Alzheimer’s risk gene discovered using imaging method that screens brain’s connections

Scientists at UCLA have discovered a new genetic risk factor for Alzheimer’s disease by screening people’s DNA and then using an advanced type of scan to visualize their brains’ connections.

Alzheimer’s disease, the most common cause of dementia in the elderly, erodes these connections, which we rely on to support thinking, emotion and memory. With no known cure for the disease, the 20 million Alzheimer’s sufferers worldwide lack an effective treatment. And we are all at risk: Our chance of developing Alzheimer’s doubles every five years after age 65.

The UCLA researchers discovered a common abnormality in our genetic code that increases the risk of Alzheimer’s. To find the gene, they used a new imaging method that screens the brain’s connections — the wiring, or circuitry, that communicates information. Switching off such Alzheimer’s risk genes (nine of them have been implicated over the last 20 years) could stop the disorder in its tracks or delay its onset by many years.

The research is published in the March 4 online edition of the journal Proceedings of the National Academy of Sciences.

"We found a change in our genetic code that boosts our risk for Alzheimer’s disease," said the study’s senior author, Paul Thompson, a UCLA professor of neurology and a member of the UCLA Laboratory of Neuro Imaging. "If you have this variant in your DNA, your brain connections are weaker. As you get older, faulty brain connections increase your risk of dementia."

The researchers, Thompson said, screened more than a thousand people’s DNA to find the common “spelling errors” in the genetic code that might heighten their risk for the disease later in life. The new study was the first of its kind to also give each person a “connectome scan,” a special type of scan that measures water diffusion in the brain, allowing scientists to map the strength of the brain’s connections.

The new scan reveals the brain’s circuitry and how information is routed around the brain, in order to discover risk factors for disease. The researchers then combined these connectivity scans with the extensive genomic screening to pinpoint what causes faulty wiring in the brain.

Hundreds of computers, calculating for months, sifted through more than 4,000 brain connections and the entire genetic code, comparing connection patterns in people with different genetic variations. In people whose genetic code differed in one specific gene called SPON1, weaker connections were found between brain centers controlling reasoning and emotion. The rogue gene also affects how senile plaques build up in the brain — one of the hallmarks of Alzheimer’s disease.

"Much of your risk for disease is written in your DNA, so the genome is a good place to look for new drug targets," said Thompson, who in 2009 founded a research network known as Project ENIGMA to pool brain scans and DNA from 26,000 people worldwide. "If we scan your brain and DNA today, we can discover dangerous genes that will undermine your ability to think and plan and will make you ill in the future. If we find these genes now, there is a better chance of new drugs that can switch them off before you or your family get ill."

Developing new therapeutics for Alzheimer’s is a hot area for pharmaceutical research, Thompson said.

It has also been found that the SPON1 gene can be manipulated to develop new treatments for the devastating disease, Thompson noted. When the rogue gene was altered in mice, it led to cognitive improvements and fewer plaques building up in the brain. Alzheimer’s patients show an accumulation of these senile plaques, which are made of a sticky substance called amyloid and are thought to kill brain cells, causing irreversible memory loss and personality changes.

Screening genomes has led to many new drug targets in the treatment of cancer, heart disease, arthritis and brain disorders such as epilepsy. But the UCLA team’s approach — screening genomes and performing brain scans of the same people — promises a faster and more efficient search.

"With a brain scan that takes half an hour and a DNA scan from a saliva sample, we can search your genes for factors that help or harm your brain’s connections," Thompson said. "This opens up a new landscape of discovery in medical science."

Green tea extract interferes with the formation of amyloid plaques in Alzheimer’s disease

Researchers at the University of Michigan have found a new potential benefit of a molecule in green tea: preventing the misfolding of specific proteins in the brain.

The aggregation of these proteins, called metal-associated amyloids, is associated with Alzheimer’s disease and other neurodegenerative conditions.

A paper published recently in the Proceedings of the National Academy of Sciences explained how Life Sciences Institute faculty member Mi Hee Lim and an interdisciplinary team of researchers used green tea extract to control the generation of metal-associated amyloid-β aggregates associated with Alzheimer’s disease in the lab.

