Degenerating Neurons Respond to NGF Gene Therapy Treatment for Alzheimer’s Disease

Degenerating neurons in patients with Alzheimer’s disease
(AD) measurably responded to an experimental gene therapy in which nerve growth factor (NGF) was injected into their brains, report researchers at University of California, San Diego School of Medicine in the current issue of JAMA Neurology.
The affected neurons displayed heightened growth, axonal sprouting and activation of functional markers, said lead author Mark H. Tuszynski, MD, PhD, professor in the Department of Neurosciences, director of the UC San Diego Translational Neuroscience Institute and a neurologist at VA Medical Center, San Diego.
The findings are derived from postmortem analyses of 10
patients who participated in phase I clinical trials launched in 2001 to assess
whether injected NGF – a protein essential to cellular growth, maintenance and
survival – might safely slow or prevent neuronal degeneration in patients with
AD.  

Humans may be harmed by endocrine disrupting chemicals released during natural gas mining

"More than 15 million Americans live within one mile of unconventional oil and gas (UOG) operations that combine directional drilling and hydraulic fracturing, or "fracking" to release natural gas from underground rock. Scientific studies still are inconclusive on the potential long-term effects on human development. Now, Susan C. Nagel and Christopher D. Kassotis, researchers with the University of Missouri, and national colleagues have conducted a review of research on health effects associated with UOG operations and concluded these activities have potential for environmental release of a complex mixture of endocrine disrupting chemicals (EDCs) that could potentially harm human development and reproduction."



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Alzheimer's disease thought to be accelerated by an abnormal build-up of fat in the brain

The researchers examined the brains of nine patients who died from Alzheimer's disease and found significantly more fat droplets compared with five healthy brains. A team of chemists from University of Montreal led by Pierre Chaurand then used an advanced mass spectrometry technique to identify these fat deposits as triglycerides enriched with specific fatty acids, which can also be found in animal fats and vegetable oils.
"We discovered that these fatty acids are produced by the brain, that they build up slowly with normal aging, but that the process is accelerated significantly in the presence of genes that predispose to Alzheimer's disease"



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A new virus in liver cancer

In the genome of tumour cells of 11 patients, the scientists observed the insertion of a viral DNA segment from adeno-associated type 2, known as AAV2. This virus has been considered non-pathogenic for humans until now. In order to confirm the virus's involvement in the cancer, the research team compared tumour tissues with normal tissues. They thus confirmed their hypothesis: the integration of viral DNA was found more often in tumour cells than in healthy cells in these 11 patients. Moreover, 8 of these patients did not have cirrhosis, and 6 of them presented no known risk factors for .

Viral metagenomics in drug-naïve, first-onset schizophrenia patients with prominent negative symptoms. - PubMed - NCBI

Although several studies suggest a virus or (endogenous) retrovirus involvement at the time of onset of schizophrenia, the unequivocal identification of one or more infectious agents, by means of an undirected catch-all technique, has never been conducted. In this study VIDISCA, a virusdiscovery method, was used in combination with Roche-454 high-throughput sequencing as a tool to determine the possible presence of viruses (known or unknown) in blood of first-onset drugs-naïve schizophrenic patients with prominent negative symptoms. Two viruses (the Anellovirus Torque Teno virus and GB virus C) were detected. Both viruses are commonly found in healthy individuals and no clear link with disease was ever established. Viruses from the family Anelloviridae were also identified in the control population (4.8%). Besides, one patient sample was positive for human endogenous retroviruses type K (HML-2) RNA but no specific predominant strain was detected, instead 119 different variants were found. In conclusion, these findings indicate no evidence for viral or endogenous retroviral involvement in sera at the time of onset of schizophrenia.

