Hypertension Could Bring Increased Risk for Alzheimer’s disease

A study in the Journal of the American Medical Association Neurology suggests that controlling or preventing risk factors, such as hypertension, earlier in life may limit or delay the brain changes associated with Alzheimer’s disease and other age-related neurological deterioration.

Dr. Karen Rodrigue, assistant professor in the UT Dallas Center for Vital Longevity (CVL), was lead author of a study that looked at whether people with both hypertension and a common gene had more buildup of a brain plaque called amyloid protein, which is associated with Alzheimer’s disease. Scientists believe amyloid is the first symptom of Alzheimer’s disease and shows up a decade or more before symptoms of memory impairment and other cognitive difficulties begin. The gene, known as APOE 4, is carried by 20 percent of the population.

Until recently, amyloid plaque could be seen only at autopsy, but new brain scanning techniques allow scientists to see plaque in living brains of healthy adults. Findings from both autopsy and amyloid brain scans show that at least 20 percent of typical older adults carry elevated levels of amyloid, a substance made up mostly of protein that is deposited in organs and tissues.

“I became interested in whether hypertension was related to increased risk of amyloid plaques in the brains of otherwise healthy people,” Rodrigue said. “Identifying the most significant risk factors for amyloid deposition in seemingly healthy adults will be critical in advancing medical efforts aimed at prevention and early detection.”

Based on evidence that hypertension was associated with Alzheimer’s disease, Rodrigue suspected that the combination of hypertension and the presence of the APOE-e4 gene might lead to particularly high levels of amyloid plaque in healthy adults.

The Unstable Repeats—Three Evolving Faces of Neurological Disease

Disorders characterized by expansion of an unstable nucleotide repeat account for a number of inherited neurological diseases. Here, we review examples of unstable repeat disorders that nicely illustrate three of the major pathogenic mechanisms associated with these diseases: loss of function typically by disrupting transcription of the mutated gene, RNA toxic gain of function, and protein toxic gain of function. In addition to providing insight into the mechanisms underlying these devastating neurological disorders, the study of these unstable microsatellite repeat disorders has provided insight into very basic aspects of neuroscience.

Sleepwalkers sometimes remember what they’ve done

Three myths about sleepwalking – sleepwalkers have no memory of their actions, sleepwalkers’ behaviour is without motivation, and sleepwalking has no daytime impact – are dispelled in a recent study led by Antonio Zadra of the University of Montreal and its affiliated Sacré-Coeur Hospital. Working from numerous studies over the last 15 years at the hospital’s Centre for Advanced Studies in Sleep Medicine at the Hôpital du Sacré-Cœur de Montréal and a thorough analysis of the literature, Zadra and his colleagues have raised the veil on sleepwalking and clarified the diagnostic criteria for researchers and clinicians. Their findings were published in Lancet Neurology.

Question: What are the causes and consequences of sleepwalking?

A.Z.: “Several indicators suggest that a genetic factor is involved. In 80% of sleepwalkers, a family history of sleepwalking exists. The concordance of sleepwalking is five times higher in monozygotic twins compared to non-identical twins. Our studies have also shown that lack of sleep and stress can lead to sleepwalking. Any situation that disrupts sleep can result in sleepwalking episodes in predisposed individuals.”

A.Z.: “Most sleepwalking episodes are harmless. Apart from the fact that the deep slow-wave sleep of sleepwalkers is fragmented, wanderings are usually brief and pose no danger, or when they do, it is minimal. In rare cases, wandering episodes may be longer, and sleepwalkers may injure themselves and put themselves or others in danger: some have even gone as far as driving a car!”

Question: It is said that the sleep disorder mainly affects children. Is this true?

A.Z.: “Many children transitionally sleepwalk between 6 and 12 years of age. It is thought that passing from sleep to wakefulness requires a certain maturation of the brain. In some children, the brain may have difficulty making this transition. Often, the problem disappears after puberty. But sleepwalking may persist into adulthood in almost 25% of cases. It decreases with age, however, because the older you get, the fewer hours of deep slow-wave sleep you enjoy, which is the stage in which sleepwalking episodes occur.”

