Sugary beverage intake and preclinical Alzheimer's disease in the community. - PubMed - NCBI


Excess sugar consumption has been linked with Alzheimer's disease (AD) pathology in animal models.


We examined the cross-sectional association of sugary beverage consumption with neuropsychological (N = 4276) and magnetic resonance imaging (N = 3846) markers of preclinical Alzheimer's disease and vascular brain injury (VBI) in the community-based Framingham Heart Study. Intake of sugary beverages was estimated using a food frequency questionnaire.


Relative to consuming less than one sugary beverage per day, higher intake of sugary beverages was associated with lower total brain volume (1-2/day, β ± standard error [SE] = -0.55 ± 0.14 mean percent difference, P = .0002; >2/day, β ± SE = -0.68 ± 0.18, P < .0001), and poorer performance on tests of episodic memory (all P < .01). Daily fruit juice intake was associated with lower total brain volume, hippocampal volume, and poorer episodic memory (all P < .05). Sugary beverage intake was not associated with VBI in a consistent manner across outcomes.


Higher intake of sugary beverages was associated cross-sectionally with markers of preclinical AD.

Sugar- and Artificially Sweetened Beverages and the Risks of Incident Stroke and Dementia | Stroke

"Background and Purpose—Sugar- and artificially-sweetened beverage intake have been linked to cardiometabolic risk factors, which increase the risk of cerebrovascular disease and dementia. We examined whether sugar- or artificially sweetened beverage consumption was associated with the prospective risks of incident stroke or dementia in the community-based Framingham Heart Study Offspring cohort.

 Methods—We studied 2888 participants aged >45 years for incident stroke (mean age 62 [SD, 9] years; 45% men) and 1484 participants aged >60 years for incident dementia (mean age 69 [SD, 6] years; 46% men). Beverage intake was quantified using a food-frequency questionnaire at cohort examinations 5 (1991–1995), 6 (1995–1998), and 7 (1998–2001). We quantified recent consumption at examination 7 and cumulative consumption by averaging across examinations. Surveillance for incident events commenced at examination 7 and continued for 10 years. We observed 97 cases of incident stroke (82 ischemic) and 81 cases of incident dementia (63 consistent with Alzheimer’s disease)

—After adjustments for age, sex, education (for analysis of dementia), caloric intake, diet quality, physical activity, and smoking, higher recent and higher cumulative intake of artificially sweetened soft drinks were associated with an increased risk of ischemic stroke, all-cause dementia, and Alzheimer’s disease dementia. When comparing daily cumulative intake to 0 per week (reference), the hazard ratios were 2.96 (95% confidence interval, 1.26–6.97) for ischemic stroke and 2.89 (95% confidence interval, 1.18–7.07) for Alzheimer’s disease. Sugar-sweetened beverages were not associated with stroke or dementia.

 Conclusions—Artificially sweetened soft drink consumption was associated with a higher risk of stroke and dementia."

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Stroke and dementia risk linked to artificial sweeteners, study suggests | Society | The Guardian

Consuming a can a day of low- or no-sugar soft drink is associated with a much higher risk of having a stroke or developing dementia, researchers claim.

Their findings have prompted renewed questions about whether drinks flavoured with artificial sweeteners can increase the risk of serious illness, as heavily sugared drinks have already been shown to do.

“Drinking at least one artificially sweetened beverage daily was associated with almost three times the risk of developing stroke or dementia compared to those who drank artificially sweetened beverages less than once a week,” according to the American researchers who carried out a study published in Stroke, the journal of the American Heart Association."

Here's the paper :-

Sugar- and Artificially Sweetened Beverages and the Risks of Incident Stroke and Dementia

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Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice | Brain | Oxford Academic

