Anxiety can damage brain

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People with mild cognitive impairment (MCI) are at increased risk of converting to Alzheimer’s disease within a few years, but a new study warns the risk increases significantly if they suffer from anxiety.

The findings were reported on Oct. 29 online by The American Journal of Geriatric Psychiatry, ahead of print publication, scheduled for May 2015.

Led by researchers at Baycrest Health Sciences’ Rotman Research Institute, the study has shown clearly for the first time that anxiety symptoms in individuals diagnosed with MCI increase the risk of a speedier decline in cognitive functions – independent of depression (another risk marker). For MCI patients with mild, moderate or severe anxiety, Alzheimer’s risk increased by 33%, 78% and 135% respectively.

The research team also found that MCI patients who had reported anxiety symptoms at any time over the follow-up period had greater rates of atrophy in the medial temporal lobe regions of the brain, which are essential for creating memories and which are implicated in Alzheimer’s.

Until now, anxiety as a potentially significant risk marker for Alzheimer’s in people diagnosed with MCI has never been isolated for a longitudinal study to gain a clearer picture of just how damaging anxiety symptoms can be on cognition and brain structure over a period of time. There is a growing body of literature that has identified late-life depression as a significant risk marker for Alzheimer’s. Anxiety has historically tended to be subsumed under the rubric of depression in psychiatry. Depression is routinely screened for in assessment and follow-up of memory clinic patients; anxiety is not routinely assessed.

“Our findings suggest that clinicians should routinely screen for anxiety in people who have memory problems because anxiety signals that these people are at greater risk for developing Alzheimer’s,” said Dr. Linda Mah, principal investigator on the study, clinician-scientist with Baycrest’s Rotman Research Institute, and assistant professor in the Department of Psychiatry at the University of Toronto. Dr. Mah is also a co-investigator in a multi-site study lead by the Centre for Addiction and Mental Health, and partially funded by federal dollars (Brain Canada), to prevent Alzheimer’s in people with late-life depression or MCI who are at high risk for developing the progressive brain disease.

“While there is no published evidence to demonstrate whether drug treatments used in psychiatry for treating anxiety would be helpful in managing anxiety symptoms in people with mild cognitive impairment or in reducing their risk of conversion to Alzheimer’s, we think that at the very least behavioural stress management programs could be recommended. In particular, there has been research on the use of mindfulness-based stress reduction in treating anxiety and other psychiatric symptoms in Alzheimer’s –and this is showing promise,” said Dr. Mah.

The Baycrest study accessed data from the large population-based Alzheimer’s Disease Neuroimaging Initiative to analyze anxiety, depression, cognitive and brain structural changes in 376 adults, aged 55 – 91, over a three-year period. Those changes were monitored every six months. All of the adults had a clinical diagnosis of amnestic MCI and a low score on the depression rating scale, indicating that anxiety symptoms were not part of clinical depression.

MCI is considered a risk marker for converting to Alzheimer’s disease within a few years. It is estimated that half-a-million Canadians aged 65-and-older have MCI, although many go undiagnosed. Not all MCI sufferers will convert to Alzheimer’s – some will stabilize and others may even improve in their cognitive powers.

The Baycrest study has yielded important evidence that anxiety is a “predictive factor” of whether an individual with MCI will convert to Alzheimer’s or not, said Dr. Mah. Studies have shown that anxiety in MCI is associated with abnormal concentrations of plasma amyloid protein levels and T-tau proteins in cerebrospinal fluid, which are biomarkers of Alzheimer’s. Depression and chronic stress have also been linked to smaller hippocampal volume and increased risk of dementia.

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The above story is based on materials provided by Baycrest Centre for Geriatric Care, Kelly Connelly.

The brain’s ‘inner GPS’ gets dismantled

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Imagine being able to recognize your car as your own but never being able to remember where you parked it. Researchers at University of California, San Diego School of Medicine have induced this all-too-common human experience – or a close version of it – permanently in rats and from what is observed perhaps derive clues about why strokes and Alzheimer’s disease can destroy a person’s sense of direction.

