A Brake in the Head: German researchers gain new insights into the working of the brain
Scientists of the Charité – Universitätsmedizin Berlin and the German Center for Neurodegenerative Diseases (DZNE) have managed to acquire new insights into the functioning of a region in the brain that normally is involved in spatial orientation, but is damaged by the Alzheimer’s disease. They investigated how nerve signals are suppressed inside the so-called entorhinal cortex. According to the researchers, this neuronal inhibition leads nerve cells to synchronize their activity. The results of this study are now published in Neuron.
The entorhinal cortex is a link between the brain’s memory centre, the hippocampus, and the other areas of the brain. It is, however, more than an interface that only transfers nervous impulses. The entorhinal cortex also has an independent role in learning and thinking processes. This is particularly applicable for spatial navigation. “We know precious little about how this happens,” says Prof. Dietmar Schmitz, a researcher at the Cluster of Excellence NeuroCure at the Charité – Universitätsmedizin Berlin and Site Speaker for the DZNE in Berlin. “This is why we are investigating in animal models how the nerve cells within the entorhinal cortex are connected with each other.“
Signals wander inside the brain as electrical impulses from nerve cell to nerve cell. In general, signals are not merely forwarded. Rather, operation of the brain critically depends on the fact that the nerve impulses in some situations are activated and in other cases suppressed. A correct balance between suppression and excitation is decisive for all brain processes. “Until now research has mainly concentrated on signal excitation within the entorhinal cortex. This is why we looked into inhibition and detected a gradient inside the entorhinal cortex,” explains Dr. Prateep Beed, lead author of the study. “This means that nerve signals are not suppressed equally. The blockage of the nerve signals is weaker in certain parts of the entorhinal cortex and stronger in others. The inhibition has, so to speak, a spatial profile.”
When the brain is busy, nerve cells often coordinate their operation. In an electroencephalogram (EEG) – a recording of the brain’s electrical activity – the synchronous rhythm of the nerve cells manifests as a periodic pattern. “It is a moot question as to how nerve cells synchronize their behavior and how they bring about such rhythms,” says Beed. As he explains, it is also unclear whether these oscillations are only just a side effect or whether they trigger other phenomena. “But it has been demonstrated that neuronal oscillations accompany learning processes and even happen during sleep. They are a typical feature of the brain’s activity,” describes the scientist. “In our opinion, the inhibitory gradient, which we detected, plays an important role in creating the synchronous rhythm of the nerve cells and the related oscillations.”
In the case of Alzheimer’s, the entorhinal cortex is among the regions of the brain that are the first to be affected. “In recent times, studies related to this brain structure have increased. Here, already in the early stages of Alzheimer’s, one finds the protein deposits that are typical of this disease,” explains Schmitz, who headed the research. “It is also known that patients affected by Alzheimer’s have a striking EEG. Our studies help us to understand how the nerve cells in the entorhinal cortex operate and how electrical activities might get interrupted in this area of the brain.”
Filed under alzheimer's disease entorhinal cortex dementia neurons hippocampus neuroscience science
Mayo Clinic Study: Blood Biomarker Could Mark Severe Cognitive Decline, Quicker Progression Among Parkinson’s Patients
A genetic mutation, known as GBA, that leads to early onset of Parkinson’s disease and severe cognitive impairment (in about 4 to 7 percent of all patients with the disease) also alters how specific lipids, ceramides and glucosylceramides are metabolized. Mayo Clinic researchers have found that Parkinson’s patients who do not carry the genetic mutation also have higher levels of these lipids in the blood. Further, those who had Parkinson’s and high blood levels were also more likely to have cognitive impairment and dementia. The research was recently published online in the journal PLOS ONE.
The discovery could be an important warning for those with Parkinson’s disease. Parkinson’s is the second most common neurodegenerative disease after Alzheimer’s disease. There is no biomarker to tell who is going to develop the disease — and who is going to develop cognitive impairment after developing Parkinson’s, says Michelle Mielke, Ph.D., a Mayo Clinic researcher and first author of the study.
