Major mental health project aims to uncover root causes of social withdrawal

A major European funding initiative aims to unpick the biological reasons underlying social withdrawal, which is a common early symptom of, Schizophrenia, Alzheimer’s disease and Major Depressive Disorder. The PRISM project (Psychiatric Ratings using Intermediate Stratified Markers), a €16.5m public-private cooperation, unites researchers from European academic centres, and major pharmaceutical companies.

Most mental health conditions are still classified and diagnosed solely based on the symptoms observed, as there are few objective biomarkers for these conditions as there are for other conditions, such as diabetes.  Many different neuropsychiatric diseases share symptoms, which makes it difficult to understand what is the underlying biological cause of a specific disease.   For example, we do not really have an idea how, if at all, the biological cause for social withdrawal in Alzheimer’s disease differs from that in schizophrenia.

This lack of understanding of the root biological causes is one of the reasons behind the dramatic slowdown in the development of new drugs to treat neuropsychiatric disorders.  Historically, many of the major drug classes for psychiatric disorders were discovered as a consequence of chance observations in human studies, an approach that suffers from a high rate of attrition and risk of drug candidate failures during development. Modern drug design aims to reduce this risk of attrition by altering a known biological process and closely monitor and quantifying the treatment effects of doing this.  The emergence of new ways of measuring brain activity (e.g. functional Magnetic Resonance Imaging (fMRI) of the brain, which registers blood flow to functioning areas of the brain) is for the first time opening the door to applying this type of drug discovery to mental health conditions.

Now a €16.5 million project, supported by the European Innovative Medicines Initiative (IMI) has been launched to seek to uncover the biology behind social withdrawal. Social withdrawal is one of the earliest indicators of the onset of several common psychiatric and neurological disorders but it is a symptom that may be caused by very different neurobiological processes. People with social withdrawal tend to retreat from friends and family, as well as from social networks at their work places. No-one knows the real underlying causes and mechanisms.

As Pierre Meulien (IMI Executive Director) said:

‘Brain disorders place an immense burden on patients, their families, and society as a whole. By bringing together leading experts from industry and academia, the PRISM project is well placed to add to our understanding of the underlying causes of brain disorders, and this will help to pave the way for new, effective treatments that patients are waiting for.’

The IMI-funded PRISM project will take a mixed group of patients and measure the brain and behavioural activities using a variety of new and existing techniques, from fMRI, EEG and blood tests to behavioural apps on smartphones.  The project will simultaneously correlate these activities with levels of social withdrawal, initially targeting Alzheimer’s disease and Schizophrenia, but also looking at Major Depressive Disorder. This should allow scientists to understand exactly which biological parameters correlate with which clinical symptoms.

As project coordinator, Prof Dr Martien Kas (University Medical Centre Utrecht and University of Groningen, Netherlands) said:

“Mental health care needs a way of seeing beyond the diagnostic boundaries to the underlying biological causes – we need biomarkers for mental health that can be measured quickly and easily as we do this for example with blood glucose levels in diabetes. If we can use the available techniques to objectively measure and to pull out the causes of social withdrawal, then the project will open a whole new way of understanding the causes and treatment of mental illness. With this ‘deep phenotyping’ of the patients, we will be able to differentiate patients on the basis of distinct biological parameters and relate these to internal neurophysiology, biochemistry and genetics. This should allow us to identify specific biological targets for drug action. At the moment, we don’t know what will drop out, but we hope that this new understanding will give us new drug targets, or even allow better targeting of old drugs.”

Concerns in the pharmaceutical industry about the lack of a systematic methodology to develop drugs for mental health led EFPIA (the European Federation of Pharmaceutical Industries and Associations) to approach the IMI to investigate the problem. As Dr Hugh Marston (Lilly) the industry project leader of the consortium said:

“This project has grown out of a pharmaceutical industry initiative led by Boehringer Ingelheim (Dr Bernd Sommer) and Lilly.  We now have 22 participant organisations, including 7 pharmaceutical companies each of whom are contributing between €1m to €2m.   Other major participants include the ECNP, several academic departments, a patient body, and five small specialist companies. The whole project is brought together by the EU under the Innovative Medicines Initiative, which also supports the project.  With this truly collaborative effort we stand an excellent chance of demonstrating for the first time that we can differentiate brain disorders based upon measurable biology rather than a classification based on the observed symptoms”.

