Posts tagged alzheimer's disease

The failing in the work of nerve cells: An international team of researchers led by Prof. Dr. Chris Meisinger from the Institute of Biochemistry and Molecular Biology of the University of Freiburg has discovered how Alzheimer’s disease damages mitochondria, the powerhouses of the cell. For several years researchers have known that the cellular energy supply of brain cells is impaired in Alzheimer’s patients. They suspect this to be the cause of premature death of nerve cells that occurs in the course of the disease. Little is known about the precise cause of this neuronal cell death, and many approaches and attempts to find an effective therapy have failed to make an impact. What is certain is that a tiny protein fragment by the name of “amyloid-beta” plays a key role in the process. Meisinger, a member of the Cluster of Excellence BIOSS Centre for Biological Signalling Studies of the University of Freiburg, and his team have now demonstrated how this protein fragment blocks the maturation of protein machines that are responsible for the production of energy inside the cellular powerhouses. The researchers demonstrated this with the help of model organisms and with brain samples from Alzheimer’s patients. “The elucidation of this key component of the disease mechanism will enable us to develop new therapies and improve diagnostics in the future,” explains Meisinger. The findings were published in the journal Cell Metabolism.

Mitochondria are made up of around 1500 different proteins. Most of them need to migrate to the cellular powerhouses before taking up their work. This import is facilitated by a so-called signaling sequence – tiny protein extensions that transport the protein into the mitochondria. Once the protein is inside, the signaling sequence is normally removed. Dirk Mossmann and Dr. Nora Vögtle from Meisinger’s research team have now discovered that the amyloid-beta peptide prevents mitochondria from removing these signaling sequences. As a consequence, incomplete proteins accumulate in the mitochondria. Since the signaling sequences remain attached, the proteins are unstable and can no longer adequately carry out their function in energy metabolism. The researchers demonstrated that modified yeast cells producing the amyloid-beta protein generate less energy and accumulate more harmful substances.

In the brain, the mechanism probably leads to the death of nerve cells: The brain shrinks and the patient suffers from dementia. The researchers are currently developing an Alzheimer’s blood test to detect the accumulation of mitochondrial precursor proteins. They suspect that the mitochondrial alterations observed in nerve cells will also be detected in the blood cells of Alzheimer’s patients.

(Source: pr.uni-freiburg.de)

Brain networks break down similarly in rare, inherited forms of Alzheimer’s disease and much more common uninherited versions of the disorder, a new study has revealed.

Scientists at Washington University School of Medicine in St. Louis have shown that in both types of Alzheimer’s, a basic component of brain function starts to decline about five years before symptoms, such as memory loss, become obvious.

The breakdown occurs in resting state functional connectivity, which involves groups of brain regions with activity levels that rise and fall in coordination with each other. Scientists believe this synchronization helps the regions form networks that work together or stay out of each other’s way during mental tasks.

“The brain networks affected by inherited Alzheimer’s disease in a 30-year-old are very similar to the networks affected by uninherited Alzheimer’s disease in a 60-, 70- or 80-year-old,” said senior author Beau Ances, MD, PhD. “This affirms that what we learn by studying inherited Alzheimer’s, which appears at younger ages, will help us better understand and treat more common forms of the disease.”

The research appears online in JAMA Neurology.

According to Ances, the results show that functional connectivity may help scientists monitor the effects of treatment as patients progress through the transition between early disease and the first appearance of obvious symptoms.

“Right now, this period when functional connectivity begins breaking down is a time when family and loved ones may start noticing little changes in personality or mental function in someone with the disease, but not significant enough changes to cause real alarm,” Ances said. “The hope is that one day treatment already will be well underway before these sorts of changes begin — we want to slow or stop the damage caused by Alzheimer’s years earlier.”

Inherited Alzheimer’s disease can strike very early in life, causing symptoms in patients as young as their 30s or 40s. Identifying the mutations that cause these forms of the disease has helped scientists find proteins that become problematic in more common forms of Alzheimer’s, which typically appear decades later.