Cognitive impairment is a frequent symptom in Parkinson’s disease and can be even more debilitating for patients and their caregivers than the characteristic motor symptoms. The early identification of Parkinson’s patients at greatest risk of developing dementia is important for preventing or delaying the onset and progression of cognitive symptoms. Changing these blood lipids could be a way to stop the progression of the disease, says Dr. Mielke.
There is a suggestion this blood lipid marker also could help to predict who will develop Parkinson’s disease and this research is ongoing.
"There is currently no cure for Parkinson’s, but the earlier we catch it — the better chance we have to fight it," says Dr. Mielke. "It’s particularly important we find a biomarker and identify it in the preclinical phase of the disease, before the onset even begins."
Dr. Mielke’s lab is researching blood-based biomarkers for Parkinson’s disease because blood tests are less invasive and cheaper than a brain scan or spinal tap — other tools used to research the disease.
Filed under neurodegenerative diseases dementia cognitive decline parkinson's disease neuroscience science
Study helps deconstruct estrogen’s role in memory
The loss of estrogens at menopause increases a woman’s risk of dementia and Alzheimer’s disease, yet hormone replacement therapy can cause harmful side effects.
Knowing the exact mechanism of estrogen activation in the brain could lead to new targets for drug development that would provide middle-aged women the cognitive benefits of hormone replacement therapy without increasing their risk for cardiovascular disease or breast cancer.
In a new study, Karyn Frick, professor of psychology at the University of Wisconsin-Milwaukee, uncovers details about estrogen’s role in the complex cellular communication system underlying memory formation.
“The receptor mechanisms that regulate estrogen’s ability to enhance memory are still poorly understood,” says Frick. “With this study, we’ve begun to sort out several of the key players needed for estrogens to mediate memory formation.”
The research, published in the The Journal of Neuroscience today, focused on estrogen effects in a brain region called the hippocampus, which deteriorates with age or Alzheimer’s disease. The researchers found that each of the two known estrogen receptors rapidly activate a specific cellular pathway necessary for memory formation in the hippocampus of female mice, but only if they interact with a certain glutamate receptor, called mGluR1.
The study revealed that when this glutamate receptor is blocked, the cell-signaling protein ERK cannot be activated by the potent estrogen, 17β-estradiol. Because ERK activation is necessary for memory formation, estradiol failed to enhance memory among mice in which mGluR1 was blocked.
Frick’s team also found evidence that estrogen receptors and mGluR1 physically interact at the cell membrane, allowing estradiol to influence memory formation within seconds to minutes. Collectively, the data provide the first evidence that the rapid signaling initiated by such interactions is essential for estradiol to enhance memory regulated by the hippocampus.
“Our data suggesting that interactions between estrogen receptors and mGluR1 at the cell membrane are critical for estradiol to enhance memory provides important new information about how estrogens regulate memory formation,” Frick says. “Because membrane proteins are better targets for drug development than proteins inside the cell, these data could lead to a new generation of therapies that provide the cognitive benefits of estrogens without harmful side effects.”
Filed under estrogen alzheimer's disease dementia memory formation memory neuroscience science
Cognitive enhancers—drugs taken to enhance concentration, memory, alertness and moods—do not improve cognition or function in people with mild cognitive impairment in the long term, according to a new study by researchers at St. Michael’s Hospital.
In fact, patients on these medications experienced significantly more nausea, diarrhea, vomiting and headaches, according to the study published today in the Canadian Medical Association Journal.
“Our findings do not support the use of cognitive enhancers for mild cognitive impairment,” wrote Dr. Andrea Tricco and Dr. Sharon Straus, who are both scientists in the hospital’s Li Ka Shing Knowledge Institute. Dr. Straus is also a geriatrician at the hospital.
Mild cognitive impairment is a condition characterized by memory complaints without significant limitations in everyday activity. Between 3 and 42 per cent of people are diagnosed with the condition each year, about 4.6 million people worldwide. Each year about 3 to 17 per cent of people with mild cognitive impairment will develop dementia, such as Alzheimer’s disease. Given the aging population, it’s estimated the number of Canadians with dementia will double to more than 1 million in the next 25 years.
It has been hypothesized that cognitive enhancers may delay the onset of dementia. Families and patients are increasingly requesting these drugs even though their efficacy for patients with mild cognitive impairment has not been established. In Canada, cognitive enhancers can be obtained only with special authorization.
