Neuroscience
Month
An international team of researchers has identified a new inherited neuromuscular disorder. The rare condition is the result of a genetic mutation that interferes with the communication between nerves and muscles, resulting in impaired muscle control.
The new disease was diagnosed in two families – one in the U.S. and the other in Great Britain – and afflicts multiple generations. The discovery was published in the American Journal of Human Genetics.
“This discovery gives us new insight into the mechanisms of diseases that are caused by a breakdown in neuromuscular signal transmission,” said David Herrmann, M.B.B.Ch., a professor in the Department of Neurology at the University of Rochester School of Medicine and Dentistry and co-lead author of the study. “It is our hope that these findings will help identify new targets for therapies that can eventually be used to treat these diseases.”
The focus of the research is the neuromuscular junction, the point at which the axon fibers that extend from peripheral nerves meet the muscle cells. The chemical signals that pass across the junction are essential for motor function.
There are a number of disorders – both acquired and inherited – that interfere with the communication that occurs at the neuromuscular junction. For example, in Lambert-Eaton myasthenic syndrome, which is most commonly triggered by certain cancers, the body’s own immune system attacks the neuromuscular junction, interrupting signal transmission. These diseases, which are rare, result in muscle weakness and fatigue, primarily in the limbs.
While the families in the study had at one point been diagnosed with other neuromuscular conditions, the researchers identified them as unique, due to their particular motor abnormalities, including problems resembling Lambert-Eaton, and because the disease was passed from one generation to the next.
The researchers compiled a genetic profile of the family members. Specifically, they analyzed the section of DNA code responsible for creating proteins using a technique called whole exome sequencing.
They discovered that the two different families had mutations in the code that creates the protein synaptotagmin 2 (SYT2). Scientists have long understood the function of this protein, but it had never before been associated with a disease in humans.
SYT2 is present at the pre-synaptic terminal, the end of the nerve cell that sits at the neuromuscular junction and helps the cells sense fluctuations in calcium levels. Calcium plays an important role in the electrical function of cells and, in the case of the neuromuscular junction, helps dictate the release of acetylcholine, a chemical responsible for passing communication between the nerve and muscle cells.
In the two families, the mutation disrupted the ability of the nerve cells to sense the changes in calcium levels that would normally trigger the release of acetylcholine. As a result, communication was disrupted and muscle control was impaired.
The authors have used the mutation in SYT2 to create a fruit fly (drosophila) model of the disease. Fruit flies are an important research tool and the study of their neurobiology has contributed greatly to our understanding of neurological development and diseases and the researchers see this as a first step to the development of potential new therapies to treat the condition.
What’s the price on your integrity? Tell the truth; everyone has a tipping point. We all want to be honest, but at some point, we’ll lie if the benefit is great enough. Now, scientists have confirmed the area of the brain in which we make that decision.
The result was published online this week in Nature Neuroscience.
Nerves and blood vessels lead intimately entwined lives. They grow up together, following similar cues as they spread throughout the body. Blood vessels supply nerves with oxygen and nutrients, while nerves control blood vessel dilation and heart rate.
Neurovascular relationships are especially important in the brain. Studies have shown that when neurons work hard, blood flow increases to keep them nourished. Scientists have been asking whether neural activity also changes the structure of local vascular networks.
According to new research published in the Sept. 3 issue of Neuron, the answer is yes.
Creating induced pluripotent stem cells or iPS cells allows researchers to establish “disease in a dish” models of conditions ranging from Alzheimer’s disease to diabetes. Scientists at Yerkes National Primate Research Center, Emory University have now applied the technology to a model of Huntington’s disease (HD) in transgenic nonhuman primates, allowing them to conveniently assess the efficacy of potential therapies on neuronal cells in the laboratory.
(Image caption: Neural progenitor cells derived from transgenic rhesus macaque iPS cells show features of Huntington’s disease pathology, making them a useful tool for therapeutic discovery.)
The results were published this week in Stem Cell Reports.
"A highlight of our model is that our progenitor cells and neurons developed cellular features of HD such as intranuclear inclusions of mutant Huntingtin protein, which most of the currently available cell models do not present," says senior author Anthony Chan, PhD, DVM, associate professor of human genetics at Emory University School of Medicine and Yerkes National Primate Research Center. "We could use these features as a readout for therapy using drugs or a genetic manipulation."
