Brain tissue loss in people with Alzheimer’s disease and mild cognitive impairment

People with Alzheimer's disease exhibit striking structural changes in the caudate nucleus, a brain structure typically associated with movement disorders such as Parkinson's disease, a new study has found.

The research was presented at Neuroscience 2010, the annual meeting of the Society for Neuroscience, held in San Diego.

"Our finding suggests that Alzheimer's disease produces broader damage in the brain than previously thought, including damage to areas not usually associated with the disease," said lead author Sarah Madsen, a graduate student working with Paul Thompson, PhD, of the University of California, Los Angeles.

For the study, Madsen and her colleagues analyzed the brains of 400 elderly participants. Of this group, 100 were healthy, 100 had diagnosed Alzheimer's disease, and 200 had mild cognitive impairment, a condition that sometimes serves as a precursor to Alzheimer's disease.

Compared with healthy individuals, the caudate nucleus was seven percent smaller in those with Alzheimer's disease and four percent smaller in those with mild cognitive impairment. It was also smaller in older and in overweight individuals.

"Our finding suggests a gradual progression of brain tissue loss in the caudate nucleus as dementia becomes more severe," said Madsen. "This brain area, which is associated with certain forms of learning and memory as well as motor control, is an important factor to consider when studying Alzheimer's disease and in predicting how the disease will progress," she said.

Research was supported by the National Institutes of Health Roadmap for Medical Research and Alzheimer's Disease Neuroimaging Initiative, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of Neurological Disorders and Stroke, National Institute of Biomedical Imaging and Bioengineering, and the Dana Foundation.

Size of hippocampus may indicate early dementia

The size of the part of the brain known as the hippocampus may be linked to future dementia, reveals a thesis from the University of Gothenburg, Sweden.

Mild cognitive impairment, or MCI, is a condition where the cognitive functions are impaired — though not as severely as in dementia — and is a precursor to several types of dementia.

"One of the challenges for the healthcare is identifying which MCI patients have an underlying dementia disorder, which is why we need new tools to detect the early signs of dementia," says Carl Eckerström, a researcher at the Sahlgrenska Academy's Department of Psychiatry and Neurochemistry, and doctor at Sahlgrenska University Hospital's memory clinic.

Atrophy of the hippocampus is common in Alzheimer's disease. The thesis shows that the hippocampus may also be affected in small vessel disease (SIVD) which, along with Alzheimer's, are the two most common types of dementia. SIVD is characterised by damage to the brain's white matter and is considered to be the most important type of vascular dementia in the elderly.

Researchers measured the extent of changes to white matter in 122 MCI patients, and compared this with the size of their hippocampus. The patients were divided into two categories — one group who subsequently developed dementia after two years, and a second group whose clinical status remained unchanged after two years. There was also a group of healthy controls. The results showed that there may be a link between damage to the white matter and a reduction in the size of the hippocampus, which means that damage to the white matter could play a part in a process that leads to hippocampal atrophy.

"I believe that measuring the hippocampus could be a useful clinical instrument for investigating whether a person is in the early stages of dementia, as our findings suggest that the size of the hippocampus is linked to a deterioration in cognitive function and dementia," says Eckerström.

Journal Reference:

  1. Eckerström, C.; Andreasson, U.; Olsson, E.; Rolstad, S.; Blennow, K.; Zetterberg, H.; Malmgren, H.; Edman, Å.; Wallin, A. Combination of Hippocampal Volume and Cerebrospinal Fluid Biomarkers Improves Predictive Value in Mild Cognitive Impairment. Dementia and Geriatric Cognitive Disorders, 2010; 29 (4): 294-300 DOI: 10.1159/000289814

New technology allows medical workers to better assess brain injuries

A Queen's University neuroscientist is launching a medical tool at the world's largest neuroscience conference in San Diego on Nov. 15. The KINARM Assessment Station will greatly improve the way healthcare workers assess patients suffering from brain injuries and disease.

The new technology, invented by Stephen Scott, is the only objective tool for assessing brain function, and clinical researchers need this tool to develop better therapies for treating brain injury or disease.

"The beauty of this system is it that it captures subtle deficits caused by a brain injury that are not measured by traditional tests," says Dr. Scott, a professor at The Centre for Neuroscience Studies at Queen's. "Traditional testing methods, such as touching a finger to the nose or bouncing a ball, just don't capture the complexity of brain processes."

KINARM combines a chair with robotic 'arms' and a virtual/augmented reality system that enables neuroscience and rehabilitation researchers to guide their patient through a series of standardized tasks, such as hitting balls with virtual paddles. Once the tests are completed, the system instantly generates a detailed report, pinpointing variations from normal behaviour.

