Posts tagged medicine
Articles and news from the latest research reports.
Researchers Discover New Way to Track Huntington’s Disease Progression Using PET Scans
Investigators at The Feinstein Institute for Medical Research have discovered a new way to measure the progression of Huntington’s disease, using positron emission tomography (PET) to scan the brains of carriers of the gene. The findings are published in the September issue of The Journal of Clinical Investigation.
Huntington’s disease causes the progressive breakdown of nerve cells in the brain, which leads to impairments in movement, thinking and emotions. Most people with Huntington’s disease develop signs and symptoms in their 40s or 50s, but the onset of disease may be earlier or later in life. Medications are available to help manage the symptoms of Huntington’s disease, but treatments do not prevent the physical, mental and behavioral decline associated with the condition.
Huntington’s disease is an inherited disease, passed from parent to child through a mutation in the normal gene. Each child of a parent with Huntington’s disease has a 50/50 chance of inheriting the Huntington’s disease gene, and a child who inherits the gene will eventually develop the disease. Genetic testing for Huntington’s disease can be performed to determine whether a person carries the gene and is developing the disease even before symptoms appear. Having this ability provides an opportunity for scientists to study how the disease first develops and how it progresses in its early, presymptomatic stages. Even though a carrier of the Huntington’s disease gene may not have experienced symptoms, changes in the brain have already taken place, which ultimately lead to severe disability. Brain imaging is one tool that could be used to track how quickly Huntington’s disease progresses in gene carriers. Having a better way to track the disease at its earliest stages will make it easier to test drugs designed to delay or even prevent the onset of symptoms.
Researchers at the Feinstein Institute used PET scanning to map changes in brain metabolism in 12 people with the Huntington’s disease gene who had not developed clinical signs of the illness. The researchers scanned the subjects repeatedly over a seven-year period and found a characteristic set (network) of abnormalities in their brains. The network was used to measure the rate of disease progression in the study participants. The Feinstein Institute investigators then confirmed the progression rate through independent measurements in scans from a separate group of Huntington’s disease gene carriers who were studied in the Netherlands. The investigators believe that progression networks similar to the one identified in Huntington’s disease carriers will have an important role in evaluating new drugs for degenerative brain disorders.
“Huntington’s disease is an extremely debilitating disease. The findings make it possible to evaluate the effects of new drugs on disease progression before symptoms actually appear. This is a major advance in the field,” said David Eidelberg, MD, Susan and Leonard Feinstein Professor and head of the Center for Neurosciences at the Feinstein Institute.
(Source: northshorelij.com)
The white arrow highlights the primary neuronal cilium, a hair-like structure on nerve cells. The neuron on the right has no cilium because of the loss of a protein linked to intellectual disability in humans. Credit: YOSHIHO IKEUCHI
Intellectual disability linked to nerve cells that lose their ‘antennae’
An odd and little-known feature of nerve cells may be linked to several forms of inherited intellectual disability, researchers at Washington University School of Medicine in St. Louis have learned.
The scientists report that a genetic mutation that causes intellectual disability also blocks formation of the neuronal primary cilium, a hair-like structure that protrudes from the bodies of nerve cells.
"The primary cilium acts as a kind of antenna for nerve cells,” said first author Yoshiho Ikeuchi, PhD, a staff scientist. “It’s covered in receptors that monitor environmental conditions outside the cell and may influence the cell’s functions.”
Learning more about how the mutation sabotages production of the nerve cell cilium eventually will help scientists develop drugs to treat intellectual disability, according to senior author Azad Bonni, MD, PhD, the Edison Professor and chairman of the Department of Anatomy and Neurobiology.
"Intellectual disability—sometimes known as mental retardation—affects 1 to 2 percent of the general population, and researchers have identified more than 100 genes on the X chromosome that can cause these conditions,” Bonni said. “But we don’t know what most of these genes do, and that information is essential for new treatments.”
The research appears online Aug. 29 in Cell Reports.
Nearly every cell in the mammalian body has a primary cilium—a structure that acts as an environmental sensor. Some cells have many cilia that move together in waves. Problems with cilia are associated with disorders throughout the body, including illnesses of the kidneys, eyes and reproductive organs.
"Some of the X-linked intellectual disorders are syndromes that not only hamper brain development but also cause problems elsewhere in the body,” Bonni said. “That makes sense in the context of this new connection we’ve identified between intellectual disability and the primary cilium.”
Scientists only recently have recognized the potential of a primary cilium malfunction to impair nerve cell development and function. Studies have suggested that the primary cilium may be where nerve cells receive the growth signals that allow them to extend branches to each other and form circuits. Other research has shown that blocking of signal receptors on the primary cilium leads to memory problems in mice.