Drs. Tricco and Straus conducted a review of existing evidence to understand the efficacy and safety of cognitive enhancers. They looked at eight randomized trials that compared one of four cognitive enhancers (donepezil, rivastigmine, galantamine or memantine) to a placebo among patients diagnosed with mild cognitive impairment.
While they found short-term benefits to using these drugs on one cognition scale, there were no long-term effects after about a year and a half. No other benefits were observed on the second cognition scale or on function, behaviour, and mortality. As well, patients on these medications experienced significantly more nausea, diarrhea, vomiting and headaches. One study also found a higher risk of a heart condition known as bradycardia (slow heartbeat) among patients who received galantamine.
“Our results do not support the use of cognitive enhancers for patients with mild cognitive impairment,” the authors wrote. “These agents were not associated with any benefit and led to an increase in harms. Patients and their families should consider this information when requesting these medications. Similarly, health care decision-makers may not wish to approve the use of these medications for mild cognitive impairment, because these drugs might not be effective and are likely associated with harm.”
This study was funded by the Drug Safety and Effectiveness Network/Canadian Institutes of Health Research.
Another St. Michael’s study published in the CMAJ in April found no evidence that drugs, herbal products or vitamin supplements help prevent cognitive decline in healthy older adults. That review, led by Dr. Raza Naqvi, a University of Toronto resident, found some evidence that mental exercises, such as computerized memory training programs, might help.
Filed under alzheimer's disease dementia memory loss cognitive impairment neuroscience science
The degeneration of a small, wishbone-shaped structure deep inside the brain may provide the earliest clues to future cognitive decline, long before healthy older people exhibit clinical symptoms of memory loss or dementia, a study by researchers with the UC Davis Alzheimer’s Disease Center has found.
The longitudinal study found that the only discernible brain differences between normal people who later developed cognitive impairment and those who did not were changes in their fornix, an organ that carries messages to and from the hippocampus, and that has long been known to play a role in memory.
“This could be a very early and useful marker for future incipient decline,” said Evan Fletcher, the study’s lead author and a project scientist with the UC Davis Alzheimer’s Disease Center.
“Our results suggest that fornix variables are measurable brain factors that precede the earliest clinically relevant deterioration of cognitive function among cognitively normal elderly individuals,” Fletcher said.
The research is published online today in JAMA Neurology.
Hippocampal atrophy occurs in the later stages of cognitive decline and is one of the most studied changes associated with the Alzheimer’s disease process. However, changes to the fornix and other regions of the brain structurally connected to the hippocampus have not been as closely examined. The study found that degeneration of the fornix in relation to cognition was detectable even earlier than changes in the hippocampus.
“Although hippocampal measures have been studied much more deeply in relation to cognitive decline, our direct comparison between fornix and hippocampus measures suggests that fornix properties have a superior ability to identify incipient cognitive decline among healthy individuals,” Fletcher said.
The study was conducted over five years in a group of 102 diverse, cognitively normal people with an average age of 73 who were recruited through community outreach at the Alzheimer’s Disease Center. The researchers conducted magnetic resonance imaging (MRI) studies of the participants’ brains that described their volumes and integrity. A different type of MRI was used to determine the integrity of the myelin, the fatty coating that sheaths and protects the axons. The axons are analogous to the copper wiring of the brain’s circuitry and the myelin is like the wiring’s plastic insulation.
Either one of those things being lost will “degrade the signal transmission” in the brain, Fletcher said.
The researchers also conducted psychological tests and cognitive evaluations of the study participants to gauge their level of cognitive functioning. The participants returned for updated MRIs and cognitive testing at approximately one-year intervals. At the outset, none of the study participants exhibited symptoms of cognitive decline. Over time about 20 percent began to show symptoms that led to diagnoses with either mild cognitive impairment (MCI) and, in a minority of cases, Alzheimer’s disease.
“We found that if you looked at various brain factors there was one — and only one — that seemed to be predictive of whether a person would have cognitive decline, and that was the degradation of the fornix,” Fletcher said.
