In vivo Detection of Alzheimer's Disease

Recent revisions to the diagnostic criteria for Alzheimer’s disease (AD) incorporated conceptual advances in the field. Specifically, AD is now recognized to encompass a continuum, spanning from preclinical (accruing brain pathology in the absence of symptoms) through symptomatic predementia (prodromal AD, mild cognitive impairment) and dementia phases. The role of biological markers (biomarkers) of both the underlying molecular pathologies and related neurodegenerative changes has also been acknowledged. In this abridged review, we provide an overview of fluid (cerebrospinal fluid and blood) and molecular imaging-based biomarkers used within the field and discuss the potential role of computer driven artificial intelligence approaches for both the early and accurate identification of AD and as a tool for population enrichment in clinical trials testing candidate disease modifying therapies

Positive Semidefiniteness and Positive Definiteness of a Linear Parametric Interval Matrix

We consider a symmetric matrix, the entries of which depend linearly on some parameters. The domains of the parameters are compact real intervals. We investigate the problem of checking whether for each (or some) setting of the parameters, the matrix is positive definite (or positive semidefinite). We state a characterization in the form of equivalent conditions, and also propose some computationally cheap sufficient\,/\,necessary conditions. Our results extend the classical results on positive (semi-)definiteness of interval matrices. They may be useful for checking convexity or non-convexity in global optimization methods based on branch and bound framework and using interval techniques

Synaptic vesicle protein 2A as a potential biomarker in synaptopathies

Measuring synaptic density in vivo using positron emission tomography (PET) imaging-based biomarkers targeting the synaptic vesicle protein 2A (SV2A) has received much attention recently due to its potential research and clinical applications in synaptopathies, including neurodegenerative and psychiatric diseases. Fluid-based biomarkers in proteinopathies have previously been suggested to provide information on pathology and disease status that is complementary to PET-based measures, and the same can be hypothesized with respect to SV2A. This review provides an overview of the current state of SV2A PET imaging as a biomarker of synaptic density, the potential role of fluid-based biomarkers for SV2A, and related future perspectives

Differences Between Plasma and Cerebrospinal Fluid Glial Fibrillary Acidic Protein Levels Across the Alzheimer Disease Continuum

Importance: Glial fibrillary acidic protein (GFAP) is a marker of reactive astrogliosis that increases in the cerebrospinal fluid (CSF) and blood of individuals with Alzheimer disease (AD). However, it is not known whether there are differences in blood GFAP levels across the entire AD continuum and whether its performance is similar to that of CSF GFAP. Objective: To evaluate plasma GFAP levels throughout the entire AD continuum, from preclinical AD to AD dementia, compared with CSF GFAP. Design, Setting, and Participants: This observational, cross-sectional study collected data from July 29, 2014, to January 31, 2020, from 3 centers. The Translational Biomarkers in Aging and Dementia (TRIAD) cohort (Montreal, Canada) included individuals in the entire AD continuum. Results were confirmed in the Alzheimer's and Families (ALFA+) study (Barcelona, Spain), which included individuals with preclinical AD, and the BioCogBank Paris Lariboisière cohort (Paris, France), which included individuals with symptomatic AD. Main Outcomes and Measures: Plasma and CSF GFAP levels measured with a Simoa assay were the main outcome. Other measurements included levels of CSF amyloid-β 42/40 (Aβ42/40), phosphorylated tau181 (p-tau181), neurofilament light (NfL), Chitinase-3-like protein 1 (YKL40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) and levels of plasma p-tau181 and NfL. Results of amyloid positron emission tomography (PET) were available in TRIAD and ALFA+, and results of tau PET were available in TRIAD. Results: A total of 300 TRIAD participants (177 women [59.0%]; mean [SD] age, 64.6 [17.6] years), 384 ALFA+ participants (234 women [60.9%]; mean [SD] age, 61.1 [4.7] years), and 187 BioCogBank Paris Lariboisière participants (116 women [62.0%]; mean [SD] age, 69.9 [9.2] years) were included. Plasma GFAP levels were significantly higher in individuals with preclinical AD in comparison with cognitively unimpaired (CU) Aβ-negative individuals (TRIAD: Aβ-negative mean [SD], 185.1 [93.5] pg/mL, Aβ-positive mean [SD], 285.0 [142.6] pg/mL; ALFA+: Aβ-negative mean [SD], 121.9 [42.4] pg/mL, Aβ-positive mean [SD], 169.9 [78.5] pg/mL). Plasma GFAP levels were also higher among individuals in symptomatic stages of the AD continuum (TRIAD: CU Aβ-positive mean [SD], 285.0 [142.6] pg/mL, mild cognitive impairment [MCI] Aβ-positive mean [SD], 332.5 [153.6] pg/mL; AD mean [SD], 388.1 [152.8] pg/mL vs CU Aβ-negative mean [SD], 185.1 [93.5] pg/mL; Paris: MCI Aβ-positive, mean [SD], 368.6 [158.5] pg/mL; AD dementia, mean [SD], 376.4 [179.6] pg/mL vs CU Aβ-negative mean [SD], 161.2 [67.1] pg/mL). Plasma GFAP magnitude changes were consistently higher than those of CSF GFAP. Plasma GFAP more accurately discriminated Aβ-positive from Aβ-negative individuals than CSF GFAP (area under the curve for plasma GFAP, 0.69-0.86; area under the curve for CSF GFAP, 0.59-0.76). Moreover, plasma GFAP levels were positively associated with tau pathology only among individuals with concomitant Aβ pathology. Conclusions and Relevance: This study suggests that plasma GFAP is a sensitive biomarker for detecting and tracking reactive astrogliosis and Aβ pathology even among individuals in the early stages of AD.

