CSF sTREM2: Marking the tipping point between preclinical AD and dementia?

Biomarkers for Alzheimer's disease (AD) have improved our understanding of the temporal sequence of biological events that lead to AD dementia (Jack et al, 2013). AD is characterized neuropathologically by amyloid plaques comprised of the amyloid‐β peptide and neurofibrillary tangles comprised of tau. Brain amyloid deposition, as evidenced by a decline in amyloid‐β peptide 42 (Aβ42) in the cerebrospinal fluid (CSF) or by binding of amyloid PET ligands, is thought to be a key initiating event in AD and begins many years prior to the onset of dementia. A rise in CSF tau and phosphorylated tau in the setting of Aβ deposition appears to reflect neurodegeneration and also begins years prior to the onset of dementia but after Aβ deposition has begun to accumulate. Individuals with “preclinical AD,” that is, normal cognition but abnormal AD biomarkers, have a much higher risk for developing AD dementia but may remain cognitively normal for years (Vos et al, 2013). While deposition of amyloid and formation of tau tangles are necessary for AD to occur, it is likely that additional events involving inflammation or other processes contribute to crossing the tipping point from preclinical AD to AD dementia. Current efforts are aimed at defining the biomarker(s) that best predict the transition from cognitive normality to abnormality. A biomarker that is closely associated with the onset of cognitive decline could help us to understand the biological events that connect amyloid deposition and tangle formation to cognitive decline and could have significant practical value in AD diagnosis and clinical trial design

Changes in insulin and insulin signaling in Alzheimer\u27s disease: Cause or consequence?

Individuals with type 2 diabetes have an increased risk for developing Alzheimer’s disease (AD), although the causal relationship remains poorly understood. Alterations in insulin signaling (IS) are reported in the AD brain. Moreover, oligomers/fibrils of amyloid-β (Aβ) can lead to neuronal insulin resistance and intranasal insulin is being explored as a potential therapy for AD. Conversely, elevated insulin levels (ins) are found in AD patients and high insulin has been reported to increase Aβ levels and tau phosphorylation, which could exacerbate AD pathology. Herein, we explore whether changes in ins and IS are a cause or consequence of AD

Controlled cortical impact traumatic brain injury in 3xTg-AD mice causes acute intra-axonal amyloid-β accumulation and independently accelerates the development of tau abnormalities

Alzheimer\u27s disease (AD) is a neurodegenerative disorder characterized pathologically by progressive neuronal loss, extracellular plaques containing the amyloid-β (Aβ) peptides, and neurofibrillary tangles composed of hyperphosphorylated tau proteins. Aβ is thought to act upstream of tau, affecting its phosphorylation and therefore aggregation state. One of the major risk factors for AD is traumatic brain injury (TBI). Acute intra-axonal Aβ and diffuse extracellular plaques occur in ∼30% of human subjects after severe TBI. Intra-axonal accumulations of tau but not tangle-like pathologies have also been found in these patients. Whether and how these acute accumulations contribute to subsequent AD development is not known, and the interaction between Aβ and tau in the setting of TBI has not been investigated. Here, we report that controlled cortical impact TBI in 3xTg-AD mice resulted in intra-axonal Aβ accumulations and increased phospho-tau immunoreactivity at 24 h and up to 7 d after TBI. Given these findings, we investigated the relationship between Aβ and tau pathologies after trauma in this model by systemic treatment of Compound E to inhibit γ-secretase activity, a proteolytic process required for Aβ production. Compound E treatment successfully blocked posttraumatic Aβ accumulation in these injured mice at both time points. However, tau pathology was not affected. Our data support a causal role for TBI in acceleration of AD-related pathologies and suggest that TBI may independently affect Aβ and tau abnormalities. Future studies will be required to assess the behavioral and long-term neurodegenerative consequences of these pathologies

The Bulge-Halo Connection in Galaxies: A Physical Interpretation of the Vcirc-sigma_0 Relation

We explore the dependence of the ratio of a galaxy's circular velocity, Vcirc, to its central velocity dispersion, sigma_0, on morphology, or equivalently total light concentration. Such a dependence is expected if light traces the mass. Over the full range of galaxy types, masses and brightnesses, and assuming that the gas velocity traces the circular velocity, we find that galaxies obey the relation log(Vcirc/sigma_0)= 0.63-0.11*C28 where C28=5log(r80/r20) and the radii are measured at 80 percent and 20 percent of the total light. Massive galaxies scatter about the Vcirc = sqrt(2)*sigma_0 line for isothermal stellar systems. Disk galaxies follow the simple relation Vcirc/sigma_0=2(1-B/T), where B/T is the bulge-to-total light ratio. For pure disks, C28~2.8, B/T -> 0, and Vcirc~=2*sigma_0. Self-consistent equilibrium galaxy models from Widrow & Dubinski (2005) constrained to match the size-luminosity and velocity-luminosity relations of disk galaxies fail to match the observed Vcirc/sigma_0 distribution. Furthermore, the matching of dynamical models for Vcirc(r)/sigma(r) with observations of dwarf and elliptical galaxies suffers from limited radial coverage and relatively large error bars; for dwarf systems, however, kinematical measurements at the galaxy center and optical edge suggest Vcirc(Rmax) > 2*sigma_0 (in contrast with past assumptions that Vcirc = sqrt(2)*sigma_0 for dwarfs.) The Vcirc-sigma_0-C28 relation has direct implications for galaxy formation and dynamical models, galaxy scaling relations, the mass function of galaxies, and the links between respective formation and evolution processes for a galaxy's central massive object, bulge, and dark matter halo.Comment: Accepted for publication in ApJL. Current version matches ApJL page requiremen

