The metabolic basis of Alzheimer disease (AD) is poorly understood, and the relationships between systemic abnormalities in metabolism and AD pathogenesis are unclear. Understanding how global ...perturbations in metabolism are related to severity of AD neuropathology and the eventual expression of AD symptoms in at-risk individuals is critical to developing effective disease-modifying treatments. In this study, we undertook parallel metabolomics analyses in both the brain and blood to identify systemic correlates of neuropathology and their associations with prodromal and preclinical measures of AD progression.
Quantitative and targeted metabolomics (Biocrates AbsoluteIDQ identification and quantification p180) assays were performed on brain tissue samples from the autopsy cohort of the Baltimore Longitudinal Study of Aging (BLSA) (N = 44, mean age = 81.33, % female = 36.36) from AD (N = 15), control (CN; N = 14), and "asymptomatic Alzheimer's disease" (ASYMAD, i.e., individuals with significant AD pathology but no cognitive impairment during life; N = 15) participants. Using machine-learning methods, we identified a panel of 26 metabolites from two main classes-sphingolipids and glycerophospholipids-that discriminated AD and CN samples with accuracy, sensitivity, and specificity of 83.33%, 86.67%, and 80%, respectively. We then assayed these 26 metabolites in serum samples from two well-characterized longitudinal cohorts representing prodromal (Alzheimer's Disease Neuroimaging Initiative ADNI, N = 767, mean age = 75.19, % female = 42.63) and preclinical (BLSA) (N = 207, mean age = 78.68, % female = 42.63) AD, in which we tested their associations with magnetic resonance imaging (MRI) measures of AD-related brain atrophy, cerebrospinal fluid (CSF) biomarkers of AD pathology, risk of conversion to incident AD, and trajectories of cognitive performance. We developed an integrated blood and brain endophenotype score that summarized the relative importance of each metabolite to severity of AD pathology and disease progression (Endophenotype Association Score in Early Alzheimer's Disease EASE-AD). Finally, we mapped the main metabolite classes emerging from our analyses to key biological pathways implicated in AD pathogenesis. We found that distinct sphingolipid species including sphingomyelin (SM) with acyl residue sums C16:0, C18:1, and C16:1 (SM C16:0, SM C18:1, SM C16:1) and hydroxysphingomyelin with acyl residue sum C14:1 (SM (OH) C14:1) were consistently associated with severity of AD pathology at autopsy and AD progression across prodromal and preclinical stages. Higher log-transformed blood concentrations of all four sphingolipids in cognitively normal individuals were significantly associated with increased risk of future conversion to incident AD: SM C16:0 (hazard ratio HR = 4.430, 95% confidence interval CI = 1.703-11.520, p = 0.002), SM C16:1 (HR = 3.455, 95% CI = 1.516-7.873, p = 0.003), SM (OH) C14:1 (HR = 3.539, 95% CI = 1.373-9.122, p = 0.009), and SM C18:1 (HR = 2.255, 95% CI = 1.047-4.855, p = 0.038). The sphingolipid species identified map to several biologically relevant pathways implicated in AD, including tau phosphorylation, amyloid-β (Aβ) metabolism, calcium homeostasis, acetylcholine biosynthesis, and apoptosis. Our study has limitations: the relatively small number of brain tissue samples may have limited our power to detect significant associations, control for heterogeneity between groups, and replicate our findings in independent, autopsy-derived brain samples.
We present a novel framework to identify biologically relevant brain and blood metabolites associated with disease pathology and progression during the prodromal and preclinical stages of AD. Our results show that perturbations in sphingolipid metabolism are consistently associated with endophenotypes across preclinical and prodromal AD, as well as with AD pathology at autopsy. Sphingolipids may be biologically relevant biomarkers for the early detection of AD, and correcting perturbations in sphingolipid metabolism may be a plausible and novel therapeutic strategy in AD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Causal mediation analysis is a useful tool for epidemiologic research, but it has been criticized for relying on a "cross-world" independence assumption that counterfactual outcome and mediator ...values are independent even in causal worlds where the exposure assignments for the outcome and mediator differ. This assumption is empirically difficult to verify and problematic to justify based on background knowledge. In the present article, we aim to assist the applied researcher in understanding this assumption. Synthesizing what is known about the cross-world independence assumption, we discuss the relationship between assumptions for causal mediation analyses, causal models, and nonparametric identification of natural direct and indirect effects. In particular, we give a practical example of an applied setting where the cross-world independence assumption is violated even without any post-treatment confounding. Further, we review possible alternatives to the cross-world independence assumption, including the use of bounds that avoid the assumption altogether. Finally, we carry out a numeric study in which the cross-world independence assumption is violated to assess the ensuing bias in estimating natural direct and indirect effects. We conclude with recommendations for carrying out causal mediation analyses.