 Signalling through the PERK/eIF2α-P branch of the unfolded protein response plays a critical role in controlling protein synthesis rates in cells. This pathway is overactivated in brains of patients with Alzheimer’s disease and related disorders and has recently emerged as a promising therapeutic target for these currently untreatable conditions. Thus, in mouse models of neurodegenerative disease, prolonged overactivation of PERK/eIF2α-P signalling causes sustained attenuation of protein synthesis, leading to memory impairment and neuronal loss. Re-establishing translation rates by inhibition of eIF2α-P activity, genetically or pharmacologically, restores memory and prevents neurodegeneration and extends survival. However, the experimental compounds used preclinically are unsuitable for use in humans, due to associated toxicity or poor pharmacokinetic properties. To discover compounds that have anti-eIF2α-P activity suitable for clinical use, we performed phenotypic screens on a NINDS small molecule library of 1040 drugs. We identified two compounds, trazodone hydrochloride and dibenzoylmethane, which reversed eIF2α-P-mediated translational attenuation in vitro and in vivo. Both drugs were markedly neuroprotective in two mouse models of neurodegeneration, using clinically relevant doses over a prolonged period of time, without systemic toxicity. Thus, in prion-diseased mice, both trazodone and dibenzoylmethane treatment restored memory deficits, abrogated development of neurological signs, prevented neurodegeneration and significantly prolonged survival. In tauopathy-frontotemporal dementia mice, both drugs were neuroprotective, rescued memory deficits and reduced hippocampal atrophy. Further, trazodone reduced p-tau burden. These compounds therefore represent potential new disease-modifying treatments for dementia. Trazodone in particular, a licensed drug, should now be tested in clinical trials in patients.

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Reovirus infection triggers inflammatory responses to dietary antigens and development of celiac disease | Science

 Viral infections have been proposed to elicit pathological processes leading to the initiation of T helper 1 (TH1) immunity against dietary gluten and celiac disease (CeD). To test this hypothesis and gain insights into mechanisms underlying virus-induced loss of tolerance to dietary antigens, we developed a viral infection model that makes use of two reovirus strains that infect the intestine but differ in their immunopathological outcomes. Reovirus is an a virulent pathogen that elicits protective immunity, but we discovered that it can nonetheless disrupt intestinal immune homeostasis at inductive and effector sites of oral tolerance by suppressing peripheral regulatory T cell (pTreg) conversion and promoting TH1 immunity to dietary antigen. Initiation of TH1 immunity to dietary antigen was dependent on interferon regulatory factor 1 and dissociated from suppression of pTreg conversion, which was mediated by type-1 interferon. Last, our study in humans supports a role for infection with reovirus, a seemingly innocuous virus, in triggering the development of CeD."

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Identification of Fungal Species in Brain Tissue from Alzheimer's Disease by Next-Generation Sequencing. - PubMed - NCBI

 The possibility that patients diagnosed with Alzheimer's disease (AD) have disseminated fungal infection has been recently advanced by the demonstration of fungal proteins and DNA in nervous tissue from AD patients. In the present study, next-generation sequencing (NGS) was used to identify fungal species present in the central nervous system (CNS) of AD patients. Initially, DNA was extracted from frozen tissue from four different CNS regions of one AD patient and the fungi in each region were identified by NGS. Notably, whereas a great variety of species were identified using the Illumina platform, Botrytis cinerea and Cryptococcus curvatus were common to all four CNS regions analyzed. Further analysis of entorhinal/cortex hippocampus samples from an additional eight AD patients revealed a variety of fungal species, although some were more prominent than others. Five genera were common to all nine patients: Alternaria, Botrytis, Candida, Cladosporium, and Malassezia. These observations could be used to guide targeted antifungal therapy for AD patients. Moreover, the differences found between the fungal species in each patient may constitute a basis to understand the evolution and severity of clinical symptoms in AD.

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Low-calorie sweeteners promote fat accumulation in human fat

 "Low-calorie, artificial sweeteners appear to play havoc with the body's metabolism, and large consumption of these sugar substitutes could promote fat accumulation, especially in people who are already obese, preliminary research suggests. The study results will be presented Monday at ENDO 2017, the Endocrine Society's 99th annual meeting in Orlando, Fla."

 Sen and his colleagues tested sucralose, a popular low-calorie , on stem cells—cells that could change into mature fat, muscle, cartilage or bone cells—taken from human fat tissue. They placed these cells in Petri dishes for 12 days in media that promotes . At a 0.2-millimolar sucralose dose similar to the concentration found in the blood of people with high consumption of low-calorie sweeteners—equal to four cans of diet soda per day—the researchers said they observed increased expression of genes that are markers of fat production and inflammation. There also was increased accumulation of  in cells, particularly at a larger dose (1 millimolar), Sen reported.

Infections more common in people with schizophrenia

The researchers adjusted the data for other factors that might affect a person's risk of infection. They still found that people with schizophrenia had about twice the risk of skin, urological or genital infections, or tuberculosis than those in the general population.
The investigators also found that addiction and having other health problems were the most important factors associated with severe infection. Each one increased the risk of serious  by 2.7 times in both  with schizophrenia and those in the general .