Bonni’s path to the primary cilium led through the nucleus, the command center that contains a cell’s DNA. Proteins found inside a cell’s nucleus often regulate the turning on or off of other genes, making them influential in orchestrating the responses and functions of cells.
Bonni and his colleagues scanned the literature on X chromosome genes linked to intellectual disability to learn which genes produce proteins found in the nucleus. When they disabled 15 such genes in individual nerve cells, they found that the loss of the gene for polyglutamine-binding protein 1 (PQBP1) produced the most dramatic effect, leaving nerve cells with shortened primary cilia or no cilia at all.
In other cell types outside the brain, PQBP1 is typically found only in the nucleus. But the new results show that in neurons the protein is present both in the nucleus and, surprisingly, at the base of the primary cilium.
The scientists learned PQBP1 binds to another protein outside the nucleus that suppresses growth of the primary cilium. By binding to the suppressor, PQBP1 gets that suppressor out of the way, allowing cilium formation to proceed normally.
Scientists may one day try to imitate this effect with drugs, potentially allowing the brain to develop more normally when PQBP1 is mutated. For now, the researchers want to learn more about the suppressor protein and also are investigating the possibility that PQBP1 may continue to influence the functions of the primary cilium after it is formed.
MR images showing a patient with recurrent glioblastoma responding to anti-angiogenic therapy by reduction on abnormal tumor vessel calibers and a change in the direction of the vessel vortex curve estimated from a combined gradient-echo (GE) and spin-echo (SE) MR signal readout. The change from a predominantly counter-clockwise vessel vortex direction at baseline (days -5 and -1) to a predominantly clockwise vessel vortex direction during anti-angiogenic therapy (days 1, 28, 56 and 112) indicates a dramatic transformation in vascular morphology during anti-angiogenic therapy and resulting in increased overall survival. Credit: Kyrre E. Emblem
New MR analysis technique reveals brain tumor response to anti-angiogenesis therapy
A new way of analyzing data acquired in MR imaging appears to be able to identify whether or not tumors are responding to anti-angiogenesis therapy, information that can help physicians determine the most appropriate treatments and discontinue ones that are ineffective. In their report receiving online publication in Nature Medicine, investigators from the Martinos Center for Biomedical Imaging at Massachusetts General Hospital (MGH), describe how their technique, called vessel architectural imaging (VAI), was able to identify changes in brain tumor blood vessels within days of the initiation of anti-angiogenesis therapy.
"Until now the only ways of obtaining similar data on the blood vessels in patients’ tumors were either taking a biopsy, which is a surgical procedure that can harm the patients and often cannot be repeated, or PET scanning, which provides limited information and exposes patients to a dose of radiation,” says Kyrre Emblem, PhD, of the Martinos Center, lead and corresponding author of the report. “VAI can acquire all of this information in a single MR exam that takes less than two minutes and can be safely repeated many times.”
Previous studies in animals and in human patients have shown that the ability of anti-angiogenesis drugs to improve survival in cancer therapy stems from their ability to “normalize” the abnormal, leaky blood vessels that usually develop in a tumor, improving the perfusion of blood throughout a tumor and the effectiveness of chemotherapy and radiation. In the deadly brain tumor glioblastoma, MGH investigators found that anti-angiogenesis treatment alone significantly extends the survival of some patients by reducing edema, the swelling of brain tissue. In the current report, the MGH team uses VAI to investigate how these drugs produce their effects and which patients benefit.
Advanced MR techniques developed in recent years can determine factors like the size, radius and capacity of blood vessels. VAI combines information from two types of advanced MR images and analyzes them in a way that distinguishes among small arteries, veins and capillaries; determines the radius of these vessels and shows how much oxygen is being delivered to tissues. The MGH team used VAI to analyze MR data acquired in a phase 2 clinical trial – led by Tracy Batchelor, MD, director of Pappas Center for Neuro-Oncology at MGH and a co-author of the current paper – of the anti-angiogenesis drug cediranib in patients with recurrent glioblastoma. The images had been taken before treatment started and then 1, 28, 56, and 112 days after it was initiated.
In some patients, VAI identified changes reflecting vascular normalization within the tumors – particularly changes in the shape of blood vessels – after 28 days of cediranib therapy and sometimes as early as the next day. Of the 30 patients whose data was analyzed, VAI indicated that 10 were true responders to cediranib, whereas 12 who had a worsening of disease were characterized as non-responders. Data from the remaining 8 patients suggested stabilization of their tumors. Responding patients ended up surviving six months longer than non-responders, a significant difference for patients with an expected survival of less than two years, Emblem notes. He adds that quickly identifying those whose tumors don’t respond would allow discontinuation of the ineffective therapy and exploration of other options.
