Blood Test Identifies Those At-Risk for Cognitive Decline, Alzheimer’s Within 3 Years

Researchers have discovered and validated a blood test that can predict with greater than 90 percent accuracy if a healthy person will develop mild cognitive impairment or Alzheimer’s disease within three years.

Described in the April issue of Nature Medicine, the study heralds the potential for developing treatment strategies for Alzheimer’s at an earlier stage, when therapy would be more effective at slowing or preventing onset of symptoms. It is the first known published report of blood-based biomarkers for preclinical Alzheimer’s.

The test identifies 10 lipids, or fats, in the blood that predict disease onset. It could be ready for use in clinical studies in as few as two years and, researchers say, other diagnostic uses are possible.

“Our novel blood test offers the potential to identify people at risk for progressive cognitive decline and can change how patients, their families and treating physicians plan for and manage the disorder,” says the study’s corresponding author Howard J. Federoff, MD, PhD, professor of neurology and executive vice president for health sciences at Georgetown University Medical Center.

There is no cure or effective treatment for Alzheimer’s. Worldwide, about 35.6 million individuals have the disease and, according to the World Health Organization, the number will double every 20 years to 115.4 million people with Alzheimer’s by 2050.

Federoff explains there have been many efforts to develop drugs to slow or reverse the progression of Alzheimer’s disease, but all of them have failed. He says one reason may be the drugs were evaluated too late in the disease process.

“The preclinical state of the disease offers a window of opportunity for timely disease-modifying intervention,” Federoff says. “Biomarkers such as ours that define this asymptomatic period are critical for successful development and application of these therapeutics.”

The study included 525 healthy participants aged 70 and older who gave blood samples upon enrolling and at various points in the study. Over the course of the five-year study, 74 participants met the criteria for either mild Alzheimer’s disease (AD) or a condition known as amnestic mild cognitive impairment (aMCI), in which memory loss is prominent. Of these, 46 were diagnosed upon enrollment and 28 developed aMCI or mild AD during the study (the latter group called converters).

In the study’s third year, the researchers selected 53 participants who developed aMCI/AD (including 18 converters) and 53 cognitively normal matched controls for the lipid biomarker discovery phase of the study. The lipids were not targeted before the start of the study, but rather, were an outcome of the study.

A panel of 10 lipids was discovered, which researchers say appears to reveal the breakdown of neural cell membranes in participants who develop symptoms of cognitive impairment or AD. The panel was subsequently validated using the remaining 21 aMCI/AD participants (including 10 converters), and 20 controls. Blinded data were analyzed to determine if the subjects could be characterized into the correct diagnostic categories based solely on the 10 lipids identified in the discovery phase.

“The lipid panel was able to distinguish with 90 percent accuracy these two distinct groups: cognitively normal participants who would progress to MCI or AD within two to three years, and those who would remain normal in the near future,” Federoff says.

The researchers examined if the presence of the APOE4 gene, a known risk factor for developing AD, would contribute to accurate classification of the groups, but found it was not a significant predictive factor in this study.

“We consider our results a major step toward the commercialization of a preclinical disease biomarker test that could be useful for large-scale screening to identify at-risk individuals,” Federoff says. “We’re designing a clinical trial where we’ll use this panel to identify people at high risk for Alzheimer’s to test a therapeutic agent that might delay or prevent the emergence of the disease.”

Protein reelin rescues cognitive impairment in animal models of Alzheimer’s disease

The scientists Eduardo Soriano and Lluís Pujadas, from the University of Barcelona (UB), and the “Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas” (CIBERNED) have led research into the role of reelin in animal models of Alzheimer’s disease.

Published today in the journal Nature Communications, the study demonstrates how an increase in the levels of reelin—a protein that is essential for cerebral cortex plasticity—has the capacity to restore cognitive capacity in mouse models of Alzheimer’s disease, delaying amyloid-beta (Αβ) fibril formation in vitro and reducing the accumulation of amyloid deposits in the brains of animals affected by this disease.

The study, which was started four years ago, has involved the collaboration of members of the Peptides and Proteins lab at the Institute for Research in Biomedicine (IRB), namely Bernat Serra-Vidal, PhD student, Ernest Giralt, group leader, and Natàlia Carulla, associate researcher whose investigation focuses on the aggregation of Αβ. Alzheimer’s disease, which affects approximately 500,000 people in Spain, is characterised by the loss of neural connections and by neuronal death, both associated mainly with the formation of senile plaques (extracellular deposits of Aβ) and the presence of neurofibrillary tangles (intracellular deposits of tau protein.

