Posts tagged neuroscience
Articles and news from the latest research reports.
Neural Activity in Bats Measured In Flight
Animals navigate and orient themselves to survive – to find food and shelter or avoid predators, for example. Research conducted by Dr. Nachum Ulanovsky and research student Michael Yartsev of the Weizmann Institute’s Neurobiology Department, published today in Science, reveals for the first time how three-dimensional, volumetric, space is perceived in mammalian brains. The research was conducted using a unique, miniaturized neural-telemetry system developed especially for this task, which enabled the measurement of single brain cells during flight.
The question of how animals orient themselves in space has been extensively studied, but until now experiments were only conducted in two-dimensional settings. These have found, for instance, that orientation relies on “place cells” – neurons located in the hippocampus, a part of the brain involved in memory, especially spatial memory. Each place cell is responsible for a spatial area, and it sends an electrical signal when the animal is located in that area. Together, the place cells produce full representations of whole spatial environments. Unlike the laboratory experiments, however, the navigation of many animals in the real world, including humans, is carried out in three dimensions. But attempts to expand the scope of experiments from two to three dimensions had encountered difficulties.
One of the more famous efforts in this area was conducted by the University of Arizona and NASA, in which they launched rats into space (aboard a space shuttle). However, although the rats moved around in zero gravity, they ran along a set of straight, one-dimensional lines. Other experiments with three-dimensional projections onto two-dimensional surfaces did not manage to produce volumetric data, either. The conclusion was that in order to understand movement in three-dimensional, volumetric space, it is necessary to allow animals to move through all three dimensions – that is, to research animals in flight.
Ulanovsky chose to study the Egyptian fruit bat, a very common bat species in Israel. Because these are relatively large, the researchers were able to attach the wireless measuring system in a manner that did not restrict the bats’ movements. Developing this sophisticated measuring system was a several-year effort. Ulanovsky, in cooperation with a US commercial company, created a wireless, lightweight (12 g, about 7% of the weight of the bat) device containing electrodes that measure the activity of individual neurons in the bat’s brain.
The next challenge the scientists faced was adapting the behavior of their bats to the needs of the experiment. Bats naturally fly toward their destination – for example, a fruit tree – in a straight line. In other words, their normal flight patterns are one-dimensional, while the experiment required their flights to fill a three-dimensional space.
The solution was to be found in a previous study in Ulanovsky’s group, which tracked wild fruit bats using miniature GPS devices. One of the discoveries was that when bats arrive at a fruit tree, they fly around it, utilizing the full volume of space surrounding the tree. To simulate this behavior in the laboratory – an artificial cave equipped with an array of bat-monitoring devices – the team installed an artificial “tree” made of metal bars and cups filled with fruit.
Measuring the activity of hippocampus neurons in the bats’ brains revealed that the representation of three-dimensional space is similar to that in two dimensions: Each place cell is responsible for identifying a particular spatial area in the “cave” and sends an electrical signal when the bat is located in that area. Together, the population of place cells provides full coverage of the cave – left and right, up and down.
A closer examination of the areas for which individual place cells are responsible provided an answer to a highly-debated question: Does the brain perceive the three dimensions of space as “equal,” that is, does it sense the height axis in the same way as that of length or width? The findings suggest that each place cell responds to a spherical volume of space, i.e., the perception of all three dimensions is uniform. The researchers note that for those non-flying animals that essentially move in flat space, the different axes might not be perceived at the same resolution. It may be that such animals are naturally more sensitive to changes along the length and width axes than that of height. This question is of particular interest when it comes to humans because on the one hand, humans evolved from apes that moved in three-dimensional space when swinging from branch to branch, but on the other hand, modern, ground-dwelling humans generally navigate in two-dimensional space.
The findings provide new insights into some basic functions of the brain: navigation, spatial memory and spatial perception. To a large extent, this is due to the development of innovative technology that allowed the first glimpse into the brain of a flying animal. Ulanovsky believes that this trend, in which research is becoming more “natural,” is the future wave of neuroscience.
Bat and Rat Brain Rhythms Differ When on the Move
To get a clear picture of how humans and other mammals form memories and find their way through their surroundings, neuroscientists must pay more attention to a broad range of animals rather than focus on a single model species, say two University of Maryland researchers, Katrina MacLeod and Cynthia Moss. Their new comparative study of bats and rats reports differences between the species that suggest the need to revise models of spatial navigation.
