Beyond the disconnectivity hypothesis of schizophrenia.

To go beyond the disconnectivity hypothesis of schizophrenia, directed (effective) connectivity was measured between 94 brain regions, to provide evidence on the source of the changes in schizophrenia and a mechanistic model. Effective connectivity (EC) was measured in 180 participants with schizophrenia and 208 controls. For the significantly different effective connectivities in schizophrenia, on average the forward (stronger) effective connectivities were smaller, whereas the backward connectivities tended to be larger. Further, higher EC in schizophrenia was found from the precuneus and posterior cingulate cortex (PCC) to areas such as the parahippocampal, hippocampal, temporal, fusiform, and occipital cortices. These are backward effective connectivities and were positively correlated with the positive symptoms of schizophrenia. Lower effective connectivities were found from temporal and other regions and were negatively correlated with the symptoms, especially the negative and general symptoms. Further, a signal variance parameter was increased for areas that included the parahippocampal gyrus and hippocampus, consistent with the hypothesis that hippocampal overactivity is involved in schizophrenia. This investigation goes beyond the disconnectivity hypothesis by drawing attention to differences in schizophrenia between backprojections and forward connections, with the backward connections from the precuneus and PCC implicated in memory stronger in schizophrenia.

Genetic effect of MTHFR C677T polymorphism on the structural covariance network and white-matter integrity in Alzheimer's disease.

The 677 C to T transition in the MTHFR gene is a genetic determinant for hyperhomocysteinemia. We investigated whether this polymorphism modulates gray matter (GM) structural covariance networks independently of white-matter integrity in patients with Alzheimer's disease (AD). GM structural covariance networks were constructed by 3D T1-magnetic resonance imaging and seed-based analysis. The patients were divided into two genotype groups: C homozygotes (n = 73) and T carriers (n = 62). Using diffusion tensor imaging and white-matter parcellation, 11 fiber bundle integrities were compared between the two genotype groups. Cognitive test scores were the major outcome factors. The T carriers had higher homocysteine levels, lower posterior cingulate cortex GM volume, and more clusters in the dorsal medial lobe subsystem showing stronger covariance strength. Both posterior cingulate cortex seed and interconnected peak cluster volumes predicted cognitive test scores, especially in the T carriers. There were no between-group differences in fiber tract diffusion parameters. The MTHFR 677T polymorphism modulates posterior cingulate cortex-anchored structural covariance strength independently of white matter integrities. Hum Brain Mapp 38:3039-3051, 2017. © 2017 The Authors Human Brain Mapping Published Wiley by Periodicals, Inc.

Genetic effect of interleukin-1 beta (C-511T) polymorphism on the structural covariance network and white matter integrity in Alzheimer's disease.

BACKGROUND: Inflammatory processes play a pivotal role in the degenerative process of Alzheimer's disease. In humans, a biallelic (C/T) polymorphism in the promoter region (position-511) (rs16944) of the interleukin-1 beta gene has been significantly associated with differences in the secretory capacity of interleukin-1 beta. In this study, we investigated whether this functional polymorphism mediates the brain networks in patients with Alzheimer's disease. METHODS: We enrolled a total of 135 patients with Alzheimer's disease (65 males, 70 females), and investigated their gray matter structural covariance networks using 3D T1 magnetic resonance imaging and their white matter macro-structural integrities using fractional anisotropy. The patients were classified into two genotype groups: C-carriers (n = 108) and TT-carriers (n = 27), and the structural covariance networks were constructed using seed-based analysis focusing on the default mode network medial temporal or dorsal medial subsystem, salience network and executive control network. Neurobehavioral scores were used as the major outcome factors for clinical correlations. RESULTS: There were no differences between the two genotype groups in the cognitive test scores, seed, or peak cluster volumes and white matter fractional anisotropy. The covariance strength showing C-carriers > TT-carriers was the entorhinal-cingulum axis. There were two peak clusters (Brodmann 6 and 10) in the salience network and four peak clusters (superior prefrontal, precentral, fusiform, and temporal) in the executive control network that showed C-carriers < TT-carriers in covariance strength. The salience network and executive control network peak clusters in the TT group and the default mode network peak clusters in the C-carriers strongly predicted the cognitive test scores. CONCLUSIONS: Interleukin-1 beta C-511 T polymorphism modulates the structural covariance strength on the anterior brain network and entorhinal-interconnected network which were independent of the white matter tract integrity. Depending on the specific C-511 T genotype, different network clusters could predict the cognitive tests.

