To determine whether oxidized LDL enhances atherogenesis by promoting monocyte recruitment into the vascular intima, we investigated whether LDL accumulation and oxidation precede intimal accumulation of monocytes in human fetal aortas (from spontaneous abortions and premature newborns who died within 12 h; fetal age 6.2 Ϯ 1.3 mo). For this purpose, a systematic assessment of fatty streak formation was carried out in fetal aortas from normocholesterolemic mothers ( n ϭ 22), hypercholesterolemic mothers ( n ϭ 33), and mothers who were hypercholesterolemic only during pregnancy ( n ϭ 27). Fetal plasma cholesterol levels showed a strong inverse correlation with fetal age ( R ϭ Ϫ 0.88, P Ͻ 0.0001). In fetuses younger than 6 mo, fetal plasma cholesterol levels correlated with maternal ones ( R ϭ 0.86, P ϭ 0.001), whereas in older fetuses no such correlation existed. Fetal aortas from hypercholesterolemic mothers and mothers with temporary hypercholesterolemia contained significantly more and larger lesions (758,651 Ϯ 87,449 and 451,255 Ϯ 37,448 m 2 per section, respectively; mean Ϯ SD) than aortas from normocholesterolemic mothers (61,862 Ϯ 9,555 m 2 ; P Ͻ 0.00005). Serial sections of the arch, thoracic, and abdominal aortas were immunostained for recognized markers of atherosclerosis: macrophages, apo B, and two different oxidation-specific epitopes (malondialdehyde-and 4-hydroxynonenal-lysine). Of the atherogenic sites that showed positive immunostaining for at least one of these markers, 58.6% were established lesions containing both macrophage/foam cells and oxidized LDL (OxLDL). 17.3% of all sites contained only native LDL, and 13.3% contained only OxLDL without monocyte/ macrophages. In contrast, only 4.3% of sites contained isolated monocytes in the absence of native or oxidized LDL. In addition, 6.3% of sites contained LDL and macrophages but few oxidation-specific epitopes. These results demonstrate that LDL oxidation and formation of fatty streaks occurs already during fetal development, and that both phenomena are greatly enhanced by maternal hypercholesterolemia. The fact that in very early lesions LDL and Ox-LDL are frequently found in the absence of monocyte/macrophages, whereas the opposite is rare, suggests that intimal LDL accumulation and oxidation contributes to monocyte recruitment in vivo. ( J. Clin. Invest. 1997. 100:2680-2690.)
Summary Background Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes—MAPT, GRN, and C9orf72—have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. All participants had European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10−8) and suggestive single-nucleotide polymorphisms. Findings We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10−8) that encompassed the HLA locus at 6p21.3 in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC, for the behavioural FTD subtype. Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation incis. Interpretation Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and possibly to shed light on the pathomechanisms contributing to FTD. Funding The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/ MRC Centre on Parkinson’s disease, Alzheimer’s Research UK, and Texas Tech University Health Sciences Center.
Abstract-Seventy-one mutations of the low density lipoprotein (LDL) receptor gene were identified in 282 unrelated Italian familial hypercholesterolemia (FH) heterozygotes. By extending genotype analysis to families of the index cases, we identified 12 mutation clusters and localized them in specific areas of Italy. To evaluate the impact of these mutations on the clinical expression of FH, the clusters were separated into 2 groups: receptor-defective and receptor-negative, according to the LDL receptor defect caused by each mutation. These 2 groups were comparable in terms of the patients' age, sex distribution, body mass index, arterial hypertension, and smoking status. In receptor-negative subjects, LDL cholesterol was higher (ϩ18%) and high density lipoprotein cholesterol lower (Ϫ5%) than the values found in receptor-defective subjects. The prevalence of tendon xanthomas and coronary artery disease (CAD) was 2-fold higher in receptor-negative subjects. In patients Ͼ30 years of age in both groups, the presence of CAD was related to age, arterial hypertension, previous smoking, and LDL cholesterol level. Independent contributors to CAD in the receptor-defective subjects were male sex, arterial hypertension, and LDL cholesterol level; in the receptor-negative subjects, the first 2 variables were strong predictors of CAD, whereas the LDL cholesterol level had a lower impact than in receptor-defective subjects. Overall, in receptor-negative subjects, the risk of CAD was 2.6-fold that of receptordefective subjects. Wide interindividual variability in LDL cholesterol levels was found in each cluster. Apolipoprotein E genotype analysis showed a lowering effect of the ⑀2 allele and a raising effect of the ⑀4 allele on the LDL cholesterol level in both groups; however, the apolipoprotein E genotype accounted for only 4% of the variation in LDL cholesterol.Haplotype analysis showed that all families of the major clusters shared the same intragenic haplotype cosegregating with the mutation, thus suggesting the presence of common ancestors. (Arterioscler Thromb Vasc Biol. 2000;20:e41-e52.)