In a paper appearing in the April 19, 2013 issue of Science, the UMD researchers and two colleagues at Boston University reported significant differences between rats’ and bats’ brain rhythms when certain cells were active in a part of the brain used in memory and navigation.
These cells behaved as expected in rats, which mostly move along surfaces. But in bats, which fly, the continuous brain rhythm did not appear, said Moss, a professor in Psychology and Biology and the Institute for Systems Research.
The finding suggests that even though rats, bats, humans and other mammals share a common neural representation of space in a part of the brain that has been linked to spatial information and memory, they may have different cellular mechanisms to create or interpret those maps, said MacLeod, an assistant research scientist in Biology.
“To understand brains, including ours, we really must study neural activity in a variety of animals,” MacLeod said. “Common features across multiple species tell us ‘Aha, this is important,’ but differences can occur because of variances in the animals’ ecology, behavior, or evolutionary history.”
The research team focused on a brain region that contains specialized “grid cells,” so named because they form a hexagonal grid of activity related to the animal’s location as it navigates through space. This brain region, the medial entorhinal cortex, sits next to the hippocampus, the place that, in humans, forms memories of events such as where a car is parked. The medial entorhinal cortex acts as a hub of neural networks for memory and navigation.
Grid cells were first noticed in rats navigating their environment, but recent work by Nachum Ulanovsky (Moss’s former postdoctoral researcher at UMD) and his research team at the Weizmann Institute in Rehovot, Israel, has shown these cells exist in bats as well.
In rats, grid cells fire in a pattern called a theta wave when the animals spatially navigate. Theta waves are fairly low-frequency electrical oscillations that also have been observed at the cellular level in the medial entorhinal cortex. The prominence of theta waves in rats suggested they were important. As a result, neuroscientists, trying to understand the relationship between theta waves and grid cells, have developed models of the brain based on the assumption that theta waves are key to spatial navigation in mammals.
However, Moss said, “recordings from the brains of bats navigating in space contain a surprise, because the expected theta rhythms aren’t continuously present as they are in the rodent.”
The new Science study doubles down on the lack of theta in bats by reporting that theta rhythms also are not present at the cellular level. “The bat neurons don’t ‘ring’ the way the rat neurons do,” says MacLeod. “This raises a lots of questions as to whether theta rhythms are actually doing what the spatial navigation theory proposes in rats or even humans.”
Helpful for robotics: brain uses old information for new movements
Information from the senses has an important influence on how we move. For instance, you can see and feel when a mug is filled with hot coffee, and you lift it in a different way than if the mug were empty. Neuroscientist Julian Tramper discovered that the brain uses two forms of old information in order to execute new movements well. This discovery can be useful for the field of robotics. Tramper will receive his doctorate on Thursday 24 April from Radboud University Nijmegen
Every time you move, the brain deals with two problems. First, there is a slight delay in the sensory information needed to execute the movement. Second, the command from the brain directing the muscles to move is not entirely clear, because neuronal signals contain a certain amount of natural static interference. According to Tramper, the brain has a clever way of getting around both problems: It combines the old information from the senses with experience gained through similar movements made in the past. This means that our senses use two forms of old information in order to make new movements.
Computer versus test subject
Understanding the brain processes behind movement can be of great importance to fields like robotics. Therefore Tramper is trying to model his findings so that it will be possible to use them in robots in the future. He has already succeeded in this for certain hand-eye coordination experiments, to the extent that a computer can perform at about the same level as human test subjects. As a post-doctoral researcher within the Donders Institute, Tramper is researching how these types of models can be integrated into bio-inspired robots (robots based on biological principles).
SpaceCog
Tramper is currently working on a project called SpaceCog. The goal of this project is to develop a robot which can independently orient itself in space, something that humans do automatically. This is difficult to achieve, because each time a robot moves, it must reinterpret the information from its cameras and other sensors in order to determine whether the changes to its input are the result of its own movement or an external cause. The researchers involved in SpaceCog want to figure out how our brain has solved this problem. Tramper has three years to come up with a good computer model addressing this issue.