Geriatric Suicide Attempt and Risk of Subsequent Dementia: A Nationwide Longitudinal Follow-up Study in Taiwan.

OBJECTIVE: It was unclear whether older people without dementia who attempted suicide were at increased risk of subsequently developing dementia. METHODS: Using the Taiwan National Health Insurance Research Database, 1,189 patients aged ≥ 65 years who attempted suicide and 4,756 age- and sex-matched control subjects were enrolled in our study and followed to the end of 2011. Those who developed dementia during the follow-up were identified. RESULTS: Cox regression analysis, after adjusting for demographic data and medical comorbidities, found that geriatric suicide attempt was associated with an increased risk of subsequent dementia (HR: 7.40; 95% CI: 6.11-8.97; Wald χ2 = 414.87, df = 1, p < 0.001). Both patients aged between 65 and 79 years (HR: 7.74; 95% CI: 6.17-9.71; Wald χ2 = 312.62, df = 1, p < 0.001) and patients aged ≥ 80 years (HR: 6.94; 95% CI: 4.73-10.17; Wald χ2 = 97.78, df = 1, p < 0.001) who attempted suicide had an increased risk of developing dementia in later life. CONCLUSION: The elderly who attempted suicide were prone to developing dementia in later life, independent of depression and medical comorbidities. Further studies are necessary to clarify the underlying mechanisms between geriatric suicide and dementia and whether the prompt intervention for geriatric suicide may reduce this risk.

Decreased resting-state brain activity complexity in schizophrenia characterized by both increased regularity and randomness.

Schizophrenia is characterized by heterogeneous pathophysiology. Using multiscale entropy (MSE) analysis, which enables capturing complex dynamics of time series, we characterized MSE patterns of blood-oxygen-level-dependent (BOLD) signals across different time scales and determined whether BOLD activity in patients with schizophrenia exhibits increased complexity (increased entropy in all time scales), decreased complexity toward regularity (decreased entropy in all time scales), or decreased complexity toward uncorrelated randomness (high entropy in short time scales followed by decayed entropy as the time scale increases). We recruited 105 patients with schizophrenia with an age of onset between 18 and 35 years and 210 age- and sex-matched healthy volunteers. Results showed that MSE of BOLD signals in patients with schizophrenia exhibited two routes of decreased BOLD complexity toward either regular or random patterns. Reduced BOLD complexity toward regular patterns was observed in the cerebellum and temporal, middle, and superior frontal regions, and reduced BOLD complexity toward randomness was observed extensively in the inferior frontal, occipital, and postcentral cortices as well as in the insula and middle cingulum. Furthermore, we determined that the two types of complexity change were associated differently with psychopathology; specifically, the regular type of BOLD complexity change was associated with positive symptoms of schizophrenia, whereas the randomness type of BOLD complexity was associated with negative symptoms of the illness. These results collectively suggested that resting-state dynamics in schizophrenia exhibit two routes of pathologic change toward regular or random patterns, which contribute to the differences in syndrome domains of psychosis in patients with schizophrenia.

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.

The APOE ɛ4 allele affects complexity and functional connectivity of resting brain activity in healthy adults.

The apolipoprotein E (APOE) gene is associated with structural and functional brain changes. We have used multiscale entropy (MSE) analysis to detect changes in the complexity of resting blood oxygen level-dependent (BOLD) signals associated with aging and cognitive function. In this study, we further hypothesized that the APOE genotype may affect the complexity of spontaneous BOLD activity in younger and older adults, and such altered complexity may be associated with certain changes in functional connectivity. We conducted a resting-state functional magnetic resonance imaging experiment in a cohort of 100 younger adults (aged 20-39 years; mean 27.2 ± 4.3 years; male/female: 53/47) and 112 older adults (aged 60-79 years; mean 68.4 ± 6.5 years; male/female: 54/58), and applied voxelwise MSE analysis to assess the main effect of APOE genotype on resting-state BOLD complexity and connectivity. Although the main effect of APOE genotype on BOLD complexity was not observed in younger group, we observed that older APOE ɛ4 allele carriers had significant reductions in BOLD complexity in precuneus and posterior cingulate regions, relative to noncarriers. We also observed that reduced BOLD complexity in precuneus and posterior cingulate regions was associated with increased functional connectivity to the superior and inferior frontal gyrus in the older group. These results support the compensatory recruitment hypothesis in older APOE ɛ4 carriers, and confer the impact of the APOE genotype on the temporal dynamics of brain activity in older adults.

