Abstract
A Genetic Answer to the Alzheimer’s Riddle?
Lexington, Kentucky—What if we could pinpoint a hereditary cause for Alzheimer’s and intervene to reduce the risk of the disease? We may be closer to that goal, thanks to a team at the University of Kentucky. Researchers affiliated with the UK Sanders-Brown Center on Aging have completed new work in Alzheimer’s genetics; the research is detailed in an article published in the Journal of Neuroscience.
Emerging evidence indicates that, much like in the case of high cholesterol, some Alzheimer’s disease risk is inherited while the remainder is environmental. Family and twin studies suggest that about 70% of total Alzheimer’s risk is hereditary.
Recently published studies identified several variations in DNA sequence that each modify Alzheimer’s risk. In their work, the UK researchers investigated how one of these sequence variations may act. They found that a “protective” genetic variation near a gene called CD33 correlated strongly with how the CD33 messenger RNA was assembled in the human brain. The authors found that a form of CD33 that lacked a critical functional domain correlates with reduced risk of Alzheimer’s disease. CD33 is thought to inhibit clearance of amyloid-β, a hallmark of Alzheimer’s disease.
The results obtained by the UK scientists indicate that inhibiting CD33 may reduce Alzheimer’s risk. A drug tested for acute myeloid leukemia targets CD33, suggesting the potential for treatments based on CD33 to mitigate the risk of Alzheimer’s disease. Additional studies must be conducted before this treatment approach could be tested in humans. (Source: EurekAlert! A service of AAAS and the University of Kentucky.)
New Biomarker Could Reveal Alzheimer’s Disease Years Before Onset
Barcelona, Spain—A study reported the identification of what may be the earliest known biomarker associated with the risk of developing Alzheimer’s disease (AD). The results suggest that this novel potential biomarker is present in cerebral spinal fluid (CSF) at least a decade before signs of dementia manifest.
“If our initial findings can be replicated by other laboratories, the results will change the way we currently think about the causes of Alzheimer's disease,” said Dr Ramon Trullas, research professor at the Spanish National Research Council (Consejo Superior de Investigaciones Cientificas, CSIC), Institute of Biomedical Research of Barcelona and lead author of the study that was published in Annals of Neurology. “This discovery may enable us to search for more effective treatments that can be administered during the preclinical stage.”
Difficult Diagnosis
Alzheimer’s disease affects more than 5 million Americans and is the sixth leading cause of death in the United States. At present, the only way to accurately diagnose the disease is by postmortem neuropathological analysis. The relationship of currently known biomarkers with the cause of the disease is unclear, making it nearly impossible to diagnose preclinical stages of the disease with any real certainty.
The CSIC researchers demonstrated that a decrease in the content of mitochondrial DNA (mtDNA) in CSF may be a preclinical indicator for Alzheimer’s disease; furthermore, there may be a directly causative relationship. The hypothesis is that decreased mtDNA levels in CSF reflect the diminished ability of mitochondria to power the brain’s neurons, triggering their death. The decrease in the concentration of mtDNA precedes the appearance of well-known biochemical Alzheimer’s biomarkers (the Aβ1-42, t-tau, and p-tau proteins), suggesting that the pathophysiological process of Alzheimer’s disease starts earlier than previously thought and that mtDNA depletion may be one of the earliest predictors of the disease.
In addition to enabling an investigation of the potential causal relationship of mtDNA and Alzheimer’s progression, the use of mtDNA as an index of preclinical Alzheimer’s disease provides an important advantage over previous biochemical markers: the detection of this novel nucleic acid biomarker is unhampered by the technical difficulties associated with protein detection. Mitochondrial DNA can be readily quantified by real-time quantitative PCR (qPCR) or droplet digital PCR (ddPCR).
Quantitation of mtDNA
Prior to this study, researchers had not reported that circulating cell-free mtDNA could be detected in human CSF. But with this study, Dr Trullas’ team was able to both detect and reproducibly quantitate mtDNA using qPCR, carefully optimized by adhering to the MIQE guidelines.
To validate their qPCR findings, Dr Trullas’ team used Bio-Rad Laboratories’ QX100 Droplet Digital PCR system. Unlike qPCR assays, the QX100 system provides an absolute quantification of target DNA molecules without the need for a standard curve. In addition, an important factor for their CSF analysis was that the Droplet Digital PCR system did not require sample purification to remove PCR inhibitors as is necessary for qPCR assays.
“Droplet Digital PCR allowed us to validate our initial qPCR measurements because it provides absolute quantitation at the single-molecule level without relying on a standard curve,” said Dr Trullas. “As the technology becomes more widely adopted, we anticipate that Droplet Digital PCR will be the future of detecting mtDNA in cerebral spinal fluid.”
