Neuroscience

The disrupted metabolism of sugar, fat and calcium is part of the process that causes the death of neurons in Alzheimer’s disease. Researchers from Karolinska Institutet in Sweden have now shown, for the first time, how important parts of the nerve cell that are involved in the cell’s energy metabolism operate in the early stages of the disease. These somewhat surprising results shed new light on how neuronal metabolism relates to the development of the disease.

In the Alzheimer’s disease brain, plaques consisting of so called amyloid-beta-peptide (Aβ) are accumulated. It is also a well-known fact that the nerve cells of patients with Alzheimer’s disease have problems metabolising for example glucose and calcium, and that these disorders are associated with cell death. The metabolism of these substances is the job of the cell mitochondria, which serve as the cell’s power plant and supply the cell with energy.

However, for the mitochondria to do this, they need good contact with another part of the cell called the endoplasmic reticulum (ER). The specialised region of ER that is in contact with mitochondria is called the MAM region. Earlier studies on yeast and other types of cells have shown that the deactivation of certain proteins in the MAM region disrupt the contact points between the mitochondria and the ER, preventing the delivery of energy to the cell and causing cell death.

Now for the first time, researchers at Karolinska Institutet have studied the MAM region in nerve cells, and examined the interaction between the mitochondria and the ER in early stage Alzheimer’s disease. Although at this point in the development of the disease Aβ has not formed large, lumpy plaques, symptoms still appear, implying that Aβ that has not yet formed plaque is toxic to neurons.

The team’s results are slightly surprising. When nerve cells are exposed to low doses of Aβ, it leads to an increase in the number of contact points between the mitochondria and the ER, causing more calcium to be transferred from the ER to the mitochondria. The resulting over-accumulation of calcium is toxic to the mitochondria and affects their ability to supply energy to the nerve cell.

“It’s urgent that we find out what causes neuronal death if we’re to develop molecules that check the disease,” says Maria Ankarcrona, docent and researcher at the Department of Neurobiology, Care Sciences and Society, and the Alzheimer’s Disease Research Centre of Karolinska Institutet. “In the long run we might be able to produce a drug that can arrest the progress of the disease at a stage when the patient is still able to manage their daily lives. If we can extend that period by a number of years, we’d have made great gains. Today there are no drugs that affect the actual disease process.”

The researchers conducted their studies on mice bred to develop symptoms of Alzheimer’s disease. They also studied nerve cells from deceased Alzheimer’s patients and neurons cultivated in the laboratory.

Researchers at Northeastern University in Boston have developed a gene therapy approach that may one day stop Parkinson’s disease (PD) in it tracks, preventing disease progression and reversing its symptoms. The novelty of the approach lies in the nasal route of administration and nanoparticles containing a gene capable of rescuing dying neurons in the brain. Parkinson’s is a devastating neurodegenerative disorder caused by the death of dopamine neurons in a key motor area of the brain, the substantia nigra (SN). Loss of these neurons leads to the characteristic tremor and slowed movements of PD, which get increasingly worse with time. Currently, more than 1% of the population over age 60 has PD and approximately 60,000 Americans are newly diagnosed every year. The available drugs on the market for PD mimic or replace the lost dopamine but do not get to the heart of the problem, which is the progressive loss of the dopamine neurons.

The focus of Dr. Barbara Waszczak’s lab at Northeastern University in Boston is to find a way to harvest the potential of glial cell line-derived neurotrophic factor (GDNF) as a treatment for PD. GDNF is a protein known to nourish dopamine neurons by activating survival and growth-promoting pathways inside the cells. Not surprisingly, GDNF is able to protect dopamine neurons from injury and restore the function of damaged and dying neurons in many animal models of PD. However, the action of GDNF is limited by its inability to cross the blood-brain barrier (BBB), thus requiring direct surgical injection into the brain. To circumvent this problem, Waszczak’s lab is investigating intranasal delivery as a way to bypass the BBB. Their previous work showed that intranasal delivery of GDNF protects dopamine neurons from damage by the neurotoxin, 6-hydroxydopamine (6-OHDA), a standard rat model of PD.

Taking this work a step further, Brendan Harmon, working in Waszczak’s lab, has adapted the intranasal approach so that cells in the brain can continuously produce GDNF. His work utilized nanoparticles, developed by Copernicus Therapeutics, Inc., which are able to transfect brain cells with an expression plasmid carrying the gene for GDNF (pGDNF). When given intranasally to rats, these pGDNF nanoparticles increase GDNF production throughout the brain for long periods, avoiding the need for frequent re-dosing. Now, in new research presented on April 20 at 12:30 pm during Experimental Biology 2013 in Boston, MA, Harmon reports that intranasal administration of Copernicus’ pGDNF nanoparticles results in GDNF expression sufficient to protect SN dopamine neurons in the 6-OHDA model of PD.