Osteoporosis and the risk of symptomatic nephrolithiasis: a population-based 5-year follow-up study in Taiwan.

This study estimates the risk of symptomatic nephrolithiasis within 5 years of newly diagnosed osteoporosis in a Taiwan population. This cohort study consisted of patients with a diagnosis of osteoporosis between Jan. 2003 and Dec. 2005 (N = 1634). Four age- and gender- matched patients for every patient in the study cohort were selected using random sampling as the comparison cohort (N = 6536). All patients were tracked for 5 years from the date of cohort entry to identify whether they developed symptomatic nephrolithiasis. Cox proportional hazard regressions were performed to evaluate the 5-year nephrolithiasis-free survival rates. During the 5-year follow-up period, 60 osteoporosis patients (3.7%) and 165 non- osteoporosis patients (2.5%) developed symptomatic nephrolithiasis. The adjusted HR of symptomatic nephrolithiasis was 1.38 times greater risk for patients with osteoporosis than for the comparison cohort (95% confidence interval (CI) 1.03-1.86; P < .05). Osteoporosis is very likely to be an independent risk factor for subsequent diagnosis of symptomatic nephrolithiasis.

The association of RAB18 gene polymorphism (rs3765133) with cerebellar volume in healthy adults.

Genetic factors are responsible for the development of the human brain. Certain genetic factors are known to increase the risk of common brain disorders and affect the brain structure. Therefore, even in healthy people, these factors have a role in the development of specific brain regions. Loss-of-function mutations in the RAB18 gene (RAB18) cause Warburg Micro syndrome, which is associated with reduced brain size and deformed brain structures. In this study, we hypothesized that the RAB18 variant might influence regional brain volumes in healthy people. The study participants comprised 246 normal volunteers between 21 and 59 years of age (mean age of 37.8 ± 12.0 years; 115 men, 131 women). Magnetic resonance imaging (MRI) and genotypes of RAB18 rs3765133 were examined for each participant. The differences in regional brain volumes between T homozygotes and A-allele carriers were tested using voxel-based morphometry. The results showed that RAB18 rs3765133 T homozygote group exhibited larger gray matter (GM) volume in the left middle temporal and inferior frontal gyrus of the cerebrum than the A-allele carriers. An opposite effect was observed in both the posterior lobes and right tonsil of the cerebellum, in which the GM volume of RAB18 rs3765133 T homozygotes was smaller than that of the A-allele carriers (all P FWE < 0.05). Our findings suggest that RAB18 rs3765133 polymorphism affects the deve-lopment of specific brain regions, particularly the cerebellum, in healthy people.

Does the dopamine hypothesis explain schizophrenia?

The dopamine hypothesis has been the cornerstone in the research and clinical practice of schizophrenia. With the initial emphasis on the role of excessive dopamine, the hypothesis has evolved to a concept of combining prefrontal hypodopaminergia and striatal hyperdopaminergia, and subsequently to the present aberrant salience hypothesis. This article provides a brief overview of the development and evidence of the dopamine hypothesis. It will argue that the current model of aberrant salience explains psychosis in schizophrenia and provides a plausible linkage between the pharmacological and cognitive aspects of the disease. Despite the privileged role of dopamine hypothesis in psychosis, its pathophysiological rather than etiological basis, its limitations in defining symptoms other than psychosis, as well as the evidence of other neurotransmitters such as glutamate and adenosine, prompt us to a wider perspective of the disease. Finally, dopamine does explain the pathophysiology of schizophrenia, but not necessarily the cause per se. Rather, dopamine acts as the common final pathway of a wide variety of predisposing factors, either environmental, genetic, or both, that lead to the disease. Other neurotransmitters, such as glutamate and adenosine, may also collaborate with dopamine to give rise to the entire picture of schizophrenia.

