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.

Depression stems from miscommunication between brain cells

A new study from the University of Maryland School of Medicine suggests that depression results from a disturbance in the ability of brain cells to communicate with each other. The study indicates a major shift in our understanding of how depression is caused and how it should be treated. Instead of focusing on the levels of hormone-like chemicals in the brain, such as serotonin, the scientists found that the transmission of excitatory signals between cells becomes abnormal in depression. The research, by senior author Scott M. Thompson, Ph.D., Professor and Interim Chair of the Department of Physiology at the University of Maryland School of Medicine, was published online in the March 17 issue of Nature Neuroscience.

"Dr. Thompson’s groundbreaking research could alter the field of psychiatric medicine, changing how we understand the crippling public health problem of depression and other mental illness," says E. Albert Reece, M.D., Ph.D., M.B.A., Vice President for Medical Affairs at the University of Maryland and John Z. and Akiko K. Bowers Distinguished Professor and Dean at the University of Maryland School of Medicine. "This is the type of cutting-edge science that we strive toward at the University of Maryland, where discoveries made in the laboratory can impact the clinical practice of medicine."

The first major finding of the study was the discovery that serotonin has a previously unknown ability to strengthen the communication between brain cells. “Like speaking louder to your companion at a noisy cocktail party, serotonin amplifies excitatory interactions in brain regions important for emotional and cognitive function and apparently helps to make sure that crucial conversations between neurons get heard,” says Dr. Thompson. “Then we asked, does this action of serotonin play any role in the therapeutic action of drugs like Prozac?”

To understand what might be wrong in the brains of patients with depression and how elevating serotonin might relieve their symptoms, the study team examined the brains of rats and mice that had been repeatedly exposed to various mildly stressful conditions, comparable to the types of psychological stressors that can trigger depression in people.

The researchers could tell that their animals became depressed because they lost their preference for things that are normally pleasurable. For example, normal animals given a choice of drinking plain water or sugar water strongly prefer the sugary solution. Study animals exposed to repeated stress, however, lost their preference for the sugar water, indicating that they no longer found it rewarding. This depression-like behavior strongly mimics one hallmark of human depression, called anhedonia, in which patients no longer feel rewarded by the pleasures of a nice meal or a good movie, the love of their friends and family, and countless other daily interactions.

A comparison of the activity of the animals’ brain cells in normal and stressed rats revealed that stress had no effect on the levels of serotonin in the ‘depressed’ brains. Instead, it was the excitatory connections that responded to serotonin in strikingly different manner. These changes could be reversed by treating the stressed animals with antidepressants until their normal behavior was restored.

"In the depressed brain, serotonin appears to be trying hard to amplify that cocktail party conversation, but the message still doesn’t get through," says Dr. Thompson. Using specially engineered mice created by collaborators at Johns Hopkins University School of Medicine, the study also revealed that the ability of serotonin to strengthen excitatory connections was required for drugs like antidepressants to work.

Sustained enhancement of communication between brain cells is considered one of the major processes underlying memory and learning. The team’s observations that excitatory brain cell function is altered in models of depression could explain why people with depression often have difficulty concentrating, remembering details, or making decisions. Additionally, the findings suggest that the search for new and better antidepressant compounds should be shifted from drugs that elevate serotonin to drugs that strengthen excitatory connections.

"Although more work is needed, we believe that a malfunction of excitatory connections is fundamental to the origins of depression and that restoring normal communication in the brain, something that serotonin apparently does in successfully treated patients, is critical to relieving the symptoms of this devastating disease," Dr. Thompson explains.

(Image: McGovern Institute, MIT)

Brainless robots swarm just like animals

Swarming patterns and herding behaviours have been observed throughout the animal kingdom. Scientists and mathematicians have pondered the cause of complex relationships and group dynamics at work that allow schools of fish, such as herring, and flocks of birds, such as starlings, to move together in apparent unity — and now, in an interesting twist to the discussion, a team of engineers from Harvard University has observed apparent collective behaviour in brainless robots.

The robot research team was looking for a way to investigate the transition that swarming groups make from random behaviour into collective motion. In order to observe a randomly moving collective, they built the simplest of “self-propelled automatons”, the charmingly named Bristle-Bot (BBots).

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Brave New Machines

Robots are here to stay. They will be smarter, more versatile, more autonomous, and more like us in many ways. We humans will need to adapt to keep up.