The study measured two relevant fornix characteristics predicting future cognitive impairment — low fornix white matter volume and reduced axonal integrity. Each of these was stronger than any other brain factor in models predicting cognitive loss, Fletcher said.
He said that routine MRI examination of the fornix could conceivably be used clinically in the future as a predictor of abnormal cognitive decline.
“Our findings suggest that if your fornix volume or integrity is within a certain range you’re at an increased risk of cognitive impairment down the road. But developing the use of the fornix as a predictor in a clinical setting will take some time, in the same way that it took time for evaluation of cholesterol levels to be used to predict future heart disease,” he said.
Fletcher also said that the finding may mark a paradigm shift toward evaluation of the brain’s white matter, rather than its gray matter, as among the very earliest indicators of developing cognitive loss. There is currently a strong research focus on understanding brain processes that lead eventually to Alzheimer’s disease. He said the current finding could fill in one piece of the picture and motivate new directions in research to understand why and how fornix and other white matter change is such an important harbinger of cognitive impairment.
“The key importance of this finding is that it suggests that white matter tract measures may prove to be promising candidate biomarkers for predicting incipient cognitive decline among cognitively normal individuals in a clinical setting, possibly more so than gray matter measures,” he said.
(Source: ucdmc.ucdavis.edu)
Filed under alzheimer's disease dementia cognitive decline fornix hippocampus neuroscience science
Mild B-12 Deficiency May Speed Dementia
Study finds that the vitamin shortage might affect more people than previously thought
Being even mildly deficient in vitamin B-12 may put older adults at a greater risk for accelerated cognitive decline, an observational study from the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts suggests.
Martha Savaria Morris, an epidemiologist in the Nutrition Epidemiology Program at the HNRCA, and colleagues examined data from 549 men and women enrolled in a cohort of the Framingham Heart Study. The subjects, who had an average age of 75 at the start, were divided into five groups based on their vitamin B-12 blood levels.
Being in the two lowest groups was associated with significantly accelerated cognitive decline, based on scores from dementia screening tests given over eight years.
“Men and women in the second-lowest group did not fare any better in terms of cognitive decline than those with the worst vitamin B-12 blood levels,” Morris says. It is well known that severe B-12 deficiency speeds up dementia, but the finding suggests that even more seniors may be affected.
The study appeared in the Journal of the American Geriatrics Society.
“While we emphasize our study does not show causation, our associations raise the concern that some cognitive decline may be the result of inadequate vitamin B-12 in older adults, for whom maintaining normal blood levels can be a challenge,” says Professor Paul Jacques, the study’s senior author and director of the HNRCA Nutrition Epidemiology Program.
Animal proteins, such as lean meats, poultry and eggs, are good sources of vitamin B-12. Because older adults may have a hard time absorbing vitamin B-12 from food, the USDAʼs 2010 Dietary Guidelines for Americans recommend that people over age 50 incorporate foods fortified with B-12 or supplements in their diets.
The subjects in this study were mostly Caucasian women who had earned at least a high school diploma. The authors said future research might include more diverse populations and explore whether vitamin B-12 status affects particular cognitive skills.
This article first appeared in the Summer 2013 issue of Tufts Nutrition magazine.
Filed under vitamin B-12 B-12 deficiency cognitive decline dementia neuroscience science
The first systematic review of related research confirms a positive impact on cognitive function, but an inconsistent effect on mild cognitive impairment.
Over recent years many pieces of research have identified a link between adherence to a Mediterranean diet and a lower risk of age-related disease such as dementia.
Until now there has been no systematic review of such research, where a number of studies regarding a Mediterranean diet and cognitive function are reviewed for consistencies, common trends and inconsistencies.
A team of researchers from the University of Exeter Medical School, supported by the National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care in the South West Peninsula (NIHR PenCLAHRC), has carried out the first such systematic review and their findings are published in Epidemiology.
The team analysed 12 eligible pieces of research, 11 observational studies and one randomised control trial. In nine out of the 12 studies, a higher adherence to a Mediterranean diet was associated with better cognitive function, lower rates of cognitive decline and a reduced risk of Alzheimer’s disease.
However, results for mild cognitive impairment were inconsistent.