In the IRB lab, researchers have performed experiments in vitro to determine whether there is an interaction between Aβ aggregation and reelin. These assays have revealed that reelin interacts with the Aβ peptide, delaying the formation of Aβ fibrils until it is trapped within them. “When reelins becomes trapped in Aβ fibrils, it loses its capacity to strengthen synaptic plasticity. This explains why an increase in reelin expression in the brain may be beneficial,” explain the authors of the study.

The hypotheses from the work in vitro have been tested in vivo using experimental animals. This study is the first to demonstrate a neuroprotective effect of reelin in neurodegenerative disease and, in addition, offers a possible explanation for this protective role.

Ever-So-Slight Delay Improves Decision-Making Accuracy

Columbia University Medical Center (CUMC) researchers have found that decision-making accuracy can be improved by postponing the onset of a decision by a mere fraction of a second. The results could further our understanding of neuropsychiatric conditions characterized by abnormalities in cognitive function and lead to new training strategies to improve decision-making in high-stake environments. The study was published in the March 5 online issue of the journal PLoS One.

“Decision making isn’t always easy, and sometimes we make errors on seemingly trivial tasks, especially if multiple sources of information compete for our attention,” said first author Tobias Teichert, PhD, a postdoctoral research scientist in neuroscience at CUMC at the time of the study and now an assistant professor of psychiatry at the University of Pittsburgh. “We have identified a novel mechanism that is surprisingly effective at improving response accuracy.

The mechanism requires that decision-makers do nothing—just briefly. “Postponing the onset of the decision process by as little as 50 to 100 milliseconds enables the brain to focus attention on the most relevant information and block out irrelevant distractors,” said last author Jack Grinband, PhD, associate research scientist in the Taub Institute and assistant professor of clinical radiology (physics). “This way, rather than working longer or harder at making the decision, the brain simply postpones the decision onset to a more beneficial point in time.”

In making decisions, the brain integrates many small pieces of potentially contradictory sensory information. “Imagine that you’re coming up to a traffic light—the target—and need to decide whether the light is red or green,” said Dr. Teichert. “There is typically little ambiguity, and you make the correct decision quickly, in a matter of tens of milliseconds.”

The decision process itself, however, does not distinguish between relevant and irrelevant information. Hence, a task is made more difficult if irrelevant information—a distractor—interferes with the processing of the target. Distractors are present all the time; in this case, it might be in the form of traffic lights regulating traffic in other lanes. Though the brain is able to enhance relevant information and filter out distractions, these mechanisms take time.  If the decision process starts while the brain is still processing irrelevant information, errors can occur.

Studies have shown that response accuracy can be improved by prolonging the decision process, to allow the brain time to collect more information. Because accuracy is increased at the cost of longer reaction times, this process is referred to as the “speed-accuracy trade-off.” The researchers thought that a more effective way to reduce errors might be to delay the decision process so that it starts out with better information.

The research team conducted two experiments to test this hypothesis. In the first, subjects were shown what looked like a swarm of randomly moving dots (the target stimulus) on a computer monitor and were asked to judge whether the overall motion was to the left or right. A second and brighter set of moving dots (the distractor) appeared simultaneously in the same location, obscuring the motion of the target.  When the distractor dots moved in the same direction as the target dots, subjects performed with near-perfect accuracy, but when the distractor dots moved in the opposite direction, the error rate increased. The subjects were asked to perform the task either as quickly or as accurately as possible; they were free to respond at any time after the onset of the stimulus.

The second experiment was similar to the first, except that the subjects also heard regular clicks, indicating when they had to respond. The time allowed for viewing the dots varied between 17 and 500 milliseconds. This condition simulates real-life situations, such as driving, where the time to respond is beyond the driver’s control. “Manipulating how long the subject viewed the stimulus before responding allowed us to determine how quickly the brain is able to block out the distractors and focus on the target dots,” said Dr. Grinband.

“In this situation, it takes about 120 milliseconds to shift attention from one stimulus (the bright distractors) to another (the darker targets),” said Dr. Grinband. “To our knowledge, that’s something that no one has ever measured before.”

The experiments also revealed that it’s more beneficial to delay rather than prolong the decision process. The delay allows attention to be focused on the target stimulus and helps prevent irrelevant information from interfering with the decision process. “Basically, by delaying decision onset—simply by doing nothing—you are more likely to make a correct decision,” said Dr. Teichert.

Finally, the results showed that decision onset is, to some extent, under cognitive control. “The subjects automatically used this mechanism to improve response accuracy,” said Dr. Teichert. “However, we don’t think that they were aware that they were doing so. The process seems to go on behind the scenes. We hope to devise training strategies to bring the mechanism under conscious control.”