The specific molecule in green tea, (—)-epigallocatechin-3-gallate, also known as EGCG, prevented aggregate formation and broke down existing aggregate structures in the proteins that contained metals—specifically copper, iron and zinc.

"A lot of people are very excited about this molecule," said Lim, noting that the EGCG and other flavonoids in natural products have long been established as powerful antioxidants. "We used a multidisciplinary approach. This is the first example of structure-centric, multidisciplinary investigations by three principal investigators with three different areas of expertise."

The research team included chemists, biochemists and biophysicists.

While many researchers are investigating small molecules and metal-associated amyloids, most are looking from a limited perspective, said Lim, assistant professor of chemistry and research assistant professor at the Life Sciences Institute, where her lab is located and her research is conducted.

"But we believe you have to have a lot of approaches working together, because the brain is very complex," she said.

The PNAS paper was a starting point, Lim said, and her team’s next step is to “tweak” the molecule and then test its ability to interfere with plaque formation in fruit flies.

"We want to modify them for the brain, specifically to interfere with the plaques associated with Alzheimer’s," she said.

Lim plans to collaborate with Bing Ye, a neurobiologist in the LSI. Together, the researchers will test the new molecule’s power to inhibit potential toxicity of aggregates containing proteins and metals in fruit flies.

Age-Related Dementia May Begin with Neurons’ Inability to Rid Themselves of Unwanted Proteins

A team of European scientists from the University Medical Center Hamburg-Eppendorf (UKE) and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) at the University of Cologne in Germany has taken an important step closer to understanding the root cause of age-related dementia. In research involving both worms and mice, they have found that age-related dementia is likely the result of a declining ability of neurons to dispose of unwanted aggregated proteins. As protein disposal becomes significantly less efficient with increasing age, the buildup of these unwanted proteins ultimately leads to the development and progression of dementia. This research appears in the March 2013 issue of the journal Genetics.

“By studying disease progression in dementia, specifically by focusing on mechanisms neurons use to dispose of unwanted proteins, we show how these are interconnected and how these mechanisms deteriorate over time,” said Markus Glatzel, M.D., a researcher involved in the work from the Institute of Neuropathology at UKE in Hamburg, Germany. “This gives us a better understanding as to why dementias affect older persons; the ultimate aim is to use these insights to devise novel therapies to restore the full capacity of protein disposal in aged neurons.”

To make this discovery, scientists carried out their experiments in both worm and mouse models that had a genetically-determined dementia in which the disease was caused by protein accumulation in neurons. In the worm model, researchers in the lab of Thorsten Hoppe, Ph.D., from the CECAD Cluster of Excellence could inactivate distinct routes used for the disposal of the unwanted proteins. Results provided valuable insight into the mechanisms that neurons use to cope with protein accumulation. These pathways were then assessed in young and aged mice. This study provides an explanation of why dementias exponentially increase with age. Additionally, neuron protein disposal methods may offer a therapeutic target for the development of drugs to treat and/or prevent dementias.

“This is an exciting study that helps us understand what’s going wrong at a cellular level in age-related dementias,” said Mark Johnston, Ph.D., Editor-in-Chief of the journal Genetics. “This research holds possibilities for future identification of substances that can prevent, stop, or reverse this cellular malfunction in humans.”

(Image: damato)

It’s Not Just Amyloid: White Matter Hyperintensities and Alzheimer’s Disease

New findings by Columbia researchers suggest that along with amyloid deposits, white matter hyperintensities (WMHs) may be a second necessary factor for the development of Alzheimer’s disease.

Most current approaches to Alzheimer’s disease focus on the accumulation of amyloid plaque in the brain. The researchers at the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, led by Adam M. Brickman, PhD, assistant professor of neuropsychology, examined the additional contribution of small-vessel cerebrovascular disease, which they visualized as white matter hyperintensities (WMHs).

The study included 20 subjects with clinically defined Alzheimer’s disease, 59 subjects with mild cognitive impairment, and 21 normal control subjects. Using data from the Alzheimer’s Disease Neuroimaging Initiative public database, the researchers found that amyloid and WHMs were equally associated with an Alzheimer’s diagnosis. Amyloid and WMHs were also equally predictive of which subjects with mildcognitive impairment would go on to develop Alzheimer’s. Among those with significant amyloid, WMHs were more prevalent in those with Alzheimer’s than in normal control subjects.