Waszczak and Harmon believe that intranasal delivery of Copernicus’ nanoparticles may provide an effective and non-invasive means of GDNF gene therapy for PD, and an avenue for transporting other gene therapy vectors to the brain. This work, which was funded in part by the Michael J. Fox Foundation for Parkinson’s Research and Northeastern University, has the potential to greatly expand treatment options for PD and many other central nervous system disorders.

For the first time, human embryonic stem cells have been transformed into nerve cells that helped mice regain the ability to learn and remember.

A study at UW-Madison is the first to show that human stem cells can successfully implant themselves in the brain and then heal neurological deficits, says senior author Su-Chun Zhang, a professor of neuroscience and neurology.

Once inside the mouse brain, the implanted stem cells formed two common, vital types of neurons, which communicate with the chemicals GABA or acetylcholine. “These two neuron types are involved in many kinds of human behavior, emotions, learning, memory, addiction and many other psychiatric issues,” says Zhang.

The human embryonic stem cells were cultured in the lab, using chemicals that are known to promote development into nerve cells — a field that Zhang has helped pioneer for 15 years. The mice were a special strain that do not reject transplants from other species.

After the transplant, the mice scored significantly better on common tests of learning and memory in mice. For example, they were more adept in the water maze test, which challenged them to remember the location of a hidden platform in a pool.

The study began with deliberate damage to a part of the brain that is involved in learning and memory.

Three measures were critical to success, says Zhang: location, timing and purity. “Developing brain cells get their signals from the tissue that they reside in, and the location in the brain we chose directed these cells to form both GABA and cholinergic neurons.”

The initial destruction was in an area called the medial septum, which connects to the hippocampus by GABA and cholinergic neurons. “This circuitry is fundamental to our ability to learn and remember,” says Zhang.

The transplanted cells, however, were placed in the hippocampus — a vital memory center — at the other end of those memory circuits. After the transferred cells were implanted, in response to chemical directions from the brain, they started to specialize and connect to the appropriate cells in the hippocampus.

The process is akin to removing a section of telephone cable, Zhang says. If you can find the correct route, you could wire the replacement from either end.

For the study, published in the current issue of Nature Biotechnology, Zhang and first author Yan Liu, a postdoctoral associate at the Waisman Center on campus, chemically directed the human embryonic stem cells to begin differentiation into neural cells, and then injected those intermediate cells. Ushering the cells through partial specialization prevented the formation of unwanted cell types in the mice.

Ensuring that nearly all of the transplanted cells became neural cells was critical, Zhang says. “That means you are able to predict what the progeny will be, and for any future use in therapy, you reduce the chance of injecting stem cells that could form tumors. In many other transplant experiments, injecting early progenitor cells resulted in masses of cells — tumors. This didn’t happen in our case because the transplanted cells are pure and committed to a particular fate so that they do not generate anything else. We need to be sure we do not inject the seeds of cancer.”

Brain repair through cell replacement is a Holy Grail of stem cell transplant, and the two cell types are both critical to brain function, Zhang says. “Cholinergic neurons are involved in Alzheimer’s and Down syndrome, but GABA neurons are involved in many additional disorders, including schizophrenia, epilepsy, depression and addiction.”

Though tantalizing, stem-cell therapy is unlikely to be the immediate benefit. Zhang notes that “for many psychiatric disorders, you don’t know which part of the brain has gone wrong.” The new study, he says, is more likely to see immediate application in creating models for drug screening and discovery.

A contact lens on the bathroom floor, an escaped hamster in the backyard, a car key in a bed of gravel: How are we able to focus so sharply to find that proverbial needle in a haystack? Scientists at the University of California, Berkeley, have discovered that when we embark on a targeted search, various visual and non-visual regions of the brain mobilize to track down a person, animal or thing.

That means that if we’re looking for a youngster lost in a crowd, the brain areas usually dedicated to recognizing other objects such as animals, or even the areas governing abstract thought, shift their focus and join the search party. Thus, the brain rapidly switches into a highly focused child-finder, and redirects resources it uses for other mental tasks.