Photo credits: Robert Clark

The findings are published online in the current issue of Cell Reports.

Grid cells and other specialized nerve cells in the brain, known as “place cells,” comprise the brain’s inner GPS, the discovery of which earned British-American and Norwegian scientists this year’s Nobel Prize for medicine.

In research that builds upon the Nobel Prize-winning science, UC San Diego scientists have developed a micro-surgical procedure that makes it possible to remove the area of the rat’s brain that contains grid cells and show what happens to this hard-wired navigational system when these grid cells are wiped out.

One effect, not surprisingly, is that the rats become very poor at tasks requiring internal map-making skills, such as remembering the location of a resting platform in a water maze test.

“Their loss of spatial memory formation was not a surprise,” said senior co-author Robert Clark, PhD, a professor of psychiatry. “It’s what would be expected based on the physiological characteristics of that area of the brain,” which is known as the entorhinal cortex and is the first brain region to break down in Alzheimer’s disease.

But the rats retained a host of other memory and navigation-related skills that scientists had previously speculated would be destroyed without grid cells.

“The surprise is the discovery of the type of memory formation that was not disrupted by the removal of the grid cell area,” Clark said.

Specifically, UC San Diego scientists were able to show that even without grid cells rats could still mark spatial changes in their environment. They could, for example, notice when an object in a familiar environment was moved a few inches and they could recognize objects, such as a coffee mug or flower vase, and remember later that they had seen these objects before.

Electrical recordings of signals transmitted from the hippocampus suggested that the animals had developed place cells – cells that are believed to convey a sense of location – and that these cells were firing when an animal passed through a familiar place.

“Their place cells were less precise and less stable, but they were present and active,” said Clark, who is also a research scientist at Veterans Affairs San Diego Healthcare System. “That was a surprise because we had removed the spatially modulated grid-cell input to these neurons.”

The axons of grid cells project into the hippocampus and it has been assumed that without this relay of information from the entorhinal cortex to the hippocampus, place cells would be unable to develop. “This is not the case,” he said.

“Our work shows a crisp division of labor within memory circuits of the brain,” he said. “Removing the grid-cell network removes memory for places but leaves completely intact a whole host of other important memory abilities like recognition memory and memory of fearful events.”

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The above story is based on materials provided by University of California – San Diego, Scott LaFee.

Production of human motor neurons from stem cells is gaining speed

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The motor neurons that innervate muscle fibres are essential for motor activity. Their degeneration in many diseases causes paralysis and often death among patients. Researchers at the Institute for Stem Cell Therapy and Exploration of Monogenic Diseases (I-Stem – Inserm/AFM/UEVE), in collaboration with CNRS and Paris Descartes University, have recently developed a new approach to better control the differentiation of human pluripotent stem cells, and thus produce different populations of motor neurons from these cells in only 14 days.

Neurons (green) are detected by TuJI whereas motoneurons are revealed in red by the visicular transporter of acetylcholine. Credit: Inserm/Martinat, Cécile

This discovery, published in Nature Biotechnology, will make it possible to expand the production process for these neurons, leading to more rapid progress in understanding diseases of the motor system, such as infantile spinal amyotrophy or amyotrophic lateral sclerosis (ALS).

Human pluripotent stem cells have the ability to give rise to every cell in the body. To understand and control their potential for differentiation in vitro is to offer unprecedented opportunities for regenerative medicine and for advancing the study of physiopathological mechanisms and the quest for therapeutic strategies. However, the development and realisation of these clinical applications is often limited by the inability to obtain specialised cells such as motor neurons from human pluripotent stem cells in an efficient and targeted manner. This inefficiency is partly due to a poor understanding of the molecular mechanisms controlling the differentiation of these cells.

Inserm researchers at the Institute for Stem Cell Therapy and Exploration of Monogenic Diseases (I-Stem – Inserm/French Muscular Dystrophy Association [AFM]/University of Évry Val d’Essonne [UEVE]), in collaboration with CNRS and Paris-Descartes University, have developed an innovative approach to study the differentiation of human stem cells and thus produce many types of cells in an optimal manner.