Because the risk factors for WMHs—which are mainly vascular—can be controlled, the findings suggest potential ways to prevent the development of Alzheimer’s in those with amyloid deposits.

“White Matter Hyperintensities and Cerebral Amyloidosis” was published online in JAMA Neurology.

Paving the way for better sleep in Alzheimer’s

A new sleep pattern monitoring system has been developed by UK researchers to help spot sleep disturbance in people diagnosed with early dementia. The system, known as PAViS, could be used remotely by healthcare workers to view sleep profiles and analyse sleep patterns based on sensory data gathered at the patient’s home.

Writing in the International Journal of Computers in Healthcare, Huiru Zheng and colleagues at the University of Ulster at Jordanstown, County Antrim, Northern Ireland explain how sleep disturbance is one of the most distressing of symptoms in Alzheimer’s disease and might also be an early indicator of the onset of the disease in some cases. They point out that so-called “telecare” systems allow healthcare workers to monitor patient activity whether in normal or supported housing.

There are almost half a million people in the UK with Alzheimer’s disease and for many of those sleep disorders and disruptive nocturnal behaviour present a significant clinical problem for healthcare workers and are a cause of distress for caregivers. Sleep-related problems generally worsen as the disease progresses and are an indicator of cognitive impairment and lead to the patient being less alert than would be expected during waking hours as well as reducing their overall wellbeing.

Various systems have been developed in recent years to monitor sleeping patients. However, these would often tend to involve other people in the patient’s home as well as simply monitoring sleep patterns rather than long-term monitoring and analysis of sleep profiles for assessing sleep quality. PAViS, pattern analysis and visualisation system, circumvents the problems and allows healthcare workers to quickly see shifts in sleep pattern and detect unusual patterns in order to assess the changes in health condition of people with early dementia over the course of weeks and months. Data are collected from infrared movement detectors and sensors on bedroom and other doors in the patient’s home. This provides a non-invasive, pervasive and objective monitoring and assessment solution, the team says.

Technique moves practical Alzheimer diagnosis one step closer to reality

Researchers at the University of Wisconsin-Madison School of Medicine and Public Health are moving closer to a significant milepost in the battle against Alzheimer’s disease: identifying the first signs of decline in the brain.

After years of frustrating failure to stop late-stage Alzheimer’s, it’s essential to find and treat the mild stages, says Sterling Johnson, professor of geriatrics. “We need to identify Alzheimer’s as early as possible, before the really destructive changes take place. Typically, by the time we diagnose Alzheimer’s disease, patients have already lost much of their brain capacity, and it’s difficult or impossible for them to recover.”

The earlier phases, before large numbers of brain cells have been killed, should be more amenable to treatment, Johnson says. Alzheimer’s disease is the largest single cause of dementia. Early symptoms include memory decline, eventually progressing to widespread cognitive and behavioral changes.

In a study published in the journal Cerebral Cortex in December, Johnson, Ozioma Okonkwo in the Department of Geriatrics, and colleagues reported on measurements of brain blood flow in 327 adults. The researchers used an advanced form of MRI to compare blood flow in people with Alzheimer’s, a preliminary stage called mild cognitive impairment, or those who had no symptoms but had a family history of Alzheimer’s.

Reduced blood flow signifies reduced activity in particular parts of the brain, often due to the atrophy of nerve cells. One affected structure, called the hippocampus, is necessary for making new memories. In mild to moderate cases of Alzheimer’s, 40 percent or more of the hippocampus has disappeared.

As expected, the Alzheimer’s patients had lower blood flow in several brain regions linked to memory. People with mild cognitive impairment had a milder version of the same deficits. And people whose mother (but not father) had Alzheimer’s had clear signs of reduced blood flow, even though they lacked symptoms.

Other techniques that can measure blood flow are more costly and require the use of radiation and injecting a drug tracer during the scan, Johnson says. If this non-invasive MRI technique continues to prove itself, it could be a key to detecting Alzheimer’s disease in its early, and hopefully more treatable, phases.