APOEε4 associates with microglial activation independently of Aβ plaques and tau tangles

Animal studies suggest that the apolipoprotein E ε4 (APOEε4) allele is a culprit of early microglial activation in Alzheimer's disease (AD). Here, we tested the association between APOEε4 status and microglial activation in living individuals across the aging and AD spectrum. We studied 118 individuals with positron emission tomography for amyloid-β (Aβ; [18F]AZD4694), tau ([18F]MK6240), and microglial activation ([11C]PBR28). We found that APOEε4 carriers presented increased microglial activation relative to noncarriers in early Braak stage regions within the medial temporal cortex accounting for Aβ and tau deposition. Furthermore, microglial activation mediated the Aβ-independent effects of APOEε4 on tau accumulation, which was further associated with neurodegeneration and clinical impairment. The physiological distribution of APOE mRNA expression predicted the patterns of APOEε4-related microglial activation in our population, suggesting that APOE gene expression may regulate the local vulnerability to neuroinflammation. Our results support that the APOEε4 genotype exerts Aβ-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition

Modeling Susceptibility versus Resistance in Allergic Airway Disease Reveals Regulation by Tec Kinase Itk

Murine models of allergic asthma have been used to understand the mechanisms of development and pathology in this disease. In addition, knockout mice have contributed significantly to our understanding of the roles of specific molecules and cytokines in these models. However, results can vary significantly depending on the mouse strain used in the model, and in particularly in understanding the effect of specific knockouts. For example, it can be equivocal as to whether specific gene knockouts affect the susceptibility of the mice to developing the disease, or lead to resistance. Here we used a house dust mite model of allergic airway inflammation to examine the response of two strains of mice (C57BL/6 and BALB/c) which differ in their responses in allergic airway inflammation. We demonstrate an algorithm that can facilitate the understanding of the behavior of these models with regards to susceptibility (to allergic airway inflammation) (Saai) or resistance (Raai) in this model. We verify that both C57BL/6 and BALB/c develop disease, but BALB/c mice have higher Saai for development. We then use this approach to show that the absence of the Tec family kinase Itk, which regulates the production of Th2 cytokines, leads to Raai in the C57BL/6 background, but decreases Saai on the BALB/c background. We suggest that the use of such approaches could clarify the behavior of various knockout mice in modeling allergic asthma

Oxygen-sensing neurons reciprocally regulate peripheral lipid metabolism via neuropeptide signaling in <i>Caenorhabditis elegans</i>

<div><p>The mechanisms by which the sensory environment influences metabolic homeostasis remains poorly understood. In this report, we show that oxygen, a potent environmental signal, is an important regulator of whole body lipid metabolism. <i>C</i>. <i>elegans</i> oxygen-sensing neurons reciprocally regulate peripheral lipid metabolism under normoxia in the following way: under high oxygen and food absence, URX sensory neurons are activated, and stimulate fat loss in the intestine, the major metabolic organ for <i>C</i>. <i>elegans</i>. Under lower oxygen conditions or when food is present, the BAG sensory neurons respond by repressing the resting properties of the URX neurons. A genetic screen to identify modulators of this effect led to the identification of a BAG-neuron-specific neuropeptide called FLP-17, whose cognate receptor EGL-6 functions in URX neurons. Thus, BAG sensory neurons counterbalance the metabolic effect of tonically active URX neurons via neuropeptide communication. The combined regulatory actions of these neurons serve to precisely tune the rate and extent of fat loss to the availability of food and oxygen, and provides an interesting example of the myriad mechanisms underlying homeostatic control.</p></div

