Alzheimer's Disease R&D Review
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Structural tract alterations predict downstream tau accumulation in amyloid-positive older individuals

Structural tract alterations predict downstream tau accumulation in amyloid-positive older individuals | Alzheimer's Disease R&D Review | Scoop.it

Our results provide in vivo evidence that higher amyloid pathology strengthens the association between HCB diffusivity and tau accumulation in the downstream posterior cingulate cortex and facilitates memory decline. This confirms amyloid’s crucial role in potentiating neural vulnerability and memory decline marking the onset of preclinical Alzheimer’s disease.

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Alzheimer's Disease R&D Review
A review of the Solanezumab (Lilly), Gantenerumab (Roche) the 2  beta amyloid monoclonal antibodies  in Phase III trials and other potential targets is provided. The failure of Bapineuzumab in Phase III trials in 2012 puta question mark on the validity of beta amyloid hypothesis. Bapineuzumab is a fully humanized monoclonal antibody which targets beta amyloid protein involved in Alzheimer's Disease. There are 26 million patients in the world, half in Asia and the rest in N America/Europe with AD.
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Created public version #237 of the knol: "Bapineuzumab (Pfizer, J&J, Elan) Review"

Created public version #237 of the knol: "Bapineuzumab (Pfizer, J&J, Elan) Review" | Alzheimer's Disease R&D Review | Scoop.it
Krishan Maggon published version 237 of a knol titled: "Bapineuzumab (Pfizer, J&J, Elan) Review"...
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Scientists find stem cell proliferation is controlled directly by nervous system

Scientists find stem cell proliferation is controlled directly by nervous system | Alzheimer's Disease R&D Review | Scoop.it
Somatic stem cells are microscopic workhorses, constantly regenerating cells throughout the body: skin and the lining of the intestine, for example. And to University of Illinois neuroscientists, they represent untapped potential.
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Clock-Generated Temporal Codes Determine Synaptic Plasticity to Control Sleep

Clock-Generated Temporal Codes Determine Synaptic Plasticity to Control Sleep | Alzheimer's Disease R&D Review | Scoop.it
Summary
Neurons use two main schemes to encode information: rate coding (frequency of firing) and temporal coding (timing or pattern of firing). While the importance of rate coding is well established, it remains controversial whether temporal codes alone are sufficient for controlling behavior. Moreover, the molecular mechanisms underlying the generation of specific temporal codes are enigmatic. Here, we show in Drosophila clock neurons that distinct temporal spike patterns, dissociated from changes in firing rate, encode time-dependent arousal and regulate sleep. From a large-scale genetic screen, we identify the molecular pathways mediating the circadian-dependent changes in ionic flux and spike morphology that rhythmically modulate spike timing. Remarkably, the daytime spiking pattern alone is sufficient to drive plasticity in downstream arousal neurons, leading to increased firing of these cells. These findings demonstrate a causal role for temporal coding in behavior and define a form of synaptic plasticity triggered solely by temporal spike patterns.
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PET staging of amyloidosis using striatum - ScienceDirect

PET staging of amyloidosis using striatum - ScienceDirect | Alzheimer's Disease R&D Review | Scoop.it
Abstract
Introduction
Amyloid positron emission tomography (PET) data are commonly expressed as binary measures of cortical deposition. However, not all individuals with high cortical amyloid will experience rapid cognitive decline. Motivated by postmortem data, we evaluated a three-stage PET classification: low cortical; high cortical, low striatal; and high cortical, high striatal amyloid; hypothesizing this model could better reflect Alzheimer's dementia progression than a model based only on cortical measures.

Methods
We classified PET data from 1433 participants (646 normal, 574 mild cognitive impairment, and 213 AD), explored the successive involvement of cortex and striatum using 3-year follow-up PET data, and evaluated the associations between PET stages, hippocampal volumes, and cognition.

Results
Follow-up data indicated that PET detects amyloid first in cortex and then in striatum. Our three-category staging including striatum better predicted hippocampal volumes and subsequent cognition than a three-category staging including only cortical amyloid.

Discussion
PET can evaluate amyloid expansion from cortex to subcortex. Using striatal signal as a marker of advanced amyloidosis may increase predictive power in Alzheimer's dementia research.