COVID-19 manifests with respiratory, systemic, and gastrointestinal (GI) symptoms.
SARS-CoV-2 RNA is detected in respiratory and fecal samples, and recent reports demonstrate viral replication in ...both the lung and intestinal tissue.2, 3, 4 Although much is known about early fecal RNA shedding, little is known about long-term shedding, especially in those with mild COVID-19. Furthermore, most reports of fecal RNA shedding do not correlate these findings with GI symptoms.
.
We analyzed the dynamics of fecal RNA shedding up to 10 months after COVID-19 diagnosis in 113 individuals with mild to moderate disease. We also correlated shedding with disease symptoms.
Fecal SARS-CoV-2 RNA is detected in 49.2% 95% confidence interval, 38.2%-60.3% of participants within the first week after diagnosis. Whereas there was no ongoing oropharyngeal SARS-CoV-2 RNA shedding in subjects at 4 months, 12.7% 8.5%-18.4% of participants continued to shed SARS-CoV-2 RNA in the feces at 4 months after diagnosis and 3.8% 2.0%-7.3% shed at 7 months. Finally, we found that GI symptoms (abdominal pain, nausea, vomiting) are associated with fecal shedding of SARS-CoV-2 RNA.
The extended presence of viral RNA in feces, but not in respiratory samples, along with the association of fecal viral RNA shedding with GI symptoms suggest that SARS-CoV-2 infects the GI tract and that this infection can be prolonged in a subset of individuals with COVID-19.
This research was supported by a Stanford ChemH-IMA grant; fellowships from the AACR and NSF; and NIH R01-AI148623, R01-AI143757, and UL1TR003142.
Abstract
We analyze pre-explosion near- and mid-infrared (IR) imaging of the site of SN 2023ixf in the nearby spiral galaxy M101 and characterize the candidate progenitor star. The star displays ...compelling evidence of variability with a possible period of ≈1000 days and an amplitude of Δ
m
≈ 0.6 mag in extensive monitoring with the Spitzer Space Telescope since 2004, likely indicative of radial pulsations. Variability consistent with this period is also seen in the near-IR
J
and
K
s
bands between 2010 and 2023, up to just 10 days before the explosion. Beyond the periodic variability, we do not find evidence for any IR-bright pre-supernova outbursts in this time period. The IR brightness (
M
K
s
=
−
10.7
mag) and color (
J
−
K
s
= 1.6 mag) of the star suggest a luminous and dusty red supergiant. Modeling of the phase-averaged spectral energy distribution (SED) yields constraints on the stellar temperature (
T
eff
=
3500
−
1400
+
800
K) and luminosity (
log
L
/
L
⊙
=
5.1
±
0.2
). This places the candidate among the most luminous Type II supernova progenitors with direct imaging constraints, with the caveat that many of these rely only on optical measurements. Comparison with stellar evolution models gives an initial mass of
M
init
= 17 ± 4
M
⊙
. We estimate the pre-supernova mass-loss rate of the star between 3 and 19 yr before explosion from the SED modeling at
M
̇
≈
3
×
10
−
5
to 3 × 10
−4
M
⊙
yr
−1
for an assumed wind velocity of
v
w
= 10 km s
−1
, perhaps pointing to enhanced mass loss in a pulsation-driven wind.
