Abstract
Brain Network Decay Detected in Early Alzheimer's
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: EurekAlert! A service of AAAS and theWashington University School of Medicine).
Alzheimer's: Newly Identified Protein Pathology Impairs RNA Splicing
Move over, plaques and tangles.
Researchers at Emory University School of Medicine's Alzheimer's Disease Research Center have identified a previously unrecognized type of pathology in the brains of patients with Alzheimer's disease.
These tangle-like structures appear at early stages of Alzheimer's and are not found in other neurodegenerative diseases such as Parkinson's disease.
What makes these tangles distinct is that they sequester proteins involved in RNA splicing, the process by which instructional messages from genes are cut and pasted together. The researchers show that the appearance of these tangles is linked to widespread changes in RNA splicing in Alzheimer's brains compared to healthy brains.
The finding could change scientists' understanding of how the disease develops and progresses, by explaining how genes that have been linked to Alzheimer's contribute their effects, and could lead to new biomarkers, diagnostic approaches, and therapies.
The results are published in the Proceedings of the National Academy of Sciences, Early Edition.
“We were very surprised to find alterations in proteins that are responsible for RNA splicing in Alzheimer's, which could have major implications for the disease mechanism,” says Allan Levey, MD, PhD, chair of neurology at Emory University School of Medicine and director of the Emory ADRC.
“This is a brand new arena,” says James Lah, MD, PhD, associate professor of neurology at Emory University School of Medicine and director of the Cognitive Neurology program. “Many Alzheimer's investigators have looked at how the disease affects alternative splicing of individual genes. Our results suggest a global distortion of RNA processing is taking place.”
This research was led by Drs. Levey, Lah, and Junmin Peng, PhD, who was previously associate professor of genetics at Emory and is now a faculty member at St Jude Children's Research Hospital. They were aided by collaborators at University of Kentucky, Rush University, and University of Washington as well as colleagues at Emory.
Accumulations of plaques and tangles in the brains of patients with Alzheimer's disease were first observed more than a century ago. Investigating the proteins in these pathological structures has been central to the study of the disease.
Most experimental treatments for Alzheimer's have aimed at curbing beta-amyloid, an apparently toxic protein fragment that is the dominant component of amyloid plaques. Other approaches target the abnormal accumulation of the protein tau in neurofibrillary tangles. Yet the development of Alzheimer's is not solely explained by amyloid and tau pathologies, Lah says.
“Two individuals may harbor similar amounts of amyloid plaques and tau tangles in their brains, but one may be completely healthy while the other may have severe memory loss and dementia,” he says.
These discrepancies led Emory investigators to take a “back to basics” proteomics approach, cataloguing the proteins that make up insoluble deposits in the brains of Alzheimer's patients.
“The Alzheimer's field has been very focused on amyloid and tau, and we wanted to use today's proteomics technologies to take a comprehensive, unbiased approach,” Levey says.
The team identified 36 proteins that were much more abundant in the detergent-resistant deposits in brain tissue from Alzheimer's patients. This list included the usual suspects: tau and beta-amyloid. Also on the list were several “U1 snRNP” proteins, which are involved in RNA splicing.
These U1 proteins are normally seen in the nucleus of normal cells, but in Alzheimer's brains they accumulated in tangle-like structures. Accumulation of insoluble U1 protein was seen in samples from patients with mild cognitive impairment (MCI), a precursor stage to Alzheimer's, but the U1 pathology was not seen in any other brain diseases that were examined.
According to Chad Hales, MD, PhD, one of the study's lead authors, “U1 aggregation is occurring early in the disease, and U1 tangles can be seen independently of tau pathology. In some cases, we see accumulation of insoluble U1 proteins before the appearance of insoluble tau, suggesting that it is a very early event.”
For most genes, after RNA is read out from the DNA (transcription), some of the RNA must be spliced out. When brain cells accumulate clumps of U1 proteins, that could mean the process of splicing is impaired. To test this, the Emory team examined RNA from the brains of Alzheimer's patients. In comparison to RNA from healthy brains, more of the RNA from Alzheimer's brain samples was unspliced.
The finding could explain how many genes that have been linked to Alzheimer's are having their effects. In cells, U1 snRNP plays multiple roles in processing RNA including the process of alternative splicing, by which one gene can make instructions for two or more proteins.
“U1 dysfunction might produce changes in RNA processing affecting many genes or specific changes affecting a few key genes that are important in Alzheimer's,” Lah says. “Understanding the disruption of such a fundamental process will almost certainly identify new ways to understand Alzheimer's and new approaches to treating patients.” (Source: EurekAlert! A service of AAAS and Emory Health Sciences).