Looking towards the future
Tramper is studying hand-eye coordination by having test subjects play a special computer game. The subjects use a game controller to move a digital right hand and left hand on a screen. They have to move the two hands independently of one another and make them each follow a particular path in order to reach a final destination (see film 1). It turned out that the test subject’s eyes moved ahead of the digital hands. In other words, the eyes looked at a point that the hands would reach in the future (see film 2). This type of eye movement is called smooth pursuit, and before now it had only been detected in the case of external stimuli, when a subject was following an object’s movement. Tramper detected smooth pursuit eye movements at locations the hands had not yet reached, meaning these movements were triggered by internal stimuli.
Smooth pursuit
Tramper explains, ‘We’d previously demonstrated for other types of eye movement that the eye anticipates and moves in advance of external movement To our surprise, this is also the case with smooth pursuit. It is probable that this is a compromise between where you are at a particular moment and where you want to get to. When moving, you need to keep track of your current location (which is constantly changing) and your target destination. Smooth pursuit eye movements can help you do this by letting your eye “hover” between both locations. If we can teach robots to do something like this, it will help make their movements much more natural. This will increase the number of ways in which robots can be put to work.’
(Source: ru.nl)
Virus-like particles provide vital clues about brain tumours
Exosomes are small, virus-like particles that can transport genetic material and signal substances between cells. Researchers at Lund University, Sweden, have made new findings about exosomes released from aggressive brain tumours, gliomas. These exosomes are shown to have an important function in brain tumour development, and could be utilised as biomarkers to assess tumour aggressiveness through a blood test.
“Current wisdom says that cells are closed entities that communicate through the secretion of soluble signalling molecules. Recent findings indicate that cells can exchange more complex information – whole packages of genetic material and signalling proteins. This is an entirely new conception of how cells communicate”, says Dr Mattias Belting, Professor of Oncology at Lund University and senior consultant in oncology at Skåne University Hospital, Lund, Sweden.
Exosomes are small vesicles of only 30–90 nm. They are produced inside cells and act as “transport vehicles” of genetic material that can be transferred to surrounding cells. Since their first discovery, exosomes have been found in blood, saliva, urine, breast milk and other body fluids.
Mattias Belting’s research group has investigated exosomes released from tumour cells of patients with gliomas. The tiny exosome particles are delivered from the tumour to healthy cells of the brain and may prime normal tissue for efficient spreading of the tumour. The researchers in Lund have now shown that the aggressiveness of the tumour is reflected in the exosome molecular profile.
“We have succeeded in developing a method for the isolation of exosomes from brain tumour patients through a relatively simple blood test. Our analyses indicate that the content of exosomes mirrors the aggressiveness of the tumour in a unique manner”, says postdoctoral researcher Paulina Kucharzewska.
Exosomes could thus be utilised as biomarkers, i.e. to provide guidance on how the patient should be treated and to monitor treatment response. This possibility is particularly attractive with brain tumours that are not readily accessible for tissue biopsy. However, analysis of exosomes from the blood may also prove important with other tumour types. The value of conventional tumour biopsies is limited by the heterogeneity of tumour tissue, i.e. the tissue specimen may not be fully representative of the biological characteristics of a particular tumour. Exosomes, however, may offer more comprehensive information, according to the researchers.
The second international meeting on exosomes has just opened in Boston, and Mattias Belting and members of his team are there.
“It is very exciting to be part of the emergence of a novel research field. It can be anticipated that the most influential researchers in this area may one day be awarded the Nobel Prize”, says Dr Belting.
The results are published in Proceedings of the National Academy of Sciences (PNAS).
(Source: lunduniversity.lu.se)
Scientists probe the source of a pulsing signal in the sleeping brain
New findings clarify where and how the brain’s “slow waves” originate. These rhythmic signal pulses, which sweep through the brain during deep sleep at the rate of about one cycle per second, are assumed to play a role in processes such as consolidation of memory. For the first time, researchers have shown conclusively that slow waves start in the cerebral cortex, the part of the brain responsible for cognitive functions. They also found that such a wave can be set in motion by a tiny cluster of neurons.