Although traumatic brain injury (TBI) acutely disrupts the cortex, most TBI-related disabilities reflect secondary injuries that accrue over time. The thalamus is a likely site of secondary damage ...because of its reciprocal connections with the cortex. Using a mouse model of mild TBI (mTBI), we found a chronic increase in C1q expression specifically in the corticothalamic system. Increased C1q expression colocalized with neuron loss and chronic inflammation and correlated with disruption in sleep spindles and emergence of epileptic activities. Blocking C1q counteracted these outcomes, suggesting that C1q is a disease modifier in mTBI. Single-nucleus RNA sequencing demonstrated that microglia are a source of thalamic C1q. The corticothalamic circuit could thus be a new target for treating TBI-related disabilities.
Abstract
Background
An important epidemiological question is understanding how vascular risk factors contribute to cognitive impairment. Using data from the Cardiovascular Health Cognition Study, we ...investigated how subclinical cardiovascular disease (sCVD) relates to cognitive impairment risk and the extent to which the hypothesized risk is mediated by the incidence of clinically manifested cardiovascular disease (CVD), both overall and within apolipoprotein E-4 (APOE-4) subgroups.
Methods
We adopted a novel “separable effects” causal mediation framework that assumes that sCVD has separably intervenable atherosclerosis-related components. We then ran several mediation models, adjusting for key covariates.
Results
We found that sCVD increased overall risk of cognitive impairment (risk ratio RR = 1.21, 95% confidence interval CI: 1.03, 1.44); however, there was little or no mediation by incident clinically manifested CVD (indirect effect RR = 1.02, 95% CI: 1.00, 1.03). We also found attenuated effects among APOE-4 carriers (total effect RR = 1.09, 95% CI: 0.81, 1.47; indirect effect RR = 0.99, 95% CI: 0.96, 1.01) and stronger findings among noncarriers (total effect RR = 1.29, 95% CI: 1.05, 1.60; indirect effect RR = 1.02, 95% CI: 1.00, 1.05). In secondary analyses restricting cognitive impairment to only incident dementia cases, we found similar effect patterns.
Conclusions
We found that the effect of sCVD on cognitive impairment does not seem to be mediated by CVD, both overall and within APOE-4 subgroups. Our results were critically assessed via sensitivity analyses, and they were found to be robust. Future work is needed to fully understand the relationship between sCVD, CVD, and cognitive impairment.
Stream temperature is an important determinant of fish growth, migration, and survival and can thus impact the structure and function of stream ecosystems. Many streams in Michigan and elsewhere in ...North America receive groundwater inputs that help regulate instream conditions by stabilizing discharge as well as stream temperature. However, groundwater withdrawal can cause reductions in streamflow which typically results in increased summer stream temperatures. Other atmospheric and hydrologic variables (i.e., overland discharge) also impact the rate at which stream temperature changes as it flows downstream. We deployed paired up‐ and downstream water pressure and temperature loggers within 21 stream reaches throughout the state of Michigan to quantify and model relationships between stream discharge, air temperature, and longitudinal change in stream temperature (i.e., temperature gradient). Using multimodel selection criteria, we evaluated the performance of a hierarchical suite of models that predict temperature gradient as a function of potential driving variables. The multimodel selection criteria identified a best‐fitting model that was able to model the diurnal, seasonal, and annual variations in rates of longitudinal temperature fluctuations across most sample streams. Partial regression analysis indicated that proxy variables representing solar radiation at the stream surface were generally the most influential predictors of longitudinal changes in stream temperature, but air temperature and components of streamflow including groundwater input were significant predictors and important in many streams.
Fungal mycelium is increasingly recognized as a central component of soil biogeochemical cycling, yet our current understanding of the ecological controls on fungal necromass decomposition is limited ...to single sites and vegetation types.
By deploying common fungal necromass substrates in a temperate oak savanna and hardwood forest in the midwestern USA, we assessed the generality of the rate at which high‐ and low‐quality fungal necromass decomposes; further, we investigated how the decomposer ‘necrobiome’ varies both across and within sites under vegetation types dominated by either arbuscular or ectomycorrhizal plants.