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Drug Duo Treats ALS – On A Chip

Drug Duo Treats ALS – On A Chip | Alzheimer's Disease R&D Review | Scoop.it
When a disease is as relentless as amyotrophic lateral sclerosis (ALS; aka Lou Gehrig's disease; aka motor neuron disease), any promising research result is welcome news. A study just published in Science Advances shows that two drugs already FDA-approved for other diseases, when teamed, halt...
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Absent forebrain replaced by embryonic stem cells

Absent forebrain replaced by embryonic stem cells | Alzheimer's Disease R&D Review | Scoop.it
A blastocyst complementation strategy for the brain.
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ALS - Amyotrophic Lateral Sclerosis

ALS - Amyotrophic Lateral Sclerosis | Alzheimer's Disease R&D Review | Scoop.it
Spread the loveSharing is caring!ShareTweetPin0sharesSharing is caring!ShareTweetPin0shares...
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Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease

Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease | Alzheimer's Disease R&D Review | Scoop.it
Prevention of dementia through moderation of risk factors presents a promising strategy to counter the rising dementia epidemic. In this Review, Kivipelto and colleagues discuss lifestyle-related risk factors for dementia, results from clinical trials of lifestyle interventions and new multinational initiatives that aim to identify and test effective dementia prevention strategies.
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Inflamed depression

Inflamed depression | Alzheimer's Disease R&D Review | Scoop.it
PERSPECTIVES|THE ART OF MEDICINE| VOLUME 392, ISSUE 10154, P1189-1190, OCTOBER 06, 2018 Inflamed depression Published:October 06, 2018DOI:https://doi.org/10.1016/S0140-6736(18)32356-0 Inflamed depression Can inflammation cause depression? I felt off-colour for a day or so after being vaccinated against typhoid. All of us, probably, have had similar mood blips after an infection or vaccination. Anecdotally, such experiences hint that inflammation might predict depressive symptoms: the inflammatory stimulus comes before the depressive response. But in the Cartesian dualist framework of western medicine, which puts mind and body poles apart, this idea that inflammation of the body might predict depression of the mind is disruptive and demands much more than anecdotal evidence if it is to be taken seriously. This article is available free of charge. Simply log in to access the full article, or register for free if you do not yet have a username and password. Already registered? Please log in. Forgot password? Not yet registered? Create a new account. Register for free Further reading Bullmore ET The inflamed mind. Short Books, London; 2018 Google Scholar Khandaker GM Pearson RM Zammit S Lewis G Jones PB Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study. JAMA Psychiatry. 2014; 71: 1121-1128 Tracey KJ The inflammatory reflex. Nature. 2002; 420: 853-859 Dantzer R O'Connor JC Freund GG Johnson RW Kelley KW From inflammation to sickness and depression: when the immune system subjugates the brain. Nature Rev Neurosci. 2008; 9: 46 Köhler O Benros ME Nordentoft M et al. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry. 2014; 71: 1381-1391 Husain MI Strawbridge R Stokes PRA Young AH Anti-inflammatory treatments for mood disorders: systematic review and meta-analysis. J Psychopharmacol. 2017; 31: 1137-1148 Raison CL Rutherford RE Wollwin BJ et al. A randomised controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory markers. JAMA Psychiatry. 2013; 70: 31-41 Chamberlain SR Cavanagh J de Boer P et al. Treatment-resistant depression and peripheral C-reactive protein. Br J Psychiatry. 2018; 16: 1-9 Crossref Google Scholar Kendler KS Karkowski LM Prescott CA Causal relationship between stressful life events and the onset of major depression. Am J Psychiatry. 1999; 56: 837-841 Weber MD Godbout JP Sheridan JF Repeated social defeat, neuroinflammation, and behavior: monocytes carry the signal. Neuropsychopharmacol. 2017; 42: 46 Danese A Moffitt TE Harrington H et al. Adverse childhood experiences and adult risk factors for age-related disease: depression, inflammation and clustering of metabolic risk markers. Arch Pediatr Adolesc Med. 2009; 163: 1135-1143 Wray NR Ripke S Mattheisen M et al. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nature Genetics. 2018; 50: 668 Klengel T Mehta D Anacker C et al. Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions. Nature Neurosci. 2013; 16: 33 Article Info Publication History Published: 06 October 2018 IDENTIFICATION DOI: 10.1016/S0140-6736(18)32356-0 Copyright © 2018 Elsevier Ltd. All rights reserved. ScienceDirect Access this article on ScienceDirect
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Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and amyloid beta production in wild type mice

Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and amyloid beta production in wild type mice | Alzheimer's Disease R&D Review | Scoop.it
Background The results from cross sectional and longitudinal studies show that periodontitis is closely associated with cognitive impairment (CI) and Alzhemer’s Disease (AD). Further, studies using animal model of periodontitis and human post-mortem brain tissues from subjects with AD strongly...
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Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing

Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing | Alzheimer's Disease R&D Review | Scoop.it
Neurodegenerative disorders of ageing (NDAs) such as Alzheimer disease, Parkinson disease, frontotemporal dementia, Huntington disease and amyotrophic lateral sclerosis represent a major socio-economic challenge in view of their high prevalence yet poor treatment. They are often called 'proteinopathies' owing to the presence of misfolded and aggregated proteins that lose their physiological roles and acquire neurotoxic properties. One reason underlying the accumulation and spread of oligomeric forms of neurotoxic proteins is insufficient clearance by the autophagic–lysosomal network. Several other clearance pathways are also compromised in NDAs: chaperone-mediated autophagy, the ubiquitin–proteasome system, extracellular clearance by proteases and extrusion into the circulation via the blood–brain barrier and glymphatic system. This article focuses on emerging mechanisms for promoting the clearance of neurotoxic proteins, a strategy that may curtail the onset and slow the progression of NDAs.
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Designer proteins activate fluorescent molecules

Designer proteins activate fluorescent molecules | Alzheimer's Disease R&D Review | Scoop.it
A method for designing β-barrels that bind to any small molecule.
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FDA approves Insightec-Siemens neurology surgery platform

FDA approves Insightec-Siemens neurology surgery platform | Alzheimer's Disease R&D Review | Scoop.it
The product, which is adopted for use in combination with Siemens's imaging devices, is already used with GE.
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Regulating microglial activity may reduce damaging inflammation in neurodegenerative diseases - Massachusetts General Hospital, Boston, MA

Regulating microglial activity may reduce damaging inflammation in neurodegenerative diseases - Massachusetts General Hospital, Boston, MA | Alzheimer's Disease R&D Review | Scoop.it
A group of Massachusetts General Hospital investigators is proposing that targeting immune checkpoints – molecules that regulate the activity of the immune system – in immune cells called microglia could reduce the inflammatory aspects of important neurodegenerative diseases like Alzheimer’s...
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Imaging the evolution and pathophysiology of Alzheimer disease

Imaging the evolution and pathophysiology of Alzheimer disease | Alzheimer's Disease R&D Review | Scoop.it
Abstract
Technologies for imaging the pathophysiology of Alzheimer disease (AD) now permit studies of the relationships between the two major proteins deposited in this disease — amyloid-β (Aβ) and tau — and their effects on measures of neurodegeneration and cognition in humans. Deposition of Aβ in the medial parietal cortex appears to be the first stage in the development of AD, although tau aggregates in the medial temporal lobe (MTL) precede Aβ deposition in cognitively healthy older people. Whether aggregation of tau in the MTL is the first stage in AD or a fairly benign phenomenon that may be transformed and spread in the presence of Aβ is a major unresolved question. Despite a strong link between Aβ and tau, the relationship between Aβ and neurodegeneration is weak; rather, it is tau that is associated with brain atrophy and hypometabolism, which, in turn, are related to cognition. Although there is support for an interaction between Aβ and tau resulting in neurodegeneration that leads to dementia, the unknown nature of this interaction, the strikingly different patterns of brain Aβ and tau deposition and the appearance of neurodegeneration in the absence of Aβ and tau are challenges to this model that ultimately must be explained.
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Researchers model how toxic proteins course through the brain, lead to disease

Researchers model how toxic proteins course through the brain, lead to disease | Alzheimer's Disease R&D Review | Scoop.it
Many neurodegenerative diseases spread by hijacking the brain's connective circuitry to transport toxic proteins, which gradually accumulate and trigger symptoms of dementias. Now, researchers at Stevens Institute of Technology ...
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Cognition or genetics? Predicting Alzheimer's disease with practice effects, APOE genotype, and brain metabolism - ScienceDirect