Dr Trullas hopes that other laboratories and hospitals will successfully replicate his group’s research results, confirming that reduced mtDNA levels should be investigated as a possible cause of Alzheimer’s disease. By finding a way to block this degeneration, clinicians may be able to diagnose and treat Alzheimer’s disease before symptoms appear. (Source: EurekAlert! A service of AAAS and Chempetitive Group.)
Neuroscientists Identify Protein Linked to Alzheimer’s-Like Afflictions
A team of neuroscientists has identified a modification to a protein in laboratory mice linked to conditions associated with Alzheimer’s disease. Their findings, which appear in the journal Nature Neuroscience, also point to a potential therapeutic intervention for alleviating memory-related disorders.
The research centered on eukaryotic initiation factor 2α (eIF2α) and 2 enzymes that modify it with a phosphate group; this type of modification is termed phosphorylation. The phosphorylation of eIF2α, which decreases protein synthesis, was previously found at elevated levels in both humans diagnosed with Alzheimer’s and in Alzheimer’s disease (AD) model mice.
“These results implicate the improper regulation of this protein in Alzheimer's-like afflictions and offer new guidance in developing remedies to address the disease,” said Eric Klann, a professor in New York University’s Center for Neural Science and the study’s senior author.
The study’s coauthors also included Douglas Cavener, a professor of biology at Pennsylvania State University; Clarisse Bourbon, Evelina Gatti, and Philippe Pierre of Université de la Méditerranée in Marseille, France; and NYU researchers Tao Ma, Mimi A. Trinh, and Alyse J. Wexler.
It has been known for decades that triggering new protein synthesis is vital to the formation of long-term memories as well as for long-lasting synaptic—the ability of the neurons to change the collective strength of their connections with other neurons. Learning and memory are widely believed to result from changes in synaptic strength.
In recent years, researchers have found that both humans with Alzheimer’s disease and AD model mice have relatively high levels of eIF2α phosphorylation. But the relationship between this characteristic and AD-related afflictions was unknown.
Klann and his colleagues hypothesized that abnormally high levels of eIF2α phosphorylation could become detrimental because, ultimately, protein synthesis would diminish, thereby undermining the ability to form long-term memories.
To explore this question, the researchers examined the neurological impact of 2 enzymes that phosphorylate eIF2α, kinases termed PERK and GCN2, in different populations of AD model mice—all of which expressed genetic mutations akin to those carried by humans with AD. These were AD model mice; AD model mice that lacked PERK; and AD model mice that lacked GCN2.
Specifically, they looked at eIF2α phosphorylation and the regulation of protein synthesis in the mice’s hippocampus region—the part of the brain responsible for the retrieval of old memories and the encoding of new ones. They then compared these levels with those of postmortem human patients with AD.
Here, they found both increased levels of phosphorylated eIF2α in the hippocampus of both patients with AD and the AD model mice. Moreover, in conjunction with these results, they found decreased protein synthesis, known to be required for long-term potentiation—a form of long-lasting synaptic plasticity—and for long-term memory.
To test potential remedies, the researchers examined phosphorylation of eIF2α in mice lacking PERK, hypothesizing that removal of this kinase would return protein synthesis to normal levels. As predicted, mice lacking PERK had levels of phosphorylated eIF2α and protein synthesis similar to those of normal mice.
They then conducted spatial memory tests in which the mice needed to navigate a series of mazes. Here, the AD model mice lacking PERK were able to successfully maneuver through the mazes at rates achieved by normal mice. By contrast, the other AD model mice lagged significantly in performing these tasks.
The researchers replicated these procedures on AD model mice lacking GCN2. The results here were consistent with those of the AD model mice lacking PERK, demonstrating that removal of both kinases diminished memory deficits associated with Alzheimer’s disease. (Source: EurekAlert! A service of AAAS and New York University.)
Receptor May Aid Spread of Alzheimer’s and Parkinson’s in Brain
Scientists at Washington University School of Medicine in St Louis have found a way that corrupted, disease-causing proteins spread in the brain, potentially contributing to Alzheimer’s disease, Parkinson’s disease, and other brain-damaging disorders.
The research identifies a specific type of receptor and suggests that blocking it may aid in the treatment of these illnesses. The receptors are called heparan sulfate proteoglycans (HSPGs).
“Many of the enzymes that create HSPGs or otherwise help them function are good targets for drug treatments,” said senior author Marc I. Diamond, MD, the David Clayson Professor of Neurology. “We ultimately should be able to hit these enzymes with drugs and potentially disrupt several neurodegenerative conditions.” The study is available online in the Proceedings of the National Academy of Sciences.
Over the last decade, Diamond has gathered evidence that Alzheimer’s disease and other neurodegenerative diseases spread through the brain in a fashion similar to conditions such as mad cow disease, which are caused by misfolded proteins known as prions.