The effects of necromass quality on decay rate were robust to site and vegetation type differences, with high‐quality fungal necromass decomposing, on average, 2.5 times faster during the initial stages of decay. Across vegetation types, bacterial and fungal communities present on decaying necromass differed from bulk soil microbial communities and were influenced by necromass quality. Moulds, yeasts and copiotrophic bacteria consistently dominated the necrobiome of high‐quality fungal substrates.
Synthesis. We show that regardless of differences in decay environments, high‐quality fungal substrates decompose faster and support different types of decomposer micro‐organisms when compared with low‐quality fungal tissues. These findings help to refine our theoretical understanding of the dominant factors affecting fast cycling components of soil organic matter and the microbial communities associated with rapid decay.
The effects of necromass quality on decay rate were robust to site and vegetation type differences, with high‐quality fungal necromass decomposing, on average, 2.5 times faster during the initial stages of decay. Across vegetation types, bacterial and fungal communities present on decaying necromass were influenced by necromass quality. Moulds, yeasts and copiotrophic bacteria consistently dominated the necrobiome of high quality fungal substrates.
Renal T cells contribute importantly to hypertension, but the underlying mechanism is incompletely understood. We reported that CD8Ts directly stimulate distal convoluted tubule cells (DCTs) to ...increase NCC (sodium chloride co-transporter) expression and salt reabsorption. However, the mechanistic basis of this pathogenic pathway that promotes hypertension remains to be elucidated.
We used mouse models of DOCA+salt (DOCA) treatment and adoptive transfer of CD8
T cells (CD8T) from hypertensive animals to normotensive animals in in vivo studies. Co-culture of mouse DCTs and CD8Ts was used as in vitro model to test the effect of CD8T activation in promoting NCC-mediated sodium retention and to identify critical molecular players contributing to the CD8T-DCT interaction. Interferon (IFNγ)-KO mice and mice receiving renal tubule-specific knockdown of PDL1 were used to verify in vitro findings. Blood pressure was continuously monitored via radio-biotelemetry, and kidney samples were saved at experimental end points for analysis.
We identified critical molecular players and demonstrated their roles in augmenting the CD8T-DCT interaction leading to salt-sensitive hypertension. We found that activated CD8Ts exhibit enhanced interaction with DCTs via IFN-γ-induced upregulation of MHC-I and PDL1 in DCTs, thereby stimulating higher expression of NCC in DCTs to cause excessive salt retention and progressive elevation of blood pressure. Eliminating IFN-γ or renal tubule-specific knockdown of PDL1 prevented T cell homing into the kidney, thereby attenuating hypertension in 2 different mouse models.
Our results identified the role of activated CD8Ts in contributing to increased sodium retention in DCTS through the IFNγ-PDL1 pathway. These findings provide a new mechanism for T cell involvement in the pathogenesis of hypertension and reveal novel therapeutic targets.
Abstract
Objectives
Studies investigating the effectiveness of intervention programs on cognitive ability in older adults are inconsistent; however, these studies generally focus on traditional ...measures of cognition, and therefore may miss some improvements by not utilizing alternate measures. We evaluate the potential for intraindividual variability in cognitive speed (IIV), a demonstrated sensitive indicator of cognitive functioning, to be used as an index of cognitive plasticity from an intervention. The current study evaluated whether older adults in a school volunteering program showed a reduction in IIV, compared to a low-activity control group over 2 years of exposure.
Method
Nondemented older adults (n = 336) participated in the Baltimore Experience Corps Trial, an evaluation of a volunteering program conducted at elementary schools designed to increase older adults’ physical, cognitive, and social engagement. Participants completed a cognitive battery that included a Stroop task at baseline and after 12 and 24 months.
Results
Traditional intent-to-treat analyses did not report significant improvements. Participants who complied at the 80th percentile or above showed a significant reduction in IIV at 24 months, with an additional trend of improved IIV with increased compliance to the treatment protocol, both at 12 months, and at 24 months. Men also showed dose-dependent improvements after 12 months.
Discussion
The Experience Corps program resulted in an improvement in cognitive performance as measured by IIV. Analyzing previously collected data with nontraditional measures of cognition, such as IIV, may be a potentially fruitful and cost-effective method for understanding how interventions impact cognition in aging populations.
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