Yearly Archives: 2015

Beyond the four-letter alphabet of the genome, a far richer code dictates when and where genes are transcribed. The epigenome—defined by an ever-expanding list of modifications to DNA and the proteins that interact with it—determines which genes are dialed up or down and gives each cell type its unique personality. Thickening an already dense plot, three recent papers suggest that the brain may have its own epigenetic lingo.

One, published in Neuron on June 17, described the epigenome of three different types of neuron from the mouse brain—one excitatory, and two inhibitory. Among a slew of other findings, the study reported that neurons harbor a striking degree of cytosine methylation beyond the well-known cytosine-guanine (CpG) sites. This novel modification more closely correlated with gene expression and with neuronal phenotype than did the more common CpG methylation.

To generate a more detailed epigenetic map of neurons in the mouse brain, the researchers employed a technique called INTACT (isolation of nuclei tagged in specific cell types) to study nuclei from three types of neuron (see image above). The technique, which uses antibodies to capture nuclei expressing a protein tag, had been established in a plant model, and later used in flies, worms, and frogs, but never in mammals. INTACT isolates nuclei from homogenized tissue that is first frozen intact. This eliminates the need to first separate or sort the different types of cells, which can damage and/or activate neurons and confound results. INTACT allows researchers to obtain enough genetic material from specific cell types to run methylation and other epigenetic analyses.

Source: AlzResearch Forum

Scientists still do not know why some people develop Parkinson's disease. Now researchers from Aarhus University and Aarhus University Hospital have taken an important step towards a better understanding of the disease. Their research indicates that Parkinson's disease may begin in the gastrointestinal tract and spread through the vagus nerve to the brain.

"We have conducted a registry study of almost 15,000 patients who have had the vagus nerve in their stomach severed. Between approximately 1970-1995 this procedure was a very common method of ulcer treatment. If it really is correct that Parkinson's starts in the gut and spreads through the vagus nerve, then these vagotomy patients should naturally be protected against developing Parkinson's disease," explains postdoc at Aarhus University Elisabeth Svensson on the hypothesis behind the study.

"Our study shows that patients who have had the the entire vagus nerve severed were protected against Parkinson's disease. Their risk was halved after 20 years. However, patients who had only had a small part of the vagus nerve severed where not protected. This also fits the hypothesis that the disease process is strongly dependent on a fully or partially intact vagus nerve to be able to reach and affect the brain," she says.

The research was recently published in the journal “Annals of Neurology”.

Source: Aarhaus University

A digital map of the ageing brain could aid the diagnosis of Alzheimer's disease and other neurodegenerative disorders in older people, a study suggests.

The atlas created using images from MRI scans of older people could aid diagnosis by comparing the patients' scans with a detailed map of the healthy ageing brain.

Most existing MRI atlases are based on the brains of young and middle-aged people, which don't reflect the normal changes that take place in the brain as we age, the team says. Researchers at the University of Edinburgh constructed a detailed atlas of the human brain using MRI scans from more than 130 healthy people aged 60 or over.

The team used their atlas to study brain scans taken of normal older subjects and those who had been diagnosed with Alzheimer's disease. The atlas was able to pinpoint changes in patients' brain structure that can be an underlying sign of the condition, researchers say.

The study is published in the journal PLOS ONE.

Dr David Alexander Dickie, of The University of Edinburgh's Brain Research Imaging Centre and SINAPSE, who was first author of the study, said: "We're absolutely delighted with these preliminary results and that our brain MRI atlases may be used to support earlier diagnoses of diseases such as Alzheimer's. Earlier diagnoses are currently our strongest defence against these devastating diseases and, while our work is preliminary and ongoing, digital brain atlases are likely to be at the core of this defence."

Source: University of Edinburgh

'Seeding' property provides new focus for treatment to delay progression of disorder

By identifying in spinal fluid how the characteristic mutant proteins of Huntington's disease spread from cell to cell, researchers have created a new method to quickly and accurately track the presence and proliferation of these neuron-damaging compounds — a discovery that may accelerate the development of new drugs to treat this incurable disease.

The researchers added that the cell-to-cell "seeding" property of these mutant proteins seems to be a critical part of the disease's progression. Their findings also advance a new drug-discovery approach: stopping the cellular transfer of the seeding compounds. Study results appear online in the journal “Molecular Psychiatry”.

