White matter differences between healthy young ApoE4 carriers and non-carriers identified with tractography and support vector machines

The apolipoprotein E4 (ApoE4) is an established risk factor for Alzheimer's disease (AD). Previous work has shown that this allele is associated with functional (fMRI) changes as well structural grey matter (GM) changes in healthy young, middle-aged and older subjects. Here, we assess the diffusion characteristics and the white matter (WM) tracts of healthy young (20-38 years) ApoE4 carriers and non-carriers. No significant differences in diffusion indices were found between young carriers (ApoE4+) and non-carriers (ApoE4-). There were also no significant differences between the groups in terms of normalised GM or WM volume. A feature selection algorithm (ReliefF) was used to select the most salient voxels from the diffusion data for subsequent classification with support vector machines (SVMs). SVMs were capable of classifying ApoE4 carrier and non-carrier groups with an extremely high level of accuracy. The top 500 voxels selected by ReliefF were then used as seeds for tractography which identified a WM network that included regions of the parietal lobe, the cingulum bundle and the dorsolateral frontal lobe. There was a non-significant decrease in volume of this WM network in the ApoE4 carrier group. Our results indicate that there are subtle WM differences between healthy young ApoE4 carriers and non-carriers and that the WM network identified may be particularly vulnerable to further degeneration in ApoE4 carriers as they enter middle and old age.     

APOE ε4 Is Associated with Disproportionate Progressive Hippocampal Atrophy in AD

Objectives

To investigate whether APOE ε4 carriers have higher hippocampal atrophy rates than non-carriers in Alzheimer''s disease (AD), mild cognitive impairment (MCI) and controls, and if so, whether higher hippocampal atrophy rates are still observed after adjusting for concurrent whole-brain atrophy rates.

Methods

MRI scans from all available visits in ADNI (148 AD, 307 MCI, 167 controls) were used. MCI subjects were divided into “progressors” (MCI-P) if diagnosed with AD within 36 months or “stable” (MCI-S) if a diagnosis of MCI was maintained. A joint multi-level mixed-effect linear regression model was used to analyse the effect of ε4 carrier-status on hippocampal and whole-brain atrophy rates, adjusting for age, gender, MMSE and brain-to-intracranial volume ratio. The difference in hippocampal rates between ε4 carriers and non-carriers after adjustment for concurrent whole-brain atrophy rate was then calculated.

Results

Mean adjusted hippocampal atrophy rates in ε4 carriers were significantly higher in AD, MCI-P and MCI-S (p≤0.011, all tests) compared with ε4 non-carriers. After adjustment for whole-brain atrophy rate, the difference in mean adjusted hippocampal atrophy rate between ε4 carriers and non-carriers was reduced but remained statistically significant in AD and MCI-P.

Conclusions

These results suggest that the APOE ε4 allele drives atrophy to the medial-temporal lobe region in AD.     

Age,Gender, and Cancer but Not Neurodegenerative and Cardiovascular Diseases Strongly Modulate Systemic Effect of the Apolipoprotein E4 Allele on Lifespan

Enduring interest in the Apolipoprotein E (ApoE) polymorphism is ensured by its evolutionary-driven uniqueness in humans and its prominent role in geriatrics and gerontology. We use large samples of longitudinally followed populations from the Framingham Heart Study (FHS) original and offspring cohorts and the Long Life Family Study (LLFS) to investigate gender-specific effects of the ApoE4 allele on human survival in a wide range of ages from midlife to extreme old ages, and the sensitivity of these effects to cardiovascular disease (CVD), cancer, and neurodegenerative disorders (ND). The analyses show that women''s lifespan is more sensitive to the e4 allele than men''s in all these populations. A highly significant adverse effect of the e4 allele is limited to women with moderate lifespan of about 70 to 95 years in two FHS cohorts and the LLFS with relative risk of death RR = 1.48 (p = 3.6×10⁻⁶) in the FHS cohorts. Major human diseases including CVD, ND, and cancer, whose risks can be sensitive to the e4 allele, do not mediate the association of this allele with lifespan in large FHS samples. Non-skin cancer non-additively increases mortality of the FHS women with moderate lifespans increasing the risks of death of the e4 carriers with cancer two-fold compared to the non-e4 carriers, i.e., RR = 2.07 (p = 5.0×10⁻⁷). The results suggest a pivotal role of non-sex-specific cancer as a nonlinear modulator of survival in this sample that increases the risk of death of the ApoE4 carriers by 150% (p = 5.3×10⁻⁸) compared to the non-carriers. This risk explains the 4.2 year shorter life expectancy of the e4 carriers compared to the non-carriers in this sample. The analyses suggest the existence of age- and gender-sensitive systemic mechanisms linking the e4 allele to lifespan which can non-additively interfere with cancer-related mechanisms.     