Cognition or genetics? Predicting Alzheimer's disease with practice effects, APOE genotype, and brain metabolism - ScienceDirect | Alzheimer's Disease R&D Review | Scoop.it
Abstract
As practice effects are common in neuropsychological assessment, this study analyzed their utility to identify individuals with amnestic mild cognitive impairment (aMCI) at the greatest risk for Alzheimer's disease (AD-risk) and compared practice effects with APOE and brain metabolism biomarkers. We regressed Auditory Verbal Learning Test delayed recall (AVLT-DR) at 6 months on baseline AVLT-DR scores in 394 individuals with normal cognition from the Alzheimer's Disease Neuroimaging Initiative database and dichotomized 816 individuals with aMCI as showing practice effect or not showing practice effects (PE−) when the discrepancy between observed and predicted scores was found in less than 10%, 7%, and 5% of normal cognition. Cox regressions analyzed the AD-risk at 6 years. More than 60% of aMCI were showing practice effects. Controlling for age, sex, education, and baseline Mini-Mental State Examination and AVLT-DR scores, the AD-risk was associated with PE− [hazard ratio (HR) = 1.93], lower brain metabolism (HR = 0.95), and APOE genotype (HR = 1.92), with narrower risk estimates for PE−. The lack of practice effects during a 6-month period might be as precise as biomarkers for predicting the 6-year AD-risk.
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The optic lobe neuroepithelium generates neural stem cells over 60 hours earlier than previously thought — The Gurdon Institute

The optic lobe neuroepithelium generates neural stem cells over 60 hours earlier than previously thought — The Gurdon Institute | Alzheimer's Disease R&D Review | Scoop.it
Hakes, Otsuki and Brand show that neuroepithelial cells in the Drosophila optic lobe produce previously unidentified neural stem cells during embryonic development...
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JCI - Macrophage migration inhibitory factor mediates metabolic dysfunction induced by atypical antipsychotic therapy

JCI - Macrophage migration inhibitory factor mediates metabolic dysfunction induced by atypical antipsychotic therapy | Alzheimer's Disease R&D Review | Scoop.it
Atypical antipsychotics are highly effective antischizophrenic medications but their clinical utility is limited by adverse metabolic sequelae. We investigated whether upregulation of macrophage migration inhibitory factor (MIF) underlies the insulin resistance that develops during treatment with the most commonly prescribed atypical antipsychotic, olanzapine. Olanzapine monotherapy increased BMI and circulating insulin, triglyceride, and MIF concentrations in drug-naive schizophrenic patients with normal MIF expression, but not in genotypic low MIF expressers. Olanzapine administration to mice increased their food intake and hypothalamic MIF expression, which led to activation of the appetite-related AMP-activated protein kinase and Agouti-related protein pathway. Olanzapine also upregulated MIF expression in adipose tissue, which reduced lipolysis and increased lipogenic pathways. Increased plasma lipid concentrations were associated with abnormal fat deposition in liver and skeletal muscle, which are important determinants of insulin resistance. Global MIF-gene deletion protected mice from olanzapine-induced insulin resistance, as did intracerebroventricular injection of neutralizing anti–MIF antibody, supporting the role of increased hypothalamic MIF expression in metabolic dysfunction. These findings uphold the potential pharmacogenomic value of MIF genotype determination and suggest that MIF may be a tractable target for reducing the metabolic side effects of atypical antipsychotic therapy.
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A new era for understanding amyloid structures and disease

A new era for understanding amyloid structures and disease | Alzheimer's Disease R&D Review | Scoop.it
The aggregation of proteins into amyloid fibrils and their deposition into plaques and intracellular inclusions is the hallmark of amyloid disease. Recent advances in structural biology techniques have provided insight into how amyloid structure may affect the ability of fibrils to spread in a prion-like manner and into their roles in disease.
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Functional analysis of a triplet deletion in the gene encoding the sodium glucose transporter 3, a potential risk factor for ADHD