"The brain is a rhythm machine, producing all kinds of rhythms all the time," says Prof. Arthur Konnerth of the Technische Universitaet Muenchen (TUM). "These are clocks that help to keep many parts of the brain on the same page." One such timekeeper produces the so-called slow waves of deep sleep, which are thought to be involved in transmuting fragments of a day’s experience and learning into lasting memory. They can be observed in very early stages of development, and they may be disrupted in diseases such as Alzheimer’s.
Previous studies, relying mainly on electrical measurements, have lacked the spatial resolution to map the initiation and propagation of slow waves precisely. But using light, Konnerth’s Munich-based team – in collaboration with researchers at Stanford and the University of Mainz – could both stimulate slow waves and observe them in unprecedented detail. One key result confirmed that the slow waves originate only in the cortex, ruling out other long-standing hypotheses. “The second major finding,” Konnerth says, “was that out of the billions of cells in the brain, it takes not more than a local cluster of fifty to one hundred neurons in a deep layer of the cortex, called layer 5, to make a wave that extends over the entire brain.”
New light on a fundamental neural mechanism
Despite considerable investigation of the brain’s slow waves, definitive answers about the underlying circuit mechanism have remained elusive. Where is the pacemaker for this rhythm? Where do the waves start, and where do they stop? This study – based on optical probing of intact brains of live mice under anesthesia – now provides the basis for a detailed, comprehensive view.
"We implemented an optogenetic approach combined with optical detection of neuronal activity to explore causal features of these slow oscillations, or Up-Down state transitions, that represent the dominating network rhythm in sleep," explains Prof. Albrecht Stroh of the Johannes Gutenberg University Mainz. Optogenetics is a novel technique that enabled the researchers to insert light-sensitive channels into specific kinds of neurons, to make them responsive to light stimulation. This allowed for selective and spatially defined stimulation of small numbers of cortical and thalamic neurons.
Access to the brain via optical fibers allowed for both microscopic recording and direct stimulation of neurons. Flashes of light near the mouse’s eyes were also used to stimulate neurons in the visual cortex. By recording the flux of calcium ions, a chemical signal that can serve as a more spatially precise readout of the electric activity, the researchers made the slow waves visible. They also correlated optical recordings with more conventional electrical measurements. As a result, it was possible to watch individual wave fronts spread – like ripples from a rock thrown into a quiet lake – first through the cortex and then through other brain structures.
A new picture begins to emerge: Not only is it possible for a tiny local cluster of neurons to initiate a slow wave that will spread far and wide, recruiting multiple regions of the brain into a single event – this appears to be typical. “In spontaneous conditions,” Konnerth says, “as it happens with you and me and everyone else every night in deep sleep, every part of the cortex can be an initiation site.” Furthermore, a surprisingly simple communication protocol can be seen in the slow wave rhythm. During each one-second cycle a single neuron cluster sends its signal and all others are silenced, as if they are taking turns bathing the brain in fragments of experience or learning, building blocks of memory. The researchers view these findings as a step toward a better understanding of learning and memory formation, a topic Konnerth’s group is investigating with funding from the European Research Council. They also are testing how the slow waves behave during disease.
Discovery of genetic defect which triggers epilepsy
Researchers at the University Department of Neurology at the MedUni Vienna have identified a gene behind an epilepsy syndrome, which could also play an important role in other idiopathic (genetically caused) epilepsies. With the so-called “next generation sequencing”, with which genetic changes can be identified within a few days, it was ascertained that the CNTN2 gene is defective in this type of epilepsy.
This was investigated by a team led by Elisabeth Stögmann in collaboration with Cairo’s Ain Shams University and the Helmholtz Centre Munich with reference to a particular Egyptian family, in which five sick children have resulted from the marriage of one healthy cousin to his, likewise healthy, second cousin. The children affected suffer from a specific epilepsy syndrome, in which different types of epileptic attacks occur. This constellation has the “advantage”, according to Stögmann, that both alleles of the gene, which is how one designates different forms of the gene, demonstrate this defect: “As a result the defect becomes symptomatic and identifiable.
"20,000 to 25,000 genes, including all the "protein coding" ones, were sequenced for this. When this was done a mutation was found in the CNTN2 gene. CNTN2 undertakes an important function in the anchoring of potassium channels to the synapses. The mutation makes it no longer possible to generate this protein and, as a consequence, the potassium channels no longer remain affixed to the synapses. The researchers suspect that the epilepsy in this family is triggered by the altered function of the potassium channels.