Longer leukocyte telomere length is associated with smaller hippocampal volume among non-demented APOE ε3/ε3 subjects

Telomere length shortens with cellular division, and leukocyte telomere length is used as a marker for systemic telomere length. The hippocampus hosts adult neurogenesis and is an important structure for episodic memory, and carriers of the apolipoprotein E ε4 allele exhibit higher hippocampal atrophy rates and differing telomere dynamics compared with non-carriers. The authors investigated whether leukocyte telomere length was associated with hippocampal volume in 57 cognitively intact subjects (29 ε3/ε3 carriers; 28 ε4 carriers) aged 49–79 yr. Leukocyte telomere length correlated inversely with left (r_s = −0.465; p = 0.011), right (r_s = −0.414; p = 0.025), and total hippocampus volume (r_s = −0.519; p = 0.004) among APOE ε3/ε3 carriers, but not among ε4 carriers. However, the ε4 carriers fit with the general correlation pattern exhibited by the ε3/ε3 carriers, as ε4 carriers on average had longer telomeres and smaller hippocampi compared with ε3/ε3 carriers. The relationship observed can be interpreted as long telomeres representing a history of relatively low cellular proliferation, reflected in smaller hippocampal volumes. The results support the potential of leukocyte telomere length being used as a biomarker for tapping functional and structural processes of the aging brain.     

Effect of the brain-derived neurotrophic factor and the apolipoprotein E polymorphisms on disease progression in preclinical Alzheimer's disease

Genetic factors, such as apolipoprotein E (ApoE) polymorphisms, are thought to play an important role in the etiology of Alzheimer's disease (AD). Recent association studies have suggested that the Val66Met polymorphism in the brain-derived neurotrophic factor ( BDNF ) gene could play a role in the development of AD. To identify genotypic effects of the BDNF and the ApoE genes on disease progression in preclinical AD, we assessed morphological changes using serial magnetic resonance imaging during the preclinical period of AD in 35 individuals. When all subjects were analyzed as one group, progressive atrophy was noted in the limbic, paralimbic and neocortical areas. Individuals of the BDNF Val/Val genotype showed progressive atrophy in the left medial temporal areas, whereas the BDNF Met allele carriers showed additional changes in the anterior cingulate cortex (ACC), posterior cingulate cortex (PCC) and the precuneus. An interaction between the BDNF genotype and progressive morphological changes was found in the PCC. The noncarriers for the ApoE ɛ4 allele showed progressive atrophy in the bilateral medial temporal areas. In addition to changes in the medial temporal areas, ɛ4 carriers showed progressive atrophy in the PCC, ACC and precuneus. An interaction between the ApoE genotype and progressive morphological change was noted in the right medial temporal area. The present preliminary study indicates that polymorphisms of the ApoE and the BDNF genes could affect disease progression in preclinical AD and implies that the Met-BDNF polymorphism could be an additional risk factor for rapid disease progression in preclinical AD.     

Influence of APOE Genotype on Hippocampal Atrophy over Time - An N=1925 Surface-Based ADNI Study