Functional analysis of a triplet deletion in the gene encoding the sodium glucose transporter 3, a potential risk factor for ADHD | Alzheimer's Disease R&D Review | Scoop.it
Sodium-glucose transporters (SGLT) belong to the solute carrier 5 family, which is characterized by sodium dependent transport of sugars and other solutes. In contrast, the human SGLT3 (hSGLT3) isoform, encoded by SLC5A4, acts as a glucose sensor that does not transport sugar but induces membrane...
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Intracerebral haemorrhage: current approaches to acute management

Intracerebral haemorrhage: current approaches to acute management | Alzheimer's Disease R&D Review | Scoop.it
Acute spontaneous intracerebral haemorrhage is a life-threatening illness of global
importance, with a poor prognosis and few proven treatments. As a heterogeneous disease,
certain clinical and imaging features help identify the cause, prognosis, and how
to manage the disease.
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Human neural stem cell transplantation improves cognition in a murine model of Alzheimer’s disease

Human neural stem cell transplantation improves cognition in a murine model of Alzheimer’s disease | Alzheimer's Disease R&D Review | Scoop.it

More recently, rapid advances in stem cell biology have led to an explosion of potential novel therapies for several neurodegenerative diseases. Stem cell-based therapies offer a particularly attractive alternative to single-target small m

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Therapeutic strategies for Parkinson disease: beyond dopaminergic drugs

Therapeutic strategies for Parkinson disease: beyond dopaminergic drugs | Alzheimer's Disease R&D Review | Scoop.it
Existing therapeutic strategies for managing Parkinson disease (PD), which focus on addressing the loss of dopamine and dopaminergic function linked with degeneration of dopaminergic neurons, are limited by side effects and lack of long-term efficacy. In recent decades, research into PD pathophysiology and pharmacology has focused on understanding and tackling the neurodegenerative processes and symptomology of PD. In this Review, we discuss the challenges associated with the development of novel therapies for PD, highlighting emerging agents that aim to target cell death, as well as new targets offering a symptomatic approach to managing features and progression of the disease.
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Space and Time: The Hippocampus as a Sequence Generator

Neural computations are often compared to instrument-measured distance or duration,
and such relationships are interpreted by a human observer. However, neural circuits
do not depend on human-made instruments but perform computations relative to an internally
defined rate-of-change. While neuronal correlations with external measures, such as
distance or duration, can be observed in spike rates or other measures of neuronal
activity, what matters for the brain is how such activity patterns are utilized by
downstream neural observers.
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Targeted epigenome editing as ‘next generation drugs’ for Parkinson’s disease | Duke GCB

Targeted epigenome editing as ‘next generation drugs’ for Parkinson’s disease | Duke GCB | Alzheimer's Disease R&D Review | Scoop.it
By Alissa Kocer By 2020, the Parkinson’s Foundation estimates that nearly one million people will be living with Parkinson’s disease (PD) in the U.S. That’s more than the number of people diagnosed with multiple sclerosis, muscular dystrophy and Lou Gehrig’s disease combined. Researchers at Duke are taking action. Ornit Chiba-Falek, GCB member and associate professor of neurology, collaborated with Boris Kantor, assistant research professor in neurobiology, to pioneer the development of a new therapeutic strategy for PD that targets the machinery that controls the expression of the SNCA gene. Their findings were published online on August 28 in the journal of Molecular Therapy Cell Press. Overexpression of the SNCA gene, while not the only way people can contract the disease, has been shown to cause PD and related disorders. If researchers can come up with a method to accurately and efficiently manipulate SNCA levels, they can create a gene therapy as a means of precision medicine for patients with PD in whom the disease is caused by SNCA dysregulation. Chiba-Falek and team created an innovative platform that allows the regulation of gene expression programs to be fine-tuned. “This approach,” Chiba-Falek said, “would be highly attractive for developing ‘smart drugs’ as disease modifying interventions for PD, Alzheimer’s disease and other neurological diseases and pathologies associated with dysregulation of gene expression.” Their project provided a proof-of-concept for moving forward with a targeted epigenome-editing approach to in vivo validation. Currently, the team is working to validate this system in an animal model using an intergrase-deficient viral delivery method for safer in vivo delivery. “These studies,” Kantor said, “will further establish, validate and determine the safety of the viral vector tool as a novel epigenome-based therapeutic approach for PD.” Chiba-Falek noted that this work will provide the foundation for implementation and further evaluation in clinical trials.
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