"This system has the potential to do for the diagnosis of brain injury what X-rays did for diagnosing muscular and skeletal injuries," says John Molloy, President and CEO of Queen's University's PARTEQ Innovations, which helped commercialize the technology along with BKIN Technologies.

Knowing the full effects of a brain injury on the ability to function in daily life means more effective rehabilitation programs for patients. It also means a better understanding of the potential impact of brain injury, whether caused by accidents or by diseases including stroke, MS, Parkinson's, cerebral palsy or fetal alcohol syndrome.

KINARM also has potential to help people in professional sports and the military, where impact-based head injuries are an occupational reality, and where there is a significant lack of effective tools for determining when patients can safely return to regular duties without the risk of a career-ending injury.

The Society for Neuroscience Conference takes place Nov. 13-17 in San Diego.

Extensive natural recovery after spinal cord injury uncovered in primate study

A study led by researchers in the Department of Neurosciences at the University of California, San Diego School of Medicine shows unexpected and extensive natural recovery after spinal cord injury in primates. The findings, to be published Nov. 14 in the advance online edition of Nature Neuroscience, may one day lead to the development of new treatments for patients with spinal cord injuries.

While regeneration after severe brain and spinal cord injury is limited, milder injuries are often followed by good functional recovery. To investigate how this occurs, UC San Diego and VA Medical Center San Diego researchers studied adult rhesus monkeys. The team was surprised to see that connections between circuits in the spinal cord re-grew spontaneously and extensively, restoring fully 60% of the connections 24 weeks after a mild spinal cord injury.

"The number of connections in spinal cord circuits drops by 80 percent immediately after the injury," said Ephron Rosenzweig, PhD, assistant project scientist in UCSD Department of Neurosciences. "But new growth sprouting from spared axons — the long fibers extending from the brain cells, or neurons, which carry signals to other neurons in the central nervous system — restored more than half of the original number of connections." He added that this was particularly surprising since the phenomenon does not appear in rodents — the traditional study model.

The research was led by Rosenzweig and Gregoire Courtine of the University of Zurich in Switzerland. Senior study director was Mark H. Tuszynski, MD, PhD, professor of neurosciences and director of the Center for Neural Repair at UC San Diego, and neurologist at the Veterans Affairs San Diego Health System.

It was not previously known that an injured spinal cord could naturally restore such a high proportion of connections. More profoundly, the spontaneous recovery was accompanied by extensive recovery of movement on the affected side of the body. Tuszynski said the team is now investigating how the nervous system is able to generate so much natural growth after injury. This knowledge could lead to development of drugs or genes that could transmit high-growth signals to spinal cord damage sites after more severe spinal cord injury.

The work highlights an important role for primate models in translating basic scientific research into practical, therapeutic treatments for people. The spinal cords of humans and other primates are different from rodents, both in overall anatomy and in specific functions. For example, the corticospinal tract — a collection of nerve cell fibers linking the cerebral cortex of the brain and the spinal cord — is much more important for muscle movement in primates than in rats.

"With similar injuries, rodents show much less regrowth and recovery of limb function," said Rosenzweig. The challenge now is to determine what exactly is prompting neuronal axons to sprout new connections, leading to recovered movement. That has exciting clinical relevance, Rosenzweig said, because discoveries resulting from further research could be applied to patients with severe injury to their central nervous system.

Additional contributors to the study include John H. Brock and Darren M. Miller, UCSD Department of Neurosciences; Gregoire Courtine, UCLA and University of Zurich; Devin L. Jindrich, Roland R. Roy, Leif A. Havton and V. Reggie Edgerton, UCLA; Adam R. Ferguson, Yvette S. Nout, Michael S. Beattie, and Jacqueline C. Bresnahan, UC Davis; and Sarah C. Strand, UC San Francisco.

This study was supported by the National Institutes of Health, the Veterans Administration, California Roman-Reed funds, the Bernard and Anne Spitzer Charitable Trust, and the Dr.Miriam and Sheldon G. Adelson Medical Research Foundation.

Journal Reference:

  1. Ephron S Rosenzweig, Gregoire Courtine, Devin L Jindrich, John H Brock, Adam R Ferguson, Sarah C Strand, Yvette S Nout, Roland R Roy, Darren M Miller, Michael S Beattie, Leif A Havton, Jacqueline C Bresnahan, V Reggie Edgerton & Mark H Tuszynski. Extensive spontaneous plasticity of corticospinal projections after primate spinal cord injury. Nature Neuroscience, 2010; DOI: 10.1038/nn.2691

Adapted MRI scan improves picture of changes to the brain

 Standard MRI scans have so far been unable to produce satisfactory images of nerve bundles. However, this is now possible using an MRI technique called Diffusion Tensor Imaging (DTI). Matthan Caan succeeded in improving the DTI method during his PhD research at TU Delft, enabling him to produce more accurate images of the damage that radiotherapy and chemotherapy cause in young leukaemia patients.