Cognitive performance in older elderly men with late-life depression and cardiovascular comorbidities: symptomatological correlation.

BACKGROUND: Whether depression or cardiovascular disease would have a greater effect on worsening cognitive impairment in the burgeoning older elderly population is uncertain. Which disorder causes greater cognitive impairment was investigated. METHODS: A cross section of 207 cognitively impaired older elderly (≥75 years old) men was recruited from outpatient clinics in southern Taiwan between 2004 and 2008. Their medical charts were reviewed for their history of medical illnesses, and those undergoing a current major depressive episode were screened using the Mini-International Neuropsychiatric Interview. Four groups of men were enrolled: 33 healthy controls (HC), 101 cognitively impaired patients with cardiovascular comorbidities (CVCs), 34 patients with late-life depression (LLD), and 49 patients with LLD and cardiovascular comorbidities (LLD + CVC). Several neuropsychological tests (e.g., Mini-Mental State Examination (MMSE), WCST, and Trail Making Test (TMT) parts A and B) were used to assess the participants. RESULTS: Cognitive function scores were highest in the HC group and lowest in the LLD + CVC group. There were no significant differences between the two groups with LLD comorbidity, and LLD was mostly associated with cognitive performance. LLD + CVC group members had the lowest recall memory, but their overall MMSE score was not significantly different. Moreover, this group had a higher but nonsignificantly different perseverative error than did the LLD group. Similarly, the LLD + CVC group was nonsignificantly slower at the TMT-A and TMT-B tasks than was the LLD group. CONCLUSIONS: LLD worsens neuropsychological function more than cardiovascular comorbidities do.

A polymorphism of the ORAI1 gene is associated with the risk and recurrence of calcium nephrolithiasis.

PURPOSE: Store-operated calcium entry has been considered an important factor to regulate inflammatory reactions in nonexcitable cells. However, the effects of genetic polymorphisms of ORAI1, a main component of store-operated calcium channels, on nephrolithiasis and stone recurrence remain unclear. We investigated the association between calcium containing nephrolithiasis and genetic variants of ORAI1 gene in Taiwanese patients. MATERIALS AND METHODS: A case-control study was performed in 136 patients with nephrolithiasis and 500 controls. Five tagging single nucleotide polymorphisms of ORAI1 were selected for genotyping. ORAI1 genotypes were determined by TaqMan® assay. Hardy-Weinberg equilibrium in cases and controls was assessed, and genetic effects were evaluated by the chi-square test and sliding window haplotype analysis. Subset analysis was done according to family history. RESULTS: Two single nucleotide polymorphisms (rs12313273 and rs6486795) of the ORAI1 gene were associated with the risk of nephrolithiasis. The C allele carrier for rs12313273 was strongly related to recurrent stone forming in patients. On sliding window analysis the results of the 2 (rs12313273 and rs7135617) and the 3 (rs12313273, rs7135617 and rs6486795) single nucleotide polymorphism haplotypes had more significant effects on the risk of nephrolithiasis than the single nucleotide polymorphism rs12313273. CONCLUSIONS: To our knowledge this is the first study identifying the novel polymorphisms of the ORAI1 gene, which may predispose to the risk of calcium nephrolithiasis and disease recurrence.

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.

Difference in urinary stone components between obese and non-obese patients.

The prevalence and incidence of urinary stone disease have been reported to be associated with body weight and body mass index (BMI). The aim of the study was to determine the difference in stone components among different BMI groups in patients with urolithiasis. Between Dec 2005 and Jan 2008, 907 urinary calculi were collected and analyzed by infrared spectroscopy. Most of the stones had been passed spontaneously, and some were collected during surgical manipulations. The data on patients' gender, age, BMI at diagnosis, and stone composition were collected. The patients were classified as normal weight (18.5≤ BMI <24), overweight (24≤ BMI <27), or obese (BMI ≥27). Of the 907 patients with urinary stone disease, 27.7% had normal weight, 33.5% were overweight, and 38.8% were obese. The prevalence of calcium oxalate stones in the normal weight, overweight, and obese groups were 23.1, 30.6, and 34.9%, respectively (P = 0.002), and the prevalence of uric acid stones in the different groups was 2.8, 7.2, and 7.7%, respectively (P = 0.002). The prevalence of calcium oxalate and uric acid stones, but not that of calcium phosphate stones, increased with body size. There was a significant correlation between BMI and uric acid stones in the overweight and obesity groups, with odds ratios of 3.28 and 4.35, respectively. The prevalence and incidence of urinary stone disease were found to be associated with BMI. The percentage of uric acid and calcium oxalate stones was higher in obese than in non-obese patients. There was no apparent difference in the prevalence of calcium phosphate stones between obese and non-obese patients.