“Our results show that our brains are much more dynamic than previously thought, rapidly reallocating resources based on behavioral demands, and optimizing our performance by increasing the precision with which we can perform relevant tasks,” said Tolga Cukur, a postdoctoral researcher in neuroscience at UC Berkeley and lead author of the study published today (Sunday April 21) in the journal Nature Neuroscience.

“As you plan your day at work, for example, more of the brain is devoted to processing time, tasks, goals and rewards, and as you search for your cat, more of the brain becomes involved in recognition of animals,” he added.

The findings help explain why we find it difficult to concentrate on more than one task at a time. The results also shed light on how people are able to shift their attention to challenging tasks, and may provide greater insight into neurobehavioral and attention deficit disorders such as ADHD.

These results were obtained in studies that used functional Magnetic Resonance Imaging (fMRI) to record the brain activity of study participants as they searched for people or vehicles in movie clips. In one experiment, participants held down a button whenever a person appeared in the movie. In another, they did the same with vehicles.

The brain scans simultaneously measured neural activity via blood flow in thousands of locations across the brain. Researchers used regularized linear regression analysis, which finds correlations in data, to build models showing how each of the roughly 50,000 locations near the cortex responded to each of the 935 categories of objects and actions seen in the movie clips. Next, they compared how much of the cortex was devoted to detecting humans or vehicles depending on whether or not each of those categories was the search target.

They found that when participants searched for humans, relatively more of the cortex was devoted to humans, and when they searched for vehicles, more of the cortex was devoted to vehicles. For example, areas that were normally involved in recognizing specific visual categories such as plants or buildings switched to become attuned to humans or vehicles, vastly expanding the area of the brain engaged in the search.

“These changes occur across many brain regions, not only those devoted to vision. In fact, the largest changes are seen in the prefrontal cortex, which is usually thought to be involved in abstract thought, long-term planning, and other complex mental tasks,” Cukur said.

The findings build on an earlier UC Berkeley brain imaging study that showed how the brain organizes thousands of animate and inanimate objects into what researchers call a “continuous semantic space.” Those findings challenged previous assumptions that every visual category is represented in a separate region of the visual cortex. Instead, researchers found that categories are actually represented in highly organized, continuous maps.

The latest study goes further to show how the brain’s semantic space is warped during a visual search, depending on the search target. Researchers have posted their results in an interactive, online brain viewer. Other co-authors of the study are UC Berkeley neuroscientists Jack Gallant, Alexander Huth and Shinji Nishimoto. Funding for the research was provided by the National Eye Institute of the National Institutes of Health.

When the brains of those who have succumbed to age-related neurodegeneration are analyzed post-mortem, they typically show significant atrophy on all scales. Not only is the cortex thinner and sparser, but the hollow ventricles inside the brain are grossly enlarged. In the absence of any specific disease, these general trends are still familiar. It has traditionally been assumed that the dynamic microfeatures of aged brains—the growth of the fine neurites and the synapses they make—would similarly be degenerate. In other words, synaptic growth would have either entered some form of stasis, or alternatively, a state of permanent decay with replacement by matrix or scar tissue. Contrary to these expectations, recent research shows increased structural plasticity in the axonal component of synapses in the aged mouse cortex. Reporting in the current issues of PNAS, researchers provide evidence that the observed behavioral deficits in these animals may be due to an inability to maintain persistent synaptic structure, rather than because of a loss of plasticity.

Specifically, the researchers found dramatic increases in the rates of synapse formation and elimination. They used two-photon microscopy to image axonal arbors and boutons in aged brains over time. Compared to young adult brains, established synaptic boutons in aged brain showed 10-fold higher rates of destabilization, and 20-fold higher turnover. The researchers also demonstrated, that while the size and density of synapses was comparable, size fluctuations were significantly higher in the aged brains.

Changes in synaptic structure are believed to be the mechanism for encoding long-term memory in the brain. In the absence of the full molecular picture underlying the way they change and grow, macroscopic appearance (size) is a convenient stand-in used to gauge relative importance of a particular synapse. Among other things, a larger synapse has greater resource at its disposal to reliably match incoming spikes to transmitter release. Not only can a larger synapse generally do this matching faster, they can do it for a longer time. The new studies suggest, however, that decreased ability to form new memories, or learn new behaviors, results from synapses being too fickle, rather than from loss of flexibility.