Chan and his colleagues were the first in the world to establish a transgenic nonhuman primate model of HD. HD is an inherited neurodegenerative disorder that leads to the appearance of uncontrolled movements and cognitive impairments, usually in adulthood. It is caused by a mutation that introduces an expanded region where one amino acid (glutamine) is repeated dozens of times in the huntingtin protein.
The non-human primate model has extra copies of the huntingtin gene that contains the expanded glutamine repeats. In the non-human primate model, motor and cognitive deficits appear more quickly than in most cases of Huntington’s disease in humans, becoming noticeable within the first two years of the monkeys’ development.
First author Richard Carter, PhD, a graduate of Emory’s Genetics and Molecular Biology doctoral program, and his colleagues created iPS cells from the transgenic monkeys by reprogramming cells derived from the skin or dental pulp. This technique uses retroviruses to introduce reprogramming factors into somatic cells and induces a fraction of them to become pluripotent stem cells. Pluripotent stem cells are able to differentiate into any type of cell in the body, under the right conditions.
Carter and colleagues induced the iPS cells to become neural progenitor cells and then differentiated neurons. The iPS-derived neural cells developed intracellular and intranuclear aggregates of the mutant huntingtin protein, a classic sign of Huntington’s pathology, as well as an increased sensitivity to oxidative stress.
The sensitivity to oxidative stress was a useful indicator; it could be ameliorated in cell culture, either by a RNA-based gene knockdown approach, or the drug memantine, which is currently being investigated for Huntington’s disease in a human clinical trial.
"We tested two known experimental interventions, but our findings are a proof of principle that this system could be a valuable tool for the discovery and evaluation of other therapies," Chan says.
Despite the barrage of visual information the brain receives, it retains a remarkable ability to focus on important and relevant items. This fall, for example, NFL quarterbacks will be rewarded handsomely for how well they can focus their attention on color and motion – being able to quickly judge the jersey colors of teammates and opponents and where they’re headed is a valuable skill. How the brain accomplishes this feat, however, has been poorly understood.
Now, University of Chicago scientists have identified a brain region that appears central to perceiving the combination of color and motion. They discovered a unique population of neurons that shift in sensitivity toward different colors and directions depending on what is being attended – the red jersey of a receiver headed toward an end zone, for example. The study, published Sept. 4 in the journal Neuron, sheds light on a fundamental neurological process that is a key step in the biology of attention.
“Most of the objects in any given visual scene are not that important, so how does the brain select or attend to important ones?” said study senior author David Freedman, PhD, associate professor of neurobiology at the University of Chicago. “We’ve zeroed in on an area of the brain that appears central to this process. It does this in a very flexible way, changing moment by moment depending on what is being looked for.”
The visual cortex of the brain possesses multiple, interconnected regions that are responsible for processing different aspects of the raw visual signal gathered by the eyes. Basic information on motion and color are known to route through two such regions, but how the brain combines these streams into something usable for decision-making or other higher-order processes remained unclear.
To investigate this process, Freedman and postdoctoral fellow Guilhem Ibos, PhD, studied the response of individual neurons during a simple task. Monkeys were shown a rapid series of visual images. An initial image showed either a group of red dots moving upwards or yellow dots moving downwards, which served as an instruction for which specific colors and directions were relevant during that trial. The subjects were rewarded when they released a lever when this image later reappeared. Subsequent images were composed of different colors of dots moving in different directions, among which was the initial image.
Dynamic neurons
Freedman and Ibos looked at neurons in the lateral intraparietal area (LIP), a region highly interconnected with brain areas involved in vision, motor control and cognitive functions. As subjects performed the task and looked for a specific combination of color and motion, LIP neurons became highly active. They did not respond, however, when the subjects passively viewed the same images without an accompanying task.
When the team further investigated the responses of LIP neurons, they discovered that the neurons possessed a unique characteristic. Individual neurons shifted their sensitivity to color and direction toward the relevant color and motion features for that trial. When the subject looked for red dots moving upwards, for example, a neuron would respond strongly to directions close to upward motion and to colors close to red. If the task was switched to another color and direction seconds later, that same neuron would be more responsive to the new combination.
