Life expectancy with and without cognitive impairment by diabetes status among older Americans

Peer reviewe

Sex- and brain region-specific acceleration of β-amyloidogenesis following behavioral stress in a mouse model of Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>It is hypothesized that complex interactions between multiple environmental factors and genetic factors are implicated in sporadic Alzheimer's disease (AD); however, the underlying mechanisms are poorly understood. Importantly, recent evidence reveals that expression and activity levels of the β-site APP cleaving enzyme 1 (BACE1), which initiates amyloid-β (Aβ) production, are elevated in AD brains. In this study, we investigated a molecular mechanism by which sex and stress interactions may accelerate β-amyloidogenesis and contribute to sporadic AD.</p> <p>Results</p> <p>We applied 5-day restraint stress (6 h/day) to the male and female 5XFAD transgenic mouse model of AD at the pre-pathological stage of disease, which showed little amyloid deposition under non-stressed control conditions. Exposure to the relatively brief behavioral stress increased levels of neurotoxic Aβ42 peptides, the β-secretase-cleaved C-terminal fragment (C99) and plaque burden in the hippocampus of female 5XFAD mice but not in that of male 5XFAD mice. In contrast, significant changes in the parameters of β-amyloidosis were not observed in the cerebral cortex of stressed male or female 5XFAD mice. We found that this sex- and brain region-specific acceleration of β-amyloidosis was accounted for by elevations in BACE1 and APP levels in response to adverse stress. Furthermore, not only BACE1 mRNA but also phosphorylation of the translation initiation factor eIF2α (a proposed mediator of the post-transcriptional upregulation of BACE1) was elevated in the hippocampus of stressed female 5XFAD mice.</p> <p>Conclusions</p> <p>Our results suggest that the higher prevalence of sporadic AD in women may be attributable to the vulnerability of female brains (especially, the hippocampus) to stressful events, which alter APP processing to favor the β-amyloidogenesis through the transcriptional and translational upregulation of BACE1 combined with elevations in its substrate APP.</p

Full characterization of vibrational coherence in a porphyrin chromophore by two-dimensional electronic spectroscopy

In this work we present experimental and calculated two-dimensional electronic spectra for a 5,15-bisalkynyl porphyrin chromophore. The lowest energy electronic Qy transition couples mainly to a single 380 cm–1 vibrational mode. The two-dimensional electronic spectra reveal diagonal and cross peaks which oscillate as a function of population time. We analyze both the amplitude and phase distribution of this main vibronic transition as a function of excitation and detection frequencies. Even though Feynman diagrams provide a good indication of where the amplitude of the oscillating components are located in the excitation-detection plane, other factors also affect this distribution. Specifically, the oscillation corresponding to each Feynman diagram is expected to have a phase that is a function of excitation and detection frequencies. Therefore, the overall phase of the experimentally observed oscillation will reflect this phase dependence. Another consequence is that the overall oscillation amplitude can show interference patterns resulting from overlapping contributions from neighboring Feynman diagrams. These observations are consistently reproduced through simulations based on third order perturbation theory coupled to a spectral density described by a Brownian oscillator model

Profiling hippocampal neuronal populations reveals unique gene expression mosaics reflective of connectivity-based degeneration in the Ts65Dn mouse model of Down syndrome and Alzheimer’s disease