“This might be the first scientific study to justify procrastination,” Dr. Teichert said. “On a more serious note, our study provides important insights into fundamental brain processes and yields clues as to what might be going wrong in diseases such as ADHD and schizophrenia. It also could lead to new training strategies to improve decision making in complex high-stakes environments, such as air traffic control towers and military combat.”

Inherited Alzheimer’s damage greater decades before symptoms appear

In a paper published in the prestigious journal Science Translational Medicine, Professor Colin Masters from the Florey Institute of Neuroscience and Mental Health and University of Melbourne – and colleagues in the UK and US – have found rapid neuronal damage begins 10 to 20 years before symptoms appear.

“As part of this research we have observed other changes in the brain that occur when symptoms begin to appear. There is actually a slowing of the neurodegeneration,” said Professor Masters.
Autosomal-dominant Alzheimer’s affects families with a genetic mutation, predisposing them to the crippling disease. These families provide crucial insight into the development of Alzheimer’s because they can be identified years before symptoms develop. The information gleaned from this group will also influence treatment offered to those living with the more common age-related version. Only about one per cent of those with Alzheimer’s have the genetic type of the disease.

The next part of the study involves a clinical trial. Using a range of imaging techniques (MRI and PET) and analysis of blood and cerebrospinal fluid, individuals from the US, UK and Australia will be observed as they trial new drugs to test their safety, side effects and changes within the brain.

 “As part of an international study, family members are invited to be part of a trial in which two experimental drugs are offered many years before symptoms appear,” Prof Masters says. “It’s going to be very interesting to see how clinical intervention affects this group of patients in the decades before symptoms appear.”

The Florey is looking to recruit more participants in the Dominantly Inherited Alzheimer Network (DIAN) study. Those who either know they have a genetic mutation that causes autosomal-dominant Alzheimer’s or who don’t know their genetic status but have a parent or sibling with the mutation are invited to email: dian@florey.edu.au

Researchers Use Computers to “See” Neurons to Better Understand Brain Function

A study conducted by local high school students and faculty from the Department of Computer and Information Science in the School of Science at Indiana University-Purdue University Indianapolis reveals new information about the motor circuits of the brain that may one day help those developing therapies to treat conditions such as stroke, schizophrenia, spinal cord injury or Alzheimer’s disease.

"MRI and CAT scans of the human brain can tell us many things about the structure of this most complicated of organs, formed of trillions of neurons and the synapses via which they communicate. But we are a long way away from having imaging techniques that can show single neurons in a complex brain like the human brain," said Gavriil Tsechpenakis, Ph.D., assistant professor of computer science in the School of Science at IUPUI.

"But using the tools of artificial intelligence, specifically computer vision and image processing, we are able to visualize and process actual neurons of model organisms. Our work in the brain of a model organism—the fruit fly—will help us and other researchers move forward to more complex organisms with the ultimate goal of reconstructing the human central nervous system to gain insight into what goes wrong at the cellular level when devastating disorders of the brain and spinal cord occur. This understanding may ultimately inform the treatment of these conditions," said Tsechpenakis.

In this study, which processed images and reconstructed neuronal motor circuitry in the brain, the researchers, who included two Indianapolis high school students—Rachel Stephens and Tiange (Tony) Qu—collected and analyzed data on minute structures over various developmental stages, efforts linking neuroscience and computer science.

"Both high school students who worked on this study performed neuroscience and computation efforts similar to that conducted elsewhere by graduate students. It was impressive to see what sophisticated and key work they could—with mentoring—do," said Tsechpenakis.

Qu said the work was initially rather scary and intimidating but that he rapidly grew to appreciate the opportunity to work in the School of Science lab. “Unlike high school, we were not told how to get from point A to point B. Dr. Tsechpenakis explained what point A and B were and taught us how to figure out how to get from A to B.” 

Qu, a 17-year-old senior at Ben Davis High School, now sees neuroscience as a potential college major with biomedical research as an eventual career goal. He continues to work in the lab after school focusing on change over time in fruit fly larvae motor neurons.

Stephens, a senior at North Central High School, said she enjoyed the collaborative nature of the research, with computer scientists and life scientists working together on a problem.

"Dr. Tsechpenakis made it clear to us that different perspectives are necessary, and the ability to think about a problem is more valuable than the education and training you’ve had,” she said. “Before I joined the lab I hadn’t really thought about how computer science could help heal." The 17-year-old plans a pre-med major in college and a career as a physician.

Discovery sheds new light on marijuana’s anxiety relief effects

An international group led by Vanderbilt University researchers has found cannabinoid receptors, through which marijuana exerts its effects, in a key emotional hub in the brain involved in regulating anxiety and the flight-or-fight response.