Clearly the full behavior of synapses is far from understood, despite it being one of the central preoccupations of experimental neuroscience. It is generally believed that the average synapse is at best able to match an incoming spike with fusion of a vesicle (and subsequent transmitter release) roughly half of the time. Many theoretical efforts have been made to account for this fact. One approach has been to do a strict accounting analysis of the energetic use of ATP by a neuron’s entire signalling tree. In other words, estimate how a neuron partitions its ATP budget between transmitting information in the form of spikes down the axon, and that spent in completing the hand-off to the next neuron at the synapse.

Detailed and painstaking measurements of axonal structural dynamics, as done here by the authors, is critical ground-floor work towards understand neural circuits. Isolated molecular details, while important, will never be sufficient to completely understand how learning and memory emerge from architectural changes. The current efforts of the BRAIN Initiative to map the complete connectome of a brain, together with a full activity map, will also need to include efforts to create what might be called, a theory of neurons. The ways in which neurons budget their energy, is likely to a central component of such a theory.

As a start, one postulate of a theory of neurons, that is consistent with the one-half probability for synaptic information transfer, might be the following: neurons tend to match the energy spent in sending spikes through their entire axonal arbor, with the sum total of the energy spent at all terminal boutons of that axon. The temporal aspects of how synapses are generated and eliminated in a short-lived animal, like a mouse, may be far different than those in a human. Understanding how these processes change with age, and with the amount of energy available to synapses to effect that change, will help complete the larger picture.

Up to 10 per cent of the population are affected by specific learning disabilities (SLDs), such as dyslexia, dyscalculia and autism, translating to 2 or 3 pupils in every classroom according to a new study.

The study – by academics at UCL and Goldsmiths - also indicates that children are frequently affected by more than one learning disability.

The research, published in Science, helps to clarify the underlying causes of learning disabilities and the best way to tailor individual teaching and learning for affected individuals and education professionals.

Specific learning disabilities arise from atypical brain development with complicated genetic and environmental causes, causing such conditions as dyslexia, dyscalculia, attention-deficit/hyperactivity disorder, autism spectrum disorder and specific language impairment.

While these conditions in isolation already provide a challenge for educators, an additional problem is that specific learning disabilities also co-occur for more often that would be expected. As, for example, in children with attention-deficit/hyperactivity disorder, 33 to 45 per cent also suffer from dyslexia and 11 per cent from dyscalculia.

Lead author Professor Brian Butterworth (UCL Institute of Cognitive Neuroscience) said: “We now know that there are many disorders of neurological development that can give rise to learning disabilities, even in children of normal or even high intelligence, and that crucially these disabilities can also co-occur far more often that you’d expect based on their prevalence.

"We are also finally beginning to find effective ways to help learners with one or more SLDs, and although the majority of learners can usually adapt to the one-size-fits-all approach of whole class teaching, those with SLDs will need specialised support tailored to their unique combination of disabilities."

As part of the study, Professor Butterworth and Dr Yulia Kovas (Goldsmiths) have summarised what is currently known about SLD’s neural and genetic basis to help clarify what is causing these disabilities to develop, helping to improve teaching for individual learners, and also training for school psychologists, clinicians and teachers.

What the team hope is that by developing an understanding of how individual differences in brain development interact with formal education, and also adapting learning pathways to individual needs, those with specific learning disabilities will produce more tailored education for such learners.

Professor Butterworth said: “Each child has a unique cognitive and genetic profile, and the educational system should be able to monitor and adapt to the learner’s current repertoire of skills and knowledge.

"A promising approach involves the development of technology-enhanced learning applications – such as games - that are capable of adapting to individual needs for each of the basic disciplines."

People with genes that make it tough for them to engage socially with others seem to be better than average at hypnotizing themselves. A study published today in Psychoneuroendocrinology concludes that such individuals are particularly good at becoming absorbed in their own internal world, and might also be more susceptible to other distortions of reality.

Psychologist Richard Bryant of the University of New South Wales in Sydney and his colleagues tested the hypnotizability of volunteers with different forms of the receptor for oxytocin, a hormone that increases trust and social bonding. (Oxytocin’s association with emotional attachment also earned it the nickname of ‘love hormone’.) Those with gene variants linked to social detachment and autism were found to be most susceptible to hypnosis.

Hypnosis has intrigued scientists since the nineteenth-century physician James Braid used it to alleviate pain in a variety of medical conditions, but it has never been fully understood. Hypnotized people can undergo a range of unusual experiences, including amnesia, anaesthesia and the loss of the ability to move their limbs. But some individuals are more affected by hypnosis than others — and no one knows why.