“Shifts in feature tuning had been postulated a long time ago by theoretical studies,” Ibos said. “This is the first time that neurons in the brain have been shown to shift their selectivity depending on which features are relevant to solve a task.”
Freedman and Ibos developed a model for how the LIP brings together both basic color and motion information. Attention likely affects that process through signals from higher-order areas of the brain that affect LIP neuron selectivity. The team believes that this region plays an important role in making sense of basic sensory information, and they are trying to better understand the brain-wide neuronal circuitry involved in this process.
“Our study suggests that this area of the brain brings together information from multiple areas throughout the brain,” Freedman said. “It integrates inputs – visual, motor, cognitive inputs related to memory and decision making – and represents them in a way that helps solve the task at hand.”
Paula Meltzer was only 38 when out of nowhere everything she looked at was blurry. For the single mother, who had a lucrative career as a gemologist and spent hours examining valuable pieces of jewelry, it seemed as if – in a split second – her life changed.
At first doctors thought Meltzer had a brain tumor. What they determined after further tests, however, was that she had multiple sclerosis, an autoimmune disease that affects the brain and central nervous system and was causing optic neuritis, an inflammation of the optic nerve that can cause a partial or complete loss of vision.
“I was living independently, doing my job, taking care of my child – and then I had to look to my parents to take care of me,” Meltzer said.
Almost two decades later, Meltzer, out of a wheelchair and walking without a cane, was one of 14 women with moderate disability due to MS who participated in a pilot trial conducted by the Rutgers School of Health Related Professions. A specially-designed yoga program for these MS patients not only improved their physical and mental well-being but also enhanced their overall quality of life.
“I felt like I became steadier and stronger in my core,” Meltzer said. Prior to yoga, she described herself as a “wall walker,” someone who felt safer holding onto the wall in order to get around. “To be able to stand on one leg and feel balanced is amazing.”
Susan Gould Fogerite, director of research for the Institute for Complementary and Alternative Medicine in the School of Health Related Professions, said that although there is widespread evidence that yoga is being used as a form of exercise by those with MS, much of the feedback has been anecdotal and there isn’t much empirical data regarding its safety and efficacy.
This is why she and her colleagues, Evan Cohen and David Kietrys, physical therapists and associate professors in the School of Health Related Professions at Stratford, decided to undertake the small pilot study, believing that a specialized yoga program for MS patients – which incorporates mind, body and spirit – would be beneficial to everyday living.
What they discovered at the end of the eight-week trial was that those who participated were better able to walk for short distances and longer periods of time, had better balance while reaching backwards, fine motor coordination, and were better able to go from sitting to standing. Their quality of life also improved in perceived mental health, concentration, bladder control, walking, and vision, with a decrease in pain and fatigue.
“Yoga is not just exercise, it is a whole system of living,” said Fogerite, an associate professor, who, along with Kietrys, will present the results on September 26 at the Symposium on Yoga Research at the Kripalu Institute in Massachusetts. “The panel of experts who advised us on the trial wanted to make sure that we provided a fully integrated program that included philosophy, breathing practices, postures, relaxation and meditation.”
The yoga pilot trial was held at Still Point Yoga Center in Laurel Springs, a southern New Jersey town close to Philadelphia. Of the 72 individuals who were interested in participating, only 16 were eligible based on medical and other criteria and availability. Of those, 15 were enrolled and 14 completed the program after one person had to withdraw because of an unrelated health problem.
Meltzer and the other women who participated in the trial ranged in age from 34 to 64. Some had been diagnosed with MS within the last two years while others had been living with the illness for up to 26 years. For 90 minutes, twice a week for two months, they practiced techniques and exercises that would improve their posture, help to increase stamina, and teach them how to relax and focus.
“This study, I hope, is one of many that will give us the clinical information we need,” said Fogerite. “Yoga is not currently being widely prescribed for people with MS, although it might turn out to be a very helpful treatment.”
The yoga practices were done by the women in the study sitting, standing, or lying on yoga mats, and using metal folding chairs situated close to the wall to provide them with more support.
“What was so nice about this experience was that although everyone was at a different level of the disease, we felt like we were all together, so I think the camaraderie helped,” said Meltzer. “And it wasn’t just about gaining more mobility and balance in our legs but our arms and necks felt stronger as well.”