Varenicline prevents affective and cognitive exacerbation during smoking abstinence in male patients with schizophrenia.

To explore the effects of varenicline on the psychopathology and cognition of chronic inpatients with schizophrenia, we conducted a non-randomized control group time series investigation between March 2009 and April 2010. In a mandatory smoking cessation intervention, 41 male inpatient smokers were scheduled to undergo either a 5-week varenicline treatment (varenicline group) or the use of no drugs (non-treatment group). Depression (HAM-D), anxiety (HAM-A), and psychosis (PANSS) were evaluated at baseline, and at the 2nd, 4th, 8th and 12th week after abstinence; four neuropsychological tests, including Digit Span Forward and Backward (DSF and DSB), and Trail Making Test-A and -B, were evaluated at baseline and at the 4th, 8th and 12th week. .Thirty patients completed the study. Among 15 patients in the non-treatment group, the HAM-D, HAM-A, DSF, and DSB scores were exacerbated during the 2-8 weeks of abstinence, but there were no changes in psychotic symptoms and the other two neuropsychological tests. Compared with the non-treatment group, varenicline users experienced less impairment in HAM-D and HAM-A scores at the 2nd and 4th weeks, and in DSF tasks at the 4th week after abstinence. In conclusions, varenicline can attenuate abstinence-induced adverse outcomes and appears to be well-tolerated in smokers with schizophrenia.

Symptomatic resolution among Chinese patients with schizophrenia and associated factors.

BACKGROUND/PURPOSE: The remission and resolution criteria for schizophrenia were defined by the Remission in Schizophrenia Working Group in 2005, using eight core items of the positive and negative symptoms scale for schizophrenia. Subsequent studies of Caucasians have reported similar remission/resolution rates of approximately one-third. However, the remission/resolution rate in Chinese patients has not previously been reported. The present study assessed symptom resolution rates and associated factors among medicated and clinically stable Chinese schizophrenia patients. METHODS: Chinese patients with a diagnosis of schizophrenia were followed-up 1 month after their last psychiatric hospitalization. Cross-sectional clinical assessments for psychopathology, side effect profiles, quality of life, psychosocial function, and neurocognition tests were performed. RESULTS: Thirty-three (36.7%) of a total of 90 patients met the resolution criteria. They had a significantly higher level of education and lower scores for positive symptoms, negative symptoms, and general psychopathology on the positive and negative symptoms scale; they had lower scores on the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale, and Simpson Angus Scale; and higher scores on the Global Assessment of Functioning and Subjective Well-being under Neuroleptics scales, compared with patients who did not meet the resolution criteria. Multiple regression analyses controlling for age, sex, duration of illness, education, duration of index hospitalization, and antipsychotic dosage revealed that a higher Udvalg for Kliniske Undersøgelser Side Effect Rating Scale score was related to lower rate of symptom resolution. The patients treated with clozapine and combinations of first generation antipsychotics and second generation antipsychotics had more severe psychopathology and side effects and showed a significantly lower resolution rate than did patients treated with first generation antipsychotics or second generation antipsychotics alone. CONCLUSION: Consistent with studies of Caucasian patients, one-third of clinically stable Chinese patients met the resolution criteria, as well as having fewer general side effects, better global functioning and subjective well-being.

Topographic diversity of structural connectivity in schizophrenia.