Researchers have long assumed that additional connections exist between inherited and uninherited Alzheimer’s disease, but until recently they have not had sufficient data to directly test many of those connections. Challenges have included the small number of people with inherited Alzheimer’s, and the slow development of both forms of the disease.

Scientists at the Charles F. and Joanne Knight Alzheimer’s Disease Research Center at Washington University began to tackle the first challenge five years ago by organizing the Dominantly Inherited Alzheimer’s Network (DIAN), an international network for identifying and studying families with inherited forms of the disease. The network now includes nearly 400 families.

To address the second challenge, Washington University researchers at the center have been gathering extensive health data on seniors through long-term projects such as the Healthy Aging and Senile Dementia Study, which is entering its 31st year.

These pools of data allowed Ances, an associate professor of neurology, to compare the effects of inherited and uninherited Alzheimer’s on functional connectivity. Scientists assess functional connectivity by scanning the brains of research participants while they daydream.

“The question was, where does the decline of functional connectivity fit in the whole picture of the development of Alzheimer’s disease?” Ances said. “And it clearly does have a place in the middle stages of the disease.”

That’s not the best place to look for an initial diagnosis, according to Ances. Ideally, scientists want to start treating Alzheimer’s disease as soon as possible. 

“What this does tell us, though, is that functional connectivity may help us track the progression of Alzheimer’s in patients who are first diagnosed when they’re beginning to show early signs of dementia,” he said.

(Source: news.wustl.edu)

Extremely low levels of the compound in marijuana known as delta-9-tetrahydrocannabinol, or THC, may slow or halt the progression of Alzheimer’s disease, a recent study from neuroscientists at the University of South Florida shows.

Findings from the experiments, using a cellular model of Alzheimer’s disease, were reported online in the Journal of Alzheimer’s Disease.

Researchers from the USF Health Byrd Alzheimer’s Institute showed that extremely low doses of THC reduce the production of amyloid beta, found in a soluble form in most aging brains, and prevent abnormal accumulation of this protein — a process considered one of the pathological hallmarks evident early in the memory-robbing disease. These low concentrations of THC also selectively enhanced mitochondrial function, which is needed to help supply energy, transmit signals, and maintain a healthy brain.

“THC is known to be a potent antioxidant with neuroprotective properties, but this is the first report that the compound directly affects Alzheimer’s pathology by decreasing amyloid beta levels, inhibiting its aggregation, and enhancing mitochondrial function,” said study lead author Chuanhai Cao, PhD and a neuroscientist at the Byrd Alzheimer’s Institute and the USF College of Pharmacy.

“Decreased levels of amyloid beta means less aggregation, which may protect against the progression of Alzheimer’s disease. Since THC is a natural and relatively safe amyloid inhibitor, THC or its analogs may help us develop an effective treatment in the future.”

The researchers point out that at the low doses studied, the therapeutic benefits of THC appear to prevail over the associated risks of THC toxicity and memory impairment.

Neel Nabar, a study co-author and MD/PhD candidate, recognized the rapidly changing political climate surrounding the debate over medical marijuana.

“While we are still far from a consensus, this study indicates that THC and THC-related compounds may be of therapeutic value in Alzheimer’s disease,” Nabar said. “Are we advocating that people use illicit drugs to prevent the disease? No. It’s important to keep in mind that just because a drug may be effective doesn’t mean it can be safely used by anyone. However, these findings may lead to the development of related compounds that are safe, legal, and useful in the treatment of Alzheimer’s disease.”

The body’s own system of cannabinoid receptors interacts with naturally-occurring cannabinoid molecules, and these molecules function similarly to the THC isolated from the cannabis (marijuana) plant.

Dr. Cao’s laboratory at the Byrd Alzheimer’s Institute is currently investigating the effects of a drug cocktail that includes THC, caffeine as well as other natural compounds in a cellular model of Alzheimer’s disease, and will advance to a genetically-engineered mouse model of Alzheimer’s shortly.

“The dose and target population are critically important for any drug, so careful monitoring and control of drug levels in the blood and system are very important for therapeutic use, especially for a compound such as THC,” Dr. Cao said.