The apolipoprotein E (APOE) e4 genotype is a powerful risk factor for late-onset Alzheimer’s disease (AD). In the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, we previously reported significant baseline structural differences in APOE e4 carriers relative to non-carriers, involving the left hippocampus more than the right—a difference more pronounced in e4 homozygotes than heterozygotes. We now examine the longitudinal effects of APOE genotype on hippocampal morphometry at 6-, 12- and 24-months, in the ADNI cohort. We employed a new automated surface registration system based on conformal geometry and tensor-based morphometry. Among different hippocampal surfaces, we computed high-order correspondences, using a novel inverse-consistent surface-based fluid registration method and multivariate statistics consisting of multivariate tensor-based morphometry (mTBM) and radial distance. At each time point, using Hotelling’s T² test, we found significant morphological deformation in APOE e4 carriers relative to non-carriers in the full cohort as well as in the non-demented (pooled MCI and control) subjects at each follow-up interval. In the complete ADNI cohort, we found greater atrophy of the left hippocampus than the right, and this asymmetry was more pronounced in e4 homozygotes than heterozygotes. These findings, combined with our earlier investigations, demonstrate an e4 dose effect on accelerated hippocampal atrophy, and support the enrichment of prevention trial cohorts with e4 carriers.     

Ageing related thyroid deficiency increases brain-targeted transport of liver-derived ApoE4-laden exosomes leading to cognitive impairment

Alzheimer’s disease (AD) is the prevalent cause of dementia in the ageing world population. Apolipoprotein E4 (ApoE4) allele is the key genetic risk factor for AD, although the mechanisms linking ApoE4 with neurocognitive impairments and aberrant metabolism remains to be fully characterised. We discovered a significant increase in the ApoE4 content of serum exosomes in old healthy subjects and AD patients carrying ApoE4 allele as compared with healthy adults. Elevated exosomal ApoE4 demonstrated significant inverse correlation with serum level of thyroid hormones and cognitive function. We analysed effects of ApoE4-containing peripheral exosomes on neural cells and neurological outputs in aged or thyroidectomised young mice. Ageing-associated hypothyroidism as well as acute thyroidectomy augmented transport of liver-derived ApoE4 reach exosomes into the brain, where ApoE4 activated nucleotide-binding oligomerisation domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome by increasing cholesterol level in neural cells. This, in turn, affected cognition, locomotion and mood. Our study reveals pathological potential of exosomes-mediated relocation of ApoE4 from the periphery to the brain, this process can represent potential therapeutic target.Subject terms: Cognitive neuroscience, Alzheimer''s disease, Cellular neuroscience     

Association between NME8 Locus Polymorphism and Cognitive Decline,Cerebrospinal Fluid and Neuroimaging Biomarkers in Alzheimer's Disease

Recently, a large meta-analysis of five genome wide association studies (GWAS) identified a novel locus (rs2718058) adjacent to NME8 that played a preventive role in Alzheimer''s disease (AD). However, this link between the single nucleotide polymorphism (SNP) rs2718058 and the pathology of AD have not been mentioned yet. Therefore, this study assessed the strength of association between the NME8 rs2718058 genotypes and AD-related measures including the cerebrospinal fluid (CSF) amyloid beta, tau, P-tau concentrations, neuroimaging biomarkers and cognitive performance, in a large cohort from Alzheimer''s Disease Neuroimaging Initiative (ADNI) database. We used information of a total of 719 individuals, including 211 normal cognition (NC), 346 mild cognitive impairment (MCI) and 162 AD. Although we didn''t observe a positive relationship between rs2718058 and AD, it was significantly associated with several AD related endophenotypes. Among the normal cognitively normal participants, the minor allele G carriers showed significantly associated with higher CDRSB score than A allele carriers (P = 0.021). Occipital gyrus atrophy were significantly associated with NME8 genotype status (P = 0.002), with A allele carriers has more atrophy than the minor allele G carriers in AD patients; lateral ventricle (both right and left) cerebral metabolic rate for glucose (CMRgl) were significantly associated with NME8 genotype (P<0.05), with GA genotype had higher metabolism than GG and AA genotypes in MCI group; the atrophic right hippocampus in 18 months is significantly different between the three group, with GG and AA genotypes had more hippocampus atrophy than GA genotypes in the whole group. Together, our results are consistent with the direction of previous research, suggesting that NME8 rs2718058 appears to play a role in lowering the brain neurodegeneration.     

