Glomerular hyperfiltration predicts the development of microalbuminuria in stage 1 hypertension: The HARVEST

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Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease

Impact of Genetic Variation in SORCS1 on Memory Retention

We previously reported that genetic variants in SORCS1 increase the risk of AD, that over-expression of SorCS1 reduces γ-secretase activity and Aβ levels, and that SorCS1 suppression increases γ-secretase processing of APP and Aβ levels. We now explored the effect of variation in SORCS1 on memory.We explored associations between SORCS1-SNPs and memory retention in the NIA-LOAD case control dataset (162 cases,670 controls) and a cohort of Caribbean Hispanics (549 cases,544 controls) using single marker and haplotype analyses.Three SNPs in intron 1, were associated with memory retention in the NIA-LOAD dataset or the Caribbean Hispanic dataset (rs10884402(A allele:β = -0.15,p = 0.008), rs7078098(C allele:β = 0.18,p = 0.007) and rs950809(C allele:β = 0.17,p = 0.008)) and all three SNPs were significant in a meta-analysis of both datasets (0.002<p<0.03). The corresponding A-T-T haplotype for these SNPs was associated with lower scores in both datasets (p = 0.02,p = 0.0009), and the complementary G-C-C haplotype was associated with higher scores in NIA-LOAD (p = 0.02). These associations were restricted to cases.Variation in intron 1 in SORCS1 is associated with memory changes in AD

Amyloid imaging in the differential diagnosis of dementia: review and potential clinical applications

In the past decade, positron emission tomography (PET) with carbon-11-labeled Pittsburgh Compound B (PIB) has revolutionized the neuroimaging of aging and dementia by enabling in vivo detection of amyloid plaques, a core pathologic feature of Alzheimer's disease (AD). Studies suggest that PIB-PET is sensitive for AD pathology, can distinguish AD from non-AD dementia (for example, frontotemporal lobar degeneration), and can help determine whether mild cognitive impairment is due to AD. Although the short half-life of the carbon-11 radiolabel has thus far limited the use of PIB to research, a second generation of tracers labeled with fluorine-18 has made it possible for amyloid PET to enter the clinical era. In the present review, we summarize the literature on amyloid imaging in a range of neurodegenerative conditions. We focus on potential clinical applications of amyloid PET and its role in the differential diagnosis of dementia. We suggest that amyloid imaging will be particularly useful in the evaluation of mildly affected, clinically atypical or early age-at-onset patients, and illustrate this with case vignettes from our practice. We emphasize that amyloid imaging should supplement (not replace) a detailed clinical evaluation. We caution against screening asymptomatic individuals, and discuss the limited positive predictive value in older populations. Finally, we review limitations and unresolved questions related to this exciting new technique

Effect of hot calendering on physical properties and water vapor transfer resistance of bacterial cellulose films

This work investigates the effect of hot calendering on bacterial cellulose (BC) films properties, aiming the achievement of good transparency and barrier property. A comparison was made using vegetal cellulose (VC) films on a similar basis weight of around 40 g.m-2. The optical-structural, mechanical and barrier property of BC films were studied and compared with those of highly beaten VC films. The Youngs moduli and tensile index of the BC films are much higher than those obtained for VC (14.5 16.2 GPa vs 10.8 8.7 GPa and 146.7 64.8 N.m.g-1 vs 82.8 40.5 N.m.g-1), respectively. Calendering increased significantly the transparency of BC films from 53.0 % to 73.0 %. The effect of BC ozonation was also studied. Oxidation with ozone somewhat enhanced the brightness and transparency of the BC films, but at the expenses of slightly lower mechanical properties. BC films exhibited a low water vapor transfer rate, when compared to VC films and this property decreased by around 70 % following calendering, for all films tested. These results show that calendering could be used as a process to obtain films suitable for food packaging applications, where transparency, good mechanical performance and barrier properties are important. The BC films obtained herein are valuable products that could be a good alternative to the highly used plastics in this industry.The authors thank FCT (Fundação para a Ciência e Tecnologia) and FEDER (Fundo Europeu de Desenvolvimento Regional) for the financial support of the project FCT PTDC/AGR-FOR/3090/2012— FCOMP-01-0124-FEDER-027948 and the awarding of a research grant for Vera Costa

Genetic variants and functional pathways associated with resilience to Alzheimer\u27s disease.

Approximately 30% of older adults exhibit the neuropathological features of Alzheimer\u27s disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modelling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5108 participants from a clinical trial of Alzheimer\u27s disease and three longitudinal cohort studies of cognitive ageing. All analyses were run across all participants and repeated restricting the sample to individuals with unimpaired cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (P-values \u3c 2.5 × 10-20), and we observed novel correlations with neuropsychiatric conditions (P-values \u3c 7.9 × 10-4). Notably, neither resilience metric was genetically correlated with clinical Alzheimer\u27s disease (P-values \u3e 0.42) nor associated with APOE (P-values \u3e 0.13). In single variant analyses, we observed a genome-wide significant locus among participants with unimpaired cognition on chromosome 18 upstream of ATP8B1 (index single nucleotide polymorphism rs2571244, minor allele frequency = 0.08, P = 2.3 × 10-8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream of ATPB81 (cg19596477; P = 2 × 10-13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway. Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical Alzheimer\u27s disease, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets

Sex differences in the genetic architecture of cognitive resilience to Alzheimer\u27s disease.

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer\u27s disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer\u27s disease neuropathology may uncover novel therapeutic targets to treat Alzheimer\u27s disease. It is well established that there are sex differences in response to Alzheimer\u27s disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified [n (males) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20-25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15-44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 [rs827389, β (females) = 0.08, P (females) = 5.76 × 10-09, β (males) = -0.01, P(males) = 0.70, β (interaction) = 0.09, P (interaction) = 1.01 × 10-04] in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus and highlighted numerous sex-specific molecular pathways that may underly resilience to Alzheimer\u27s disease pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer\u27s disease may be personalized based on their biological sex and genetic context