This is the first time cannabinoid receptors have been identified in the central nucleus of the amygdala in a mouse model, they report in the current issue of the journal Neuron.

The discovery may help explain why marijuana users say they take the drug mainly to reduce anxiety, said Sachin Patel, M.D., Ph.D., the paper’s senior author and professor of Psychiatry and of Molecular Physiology and Biophysics.

Led by first author Teniel Ramikie, a graduate student in Patel’s lab, the researchers also showed for the first time how nerve cells in this part of the brain make and release their own natural “endocannabinoids.”

The study “could be highly important for understanding how cannabis exerts its behavioral effects,” Patel said. As the legalization of marijuana spreads across the country, more people — and especially young people whose brains are still developing — are being exposed to the drug.
Previous studies at Vanderbilt and elsewhere, Patel said, have suggested the following:

• The natural endocannabinoid system regulates anxiety and the response to stress by dampening excitatory signals that involve the neurotransmitter glutamate.

• Chronic stress or acute, severe emotional trauma can cause a reduction in both the production of endocannabinoids and the responsiveness of the receptors. Without their “buffering” effect, anxiety goes up.

• While marijuana’s “exogenous” cannabinoids also can reduce anxiety, chronic use of the drug down-regulates the receptors, paradoxically increasing anxiety. This can trigger “a vicious cycle” of increasing marijuana use that in some cases leads to addiction.

In the current study, the researchers used high-affinity antibodies to “label” the cannabinoid receptors so they could be seen using various microscopy techniques, including electron microscopy, which allowed very detailed visualization at individual synapses, or gaps between nerve cells.

“We know where the receptors are, we know their function, we know how these neurons make their own cannabinoids,” Patel said. “Now can we see how that system is affected by … stress and chronic (marijuana) use? It might fundamentally change our understanding of cellular communication in the amygdala.”

(Image: Shutterstock)

Scientists Create Most Detailed Picture Ever of Membrane Protein Linked to Learning, Memory, Anxiety, Pain and Brain Disorders

Researchers at The Scripps Research Institute (TSRI) and Vanderbilt University have created the most detailed 3-D picture yet of a membrane protein that is linked to learning, memory, anxiety, pain and brain disorders such as schizophrenia, Parkinson’s, Alzheimer’s and autism.

"This receptor family is an exciting new target for future medicines for treatment of brain disorders," said P. Jeffrey Conn, PhD, Lee E. Limbird Professor of Pharmacology and director of the Vanderbilt Center for Neuroscience Drug Discovery, who was a senior author of the study with Raymond Stevens, PhD, a professor in the Department of Integrative Structural and Computational Biology at TSRI. "This new understanding of how drug-like molecules engage the receptor at an atomic level promises to have a major impact on new drug discovery efforts."

The research—which focuses on the mGlu₁ receptor—was reported in the March 6, 2014 issue of the journal Science.

A Family of Drug Targets

The mGlu₁ receptor, which helps regulate the neurotransmitter glutamate, belongs to a superfamily of molecules known as G protein-coupled receptors (GPCRs).

GPCRs sit in the cell membrane and sense various molecules outside the cell, including odors, hormones, neurotransmitters and light. After binding these molecules, GPCRs trigger a specific response inside the cell. More than one-third of therapeutic drugs target GPCRs—including allergy and heart medications, drugs that target the central nervous system and anti-depressants.

The Stevens lab’s work has revolved around determining the structure and function of GPCRs. GPCRs are not well understood and many fundamental breakthroughs are now occurring due to the understanding of GPCRs as complex machines, carefully regulated by cholesterol and sodium. 

When the Stevens group decided to pursue the structure of mGlu₁ and other key members of the mGlu family, it was natural the scientists reached out to the researchers at Vanderbilt. “They are the best in the world at understanding mGlu receptors,” said Stevens. “By collaborating with experts in specific receptor subfamilies, we can reach our goal of understanding the human GPCR superfamily and how GPCRs control human cell signaling.”

Colleen Niswender, PhD, director of Molecular Pharmacology and research associate professor of Pharmacology at the Vanderbilt Center for Neuroscience Drug Discovery, also thought the collaboration made sense. “This work leveraged the unique strengths of the Vanderbilt and Scripps teams in applying structural biology, molecular modeling, allosteric modulator pharmacology and structure-activity relationships to validate the receptor structure,” she said.

The Challenge of the Unknown

mGlu₁ was a particularly challenging research topic.