Hormones and hypnotism

How susceptible someone is to persuasion is an important factor in how easily they can be hypnotized by someone else. Bryant and his colleagues have previously shown that spraying a shot of oxytocin up people’s noses makes them more hypnotizable, and more likely to engage in potentially embarrassing activities such as swearing or dancing at a hypnotist’s suggestion.

When it comes to self-hypnosis, however, the team wondered whether people who can easily disengage from the external world and become lost in their own imagination might do better. In their latest study, they asked 185 volunteers to hypnotize themselves with the aid of an audio recording, then assessed the depth of their hypnosis using checks such as whether they were unable to open their eyes, or could hallucinate a sound.

The researchers used a questionnaire to test the participants’ ability to become absorbed in internal and imagined experiences, and tested them for variants of the oxytocin-receptor gene at two places in the gene sequence — rs53576 and rs2254298 — that that increase the risk of social detachment and autism. Participants with these variants scored highest for hypnotizability and absorption.

Bryant suggests that as well as being more hypnotizable, such individuals might “be influenced to have a range of experiences that more reality-based people cannot”. For example, this capacity might help to explain why some people respond better to placebos, or are more likely to accept paranormal or religious experiences.

“At this point we do not know anything about genetic bases of suggestibility per se,” says Bryant. “The current finding does provide some direction for exploring this.”

Aleksandr Kogan of the University of Cambridge, UK, who works on the genetics of social psychology, says that the results fit well with what is known about the oxytocin-receptor gene, particularly for variants at site rs53576. Among white people, these influence an individual’s sensitivity to social cues, he says. “That this would reflect a difference in internal experiences makes sense.”

When minor wounds heal, the fine nerve endings that sense touch, or control sweating, are usually able to regrow. Like many processes in the body, the ability to regenerate new tissues changes throughout the lifecycle, typically diminishing with age. To investigate the molecular details of regeneration, the nervous system of the worm, C. Elegans, is ideal because its entire blueprint—the connectome—is available. The close-knit cadre of researchers who study C. elegans are the true veterinarians of neuroscience in that they command nearly every tool in the field to study this microcosm of biology. Publishing today in Science, a group of these researchers has uncovered a genetic circuit that regulates the regrowth of axons after they are experimentally cut with a laser. While the integrity of these mechanisms insures stability in the adult nervous system, manipulation of them could allow insults to the system to be restored to normal function.

(C. Elegans neuron. Credit: Technion-Israel Institute of Technology)

In order to develop properly in the first place, the expression of the genes controlling tissue construction proceeds in a choreographed rhythm, with each having its proper time and place. Once the organism has developed, many of these genes are decommissioned, or their cycles of expression dephased. Sometimes two components that act together in the larval stage, oppose each other in the adult. Two players in this genetic tit-for-tat, lin-41 and let-7, have previously been found to act as timers during these transitions. The researchers in the study described here, stumbled upon this particular circuit while they were looking at the effect of yet another gene, alg-1, on axon regeneration. Specifically, they had found that worms with a mutant form of alg-1, could regenerate certain axons up to 2.5 times longer than the axons of normal adult worms.

One particular sensory neuron, the AVM (anterior ventral microtubule) neuron, has a clearly defined axon that can regrow in larva, in not in adults. This strangely-named neuron has an even stranger subcellular feature. Its dendrites, in addition to the axon, are filled with a unique kind of microtubule, one that is composed of 15 protofilaments. Most mammals use a microtubule form-factor specifically made from 13 protofilaments, but many invertebrates use anywhere from 10 to 15. The avm neuron is also unique in that is one of just a few neurons that migrates to an asymmetric position in the body of the worm—it has no counterpart on the opposite side.

(Let-7 microRNA. Credit: Wikipedia commons)

The AVM neuron shows clear expression not only the alg-1 gene, but also another factor regulated by alg-1 known as let-7. The researchers were able to show that let-7 is responsible for inhibiting adult regrowth in the AVM neuron. Inhibiting let-7 directly, or alternatively, increasing the level of its reciprocal inhibitor, lin-41, completely restored the regeneration capabilities of the larval axons. From this they conclude that cyclic interactions between let-7 and lin-41 are a general strategy used not only in determining cell fate in development, but also in controlling axon regeneration.

Expression of let-7 was controlled by using a version of the gene which is temperature-sensitive. The particular allele used has normal activity at 15 degrees C, but can be completely turned off at 20 degrees C. The actual product of the let-7 gene is ultimately not a protein, but one of a class of newly-discovered regulators known as microRNAs. The full functionality of microRNAs has yet to be completely defined, but they seem to be able to regulate proteins, DNA, and mRNA.