University of Utah scientists have developed a genetically engineered line of mice that is expected to open the door to new research on epilepsy, Alzheimer’s and other diseases.

The mice carry a protein marker, which changes in degree of fluorescence in response to different calcium levels. This will allow many cell types, including cells called astrocytes and microglia, to be studied in a new way.

"This is opening up the possibility to decipher how the brain works," said Petr Tvrdik, Ph.D., a research fellow in human genetics and a senior author on the study.

The research was published Aug. 14, 2014, in Neuron, a world-leading neuroscience journal. The work is the result of a three-year study involving multiple labs connected with The Brain Institute at the University of Utah. The lead author is J. Michael Gee, who is pursuing both a medical degree and a graduate degree in bioengineering at the university.

"We’re really in the era of team science," said John White, Ph.D., professor of bioengineering, executive director of the Brain Institute and the study’s corresponding author.

With the new mouse line, scientists can use a laser-based fluorescence microscope to study the calcium indicator in the glial cells of the living mouse, either when the mouse is anesthetized or awake. Calcium is studied because it is an important signaling molecule in the body and it can reveal how well the brain is functioning.

Using this method, the scientists are essentially creating a window into the working brain to study the interactions between neurons, astrocytes and microglia.

"We believe this will give us new insights for treatments of epilepsy and for new views of how the immune system of the brain works," White said.

About one-third of the 3 million Americans estimated to have epilepsy lack adequate treatment to manage the disease.

Describing a long-standing collaboration with fellow university researcher and professor of pharmacology and toxicology Karen Wilcox, Ph.D., White said, “We believe the glial cells are malfunctioning in epilepsy. What we’re trying to do is find out in what ways astrocytes participate in the disease.”

This research is expected to lead to new classes of drugs.

The ability to track calcium changes in microglial cells will also open up the possibility of studying inflammatory diseases of the brain. Every neurological disease, including Multiple Sclerosis and Alzheimer’s, appears to include components of inflammation, the scientists said.

"Live imaging and monitoring microglial activity and responses to inflammation was not possible before," said Tvrdik, particularly in living animals. In the past, researchers studied post-mortem tissue or relied on invasive approaches using synthetic dyes.

(Source: eurekalert.org)

Epigenetic changes affect the expression or activity of genes without changing the underlying DNA sequence and are believed to be one mechanism by which the environment can interact with the genome. Importantly, epigenetic changes are potentially reversible and may therefore provide targets for the development of new therapies.

Globally, more than 26 million people are currently affected by Alzheimer’s Disease. As this number grows in line with an increasingly aging population, the need to identify new disease mechanisms is more important than ever. Post-mortem examinations have revealed much about how Alzheimer’s damages the brain, with some regions, such as the entorhinal cortex, being particularly susceptible, while others, such as the cerebellum, remain virtually unscathed. However, little is yet known about how and why the disease develops in specific brain regions.

The current study found that chemical modifications to DNA within the ANK1 gene are strongly associated with measures of neuropathology in the brain. The study, published in Nature Neuroscience, found that people with more Alzheimer’s disease-related neuropathology in their brains had higher levels of DNA modifications within the ANK1 gene. The finding was particularly strong in the entorhinal cortex, and also detected in other cortical regions affected by the disease. In contrast, no significant changes were observed in less affected brain regions or blood.

Professor Jonathan Mill, of the University of Exeter Medical School and King’s College London, who headed the study, said: “This is the strongest evidence yet to suggest that epigenetic changes in the brain occur in Alzheimer’s disease, and offers potential hope for understanding the mechanisms involved in the onset of dementia. We don’t yet know why these changes occur – it’s possible that they are involved in disease onset, but they may also reflect changes induced by the disease itself.”

Dr Katie Lunnon, first author on the study, from the University of Exeter Medical School, added: “It’s intriguing that we find changes specifically in the regions of the brain involved in Alzheimer’s disease. Future studies will focus on isolating different cell-types from the brain to see whether these changes are neuron-specific.”