In general, GPCRs are exceedingly flimsy, fragile proteins when not anchored within their native cell membranes. Coaxing them to line up to form crystals, so that their structures can be determined through X-ray crystallography, has been a formidable challenge. And the mGlu₁ receptor is particularly tricky as, in addition to the domain spanning the membrane, it has a large domain extending into the extracellular space. Moreover, two copies of this multidomain receptor associating in a dimer are needed to transmit glutamate’s signal across the membrane.   

The task was made more difficult because there was no template for mGlu₁ from closely related GPCR proteins to guide the researchers.

“mGlu₁ belongs to class C GPCRs, of which no structure has been solved before,” said TSRI graduate student Chong Wang, a first author of the new study with TSRI graduate student Huixian Wu. “This made the project much harder. We could not use other GPCRs as a template to design constructs for expression and stabilization or to help interpret diffraction data. The structure was so different that old school methods in novel protein structure determination had to be used.”

Surprising Results

The team decided to try to determine the structure of mGlu₁ bound to novel “allosteric modulators” of mGlu₁ contributed by the Vanderbilt group. Allosteric modulators bind to a site far away from the binding site of the natural activator (in this case, presumably the glutamate molecule), but change the shape of the molecule enough to affect receptor function. In the case of allosteric drug candidates, the hope is that the compounds affect the receptor function in a desirable, therapeutic way.

"Allosteric modulators are promising drug candidates as they can ‘fine-tune’ GPCR function,” said Karen Gregory, a former postdoctoral fellow at Vanderbilt University, now at Monash Institute of Pharmaceutical Sciences. “However, without a good idea of how drug-like compounds interact with the receptor to adjust the strength of the signal, discovery efforts are challenging."

The team proceeded to apply a combination of techniques, including X-ray crystallography, structure-activity relationships, mutagenesis and full-length dimer modeling. At the end of the study, they had achieved a high-resolution image of mGlu₁ in complex with one of the drug candidates, as well as a deeper understanding of the receptor’s function and pharmacology.

The findings show that mGlu₁ possesses structural features both similar to and distinct from those seen in other GPCR classes, but in ways that would have been impossible to predict in advance.

“Most surprising is that the entrance to a binding pocket in the transmembrane domain is almost completely covered by loops, restricting access for the binding of allosteric modulators,” said Vsevolod “Seva” Katritch, assistant professor of molecular biology at TSRI and a co-author of the paper. “This is very important for understanding action of the allosteric modulator drugs and may partially explain difficulties in screening for such drugs.

“The mGlu₁ receptor structure now provides a solid platform for much more reliable modeling of closely related receptors,” he continued, “some of which are equally important in drug discovery.”

Motion-Sensing Cells in the Eye Let the Brain ‘Know’ About Directional Changes

How do we “know” from the movements of speeding car in our field of view if it’s coming straight toward us or more likely to move to the right or left?

Scientists have long known that our perceptions of the outside world are processed in our cortex, the six-layered structure in the outer part of our brains. But how much of that processing actually happens in cortex? Do the eyes tell the brain a lot or a little about the content of the outside world and the objects moving within it?

In a detailed study of the neurons linking the eyes and brains of mice, biologists at UC San Diego discovered that the ability of our brains and those of other mammals to figure out and process in our brains directional movements is a result of the activation in the cortex of signals that originate from the direction-sensing cells in the retina of our eyes.

“Even though direction-sensing cells in the retina have been known about for half a century, what they actually do has been a mystery- mostly because no one knew how to follow their connections deep into the brain,” said Andrew Huberman, an assistant professor of neurobiology, neurosciences and ophthalmology at UC San Diego, who headed the research team, which also involved biologists at the Salk Institute for Biological Sciences. “Our study provides the first direct link between direction-sensing cells in the retina and the cortex and thereby raises the new idea that we ‘know’ which direction things are moving specifically because of the activation of these direction-selective retinal neurons.” The study, recently published online, will appear in the March 20 print issue of Nature.

The discovery of the link between direction-sensing cells in the retina and the cortex has a number of practical implications for neuroscientists who treat disabilities in motion processing, such as dysgraphia, a condition sometimes associated with dyslexia that affects direction-oriented skills.

“Understanding the cells and neural circuits involved in sensing directional motion may someday help us understand defects in motion processing, such as those involved dyslexia, and it may inform strategies to treat or even re-wire these circuits in response to injury or common neurodegenerative diseases, such as glaucoma or Alzheimer’s,” said Huberman.

He and his team discovered the link in mice by using new types of modified rabies viruses that were pioneered by Ed Callaway, a professor at the Salk Institute, and by imaging the activity of neurons deep in the brain during visual experience.