A longitudinal examination of plasma neurofilament light and total tau for the clinical detection and monitoring of Alzheimer's disease

We examined baseline and longitudinal associations between plasma neurofilament light (NfL) and total tau (t-tau), and the clinical presentation of Alzheimer's disease (AD). A total of 579 participants (238, normal cognition [NC]; 185, mild cognitive impairment [MCI]; 156, AD dementia) had baseline blood draws; 82% had follow-up evaluations. Plasma samples were analyzed for NfL and t-tau using Simoa technology. Baseline plasma NfL was higher in AD dementia than MCI (standardized mean difference = 0.55, 95% CI: 0.37–0.73) and NC (standardized mean difference = 0.68, 95% CI: 0.49–0.88), corresponded to Clinical Dementia Rating scores (OR = 1.94, 95% CI: 1.35–2.79]), and correlated with all neuropsychological tests (r's = 0.13–0.42). Longitudinally, NfL did not predict diagnostic conversion but predicted decline on 3/10 neuropsychological tests. Baseline plasma t-tau was higher in AD dementia than NC with a small effect (standardized mean difference = 0.33, 95% CI: 0.10–0.57) but not MCI. t-tau did not statistically significant predict any longitudinal outcomes. Plasma NfL may be useful for the detection of AD dementia and monitoring of disease progression. In contrast, there was minimal evidence in support of plasma t-tau

Human bipedal instability in tree canopy environments is reduced by “light touch” fingertip support

Whether tree canopy habitats played a sustained role in the ecology of ancestral bipedal hominins is unresolved. Some argue that arboreal bipedalism was prohibitively risky for hominins whose increasingly modern anatomy prevented them from gripping branches with their feet. Balancing on two legs is indeed challenging for humans under optimal conditions let alone in forest canopy, which is physically and visually highly dynamic. Here we quantify the impact of forest canopy characteristics on postural stability in humans. Viewing a movie of swaying branches while standing on a branch-like bouncy springboard destabilised the participants as much as wearing a blindfold. However “light touch”, a sensorimotor feedback strategy based on light fingertip support, significantly enhanced their balance and lowered their thigh muscle activity by up to 30%. This demonstrates how a light touch strategy could have been central to our ancestor’s ability to avoid falls and reduce the mechanical and metabolic cost of arboreal feeding and movement. Our results may also indicate that some adaptations in the hand that facilitated continued access to forest canopy may have complemented, rather than opposed, adaptations that facilitated precise manipulation and tool use

Urban and Transport Scaling: Northern Mesopotamia in the Late Chalcolithic and Bronze Age

Scaling methods have been applied to study modern urban areas and how they create accelerated, feedback growth in some systems while efficient use in others. For ancient cities, results have shown that cities act as social reactors that lead to positive feedback growth in socioeconomic measures. In this paper, we assess the relationship between settlement area expressed through mound area from Late Chalcolithic and Bronze Age sites and mean hollow way widths, which are remains of roadways, from the Khabur Triangle in northern Mesopotamia. The intent is to demonstrate the type of scaling and relationship present between sites and hollow ways, where both feature types are relatively well preserved. For modern roadway systems, efficiency in growth relative to population growth suggests roads should show sublinear scaling in relation to site size. In fact, similar to modern systems, such sublinear scaling results are demonstrated for the Khabur Triangle using available data, suggesting ancient efficiency in intensive transport growth relative to population levels. Comparable results are also achieved in other ancient Near East regions. Furthermore, results suggest that there could be a general pattern relevant for some small sites (0–2 ha) and those that have fewer hollow ways, where β, a measure of scaling, is on average low (≈ < 0.2). On the other hand, a second type of result for sites with many hollow ways (11 or more) and that are often larger suggests that β is greater (0.23–0.72), but still sublinear. This result could reflect the scale in which larger settlements acted as greater social attractors or had more intensive economic activity relative to smaller sites. The provided models also allow estimations of past roadway widths in regions where hollow ways are missing

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Modeling and simulation of the endogenous CYP3A induction marker 4&beta;-hydroxycholesterol during enasidenib treatment

Yan Li,1 Jamie N Connarn,1 Jian Chen,2 Zeen Tong,2 Maria Palmisano,1 Simon Zhou1 1Translational Development and Clinical Pharmacology, Celgene Corporation, Summit, NJ, USA; 2Non-Clinical Development, Celgene Corporation, Summit, NJ, USA Background: Enasidenib (IDHIFA&reg;, AG-221) is a first-in-class, targeted inhibitor of mutant IDH2 proteins for treatment of relapsed or refractory acute myeloid leukemia. This was a Phase I/II study evaluating safety, efficacy, and pharmacokinetics/pharmacodynamics (PK/PD) of orally administered enasidenib in subjects with advanced hematologic malignancies with an IDH2 mutation. Methods: Blood samples for PK and PD assessment were collected. A semi-mechanistic non-linear mixed effect PK/PD model was successfully developed to characterize enasidenib plasma PK and to assess enasidenib-induced CYP3A activity. Results: The PK model showed that enasidenib plasma concentrations were adequately described by a one-compartment model with first-order absorption and elimination; the PD model showed a high capacity to induce CYP3A (Emax=7.36) and a high enasidenib plasma concentration to produce half of maximum CYP3A induction (EC50 =31,400 ng/mL). Monte Carlo simulations based on the final PK/PD model showed that at 100 mg once daily dose there was significant drug accumulation and a maximum of three-fold CYP3A induction after multiple doses. Although the EC50 value for CYP3A induction by enasidenib is high, CYP3A induction was observed due to significant drug accumulation. Conclusion: CYP3A induction following enasidenib dosing should be considered when prescribing concomitant medication metabolized via this pathway. Keywords: enasidenib, modeling and simulation, CYP3A induction, 4&beta;-hydroxycholestero

Plasma p-tau(181) shows stronger network association to Alzheimer's disease dementia than neurofilament light and total tau

Introduction: We examined the ability of plasma hyperphosphorylated tau (p-tau)181 to detect cognitive impairment due to Alzheimer's disease (AD) independently and in combination with plasma total tau (t-tau) and neurofilament light (NfL). Methods: Plasma samples were analyzed using the Simoa platform for 235 participants with normal cognition (NC), 181 with mild cognitive impairment due to AD (MCI), and 153 with AD dementia. Statistical approaches included multinomial regression and Gaussian graphical models (GGMs) to assess a network of plasma biomarkers, neuropsychological tests, and demographic variables. Results: Plasma p-tau181 discriminated AD dementia from NC, but not MCI, and correlated with dementia severity and worse neuropsychological test performance. Plasma NfL similarly discriminated diagnostic groups. Unlike plasma NfL or t-tau, p-tau181 had a direct association with cognitive diagnosis in a bootstrapped GGM. Discussion: These results support plasma p-tau181 for the detection of AD dementia and the use of blood-based biomarkers for optimal disease detection