IntroductionIndividuals with Down syndrome (DS) exhibit neurological deficits throughout life including the development of in Alzheimer’s disease (AD) pathology and cognitive impairment. At the cellular level, dysregulation in neuronal gene expression is observed in postmortem human brain and mouse models of DS/AD. To date, RNA-sequencing (RNA-seq) analysis of hippocampal neuronal gene expression including the characterization of discrete circuit-based connectivity in DS remains a major knowledge gap. We postulate that spatially characterized hippocampal neurons display unique gene expression patterns due, in part, to dysfunction of the integrity of intrinsic circuitry.MethodsWe combined laser capture microdissection to microisolate individual neuron populations with single population RNA-seq analysis to determine gene expression analysis of CA1 and CA3 pyramidal neurons and dentate gyrus granule cells located in the hippocampus, a region critical for learning, memory, and synaptic activity.ResultsThe hippocampus exhibits age-dependent neurodegeneration beginning at ~6 months of age in the Ts65Dn mouse model of DS/AD. Each population of excitatory hippocampal neurons exhibited unique gene expression alterations in Ts65Dn mice. Bioinformatic inquiry revealed unique vulnerabilities and differences with mechanistic implications coinciding with onset of degeneration in this model of DS/AD.ConclusionsThese cell-type specific vulnerabilities may underlie degenerative endophenotypes suggesting precision medicine targeting of individual populations of neurons for rational therapeutic development

Application of robust regression in translational neuroscience studies with non-Gaussian outcome data

Linear regression is one of the most used statistical techniques in neuroscience, including the study of the neuropathology of Alzheimer’s disease (AD) dementia. However, the practical utility of this approach is often limited because dependent variables are often highly skewed and fail to meet the assumption of normality. Applying linear regression analyses to highly skewed datasets can generate imprecise results, which lead to erroneous estimates derived from statistical models. Furthermore, the presence of outliers can introduce unwanted bias, which affect estimates derived from linear regression models. Although a variety of data transformations can be utilized to mitigate these problems, these approaches are also associated with various caveats. By contrast, a robust regression approach does not impose distributional assumptions on data allowing for results to be interpreted in a similar manner to that derived using a linear regression analysis. Here, we demonstrate the utility of applying robust regression to the analysis of data derived from studies of human brain neurodegeneration where the error distribution of a dependent variable does not meet the assumption of normality. We show that the application of a robust regression approach to two independent published human clinical neuropathologic data sets provides reliable estimates of associations. We also demonstrate that results from a linear regression analysis can be biased if the dependent variable is significantly skewed, further indicating robust regression as a suitable alternate approach

Evidence that cholinergic mechanisms contribute to hyperexcitability at early stages in Alzheimer’s disease

A long-standing theory for Alzheimer’s disease (AD) has been that deterioration of synapses and depressed neuronal activity is a major contributing factor. We review the increasing evidence, in humans and in mouse models, that show that there is often neuronal hyperactivity at early stages rather than decreased activity. We discuss studies in mouse models showing that hyperexcitability can occur long before plaque deposition and memory impairment. In mouse models, a generator of the hyperactivity appears to be the dentate gyrus. We present evidence, based on mouse models, that inhibition of muscarinic cholinergic receptors or medial septal cholinergic neurons can prevent hyperactivity. Therefore, we hypothesize the novel idea that cholinergic neurons are overly active early in the disease, not depressed. In particular we suggest the medial septal cholinergic neurons are overly active and contribute to hyperexcitability. We further hypothesize that the high activity of cholinergic neurons at early ages ultimately leads to their decline in function later in the disease. We review the effects of a prenatal diet that increases choline, the precursor to acetylcholine and modulator of many other functions. In mouse models of AD, maternal choline supplementation (MCS) reduces medial septal cholinergic pathology, amyloid accumulation and hyperexcitability, especially in the dentate gyrus, and improves cognition

Nerve Growth Factor Pathobiology During The Progression Of Alzheimer\u27s Disease