Fogerite said a larger randomized controlled trial would be needed to determine whether yoga could be used as a prescribed treatment for individuals with moderate disability due to MS. More than 2.3 million people – two to three times more women than men – throughout the world are diagnosed with this disease which can cause poor coordination, loss of balance, slurred speech, tremors, numbness, extreme fatigue and problems with memory and concentration.
“When I was first diagnosed I no longer felt safe in my own body,” Meltzer said. “I didn’t trust my body at all. What the program did was really bring that trust back.”
Sleep difficulties may be linked to faster rates of decline in brain volume, according to a study published in the September 3, 2014, online issue of Neurology®, the medical journal of the American Academy of Neurology.
Sleep has been proposed to be “the brain’s housekeeper”, serving to repair and restore the brain.
The study included 147 adults 20 and 84 years old. Researchers examined the link between sleep difficulties, such as having trouble falling asleep or staying asleep at night, and brain volume.
All participants underwent two MRI brain scans, an average of 3.5 years apart, before completing a questionnaire about their sleep habits.
A total of 35 percent of the participants met the criteria for poor sleep quality, scoring an average of 8.5 out of 21 points on the sleep assessment. The assessment looked at how long people slept, how long it took them to fall asleep at night, use of sleeping medications, and other factors.
The study found that sleep difficulties were linked with a more rapid decline in brain volume over the course of the study in widespread brain regions, including within frontal, temporal and parietal areas.
The results were more pronounced in people over 60 years old.
“It is not yet known whether poor sleep quality is a cause or consequence of changes in brain structure,” said study author Claire E. Sexton, DPhil, with the University of Oxford in the United Kingdom. “There are effective treatments for sleep problems, so future research needs to test whether improving people’s quality of sleep could slow the rate of brain volume loss. If that is the case, improving people’s sleep habits could be an important way to improve brain health.”
A gene crucial for brain and heart development may also be associated with sudden unexplained death in epilepsy (SUDEP), the most common cause of early mortality in epilepsy patients.
Scientists at The University of Texas MD Anderson Cancer Center have created a new animal model for SUDEP and have shown that mice who have a partial deficiency of the gene SENP2 (Sentrin/SUMO-specific protease 2) are more likely to develop spontaneous seizures and sudden death. The finding occurred when observing mice originally bred for studying a link between SENP2 deficiency and cancer.
"SENP2 is highly present in the hippocampus, a critical brain region for seizure genesis," said Edward Yeh, M.D., chair of cardiology at MD Anderson. "Understanding the genetic basis for SUDEP is crucial given that the rate of sudden death in epilepsy patients is 20-fold that of the general population, with SUDEP the most common epilepsy-related cause of death."
Yeh’s findings were published in this month’s issue of Neuron.
Although it’s not yet known what causes SUDEP in humans, inactivation of potassium channels genes have been linked to SUDEP in animal models. Potassium channels are found in most cell types and control a large variety of cell functions.
"These animal models demonstrated an important connection between the brain and heart. However, it remains unclear whether seizure and sudden death are two separate manifestations of potassium channel deficiency in the brain and the heart, or whether seizures predispose the heart to lethal cardiac arrhythmia," said Yeh.
The study revealed that when SENP2 was deficient in the brain, seizures activated a part of the nervous system responsible for regulating the heart’s electrical system. This resulted in a phenomenon known as atrioventricular conduction block, which effectively slowed down and then stopped the heart.
Yeh’s team observed that the SENP2-deficient mice appeared normal at birth, but by 6 to 8 weeks, experienced convulsive seizures, and then sudden death. He believes the reason may lie with protein modifiers called SUMO. SENP2 deficiency results in a process known as hyper-SUMOylation, which dramatically impacts potassium channels in the brain.
"One of the channels, Kv7, is significantly diminished or ‘closed’ due to the lack of SENP2," said Yeh. "In mice this led to seizures and cardiac arrest."
In humans, the good news is that an FDA-approved drug, retigabine works by “opening” the Kv7 channel. The therapy was developed for treating partial-onset seizures. The findings in Yeh’s new mouse model clearly demonstrate a previously unknown cause of SUDEP, which may open up new opportunities for study and treatment in the future.