Altering the immune system to reverse paralysis

 "In the ultimate betrayal, one's own immune system can turn against the protective sheath that envelops neurons in the brain, leaving the body paralyzed. Researchers have developed an experimental treatment that tames the wayward immune system in rodents, returning the power of movement to paralyzed mice. The approach may someday combat autoimmune diseases, such as multiple sclerosis and type 1 diabetes, in humans."

Exposure to BPA substitute, BPS, multiplies breast cancer cells

The blood DNA virome in 8,000 humans

 The characterization of the blood virome is important for the safety of blood-derived transfusion products, and for the identification of emerging pathogens. We explored non-human sequence data from whole-genome sequencing of blood from 8,240 individuals, none of whom were ascertained for any infectious disease. Viral sequences were extracted from the pool of sequence reads that did not map to the human reference genome. Analyses sifted through close to 1 Petabyte of sequence data and performed 0.5 trillion similarity searches. With a lower bound for identification of 2 viral genomes/100,000 cells, we mapped sequences to 94 different viruses, including sequences from 19 human DNA viruses, proviruses and RNA viruses (herpesviruses, anelloviruses, papillomaviruses, three polyomaviruses, adenovirus, HIV, HTLV, hepatitis B, hepatitis C, parvovirus B19, and influenza virus) in 42% of the study participants. Of possible relevance to transfusion medicine, we identified Merkel cell polyomavirus in 49 individuals, papillomavirus in blood of 13 individuals, parvovirus B19 in 6 individuals, and the presence of herpesvirus 8 in 3 individuals. The presence of DNA sequences from two RNA viruses was unexpected: Hepatitis C virus is revealing of an integration event, while the influenza virus sequence resulted from immunization with a DNA vaccine. Age, sex and ancestry contributed significantly to the prevalence of infection. The remaining 75 viruses mostly reflect extensive contamination of commercial reagents and from the environment. These technical problems represent a major challenge for the identification of novel human pathogens. Increasing availability of human whole-genome sequences will contribute substantial amounts of data on the composition of the normal and pathogenic human blood virome. Distinguishing contaminants from real human viruses is challenging.

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Are the Infectious Roots of Alzheimer’s Buried Deep in the Past?

Recent literature shows a controversial new push to tie microorganisms to
Alzheimer’s disease (AD). Study after study, in which scientists have injected human
Alzheimer-diseased brain tissue into mice and other laboratory animals that later
developed the disease have left little doubt that Alzheimer’s disease (AD) arises
from an infectious process. By 2013 Mawanda and Wallace’s “Can Infections Cause
Alzheimer’s Disease” struck down some of the commonly entertained pathogens
for AD such as herpes simplex virus type 1, Chlamydia pneumoniae, and several
types of spirochetes. Instead they pointed to two prime suspects for Alzheimer’s
amyloid-beta deposition: “especially chronic infections like tuberculosis and
leprosy.” To be sure, it was German neuropathologist Oskar Fischer of the Prague
school of Neuropathology, Alzheimer’s great rival, who was the first to suggest that
infection might be causative for Alzheimer’s. Fischer’s credentials: he was the codiscoverer
of Alzheimer’s disease. His suspected germ was the Streptothrix, today
classified as Actinomycetes, a rare central nervous system pathogen which at the
time was so constantly and consistently mistaken for tuberculosis that ChoppenJones
suggested that TB be called tuberculomycosis. And Just ten years before
Oskar Fischer found Actinomycosis-like forms in Alzheimer’s cerebral plaque,
Babèş and immunologist Levaditi reported in “On the Actinomycotic Shape of the
Tuberculous Bacilli” that Fischer’s typical Actinomyces-like clusters (Drüsen) with
clubs appeared in the tissue of rabbits inoculated with tubercle bacilli beneath
the dura mater of their brains. Investigators who supported a

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Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders

 In animal models of autism spectrum disorder (ASD), the NKCC1 chloride-importer inhibitor bumetanide restores physiological (Cl−)i levels, enhances GABAergic inhibition and attenuates electrical and behavioral symptoms of ASD. In an earlier phase 2 trial; bumetanide reduced the severity of ASD in children and adolescents (3–11 years old). Here we report the results of a multicenter phase 2B study primarily to assess dose/response and safety effects of bumetanide. Efficacy outcome measures included the Childhood Autism Rating Scale (CARS), the Social Responsive Scale (SRS) and the Clinical Global Impressions (CGI) Improvement scale (CGI-I). Eighty-eight patients with ASD spanning across the entire pediatric population (2–18 years old) were subdivided in four age groups and randomized to receive bumetanide (0.5, 1.0 or 2.0 mg twice daily) or placebo for 3 months. The mean CARS value was significantly improved in the completers group (P: 0.015). Also, 23 treated children had more than a six-point improvement in the CARS compared with only one placebo-treated individual. Bumetanide significantly improved CGI (P: 0.0043) and the SRS score by more than 10 points (P: 0.02). The most frequent adverse events were hypokalemia, increased urine elimination, loss of appetite, dehydration and asthenia. Hypokalemia occurred mainly at the beginning of the treatment at 1.0 and 2.0 mg twice-daily doses and improved gradually with oral potassium supplements. The frequency and incidence of adverse event were directly correlated with the dose of bumetanide. Therefore, bumetanide improves the core symptoms of ASD and presents a favorable benefit/risk ratio particularly at 1.0 mg twice daily."