"In the new paper, we showed that the same areas that show up with more established scanning techniques also are identified with this MRI blood flow technique, in people with Alzheimer’s and mild cognitive impairment," says Johnson. "So this method is valid and reliable, and is now ready to begin deployment in treatment research with people at risk."

How Neuroscience Will Fight Five Age-Old Afflictions

SEIZURES

A device delivers targeted drugs to calm overactive neurons

For years, large clinical trials have treated people with epilepsy using so-called deep-brain stimulation: surgically implanted electrodes that can detect a seizure and stop it with an electrical jolt. The technology leads to a 69 percent reduction in seizures after five years, according to the latest results.

Tracy Cui, a biomedical engineer at the University of Pittsburgh, hopes to improve upon that statistic. Her group has designed an electrode that would deliver both an electrical pulse and antiseizure medication. “We know where we want to apply the drug,” Cui says, “so you would not need a lot of it.”

To build the device, Cui’s team immersed a metal electrode in a solution containing two key ingredients: a molecule called a monomer and the drug CNQX. Zapping the solution with electricity causes the monomers to link together and form a long chain called a polymer. Because the polymer is positively charged, it attracts the negatively charged CNQX, leaving the engineers with their target product: an electrode coated in a film that’s infused with the drug.

The researchers then placed the electrodes in a petri dish with rat neurons. Another zap of electricity disrupted the electrostatic attraction in the film, causing the polymer to release its pharmacological payload—and nearby cells to quiet their erratic firing patterns. Cui says her team has successfully repeated the experiment in living rats. Next, she’d like to test the electrodes in epileptic rats and then begin the long process of regulatory approval for human use.

The body’s blood-brain barrier protects the organ from everything but the smallest molecules, rendering most drugs ineffective. As a result, this drug-​delivery mechanism could treat other brain disorders, Cui says. The electrodes can be loaded with any kind of small drug—like dopamine or painkillers—making it useful for treating Parkinson’s disease, chronic pain, or even drug addiction.

DEMENTIA

Electrode arrays stimulate mental processing

Dementia is one of the most well-known and frustrating brain afflictions. It damages many of the fundamental cognitive functions that make us human: working memory, decision-making, language, and logical reasoning. Alzheimer’s, Huntington’s, and Parkinson’s diseases all lead to dementia, and it’s also sometimes associated with multiple sclerosis, AIDS, and the normal process of aging.

Theodore Berger, a biomedical engineer at the University of Southern California, hopes to help people stave off the symptoms of dementia with a device implanted in the brain’s prefrontal cortex, a region crucial for sophisticated cognition. He and colleagues at Wake Forest Baptist Medical Center tested the device in a study involving five monkeys and a memory game.

First the team implanted an electrode array so that it could record from layers 2/3 and 5 of the prefrontal cortex and stimulate layer 5. The neural signals that jet back and forth between these areas relate to attention and decision-making. The team then trained the monkeys to play a computer game in which they saw a cartoon picture—such as a truck, lion, or paint palette—and had to select the same image from a panel of pictures 90 seconds later.

The scientists initially analyzed the electrical signals sent between the two cortical layers when the monkeys made a correct match. In later experiments, the team caused the array to emit the same signal just before the monkey made its decision. The animals’ accuracy improved by about 10 percent. That effect may be even more profound in an impaired brain. When the monkeys played the same game after receiving a hit of cocaine, their performance dropped by about 20 percent. But electrical stimulation restored their accuracy to normal levels.

Dementia involves far more complicated circuitry than these two layers of the brain. But once scientists better understand exactly how dementia works, it may be possible to combine several implants to each target a specific region.

BLINDNESS

Gene therapy converts cells into photoreceptors, restoring eyesight

Millions of people lose their eyesight when disease damages the photoreceptor cells in their retinas. These cells, called rods and cones, play a pivotal role in vision: They convert incoming light into electrical impulses that the brain interprets as an image.

In recent years, a handful of companies have developed electrode-array implants that bypass the damaged cells. A microprocessor translates information from a video camera into electric pulses that stimulate the retina; as a result, blind subjects in clinical trials have been able to distinguish objects and even read very large type. But the implanted arrays have one big drawback: They stimulate only a small number of retinal cells—about 60 out of 100,000—which ultimately limits a person’s visual resolution.