With MRI, images can be obtained of various parts of the body. Unfortunately, these scans are not sufficiently refined for the imaging of nerve bundles. Matthan Caan concentrated on adjusting the conventional MRI technique via diffusion tensor imaging (DTI), so that better images of the nerve bundles could be obtained.

Via DTI, a method that is under considerable development, changes in the so-called white matter of the brain can be mapped. These changes can be caused by the ageing process or by Alzheimer's disease, among other things.

White matter

The white matter contains the connections between the nerve cells, and the principle of DTI concerns the movement of water molecules within the white matter. The molecules can move easily along the length of the nerve bundle, but not so easily on the perpendicular. This is because they are obstructed by the wall of the nerve cell and a protective layer (of myelin). Using DTI, the difference in the water molecules' freedom of movement allows conclusions to be drawn on the health of the nerve bundles in the white matter.

Caan succeeded in improving the DTI method during his research in collaboration with his supervisor, Dr Frans Vos. He demonstrated this at the Academic Medical Centre in Amsterdam, through research into the side effects of chemotherapy on the brains of young cancer patients. "Usually, the scans are examined point by point. We combine measurements over a much bigger range, examining the whole nerve bundle." This allowed Caan to show that a lower dose of chemotherapy treatment causes much less damage to the brain.

"In a conventional DTI analysis, all the voxels (3D pixels) are considered independently," says Caan. "However, we expect that, because of the many connections in the brain, more areas are involved in complex brain diseases, such as schizophrenia. We have therefore introduced a self-learning system that can perform a comparative study of these areas."

Rotterdam Scan Study

DTI images could eventually be used for early diagnosis of Alzheimer's disease, for example. This would be possible by analysing changes in the white matter among large groups. Extensive population studies are necessary in order to allow differences between groups of patients to be shown statistically.

In the coming years, the Delft research group, Quantitative Imaging, led by Professor Lucas van Vliet and in which Caan carried out his research, will benefit from the Rotterdam Scan Study, in which 5,000 people are participating. It is expected that a substantial statistical basis will be available in five years.

Trojan Horse ploy to sneak protective drug into brains of stroke patients

Scientists are reporting development of a long-sought method with the potential for getting medication through a biological barrier that surrounds the brain, where it may limit the brain damage caused by stroke. Their approach for sneaking the nerve-protective drug erythropoietin into the brain is medicine's version of the Trojan Horse ploy straight out of ancient Greek legend. It also could help people with traumatic head injuries, Parkinson's disease, and other chronic brain disorders.

Their report appears in ACS' Molecular Pharmaceutics, a bi-monthly journal.

William Pardridge and colleagues explain that erythropoietin is a protective protein that has engendered great medical interest for its potential in protecting brain cells cut off from their normal blood supply by a stroke, or brain attack. Tests, however, show that erythropoietin, like other drugs, cannot penetrate a tightly-knit layer of cells called the blood-brain-barrier that surrounds and protects the brain from disease-causing microbes and other harmful material. Other proteins, however, can penetrate the barrier, and the scientists decided to test one of them as a Trojan Horse to sneak in erythropoietin.

The researchers found an antibody that can go through the blood brain barrier and linked it to erythropoietin to make a hybrid protein. Tests showed that the approach worked in laboratory mice, with the hybrid protein successfully penetrating the blood-brain barrier. The advance will allow scientists to begin testing erythropoietin's effects on mice with simulated stroke and other brain disorders, so that scientists can establish the most effective dose and best timing for possible future tests in humans.

Journal Reference:

  1. Qing-Hui Zhou, Ruben J. Boado, Jeff Zhiqiang Lu, Eric Ka-Wai Hui, William M. Pardridge. Re-Engineering Erythropoietin as an IgG Fusion Protein That Penetrates the Blood−Brain Barrier in the Mouse. Molecular Pharmaceutics, 2010; : 101007165407011 DOI: 10.1021/mp1001763

Molecular program for brain repair following stroke identified

A stroke wreaks havoc in the brain, destroying its cells and the connections between them. Depending on its severity and location, a stroke can impact someone's life forever, affecting motor activity, speech, memories, and more.

The brain makes an attempt to rally by itself, sprouting a few new connections, called axons, that reconnect some areas of the brain. But the process is weak, and the older the brain, the poorer the repair. Still, understanding the cascade of molecular events that drive even this weak attempt could lead to developing drugs to boost and accelerate this healing process.