In addition to the University of Exeter Medical School and King’s College London, the team included contributors from The Icahn School of Medicine at Mount Sinai, the JJ Peters VA Medical Center, The Johns Hopkins University School of Medicine, Harvard Medical School, the University of Oxford, and Rush University Medical Center, Chicago. They used cutting-edge technology to examine brain tissue from different areas of the brain across three cohorts - the MRC London Brain Bank for Neurodegenerative Disease, the Oxford Thomas Willis Brain Bank, and the Mount Sinai Alzheimer’s Disease and Schizophrenia Brain Bank. They analysed three cortical regions, cerebellum, and blood obtained from several hundred individuals representing the spectrum of disease; from those with no evidence of dementia and neurodegeneration, through to patients with very advanced disease.

The research was primarily funded by the National Institutes of Health (NIH), U.S. Department of Health and Human Services, as part of its Epigenomics Roadmap Initiative (grant number R01-AG036039 awarded to Jonathan Mill). To learn more about the NIH initiative that seeks to accelerate research into the relatively new and fast-developing area of epigenetics, go to: https://commonfund.nih.gov/epigenomics/index.

Dr Simon Ridley, Head of Research at Alzheimer’s Research UK, the UK’s leading dementia research charity, who also provided funding for the study said:“We know that changes to the DNA code of certain genes are associated with an increased risk of developing Alzheimer’s disease. Investigating how epigenetic changes influence genes in Alzheimer’s is still a relatively new area of study. The importance of understanding this area of research is highlighted by the fact that epigenetic changes have been associated with development of other diseases, including cancer.

“This innovative research has discovered a potential new mechanism involved in Alzheimer’s by linking the ANK1 gene to the disease. We will be interested to see further research into the role of ANK1 in Alzheimer’s and whether other epigenetic changes may be involved in the disease.

“Alzheimer’s affects millions of people worldwide and we need pioneering research to understand exactly why the disease occurs. Alzheimer’s Research UK is helping to fund research which will take us a step closer to understanding and defeating this devastating disease.”

(Source: exeter.ac.uk)

A new study led by researchers at Brigham and Women’s Hospital (BWH) and Rush University Medical Center, reveals how early changes in brain DNA methylation are involved in Alzheimer’s disease. DNA methylation is a biochemical alteration of the building blocks of DNA and is one of the markers that indicate whether the DNA is open and biologically active in a given region of the human genome.

The study is published online August 17, 2014 in Nature Neuroscience.

According to the researchers, this is the first large-scale study employing epigenome-wide association (EWAS) studies—which look at chromosomal make-up and changes—in relation to the brain and Alzheimer’s disease.

"Our study approach may help us to better understand the biological impact of environmental risk factors and life experiences on Alzheimer’s disease," said Philip L. De Jager, MD, PhD, Program in Translational Neuropsychiatric Genomics, BWH Departments of Neurology and Psychiatry, lead study author. "There are certain advantages to studying the epigenome, or the chemical changes that occur in DNA. The epigenome is malleable and may harbor traces of life events that influence disease susceptibility, such as smoking, depression and menopause, which may influence susceptibility to Alzheimer’s and other diseases."

The researchers analyzed samples from 708 donated brains from subjects in the Religious Orders Study and Rush Memory and Aging Project, conducted by study co-author, David A. Bennett, MD, Rush Alzheimer’s Disease Center in Chicago. They found that methylation levels correlated with Alzheimer’s disease in 71 of 415,848 CpG markers analyzed (these are a pair of DNA building blocks consisting of a cytosine and a guanine nucleotide that are located next to each other). These 71 markers were found in the ANK1 and RHBDF2 genes, as well as ABCA7 and BIN1 which harbor known Alzheimer’s disease susceptibility variants.

Further, investigation of these CpG associations revealed nearby genes whose RNA expression was altered in brain samples with Alzheimer’s disease: ANK1, CDH23, DIP2A, RHBDF2, RPL13, RNF34, SERPINF1 and SERPINF2. This suggests that the CpG associations identify genes whose function is altered in Alzheimer’s disease.