The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 115916. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.”  www.imi.europa.eu

Kanazawa University research: Mechanism revealed linking liver disease and obesity

 Kanazawa University researchers find similarities in the impeded signalling between central insulin activity and glucose production in the liver for both obese mice and mice that have had the vagus nerve removed. The results are published in Cell Reports, March 2016.

The vital role of insulin in controlling glucose production is often disrupted in people suffering from obesity, a condition approaching global epidemic levels. Previous work has shown that central insulin action suppresses glucose production in the liver by increasing levels of the ligand interleukin 6 (IL-6) in the liver. The ligand activates the transcription factor STAT3, which in turn suppresses gene expression of glucose-producing enzymes. However, how the liver communicates with central nervous system and the vagus nerve, which controls unconscious processes like digestion, has so far not been understood. Now a collaboration of researchers in Japan led by Hiroshi Inoue at Kanazawa University’s Institute for Frontier Science Initiative (InFiniti) has identified the molecular mechanism for this communication.

Acetylcholine is the main neurotransmitter in the vagus nerve. It also suppresses IL-6 via the α7-nicotinic acetylcholine receptor. The researchers administered insulin and monitored subsequent vagal nerve activity, as well as IL-6 levels in a type of white blood cell in the liver known as “Kupffer cells”. They noticed a decrease in vagal nerve activity accompanied by increases in IL-6 in the Kupffer cells, resulting in decreased glucose production.

The researchers then investigated the effects of administering methyllycaconitine, which prevents α7-nicotinic acetylcholine receptor activity, as well as removal of the vagal nerve. They found that while STAT3 phosphorylation and IL-6 expression in the liver increased only slightly the IL-6/STAT3 signalling response to administered insulin was lost.

The researchers compared the response in lean and obese mice and found that the administered insulin “failed to elicit changes in vagus nerve activity of high-fat diet-induced obese mice.” They conclude, “These findings suggest that the aberrant regulation of Kupffer cells via the vagus nerve and α7-nAchR-mediated cholinergic action by central insulin action may have a significant role in the pathogenesis of chronic hepatic inflammation in obesity and of dysregulation of hepatic glucose production.”

Background

Glucose metabolism

Insulin is a hormone responsible for maintaining glucose levels and regulating glucose production in the liver. It also interacts with the central nervous system to regulate glucose metabolism. These metabolic processes include glucose oxidation to release ATP - which powers cells – glucose storage as glycogen, and the production of fatty acids and other substances.

Obesity-related diseases

Excessive body weight and insufficient exercise has been linked to insulin resistance, which can develop into a lack of insulin and type 2 diabetes. The surge in global obesity levels has been reflected in the numbers of people suffering from type 2 diabetes, a disease that is reported to cause over a million deaths each year. In 2014 90% of the 387 million cases of diabetes registered were type 2 and this is expected to increase to 587 million by 2035.

Obesity is also closely linked to inflammation and cancer of the liver. Interleukin 6 is a cytokine that can cause inflammation. The researchers found that the ability of the vagus nerve to regulate IL-6 expression was impeded in high-fat diet-induced obese mice. As well as the detrimental effects on glucose homeostasis, the results of this research suggest a molecular mechanism that links obesity to liver inflammation. Administration of neostigmine – which has a cholinergic action – suppressed expression of inflammatory cytokines in the Kupffer cells of obese insulin-resistant mice.

Okayama University research: Lack of enzyme promotes fatty liver disease in thin patients‏

 Researchers observe protection against obesity and insulin resistance but at the cost of prominent fatty liver disease in mice lacking the PEMT enzyme and patients with low levels of PEMT.