Oral inflammation, tooth loss, risk factors, and association with progression of Alzheimer's disease. - PubMed - NCBI

Periodontitis is a polymicrobial chronic inflammatory disease of tooth-supporting tissues with bacterial etiology affecting all age groups, becoming chronic in a subgroup of older individuals. Periodontal pathogens Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola are implicated in the development of a number of inflammatory pathologies at remote organ sites, including Alzheimer's disease (AD). The initial inflammatory hypothesis proposed that AD hallmark proteins were the main contributors of central nervous system (CNS) inflammation. This hypothesis is expanding to include the role of infections, lifestyle, and genetic and environmental factors in the pathogenesis of AD. Periodontal disease (PD) typifies a condition that encompasses all of the above factors including pathogenic bacteria. These bacteria not only are the source of low-grade, chronic infection and inflammation that follow daily episodes of bacteremia arising from everyday tasks such as brushing, flossing teeth, chewing food, and during dental procedures, but they also disseminate into the brain from closely related anatomical pathways. The long-term effect of inflammatory mediators, pathogens, and/or their virulence factors, reaching the brain systemically or otherwise would, over time, prime the brain's own microglia in individuals who have inherent susceptibility traits. Such susceptibilities contribute to inadequate neutralization of invading agents, upon reaching the brain. This has the capacity to create a vicious cycle of sustained local inflammatory milieu resulting in the loss of cytoarchitectural integrity and vital neurons with subsequent loss of function (deterioration in memory). The possible pathways between PD and AD development are considered here, as well as environmental factors that may modulate/exacerbate AD symptoms.

Characterizing Apolipoprotein E ε4 Carriers and Noncarriers With the Clinical Diagnosis of Mild to Moderate Alzheimer Dementia and Minimal β-Amyloid Peptide Plaques

Importance  β-Amyloid peptide (Aβ) plaques are a cardinal neuropathologic feature of Alzheimer disease (AD), yet more than one-third of apolipoprotein E ε4 (APOE4) noncarriers with the clinical diagnosis of mild to moderate Alzheimer dementia may not meet positron emission tomographic criteria for significant cerebral amyloidosis.
Objectives  To clarify the percentage of APOE4 carriers and noncarriers with the primary clinical diagnosis of mild to moderate Alzheimer dementia near the end of life and minimal Aβ plaques noted at autopsy and the extent to which these cases are associated with appreciable neurofibrillary degeneration or a primary neuropathologic diagnosis other than AD.
Design, Setting, and Participants  Data on participants included in this study were obtained from the National Alzheimer Coordinating Center’s Uniform Data Set, which comprises longitudinal clinical assessments performed at the AD centers funded by the National Institute on Aging. Neuropathology data are available for the subset of participants who died. A total of 100 APOE4 noncarriers and 100 APOE4 carriers had the primary clinical diagnosis of mild to moderate Alzheimer dementia at their last visit, known APOE4 genotype, died within the ensuing 24 months, and underwent neuropathologic evaluation on autopsy. The study was conducted from September 1, 2005, to September 1, 2012; analysis was performed from October 9, 2012, to March 20, 2015.
Main Outcomes and Measures  Standardized histopathologic assessments of AD neuropathologic changes were the primary measures of interest in this study, specifically Consortium to Establish a Registry for Alzheimer’s Disease neuritic plaque density score, diffuse plaque density score, and Braak stage for neurofibrillary degeneration. The distributions of scores for these measures were the primary outcomes.
Results  Of the 37 APOE4 noncarriers with minimal neuritic plaques, 16 individuals (43.2%) had Braak stages III to VI ratings, and 15 of the others (75.0%) met neuropathologic criteria for other dementia-related diseases. Of the 13 APOE4carriers with minimal neuritic plaques, 6 individuals (46.2%) had Braak stages III to VI ratings and met neuropathologic criteria for other dementia-related diseases. Similarly, of the 7 APOE4 carriers with minimal neuritic plaques and Braak stages 0 to II, 4 participants (57.1%) were thought to have pathologic changes and alterations resulting from non-AD neuropathologic features.
Conclusions and Relevance  In this study, more than one-third of APOE4 noncarriers with the primary clinical diagnosis of mild to moderate Alzheimer dementia had minimal Aβ plaque accumulation in the cerebral cortex and, thus, may show limited or no benefit from otherwise effective anti-Aβ treatment. Almost half of the participants with a primary clinical diagnosis of mild to moderate Alzheimer dementia and minimal Aβ plaque accumulation had an extensive topographic distribution of neurofibrillary degeneration. Additional studies are needed to better understand and provide treatment for patients with this unexpectedly common cliniconeuropathologic condition.