Swinburne researchers have developed a technique to create a highly sensitive surface for measuring the concentration of a peptide that is a biomarker for early stage Alzheimer’s disease.
(Image caption: Ultrashort-laser pulses were used to write ripples on the surface of sapphire. The self-organised nano-structure of ripples (seen in the image) is a perfect sensing surface after coating with a nanometre-thin layer of gold made by evaporation or sputtering. Such surface ripples were used in the study of amyloid detection.)
Alzheimer’s disease was first recorded more than 100 years ago, but there is still no effective therapy to stop or slow the progression of the disease. Sufferers can lose up to 60 per cent of their neuronal cells before a diagnosis is obtained.
Diagnosis at the very early stages before neuronal degeneration has begun is vital for testing and developing new treatments.
Abnormality of the beta amyloid peptide in cerebrospinal fluid appears to be the earliest and most significant marker of Alzheimer’s. Currently there are no standardised tests to detect these biomarkers.
The researchers have developed a sensor based on nanotechnology that outperforms commercial sensors and demonstrates fast and reliable measurement of beta amyloid oligomers at low concentrations.
The key to the high sensitivity is the laser nano-textured gold coated surface. This sensor can identify concentrations of beta amyloid in a quantitative manner for the first time.
“We showed that sensors based on light scattering can indeed deliver QUANTATIVE measurements and they can be made fast,” Professor of Nanophotonics Saulius Juodkazis said.
“The sensor platform we developed by laser nano-texturing of surfaces is delivering results of the highest sensitivity and repeatability.
“The challenge is to create fast and efficient fabrication of sensors based on nanotechnology and develop new analytical methods of detection. This means we should be able to detect markers of diseases at far lower levels.”
Surface enhanced Raman spectroscopy (SERS) is one of the most sensitive and highly specific label-free detection methods which may evolve as a detection technique for different forms of beta amyloid or as a rapid, low cost technique to validate new biomarkers before developing standard assays for enzyme-linked immunosorbent assays (ELISAs).
This research is a PhD project work of Dr Ricardas Buividas who received his doctorate in May 2014. It was published in the Journal of Biophotonics.
While reading, children and adults alike must avoid confusing mirror-image letters (like b/d or p/q). Why is it difficult to differentiate these letters? When learning to read, our brain must be able to inhibit the mirror-generalization process, a mechanism that facilitates the recognition of identical objects regardless of their orientation, but also prevents the brain from differentiating letters that are different but symmetrical. A study conducted by the researchers of the Laboratoire de Psychologie du Développement et de l’Education de l’Enfant (CNRS / Université Paris Descartes / Université de Caen Basse-Normandie) is available on the website of the Psychonomic Bulletin & Review (Online First Articles).
In recent years, many studies on the process of learning to read have been based on the neuronal recycling hypothesis: the reuse of old brain mechanisms in a new adaptive role —a kind of “biological trick.” Specifically, neurons that are originally dedicated to the rapid identification of objects in the environment, through the mirror-generalization process, are “repurposed” during childhood to specialize in the visual recognition of letters and words.
In this study, the researchers showed 80 young adults pairs of images, first two letters and then two animals, asking them to determine whether they were identical. The readers consistently spent more time determining that two animal images, when preceded by mirror-image letters, were indeed identical. This increase in response time is called “negative priming”: the readers had to inhibit the mirror-generalization process in order to distinguish letters like b/d or p/q. They then needed a little more time to reactivate this strategy when it became useful again to quickly identify animals.
These results show that even adults need to inhibit the mirror-generalization process to avoid reading errors. Children must therefore learn to inhibit this strategy when learning to read. A failure of cognitive inhibition during the recycling of visual neurons in the brain could thus be a factor in dyslexia— a direction worth exploring, in light of these findings.
New York University biologists have identified a mechanism that helps explain how the diversity of neurons that make up the visual system is generated.
“Our research uncovers a process that dictates both timing and cell survival in order to engender the heterogeneity of neurons used for vision,” explains NYU Biology Professor Claude Desplan, the study’s senior author.
The study’s other co-authors were: Claire Bertet, Xin Li, Ted Erclik, Matthieu Cavey, and Brent Wells—all postdoctoral fellows at NYU.