Non-alcoholic fatty liver disease – steatohepatitis - is an increasingly common chronic form of hepatitis. As Jun Wada and colleagues at Okayama University Graduate School of Medicine, Shigei Medical Research Institute and Dainippon Sumitomo Pharma explain in a recent report, “Although obesity is undoubtedly one of the main risk factors for the development of non-alcoholic fatty liver disease, many clinical observations demonstrated the presence of lean NAFLD patients with normal body mass index (BMI).” The team’s latest work shows that absence of the enzyme phosphatidylethanolamine N-methyltransferase (PEMT), while protecting from diet-induced obesity and diabetes, leads to the prominent development of fatty liver disease and tumours in response to a high-fat high-sucrose diet.

PEMT catalyses methylation of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) in liver cells using S-adenosyl methionine as a methyl donor. The ratio of PE to PC is known to be crucial to cell membrane integrity and resistance to endoplasmic reticulum stress and the infiltration of the liver with fat. 

Wada and colleagues fed mice lacking the PEMT enzyme a high-fat high-sucrose diet for up to 90 weeks. They monitored the fat accumulation and insulin resistance before dissecting them to examine their livers. The researchers noted enhanced apoptosis and cell proliferation in the liver, which they explain through transactivation of the protein p53, which is inhibited in the presence of PEMT. The researchers also note a similarity in the response of the PEMT knock-out mice to that of lean human patients suffering from non-alcoholic steatohepatitis.

The researchers then performed genome-wide sequencing-based DNA methylation analysis. Further investigation revealed that PEMT mRNA expression in liver tissues of human non-alcoholic steatohepatitis patients was significantly lower than for simple steatosis, and as they add “lower quartiles of PEMT mRNA demonstrated lower BMI and platelet counts, suggesting lower expression of PEMT is critically linked to the pathogenesis of lean non-alcoholic steatohepatitis.”

Background
Non-alcoholic fatty liver disease (NAFLD)
Extensive build-up of fat in the liver is responsible for a range of diseases including simple steatosis and non-alcoholic steatohepatitis (NASH). The increased instances of NAFLD are linked with the rise in obesity and diabetes, which are now considered to have reached epidemic proportions. However, NASH has also been reported in patients with a normal body mass index (BMI), and the prevalence of “lean NAFLD” was recently reported at 12% in Greece, 20% in India and 15% in China.

Choline deficiency and lean NAFLD
Mice fed a methionine- and choline-deficient diet (MCD) are a widely used mouse models for NASH research. An absence of obesity and insulin resistance has been observed in both MCD mice and PEMT knockout mice fed high-fat high-sucrose diets.

PC is synthesized from choline, and a balance in PE and PC levels is thought to be important for maintaining cell membrane integrity, stabilising lipid droplets and the normal distribution of fat. Disrupting this balance appears to cause accumulation of fat in the liver. 

PEMT catalyses methylation of PE, which also produces PC. The similar effects – lack of obesity and prominent steatohepatitis – is also observed in PEMT knock-out mice and human NAFLD patients with low levels of PEMT.

DNA methylation analysis
The genome-wide sequencing-based DNA methylation analysis by the researchers revealed enhanced methylation of two genes associated with cyclin D1 degradation and negative regulation. These results implicate the upregulation of cyclin D1 in the development of liver disease and tumours in PEMT knock-out mice.

 Caption

Phenotype of Pemt+/+, Pemt+/− and Pemt−/− mice under high fat-high sucrose (HFHS)
diet at 60 weeks of age. (a–c) Gross appearance of liver. Bar = 1 cm. Regenerative nodules and adenoma are indicated by arrow heads (c). (d–f) Masson-Trichrome staining of liver tissues. Bar = 100 μ m.