The current review summarizes the pathobiology of nerve growth factor (NGF) and its cognate receptors during the progression of Alzheimer’s disease (AD). Both transcript and protein data indicate that cholinotrophic neuronal dysfunction is related to an imbalance between TrkA-mediated survival signaling and the NGF precursor (proNGF)/p75NTR-mediated pro-apoptotic signaling, which may be related to alteration in the metabolism of NGF. Data indicate a spatiotemporal pattern of degeneration related to the evolution of tau pathology within cholinotrophic neuronal subgroups located within the nucleus basalis of Meynert (nbM). Despite these degenerative events the cholinotrophic system is capable of cellular resilience and/or plasticity during the prodromal and later stages of the disease. In addition to neurotrophin dysfunction, studies indicate alterations in epigenetically regulated proteins occur within cholinotrophic nbM neurons during the progression of AD, suggesting a mechanism that may underlie changes in transcript expression. Findings that increased cerebrospinal fluid levels of proNGF mark the onset of MCI and the transition to AD suggests that this proneurotrophin is a potential disease biomarker. Novel therapeutics to treat NGF dysfunction include NGF gene therapy and the development of small molecule agonists for the cognate prosurvival NGF receptor TrkA and antagonists against the pan-neurotrophin p75NTR death receptor for the treatment of AD

Increased Mortality Exposure within the Family Rather than Individual Mortality Experiences Triggers Faster Life-History Strategies in Historic Human Populations

Life History Theory predicts that extrinsic mortality risk is one of the most important factors shaping (human) life histories. Evidence from contemporary populations suggests that individuals confronted with high mortality environments show characteristic traits of fast life-history strategies: they marry and reproduce earlier, have shorter birth intervals and invest less in their offspring. However, little is known of the impact of mortality experiences on the speed of life histories in historical human populations with generally higher mortality risk, and on male life histories in particular. Furthermore, it remains unknown whether individual-level mortality experiences within the family have a greater effect on life-history decisions or family membership explains life-history variation. In a comparative approach using event history analyses, we study the impact of family versus individual-level effects of mortality exposure on two central life-history parameters, ages at first marriage and first birth, in three historical human populations (Germany, Finland, Canada). Mortality experience is measured as the confrontation with sibling deaths within the natal family up to an individual's age of 15. Results show that the speed of life histories is not adjusted according to individual-level mortality experiences but is due to family-level effects. The general finding of lower ages at marriage/reproduction after exposure to higher mortality in the family holds for both females and males. This study provides evidence for the importance of the family environment for reproductive timing while individual-level mortality experiences seem to play only a minor role in reproductive life history decisions in humans

Biopsychosocial predictors of perceived life expectancy in a national sample of older men and women.

Perceived life expectancy (PLE) is predictive of mortality risk in older adults, but the factors that may contribute to mental conceptions of PLE are unknown. We aimed to describe the sociodemographic, biomedical, behavioral, and psychological predictors of self-reported PLE estimates among older English adults. Data were from 6662 adults aged 50-79 years in the population-based English Longitudinal Study of Ageing (cross-sectional sample from 2012/13). PLE was assessed in the face-to-face study interview ("What are the chances you will live to be age x or more?" where x = current age plus 10-15 years). Responses were categorized as 'low' (0-49%), 'medium' (50-74%), and 'high' (75-100%). Adjusted prevalence ratios (PRs) and 95% confidence intervals (CIs) for low vs. high PLE were estimated using population-weighted modified Poisson regression with robust error variance. Overall, 1208/6662 (18%) participants reported a low PLE, 2806/6662 (42%) reported a medium PLE, and 2648/6662 (40%) reported a high PLE. The predictors of reporting a low PLE included older age (PR = 1.64; 95% CI: 1.50-1.76 per 10 years), male sex (PR = 1.14; 95% CI: 1.02-1.26), being a smoker (PR = 1.39; 95% CI: 1.22-1.59 vs. never/former smoker), and having a diagnosis of cancer or diabetes. A low sense of control over life was associated with low PLE, as was low satisfaction with life and worse self-rated health. Those with a higher perceived social standing were less likely to report a low PLE (PR = 0.90; 95% CI: 0.87-0.93 per 10-point increase, out of 100). This study provides novel insight into potential influences on older adults' expectations of their longevity, including aspects of psychological well-being. These results should be corroborated to better determine their implications for health-related decision-making, planning, and behavior among older adults