Composition, taxonomy and functional diversity of the oropharynx microbiome in individuals with schizophrenia and controls [PeerJ]

The role of the human microbiome in schizophrenia remains largely unexplored. The microbiome has been shown to alter brain development and modulate behavior and cognition in animals through gut-brain connections, and research in humans suggests that it may be a modulating factor in many disorders. This study reports findings from a shotgun metagenomic analysis of the oropharyngeal microbiome in 16 individuals with schizophrenia and 16 controls. High-level differences were evident at both the phylum and genus levels, with Proteobacteria, Firmicutes, Bacteroidetes, and Actinobacteria dominating both schizophrenia patients and controls, and Ascomycota being more abundant in schizophrenia patients than controls. Controls were richer in species but less even in their distributions, i.e., dominated by fewer species, as opposed to schizophrenia patients. Lactic acid bacteria were relatively more abundant in schizophrenia, including species of Lactobacilli and Bifidobacterium, which have been shown to modulate chronic inflammation. We also found Eubacterium halii, a lactate-utilizing species. Functionally, the microbiome of schizophrenia patients was characterized by an increased number of metabolic pathways related to metabolite transport systems including siderophores, glutamate, and vitamin B12. In contrast, carbohydrate and lipid pathways and energy metabolism were abundant in controls. These findings suggest that the oropharyngeal microbiome in individuals with schizophrenia is significantly different compared to controls, and that particular microbial species and metabolic pathways differentiate both groups. Confirmation of these findings in larger and more diverse samples, e.g., gut microbiome, will contribute to elucidating potential links between schizophrenia and the human microbiota.

Researchers Identify Signature of Microbiomes Associated With Schizophrenia | Office of Media Relations | The George Washington University

"In the most comprehensive study to date, researchers at the George Washington University have identified a potential link between microbes (viruses, bacteria and fungi) in the throat and schizophrenia. This link may offer a way to identify causes and develop treatments of the disease and lead to new diagnostic tests.

“The oropharynx of schizophrenics seems to harbor different proportions of oral bacteria than healthy individuals,” said Eduardo Castro-Nallar, a Ph.D. candidate at GW’s Computational Biology Institute (CBI) and lead author of the study. “Specifically, our analyses revealed an association between microbes such as lactic-acid bacteria and schizophrenics.”

Recent studies have shown that microbiomes—the communities of microbes living within our bodies—can affect the immune system and may be connected to mental health. Research linking immune disorders and schizophrenia has also been published, and this study furthers the possibility that shifts in oral communities are associated with schizophrenia.
 "



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Autoantibodies in CNS Trauma and Neuropsychiatric Disorders: A New Generation of Biomarkers - PubMed - NCBI

Autoimmune response mechanisms have been observed in a number of CNS disorders involving multiple sclerosis (MS), paraneoplastic syndromes, brain trauma, and dementia-related disorders . A number of neurological disorders are associated with blood–brain barrier (BBB) disruption or increased permeability observed in Alzheimer disease (AD), stroke, TBI, and schizophrenia . Injury to the BBB such as in brain injury may lead to the release of intracellular proteins either intact or proteolytic fragments from protease activation into the cerebrospinal fluid (CSF) or blood stream. The leakage of such entities into the circulation may lead to the formation of autoantibodies that have been defined as brain-reactive antibodies that recognize self- (auto-) antigens i.e., an antigen that is normally found in a subject tissue or cell or organelles.

Bacterial infection and Alzheimer's disease: a meta-analysis. - PubMed - NCBI

The possibility of an infectious etiology for Alzheimer's disease (AD) has been repeatedly postulated over the past three decades. We provide the first meta-analysis to address the relationship between bacterial infection and AD. Studies examining the association between AD and spirochetal bacteria or Chlamydophila pneumoniae (Cpn) were identified through a systematic search of the databases MEDLINE, EMBASE, PubMed, and Google Scholar. Data combined from 25 relevant, primarily case-control studies demonstrated a statistically significant association between AD and detectable evidence of infection of either bacterial group. We found over a ten-fold increased occurrence of AD when there is detectable evidence of spirochetal infection (OR: 10.61; 95% CI: 3.38-33.29) and over a four-fold increased occurrence of AD in a conservative risk estimate (OR: 4.45; 95% CI: 2.33-8.52). We found over a five-fold increased occurrence of AD with Cpn infection (OR: 5.66; 95% CI: 1.83-17.51). This study shows a strongly positive association between bacterial infection and AD. Further detailed investigation of the role of bacterial infection is warranted.