Reference 
Atsuko Nakatsuka, Makoto Matsuyama, Satoshi Yamaguchi, Akihiro Katayama, Jun Eguch, Kazutoshi Murakami, Sanae Teshigawara, Daisuke Ogawa, Nozomu Wada, Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Eijiro Watanabe & Jun Wada. Insufficiency of phosphatidylethanolamine N-methyltransferase is risk for lean non-alcoholic steatohepatitis, Scientific Reports 6 21721 (2016). 
DOI: 10.1038/srep21721
http://www.nature.com/articles/srep21721

Vitamin D pill a day may improve exercise performance and lower risk of heart disease

Taking vitamin D supplements can improve exercise performance and lower the risk of heart disease, according to the findings of a preliminary study presented today at the Society for Endocrinology annual conference in Edinburgh.

Vitamin D, which is both a vitamin and a hormone, helps control levels of calcium and phosphate in the blood and is essential for the formation of bones and teeth. Sources of Vitamin D include oily fish and eggs, but it can be difficult to get enough through diet alone. Most people generate vitamin D by exposing their skin to ultraviolet B rays in sunlight.

Previous studies suggest that vitamin D can block the action of enzyme 11-βHSD1, which is needed to make the “stress hormone” cortisol.  High levels of cortisol may raise blood pressure by restricting arteries, narrowing blood vessels and stimulating the kidneys to retain water. As Vitamin D may reduce circulating levels of cortisol, it could theoretically improve exercise performance and lower cardiovascular risk factors.

In this study, researchers from Queen Margaret University in Edinburgh gave 13 healthy adults matched by age and weight 50μg of vitamin D per day or a placebo over a period of two weeks.

Adults supplementing with vitamin D had lower blood pressure compared to those given a placebo, as well as having lower levels of the stress hormone cortisol in their urine. A fitness test found that the group taking vitamin D could cycle 6.5km in 20 minutes, compared to just 5km at the start of the experiment. Despite cycling 30% further in the same time, the group taking vitamin D supplements also showed lower signs of physical exertion.

Around ten million people in England may have low vitamin D levels. On average, one in ten adults has low levels of vitamin D in summer, compared to two in five in winter. Because people with darker skin are less efficient at using sunlight to make vitamin D, up to three out of four adults with dark skin are deficient in winter.

“Our pilot study suggests that taking vitamin D supplements can improve fitness levels and lower cardiovascular risk factors such as blood pressure”, said Dr Raquel Revuelta Iniesta, co-author of the study. “Our next step is to perform a larger clinical trial for a longer period of time in both healthy individuals and large groups of athletes such as cyclists or long-distance runners”.

"Vitamin D deficiency is a silent syndrome linked to insulin resistance, diabetes, rheumatoid arthritis, and a higher risk for certain cancers", said lead author of the study Dr Emad Al-Dujaili. “Our study adds to the body of evidence showing the importance of tackling this widespread problem”.

Super-sensitive tests could detect diseases earlier

Scientists have developed an ultra-sensitive test that should enable them to detect signs of a disease in its earliest stages, in research published May 27in the journal Nature Materials. The scientists, from Imperial College London and the University of Vigo, have created a test to detect particular molecules that indicate the presence of disease, even when these are in very low concentrations. There are already tests available for some diseases that look for such biomarkers using biological sensors or 'biosensors'. However, existing biosensors become less sensitive and predictable at detecting biomarkers when they are in very low concentrations, as occurs when a disease is in its early stages.

In the new study, the researchers demonstrated that the new biosensor test can find a biomarker associated with prostate cancer, called Prostate Specific Antigen (PSA). However, the team say that the biosensor can be easily reconfigured to test for other diseases or viruses where the related biomarker is known.

Professor Molly Stevens, senior author of the study from the Departments of Materials and Bioengineering at Imperial College London, said: "It is vital to detect diseases at an early stage if we want people to have the best possible outcomes -- diseases are usually easier to treat at this stage, and early diagnosis can give us the chance to halt a disease before symptoms worsen. However, for many diseases, using current technology to look for early signs of disease can be like finding the proverbial needle in a haystack. Our new test can actually find that needle. We only looked at the biomarker for one disease in this study, but we're confident that the test can be adapted to identify many other diseases at an early stage."

