Cardiovascular Damage in Alzheimer Disease: Autopsy Findings From the Bryan ADRC

Autopsy information on cardiovascular damage was investigated for pathologically confirmed Alzheimer disease (AD) patients (n = 84) and non-AD control patients (n = 60). The 51 relevant items were entered into a grade-of-membership model to describe vascular damage in AD. Five latent groups were identified “I: early-onset AD,” “II: controls, cancer,” “III: controls, extensive atherosclerosis,” “IV: late-onset AD, male,” and “V: late-onset AD, female.” Expectedly, Groups IV and V had elevated APOE ϵ4 frequency. Unexpectedly, there was limited atherosclerosis and frequent myocardial valve and ventricular damage. The findings do not indicate a strong relationship between atherosclerosis and AD, although both are associated with the APOE ϵ4. Instead, autopsy findings of extensive atherosclerosis were associated with possible, not probable or definite AD, and premature death. They are consistent with the hypothesis that brain hypoperfusion contributes to dementia, possibly to AD pathogenesis, and raise the possibility that the APOE allele ϵ4 contributes directly to heart valve and myocardial damage

Corpora amylacea are associated with tau burden and cognitive status in Alzheimer\u27s disease

Corpora amylacea (CA) and their murine analogs, periodic acid Schiff (PAS) granules, are age-related, carbohydrate-rich structures that serve as waste repositories for aggregated proteins, damaged cellular organelles, and other cellular debris. The structure, morphology, and suspected functions of CA in the brain imply disease relevance. Despite this, the link between CA and age-related neurodegenerative diseases, particularly Alzheimer\u27s disease (AD), remains poorly defined. We performed a neuropathological analysis of mouse PAS granules and human CA and correlated these findings with AD progression. Increased PAS granule density was observed in symptomatic tau transgenic mice and APOE knock-in mice. Using a cohort of postmortem AD brain samples, we examined CA in cognitively normal and dementia patients across Braak stages with varying APOE status. We identified a Braak-stage dependent bimodal distribution of CA in the dentate gyrus, with CA accumulating and peaking by Braak stages II-III, then steadily declining with increasing tau burden. Refined analysis revealed an association of CA levels with both cognition and APOE status. Finally, tau was detected in whole CA present in human patient cerebrospinal fluid, highlighting CA-tau as a plausible prodromal AD biomarker. Our study connects hallmarks of the aging brain with the emergence of AD pathology and suggests that CA may act as a compensatory factor that becomes depleted with advancing tau burden

Prostate-Specific Antigen is Unlikely to Be a Suitable Biomarker of Semen Exposure From Recent Unprotected Receptive Anal Intercourse in Men Who Have Sex With Men

A biomarker of unprotected receptive anal intercourse (RAI) could improve validity of sexual behavior measurement. We quantified prostate-specific antigen (PSA) from rectal swabs from men who have sex with men (MSM). One swab was PSA-positive. Using current methods, PSA is an inadequate biomarker of recent unprotected RAI in MSM

Association of Genetic Variants With Primary Open-Angle Glaucoma Among Individuals With African Ancestry.

Importance:Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. Objectives:To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and Participants:A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Exposures:Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures:Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data. Results:A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-β A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry. Conclusions and Relevance:In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies

Relative fat oxidation is higher in children than adults

Background: Prepubescent children may oxidize fatty acids more readily than adults. Therefore, dietary fat needs would be higher for children compared with adults. The dietary fat recommendations are higher for children 4 to 18 yrs (i.e., 25 to 35% of energy) compared with adults (i.e., 20 to 35% of energy). Despite this, many parents and children restrict dietary fat for health reasons. Methods: This study assessed whether rates of fat oxidation are similar between prepubescent children and adults. Ten children (8.7 ± 1.4 yr, 33 ± 13 kg mean ± SD) in Tanner stage 1 and 10 adults (41.6 ± 8 yr, 74 ± 13 kg) were fed a weight maintenance diet for three days to maintain body weight and to establish a consistent background for metabolic rate measurements (all foods provided). Metabolic rate was measured on three separate occasions before and immediately after breakfast and for 9 hrs using a hood system (twice) or a room calorimeter (once) where continuous metabolic measurements were taken. Results: During all three sessions whole body fat oxidation was higher in children (lower RQ) compared to adults (mean RQ= 0.84 ± .016 for children and 0.87 ± .02, for adults, p < 0.02). Although, total grams of fat oxidized was similar in children (62.7 ± 20 g/24 hrs) compared to adults (51.4 ± 19 g/24 hrs), the grams of fat oxidized relative to calorie expenditure was higher in children (0.047 ± .01 g/kcal, compared to adults (0.032 ± .01 p < 0.02). Females oxidized more fat relative to calorie expenditure than males of a similar age. A two way ANOVA showed no interaction between gender and age in terms of fax oxidation. Conclusion: These data suggest that fat oxidation relative to total calorie expenditure is higher in prepubescent children than in adults. Consistent with current dietary guidelines, a moderate fat diet is appropriate for children within the context of a diet that meets their energy and nutrient needs. Originally published Nutrition Journal, Vol. 6, No. 19, Aug 200

The human brainome: network analysis identifies \u3ci\u3eHSPA2\u3c/i\u3e as a novel Alzheimer’s disease target

Our hypothesis is that changes in gene and protein expression are crucial to the development of late-onset Alzheimer’s disease. Previously we examined how DNA alleles control downstream expression of RNA transcripts and how those relationships are changed in late-onset Alzheimer’s disease. We have now examined how proteins are incorporated into networks in two separate series and evaluated our outputs in two different cell lines. Our pipeline included the following steps: (i) predicting expression quantitative trait loci; (ii) determining differential expression; (iii) analysing networks of transcript and peptide relationships; and (iv) validating effects in two separate cell lines. We performed all our analysis in two separate brain series to validate effects. Our two series included 345 samples in the first set (177 controls, 168 cases; age range 65–105; 58% female; KRONOSII cohort) and 409 samples in the replicate set (153 controls, 141 cases, 115 mild cognitive impairment; age range 66–107; 63% female; RUSH cohort). Our top target is heat shock protein family A member 2 (HSPA2), which was identified as a key driver in our two datasets. HSPA2 was validated in two cell lines, with overexpression driving further elevation of amyloid-B40 and amyloid-B42 levels in APP mutant cells, as well as significant elevation of microtubule associated protein tau and phosphorylated-tau in a modified neuroglioma line. This work further demonstrates that studying changes in gene and protein expression is crucial to understanding late onset disease and further nominates HSPA2 as a specific key regulator of late-onset Alzheimer’s disease processes

Role of Conserved Non-Coding Regulatory Elements in LMW Glutenin Gene Expression

Transcriptional regulation of LMW glutenin genes were investigated in-silico, using publicly available gene sequences and expression data. Genes were grouped into different LMW glutenin types and their promoter profiles were determined using cis-acting regulatory elements databases and published results. The various cis-acting elements belong to some conserved non-coding regulatory regions (CREs) and might act in two different ways. There are elements, such as GCN4 motifs found in the long endosperm box that could serve as key factors in tissue-specific expression. Some other elements, such as the AACA/TA motifs or the individual prolamin box variants, might modulate the level of expression. Based on the promoter sequences and expression characteristic LMW glutenin genes might be transcribed following two different mechanisms. Most of the s- and i-type genes show a continuously increasing expression pattern. The m-type genes, however, demonstrate normal distribution in their expression profiles. Differences observed in their expression could be related to the differences found in their promoter sequences. Polymorphisms in the number and combination of cis-acting elements in their promoter regions can be of crucial importance in the diverse levels of production of single LMW glutenin gene types