Genotypes and haplotypes in the IL-1 gene cluster: analysis of two genetically and diagnostically distinct groups of Alzheimer patients

Increased risk of Alzheimer's disease (AD) has been associated with polymorphisms in the IL-1 gene cluster, and in particular with the IL-1alpha-889 T/T genotype. However, this association is still unclear, and needs further investigation. In order to clarify the role of these polymorphisms in the complex pathogenesis of AD we examined genotype and haplotype frequencies of the two C-to-T SNPs at position -889 and -551 in the IL-1alpha and IL-1beta genes, respectively, and of the 86 bp VNTR intron-2 polymorphisms in the IL-1Ra gene. The analysis was performed in two genetically and diagnostically distinct groups of sporadic AD from Italy and the USA. In the Italian group a significant association between the IL-1alpha-889 T/T genotype and AD (OR=3.022, 95% CI: 1.001-9.119) was found, whereas no difference was found in the group from the USA. Results were also compared with previously published studies that analyzed the same IL-1 polymorphisms in AD. In both groups, the analysis of the estimated haplotypes shows that AD patients and controls who carry the IL-1beta-511 C allele, were also more frequently carriers of the IL-1Ra 1 allele (haplotypes -C-1). The total frequency of the two -C-1 haplotypes (C-C-1 plus T-C-1) was about one half of the total frequency of the eight estimated haplotypes. This was confirmed by significant linkage disequilibrium between these two loci in both the Italian and USA groups. In the Italian group a weak association of the T-C-2 haplotype with the disease (OR=1.648, 95% CI: 1.519-1.788) was also found, whereas in the USA group no difference was found. Although ours and other published data on different samples of Caucasian and non-Caucasian AD show a great heterogeneity in the frequencies of the IL-1alpha-889, the IL-1beta-511 and the IL-1Ra VNTR gene polymorphisms, we confirm the role of the IL-1alpha-889 T/T genotype as a risk factor for sporadic AD, and show the presence of an allelic association between IL-1beta C and IL-1Ra 1 alleles in both the Italian and the USA groups, confirmed by the presence of significant levels of linkage disequilibrium between these two loci.     

Contrast-Enhanced Spectral Mammography and tumor size assessment: a valuable tool for appropriate surgical management of breast lesions

Purpose

To compare the accuracy of Contrast-Enhanced Spectral Mammography (CESM), MG, US, and breast MRI in estimating the size of breast lesions requiring surgery. The postoperative histology size of the lesion was used as the gold standard.

Material and methods

Two hundred thirty-three non-benign lesions in 189 patients were included in the analyses. All the selected patients underwent CESM and at least one other conventional diagnostic exam (US, MG, or MRI). Subsequently, all the patients underwent surgery preceded by cytological/histological examination. The largest diameter of the lesion at imaging was measured by a radiologist with more than 10 years’ experience and then compared with the size of the lesion in the histological sample at the surgery (gold standard).

Results

Among the 233 breast lesions, 196 were evaluated with US, 206 with MG and 160 with MRI. We found no statistically significant differences between size measurements using CESM and MRI compared with the measurements at the surgery (p value 0.63 and 0.51), whereas a significant difference was found for MG and US (p?<?0.001).

Conclusion

CESM is a reliable method for estimating the size of breast lesions: its performance seems superior to US and MG and comparable to MRI.

     

Modulation of human longevity by SIRT3 single nucleotide polymorphisms in the prospective study “Treviso Longeva (TRELONG)”

Human sirtuins are seven proteins with deacetylase activity that are emerging as key modulators of basic physiological functions. Some evidence links SIRT3 to longevity in mammals. This study aimed to investigate whether variants within SIRT3 gene were associated to human longevity. We analyzed 549 genomic DNA collected during the prospective study “Treviso Longeva,” including elderly over 70 years of age from the municipality of Treviso, a small city in the northeast of Italy. We genotyped SIRT3 rs3825075, rs4980329, and rs11555236 single nucleotide polymorphisms (SNPs) by real-time polymerase chain reaction allelic discrimination assay. A cross-sectional analysis performed by comparing people over and under 85 years of age did not evidence association among the SIRT3 SNPs and longevity. However, when we performed a longitudinal analysis considering mortality as a dependent variable, we observed an association of SIRT3 rs11555236 and rs4980329 with longevity in the whole population (p values corrected for potential confounders = 0.04 and 0.03, respectively). After stratification according to gender, the same SNPs were associated to female longevity only (p values corrected for potential confounders = 0.03 and 0.02, respectively). Finally, as rs11555236 was reported to be in linkage disequilibrium with a putative functional enhancer within the SIRT3 gene, we assessed whether rs11555236 genotypes correlated with a different level of SIRT3 protein in peripheral blood mononuclear cells. We found an increased level of SIRT3 in subjects homozygous for the (T) allele. We suggest that SIRT3 genetic variability might be relevant for the modulation of human longevity in the Italian population.

Electronic supplementary material

The online version of this article (doi:10.1007/s11357-013-9559-2) contains supplementary material, which is available to authorized users.     

Choline acetyltransferase and acetylcholinesterase abnormalities in senile dementia: Importance of biochemical measurements in human post-mortem brain specimens

Choline acetyltransferase and acetylcholinesterase have been assessed in human aging brains, in demented and agonal states. Choline acetyl transferase decreased during aging in normal brain when measured in the cerebral cortex. Choline acetyltransferase was also reduced in several other brain areas in patients with Alzheimer's disease and in one patient with Creutzfeldt-Jakob disease. Choline acetyltransferase was also reduced in bronchopneumonia and in some terminal conditions. On the contrary, the activity was not reduced in patients who died after cerebrovascular accidents. Acetylcholine esterase, although it followed the general trend of choline acetyltransferase, did not yield significant results.