Simultaneously evaluating resting-state brain glucose metabolism and intrinsic functional activity has potential to impact the clinical neurosciences of Alzheimer Disease (AD). Indeed, integrating such combined information obtained in the same physiological setting may clarify how impairments in neuroenergetic and neuronal function interact and contribute to the mechanisms underlying AD. The present study used this multimodality approach to investigate, by means of a hybrid PET/MR scanner, the coupling between glucose consumption and intrinsic functional activity in 23 patients with AD-related cognitive impairment ranging from amnestic mild cognitive impairment (MCI) to mild-moderate AD (aMCI/AD), in comparison with a group of 23 healthy elderly controls. Between-group (Controls > Patients) comparisons were conducted on data from both imaging modalities using voxelwise 2-sample t-tests, corrected for partial-volume effects, head motion, age, gender and multiple tests. FDG-PET/fMRI relationships were assessed within and across subjects using Spearman partial correlations for three different resting-state fMRI (rs-fMRI) metrics sensitive to AD: fractional amplitude of low frequency fluctuations (fALFF), regional homogeneity (ReHo) and group independent component analysis with dual regression (gICA-DR). FDG and rs-fMRI metrics distinguished aMCI/AD from controls according to spatial patterns analogous to those found in stand-alone studies. Within-subject correlations were comparable across the three rs-fMRI metrics. Correlations were overall high in healthy controls (ρ = 0.80 ± 0.04), but showed a significant 17% reduction (p < 0.05) in aMCI/AD patients (ρ = 0.67 ± 0.05). Positive across-subject correlations were overall moderate (ρ = 0.33 ± 0.07) and consistent across rs-fMRI metrics. These were confined around AD-target posterior regions for metrics of functional connectivity (ReHo and gICA-DR). In contrast, FDG/fALFF correlations were distributed in the frontal gyrus, thalami and caudate nuclei. Taken together, these results support the presence of bioenergetic coupling between glucose utilization and rapid transmission of neural information in healthy ageing, which is substantially reduced in aMCI/AD, suggesting that abnormal glucose utilization is in some way linked to communication breakdown among brain regions impacted by the underlying pathological process.
Aim To evaluate the effects of the COVID-19 emergency lockdown on the psychological outcome in caregivers of patients with dementia and on the loss of welfare services in these patients. Findings Time of isolation, education and gender had a significant effect on anxiety and depression. A marked reduction of health services was observed in all patients with dementia. Message The lockdown registered a particularly negative impact on people with dementia and their caregivers.
Frontotemporal dementia (FTD) is the second most prevalent form of early onset dementia after Alzheimer's disease (AD). We performed a case-control association study in an Italian FTD cohort (n = 530) followed by the novel single nucleotide polymorphisms (SNPs)-to-genes approach and functional annotation analysis. We identified 2 novel potential loci for FTD. Suggestive SNPs reached p-values ∼10−7 and odds ratio > 2.5 (2p16.3) and 1.5 (17q25.3). Suggestive alleles at 17q25.3 identified a disease-associated haplotype causing decreased expression of –cis genes such as RFNG and AATK involved in neuronal genesis and differentiation and axon outgrowth, respectively. We replicated this locus through the SNPs-to-genes approach. Our functional annotation analysis indicated significant enrichment for functions of the brain (neuronal genesis, differentiation, and maturation), the synapse (neurotransmission and synapse plasticity), and elements of the immune system, the latter supporting our recent international FTD–genome-wide association study. This is the largest genome-wide study in Italian FTD to date. Although our results are not conclusive, we set the basis for future replication studies and identification of susceptible molecular mechanisms involved in FTD pathogenesis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.