This discovery, which has now been published in the top journal “Brain”, is providing the stimulus for further research to investigate this particular gene in other epilepsy patients as well. Approximately one percent of the population suffers from active epilepsy in which regular epileptic fits occur. The danger of suffering from an epileptic fit once in your life lies at approximately four to five percent. Genetic factors play a major part in the occurrence of epilepsies.
(Source: meduniwien.ac.at)
Researchers discover new treatment possibilities for Lou Gehrig’s disease
A team led by Dr. Alex Parker, a professor of pathology and cellular biology and a researcher at the University of Montreal Hospital Research Centre (CRCHUM), has identified an important therapeutic target for alleviating the symptoms of Lou Gehrig’s disease, also known as amyotrophic lateral sclerosis (ALS), and other related neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease.
In a study published in the online version of Neurobiology of Disease, the team both confirmed the importance of this new target as well as a series of compounds that can be used to attenuate the dysregulation of one of the important cellular processes that lead to neuronal dysfunction and ultimately to brain cell death.
Although scientists are unclear about causes of ALS, they have made headway in identifying the cellular process potentially implicated in disease onset and progression. One such process which has attracted researcher interest involves the endoplasmic reticulum (ER), a component of cells that plays an important role in maintaining cell health. In collaboration with Dr. Pierre Drapeau at the University of Montreal and using worm and zebrafish models of ALS, Parker’s team not only confirmed that incapacitated ER leads to the motor neuron death typical of ALS, but also identified a series of compounds that alleviate the fatal consequences of defective ER.
“Since Riluzole, the one approved treatment compound for treating ALS, only has a modest effect on slowing disease progression, we set out to test a number of other compounds, and in so doing we discovered that they work by compensating for defective ER” explains Dr Parker. The compounds in question, Methylene blue, Salubrinal, Guanabenz and Phenazine, were each tested individually and in different combinations.
With the exception of Phenazine, these compounds have known benefits for treating neurodegenerative diseases. Parker and his team showed that each of these compounds reduces paralysis and neurodegeneration and that each acts on different parts of the ER pathway to achieve neuroprotection. More importantly, the researchers found that using these compounds in different combinations can enhance their therapeutic effects.
“These results are quite encouraging,” says Dr Parker, “and have given us a much better understanding of ER’s role in ALS as well as showing the way for improved treatments”. Parker’s team plans to test and confirm these findings with more complex animal models, a necessary step in developing medication that can be of benefit to human beings.
(Source: nouvelles.umontreal.ca)
Going Places: Rat Brain ‘GPS’ Maps Routes to Rewards
Research has implications for understanding memory and imagination
While studying rats’ ability to navigate familiar territory, Johns Hopkins scientists found that one particular brain structure uses remembered spatial information to imagine routes the rats then follow. Their discovery has implications for understanding why damage to that structure, called the hippocampus, disrupts specific types of memory and learning in people with Alzheimer’s disease and age-related cognitive decline. And because these mental trajectories guide the rats’ behavior, the research model the scientists developed may be useful in future studies on higher-level tasks, such as decision-making.
The details of their work were published online in the journal Nature on April 17.
“For the first time, we believe we have evidence that before a rat returns to an important place, it actually plans out its path,” says David Foster, Ph.D., assistant professor of neuroscience at the Johns Hopkins University School of Medicine. “The rat finds that location in its mind’s eye and knows how to get there.”
Foster and his team found that, at least for the purposes of navigation, the “mind’s eye” is located in the hippocampus, which is composed of two banana-shaped segments under the cerebral cortex on both sides of the brain. It is best known for creating memories. In people with Alzheimer’s, it is one of the first parts of the brain to sustain damage.
The Foster lab experiments focused on a group of neurons in the hippocampus called place cells because they are known to fire when animals are at a given location within a given environment. What was not known, Foster says, was how and when the brain uses that information.
By miniaturizing an existing technology, Foster and a postdoc in his lab, Brad Pfeiffer, Ph.D., were able to implant 20 microwires into each side of the hippocampus of four rats. The tiny wires let them record electrical activity from as many as 250 individual place cells at the same time, more than ever achieved before.