Alzheimer's Patients Show Striking Individual Differences in Molecular Basis of Disease
Alzheimer's disease is thought to be caused by the buildup of abnormal, thread-like protein deposits in the brain, but little is known about the molecular structures of these so-called beta-amyloid fibrils. A study published by Cell Press September 12th in the journal Cell has revealed that distinct molecular structures of beta-amyloid fibrils may predominate in the brains of Alzheimer's patients with different clinical histories and degrees of brain damage. The findings pave the way for new patient-specific strategies to improve diagnosis and treatment of this common and debilitating disease.
“This work represents the first detailed characterization of the molecular structures of beta-amyloid fibrils that develop in the brains of patients with Alzheimer's disease,” says senior study author Robert Tycko of the National Institutes of Health. “This detailed structural model may be used to guide the development of chemical compounds that bind to these fibrils with high specificity for purposes of diagnostic imaging, as well as compounds that inhibit fibril formation for purposes of prevention or therapy.”
Tycko and his team had previously noticed that beta-amyloid fibrils grown in a dish have different molecular structures, depending on the specific growth conditions. Based on this observation, they suspected that fibrils found in the brains of patients with Alzheimer's disease are also variable and that these structural variations might relate to each patient's clinical history. But it has not been possible to directly study the structures of fibrils found in patients because of their low abundance in the brain.
To overcome this hurdle, Tycko and his collaborators developed a new experimental protocol. They extracted beta-amyloid fibril fragments from the brain tissue of two patients with different clinical histories and degrees of brain damage and then used these fragments to grow a large quantity of fibrils in a dish. They found that a single fibril structure prevailed in the brain tissue of each patient, but the molecular structures were different between the two patients.
“This may mean that fibrils in a given patient appear first at a single site in the brain, then spread to other locations while retaining the identical molecular structure,” Tycko says. “Our study also shows that certain fibril structures may be more likely than others to cause Alzheimer's disease, highlighting the importance of developing imaging agents that target specific fibril structures to improve the reliability and specificity of diagnosis.” (Source: EurekAlert! A service of AAAS and Cell Press).
Genetic Mutation Linked to Alzheimer's Disease Doubles Rate of Brain Tissue Loss
People who carry a genetic mutation associated with Alzheimer's disease may develop the disease three years earlier than expected, according to a new study from Keck Medicine of the University of Southern California (USC).
Scientists at the Keck School of Medicine of USC have mapped the effects of that genetic mutation, showing for the first time how the Alzheimer's risk factor affects the living human brain. The discovery is detailed in the Oct. 17 edition of The New England Journal of Medicine alongside five other studies focused on the TREM2 gene variant, whose link to Alzheimer's was first reported in January.
“Our lab studies the rate of brain tissue loss in elderly people, trying to discover factors that protect you as you age,” said Paul M. Thompson, Ph.D., USC professor of neurology, psychiatry, engineering, radiology and ophthalmology and the study's principal investigator. “We have never seen such a dramatic effect as with this genetic variant. If you carry this genetic mutation, we've found that there is this wildfire of tissue loss in the brain.”
Healthy people typically lose less than 1 percent of their brain tissue a year, offset by normal tissue generation from mental stimulation, Thompson said. Symptoms of Alzheimer's begin to manifest when approximately 10 percent of the brain's tissue has eroded away.
“This is the first study to use brain scans to show what this gene variant does, and it's very surprising,” Thompson said. “This gene speeds up brain loss at a terrific pace. Carriers of this genetic mutation, who comprise about 1 percent of the population, lose about 3 percent of their brain tissue per year. This is a silent time bomb in 1 percent of the world.”
Thompson and colleagues compared brain magnetic resonance imaging (MRI) scans of 478 adults (average age 76 years old) participating in the Alzheimer's Disease Neuroimaging Initiative over two years. The group included 283 men and 195 women from across North America; 100 participants had Alzheimer's disease, 221 had mild cognitive impairment and 157 were healthy elderly adults.
Keck researchers found that mutation carriers lost 1.4 percent to 3.3 percent more of their brain tissue than non-carriers, and twice as fast. The loss appears to be concentrated in the brain's temporal lobe and hippocampus, areas that play important roles in memory.
“This TREM2 mutation appears to multiply the risk of Alzheimer's by three or four times, which is very useful information. Enrolling those people who carry the mutation in clinical trials for Alzheimer's treatments could help us reach quicker and more meaningful results,” Thompson said. (Source: EurekAlert! A service of AAAS and theUniversity of Southern California-Health Sciences).
International Group Finds 11 New Alzheimer's Genes to Target for Drug Discovery
PHILADELPHIA - The largest international Alzheimer's disease genetics collaboration to date has found 11 new genetic areas of interest that contribute to late onset Alzheimer's Disease (LOAD), doubling the number of potential genetics-based therapeutic targets to interrogate. The study, published in Nature Genetics, provides a broader view of genetic factors contributing to the disease and expands the scope of disease understanding to include new areas including the immune system, where a genetic overlap with other neurodegenerative diseases such as multiple sclerosis and Parkinson's disease was identified.