A gene therapy being developed by Michigan-based RetroSense could replace thousands of damaged retinal cells. The company’s technology targets the layer of the retina containing ganglion cells. Normally, ganglion cells transmit the electric signal from the rods and cones to the brain. But RetroSense inserts a gene that makes the ganglion cells sensitive to light; they take over the job of the photoreceptors. So far, scientists have successfully tested the technology on rodents and monkeys. In rat studies, the gene therapy allowed the animals to see well enough to detect the edge of a platform as they neared it.

The company plans to launch the first clinical trial of the technology next year, with nine subjects blinded by a disease called retinitis pigmentosa. Unlike the surgeries to implant electrode arrays, the procedure to inject gene therapy will take just minutes and requires only local anesthesia. “The visual signal that comes from the ganglion cells may not be encoded in exactly the fashion that they’re used to,” says Peter Francis, chief medical officer of RetroSense. “But what is likely to happen is that their brain is going to adapt.”

PARALYSIS

A brain-machine interface controls limbs while sensing what they touch

Last year, clinical trials involving brain implants gave great hope to people with severe spinal cord injuries. Two paralyzed subjects imagined picking up a cup of coffee. Electrode arrays decoded those neural instructions in real time and sent them to a robotic arm, which brought the coffee to their lips.

But to move limbs with any real precision, the brain also requires tactile feedback. Miguel Nicolelis, a biomedical engineer at Duke University, has now demonstrated that brain-machine interfaces can simultaneously control motion and relay a sense of touch—at least in virtual reality.

For the experiment, Nicolelis’s team inserted electrodes in two brain areas in monkeys: the motor cortex, which controls movement, and the nearby somatosensory cortex, which interprets touch signals from the outside world. Then the monkeys played a computer game in which they controlled a virtual arm—first by using a joystick and eventually by simply imagining the movement. The arm could touch three identical-looking gray circles. But each circle had a different virtual “texture” that sent a distinct electrical pattern to the monkeys’ somatosensory cortex. The monkeys learned to select the texture that produced a treat, proving that the implant was both sending and receiving neural messages.

This year, a study in Brazil will test the ability of 10 to 20 patients with spinal cord injuries to control an exoskeleton using the implant. Nicolelis, an ardent fan of Brazilian soccer, has set a strict timetable for his team: A nonprofit consortium he created, the Walk Again Project, plans to outfit a paraplegic man with a robotic exoskeleton and take him to the 2014 World Cup in São Paulo, where he will deliver the opening kick.

DEAFNESS

Stem cells repair a damaged auditory nerve, improving hearing

Over the past 25 years, more than 30,000 people with hearing loss have received an electronic implant that replaces the cochlea, the snail-shaped organ in the inner ear whose cells transform sound waves into electrical signals. The device acts as a microphone, picking up sounds from the environment and transmitting them to the auditory nerve, which carries them on to the brain.

But a cochlear implant won’t help the 10 percent of people whose profound hearing loss is caused by damage to the auditory nerve. Fortunately for this group, a team of British scientists has found a way to restore that nerve using stem cells.

The researchers exposed human embryonic stem cells to growth factors, substances that cause them to differentiate into the precursors of auditory neurons. Then they injected some 50,000 of these cells into the cochleas of gerbils whose auditory nerves had been damaged. (Gerbils are often used as models of deafness because their range of hearing is similar to that of people.) Three months after the transplant, about one third of the original number of auditory neurons had been restored; some appeared to form projections that connected to the brain stem. The animals’ hearing improved, on average, by 46 percent.

It will be years before the technique is tested in humans. Once it is, researchers say, it has the potential to help not only those with nerve damage but also people with more widespread impairment whose auditory nerve must be repaired in order to receive a cochlear implant.

My gray matter might be waning. Then again, it might not be. But I swear that I can feel memories — as I’m making them — slide off a neuron and into a tangle of plaque. I steel myself for those moments to come when I won’t remember what just went into my head.