A.Z.: “Both children and adults are in a state of so-called dissociated arousal during wandering episodes: parts of the brain are asleep while others are awake. There are elements of wakefulness since sleepwalkers can perform actions such as washing, opening and closing doors, or going down stairs. Their eyes are open and they can recognize people. But there are also elements specific to sleep: sleepwalkers’ judgment and their ability for self-thought are altered, and their behavioural reactions are nonsensical.”

Question: According to you, the idea that people are partially awake and partially asleep is something that must be considered in conceptualizing sleepwalking?

A.Z.: “Absolutely. This is one of the points we outline in our article. There are increasing signs that even in normal subjects the brain does not fall asleep in a single block all at once. Sleep may occur in a localized manner. Parts of the brain can fall asleep before others.”

Question: This may explain why the amnesia of sleepwalkers is not always complete. But can sleepwalkers really remember their actions while sleeping vertically?

A.Z.: “Yes. In children and adolescents, amnesia is more frequent, probably due to neurophysiological reasons. In adults, a high proportion of sleepwalkers occasionally remember what they did during their sleepwalking episodes. Some even remember what they were thinking and the emotions they felt.”

Question: Your work has also shown that the behaviour of sleepwalkers is not simply automatic. Can you explain?

A.Z.: “This is another popular myth. There is a misconception that sleepwalkers do things without knowing why. However, there is a significant proportion of sleepwalkers who remember what they have done and can explain the reasons for their actions. They are the first to say, once awake, that their explanations are nonsensical. However, during the episode, there is an underlying rationale. For example, a man once took his dog that had been sleeping at the foot of his bed to the bathtub to douse it with water. He thought his dog was on fire! There was neither the logic nor the judgment typical of wakefulness. But the behaviour was not automatic in the sense that a motivation accompanied and explained the action.”

Question: Another myth you are interested in relates to impact on the waking state. According to you, beyond the nocturnal phenomenon, sleepwalking is associated with diurnal disorders characterized by somnolence.

A.Z.: “Around 45% of sleepwalkers are clinically somnolent during the day. Younger sleepwalkers are able to hide it more easily. Compared to control subjects, however, they perform less well in vigilance tests. And if given the opportunity to take a nap, they fall asleep faster than normal subjects do.”

A.Z.: “Over the last few years, we have shown that the deep slow-wave sleep of sleepwalkers is atypical. Fragmented by numerous micro-arousals of 3 to 10 seconds, their sleep is less restorative. Sleepwalking is therefore not only a problem of transitioning between deep sleep and wakefulness. There is something more fundamental in their sleep every night, whether or not they have sleepwalking episodes.”

You’re such a jerk

If that headline makes you feel bad, an expert says it’s because we’re genetically wired to take offense.

Insults are painful because we have certain social needs. We seek to be among other people, and once among them, we seek to form relationships with them and to improve our position on the social hierarchy. They are also painful because we have a need to project our self-image and to have other people not only accept this image, but support it. If we didn’t have these needs, being insulted wouldn’t feel bad. Furthermore, although different people experience different amounts of pain on being insulted, almost everyone will experience some pain. Indeed, we would search long and hard to find a person who is never pained by insults—or who himself never feels the need to insult others.

These observations raise a question: why do we have the social needs we do? According to evolutionary psychologists, our social needs—and, more generally, our psychological propensities—are the result of nature rather than nurture. More precisely, they are a consequence of our evolutionary past. The views of evolutionary psychologists are of interest in this, a study of insults, for the simple reason that they allow us to gain a deeper understanding of why it is painful when others insult us and why we go out of our way to cause others pain by insulting them.

We humans find some things to be pleasant and other things to be unpleasant. We find it pleasant, for example, to eat sweet, fattening foods or to have sex, and we find it unpleasant to be thirsty, swallow bitter substances, or get burned. Notice that we don’t choose for these things to be pleasant or unpleasant. It is true that we can, if we are strong-willed, voluntarily do things that are unpleasant, such as put our finger in a candle flame. We can also refuse to do things that are pleasant: we might, for example, forgo opportunities to have sex. But this doesn’t alter the basic biological fact that getting burned is painful and having sex is pleasurable. Whether or not an activity is pleasant is determined, after all, by our wiring, and we do not have it in our power—not yet, at any rate—to alter this wiring.