Now researchers at UCLA have achieved a promising first step. Reporting in the current online edition of the journal Nature Neuroscience, senior author Dr. S. Thomas Carmichael, a UCLA associate professor of neurology, and colleagues have, for the first time, identified in the mouse the molecular cascade that drives the process of reconnection or sprouting in the adult brain after stroke.

"We set out to learn three things," said Carmichael, a member of the UCLA Stroke Center and the Brain Research Institute. "We hoped to identify the molecular program that activates brain cells — neurons — to form new connections after stroke; to understand how this molecular program changes in the aged versus the young adult brain, and the role each specific molecule plays in this program to control the sprouting of new connections after stroke."

Investigators have long tried to identify molecules that control brain recovery after stroke, said Carmichael. The ideal way to do this is to isolate the actual neurons that are recovering, then determine what molecules control this process. However, until now that has not been possible. "Sprouting neurons" are relatively few in number, and they are sitting in brain regions amidst many more cells that are not recovering. "As a result, the unique signals that the recovering neurons are using are lost when all of the tissue in a particular brain region after stroke is sampled," he said.

So the researchers developed two different fluorescent tracers to label cells that sprout a new connection after stroke. Once the cells were identified, the researchers could then isolate and study them. "This allowed us to identify the 'sprouting transcriptome,' " said Carmichael. "The term means that the results identify all of the genes that a brain cell activates to form new connections after stroke. That was the first step; then we set out to identify several key molecules that play a role in axonal sprouting after stroke that were previously not recognized."

The researchers were surprised by two things, said Carmichael.

First, they found that the neurons that sprout new connections after stroke activate a set of genes that broadly control the structure and accessibility of DNA. One such gene, termed ATRX, has not been linked before to axonal sprouting or brain recovery after injury. But, said Carmichael, it is important in brain development. "Our results show that brain cells activate this gene to form new connections after stroke."

Secondly, the molecular program that controls the formation of new connections in the brain after stroke differs considerably between aged and young adults. "Stroke, of course, usually happens to the elderly," he said. "These differences may explain in part why recovery is diminished in aged individuals; they respond to stroke with a very different genetic program of recovery." And there was a more intriguing discovery: In the aged brain, neurons that sprout new connections not only activate genes to induce these new connections, they simultaneously activate genes that slow down or collapse these new connections. "It's as if you are accelerating a car while at the same time hitting the brakes," he said. "This response of aged brain cells may show why the aged brain does not respond and recover after stroke like the young adult's."

Finally, the researchers developed a new method of drug delivery in the brain after stroke to test the role of specific molecules in the sprouting transcriptome. After stroke, the area of damage gets absorbed and becomes a cavity. This cavity sits right next to the "peri-infarct tissue," the part of the brain that is sprouting new connections and recovering. "We developed a way to fill the cavity with a natural biological material that releases brain repair drugs slowly over time directly to this peri-infarct tissue," said Carmichael. The researchers added normal brain proteins to a sponge-like biopolymer hydrogel, which slowly released the neural repair agents. This promoted axonal sprouting in the brain after stroke. "This approach takes advantage of now-standard human neurosurgical approaches, in which injections can be targeted precisely to brain structures," he said.

This research into stroke closely follows other research published by Carmichael last week in the journal Nature. That study showed another factor in the brain that limits recovery after stroke. Carmichael and colleagues found that stroke causes the brain to over-activate inhibitory signaling, causing the brain to be hypo-excitable. The UCLA team determined what molecules led to this increased brain inhibition after stroke, reversed the inhibitory signaling and enhanced recovery of function. The research also identified a promising drug therapy to help reverse the damaging effects of stroke.

Other authors in this study included Giovanni Coppola, Daniel H. Geschwind, Diana Katsman, Songlin Li and Justine J. Overman, UCLA Department of Neurology; Christopher J. Donnelly and Jeffery L. Twiss, Drexel University; Roman J. Giger, University of Michigan; and Serguei V. Kozlov, National Cancer Institute. The research was funded by The Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Larry L. Hillblom Foundation, the National Institutes of Health, the American Federation of Aging Research, and the American Heart Association. The authors report no conflict of interest.

Journal Reference:

  1. Songlin Li, Justine J Overman, Diana Katsman, Serguei V Kozlov, Christopher J Donnelly, Jeffery L Twiss, Roman J Giger, Giovanni Coppola, Daniel H Geschwind, S Thomas Carmichael. An age-related sprouting transcriptome provides molecular control of axonal sprouting after stroke. Nature Neuroscience, 2010; DOI: 10.1038/nn.2674