Comparison of pain, cortisol levels, and psychological distress in women undergoing surgical termination of pregnancy under local anaesthesia versus intravenous sedation

<p>Abstract</p> <p>Background</p> <p>The weight of evidence suggests that women who freely choose to terminate a pregnancy are unlikely to experience significant mental health risks, however some studies have documented psychological distress in the form of posttraumatic stress disorder and depression in the aftermath of termination. Choice of anaesthetic has been suggested as a determinant of outcome. This study compared the effects of local anaesthesia and intravenous sedation, administered for elective surgical termination, on outcomes of pain, cortisol, and psychological distress.</p> <p>Methods</p> <p>155 women were recruited from a private abortion clinic and state hospital (mean age: 25.4 ± 6.1 years) and assessed on various symptom domains, using both clinician-administered interviews and self-report measures just prior to termination, immediately post-procedure, and at 1 month and 3 months post-procedure. Morning salivary cortisol assays were collected prior to anaesthesia and termination.</p> <p>Results</p> <p>The group who received local anaesthetic demonstrated higher baseline cortisol levels (mean = 4.7 vs 0.2), more dissociative symptoms immediately post-termination (mean = 14.7 vs 7.3), and higher levels of pain before (mean = 4.9 vs 3.0) and during the procedure (mean = 8.0 vs 4.4). However, in the longer-term (1 and 3 months), there were no significant differences in pain, psychological outcomes (PTSD, depression, self-esteem, state anxiety), or disability between the groups. More than 65% of the variance in PTSD symptoms at 3 months could be explained by baseline PTSD symptom severity and disability, and post-termination dissociative symptoms. Of interest was the finding that pre-procedural cortisol levels were positively correlated with PTSD symptoms at both 1 and 3 months.</p> <p>Conclusion</p> <p>High rates of PTSD characterise women who have undergone surgical abortions (almost one fifth of the sample meet criteria for PTSD), with women who receive local anaesthetic experiencing more severe acute reactions. The choice of anesthetic, however, does not appear to impact on longer-term psychiatric outcomes or functional status.</p

Regulators of AWC-Mediated Olfactory Plasticity in Caenorhabditis elegans

While most sensory neurons will adapt to prolonged stimulation by down-regulating their responsiveness to the signal, it is not clear which events initiate long-lasting sensory adaptation. Likewise, we are just beginning to understand how the physiology of the adapted cell is altered. Caenorhabditis elegans is inherently attracted to specific odors that are sensed by the paired AWC olfactory sensory neurons. The attraction diminishes if the animal experiences these odors for a prolonged period of time in the absence of food. The AWC neuron responds acutely to odor-exposure by closing calcium channels. While odortaxis requires a Gα subunit protein, cGMP-gated channels, and guanylyl cyclases, adaptation to prolonged odor exposure requires nuclear entry of the cGMP-dependent protein kinase, EGL-4. We asked which candidate members of the olfactory signal transduction pathway promote nuclear entry of EGL-4 and which molecules might induce long-term adaptation downstream of EGL-4 nuclear entry. We found that initiation of long-term adaptation, as assessed by nuclear entry of EGL-4, is dependent on G-protein mediated signaling but is independent of fluxes in calcium levels. We show that long-term adaptation requires polyunsaturated fatty acids (PUFAs) that may act on the transient receptor potential (TRP) channel type V OSM-9 downstream of EGL-4 nuclear entry. We also present evidence that high diacylglycerol (DAG) levels block long-term adaptation without affecting EGL-4 nuclear entry. Our analysis provides a model for the process of long-term adaptation that occurs within the AWC neuron of C. elegans: G-protein signaling initiates long-lasting olfactory adaptation by promoting the nuclear entry of EGL-4, and once EGL-4 has entered the nucleus, processes such as PUFA activation of the TRP channel OSM-9 may dampen the output of the AWC neuron