Subcortical and limbic structures and <Emphasis Type="Italic">P</Emphasis>300 in schizophrenia

The correlations between the volumes of the caudate nucleus, putamen, amygdala, and hippocampus, on the one hand, and the P300 amplitude and latency of auditory evoked potentials, on the other hand, were studied in 14 schizophrenics. Significant positive correlations were found between the parameters of the late cognitive potential P300 (predominantly in the left hemisphere) and the caudate nucleus and putamen volumes, as well as between the right amygdala volume and the P300 amplitude in the left temporal region. The results testify again to the role of changes in the left hemisphere in the pathogenesis of schizophrenia and pose the question of the structural and functional features of left frontosubcortical communications.Translated from Fiziologiya Cheloveka, Vol. 31, No. 2, 2005, pp. 18–23.Original Russian Text Copyright © 2005 by Voronkova, Lebedeva, Gubsky, Orlova, Voscresenskaya, Kupriyanov, Anisimov, Solokhina.     

APOE-ε4 Allele Altered the Rest-Stimulus Interactions in Healthy Middle-Aged Adults

The apolipoprotein E-ε4 allele is a well-known genetic risk factor for late-onset Alzheimer’s disease, which also impacts the cognitive functions and brain network connectivity in healthy middle-aged adults without dementia. Previous studies mainly focused on the effects of apolipoprotein E-ε4 allele on single index using task or resting-state fMRI. However, how these evoked and spontaneous BOLD indices interact with each other remains largely unknown. Therefore, we evaluated the ‘rest-stimulus interaction’ between working-memory activation and resting-state connectivity in middle-aged apolipoprotein E-ε4 carriers (n=9) and non-carriers (n=8). Four n-back task scans (n = 0, 1, 2, 3) and one resting-state scan were acquired at a 3T clinical MRI scanner. The working-memory beta maps of low-, moderate-, and high-memory loads and resting-state connectivity maps of default mode, executive control, and hippocampal networks were derived and compared between groups. Apolipoprotein E-ε4 carriers presented declined working-memory activation in the high-memory load across whole brain regions and reduced hippocampal connectivity compared with non-carriers. In addition, disrupted rest-stimulus interactions were found in the right anterior insula and bilateral parahippocampal regions for middle-aged adults with apolipoprotein E-ε4 allele. The rest-stimulus interaction improved the detectability of network integrity changes in apolipoprotein E-ε4 carriers, demonstrating the disrupted intrinsic connectivity within the executive-functional regions and the modulated memory-encoding capability within hippocampus-related regions.     

Macrostructural alterations of subcortical grey matter in psychogenic erectile dysfunction

Psychogenic erectile dysfunction (ED) has been defined as the persistent inability to attain and maintain an erection sufficient to permit sexual performance. It shows a high incidence and prevalence among men, with a significant impact on the quality of life. Few neuroimaging studies have investigated the cerebral basis of erectile dysfunctions observing the role played by prefrontal, cingulate, and parietal cortices during erotic stimulation. In spite of the well-known involvement of subcortical regions such as hypothalamus and caudate nucleus in male sexual response, and the key role of nucleus accumbens in pleasure and reward, poor attention was paid to their role in male sexual dysfunction. In this study, we determined the presence of grey matter (GM) atrophy patterns in subcortical structures such as amygdala, hippocampus, nucleus accumbens, caudate nucleus, putamen, pallidum, thalamus, and hypothalamus in patients with psychogenic ED and healthy men. After Rigiscan evaluation, urological, general medical, metabolic and hormonal, psychological and psychiatric assessment, 17 outpatients with psychogenic ED and 25 healthy controls were recruited for structural MRI session. Significant GM atrophy of nucleus accumbens was observed bilaterally in patients with respect to controls. Shape analysis showed that this atrophy was located in the left medial-anterior and posterior portion of accumbens. Left nucleus accumbens volumes in patients correlated with low erectile functioning as measured by IIEF-5 (International Index of Erectile Function). In addition, a GM atrophy of left hypothalamus was also observed. Our results suggest that atrophy of nucleus accumbens plays an important role in psychogenic erectile dysfunction. We believe that this change can influence the motivation-related component of sexual behavior. Our findings help to elucidate a neural basis of psychogenic erectile dysfunction.     