Analysis of health insurance data suggests preventive effect

Type 2 diabetes most commonly occurs in late adulthood, and it has long been known that it can affect the patient's mental health: Patients have a greater risk of developing dementia than non-diabetics. However, how does antidiabetic medication influence this risk? Researchers have investigated this issue in a new study based on data from the years 2004 to 2010 provided by the German public health insurance company AOK. These data set comprises information about diseases and medication related to more than 145,000 men and women aged 60 and over.

The analysis confirmed previous findings that diabetics have an increased risk of developing dementia. However, it was also found that this risk can significantly be modified by pioglitazone. This drug is taken as tablets. It is applied in short-term as well as in long-term treatment of diabetes as long as the body is still capable of producing its own insulin.

"Treatment with pioglitazone showed a remarkable side benefit. It was able to significantly decrease the risk of dementia," says co-author Gabriele Doblhammer. "The longer the treatment, the lower the risk." Risk reduction was most noticeable when the drug was administered for at least two years. Diabetics given this treatment developed dementia less often than non-diabetics. "The risk of developing dementia was around 47 percent lower than in non-diabetics, i.e. only about half as large.", she said.

Protection against nerve cell damage

Pioglitazone improves the effect of the body's own insulin. Moreover, laboratory tests have long indicated that it also protects the nerve cells. The current results are therefore no surprise to neuroscientist Michael Heneka. "Pioglitazone is an anti-inflammatory drug that also inhibits the deposition of harmful proteins in the brain," he says.

However, Heneka emphasizes that the exact mechanisms are not yet understood: "Our study suggests that pioglitazone has a preventive effect. This happens when the drug is taken before symptoms of dementia manifest. Thus, it protects in particular against Alzheimer's, the most common form of dementia. The causes for this, whether pioglitazone only has this protective effect in diabetics or if it would also work in non-diabetics – all these questions have yet to be answered. The next logical step would therefore be clinical studies. These studies would specifically investigate the effect of pioglitazone and other antidiabetics on dementia.

Source: Eurekalert

Scientists have identified a single blood protein that may indicate the development of Mild Cognitive Impairment (MCI) years before symptoms appear, a disorder that has been associated with an increased risk of Alzheimer's disease or other dementias.

The research, published in the journal “Translational Psychiatry”, used data from over 100 sets of twins from TwinsUK, the biggest adult twin cohort in the UK. The use of 55 identical twin-pairs in the study allowed researchers to show that the association between the blood protein and a ten year decline in cognitive ability was independent of age and genetics, both of which are already known to affect the risk of developing Alzheimer’s disease, the most common form of dementia.

The study, the largest of its kind to date, measured over 1,000 proteins in the blood of over 200 healthy individuals using a laboratory test called SOMAscan*, a protein biomarker discovery tool that simultaneously measures a wide range of different proteins. Using a computerised test, the researchers then assessed each individual’s cognitive ability, and compared the results with the measured levels of each different protein in the blood.

For the first time, they found that the blood level of a protein called MAPKAPK5 was, on average, lower in individuals whose cognitive ability declined over a ten year period.

Source: Medical Research Council, UK

An international team of researchers has developed a method for fabricating nano-scale electronic scaffolds that can be injected via syringe. Once connected to electronic devices, the scaffolds can be used to monitor neural activity, stimulate tissues and even promote regenerations of neurons.

The study entitled “Syringe-injectable electronics” was recently published in the journal Nature.

Nanotechnology and revealed an innovative method to employ tiny electronic devices in the brain, or other parts of the body, as a potential therapy for a wide range of disorders, including neurodegenerative diseases like amyotrophic lateral sclerosis (ALS). The study was performed by researchers at the Harvard University in Cambridge, Massachusetts and the National Center for Nanoscience and Technology in China.

The team had previously shown that cardiac or nerve cells grown with embedded nano-scale electronic scaffolds could generate a so-called “cyborg” tissue. The electronic devices could then record the electrical signals generated by the tissues, and measure signal changes when cardio- or neuro-stimulating drugs were administered to the cells.

Minimally invasive targeted delivery of electronics into artificial or natural structures is however a challenge. “We were able to demonstrate that we could make this scaffold and culture cells within it, but we didn’t really have an idea how to insert that into pre-existing tissue,” explained the study’s senior author Dr. Charles Lieber in a news release. Now, Dr. Lieber and colleagues have developed a pioneering method where sub-micrometer-thick mesh electronics can be delivered to their target through injection via a syringe.

Though not the first attempts at implanting electronics into the brain — deep brain stimulation has been used to treat a variety of disorders for decades — the nano-fabricated scaffolds operate on a completely different scale.