Why are we wired to be able to experience pleasure and pain? Why aren’t we wired to be immune to pain while retaining our ability to experience pleasure? And given that we possess the ability to experience both pleasure and pain, why do we find a particular activity to be pleasant rather than painful? Why, for example, do we find it pleasant to have sex but unpleasant to get burned? Why not the other way around? I have given the long answer to these questions elsewhere. For our present purposes—namely, to explain why we have the social needs we do—the short answer will suffice.

We have the ability to experience pleasure and pain because our evolutionary ancestors who had this ability were more likely to survive and reproduce than those who didn’t. Creatures with this ability could, after all, be rewarded (with pleasurable feelings) for engaging in certain activities and punished (with unpleasant feelings) for engaging in others. More precisely, they could be rewarded for doing things (such as having sex) that would increase their chances of surviving and reproducing, and be punished for doing things (such as burning themselves) that would lessen their chances.

This makes it sound as if a designer was responsible for our wiring, but evolutionary psychologists would reject this notion. Evolution, they would remind us, has no designer and no goal. To the contrary, species evolve because some of their members, thanks to the genetic luck-of-the-draw, have a makeup that increases their chances of surviving and reproducing. As a result, they (probably) have more descendants than genetically less fortunate members of their species. And because they spread their genes more effectively, they have a disproportionate influence on the genetic makeup of future members of their species.

Evolutionary psychologists would go on to remind us that if our evolutionary ancestors had found themselves in a different environment, we would be wired differently and as a result would find different things to be pleasant and unpleasant. Suppose that getting burned, rather than being detrimental to our evolutionary ancestors, had somehow increased their chances of surviving and reproducing. Under these circumstances, those individuals who were wired so that it felt good to get burned would have been more effective at spreading their genes than those who were wired so that it felt bad. And as a result we, their descendants, would also be wired so that it felt good to get burned.

Evolutionary psychologists would also remind us that the evolutionary process is imperfect. For one thing, although the wiring we inherited from our ancestors might have allowed them to flourish on the savannahs of Africa, it isn’t optimal for the rather different environment in which we today find ourselves. Our ancestors who had a penchant for consuming sweet, fattening foods, for example, were less likely to starve than those who didn’t. The problem is that we who have inherited that penchant live in an environment in which sweet, fattening foods are abundant. In this environment, being wired so that it is pleasant to consume, say, ice cream, increases our chance of getting heart disease and other illnesses, and thereby arguably lessens our chance of surviving.

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."

Single gene might explain dramatic differences among people with schizophrenia

Some of the dramatic differences seen among patients with schizophrenia may be explained by a single gene that regulates a group of other schizophrenia risk genes. These findings appear in a new imaging-genetics study from the Centre for Addiction and Mental Health (CAMH).

The study revealed that people with schizophrenia who had a particular version of the microRNA-137 gene (or MIR137), tended to develop the illness at a younger age and had distinct brain features – both associated with poorer outcomes – compared to patients who did not have this version. This work, led by Drs. Aristotle Voineskos and James Kennedy, appears in the latest issue of Molecular Psychiatry.

Treating schizophrenia is particularly challenging as the illness can vary from patient to patient. Some individuals stay hospitalized for years, while others respond well to treatment.

"What’s exciting about this study is that we could have a legitimate answer as to why some of these differences occur," explained Dr. Voineskos, a clinician-scientist in CAMH’s Campbell Family Mental Health Research Institute. "In the future, we might have the capability of using this gene to tell us about prognosis and how a person might respond to treatment."

"Drs. Voineskos and Kennedy’s findings are very important as they provide new insights into the genetic bases of this condition that affects thousands of Canadians and their families," said Dr. Anthony Phillips, Scientific Director at the Canadian Institutes of Health Research Institute of Neurosciences, Mental Health and Addiction.

Also, until now, sex has been the strongest predictor of the age at which schizophrenia develops in individuals. Typically, women tend to develop the illness a few years later than men, and experience a milder form of the disease.