Proteins are long chains of amino acids that perform many basic biological functions. Proteins’ abilities are partially determined by the way it folds into a 3-dimensional shape. Prions are proteins that have become folded in a fashion that makes them harmful.
Prions spread across the brain by causing other copies of the same protein to misfold. Among the most infamous prion diseases are mad cow disease, which rapidly destroys the brain in cows, and a similar inherited condition in humans called Creutzfeldt-Jakob disease.
Diamond and his colleagues have shown that a part of nerve cells’ inner structure known as tau protein can misfold into a configuration called an amyloid. These corrupted versions of tau stick to each other in clumps within the cells. Like prions, the clumps spread from one cell to another, seeding further spread by causing copies of tau protein in the new cell to become amyloids.
In the new study, first author Brandon Holmes, an MD/PhD student, showed that HSPGs are essential for binding, internalizing, and spreading clumps of tau. When he genetically disabled or chemically modified the HSPGs in cell cultures and in a mouse model, clumps of tau could not enter cells, thus inhibiting the spread of misfolded tau from cell to cell.
Holmes also found that HSPGs are essential for the cell-to-cell spread of corrupted forms of α-synuclein, a protein linked to Parkinson’s disease.
“This suggests that it may one day be possible to unify our understanding and treatment of two or more broad classes of neurodegenerative disease,” Diamond said.
“We’re now sorting through about 15 genes to determine which are the most essential for HSPGs' interaction with tau,” Holmes said. “That will tell us which proteins to target with new drug treatments.” (Source: EurekAlert! A service of AAAS and Washington University School of Medicine.)
UCLA Study Suggests Iron Is at Core of Alzheimer’s Disease
Findings Challenge Conventional Thinking About Possible Causes of Disorder
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 1 of the 2 proteins, one called tau and the other β-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 2 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 appeared in the August edition of the Journal of Alzheimer's Disease.
Although most Alzheimer’s researchers focus on the buildup of τ or β-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 the 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 the disease.
The researchers used a magnetic resonance imaging (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 participants.
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: EurekAlert! A service of AAAS and the University of California - Los Angeles.)
Brain Network Decay Detected in Early Alzheimer’s
Researchers at Washington University School of Medicine in St Louis have shown that 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.
Although 2 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 2 markers of early Alzheimer’s: changes in amyloid-β, 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-β 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 2 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 Washington University School of Medicine.)
What Is the New Target Inhibiting the Progression of Alzheimer’s Disease?
To stop the progression of Alzheimer’s disease in the early stage, it is necessary to identify new therapeutic targets. Professor Yunpeng Cao and team from the First Affiliated Hospital of China Medical University examined striatal-enriched phosphatase 61 expression in the brain tissues of Alzheimer’s disease rats using in vivo and in vitro models and analyzed the molecular mechanism by which striatal-enriched phosphatase 61 regulates N-methyl-D- aspartate receptor 2B transport. The researchers found that valeric acid (AP5), an N-methyl-D-aspartate receptor antagonist, significantly inhibited amyloid-β1–induced increased activity of striatal-enriched phosphatase 61. In addition, the phosphorylation of N-methyl-D-aspartate receptor 2B at Tyr1472 was impaired in amyloid-β1–treated cortical neurons, but knockdown of striatal-enriched phosphatase 61 enhanced the phosphorylation of N-methyl-D-aspartate receptor 2B. Collectively, these findings, published in the Neural Regeneration Research (Vol 8, No. 21, 2013), indicate that striatal-enriched phosphatase 61 can disturb N-methyl-D-aspartate receptor transport and inhibit the progression of learning and study disturbances induced by Alzheimer’s disease. Thus, striatal-enriched phosphatase 61 may represent a new target for inhibiting the progression of Alzheimer’s disease. (Source: EurekAlert! A service of AAAS and Neural Regeneration Research.)
Over 90% of Dementia Cases in China Are Undetected
An International Team of Researchers Has Found That Over 90% of Dementia Cases in China Go Undetected, With a High Level of Undiagnosed Dementia in Rural Areas
An international team of researchers has found that over 90% of dementia cases in China go undetected, with a high level of undiagnosed dementia in rural areas. The team of public health experts led by Dr Ruoling Chen at King’s College London argues that more mental health education targeting high-risk populations is now needed to improve diagnosis rates and increase support for sufferers and their families.
Dementia affects 10 million in China and up to 50 million worldwide, of which around 35 million sufferers are undiagnosed. Dementia causes deterioration in memory, thinking, behavior, and the ability to perform everyday activities. Although the condition mainly affects older people, it is not a normal part of aging. Dementia is one of the major causes of disability and dependency among older people worldwide. Early diagnosis is crucial to alleviating the significant physical, psychological, social, and economical impact the condition has on caregivers, families, and society.