“The targeted differentiation of human pluripotent stem cells is often a long and rather inefficient process. This is the case when obtaining motor neurons, although these are affected in many diseases. Today, we obtain these neurons with our approach in only 14 days, nearly twice as fast as before, and with a homogeneity rarely achieved,” explains Cécile Martinat, an Inserm Research Fellow at I-Stem.

To achieve this result, the researchers studied the interactions between some molecules that control embryonic development. These studies have made it possible to both better understand the mechanisms governing the generation of these neurons during development, and develop an optimal “recipe” for producing them efficiently and rapidly.

“We are now able to produce and hence study different populations of neurons affected to various degrees in diseases that cause the degeneration of motor neurons. We plan to study why some neurons are affected and why others are preserved,” adds Stéphane Nedelec, an Inserm researcher in Cécile Martinat’s team.

In the medium term, the approach should contribute to the development of treatments for paralytic diseases such as infantile spinal muscular amyotrophy or amyotrophic lateral sclerosis. “Rapid access to large quantities of neurons will be useful for testing a significant number of pharmacological drugs in order to identify those capable of preventing the death of motor neurons,” concludes Cécile Martinat.

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The above story is based on materials provided by INSERM (Institut national de la santé et de la recherche médicale), Cécile Martinat

Scientists create Parkinson’s disease in a dish

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A team of scientists led by The New York Stem Cell Foundation (NYSCF) Research Institute successfully created a human stem cell disease model of Parkinson’s disease in a dish.

Susan L. Solomon, NYSCF Chief Executive Officer

Studying a pair of identical (monozygotic) twins, one affected and one unaffected with Parkinson’s disease, another unrelated Parkinson’s patient, and four healthy control subjects, the scientists were able to observe key features of the disease in the laboratory, specifically differences in the patients’ neurons’ ability to produce dopamine, the molecule that is deficient in Parkinson’s disease. In addition, the scientists also identified a potential strategy for developing novel therapies for Parkinson’s disease.

Attributed to a combination of genetic and nongenetic factors, Parkinson’s disease has no completely effective therapy or cure. Parkinson’s disease is moderately heritable, but the mechanisms of this inheritance are not well understood. While genetic forms of the disease exist, sporadic forms are far more common.

“The unique scenario of identical twins, one with this disease and one without, allowed our scientists an unprecedented look into the mechanisms of Parkinson’s disease,” said Susan L. Solomon, NYSCF Chief Executive Officer. “Advanced stem cell research techniques allow us to push the boundaries of science and see what actually goes wrong at the cellular level, step by step during the disease process.”

DNA mutations resulting in the production of a specific enzyme called glucocerebrosidase (GBA) have been linked to a five-fold greater risk of developing Parkinson’s disease; however, only 30% of individuals with this mutation have been shown to develop Parkinson’s disease by the age of 80. This discordance suggests that multiple factors contribute to the development of Parkinson’s disease, including both genetic and non-genetic factors. To date, there has been no appropriate model to identify and test multiple triggers leading to the onset of the disease.

In this study, published in Cell Reports, a set of identical twins, both with a GBA mutation, provided a unique opportunity to evaluate and dissect the genetic and non-genetic contributions to the development of Parkinson’s disease in one twin, and the lack of disease in the other. The scientists made induced pluripotent stem (iPS) cells from skin samples from both twins to generate a cellular model of Parkinson’s in a dish, recapitulating key features of the disease, specifically the accumulation of α-synuclein and dopamine deficiency.

Upon analyzing the cell models, the scientists found that the dopamine-producing neurons from both twins had reduced GBA enzymatic activity, elevated α-synuclein protein levels, and a reduced capacity to synthesize and release dopamine. In comparison to his unaffected brother, the neurons generated from the affected twin produced less dopamine, had higher levels of an enzyme called monoamine oxidase B (MAO-B), and poor ability to connect with each other. Treating the neurons with molecules that lowered the activity of MAO-B together with overexpressed GBA normalized α -synuclein and dopamine levels in the cell models. This suggests that a combination therapy for the affected twin may be possible by simultaneously targeting these two enzymes.