The team demonstrated the effectiveness of their biosensor by testing PSA biomarker samples in solutions containing a complex mixture of blood derived serum proteins. Monitoring the levels of PSA at ultralow concentrations can be crucial in the early diagnosis of the reoccurrence of prostate cancer, but classic detection approaches are not sensitive enough to carry out this analysis with a high degree of accuracy. The new test could enable more reliable diagnosis, but more research will need to be done to further explore its potential.

In their study, the team detected PSA at 0.000000000000000001 grams per millilitre, which is at the limits of current biosensor performance. By comparison, an existing test called an Enzyme-Linked Immunosorbent Assay (ELISA) test can detect PSA at 0.000000001 grams per millilitre, which is nine orders of magnitude more concentrated.

The biosensors used in the new study consist of nanoscopic-sized gold stars floating in a solution containing other blood derived proteins. Attached to the surface of these gold stars are antibodies, which latch onto PSA when they detect it in a sample. A secondary antibody, which has an enzyme called glucose oxidase attached to it, recognises the PSA and creates a distinctive silver crystal coating on the gold stars, which is more apparent when the PSA biomarkers are in low concentrations. This silver coating acts like a signal that PSA is present, and it can be easily detected by scientists using optical microscopes.

The next stage of the research will see the team carrying out further clinical testing to assess the efficacy of the biosensor in detecting a range of different biomarkers associated with conditions such as HIV and other infections. They will also explore ways of commercialising their product.

This research was funded by the European Research Council and via a Marie Curie fellowship.

**Source: Imperial College London

Long-term exposure to air pollution increases risk of hospitalization for lung, heart disease

Older adults may be at increased risk of being hospitalized for lung and heart disease, stroke, and diabetes following long-term exposure to fine-particle air pollution, according to a new study by researchers at Harvard School of Public Health (HSPH). It is the first study to look at the link between long-term effects of exposure to fine particles in the air and rates of hospital admissions. The study was published online April 17, 2012 in PLoS ONE.
Prior studies have reported an association between hospitalization and short-term air particle exposure (i.e. exposure to air particles on day of hospital admission or several days before). However, these short-term studies left unclear how many extra admissions occurred in the long run, and only included people who live near air pollution monitors, typically located in cities. No studies of long-term exposure to fine air particles (over the course of a year or two years) and rates of hospitalizations had been done.
"Our study found that long-term rates of admissions for pneumonia, heart attacks, strokes, and diabetes are higher in locations with higher long-term average particle concentrations," said lead author Itai Kloog, a research fellow in the Department of Environmental Health at HSPH.
Kloog and his colleagues, including senior author Joel Schwartz, professor of environmental epidemiology at HSPH and director of the Harvard Center for Risk Analysis, used novel prediction models, based on satellite observations, emissions, traffic, and weather data to predict levels of fine air particles in the air all over New England, which allowed the researchers to include rural and suburban areas. The researchers compared their findings with hospital admission records on all Medicare patients, ages 65 and older, admitted to 3,000 hospitals throughout New England from 2000-2006.
The researchers estimated zip code concentrations of fine air particles known as PM2.5 -- air matter with a diameter of 2.5 microns or less and more narrow than the width of a human hair. These particles, such as soot from vehicles, and other particles from power plants, wood burning, and certain industrial processes, are a significanthealth riskwhen they lodgein the lungs, causing inflammation there and in the rest of the body, and contributing to lung and heart disease.
The results showed an association between long-term exposure to fine air particles for all hospital admissions examined. For example, for every 10-µg/m³ increase in long-term PM2.5 exposure, the researchers found a 4.22% increase in respiratory admissions, a 3.12% increase in cardiovascular disease admissions, a 3.49% increase in stroke admissions, and a 6.33% increase in diabetes admissions.
"Particulate air pollution is one of the largest avoidable causes of death and illness in the United States, and unlike diet and exercise, does not require behavioral change. Off-the-shelf technology can be retrofitted onto sources of pollution at modest cost, with a large health benefit. This study shows that in addition to avoiding deaths, such measures will reduce chronic disease and medical care costs," said Schwartz.

**Source: Harvard School of Public Health