“Human genetic studies are being used with increased frequency to validate new drug targets in many diseases. Here we greatly increased the list of possible drug target candidates for Alzheimer's disease, finding as many new significant genes in this one study as have been found in the last 15 years combined,” said co-senior author Gerard Schellenberg, PhD, director of the Alzheimer's Disease Genetics Consortium (ADGC) and professor of Pathology and Laboratory Medicine in the Perelman School of Medicine at the University of Pennsylvania. “This international effort has given us new clues into the steps leading to and accelerating Alzheimer's disease. We can add these new genetic clues to what we already know and try to piece together the mechanism of this complex disease.”
Pooling resources through the International Genomics of Alzheimer's Project (IGAP), the collaborative team collected 74,076 patients and controls from 15 countries. After a two stage meta-analysis, the group found some genes which confirmed known biological pathway of Alzheimer's disease, including the role of the amyloid pathway (SORL1, CASS4) and tau (CASS4, FERMT2). Newly discovered genes involved in the immune response and inflammation (HLA-DRB5/DRB1, INPP5D, MEF2C) reinforced a pathway implied by previous work (on CR1, TREM2). Additional genes related to cell migration (PTK2B), lipid transport and endocytosis (SORL1) were also confirmed. And new hypotheses emerged related to hippocampal synaptic function (MEF2C, PTK2B), the cytoskeleton and axonal transport (CELF1, NME8, CASS4) as well as myeloid and microglial cell functions (INPP5D).
One of the more significant new associations was found in the HLA-DRB5 - DRB1 region, one of the most complex parts of the genome, which plays a role in the immune system and inflammatory response. It has also been associated with multiple sclerosis and Parkinson's disease, suggesting that the diseases where abnormal proteins accumulate in the brain may have a common mechanism involved, and possibly have a common drug target, Dr. Schellenberg noted.
“We know that healthy cells are very good at clearing out debris, thanks in part to the immune response system, but in these neurodegenerative diseases where the brain has an inflammatory response to bad proteins and starts forming plaques and tangle clumps, perhaps the immune response can get out of hand and do damage,” said Dr. Schellenberg. “Through this powerful international group as well as our own US collaborations, we'll expand the data set even further to look for rare variants and continue our analysis to find more opportunities to better understand the disease and find viable therapeutic targets. Large-scale sequencing will certainly play a part in the next phase of our genetics studies.” (Source: EurekAlert! A service of AAAS and theUniversity of Pennsylvania School of Medicine).
Dementia Risk Greatest for Older Native-Americans and African-Americans with Diabetes
OAKLAND, Calif. — In the first study to look at racial and ethnic differences in dementia risk among older adults with type 2 diabetes, researchers found that dementia was much higher among Native Americans and African-Americans and lowest among Asian-Americans.
The study, published in Diabetes Care, included a group of more than 22,000 patients aged 60 or older who were members of the Kaiser Permanente Northern California Diabetes Registry. Dementia was diagnosed in 3,796 patients (17.1 percent of the study cohort) during a follow-up of up to 10 years. Dementia was not present in any of the patients at the start of the study.
Compared to Asian-Americans, Native Americans were 64 percent more likely to develop dementia, and African-Americans were 44 percent more likely. Almost 20 percent (or one in five) African-Americans and Native Americans were diagnosed with dementia during the 10-year study.
“We found that in a population of elderly individuals with type 2 diabetes, there were marked differences in rates of dementia over a 10-year period by racial and ethnic groups,” said senior author Rachel Whitmer, PhD, research scientist at the Kaiser Permanente Division of Research. “Moreover, the differences were not explained by diabetes-related complications, glycemic control or duration of diabetes. Nor were they altered by factors of age, gender, neighborhood deprivation index, body mass index, or hypertension.”
Among people aged 60 and above, those with type 2 diabetes have double the risk of developing dementia. Certain racial and ethnic groups in the U.S., including Latinos, African-Americans, some Asian American groups, and Native Americans, are disproportionally affected by type 2 diabetes. However, the interplay of type 2 diabetes and race/ethnicity on long-term dementia risk has not been explored previously.
“Since ethnic minorities are the fastest-growing segment of the elderly population in the United States, it is critical to determine if they are at higher risk of dementia, especially among those with type 2 diabetes,” said Elizabeth Rose Mayeda, PhD, lead author and postdoctoral fellow at University of California San Francisco. “It's eye-opening to see the magnitude of ethnic and racial differences in dementia risk in a study where everyone already has type 2 diabetes.”