The word “robot” was used for the first time only about 80 years ago, in the play “RUR” by the Czech author Karel Capek. The robots in that book were artificial humans, chemically synthesized using appropriate formulas. Robots at present and in the future will be made largely of inorganic materials, both mechanical and electronic. However, some form of hybridization between electromechanical and biological subsystems is possible and will occur. I believe that the major developments in robotics in the next 100 years will be the following areas:

Robot intelligence: The ability of a robot to solve problems, to learn, to interact with humans and other robots, and related skills are all measures of intelligence. Robots will indeed be increasingly intelligent, because:

- High speed memory, long term storage capacity, and speed of the on-board computers will continue to increase. Futurist Ray Kurzweil has predicted that the capacity of robot brains will exceed that of human brains within the next 20 years.

- Neuroscience is rapidly obtaining better and better models of the information processing ability of the human brain. These models will lead to the development of software to enable robot brains to emulate more and more of the features of the human brain.

- Research in learning will enable robots to learn by imitating humans, from their own mistakes and from their successes.

Human-robot interaction: This is an area of significant research activity at the present time. I believe that during the coming decades robots will be able to interact with humans (and with each other) in increasingly human-like ways, including speech and gestures. Robots will be able to understand the semantic as well as the emotional aspects of speech, so that they will understand the significance of increasing loudness, irritation, affection, and other emotional aspects in spoken utterances, and they will be able to include these aspects in their own speech as well.

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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.

New structural insight into neurodegenerative disease

A research team from the Korea Advanced Institute of Science and Technology (KAIST) released their results on the structure and molecular details of the neurodegenerative disease-associated protein Ataxin-1. Mutations in Ataxin-1 cause the neurological disease, Spinocerebellar Ataxia Type 1 (SCA1), which is characterized by a loss of muscular coordination and balance (ataxia), as is seen in Parkinson’s, Alzheimer’s, and Huntington’s diseases.

SCA1-causing mutations in the ATAXIN1 gene alter the length of a glutamine stretch in the Ataxin-1 protein. The research team provides the first structural insight into the complex formation of ATAXIN-1 with its binding partner, Capicua (CIC). The team, led by Professor Ji-Joon Song from the Department of Biological Sciences at KAIST, solved the structure of Ataxin-1 and CIC complex in atomic level revealing molecular details of the interaction between Ataxin-1 and CIC.

Professor Song explained his recent research work, “We are able to see the intricate process of complex formation and reconfiguration of the two proteins when they interact with each other. Our work, we expect, will provide a new therapeutic target to modulate SCA1 neurodegenerative disease.”

Understanding structural and molecular details of proteins at the atomic level will help researchers to track the molecular pathogenesis of the disease and, ultimately, design targeted therapies or treatments for patients, rather than just relieving the symptoms of diseases.

Professor Song’s research paper, entitled “Structural Basis of Protein Complex Formation and Reconfiguration by Polyglutamine Disease Protein ATAXIN-1 and Capicua,” will be published in the March 15th issue of Genes & Development

Ten extraordinary Pentagon mind experiments

It’s been 30 years since the first message was sent over initial nodes of the Arpanet, the Pentagon-sponsored precursor to the internet. But this month, researchers announced something that could be equally historic: the passing of messages between two rat brains, the first step toward what they call the “brain net”.

Connecting the brains of two rats through implanted electrodes, scientists at Duke University demonstrated that in response to a visual cue, the trained response of one rat, called an encoder, could be mimicked without a visual cue in a second rat, called the decoder. In other words, the brain of one rat had communicated to the other.

"These experiments demonstrated the ability to establish a sophisticated, direct communication linkage between rat brains, and that the decoder brain is working as a pattern-recognition device,” said Miguel Nicolelis, a professor at Duke University School of Medicine. “So basically, we are creating an organic computer that solves a puzzle.”

Whether or not the Duke University experiments turn out to be historic (some skepticism has already been raised), the work reflects a growing Pentagon interest in neuroscience for applications that range from such far-off ideas as teleoperation of military devices (think mind-controlled drones), to more near-term and less controversial technology, like prosthetics controlled by the human brain. In fact, like the Arpanet, the experiment on the rat “brain net” was sponsored by the Defense Advanced Research Projects Agency (Darpa).

The Pentagon’s expanding work in neuroscience in recent years has focused heavily on medical applications, like research to understand traumatic brain injury, but a good portion of the past decade’s work has also been on concepts that are intended to help the military fight wars more effectively, such as studying ways to keep soldiers’ brains alert even after days without sleep. Under the rubric of “Augmented Cognition,” Darpa has also pursued a number of military technologies, like goggles that would monitor a soldier’s brain signals to pick up potential threats before the conscious mind is aware of them.

Now, such work may get an even bigger boost: President Barack Obama is set to announce an initiative that could funnel billions of dollars to the field of neuroscience. That could mean more money for the Pentagon’s forays into brain science.