A Mediterranean diet typically consists of higher levels of olive oil, vegetables, fruit and fish. A higher adherence to the diet means higher daily intakes of fruit and vegetables and fish, and reduced intakes of meat and dairy products.
The study was led by researcher Iliana Lourida. She said: “Mediterranean food is both delicious and nutritious, and our systematic review shows it may help to protect the ageing brain by reducing the risk of dementia. While the link between adherence to a Mediterranean diet and dementia risk is not new, ours is the first study to systematically analyse all existing evidence.”
She added: “Our review also highlights inconsistencies in the literature and the need for further research. In particular research is needed to clarify the association with mild cognitive impairment and vascular dementia. It is also important to note that while observational studies provide suggestive evidence we now need randomized controlled trials to confirm whether or not adherence to a Mediterranean diet protects against dementia.”
(Source: exeter.ac.uk)
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Scientists from Freie Universität Berlin and the University of Graz Have Shown That Feeding Fruit Flies with Spermidin Suppresses Age-dependent Memory Impairment
Age-induced memory impairment can be suppressed by administration of the natural substance spermidin. This was found in a recent study conducted by Prof. Dr. Stephan Sigrist from Freie Universität Berlin and the Neurocure Cluster of Excellence and Prof. Dr. Frank Madeo from Karl-Franzens-Universität Graz. Both biologists, they were able to show that the endogenous substance spermidine triggers a cellular cleansing process, which is followed by an improvement in the memory performance of older fruit flies. At the molecular level, memory processes in animal organisms such as fruit flies and mice are similar to those in humans. The work by Sigrist and Madeo has potential for developing substances for treating age-related memory impairment. The study was first published in the online version of Nature Neuroscience.
Aggregated proteins are potential candidates for causing age-related dementia. With increasing age, the proteins accumulate in the brains of fruit flies, mice, and humans. In 2009 Madeo’s group in Graz already found that the spermidin molecule has an anti-aging effect by setting off autophagy, a cleaning process at the cellular level. Protein aggregates and other cellular waste are delivered to lysosomes, the digestive apparatus in cells, and degraded.
Feeding the fruit flies spermidin significantly reduced the amount of protein aggregates in their brains, and their memories improved to juvenile levels. This can be measured because flies can learn under classical Pavovian conditioning and adjust their behavior accordingly.
In humans, memory capacity decreases beginnning around the age of 50. This loss accelerates with increasing age. Due to increasing life expectancy, age-related memory impairment is expected to increase drastically. The spermidine concentration increases with age in flies as in humans. If it were possible to delay the onset of age-related dementia by giving individuals spermidin as a food supplement, it would be a great breakthrough for individuals and for society. Patient studies are the next step for Sigrist and Madeo.
(Source: fu-berlin.de)
Filed under spermidin fruit flies memory impairment dementia aging neuroscience science
Alzheimer’s disease has proven to be a difficult enemy to defeat. After all, aging is the No. 1 risk factor for the disorder, and there’s no stopping that.
Most researchers believe the disease is caused by one of two proteins, one called tau, the other beta-amyloid. As we age, most scientists say, these proteins either disrupt signaling between neurons or simply kill them.
Now, a new UCLA study suggests a third possible cause: iron accumulation.
Dr. George Bartzokis, a professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA and senior author of the study, and his colleagues looked at two areas of the brain in patients with Alzheimer’s. They compared the hippocampus, which is known to be damaged early in the disease, and the thalamus, an area that is generally not affected until the late stages. Using sophisticated brain-imaging techniques, they found that iron is increased in the hippocampus and is associated with tissue damage in that area. But increased iron was not found in the thalamus.
The research appears in the August edition of the Journal of Alzheimer’s Disease.
While most Alzheimer’s researchers focus on the buildup of tau or beta-amyloid that results in the signature plaques associated with the disease, Bartzokis has long argued that the breakdown begins much further “upstream.” The destruction of myelin, the fatty tissue that coats nerve fibers in the brain, he says, disrupts communication between neurons and promotes the buildup of the plaques. These amyloid plaques in turn destroy more and more myelin, disrupting brain signaling and leading to cell death and the classic clinical signs of Alzheimer’s.