"Existing techniques are crude relative to the way the brain is wired," Lieber explained. "Whether it's a silicon probe or flexible polymers…they cause inflammation in the tissue that requires periodically changing the position or the stimulation. But with our injectable electronics, it's as if it's not there at all. They are one million times more flexible than any state-of-the-art flexible electronics and have subcellular feature sizes. They're what I call "neuro-philic" — they actually like to interact with neurons.

Source: Science Daily

Two studies in the May 19 issue of JAMA analyze the prevalence of the plaque amyloid among adults of varying ages, with and without dementia, and its association with cognitive impairment.

The earliest recognizable pathological event in Alzheimer’s Disease (AD) is cerebral amyloid-beta aggregation (protein fragments that clump together to form plaque).This pathology may be present up to 20 years before the onset of dementia.

Therefore, estimates of the prevalence of amyloid pathology in persons without dementia are needed to better understand the development of AD and to facilitate the design of AD prevention studies. Initiation of treatment for AD in the pre-dementia phase, when neuronal damage is still limited, may be crucial to have clinical benefit.

Led by Pieter Jelle Visser at VU University Medical Center in Amsterdam and Maastricht University, The Netherlands, these two studies compiled amyloid PET and cerebrospinal fluid (CSF) biomarker data from thousands of participants, and represent the largest data sets to date on how commonly amyloid builds up in people’s brains.

One meta-analysis looked at the prevalence of amyloid in cognitively normal people, and concluded that amyloid creeps into the brain 20 to 30 years before dementia can be diagnosed. This was particularly true for people who carry an ApoE4 allele; indeed, they developed amyloid at a younger age.

In the second study, the researchers compared amyloid prevalence among people clinically diagnosed with AD or other dementias, including dementia with Lewy bodies, frontotemporal dementia, and corticobasal syndrome. They found that the prevalence of brain amyloid in people diagnosed with most non-AD dementias was higher with increasing age. They concluded that older people may be likelier to have multiple pathologies, or to have been misdiagnosed. The data may help researchers set inclusion criteria for clinical trials, or make better diagnoses.

“The observation that key risk factors for AD-type dementia are also risk factors for amyloid positivity in cognitively normal persons provides further evidence for the hypothesis that amyloid positivity in these individuals reflects early AD,” the researchers wrote. “Our study also indicates that development of AD pathology can start as early as age 30 years, depending on the APOE genotype. Comparison with prevalence and lifetime risk estimates of AD-type dementia suggests a 20- to 30-year interval between amyloid positivity and dementia, implying that there is a large window of opportunity to start preventive treatments.”

However, the authors point out that follow-up studies need to be conducted since not all people with amyloid pathology develop dementia in their lifetime, and not all people with a clinical diagnosis of Alzheimer's dementia have amyloid pathology.

“Because of the uncertainty about whether and when an amyloid-positive individual without dementia will develop dementia, amyloid positivity in these individuals should not be equated with impending clinical dementia but rather be seen as a risk state,” they wrote. “Our prevalence rates can be used as an inexpensive and noninvasive approach to select persons at risk for amyloid positivity.”

The Innovative Medicines Initiative 2 (IMI 2) indicative topic text for Call 5 is now available, with heavy emphasis on Alzheimer’s Disease. The following topics are under consideration for inclusion in the call:

Patient perspective elicitation on benefits and risks of medicinal products from development through the entire life cycle, for integration into benefit risk assessments by regulators and health technology assessment bodies
Diabetic kidney disease biomarkers (DKD-BM)
Inflammation and Alzheimer’s disease (AD): modulating microglia function – focussing on TREM2 and CD33
Understanding the role of amyloid biomarkers in the current and future diagnosis and management of patients across the spectrum of cognitive impairment (from pre-dementia to dementia)
Evolving models of patient engagement and access for earlier identification of Alzheimer’s disease: phased expansion study
Apolipoprotein E (ApoE) biology to validated Alzheimer’s disease targets

Note: All information regarding future IMI Call topics is indicative and subject to change. Final information about future IMI Calls will be communicated after approval by the IMI Governing Board.

Most neurodegenerative diseases that afflict humans are associated with the intracytoplasmic deposition of aggregate-prone proteins in neurons and with mitochondrial dysfunction.

Autophagy is a powerful process for removing such proteins and for maintaining mitochondrial homeostasis. Over recent years, evidence has accumulated to demonstrate that upregulation of autophagy may protect against neurodegeneration.However, autophagy dysfunction has also been implicated in the pathogenesis of various diseases.

This Review summarizes the progress that has been made in our understanding of how perturbations in autophagy are linked with neurodegenerative diseases and the potential therapeutic strategies resulting from the modulation of this process.