“The subject of Parkinson’s disease discordant twins gave us an incredible opportunity to utilize stem cell models of disease in a dish to unlock some of the biological mechanisms of disease,” said Dr. Scott Noggle, NYSCF Vice President, Stem Cell Research and The NYSCF — Charles Evans Senior Research Fellow for Alzheimer’s Disease. “Working with these various different groups and scientists added to the depth and value of the research and we hope our findings will be applicable to other Parkinson’s disease patients and other neurodegenerative disorders.”

In this particular scenario, genetic and stem cell analysis identified an avenue for a potentially useful combination therapy for the twin affected by Parkinson’s disease and may be applicable more broadly to other Parkinson’s patients. While this case study is unique, this type of research and cellular analysis could yield further clues to all cases of genetic and sporadic Parkinson’s disease and other related neurological disorders.

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The above story is based on materials provided by New York Stem Cell Foundation.

2014 Nobel Prize in Physiology or Medicine: Cells that constitute a positioning system in the brain

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How do we know where we are? How can we find the way from one place to another? And how can we store this information in such a way that we can immediately find the way the next time we trace the same path? This year´s Nobel Laureates have discovered a positioning system, an “inner GPS” in the brain that makes it possible to orient ourselves in space, demonstrating a cellular basis for higher cognitive function.

In 1971, John O´Keefe discovered the first component of this positioning system. He found that a type of nerve cell in an area of the brain called the hippocampus that was always activated when a rat was at a certain place in a room. Other nerve cells were activated when the rat was at other places. O´Keefe concluded that these “place cells” formed a map of the room.

More than three decades later, in 2005, May-Britt and Edvard Moser discovered another key component of the brain’s positioning system. They identified another type of nerve cell, which they called “grid cells,” that generate a coordinate system and allow for precise positioning and pathfinding. Their subsequent research showed how place and grid cells make it possible to determine position and to navigate.

The discoveries of John O´Keefe, May-Britt Moser and Edvard Moser have solved a problem that has occupied philosophers and scientists for centuries — how does the brain create a map of the space surrounding us and how can we navigate our way through a complex environment?

How do we experience our environment?

The sense of place and the ability to navigate are fundamental to our existence. The sense of place gives a perception of position in the environment. During navigation, it is interlinked with a sense of distance that is based on motion and knowledge of previous positions.

Questions about place and navigation have engaged philosophers and scientists for a long time. More than 200 years ago, the German philosopher Immanuel Kant argued that some mental abilities exist as a priori knowledge, independent of experience. He considered the concept of space as an inbuilt principle of the mind, one through which the world is and must be perceived. With the advent of behavioural psychology in the mid-20th century, these questions could be addressed experimentally. When Edward Tolman examined rats moving through labyrinths, he found that they could learn how to navigate, and proposed that a “cognitive map” formed in the brain allowed them to find their way. But questions still lingered — how would such a map be represented in the brain?

John O´Keefe and the place in space

John O´Keefe was fascinated by the problem of how the brain controls behaviour and decided, in the late 1960s, to attack this question with neurophysiological methods. When recording signals from individual nerve cells in a part of the brain called the hippocampus, in rats moving freely in a room, O’Keefe discovered that certain nerve cells were activated when the animal assumed a particular place in the environment. He could demonstrate that these “place cells” were not merely registering visual input, but were building up an inner map of the environment. O’Keefe concluded that the hippocampus generates numerous maps, represented by the collective activity of place cells that are activated in different environments. Therefore, the memory of an environment can be stored as a specific combination of place cell activities in the hippocampus.

May-Britt and Edvard Moser find the coordinates

May-Britt and Edvard Moser were mapping the connections to the hippocampus in rats moving in a room when they discovered an astonishing pattern of activity in a nearby part of the brain called the entorhinal cortex. Here, certain cells were activated when the rat passed multiple locations arranged in a hexagonal grid. Each of these cells was activated in a unique spatial pattern and collectively these “grid cells” constitute a coordinate system that allows for spatial navigation. Together with other cells of the entorhinal cortex that recognize the direction of the head and the border of the room, they form circuits with the place cells in the hippocampus. This circuitry constitutes a comprehensive positioning system, an inner GPS, in the brain.