"We showed that this gene has a bigger effect on age-at-onset than one’s gender has," said Dr. Voineskos, who heads the Kimel Family Translational Imaging-Genetics Research Laboratory at CAMH. "This may be a paradigm shift for the field."

The researchers studied MIR137 — a gene involved in turning on and off other schizophrenia-related genes — in 510 individuals living with schizophrenia. The scientists found that patients with a specific version of the gene tended to develop the illness at a younger age, around 20.8 years of age, compared to 23.4 years of age among those without this version.

"Although three years of difference in age-at-onset may not seem large, those years are important in the final development of brain circuits in the young adult," said Dr. Kennedy, Director of CAMH’s Neuroscience Research Department. "This can have major impact on disease outcome."

In a separate part of the study involving 213 people, the researchers used MRI and diffusion tensor-magnetic resonance brain imaging (DT-MRI). They found that individuals who had the particular gene version tended to have unique brain features. These features included a smaller hippocampus, which is a brain structure involved in memory, and larger lateral ventricles, which are fluid-filled structures associated with disease outcome. As well, these patients tended to have more impairment in white matter tracts, which are structures connecting brain regions, and serving as the information highways of the brain.

Developing tests that screen for versions of this gene could be helpful in treating patients earlier and more effectively.

"We’re hoping that in the near future we can use this combination of genetics and brain imaging to predict how severe a version of illness someone might have," said Dr. Voineskos. "This would allow us to plan earlier for specific treatments and clinical service delivery and pursue more personalized treatment options right from the start."

(Image: Akelei van Dam)

“Seq-ing” Insights into the Epigenetics of Neuronal Gene Regulation

The epigenetic control of neuronal gene expression patterns has emerged as an underlying regulatory mechanism for neuronal function, identity, and plasticity, in which short- to long-lasting adaptation is required to dynamically respond and process external stimuli. To achieve a comprehensive understanding of the physiology and pathology of the brain, it becomes essential to understand the mechanisms that regulate the epigenome and transcriptome in neurons. Here, we review recent advances in the study of regulated neuronal gene expression, which are dramatically expanding as a result of the development of new and powerful contemporary methodologies, based on next-generation sequencing. This flood of new information has already transformed our understanding of many biological processes and is now driving discoveries elucidating the molecular mechanisms of brain function in cognition, behavior, and disease and may also inform the study of neuronal identity, diversity, and neuronal reprogramming.

Researchers find controlling element of Huntington’s disease: Molecular troika regulates production of harmful protein

A three molecule complex may be a target for treating Huntington’s disease, a genetic disorder affecting the brain. This finding by an international research team including scientists from the German Center for Neurodegenerative Diseases (DZNE) in Bonn and the University of Mainz was published in the online journal “Nature Communications”. The report states that the so-called MID1 complex controls the production of a protein which damages nerve cells.

The long DNA sequences in Huntington’s disease lead to changes in a certain protein called “Huntingtin”. The DNA is like an archive of blueprints for proteins. Errors in the DNA therefore result in defective proteins. “Huntingtin is essential for the organism’s survival. It is a multi-talent which is important for many processes,” emphasises Krauss. “If the protein is defective, brain cells may die.“

In the spotlight: protein synthesis
In the current study, the scientists around Sybille Krauss and the Mainz-based human geneticist Susann Schweiger took a closer look at a critical stage of protein production – translation. At this step, a copy of the DNA, the so-called messenger RNA, is processed by the cell’s protein factories. In patients with Huntington’s disease, the messenger RNA contains an unusually high number of consecutive CAG sequences – CAG representing the building plan for the amino acid glutamine.

These repetitive sequences have a direct consequence: more glutamine than normal is built into Huntingtin, which is therefore defective. Sybille Krauss and her colleagues have now identified a group of three molecules, which regulate the production of this protein. “We were able to show that this complex binds to the messenger RNA and controls the synthesis of defective Huntingtin,” says Krauss. When the scientists reduced the concentration of this so-called MID1 complex in the cell, production of the defective protein declined.

“If we could find a way of influencing this complex, for example with pharmaceuticals, it is quite possible that we could directly affect the production of defective Huntingtin. This kind of treatment would not just treat the symptoms but also the causes of Huntington’s disease,” says Krauss.