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Sommario L'attività degli enzimi colina-acetil-transferasi e acetil-colina-esterasi è stata studiata nell'encefalo umano durante l'invecchiamento, nella demenza e nelle patologie terminali. La colina-acetil-transferasi è risultata decrescere con l'età nella corteccia frontale e significativamente diminuita in varie regioni dell'encefalo di soggetti affetti da malattia di Alzheimer e di Creutzfeldt Jacob. Corrispondentemente l'attività della colinoacetil-transferasi è risultata significativamente compromessa anche nelle patologie terminali quali il coma e la broncopolmonite terminale. In contrasto a questi risultati nell'encefalo di soggetti deceduti per accidenti cerebrovascolari la attività enzimatica è risultata normale. In oltre l'attività della acetilcolina-esterasi non ha mostrato significative variazioni in alcuno dei gruppi studiati.

     

Alzheimer disease risk associated with APOE4 is modified by STH gene polymorphism

The association of the STH gene polymorphism with Alzheimer disease (AD) is debated. In the analysis of two genetically and diagnostically distinct groups of Alzheimer patients from the USA and Italy, the authors did not find an association with the STH polymorphism. However, the APOE-4-associated risk of AD greatly increased if the STH-G allele was also present. The STH-G allele appears to be a risk modifier for AD.     

Codon 129 polymorphism of prion protein gene in sporadic Alzheimer's disease

Codon 129 polymorphism of the prion protein gene represents a major genetic risk factor for Creutzfeldt-Jakob disease (CJD). Both CJD and Alzheimer's disease (AD) are brain amyloidoses and it would be possible that codon 129 polymorphism plays a role in the susceptibility to AD. In order to investigate this polymorphism in AD the distribution of polymorphic codon 129 of the PRNP gene in 194 probable AD and 124 controls selected in Italy and 109 neuropathologically verified AD and 58 matched controls recruited in the USA was studied. No significant association was found for the PRNP polymorphism in AD compared to controls either in Probable or in Definite AD series even after stratification for APOE polymorphism. This study does not support a role of PRNP polymorphism as a susceptibility factor for AD.     

Neural correlates of the interactive relationship between memory deficits and depressive symptoms in nondemented elderly: resting fMRI study

Prospective studies have shown an association between depressive symptoms and cognitive impairment among older adults. However, the neural correlates of this relationship are poorly understood. Our aim was to examine whether interactive effects of memory deficits and depressive symptoms are present in the memory-associated functional networks, in nondemented elderly subjects. Fifteen subjects with amnestic mild cognitive impairment (aMCI) and 20 age-matched normal (CN) elderly subjects participated in this cross-sectional study. Resting-state functional connectivity MRI (R-fMRI) measured the hippocampal functional connectivity (HFC) alterations between the two groups. Voxelwise linear regression analysis was performed to correlate hippocampal network strength with the Rey Auditory Verbal Learning Test delayed recall and the Geriatric Depression Scale scores, after adjusting for age and group effects. Poorer memory performance was associated with decreased positively correlated HFC connectivity in the specific frontal lobe and default mode network (DMN) structures. Poorer memory performance also was associated with decreased anticorrelated HFC connectivity in the bilateral inferior parietal and right dorsolateral prefrontal cortices. In contrast, greater depressive symptom severity was associated with increased HFC connectivity in several frontal lobes and DMN regions. Depressive symptoms and memory functions had interactive effects on the HFC, in the frontal, temporal, and PCC structures. Our findings suggest that the R-fMRI technique can be used to examine the changes in functional neural networks where memory deficits and depressive symptoms coexist in the geriatric population.     

Changes in regional cerebral blood flow and functional connectivity in the cholinergic pathway associated with cognitive performance in subjects with mild Alzheimer's disease after 12-week donepezil treatment

Acetylcholinesterase inhibitors (AChEIs), such as donepezil, have been shown to improve cognition in mild to moderate Alzheimer's disease (AD) patients. In this paper, our goal is to determine the relationship between altered cerebral blood flow (CBF) and intrinsic functional network connectivity changes in mild AD patients before and after 12-week donepezil treatment. An integrative neuroimaging approach was employed by combining pseudocontinuous arterial spin labeling (pCASL) MRI and resting-state functional MRI (R-fMRI) methods to determine the changes in CBF and functional connectivity (FC) in the cholinergic pathway. Linear regression analyses determined the correlations of the regional CBF alterations and functional connectivity changes with cognitive responses. These were measured with the Mini-Mental Status Examination (MMSE) scores and Alzheimer's disease Assessment Scale-Cognitive subscale (ADAS-cog) scores. Our results show that the regional CBF in mild AD subjects after donepezil treatment was significantly increased in the middle cingulate cortex (MCC) and posterior cingulate cortex (PCC), which are the neural substrates of the medial cholinergic pathway. In both brain regions, the baseline CBF and its changes after treatment were significantly correlated with the behavioral changes in ADAS-cog scores. The intrinsic FC was significantly enhanced in the medial cholinergic pathway network in the brain areas of the parahippocampal, temporal, parietal and prefrontal cortices. Finally, the FC changes in the medial prefrontal areas demonstrated an association with the CBF level in the MCC and the PCC, and also were correlated with ADAS-cog score changes. These findings indicate that regional CBF and FC network changes in the medial cholinergic pathway were associated with cognitive performance. It also is suggested that the combined pCASL-MRI and R-fMRI methods could be used to detect regional CBF and FC changes when using drug treatments in mild AD subjects.