The researchers were also partial to speculation as to why the organism appears to take pains to inhibit regrowth in the adult. Axotomy by laser may not have been a primary selection criteria during the evolution of the worm, but some ability for tissue repair would be important in the life of a worm. In the greater scheme of things, it would seem that loss of certain capabilities in the adult, may be a small price to pay for the greater stability of connections that may come along with it.

We recently reported on a study in mice, which demonstrated that mature brains continue to remodel their fine structure throughout the entire life of the organism. Mammalian axons have the further complication that while myelination is required to conduct signals over appreciable distances, it can also be an impediment to regrowth. For axons that have been compromised by trauma, or through developmental fault, turning back the clock on a few genes may be only part of the puzzle.

A new Swedish study published in the journal Neurology shows that the risk of developing dementia may have declined over the past 20 years, in direct contrast to what many previously assumed. The result is based on data from SNAC-K, an ongoing study on aging and health that started in 1987.

"We know that cardiovascular disease is an important risk factor for dementia. The suggested decrease in dementia risk coincides with the general reduction in cardiovascular disease over recent decades", says Associate Professor Chengxuan Qiu of the Aging Research Center, established by Karolinska Institutet and Stockholm University. "Health check-ups and cardiovascular disease prevention have improved significantly in Sweden, and we now see results of this improvement reflected in the risk of developing dementia."

Dementia is a constellation of symptoms characterized by impaired memory and other mental functions. After age 75, dementia is commonly due to multiple causes, mainly Alzheimers disease and vascular dementia. In the current study, more than 3000 persons 75 years and older living in the central Stockholm neighborhood of Kungsholmen participated. Of the participants, 523 were diagnosed with some form of dementia. The key members of the research group have been essentially the same since 1987, including the neurologist responsible for the clinical diagnoses of dementia. All study participants were assessed by a nurse, a physician, and a psychologist.

The result shows the prevalence of dementia was stable in both men and women across all age groups after age 75 during the entire study period (1987-1989 and 2001-2004), despite the fact that the survival of persons with dementia increased since the end of the 1980s. This means that the overall risk of developing dementia must have declined during the period, possibly thanks to prevention and better treatment of cardiovascular disease.

"The reduction of dementia risk is a positive phenomenon, but it is important to remember that the number of people with dementia will continue to rise along with the increase in life expectancy and absolute numbers of people over age 75", says Professor Laura Fratiglioni, Director of the Aging Research Center. "This means that the societal burden of dementia and the need for medical and social services will continue to increase. Today there’s no way to cure patients who have dementia. Instead we must continue to improve health care and prevention in this area."

Using a new, stem cell-based, drug-screening technology that could reinvent and greatly reduce the cost of developing pharmaceuticals, researchers at the Harvard Stem Cell Institute (HSCI) have found a compound that is more effective in protecting the neurons killed in amyotrophic lateral sclerosis (ALS) than are two drugs that failed in human clinical trials after large sums were invested in them.

The new screening technique developed by Lee Rubin, a member of HSCI’s executive committee and a professor in Harvard’s Department of Stem Cell and Regenerative Biology (SCRB), had predicted that the two drugs that eventually failed in the third and final stage of human testing would do just that.

“It’s a deep, dark secret of drug discovery that very few drugs have been tested on human-diseased cells before being tested in a live person,” said Rubin, who heads HSCI’s program in translational medicine. “We were interested in the notion that we can use stem cells to correct that situation.”

Rubin’s model is built on an earlier proof of concept developed by HSCI principal faculty member Kevin Eggan, who demonstrated that it was possible to move a neuron-based disease into a laboratory dish using stem cells carrying the genes of patients with the disease.

In a paper published today in the journal Cell Stem Cell, Rubin laid out how he and his colleagues applied their new method of stem cell-based drug discovery to ALS, also known as Lou Gehrig’s disease. The illness is associated with the progressive death of motor neurons, which pass information between the brain and the muscles. As cells die, people with ALS experience weakness in their limbs, followed by rapid paralysis and respiratory failure. The disease typically strikes later in life. Ten percent of cases are genetically predisposed, but for most patients there is no known trigger.

Rubin’s lab began by studying the disease in mice, growing billions of motor neurons from mouse embryonic stem cells, half normal and half with a genetic mutation known to cause ALS. Investigators starved the cells of nutrients and then screened 5,000 druglike molecules to find any that would keep the motor neurons alive.