Over a two-week training period, the rats became familiar with the testing area which was surrounded by a variety of objects, so that the rats could tell where they were in relation to the objects outside. The space was 2 meters square with 36 tiny “dishes” placed at regular intervals in a grid. A single dish at a time would be filled with the rats’ reward: liquid chocolate.
The rats’ navigation tests involved as many as 40 sets of alternating “odd” and “even” trials per day. The odd trials required the rats to “forage” through the arena to find a chocolate-filled dish in a random location; the even trials required the rats to return each time to a “home” dish to receive their reward. While the rats fulfilled their tasks, the researchers recorded the firing of their place cells.
They found that as a rat travels randomly through the box without knowing where it needs to go, different combinations of place cells fire at each location along its path. The same set of cells fires every time the rat travels the same spot. These unique combinations of firings “mark” each spot in the rat’s brain and can be reconstructed into what seems like a virtual map, when needed.
When a rat is about to go to a specific location, e.g., “home,” place cells in its hippocampus fire in a sequence that creates a predictive path, which the rat then follows, somewhat like Hansel and Gretel following an imagined bread crumb trail.
Foster says that “unlike a Hansel and Gretel bread crumb trail, which only allows you to leave by the same route by which you entered, the rats’ memories of their surroundings are flexible and can be reconstructed in a way that allows them to ‘picture’ how to quickly get from point A to point B.” In order to do this, he says, the rats must already be familiar with the terrain between point A and point B, but, like a GPS, they don’t have to have previously started at point A with the goal of reaching point B.
Foster says the elderly can get lost easily, and research on aged mice shows that their place cells can fail to distinguish between different environments. His team’s research suggests that defective place cells would also affect a person’s ability to “look ahead” in their imaginations to predict a way home. Similarly, he says, higher-order brain functions, like problem solving, also require people to “look ahead” and imagine themselves in a different scenario.
“The hippocampus seems to be directing the movement of the rats, making decisions for them in real time,” says Foster. “Our model allows us to see this happening in a way that’s not been possible before. Our next question is, what will these place cells do when we put obstacles in the rats’ paths?”
Ever since the appetite-regulation hormone called leptin was discovered in 1994, scientists have sought to understand the mechanisms that control its action. It was known that leptin was made by fat cells, reduced appetite and interacted with insulin , but the precise molecular details of its function —details that might enable the creation of a new treatment for obesity — remained elusive.
Now, University of Texas Medical Branch at Galveston researchers have revealed a significant part of one of those mechanisms, identifying a protein that can interfere with the brain’s response to leptin. They’ve also created a compound that blocks the protein’s action — a potential forerunner to an anti-obesity drug.
In experiments with mice fed a high-fat diet, scientists from UTMB and the University of California, San Diego explored the role of the protein, known as Epac1, in blocking leptin’s activity in the brain. They found that mice genetically engineered to be unable to produce Epac1 had lower body weights, lower body fat percentages, lower blood-plasma leptin levels and better glucose tolerance than normal mice.
When the researchers used a specially developed “Epac inhibitor” to treat brain-slice cultures taken from normal laboratory mice, they found elevated levels of proteins associated with greater leptin sensitivity. Similar results were seen in the genetically engineered mice that lacked the Epac1 gene. In addition, normal mice treated with the inhibitor had significantly lower levels of leptin in their blood plasma — an indication that Epac1 also affected their leptin levels.
“We found that we can increase leptin sensitivity by creating mice that lack the genes for Epac1 or through a pharmacological intervention with our Epac inhibitor,” said UTMB professor Xiaodong Cheng, lead author of a paper on the study that recently appeared on the cover of Molecular and Cellular Biology. “The knockout mice gave us a way to tease out the function of the protein, and the inhibitor served as a pharmacological probe that allowed us to manipulate these molecules in the cells.”
Cheng and his colleagues suspected a connection between Epac1 and leptin because Epac1 is activated by cyclic AMP, a signaling molecule linked to metabolism and leptin production and secretion. Cyclic AMP is tied to a multitude of other cell signaling processes, many of which are targeted by current drugs. Cheng believes that understanding how it acts through Epac1 (and another form of the protein called Epac2) will also generate new pharmaceutical possibilities — possibly including a drug therapy that will help fight obesity and diabetes.