The Efficacy of Supportive Services in the Early Stages of Outpatient Methadone Maintenance Treatment

Background Over the past 25 years, the United States has experienced an opioid epidemic that has cost hundreds of thousands of lives and which now constitutes as the worst drug overdose epidemic in U.S. history. Increases in opioid use and abuse have been found among men and women, most age groups, and all income levels (CDC, 2017). Methadone Maintenance Treatment (MMT) is one the most effective forms of treatment for opioid addiction, and has been found to reduce substance use, the risk of HIV, overdose, and criminal behaviors (Joseph et al., 2000; Mattick, Breen, Kimber, & Davoli, 2009). Both clinical experience and research show that MMT programs suffer from low retention and patient engagement in treatment and that patients are particularly vulnerable to disengagement or withdrawal during the early stages of treatment (Baxter et al., 2013). To address this problem, Thomas Jefferson University Hospital Narcotic Addiction Rehabilitation Program (TJUH NARP) utilized funds from Governor Wolf’s administration to implement a program entitled the Center of Excellence (COE) to provide patients with increased support during the early stages of treatment. This support occurred in the form of one-on-one support from a Certified Recovery Specialist (CRS) who provided counselling, case management, and care coordination. As MMT treatment providers develop new programs such as the COE to address the problem of patient engagement and retention, it is critical that researchers assess their efficacy. In light of this, this dissertation has two specific aims. First, to examine the efficacy of COE program in improving patient retention, engagement in treatment, and opioid use. Second, to identify predictors of outcome within and across the conditions. Methods A case comparison study was conducted in which a control (N=57) and a treatment group (N=57) were compared regarding patient attendance, engagement, and opioid use. The control group consisted of a group admitted a year prior to the implementation of the COE while the treatment group received the supportive services of the COE. Data was collected from clinical documentation in the TJUH database. A convenience sample was used that consisted of all patients admitted during a specific time frame and who met criteria. Patient outcomes were analyzed through T-tests and chi-squared tests. Findings Patients within the treatment group had lower opioid use in months 1-3 (P=.02). This group also experienced lower attendance during month 1 (P=.04), month 2 (P=.05), month 3 (P=.02), and month 4 (P=.03). No other significant differences were found between groups regarding patient retention, engagement, or opioid use. However, while not significant, the treatment group had trends towards higher average medication doses (P=.13) and IOP attendance (P=.12). When outcomes were analyzed across conditions, patient admitted via transfer were found to have higher methadone doses on average when compared to patients admitted via self-referral (P=.01). Discussion The finding of reduced opioid use among the treatment group in months 1-3, as well as trends towards higher dosing and treatment attendance, suggests that the COE met with success in improving patient outcomes. At the same time, the lack of significant findings regarding patient attendance and engagement, as well as the treatment group’s lower attendance during months 1-4, suggests that the COE program implemented at TJUH NARP may not be entirely successful in meeting its goals. The significance of referral method challenges the efficacy of self-referral routes of entry into outpatient MMT. While further research is needed, these findings suggest that patients may benefit from inpatient stabilization prior to admittance into outpatient MMT

Altered sleep and EEG power in the P301S Tau transgenic mouse model

OBJECTIVE: Sleep disturbances are prevalent in human tauopathies yet despite the importance of sleep, little is known about its relationship with tau pathology. Here, we investigate this interaction by analyzing sleep and tau pathology throughout tauopathy disease progression in P301S human tau transgenic mice. METHODS: P301S and wild‐type mice were analyzed by electroencephalography (EEG)/electromyography at 3, 6, 9, and 11 months of age for sleep/wake time, EEG power, and homeostatic response. Cortical volume and tau pathology was also assessed by anti‐phospho‐tau AT8 staining. RESULTS: P301S tau mice had significantly decreased rapid eye movement (REM) sleep at 9 months of age and decreased REM and non‐REM (NREM) sleep as well as increased wakefulness at 11 months. Sleep loss was characterized by fewer wake, REM, and NREM bouts, increased wake bout duration, and decreased sleep bout duration. Decreased REM and NREM sleep was associated with increased brainstem tau pathology in the sublaterodorsal area and parafacial zone, respectively. P301S mice also showed increased EEG power at 6 and 9 months of age and decreased power at 11 months. Decreased EEG power was associated with decreased cortical volume. Despite sleep disturbances, P301S mice maintained homeostatic response to sleep deprivation. INTERPRETATION: Our results indicate that tau pathology is associated with sleep disturbances that worsen with age and these changes may be related to tau pathology in brainstem sleep regulating regions as well as neurodegeneration. Tau‐induced sleep changes could affect disease progression and be a marker for therapeutic efficacy in this and other tauopathy models

APOE mediated neuroinflammation and neurodegeneration in Alzheimer\u27s disease

Neuroinflammation is a central mechanism involved in neurodegeneration as observed in Alzheimer\u27s disease (AD), the most prevalent form of neurodegenerative disease. Apolipoprotein E4 (APOE4), the strongest genetic risk factor for AD, directly influences disease onset and progression by interacting with the major pathological hallmarks of AD including amyloid-β plaques, neurofibrillary tau tangles, as well as neuroinflammation. Microglia and astrocytes, the two major immune cells in the brain, exist in an immune-vigilant state providing immunological defense as well as housekeeping functions that promote neuronal well-being. It is becoming increasingly evident that under disease conditions, these immune cells become progressively dysfunctional in regulating metabolic and immunoregulatory pathways, thereby promoting chronic inflammation-induced neurodegeneration. Here, we review and discuss how APOE and specifically APOE4 directly influences amyloid-β and tau pathology, and disrupts microglial as well as astroglial immunomodulating functions leading to chronic inflammation that contributes to neurodegeneration in AD