Several hits were identified, but the molecule that best prolonged the life of both normal and ALS motor neurons was kenpaullone, previously known for blocking the action of an enzyme (GSK-3) that switches on and off several cellular processes, including cell growth and death. “Shockingly, this molecule keeps cells alive better than the standard culture medium that everybody keeps motor neurons in,” Rubin said.

Kenpaullone proved effective in several follow-up experiments that put mouse motor neurons in situations of certain death. Neuron survival increased in the presence of the molecule whether the cells were programmed to die or were placed in a toxic environment.

After further investigation, Rubin’s lab discovered that kenpaullone’s potency came from its ability also to inhibit HGK, an enzyme that sets off a chain of reactions that leads to motor neuron death. This enzyme was not previously known to be important in motor neurons or associated with ALS, marking the discovery of a new drug target for the disease.

“I think that stem cell screens will discover new compounds that have never been discovered before by other methods,” Rubin said. “I’m excited to think that someday one of them might actually be good enough to go into the clinic.”

To find out if kenpaullone worked in diseased human cells, Rubin’s lab exposed patient motor neurons and motor neurons grown from human embryonic stem cells to the molecule, as well as two drugs that did well in mice but failed in phase III human clinical trials for ALS. Once again, kenpaullone increased the rate of neuron survival, while one drug saw little response, and the other drug failed to keep any cells alive.

According to Rubin, before kenpaullone could be used as a drug, it would need a substantial molecular makeover to make it better able to target cells and find its way into the spinal cord so it can access motor neurons.

“This is kind of a proof of principle on the do-ability of the whole thing,” he said. “I think it’s possible to use this method to discover new drug targets and to prevalidate compounds on real human disease cells before putting them in the clinic.”

Rubin’s next steps will be to continue searching for better druglike compounds that can inhibit HGK and thus enhance motor neuron survival. He believes that the new information that comes out of this research will be useful to academia and the pharmaceutical industry.

“These kinds of exploratory screens are hard to fund, so being part of the HSCI” — which provided some of the funding — “has been absolutely essential,” Rubin said.

A bizarre twist on the usual way proteins are made may explain mysterious symptoms in the grandparents of some children with mental disabilities.

The discovery, made by a team of scientists at the University of Michigan Medical School, may lead to better treatments for older adults with a recently discovered genetic condition.

The condition, called Fragile X-associated Tremor Ataxia Syndrome (FXTAS), causes shakiness and balance problems and is often misdiagnosed as Parkinson’s disease. The grandchildren of people with the disease have a separate disorder called Fragile X syndrome, caused by problems in the same gene. The new discovery may also help shine light on that disease, though indirectly.

In a new paper published in the journal Neuron, the U-M-led team presents evidence that a toxic protein they’ve named FMRpolyG contributes to the death of nerve cells in FXTAS – and that this protein is made in a very unusual way.

Normally, DNA is transcribed into RNA, and then a part of the RNA is translated into a protein that performs its function in cells. Where this translation process starts on the RNA is usually determined by a specific sequence called a start codon.

The gene mutation that causes FXTAS is a repeated DNA sequence that is made into RNA but normally is not made into protein because it lacks a start codon. However, the investigators discovered that when this repeat expands, it can trigger protein production by a new mechanism known as RAN translation.

Corresponding author Peter Todd, M.D., Ph.D., notes that this unusual translation process appears to stem from a long chain of repeated DNA “letters” found in the genes of both grandparents and kids with Fragile X mutations. Todd is the Bucky and Patti Harris Professor in the U-M Department of Neurology

"Essentially, we’ve found that a sequence of DNA which shouldn’t be made into protein is being made into protein – and that this causes a toxicity in nerve cells," he explains. "We believe that the protein forms aggregates, and that this is a major contributor to toxicity and symptoms in FXTAS."

The U-M group went on to show how this RAN translation occurs in FXTAS and demonstrated that blocking it prevents the repeat mutation from being toxic, suggesting a new target for future treatments.

Fragile X tremor/ataxia syndrome or FXTAS was only discovered a decade ago. It may affect as many as one in every 3,000 men and one in 20,000 women, who have a repeat mutation in the gene known as FMR1. However, these patients don’t usually develop symptoms until late middle age, allowing them to pass the mutation on to their daughters, who can then have children where the DNA repeat that has grown much longer. In those children, especially in boys, it can cause severe intellectual disability and autism-like symptoms as the FMR1 gene shuts down and none of the normal protein is produced.