The new study, led by Dr Chen, a research leader in global health in the School of Medicine at King’s, found that in China 93% of dementia cases in people aged 60 and older went undetected. The level of undetected dementia is much higher than has been seen in studies undertaken in high-income countries where about 60% of older adults with dementia are not diagnosed.
Published today in the British Journal of Psychiatry and funded by Alzheimer’s Research United Kingdom and the BUPA Foundation, the large population-based study is a collaboration between scientists at King's College London and other universities in the United Kingdom and Anhui Medical University and 5 other medical universities in China. The study is the first to examine factors influencing the poor diagnosis of dementia in older people in low-income countries where there are more people with dementia than in high-income countries.
Dr Chen and his team interviewed a random sample of 7072 older adults in 6 provinces across China, with 1 rural and 1 urban community in each province. They identified 359 older adults with dementia and 328 with depression. There were only 26 participants who had doctor-diagnosed dementia and 26 who had doctor-diagnosed depression. Overall, 93% of dementia cases and 93% of depression were not detected.
The team found that, in China, undetected dementia among older adults is strongly associated with low-socioeconomic status such as a low educational and occupational class and living in a rural area.
In rural China, the average annual income is 2 to 5 times lower than in urban areas and about 90% of older people are illiterate. Medical coverage and health services are often insufficient in rural areas, with primary care clinics mainly staffed by health workers with limited training. In high-income countries, most studies have not shown a strong association between low-socioeconomic status and undetected dementia, which could be due to better access to health care.
The research team also identified that Chinese cultural factors may play a role in poor detection rates of dementia. Unlike in high-income countries, most of older Chinese people live with their families. A surprising, important finding was that undetected dementia is related to strong social support. Such “help available when needed” may mask the disease and hinder detection. In addition, Chinese may interpret dementia symptoms in older people as being an acceptable part of the aging process rather than as an illness.
Dr Ruoling Chen said, “Dementia is increasingly a major global health challenge given that the world's population is ageing. China has the most dementia sufferers of any country in the world, but at the same time it is a poorly recognised condition.
Mental health services need to be prioritised as economic development extends throughout China. Mental health campaigns will ensure that health workers and the general population are able to recognise the condition, so that sufferers receive the support they need.
Our hope is that by looking at the rate of undetected dementia in China we can offer globally applicable insights into the common risk factors, aid earlier diagnosis, ultimately improve prognosis for sufferers and maintain caregivers’ health and wellbeing.”
Professor Martin Prince, global mental health expert from the Institute of Psychiatry at King’s College London, who was not involved in the research, commented “This is an important study, highlighting the very low detection rate by Chinese health services of dementia among older people.
Large treatment gaps for mental and neurological disorders have been observed in low income countries, but this is the first study to focus on older adults, among whom dementia is a major concern.
Detection is the first step in accessing evidence-based treatment and care. Limited knowledge, skills and confidence among health care workers, and a lack of understanding of the benefits that may stem from diagnosis and intervention are all likely to contribute.”
In a related recent commentary in the Lancet, Professor Prince argued “… the Chinese Government faces a daunting task in addressing future needs for long-term care. Previously, these needs have been met by families, consistent with traditional values and enforced through the Elderly Rights and Protection Law of 1996. However, central government policy is shifting towards new social care initiatives and increased investment in social protection, as outlined in a radically amended version of the 1996 law which will take force from July, 2013.”
Dr Simon Ridley, Head of Research at Alzheimer's Research United Kingdom, said, “We know that dementia is a global problem and it is important to understand more about the risk factors and barriers to diagnosis across different countries. Investigating the social, economic and cultural factors influencing attitudes and access to dementia diagnosis can help shape strategies that could benefit multiple countries across the world. We must ensure long-term investment for dementia research if we are to improve the lives of millions living with this condition worldwide.” (Source: EurekAlert! A service of AAAS King's College London.)
Chinese Herbal Medicines Are Safe and Effective for Vascular Dementia
Chinese herbal medicine, which has been used for thousands of years in China, has long been considered an effective treatment for vascular dementia. There are already meta-analyses of the effects of herbal extracts (ginkgo biloba and huperzine A) on vascular dementia. However, there has been no systematic review of the efficacy and safety of Chinese herbal medicines for vascular dementia despite its wide use in clinical practice. A recent study published in the Neural Regeneration Research (Vol 8, No. 18, 2013) evaluated the efficacy and safety of Chinese herbal medicines for vascular dementia, using efficacy, Mini-Mental State Examination score, Hasegawa Dementia Scale score, and adverse reactions as evaluation indices by performing a meta-analysis. The results suggested that Chinese herbal medicine appears to be safer and more effective than control measures in the treatment of vascular dementia. Chinese herbal medicines for vascular dementia exert characteristics of syndrome differentiation of traditional Chinese medicine and have good potential in the clinic. (Source: EurekAlert! A service of AAAS and Neural Regeneration Research.)