The researchers concluded that more work is needed to identify factors that will reduce dementia risk for those with diabetes, particularly for ethnic and minority groups at highest risk. While future research is greatly needed on potential dementia prevention efforts in general, these findings suggest that certain ethnic groups within the type 2 diabetes population may benefit the most.
This study is part of an ongoing body of work to better understand dementia. Earlier this year, Kaiser Permanente researchers created the first risk score that predicts the 10-year individualized dementia risk for patients with type 2 diabetes. (Source: EurekAlert! A service of AAAS and Kaiser Permanente).
Speaking a Second Language May Delay Dementia, Study Shows
People who speak more than one language and who develop dementia tend to do so up to five years later than those who are monolingual, according to a study.
A team of scientists examined almost 650 dementia patients and assessed when each one had been diagnosed with the condition. The study was carried out by researchers from the University of Edinburgh and Nizam's Institute of Medical Sciences in Hyderabad (India).
They found that people who spoke two or more languages experienced a later onset of Alzheimer's disease, vascular dementia and frontotemporal dementia.
The bilingual advantage extended to illiterate people who had not attended school. This confirms that the observed effect is not caused by differences in formal education.
It is the largest study so far to gauge the impact of bilingualism on the onset of dementia – independent of a person's education, gender, occupation and whether they live in a city or in the country, all of which have been examined as potential factors influencing the onset of dementia.
The team of researchers say further studies are needed to determine the mechanism, which causes the delay in the onset of dementia. The researchers suggest that bilingual switching between different sounds, words, concepts, grammatical structures and social norms constitutes a form of natural brain training, likely to be more effective than any artificial brain training programme.
However, studies of bilingualism are complicated by the fact that bilingual populations are often ethnically and culturally different from monolingual societies. India offers in this respect a unique opportunity for research. In places like Hyderabad, bilingualism is part of everyday life: knowledge of several languages is the norm and monolingualism an exception.
Thomas Bak, of the University of Edinburgh's School of Philosophy, Psychology and Language Sciences said: “These findings suggest that bilingualism might have a stronger influence on dementia that any currently available drugs. This makes the study of the relationship between bilingualism and cognition one of our highest priorities.”
RNA Build-Up Linked to Dementia and Motor Neuron Disease
A new toxic entity associated with genetically inherited forms of dementia and motor neuron disease has been identified by scientists at the UCL Institute of Neurology. The toxin is the result of a genetic mutation that leads to the production of RNA molecules which could be responsible for the diseases. The findings are published in the journal ActaNeuropathologica.
Frontotemporal dementia and motor neuron disease are related neurodegenerative diseases that affect approximately 15,000 people in the UK. Frontotemporal dementia causes profound personality and behaviour changes. Motor neuron disease leads to muscle weakness and eventual paralysis.
The most common known cause for both frontotemporal dementia and motor neuron disease is an unusual genetic mutation in the C9orf72 gene. The mutation involves a small string of DNA letters at the beginning of the gene, which expand massively to produce thousands of copies.
The new research, funded by Alzheimer's Research UK and the Medical Research Council, has shown that this DNA expansion acts in a peculiar way, leading to the generation of unexpected RNA molecules that could cause the disease.
When a gene is turned on, an RNA copy of the gene's DNA is generated. The gene's DNA code has directionality, so that it is normally turned on in only one direction, termed the `sense direction'. The new research shows that the DNA expansion is turned on in both directions.
This leads to the normal sense RNA being produced, as well as RNA in the opposite direction, termed `antisense RNA'. Both RNA types accumulate into aggregates in the neurons of people with frontotemporal dementia.
Intriguingly, the research showed that people with more of these aggregates in their brains developed the disease earlier than people with less RNA aggregates. This correlation suggests that the build-up may be important in causing frontotemporal dementia and motor neuron disease, making the C9orf72 DNA expansion a potential target for therapy.
Dr Adrian Isaacs, lead researcher at the UCL Institute of Neurology, said: “These findings identify new, potentially toxic molecules in diseases caused by DNA expansions. The next steps will be to determine how they might kill neurons and how to stop them building up.”
Dr Simon Ridley, Head of Research at Alzheimer's Research UK, the UK's leading dementia research charity, said: “The discovery of the C9ORF72 gene was a major step forward for research into frontotemporal dementia and motor neuron disease, and it's positive to see researchers beginning to untangle how this gene may cause these diseases in some people.
“Alzheimer's Research UK is delighted to have supported this promising study. By unravelling some of the biological mechanisms at play, this research could take us further on the road to new treatments that are so desperately needed by the thousands of people with these devastating diseases. For these results to reach their full potential it's vital that we continue to invest in research.” (Source: EurekAlert! A service of AAAS and University College London).