In fact, says Todd, it’s often only after a child is diagnosed with Fragile X syndrome through genetic testing that their grandfather or grandmother finds out that their own symptoms stem from FXTAS. Doctors in U-M’s Neurogenetics clinic for adults, and the Pediatric Genetics Clinic at U-M’s C.S. Mott Children’s Hospital, routinely work together to address the needs of Fragile X families.

"We have some treatments for the symptoms that FXTAS patients have, but we do not yet have a cure," says Todd, who regularly sees patients with FXTAS and related disorders. "Better treatments are needed – and this new discovery might help lead to novel strategies for clearing away or preventing the buildup of this toxic protein."

In addition, he says, the discovery that Fragile X ataxia results in part from RAN translation could have significance both for other diseases like amyotrophic lateral sclerosis (ALS, also called Lou Gehrig’s disease) and certain forms of dementia that are caused by DNA repeats. It can also aid our understanding of basic biology. “This may represent a new way in which translational initiation events occur, and may have importance beyond this one disease,” he notes. Further research on how RAN translation occurs, and why, is needed.

The idea that proteins can be created without a “start site” flies in the face of what most students of biology have learned in the last century. “In biology, we’re finding that the rules we once thought were hard and fast have some wiggle room,” Todd says.

TAU reveals the missing link between brain patterns and Alzheimer’s

Evidence indicates that the accumulation of amyloid-beta proteins, which form the plaques found in the brains of Alzheimer’s patients, is critical for the development of Alzheimer’s disease, which impacts 5.4 million Americans. And not just the quantity, but also the quality of amyloid-beta peptides is crucial for Alzheimer’s initiation. The disease is triggered by an imbalance in two different amyloid species — in Alzheimer’s patients, there is a reduction in a relative level of healthy amyloid-beta 40 compared to 42.

Now Dr. Inna Slutsky of Tel Aviv University’s Sackler Faculty of Medicine and the Sagol School of Neuroscience, with postdoctoral fellow Dr. Iftach Dolev and PhD student Hilla Fogel, have uncovered two main features of the brain circuits that impact this crucial balance. The researchers have found that patterns of electrical pulses (called “spikes”) in the form of high-frequency bursts and the filtering properties of synapses are crucial to the regulation of the amyloid-beta 40/42 ratio. Synapses that transfer information in spike bursts improve the amyloid-beta 40/42 ratio.

This represents a major advance in understanding that brain circuits regulate composition of amyloid-beta proteins, showing that the disease is not just driven by genetic mutations, but by physiological mechanisms as well. Their findings were recently reported in the journal Nature Neuroscience.

Tipping the balance

High-frequency bursts in the brain are critical for brain plasticity, information processing, and memory encoding. To check the connection between spike patterns and the regulation of amyloid-beta 40/42 ratio, Dr. Dolev applied electrical pulses to the hippocampus, a brain region involved in learning and memory.

When increasing the rate of single pulses at low frequencies in rat hippocampal slices, levels of both amyloid-beta 42 and 40 grew, but the 40/42 ratio remained the same. However, when the same number of pulses was distributed in high-frequency bursts, researchers discovered an increased amyloid-beta 40 production. In addition, the researchers found that only synapses optimized to transfer encoded by bursts contributed towards tipping the balance in favor of amyloid-beta 40. Further investigations conducted by Fogel revealed that the connection between spiking patterns and the type of amyloid-beta produced could revolve around a protein called presenilin. “We hypothesize that changes in the temporal patterns of spikes in the hippocampus may trigger structural changes in the presenilin, leading to early memory impairments in people with sporadic Alzheimer’s,” explains Dr. Slutsky.

Behind the bursts

According to Dr. Slutsky, different kinds of environmental changes and experiences — including sensory and emotional experience — can modify the properties of synapses and change the spiking patterns in the brain. Previous research has suggested that a stimulant-rich environment could be a contributing factor in preventing the development of Alzheimer’s disease, much as crossword and similar puzzles appear to stimulate the brain and delay the onset of Alzheimer’s. In the recent study, the researchers discovered that changes in sensory experiences also regulate synaptic properties — leading to an increase in amyloid-beta 40.

In the next stage, Dr. Slutsky and her team are aiming to manipulate activity patterns in the specific hippocampal pathways of Alzheimer’s models to test if it can prevent the initiation of cognitive impairment. The ability to monitor dynamics of synaptic activity in humans would be a step forward early diagnosis of sporadic Alzheimer’s.

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.’

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).

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.

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.

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?”

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.