Further, “because these findings are also found in the subset of subjects that are not cognitively impaired at the time of death, it appears that these DNA methylation changes may play a role in the onset of Alzheimer’s disease,” said De Jager. “Moreover, our work has helped identify regions of the human genome that are altered over the life-course in a way that is associated with Alzheimer’s disease. This may provide clues to treating the disease by using drugs that influence epigenomic function.”

(Source: eurekalert.org)

In a long-term, large-scale population-based study of individuals aged 55 years or older in the general population researchers found that those diagnosed with mild cognitive impairment (MCI) had a four-fold increased risk of developing dementia or Alzheimer’s disease (AD) compared to cognitively healthy individuals. Several risk factors including older age, positive APOE-ɛ4 status, low total cholesterol levels, and stroke, as well as specific MRI findings were associated with an increased risk of developing MCI. The results are published in a supplement to the Journal of Alzheimer’s Disease.

“Mild cognitive impairment has been identified as the transitional stage between normal aging and dementia,” comments M. Arfan Ikram, MD, PhD, a neuroepidemiologist at Erasmus MC University Medical Center (Rotterdam). “Identifying persons at a higher risk of dementia could postpone or even prevent dementia by timely targeting modifiable risk factors.”

Unlike a clinical trial, the Rotterdam study is an observational cohort study focusing on the general population, instead of persons referred to a memory clinic. The Rotterdam study began in 1990, when almost 8,000 inhabitants of Rotterdam aged 55 years or older agreed to participate in the study. Ten years later, another 3,000 individuals were added. Participants undergo home interviews and examinations every four years.

“This important prospective study adds to the accumulating evidence that strokes, presumably related to so called ‘vascular’ risk factors, also contribute to the appearance of dementia in Alzheimer’s disease. This leads to the conclusion that starting at midlife people should minimize those risk factors. The recent results of the Finish FINGER study corroborate this idea. It should be remembered that delaying the onset of dementia by five years will reduce the prevalence of the disease by half. And of course, since there is no cure for AD, prevention is the best approach at present,” explains Professor Emeritus Amos D Korczyn, Tel Aviv University, Ramat Aviv, Israel, and Guest Editor of the Supplement.

To be diagnosed with MCI in the study, individuals were required to meet three criteria: a self-reported awareness of having problems with memory or everyday functioning; deficits detected on a battery of cognitive tests; and no evidence of dementia. They were categorized into those with memory problems (amnestic MCI) and those with normal memory (non-amnestic MCI).

Of 4,198 persons found to be eligible for the study, almost 10% were diagnosed with MCI. Of these, 163 had amnestic MCI and 254 had non-amnestic MCI.

The risk of dementia was especially high for people with amnestic MCI. Similar results were observed regarding the risk for Alzheimer’s disease. Those with MCI also faced a somewhat higher risk of death. 

The research team investigated possible determinants of MCI, considering factors such as age, APOE-ɛ status, waist circumference, hypertension, diabetes mellitus, total and HDL-cholesterol levels, smoking, and stroke. Only older age, being an APOE-ɛ4 carrier, low total cholesterol levels, and stroke at baseline were associated with developing MCI. Having the APOE-ɛ4 genotype and smoking were related only to amnestic MCI.

When the investigators analysed MRI studies of the brain, they found that participants with MCI, particularly those with non-amnestic MCI, had larger white matter lesion volumes and worse microstructural integrity of normal-appearing white matter compared to controls. They were also three-times more likely than controls to have lacunes (3 to 15 mm cerebrospinal fluid (CSF)-filled cavities in the basal ganglia or white matter, frequently observed when imaging older people). MCI was not associated with total brain volume, hippocampal volume, or cerebral microbleeds.

“Our results suggest that accumulating vascular damage plays a role in both amnestic and non-amnestic MCI,” says Dr. Ikram. “We propose that timely targeting of modifiable vascular risk factors might contribute to the prevention of MCI and dementia.”

