency of cognitive function were specifically associated with loneliness, and the domain of orientation was associated with depression after controlling the factors age and years of education. Conclusions Our findings suggest that loneliness and depression may have negative impacts on global and specific domains of cognitive function in non-demented elderly males. Both loneliness and depression should be actively recognized earlier and appropriately treated because they are significant sources of cognitive impairment in the elderly.

APOE ɛ4 polymorphism and cognitive deficit among the very old Chinese veteran men without dementia

Apolipoprotein E (APOE) gene polymorphism has been reported to be associated with cognitive dysfunction in healthy individuals, however the results were controversial in the very old elderly. The aim of this study is to assess the possible association of the APOE polymorphism with cognitive dysfunction in people aged 75 years and over. Four hundred and twenty-five aged Chinese veteran men without dementia were enrolled for APOE genotyping and neuropsychological tests including Mini-Mental Status Examination (MMSE), Digit Span Forward and Backward, and Cognitive Ability Screening Instrument Chinese language version (CASI C-2.0) were evaluated in these subjects. Among the elderly veterans, people who carry APOE ɛ4 were found to have worse performance on the total CASI scores, the abstraction/judgment subscores and the list-generating fluency subscores. This study suggests that the APOE ɛ4 alleles contributed detrimental effects on cognitive function in the very old veterans who do not have dementia.