Their work, which appears in the latest issue of the journal Cell, centers on neurogenesis—the process by which neurons are created.
A central challenge in developmental neurobiology is to understand how progenitors—stem cells that differentiate to form one or more kinds of cells—produce the vast diversity of neurons, glia, and non-neuronal cells found in the adult Central Nervous System (CNS). Temporal patterning is one of the core mechanisms generating this diversity in both invertebrates and vertebrates. This process relies on the sequential expression of transcription factors into progenitors, each specifying the production of a distinct neural cell type.
In the Cell paper, the researchers studied the formation of the visual system of the fruit fly Drosophila. Their findings revealed that this process, which relies on temporal patterning of neural progenitors, is more complex than previously thought.
They demonstrate that in addition to specifying the production of distinct neural cell type over time, temporal factors also determine the survival or death of these cells as well as the mode of division of progenitors. Thus, temporal patterning of neural progenitors generates cell diversity in the adult visual system by specifying the identity, the survival, and the number of each unique neural cell type.
How nerve cells within the brain communicate with each other over long distances has puzzled scientists for decades. The way networks of neurons connect and how individual cells react to incoming pulses in principle makes communication over large distances impossible. Scientists from Germany and France provide now a possible answer how the brain can function nonetheless: by exploiting the powers of resonance.
(Image caption: Resonance in the activity of nerve cells (left) allows activity within the brain to travel over large distances, e.g. from the back of the head to the front during the processing of visual stimuli. Credit: Gunnar Grah/BrainLinks-BrainTools)
As Gerald Hahn, Alejandro F. Bujan and colleagues describe in the journal “PLoS Computational Biology”, the ability of networks of neurons to resonate can amplify oscillations in the activity of nerve cells, allowing signals to travel much farther than in the absence of resonance. The team from the cluster of excellence BrainLinks-BrainTools and the Bernstein Center at the University of Freiburg and the UNIC department of the French Centre national de la recherche scientifique in Gif-sur-Yvette created a computer model of networks of nerve cells and analyzed its properties for signal propagation.
Earlier propositions how information travels through the brain had the flaw of being biologically implausible. They either postulated strong connections between distant brain areas for which there was no evidence, or they required a global mechanism setting these distant parts of the brain into linked oscillations. However, nobody could explain how this could actually be implemented.
The simulation study of Hahn and Bujan required neither unrealistic network properties nor the existence of a pacemaker for the brain. Instead, they found that resonance could be the key to long-distance communication in networks with relatively few and weak connections, as it is the case in the brain. Not all nerve cells excite other cells; some inhibit the activity of others. This means that the activity in a network can oscillate around a certain level of activity as a result of the interplay of excitation and inhibition. These networks typically have preferred frequencies at which oscillations are particularly strong, just as a taut string on a violin has a preferred frequency. If the activity tunes into this frequency, pulses propagate much farther. As the scientists point out, the combination of oscillatory signals together with resonance induced amplification may be the only possible form of long distance communication in certain cases. They further suggest that a network’s ability to change its preferred frequency may play a role in the way how information is at times processed differently in the brain.
The failing in the work of nerve cells: An international team of researchers led by Prof. Dr. Chris Meisinger from the Institute of Biochemistry and Molecular Biology of the University of Freiburg has discovered how Alzheimer’s disease damages mitochondria, the powerhouses of the cell. For several years researchers have known that the cellular energy supply of brain cells is impaired in Alzheimer’s patients. They suspect this to be the cause of premature death of nerve cells that occurs in the course of the disease. Little is known about the precise cause of this neuronal cell death, and many approaches and attempts to find an effective therapy have failed to make an impact. What is certain is that a tiny protein fragment by the name of “amyloid-beta” plays a key role in the process. Meisinger, a member of the Cluster of Excellence BIOSS Centre for Biological Signalling Studies of the University of Freiburg, and his team have now demonstrated how this protein fragment blocks the maturation of protein machines that are responsible for the production of energy inside the cellular powerhouses. The researchers demonstrated this with the help of model organisms and with brain samples from Alzheimer’s patients. “The elucidation of this key component of the disease mechanism will enable us to develop new therapies and improve diagnostics in the future,” explains Meisinger. The findings were published in the journal Cell Metabolism.