“We refer to these Epac inhibitors as pharmacological probes, and while they are still far away from drugs, pharmaceutical intervention is always our eventual goal,” Cheng said. “We were the first to develop Epac inhibitors, and now we’re working very actively with Dr. Jia Zhou, a UTMB medicinal chemist, to modify them and improve their properties. In addition, we are collaborating with colleagues at the NIH National Center for Advancing Translational Sciences in searching for more potent and selective pharmacological probes for Epac proteins.”
Family history of Alzheimer’s associated with abnormal brain pathology
Close family members of people with Alzheimer’s disease are more than twice as likely as those without a family history to develop silent buildup of brain plaques associated with Alzheimer’s disease, according to researchers at Duke Medicine.
The study, published online in the journal PLOS ONE on April 17, 2013, confirms earlier findings on a known genetic variation that increases one’s risk for Alzheimer’s, and raises new questions about other genetic factors involved in the disease that have yet to be identified.
An estimated 25 million people worldwide have Alzheimer’s disease, and the number is expected to triple by 2050. More than 95 percent of these individuals have late-onset Alzheimer’s, which usually occurs after the age of 65. Research has shown that Alzheimer’s begins years to decades before it is diagnosed, with changes to the brain measurable through a variety of tests.
Family history is a known risk factor and predictor of late-onset Alzheimer’s disease, and studies suggest a two- to four-fold greater risk for Alzheimer’s in individuals with a mother, father, brother or sister who develop the disease. These first-degree relatives share roughly 50 percent of their genes with another member of their family. Common genetic variations, including changes to the APOE gene, account for around 50 percent of the heritability of Alzheimer’s, but the disease’s other genetic roots are still unexplained.
“In this study, we sought to understand whether simply having a positive family history, in otherwise normal or mildly forgetful people, was enough to trigger silent buildup of Alzheimer’s plaques and shrinkage of memory centers,” said senior author P. Murali Doraiswamy, professor of psychiatry and medicine at Duke.
Duke neuroscience research trainee Erika J. Lampert, Doraiswamy and colleagues analyzed data from 257 adults, ages 55 to 89, both cognitively healthy and with varying levels of impairment. The participants were part of the Alzheimer’s Disease Neuroimaging Initiative, a national study working to define the progression of Alzheimer’s through biomarkers.
The researchers looked at participants’ age, gender and family history of the disease, with a positive family history defined as having a parent or sibling with Alzheimer’s. This information was compared with cognitive assessments and other biological tests, including APOE genotyping, MRI scans measuring hippocampal volume, and studies of three different pathologic markers (Aβ42, t-tau, and t-tau/Aβ42 ratio) found in cerebrospinal fluid.
As expected, the researchers found that a variation in the APOE gene associated with a greater risk and earlier onset of Alzheimer’s was overrepresented in participants with a family history of the disease. However, other biological differences were also seen in those with a family history, suggesting that unidentified genetic factors may influence the disease’s development before the onset of dementia.
Nearly half of all healthy people with a positive family history would have met the criteria for preclinical Alzheimer’s disease based on measurements of their cerebrospinal fluid, but only about 20 percent of those without a family history would have met such criteria.
“We already knew that family history increases one’s risk for developing Alzheimer’s, but we now are showing that people with a positive family history may also have higher levels of Alzheimer’s pathology earlier, which could be a reason why they experience a faster cognitive decline than those without a family history,” Lampert said.
The findings may influence the design of future studies developing new diagnostic tests for Alzheimer’s, as researchers may choose to exclude those with a positive family history – a group that has historically volunteered to participate in studies to better understand the disease – as healthy controls, given that they are more likely to develop Alzheimer’s pathology.
“Our study shows the power of a simple one-minute questionnaire about family history to predict silent brain changes,” Doraiswamy said. “In the absence of full understanding of all genetic risks for late-onset Alzheimer’s, family history information can serve as a risk stratification tool for prevention research and personalizing care.” He encouraged those with a known positive family history to seek out clinical trials specific to preventing the disease.
(Source: dukehealth.org)