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Molecular Psychiatry - Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder

 Maternal immune activation (MIA) via infection during pregnancy is known to increase risk for autism spectrum disorder (ASD). However, it is unclear how MIA disrupts fetal brain gene expression in ways that may explain this increased risk. Here we examine how MIA dysregulates rat fetal brain gene expression (at a time point analogous to the end of the first trimester of human gestation) in ways relevant to ASD-associated pathophysiology. MIA downregulates expression of ASD-associated genes, with the largest enrichments in genes known to harbor rare highly penetrant mutations. MIA also downregulates expression of many genes also known to be persistently downregulated in the ASD cortex later in life and which are canonically known for roles in affecting prenatally late developmental processes at the synapse. Transcriptional and translational programs that are downstream targets of highly ASD-penetrant FMR1 and CHD8 genes are also heavily affected by MIA. MIA strongly upregulates expression of a large number of genes involved in translation initiation, cell cycle, DNA damage and proteolysis processes that affect multiple key neural developmental functions. Upregulation of translation initiation is common to and preserved in gene network structure with the ASD cortical transcriptome throughout life and has downstream impact on cell cycle processes. The cap-dependent translation initiation gene, EIF4E, is one of the most MIA-dysregulated of all ASD-associated genes and targeted network analyses demonstrate prominent MIA-induced transcriptional dysregulation of mTOR and EIF4E-dependent signaling. This dysregulation of translation initiation via alteration of the Tsc2–mTor–Eif4e axis was further validated across MIA rodent models. MIA may confer increased risk for ASD by dysregulating key aspects of fetal brain gene expression that are highly relevant to pathophysiology affecting ASD.

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DNA replication is the target for the antibacterial effects of nonsteroidal anti-inflammatory drugs.

 Evidence suggests that some nonsteroidal anti-inflammatory drugs (NSAIDs) possess antibacterial properties with an unknown mechanism. We describe the in vitro antibacterial properties of the NSAIDs carprofen, bromfenac, and vedaprofen, and show that these NSAIDs inhibit the Escherichia coli DNA polymerase III β subunit, an essential interaction hub that acts as a mobile tether on DNA for many essential partner proteins in DNA replication and repair. Crystal structures show that the three NSAIDs bind to the sliding clamp at a common binding site required for partner binding. Inhibition of interaction of the clamp loader and/or the replicative polymerase α subunit with the sliding clamp is demonstrated using an in vitro DNA replication assay. NSAIDs thus present promising lead scaffolds for novel antibacterial agents targeting the sliding clamp.

World's largest autism genome database shines new light on many 'autisms'

Through its research platform on the Google Cloud, Autism Speaks is making all of MSSNG's fully sequenced genomes directly available to researchers free of charge, along with analytic tools. In the coming weeks, the MSSNG team will be uploading an additional 2,000 fully sequenced autism genomes, bringing the total over 7,000.
Currently, more than 90 investigators at 40 academic and medical institutions are using the MSSNG database to advance autism research around the world."

Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder, Nature Neuroscience (2017). DOI: 10.1038/nn.4524 

Fluorene-9-bisphenol is anti-oestrogenic and may cause adverse pregnancy outcomes in mice : Nature Communications

 Bisphenol A (BPA) is used in the production of plastic but has oestrogenic activity. Therefore, BPA substitutes, such as fluorene-9-bisphenol (BHPF), have been introduced for the production of so-called ‘BPA-free’ plastics. Here we show that BHPF is released from commercial ‘BPA-free’ plastic bottles into drinking water and has anti-oestrogenic effects in mice. We demonstrate that BHPF has anti-oestrogenic activity in vitro and, in an uterotrophic assay in mice, induces low uterine weight, atrophic endometria and causes adverse pregnancy outcomes, even at doses lower than those of BPA for which no observed adverse effect have been reported. Female mice given water containing BHPF released from plastic bottles, have detectable levels of BHPF in serum, low uterine weights and show decreased expressions of oestrogen-responsive genes. We also detect BHPF in the plasma of 7/100 individuals, who regularly drink water from plastic bottles. Our data suggest that BPA substitutes should be tested for anti-oestrogenic activity and call for further study of the toxicological effects of BHPF on human health."