Background:Three molecules come together
The complex consists of MID1, from which it gets its name, and the proteins PP2Ac and S6K. “Every single one of these proteins is known to be important for translation. We have discovered that in the specific case of Huntington’s disease, they together bind to the CAG sequences. This was previously unknown. We also found that binding increases with repeat lengths,” says Krauss. “In sequences of normal length, we found only weak binding or none at all.”

The Bonn-based molecular biologist and her colleagues investigated the effect of the MID1 complex and the interaction between its components in a series of elaborate laboratory experiments. “This project took several years of research work,” says Krauss. Along with biochemical procedures, the scientists used cell cultures and analysed proteins from the brains of mice. The mice’s genetic code had been modified in such a way that it contained elongated CAG-repeats as it is typical for Huntington’s disease.

From previous studies it was already known that the protein MID1 tends to bind messenger RNAs. The scientists were now able to show that MID1 also attaches to messenger RNAs with excessively long CAG sequences. Furthermore, experiments showed that PP2Ac and S6K also bound the RNA in the presence of MID1. However, if the MID1 was depleted, this binding did not occur. “From this, we can conclude that these three proteins form a molecular complex, which binds to the RNA. MID1 is a key component. It actually seems to keep together its binding partners,” Krauss comments on the results of the experiments.

Complex controls protein production
The researchers were also able to prove that the MID1 complex controls the translation of RNA with excessively long CAG sequences. For this, they investigated various cell cultures. The cells produced either normal Huntingtin or – due to excessively long sequences in their DNA – a defective version of this protein. The scientists reduced the occurrence of MID1 inside the cells using a procedure known as “knock-down”. The elimination of this protein, which is a major part of the MID1 complex, had direct consequences: the production of defective Huntingtin declined. “However, it did not affect the production of normal Huntingtin,” emphazises Krauss. “This further proves that the MID1 complex specifically targets RNAs with excessively long CAG sequences.”

Highly specific
The Bonn-based molecular biologist sees this specific influence as a chance to treat Huntington’s disease: “The MID1 complex is a promising target for therapy. It indicates a possibility to suppress the production of defective Huntingtin only, while not affecting the production of normal Huntingtin. This is of particular significance, because the normal protein is also being produced in the patients’ bodies and it is important for the organism.”

A suitable active substance has yet to be found, says Krauss. However, the next developments are in sight: “We now want to test potential substances in the laboratory,” she says.

A how-to manual for fruit fly research has been created

The first ever basic training package to teach students and scientists how to best use the fruit fly, Drosophila, for research has been published. It’s hoped it will encourage more researchers working on a range of conditions from cancer to Alzheimer’s disease to use the humble fly.

The unique scheme has been put together by Dr Andreas Prokop from the Faculty of Life Sciences at the University of Manchester and John Roote from the Department of Genetics at the University of Cambridge.

John Roote said, “In 1910 Thomas Hunt Morgan isolated the first Drosophila sex-linked mutation, white.  Since then many thousands of research workers have realised the potential of the humble fruit fly.

“The powerful research tools that we have today combined with a century of background knowledge, the vast collections of stocks that are available to everyone and the fortuitous ‘pre-adaptation’ of the fly for life in a laboratory ensure that Drosophila melanogaster maintains its position as the pre-eminent model organism for research in genetics.  However, until now a comprehensive teaching programme to guide students through the often daunting first few steps has been surprisingly absent.”

Dr Prokop said: “People don’t realise just how useful the tiny fruit fly can be when it comes to research. Fellow scientists are often not aware of their genetic value for research. For example, about 75% of known human disease genes have a recognisable match in the genome of fruit flies which means they can be used to study the fundamental biology behind complex conditions such as epilepsy or neurodegeneration.”

Fruit flies have been used for scientific research for more than a hundred years. They have allowed scientific breakthroughs in genetics, body structure and function. The first jet lag gene and the first learning gene were identified in flies as well as breakthroughs in neuroscience, such as the discovery of the first channel proteins.

Training package: How to design a genetic mating scheme: a basic training package for Drosophila genetics