In Thai Nationals,the ApoE4 Allele Affects Multiple Domains of Neuropsychological,Biobehavioral, and Social Functioning Thereby Contributing to Alzheimer’s Disorder,while the ApoE3 Allele Protects Against Neuropsychiatric Symptoms and Psychosocial Deficits

The apolipoprotein E epsilon 4 (ApoE4) allele is the strongest genetic risk factor for Alzheimer’s disorder (AD) and is associated with semantic and episodic memory deficits. The aim of this study was to examine the associations between ApoE alleles (E2, E3, E4) and genotypes and neuropsychological tests, behavioral functions, and dementia symptoms as assessed using Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). This study included 60 patients with Alzheimer’s disorder (AD), 60 with mild cognitive disorder (MCI), and 62 normal volunteers. ApoE4 carriers and individuals with E3/E4 and E4/E4 genotypes show an increased incidence of AD, but not MCI. ApoE4 carriers and especially E4/E4 homozygotes show a worse outcome on the CERAD total score, Blessed Dementia Scale, and Short Blessed Test and lower scores on the Verbal Fluency Test, Boston Naming Test, Constructional Praxis Recall, and Word List Memory, Recall, and Recognition. ApoE4 carriers and E4/E3 heterozygotes show higher scores on the Clock Drawing Test. ApoE4 carriers show a worse outcome on the CERAD clinical history scores of memory, language, personality, ADL, orientation, and social skills, while allele AopE3 carriers show better scores on activities of daily living (ADL) and social skills. ApoE3 carriers show lower total weighted, irritability/aggression, and behavioral dysregulation scores on the Behavior Rating Scale for Dementia. The results show that in Thai individuals, the presence of ApoE4 allele is accompanied by a multifarious decline in neurocognitive functions and behavioral features and that ApoE3 may convey protection against neuropsychiatric symptoms and a decline in social skills. ApoE4 and especially the E4/E4 genotype may affect multiple domains of cognitive, biobehavioral, and social functioning thereby contributing to AD phenomenology.     

Impact of the genome wide supported NRGN gene on anterior cingulate morphology in schizophrenia

Background

The rs12807809 single-nucleotide polymorphism in NRGN is a genetic risk variant with genome-wide significance for schizophrenia. The frequency of the T allele of rs12807809 is higher in individuals with schizophrenia than in those without the disorder. Reduced immunoreactivity of NRGN, which is expressed exclusively in the brain, has been observed in Brodmann areas (BA) 9 and 32 of the prefrontal cortex in postmortem brains from patients with schizophrenia compared with those in controls.

Methods

Genotype effects of rs12807809 were investigated on gray matter (GM) and white matter (WM) volumes using magnetic resonance imaging (MRI) with a voxel-based morphometry (VBM) technique in a sample of 99 Japanese patients with schizophrenia and 263 healthy controls.

Results

Although significant genotype-diagnosis interaction either on GM or WM volume was not observed, there was a trend of genotype-diagnosis interaction on GM volume in the left anterior cingulate cortex (ACC). Thus, the effects of NRGN genotype on GM volume of patients with schizophrenia and healthy controls were separately investigated. In patients with schizophrenia, carriers of the risk T allele had a smaller GM volume in the left ACC (BA32) than did carriers of the non-risk C allele. Significant genotype effect on other regions of the GM or WM was not observed for either the patients or controls.

Conclusions

Our findings suggest that the genome-wide associated genetic risk variant in the NRGN gene may be related to a small GM volume in the ACC in the left hemisphere in patients with schizophrenia.     

A case–control study on the effects of the apolipoprotein E genotypes in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions being the most common cause of chronic liver disease in Western countries. The Apolipoprotein E (ApoE) gene has three major isoforms encoded by the ε2, ε3, and ε4 alleles, with the ε4 allele associated with hypercholesterolemia and the ε2 allele with the opposite effect. The role of apoE genotypes on NAFLD has been previously investigated with conflicting results. Our hospital-based case-control study conducted in Italy aims to explore the effect of the apoE genotypes on NAFLD risk and their effect on the clinical features of NAFLD patients. 310 NAFLD cases and 422 controls were genotyped for apoE. Adjusted odds ratios (ORs) and 95% confidence intervals (CI) from logistic regression were used to explore the relationship between NAFLD and apoE genotypes, as well as their interaction with selected demographic and lifestyle factors. ApoE ε4 allele carriers showed a statistically significant two-fold reduction of NAFLD risk (OR = 0.51, 95% CI: 0.28-0.93) compared with ε3 homozygotes. A statistically significant lower HDL cholesterol level was observed for ApoE ε4 carriers if compared with ε3/ε3 genotype or ApoE ε2 carriers with a nearly linear decreasing trend from ApoE ε2 to ApoE ε4 carriers. Our study reports for the first time a protective effect of the ε4 allele towards NAFLD that might be attributable to its role in the regulation of hepatic triglycerides rich very low-density lipoproteins secretion.     