Nine risk factors may contribute to two thirds of Alzheimer's cases worldwide - Medical News Today

They found grade 1 level evidence in favour of a protective effect for the female hormone oestrogen, cholesterol lowering drugs (statins), drugs to lower high blood pressure, and anti-inflammatory drugs (NSAIDs).

They found the same level of evidence for folate, vitamins C and E, and coffee, all of which were associated with helping to stave off the disease.

Similarly, the pooled data indicated a strong association between high levels of homocysteine - an amino acid manufactured in the body - and depression and a significantly heightened risk of developing Alzheimer's disease.

The evidence also strongly pointed to the complex roles of pre-existing conditions as either heightening or lowering the risk.

The factors associated with a heightened risk included frailty, carotid artery narrowing, high and low blood pressure, and type 2 diabetes (in the Asian population). Those associated with a lowered risk included a history of arthritis, heart disease, metabolic syndrome, and cancer.

Intrinsic mutagenic properties of 5-chlorocytosine: A mechanistic connection between chronic inflammation and cancer: PNAS

During chronic inflammation, neutrophil-secreted
hypochlorous acid can damage nearby cells inducing the genomic accumulation of 5-chlorocytosine (5ClC), a known inflammation biomarker. Although 5ClC has been shown to promote epigenetic changes, it has been unknown heretofore if 5ClC directly perpetrates a mutagenic outcome within the cell. The present work shows that 5ClC is intrinsically mutagenic, both in vitro and, at a level of a
single molecule per cell, in vivo. Using biochemical and genetic approaches, we
have quantified the mutagenic and toxic properties of 5ClC, showing that this
lesion caused C→T transitions at frequencies ranging from 3–9% depending on the polymerase traversing the lesion. X-ray crystallographic studies provided a
molecular basis for the mutagenicity of 5ClC; a snapshot of human polymerase β
replicating across a primed 5ClC-containing template uncovered 5ClC engaged in a nascent base pair with an incoming dATP analog. Accommodation of the chlorine substituent in the template major groove enabled a unique interaction between 5ClC and the incoming dATP, which would facilitate mutagenic lesion bypass. The type of mutation induced by 5ClC, the C→T transition, has been previously shown to occur in substantial amounts both in tissues under inflammatory stress and in the genomes of many inflammation-associated cancers. In fact, many sequence-specific mutational signatures uncovered in sequenced cancer genomes feature C→T mutations. Therefore, the mutagenic ability of 5ClC documented in the present study may constitute a direct functional link between chronic inflammation and the genetic changes that enable and promote malignant transformation.

Neutrophils promote Alzheimer's disease-like pathology and cognitive decline via LFA-1 integrin : Nature Medicine : Nature Publishing Group

Inflammation is a pathological hallmark of Alzheimer's disease, and innate immune cells have been shown to contribute to disease pathogenesis. In two transgenic models of Alzheimer's disease (5xFAD and 3xTg-AD mice), neutrophils extravasated and were present in areas with amyloid-β (Aβ) deposits, where they released neutrophil extracellular traps (NETs) and IL-17. Aβ42 peptide triggered the LFA-1 integrin high-affinity state and rapid neutrophil adhesion to integrin ligands. In vivo, LFA-1 integrin controlled neutrophil extravasation into the CNS and intraparenchymal motility. In transgenic Alzheimer's disease models, neutrophil depletion or inhibition of neutrophil trafficking via LFA-1 blockade reduced Alzheimer's disease–like neuropathology and improved memory in mice already showing cognitive dysfunction. Temporary depletion of neutrophils for 1 month at early stages of disease led to sustained improvements in memory. Transgenic Alzheimer's disease model mice lacking LFA-1 were protected from cognitive decline and had reduced gliosis. In humans with Alzheimer's disease, neutrophils adhered to and spread inside brain venules and were present in the parenchyma, along with NETs. Our results demonstrate that neutrophils contribute to Alzheimer's disease pathogenesis and cognitive impairment and suggest that the inhibition of neutrophil trafficking may be beneficial in Alzheimer's disease.