A place for maps in the human brain

Recent investigations with brain imaging techniques, as well as studies of patients undergoing neurosurgery, have provided evidence that place and grid cells exist also in humans. In patients with Alzheimer´s disease, the hippocampus and entorhinal cortex are frequently affected at an early stage, and these individuals often lose their way and cannot recognize the environment. Knowledge about the brain´s positioning system may, therefore, help us understand the mechanism underpinning the devastating spatial memory loss that affects people with this disease.

The discovery of the brain’s positioning system represents a paradigm shift in our understanding of how ensembles of specialized cells work together to execute higher cognitive functions. It has opened new avenues for understanding other cognitive processes, such as memory, thinking and planning.

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The above story is based on materials provided by Nobel Foundation.

Mimicking brain cells to boost computer memory power

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Researchers have brought ultra-fast, nano-scale data storage within striking reach, using technology that mimics the human brain.

Dr Sharath Sriram, RMIT University. Photo Credit: RMIT University

The researchers have built a novel nano-structure that offers a new platform for the development of highly stable and reliable nanoscale memory devices.

The pioneering work will feature on a forthcoming cover of prestigious materials science journal Advanced Functional Materials (11 November).

Project leader Dr Sharath Sriram, co-leader of the RMIT Functional Materials and Microsystems Research Group, said the nanometer-thin stacked structure was created using thin film, a functional oxide material more than 10,000 times thinner than a human hair.

“The thin film is specifically designed to have defects in its chemistry to demonstrate a ‘memristive’ effect – where the memory element’s behaviour is dependent on its past experiences,” Dr Sriram said.

“With flash memory rapidly approaching fundamental scaling limits, we need novel materials and architectures for creating the next generation of non-volatile memory.

“The structure we developed could be used for a range of electronic applications – from ultrafast memory devices that can be shrunk down to a few nanometers, to computer logic architectures that replicate the versatility and response time of a biological neural network.

“While more investigation needs to be done, our work advances the search for next generation memory technology can replicate the complex functions of human neural system – bringing us one step closer to the bionic brain.”

The research relies on memristors, touted as a transformational replacement for current hard drive technologies such as Flash, SSD and DRAM. Memristors have potential to be fashioned into non-volatile solid-state memory and offer building blocks for computing that could be trained to mimic synaptic interfaces in the human brain.

The research, which was supported by an Australian Research Council Discovery grant, was a collaboration between members of the Functional Materials and Microsystems Research Group and Professor Dmitri Strukov from the University of California, Santa Barbara.

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The above story is based on materials provided by RMIT University.

Stem Cell Discovery: Treatments for Blindness?

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Scientists at the University of Southampton have discovered that a region on the front surface of the eye harbours special stem cells that could treat blinding eye conditions.

This part of the eye is called the ‘corneal limbus’ and is a narrow gap lying between the transparent cornea and white sclera.

The research, published in PLOS ONE, showed that stem cells can be cultured from the corneal limbus in vitro. Under the correct culture conditions, these cells could be directed to behave like the cells needed to see light – photoreceptor cells.

The loss of photoreceptors cells causes irreversible blindness and researchers hope that this discovery could lead to new treatments for conditions such as age related macular degeneration, the leading cause of blindness in the developed world which affects around one in three people in the UK by age of 75.

Professor Andrew Lotery, of the University of Southampton and a Consultant Ophthalmologist at Southampton General Hospital led the study. He comments: “These cells are readily accessible, and they have surprising plasticity, which makes them an attractive cell resource for future therapies. This would help avoid complications with rejection or contamination because the cells taken from the eye would be returned to the same patient. More research is now needed to develop this approach before these cells are used in patients.”

Furthermore, these stem cells also exist in aged human eyes, and can be cultured even from the corneal limbus of 97 year olds. Therefore this discovery opens up the possibility of new treatments for the older generations, researchers believe.

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The above story is based on materials provided by University of Southampton.