Mitochondria are made up of around 1500 different proteins. Most of them need to migrate to the cellular powerhouses before taking up their work. This import is facilitated by a so-called signaling sequence – tiny protein extensions that transport the protein into the mitochondria. Once the protein is inside, the signaling sequence is normally removed. Dirk Mossmann and Dr. Nora Vögtle from Meisinger’s research team have now discovered that the amyloid-beta peptide prevents mitochondria from removing these signaling sequences. As a consequence, incomplete proteins accumulate in the mitochondria. Since the signaling sequences remain attached, the proteins are unstable and can no longer adequately carry out their function in energy metabolism. The researchers demonstrated that modified yeast cells producing the amyloid-beta protein generate less energy and accumulate more harmful substances.
In the brain, the mechanism probably leads to the death of nerve cells: The brain shrinks and the patient suffers from dementia. The researchers are currently developing an Alzheimer’s blood test to detect the accumulation of mitochondrial precursor proteins. They suspect that the mitochondrial alterations observed in nerve cells will also be detected in the blood cells of Alzheimer’s patients.
Brain networks break down similarly in rare, inherited forms of Alzheimer’s disease and much more common uninherited versions of the disorder, a new study has revealed.
Scientists at Washington University School of Medicine in St. Louis have shown that in both types of Alzheimer’s, a basic component of brain function starts to decline about five years before symptoms, such as memory loss, become obvious.
The breakdown occurs in resting state functional connectivity, which involves groups of brain regions with activity levels that rise and fall in coordination with each other. Scientists believe this synchronization helps the regions form networks that work together or stay out of each other’s way during mental tasks.
“The brain networks affected by inherited Alzheimer’s disease in a 30-year-old are very similar to the networks affected by uninherited Alzheimer’s disease in a 60-, 70- or 80-year-old,” said senior author Beau Ances, MD, PhD. “This affirms that what we learn by studying inherited Alzheimer’s, which appears at younger ages, will help us better understand and treat more common forms of the disease.”
The research appears online in JAMA Neurology.
According to Ances, the results show that functional connectivity may help scientists monitor the effects of treatment as patients progress through the transition between early disease and the first appearance of obvious symptoms.
“Right now, this period when functional connectivity begins breaking down is a time when family and loved ones may start noticing little changes in personality or mental function in someone with the disease, but not significant enough changes to cause real alarm,” Ances said. “The hope is that one day treatment already will be well underway before these sorts of changes begin — we want to slow or stop the damage caused by Alzheimer’s years earlier.”
Inherited Alzheimer’s disease can strike very early in life, causing symptoms in patients as young as their 30s or 40s. Identifying the mutations that cause these forms of the disease has helped scientists find proteins that become problematic in more common forms of Alzheimer’s, which typically appear decades later.
Researchers have long assumed that additional connections exist between inherited and uninherited Alzheimer’s disease, but until recently they have not had sufficient data to directly test many of those connections. Challenges have included the small number of people with inherited Alzheimer’s, and the slow development of both forms of the disease.
Scientists at the Charles F. and Joanne Knight Alzheimer’s Disease Research Center at Washington University began to tackle the first challenge five years ago by organizing the Dominantly Inherited Alzheimer’s Network (DIAN), an international network for identifying and studying families with inherited forms of the disease. The network now includes nearly 400 families.
To address the second challenge, Washington University researchers at the center have been gathering extensive health data on seniors through long-term projects such as the Healthy Aging and Senile Dementia Study, which is entering its 31st year.
These pools of data allowed Ances, an associate professor of neurology, to compare the effects of inherited and uninherited Alzheimer’s on functional connectivity. Scientists assess functional connectivity by scanning the brains of research participants while they daydream.
“The question was, where does the decline of functional connectivity fit in the whole picture of the development of Alzheimer’s disease?” Ances said. “And it clearly does have a place in the middle stages of the disease.”
That’s not the best place to look for an initial diagnosis, according to Ances. Ideally, scientists want to start treating Alzheimer’s disease as soon as possible.
“What this does tell us, though, is that functional connectivity may help us track the progression of Alzheimer’s in patients who are first diagnosed when they’re beginning to show early signs of dementia,” he said.