I’m not losing track of my car keys, which is pretty standard in aging minds. Nor have I ever forgotten to turn off the oven after use, common in menopausal women. I can always find my car in the parking lot, although lots of “normal” folk can’t.

Rather, I suddenly can’t remember the name of someone with whom I’ve worked for years. I cover by saying “sir” or “madam” like the Southerner I am, even though I live in Vermont and grown people here don’t use such terms. Better to think I’m quirky than losing my faculties. Sometimes I’ll send myself an e-mail to-do reminder and then, seconds later, find myself thrilled to see a new entry pop into my inbox. Oops, it’s from me. Worse yet, a massage therapist kicked me out of her practice for missing three appointments. I didn’t recall making any of them. There must another Nancy.

Am I losing track of me?

Waiting for the Forgetting to Begin by Nancy Stearns Bercaw

Translation error tracked in the brain of dementia patients

In certain dementias silent areas of the genetic code are translated into highly unusual proteins by mistake. An international team of scientists including researchers from the German Center for Neurodegenerative Diseases (DZNE) in Munich and the Ludwig-Maximilians-Universität (LMU) present this finding in the online edition of “Science”. The proteins that have now been identified shouldn’t actually exist. Nevertheless, they build the core of cellular aggregates whose identity has been enigmatic until now. These aggregates are typically associated with hereditary neurodegenerative diseases including variants of frontotemporal dementia (FTD), also known as frontotemporal lobar degeneration (FTLD), and amyotrophic lateral sclerosis (ALS). They are likely to be damaging and might be a target for therapy.

FTD and ALS are part of a group of neurodegenerative diseases that show a broad and overlapping variety of symptoms: Patients often suffer from dementia, personality changes and may also be affected by language abnormalities and movement disorders. The problems often arise before the age of 65 without a clear cause. However, about 30 percent of cases are linked to a genetic cause. In Europe approximately 10 percent of patients show a common genetic feature: In their DNA (the carrier of the genetic code) a particular short sequence appears in numerous copies one after another. Furthermore, proteins of unknown identity accumulate inside the brain of these patients. As it turns out both findings are directly related – that is what the team of researchers including molecular biologists Dieter Edbauer and Christian Haass has now been able to show.

“We have found that the proteins are linked to a genetic peculiarity which many patients have in common. At a certain location inside the gene C9orf72 there are several hundred repeats of the sequence GGGGCC, while healthy people display less than 20 such copies,” explains Prof. Edbauer, who researches at the DZNE and the LMU. “But it is surprising that these proteins are actually made, because these repeats fall into a region of the DNA that should not be translated into proteins.”

An area of DNA assumed to be silent

The DNA holds the blueprints for building proteins. In general, the beginning of such a blueprint is indicated by a certain molecular start signal, but the usual signal is missing in this case. The region of DNA comprising the numerous repeats should therefore not be translated into proteins. It seems that the process of protein synthesis is initiated in a non-textbook way. “Although quite rare there are two known alternatives to the common mechanism. Which procedure applies here, we don’t know yet,” says Prof. Haass, Site Speaker of the DZNE in Munich and chair of Metabolic Biochemistry at LMU.

Nevertheless, in cell culture experiments the researchers were able to show that long repeats of the sequence GGGGCC may in fact lead to the production of proteins, even though the usual start signal is missing. Furthermore, they identified the same proteins in the particles that typically accumulate in the brain of patients. The scientist could also identify their composition: They turned out to be dipeptid-repeat proteins, which comprise a very large number of identical building blocks.

“These are very extraordinary proteins that usually don’t show-up in the organism,” Edbauer notes. “As far as we know, they are completely useless and scarcely soluble. Therefore, they tend to aggregate and seem to damage the nerve cells. We haven’t formally proven toxicity, but there is ample evidence.” Because of their peculiarity these proteins might be an interesting target for new therapies. “As the mechanism of their production is so unusual, we may find ways to inhibit their synthesis without interfering with the formation of other proteins. One could also try to block their aggregation and accelerate their decomposition.”

The scientists have applied for a patent and are pursuing a major goal. “At the DZNE in Munich it is our dream to develop a therapy against these devastating diseases,“ Haass and Edbauer conclude.