Evolution of multiple sclerosis in France since the beginning of hepatitis B vaccination.

Since the implementation of the mass vaccination campaign against hepatitis B in France, the appearance of multiple sclerosis, sometimes occurring in the aftermath of vaccinations, led to the publication of epidemiological international studies. This was also justified by the sharp increase in the annual incidence of multiple sclerosis reported to the French health insurance in the mid-1990s. Almost 20 years later, a retrospective reflection can be sketched from these official data and also from the national pharmacovigilance agency. Statistical data from these latter sources seem to show a significant correlation between the number of hepatitis B vaccinations performed and the declaration to the pharmacovigilance of multiple sclerosis occurring between 1 and 2 years later. The application of the Hill’s criteria to these data indicates that the correlation between hepatitis B vaccine and multiple sclerosis may be causal.


Consuming highly refined carbohydrates increases risk of depression -- ScienceDaily

"The study by James Gangwisch, PhD and colleagues in the department of psychiatry at Columbia University Medical Center (CUMC) looked at the dietary glycemic index, glycemic load, types of carbohydrates consumed, and depression in data from more than 70,000 postmenopausal women who participated in the National Institutes of Health's Women's Health Initiative Observational Study between 1994 and 1998.

Consumption of carbohydrates increases blood sugar levels to varying degrees, depending on the type of food ingested. The more highly refined the carbohydrate, the higher its score on the glycemic index (GI) scale. The GI scale, which goes from 0-100, measures the amount of sugar found in the blood after eating. Refined foods such as white bread, white rice, and soda trigger a hormonal response in the body to reduce blood sugar levels. This response may also cause or exacerbate mood changes, fatigue and other symptoms of depression.

The investigators found that progressively higher dietary GI scores and consumption of added sugars and refined grains were associated with increased risk of new-onset depression in post-menopausal women. Greater consumption of dietary fiber, whole grains, vegetables and non-juice fruits was associated with decreased risk. This suggests that dietary interventions could serve as treatments and preventive measures for depression. Further study is needed to examine the potential of this novel option for treatment and prevention, and to see if similar results are found in the broader population."



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Drugging the Environment | The Scientist Magazine®

Humans have spiked ecosystems with a flood of active pharmaceuticals. The drugs are feminizing male fish, confusing birds, and worrying scientists.

Viruses transfer the antiviral second messenger cGAMP between cells

 "Cyclic GMP-AMP synthase (cGAS) detects cytosolic DNA during virus infection and induces an antiviral state. cGAS signals by synthesis of a second messenger, cyclic GMP-AMP (cGAMP), which activates stimulator of interferon genes (STING). We show that cGAMP is incorporated into viral particles, including lentivirus and herpesvirus virions, when these are produced in cGAS-expressing cells. Virions transferred cGAMP to newly infected cells and triggered a STING-dependent antiviral program. These effects were independent of exosomes and viral nucleic acids. Our results reveal a way by which a signal for innate immunity is transferred between cells, potentially accelerating and broadening antiviral responses. Moreover, infection of dendritic cells with cGAMP-loaded lentiviruses enhanced their activation. Loading viral vectors with cGAMP therefore holds promise for vaccine development."



Metagenome-wide association study on oral microbiome uncovered markers for rheumatoid arthritis

"Metagenome-wide association studies (MGWAS) have proved to be a powerful approach to study gut microbiome for type 2 diabetes, colorectal cancer, etc. This is the first study on dental and saliva microbiomes. The researchers found that, Haemophilus sp. is depleted in rheumatoid arthritis (RA) patients at all three gut and oral sites and negatively correlates with RA auto-antibodies, while Lactobacillus salivarius is over-represented in RA patients at all three sites, especially in the very active cases.
Functional convergence was also observed—the RA gut and oral microbiomes show abnormalities in the redox environment, iron, sulfur, zinc and arginine transport and metabolism, and possible molecular mimicry to RA-related human antigens."