The Polymorphism of YWHAE,a Gene Encoding 14-3-3Epsilon,and Brain Morphology in Schizophrenia: A Voxel-Based Morphometric Study

Background

YWHAE is a possible susceptibility gene for schizophrenia that encodes 14-3-3epsilon, a Disrupted-in-Schizophrenia 1 (DISC1)-interacting molecule, but the effect of variation in its genotype on brain morphology remains largely unknown.

Methods

In this voxel-based morphometric magnetic resonance imaging study, we conducted whole-brain analyses regarding the effects of YWHAE single-nucleotide polymorphisms (SNPs) (rs28365859, rs11655548, and rs9393) and DISC1 SNP (rs821616) on gray matter volume in a Japanese sample of 72 schizophrenia patients and 86 healthy controls. On the basis of a previous animal study, we also examined the effect of rs28365859 genotype specifically on hippocampal volume.

Results

Whole-brain analyses showed no significant genotype effect of these SNPs on gray matter volume in all subjects, but we found significant genotype-by-diagnosis interaction for rs28365859 in the left insula and right putamen. The protective C allele carriers of rs28365859 had a significantly larger left insula than the G homozygotes only for schizophrenia patients, while the controls with G allele homozygosity had a significantly larger right putamen than the C allele carriers. The C allele carriers had a larger right hippocampus than the G allele homozygotes in schizophrenia patients, but not in healthy controls. No significant interaction was found between rs28365859 and DISC1 SNP on gray matter volume.

Conclusions

These different effects of the YWHAE (rs28365859) genotype on brain morphology in schizophrenia and healthy controls suggest that variation in its genotype might be, at least partly, related to the abnormal neurodevelopment, including in the limbic regions, reported in schizophrenia. Our results also suggest its specific role among YWHAE SNPs in the pathophysiology of schizophrenia.     

Impact of Chemotherapy for Childhood Leukemia on Brain Morphology and Function

Objective

Using multidisciplinary treatment modalities the majority of children with cancer can be cured but we are increasingly faced with therapy-related toxicities. We studied brain morphology and neurocognitive functions in adolescent and young adult survivors of childhood acute, low and standard risk lymphoblastic leukemia (ALL), which was successfully treated with chemotherapy. We expected that intravenous and intrathecal chemotherapy administered in childhood will affect grey matter structures, including hippocampus and olfactory bulbs, areas where postnatal neurogenesis is ongoing.

Methods

We examined 27 ALL-survivors and 27 age-matched healthy controls, ages 15–22 years. ALL-survivors developed disease prior to their 11th birthday without central nervous system involvement, were treated with intrathecal and systemic chemotherapy and received no radiation. Volumes of grey, white matter and olfactory bulbs were measured on T1 and T2 magnetic resonance images manually, using FIRST (FMRIB’s integrated Registration and Segmentation Tool) and voxel-based morphometry (VBM). Memory, executive functions, attention, intelligence and olfaction were assessed.

Results

Mean volumes of left hippocampus, amygdala, thalamus and nucleus accumbens were smaller in the ALL group. VBM analysis revealed significantly smaller volumes of the left calcarine gyrus, both lingual gyri and the left precuneus. DTI data analysis provided no evidence for white matter pathology. Lower scores in hippocampus-dependent memory were measured in ALL-subjects, while lower figural memory correlated with smaller hippocampal volumes.

Interpretation

Findings demonstrate that childhood ALL, treated with chemotherapy, is associated with smaller grey matter volumes of neocortical and subcortical grey matter and lower hippocampal memory performance in adolescence and adulthood.     