Myelin is produced by cells called oligodendrocytes. These cells, along with myelin, have the highest levels of iron of any cells in the brain, Bartzokis says, and circumstantial evidence has long supported the possibility that brain iron levels might be a risk factor for age-related diseases like Alzheimer’s. Although iron is essential for cell function, too much of it can promote oxidative damage, to which the brain is especially vulnerable.
In the current study, Bartzokis and his colleagues tested their hypothesis that elevated tissue iron caused the tissue breakdown associated with Alzheimer’s disease. They targeted the vulnerable hippocampus, a key area of the brain involved in the formation of memories, and compared it to the thalamus, which is relatively spared by Alzheimer’s until the very late stages of disease.
The researchers used an MRI technique that can measure the amount of brain iron in ferritin, a protein that stores iron, in 31 patients with Alzheimer’s and 68 healthy control subjects.
In the presence of diseases like Alzheimer’s, as the structure of cells breaks down, the amount of water increases in the brain, which can mask the detection of iron, according to Bartzokis.
"It is difficult to measure iron in tissue when the tissue is already damaged," he said. "But the MRI technology we used in this study allowed us to determine that the increase in iron is occurring together with the tissue damage. We found that the amount of iron is increased in the hippocampus and is associated with tissue damage in patients with Alzheimer’s but not in the healthy older individuals — or in the thalamus. So the results suggest that iron accumulation may indeed contribute to the cause of Alzheimer’s disease."
But it’s not all bad news from this study, Bartzokis noted.
"The accumulation of iron in the brain may be influenced by modifying environmental factors, such as how much red meat and iron dietary supplements we consume and, in women, having hysterectomies before menopause," he said.
In addition, he noted, medications that chelate and remove iron from tissue are being developed by several pharmaceutical companies as treatments for the disorder. This MRI technology may allow doctors to determine who is most in need of such treatments.
(Source: newsroom.ucla.edu)
Filed under alzheimer's disease dementia iron accumulation aging hippocampus oligodendrocytes neuroscience science
In patients with early Alzheimer’s disease, disruptions in brain networks emerge about the same time as chemical markers of the disease appear in the spinal fluid, researchers at Washington University School of Medicine in St. Louis have shown.
While two chemical markers in the spinal fluid are regarded as reliable indicators of early disease, the new study, published in JAMA Neurology, is among the first to show that scans of brain networks may be an equally effective and less invasive way to detect early disease.
“Tracking damage to these brain networks may also help us formulate a more detailed understanding of what happens to the brain before the onset of dementia,” said senior author Beau Ances, MD, PhD, associate professor of neurology and of biomedical engineering.
Diagnosing Alzheimer’s early is a top priority for physicians, many of whom believe that treating patients long before dementia starts greatly improves the chances of success.
Ances and his colleagues studied 207 older but cognitively normal research volunteers at the Charles F. and Joanne Knight Alzheimer’s Disease Research Center at Washington University. Over several years, spinal fluids from the volunteers were sampled multiple times and analyzed for two markers of early Alzheimer’s: changes in amyloid beta, the principal ingredient of Alzheimer’s brain plaques, and in tau protein, a structural component of nerve cells.
The volunteers were also scanned repeatedly using a technique called resting state functional magnetic resonance imaging (fMRI). This scan tracks the rise and fall of blood flow in different brain regions as patients rest in the scanner. Scientists use the resulting data to assess the integrity of the default mode network, a set of connections between different brain regions that becomes active when the mind is at rest.
Earlier studies by Ances and other researchers have shown that Alzheimer’s damages connections in the default mode network and other brain networks.
The new study revealed that this damage became detectable at about the same time that amyloid beta levels began to fall and tau levels started to rise in spinal fluid. The part of the default mode network most harmed by the onset of Alzheimer’s disease was the connection between two brain areas associated with memory, the posterior cingulate and medial temporal regions.
The researchers are continuing to study the connections between brain network damage and the progress of early Alzheimer’s disease in normal volunteers and in patients in the early stages of Alzheimer’s-associated dementia.
(Source: news.wustl.edu)
Filed under alzheimer's disease dementia neuroimaging beta amyloid neuroscience science