The neurobiological heterogeneity of schizophrenia is widely accepted, but it is unclear how mechanistic differences converge to produce the observed phenotype. Establishing a pathophysiological model that accounts for both neurobiological heterogeneity and phenotypic similarity is essential to inform stratified treatment approaches. In this cross-sectional diffusion tensor imaging study, we recruited 77 healthy controls, and 70 patients with DSM-IV diagnosis of schizophrenia. We first confirmed the heterogeneity in structural connectivity by showing a reduced between-individual similarity of the structural connectivity in patients compared to healthy controls. Second, at a system level, we found the diversity of the topographic distribution of the strength of structural connectivity was significantly reduced in patients (P = 7.21 × 10-7, T142 = 5.19 [95% CI: 3.37-7.52], Cohen's d = 0.91), and this affected 65 of the 90 brain regions examined (False Discovery Rate <5%). Third, when topographic diversity was used as a discriminant feature to train a model for classifying patients from controls, it significantly improved the accuracy on an independent sample (T99 = 5.54; P < 0.001). These findings suggest a highly individualized pattern of structural dysconnectivity underlies the heterogeneity of schizophrenia, but these disruptions likely converge on an emergent common pathway to generate the clinical phenotype of the disorder.

MAOA-VNTR Genotype Effects on Ventral Striatum-Hippocampus Network in Alzheimer's Disease: Analysis Using Structural Covariance Network and Correlation with Neurobehavior Performance.

Functional polymorphisms in the promoter region of the monoamine oxidase A (MAOA) gene are associated with brain MAOA activity and transcriptional efficiency in patients with Alzheimer's disease (AD). This study investigated structural covariance networks mediated by MAOA-variable number tandem repeat (VNTR) genotypes in patients with AD, and assessed whether this effect was associated with sex. A total of 193 patients with AD were classified into four genotype groups based on MAOA transcriptional efficiency (female low [L], low-high + high activity groups [LH + H]; male L, male H groups). Structural covariance networks were constructed focusing on triple-network and striatal networks. Covariance strength was analyzed in the four groups, and the genotype and sex main effects and their interactions were analyzed. Significant peak cluster volumes were correlated with neurobehavioral scores to establish the clinical significance. MAOA genotypes mediated the structural covariance strength on the dorsolateral prefrontal cortex (dLPFC)-caudate axis in both sexes, but a higher covariance strength was shown in the female L group and male H group. The independent effect of male sex was related to higher covariance strength in the frontal medial superior region in the dLPFC, dorsal caudate (DC), and ventral superior striatum (VSs) seeds. In contrast, female sex had higher covariance strength in the frontal opercular areas anchored by the dLPFC, DC, and VSs seeds. Topographies showing higher covariance strength with sex interactions were found in the male H group and female L group in the dLPFC supplementary motor axis, DC-SMA, and DC-precentral axis. In our patients with AD, MAOA-VNTR polymorphisms and sex had independent and interactive effects on structural covariance networks, of which the dLPFC-, VSs-, and DC-anchored networks represented major endophenotypes that determined cognitive outcomes. The sex-genotype interaction model suggested that male high activity and female low activity may modulate brain morphometric connectivity and determine cognitive scores.

Association study of brain-derived neurotrophic factor and apolipoprotein E polymorphisms and cognitive function in aged males without dementia.

Genetic factors for inter-individual variation in cognition have been arousing great interest among researchers. Among the many associated genes, brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE), as two of the most frequently studied, might be good prospects for cognitive genetics. Thus, the aim of this study was to investigate both the isolated and cooperative effect of BDNF and APOE on normal cognitive ageing. A homogeneous population of Chinese aged males (N=161) were genotyped for functional genetic variants of BDNF (BDNF-G196A) and APOE (APOE-epsilon4) and assessed by a comprehensive neuropsychological measurement (Cognitive Abilities Screening Instrument Chinese version; CASI C-2.0). Thereafter genotypic group differences of BDNF and APOE in CASI cognitive profiles were tested. Results from the present study suggest the possible influence of APOE on specific cognitive domains (CASI orientation and language domains; p=0.010 and 0.028, respectively), whereas there was no significant role of BDNF, either solely or with APOE, in cognition in the elderly. Our findings suggest a possible association between APOE-epsilon4 and specific cognitive domains in the aged male, whereas the functional genetic variant of BDNF (BDNF-G196A) played no significant role in normal cognitive ageing.