Estrogen receptor alpha and vitamin D receptor gene polymorphisms and bone mineral density: association study of healthy pre- and postmenopausal Chinese women

In the present study, we tested the association between the estrogen receptor alpha (ER-alpha) and vitamin D receptor (VDR) genes with bone mineral density (BMD). A total of 649 healthy Chinese women, classified as pre-menopausal (N=388) and post-menopausal (N=261) groups, were genotyped at the ER-alpha PvuII, XbaI, and VDR ApaI sites. BMDs at the lumbar spine (L(1)-L(4)) and total hip were measured by dual-energy X-ray absorptiometry. For the VDR ApaI locus, AA carriers had lower spine BMD than Aa (p=0.02) and aa carriers (p<0.01) in the pre-menopausal group. For the ER-alpha gene, carriers of haplotype px had lower spine BMD than the non-carriers (p=0.03) in the pre-menopausal group. Furthermore, we observed significant interaction between the ER-alpha and VDR genes in the post-menopausal group: with AA genotype (or A allele) at the VDR ApaI locus, pX carriers had higher spine BMD than the non-carriers (p=0.02), and PX carriers had lower hip BMD than the non-carriers (p=0.04). Our data suggest that the ER-alpha and VDR genes may be associated with the BMD variation in Chinese women.     

Mitochondrial DNA haplogroups and APOE4 allele are non-independent variables in sporadic Alzheimer's disease

Allele epsilon4 of the nuclear APOE gene is a leading genetic risk factor for sporadic Alzheimer's disease (AD). Moreover, an allele-specific effect of APOE isoforms on neuronal cell oxidative death is known. Because of the role of the mitochondrial genome (mtDNA) in oxidative phosphorylation and oxidative stress, an interaction between APOE polymorphism and mtDNA inherited variability in the genetic susceptibility to sporadic AD can be hypothesized. We have explored this hypothesis by analyzing mtDNA germline variants (mtDNA haplogroups) in a sample of AD patients (213 subjects) genotyped for APOE and classified as APOE epsilon4 carriers and non-carriers. We found that the frequency distribution of mtDNA haplogroups is different between epsilon4 carriers and non-carriers (P=0.018), thus showing non-random association between APOE and mtDNA polymorphisms. The same analysis, carried out in two samples of healthy subjects (179 age-matched and 210 individuals aged more than 100 years), showed independence between epsilon4 allele and mtDNA haplogroups. Therefore, the APOE/mtDNA interaction is restricted to AD and may affect susceptibility to the disease. In particular, some mtDNA haplogroups (K and U) seem to neutralize the harmful effect of the APOE epsilon4 allele, lowering the epsilon4 odds ratio from statistically significant to non-significant values.     

Neuromedin beta: P73T polymorphism in overweight and obese subjects

Neuromedin beta (NMB) is a member of the bombesin-like peptide family expressed in brain, gastrointestinal tract, pancreas, adrenals and adipose tissue. The aim of our study was to compare the frequency of P73T polymorphism in overweight and obese patients (37 men: age 50.6+/-11.7 years, BMI 41.1+/-7.8 kg/m(2); 255 women: age 49.0+/-11.9 years, BMI 37.9+/-6.8 kg/m(2)) with that of healthy normal weight subjects (51 men: age 28.2+/-7.1 years, BMI 22.3+/-2.0 kg/m(2); 104 women: age 29.1+/-9.1 years, BMI 21.5+/-1.9 kg/m(2)) and to investigate the polymorphism's influence on anthropometric, nutritional and psychobehavioral parameters in overweight/obese patients both at the baseline examination and at a control visit carried out 2.5 years later, regardless of the patient s compliance with the weight reduction program. No significant differences in the genotype distribution were demonstrated between normal weight and overweight/obese subjects. Male T allele non-carriers compared to T allele carriers had higher energy (p=0.009), protein (p=0.018) and fat (p=0.002) intakes and hunger score (p=0.015) at the beginning of treatment. Male T allele non-carriers had a more favorable response to weight management at the follow-up, as they exhibited a significant reduction in waist circumference, energy intake and depression score as well as a significant increase in dietary restraint. No significant differences between carriers and non-carriers were demonstrated in women at the baseline examination. Both female T allele carriers and non-carriers demonstrated similar significant changes in nutritional parameters and in restraint score at the follow-up. Nevertheless, only female non-carriers showed a significant decrease in the hunger score.