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Parkinson's disease and Parkinson's disease medications have distinct signatures of the gut microbiome - Hill-Burns - 2017 - Movement Disorders - Wiley Online Library


There is mounting evidence for a connection between the gut and Parkinson's disease (PD). Dysbiosis of gut microbiota could explain several features of PD.


The objective of this study was to determine if PD involves dysbiosis of gut microbiome, disentangle effects of confounders, and identify candidate taxa and functional pathways to guide research.

A total of 197 PD cases and 130 controls were studied. Microbial composition was determined by 16S rRNA gene sequencing of DNA extracted from stool. Metadata were collected on 39 potential confounders including medications, diet, gastrointestinal symptoms, and demographics. Statistical analyses were conducted while controlling for potential confounders and correcting for multiple testing. We tested differences in the overall microbial composition, taxa abundance, and functional pathways.


Independent microbial signatures were detected for PD (P = 4E-5), participants' region of residence within the United States (P = 3E-3), age (P = 0.03), sex (P = 1E-3), and dietary fruits/vegetables (P = 0.01). Among patients, independent signals were detected for catechol-O-methyltransferase-inhibitors (P = 4E-4), anticholinergics (P = 5E-3), and possibly carbidopa/levodopa (P = 0.05). We found significantly altered abundances of the Bifidobacteriaceae, Christensenellaceae, [Tissierellaceae], Lachnospiraceae, Lactobacillaceae, Pasteurellaceae, and Verrucomicrobiaceae families. Functional predictions revealed changes in numerous pathways, including the metabolism of plant-derived compounds and xenobiotics degradation.


 PD is accompanied by dysbiosis of gut microbiome. Results coalesce divergent findings of prior studies, reveal altered abundance of several taxa, nominate functional pathways, and demonstrate independent effects of PD medications on the microbiome. The findings provide new leads and testable hypotheses on the pathophysiology and treatment of PD. "

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What is wrong with Alzheimer’s disease clinical research? | Journal of Alzheimer's Disease

...............................what happens when causal reasoning is abandoned in repetitive clinical trials testing the effectiveness of an intervention that consistently yields negative results? This has been the invariable fate of anti-amyloid-β (Aβ) drugs. These drugs were designed to eliminate excessive Aβ deposition in the brain of those afflicted with AD. The drug treatment rationale was based on the Aβ hypothesis, also known as the amyloid cascade hypothesis. This concept has been the prevailing but unproven paradigm in explaining AD causality for the last 20 years. Oddly, there have been more than 100 drugs tested in dozens of clinical trials and not one anti-Aβ drug has succeeded in slowing down AD destructive pathology or prevent declining cognition [2].

"The multiple difficulties festering the Aβ hypothesis have been described in countless medical and scientific articles [3]. One lethal blow to the Aβ hypothesis are the numerous clinicopathological studies revealing that heavy brain amyloid deposition does not equate with dementia [3]. Most of the criticisms leveled at the Aβ hypothesis have been largely ignored by big pharma, its supporters, peer reviewers, and granting bodies as if no real challenge could lessen the power of this enduring paradigm. The best that can be said (to paraphrase big pharma executives) is that anti-Aβ therapy display ‘tolerability and safety’ when given to AD patients. But… so does chicken soup.

How do any of these help stop the meltdown of AD?

Let’s play devil’s advocate for the sake of balance. What is wrong with pursuing a failed hypothesis? In the case of Aβ, it has provided jobs and resources for researchers who might not otherwise have had the financial capital to keep their labs open; moreover, such monies from big pharma to investigators could even uncover collateral information that could help clarify the process of neurodegeneration. On the other hand, ethical behavior may have been misplaced in this difficult time of financial hardship that threatens research survival.

However, it is unacceptable, in my judgment, when medical researchers (for whatever reasons) steadfastly hold onto a hypothesis that does not help sick patients in any manner despite being paid to do it. Rationalizing such behavior blocks medical progress resulting in dire consequences for the patients’ clinical outlook. Equally disturbing is the callous effect such conduct has on devaluing the scientific spirit and the search for truth."

by Jack de la Torre, MD, PhD 

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