Reference:

Determinants, MRI Correlates, and Prognosis of Mild Cognitive Impairment: The Rotterdam Study. Renée F.A.G. de Bruijn, Saloua Akoudad, Lotte G.M. Cremers, Albert Hofman, Wiro J. Niessen, Aad van der Lugt, Peter J. Koudstaal, Meike W. Vernooij, M. Arfan Ikram. Journal of Alzheimer’s Disease, Volume 42/Supplement 3 (August 2014): 2013 International Congress on Vascular Dementia (Guest Editor: Amos D. Korczyn)

(Source: iospress.nl)

The team studied elderly Americans who took part in the Cardiovascular Health Study. They discovered that adults in the study who were moderately deficient in vitamin D had a 53 per cent increased risk of developing dementia of any kind, and the risk increased to 125 per cent in those who were severely deficient.

Similar results were recorded for Alzheimer’s disease, with the moderately deficient group 69 per cent more likely to develop this type of dementia, jumping to a 122 per cent increased risk for those severely deficient.

The study was part-funded by the Alzheimer’s Association, and is published in August 6 2014 online issue of Neurology, the medical journal of the American Academy of Neurology. It looked at 1,658 adults aged 65 and over, who were able to walk unaided and were free from dementia, cardiovascular disease and stroke at the start of the study. The participants were then followed for six years to investigate who went on to develop Alzheimer’s disease and other forms of dementia.

Dr Llewellyn said: “We expected to find an association between low Vitamin D levels and the risk of dementia and Alzheimer’s disease, but the results were surprising – we actually found that the association was twice as strong as we anticipated.

“Clinical trials are now needed to establish whether eating foods such as oily fish or taking vitamin D supplements can delay or even prevent the onset of Alzheimer’s disease and dementia. We need to be cautious at this early stage and our latest results do not demonstrate that low vitamin D levels cause dementia. That said, our findings are very encouraging, and even if a small number of people could benefit, this would have enormous public health implications given the devastating and costly nature of dementia.”

Research collaborators included experts from Angers University Hospital, Florida International University, Columbia University, the University of Washington, the University of Pittsburgh and the University of Michigan. The study was supported by the Alzheimer’s Association, the Mary Kinross Charitable Trust, the James Tudor Foundation, the Halpin Trust, the Age Related Diseases and Health Trust, the Norman Family Charitable Trust, and the National Institute for Health Research Collaboration for Leadership in Applied Research and Care South West Peninsula (NIHR PenCLAHRC).

Dementia is one of the greatest challenges of our time, with 44 million cases worldwide – a number expected to triple by 2050 as a result of rapid population ageing. A billion people worldwide are thought to have low vitamin D levels and many older adults may experience poorer health as a result.

The research is the first large study to investigate the relationship between vitamin D and dementia risk where the diagnosis was made by an expert multidisciplinary team, using a wide range of information including neuroimaging. Previous research established that people with low vitamin D levels are more likely to go on to experience cognitive problems, but this study confirms that this translates into a substantial increase in the risk of Alzheimer’s disease and dementia.

Vitamin D comes from three main sources – exposure of skin to sunlight, foods such as oily fish, and supplements. Older people’s skin can be less efficient at converting sunlight into Vitamin D, making them more likely to be deficient and reliant on other sources. In many countries the amount of UVB radiation in winter is too low to allow vitamin D production.

The study also found evidence that there is a threshold level of Vitamin D circulating in the bloodstream below which the risk of developing dementia and Alzheimer’s disease increases.  The team had previously hypothesized that this might lie in the region of 25-50 nmol/L, and their new findings confirm that vitamin D levels above 50 nmol/L are most strongly associated with good brain health.

Commenting on the study, Dr Doug Brown, Director of Research and Development at Alzheimer’s Society said: “Shedding light on risk factors for dementia is one of the most important tasks facing today’s health researchers. While earlier studies have suggested that a lack of the sunshine vitamin is linked to an increased risk of Alzheimer’s disease, this study found that people with very low vitamin D levels were more than twice as likely to develop any kind of dementia.

“During this hottest of summers, hitting the beach for just 15 minutes of sunshine is enough to boost your vitamin D levels. However, we’re not quite ready to say that sunlight or vitamin D supplements will reduce your risk of dementia. Large scale clinical trials are needed to determine whether increasing vitamin D levels in those with deficiencies can help prevent the dementia from developing.”

(Source: exeter.ac.uk)