While some of the applications might be a generation away, or may never arrive, like mind-controlled drones, others, like the brain-monitoring goggles, are already in testing (though probably not ready for use in the field). That’s raising questions from ethicists, who are pushing for the government to begin now to think about “neuro ethics.”

In a 2012 article published last year in the journal Plos Biology, Jonathan Moreno, a professor of medical ethics, and Michael Tennison, a professor of neurology, argued that many neuroscientists don’t think about the contribution of their work to warfare, or consider the ethical implication of such work.

The question they raise is what choice future soldiers might have in such cognitively enhanced warfare. “If a warfighter is allowed no autonomous freedom to accept or decline an enhancement intervention, and the intervention in question is as invasive as remote brain control,” they write, “then the ethical implications are immense.”

Whether this era will come to pass, remains to be seen. But, for now, expect many more advances in the world of neuroscience to come from the Pentagon.

Improved Detection of Frontotemporal Degeneration May Aid Clinical Trial Efforts

A series of studies demonstrate improved detection of the second most common form of dementia, providing diagnostic specificity that clears the way for refined clinical trials testing targeted treatments. The new research is being presented by experts from the Perelman School of Medicine at the University of Pennsylvania at the American Academy of Neurology’s 65th Annual Meeting in San Diego March 16-23, 2013.

Frontotemporal degeneration, the most common dementia in people under 60, can be hereditary or sporadic in nature and caused by one of two different mutated proteins (tau or TDP-43). The disease results in damage to the anterior temporal and/or frontal lobes of the brain. As the disease progresses, it becomes increasingly difficult for people to plan or organize activities, behave appropriately in social or work settings, interact with others, and care for oneself, resulting in increasing dependency.

In one study, the team confirmed that a novel multimodal imaging approach was more accurate (88 percent) than using either MRI (72 percent) or DTI (81 percent) alone to detect FTD versus Alzheimer’s disease. The two imaging techniques integrate measures of white matter and grey matter, providing a statistically powerful method for predicting underlying pathology in order to screen patients for clinical trials.

“We are moving forward on our biomarker work to optimize our ability to identify the specific cause of an individual’s difficulties during life, said senior author Murray Grossman, MD, EdD, professor of Neurology and director of the Penn FTLD Center. “We use a novel multi-modality approach involving behavioral, imaging and biofluid biomarker measures.”

In a second study, researchers found that a brief series of neuropsychological tests of memory, word generation and conceptual flexibility (needed for creative problem-solving) helped differentiate people with very mild behavioral variant FTD (bvFTD) and those with mild cognitive impairment (MCI). The combination of tests correctly classified 85.7 percent of bvFTD cases and 83.3 percent of MCI cases at early stages of disease.

“This is particularly important because treatment trials with disease-modifying agents are emerging, often based on animal studies, yet we still don’t have all the tools we need to identify who is most appropriate to participate in one of these trials. Moreover, we can use this information we ascertain to help determine who is responding to a treatment in a clinical trial.” 

The third study being presented at the meeting showed that hereditary forms of FTD appear to have more rapid cognitive decline and differing tau profiles compared with sporadic forms of the disease. For clinical trials testing whether a drug can delay damage caused by tau, any known differences in the speed of disease progression could interfere with trial results.

(Image courtesy: University of Pennsylvania)

Tau Transmission Model Opens Doors for New Alzheimer’s, Parkinson’s Therapies

Injecting synthetic tau fibrils into animal models induces Alzheimer’s-like tau tangles and imitates the spread of tau pathology, according to research from the Perelman School of Medicine at the University of Pennsylvania being presented at the American Academy of Neurology’s 65th Annual Meeting in San Diego March 16-23, 2013.

This Alzheimer’s research, along with additional Parkinson’s research from Penn and beyond, further demonstrates the cell-to-cell transmission of neurodegenerative proteins. John Q. Trojanowski, MD, PhD, co-director of the Center for Neurodegenerative Disease Research (CNDR) and professor of Pathology and Laboratory Medicine at the Perelman School of Medicine, University of Pennsylvania, will present the research in the Hot Topics plenary session on Tuesday, March 19 starting at 5:15pm.

"The transmission model better explains the spread of disease within neurodegenerative disease, and has uncovered new therapeutic opportunities which we are exploring vigorously," said Dr. Trojanowski. “However, it is important to emphasize that the spread of Alzheimer’s and Parkinson’s pathology does not mean these diseases are infectious, like Mad Cow disease, based on data from another recent study from our group.”

For supplemental information on the transmission of tau pathology, the laboratory of senior author Virginia M.-Y. Lee, Ph.D., MBA, director of CNDR and professor of Pathology and Laboratory Medicine at the Perelman School of Medicine, University of Pennsylvania, published additional findings in the Journal of Neuroscience.