Gregory Sorensen, MD, senior author of the Nature Medicine report, explains, “One of the biggest problems in cancer today is that we do not know who will benefit from a particular drug. Since only about half the patients who receive a typical anti-cancer drug benefit and the others just suffer side effects, knowing whether or not a patient’s tumor is responding to a drug can bring us one step closer to truly personalized medicine – tailoring therapies to the patients who will benefit and not wasting time and resources on treatments that will be ineffective.” Formerly with the Martinos Center, Sorensen is now with Siemens Healthcare.
Study co-author Rakesh Jain, PhD, director of the Steele Laboratory in the MGH Department of Radiation Oncology, adds, “This is the most compelling evidence yet of vascular normalization with anti-angiogenic therapy in cancer patients and how this concept can be used to select patients likely to benefit from these therapies.”
Lead author Emblem notes that VAI may help further improve understanding of how abnormal tumor blood vessels change during anti-angiogenesis treatment and could be useful in the treatment of other types of cancer and in vascular conditions like stroke. He and his colleagues are also exploring whether VAI can identify which glioblastoma patients are likely to respond to anti-angiogenesis drugs even before therapy is initiated, potentially eliminating treatment destined to be ineffective. A postdoctoral research fellow at the Martinos Center at the time of the study, Emblem is now a principal investigator at Oslo University Hospital in Norway and maintains an affiliation with the Martinos Center.
Researchers Gain Insight into How Ion Channels Control Heart and Brain Electrical Activity
Virginia Commonwealth University researchers studying a special class of potassium channels known as GIRKs, which serve important functions in heart and brain tissue, have revealed how they become activated to control cellular excitability.
The findings advance the understanding of the interaction between a family of signaling proteins called G proteins, and a special type of cell membrane ion pore called G protein-sensitive, inwardly rectifying potassium (GIRK) channels. The findings may one day help researchers develop targeted drugs to treat conditions of the heart such as atrial fibrillation.
In the study, published this week in the Online First section of Science Signaling, a publication of the American Association for the Advancement of Science (AAAS), researchers used a computational approach to predict the interactions between G proteins and a GIRK channel.
Rahul Mahajan, a M.D./Ph.D. candidate in the VCU School of Medicine’s Department of Physiology and Biophysics, undertook this problem for his dissertation work, under the mentorship of Diomedes E. Logothetis, Ph.D., chair of the Department of Physiology and Biophysics and the John D. Bower Endowed Chair in Physiology in the VCU School of Medicine. They developed a model and tested its predictions in cells, demonstrating how G proteins cause activation of GIRKs.
“Malfunctions of GIRK channels have been implicated in chronic atrial fibrillation, as well as in drug abuse and addiction,” said Logothetis, who is an internationally recognized leader in the study of ion channels and cell signaling mechanisms.
“Understanding the structural mechanism of Gβγ activation of GIRK channels could lead to rational based drug design efforts to combat chronic atrial fibrillation.”
In chronic atrial fibrillation, the GIRK channel is believed to be inappropriately open. According to Logothetis, if researchers are able to target only the specific site that keeps the channel inappropriately open, then any unrelated channels could be left unaltered, thus avoiding unwanted side effects.
Crystal structures of GIRK channels, which preceded the current study, have revealed two constrictions of the ion permeation pathway that researchers call “gates”: one at the inner leaflet of the membrane bilayer and the other close by in the cytosol, which is the liquid found inside cells.
“The structure of the Gβγ -GIRK1 complex reveals that Gβγ inserts a part of it in a cleft formed by two cytosolic loops of two adjacent channel subunits,” Logothetis said. “This is also the place where alcohols bind to activate the channel. One can think of this cleft as a clam that has its shells either open or shut closed. Stabilization of this cleft in the ‘open’ position stabilizes the cytosolic gate in the open state.”
GIRKs are activated when they interact with G proteins coupled to receptors bound to stimulatory hormones or neurotransmitters. In heart tissue, acetylcholine released by the vagus nerve activates these channels, which hyperpolarize the membrane potential and slow heart rate. In brain tissue, GIRKs inhibit excitation by acting at postsynaptic cells.
G proteins are composed of three subunits, a, b, and g. Since 1987, researchers have known that the Gbgsubunits directly activate the atrial GIRK channel, but an atomic resolution picture of how the two proteins interact remained elusive until now.
Moving forward, the team would like to use computational and experimental approaches to build and test the structures of the rest of the components of the G protein complex – for example, the Ga subunits and the G protein-coupled receptor – around the Gβγ-channel complex, which is the structure the team has already achieved.
Your eyes may hold clues to stroke risk
Your eyes may be a window to your stroke risk.
In a study reported in the American Heart Association journal Hypertension, researchers said retinal imaging may someday help assess if you’re more likely to develop a stroke — the nation’s No. 4 killer and a leading cause of disability.
“The retina provides information on the status of blood vessels in the brain,” said Mohammad Kamran Ikram, M.D., Ph.D., lead author of the study and assistant professor in the Singapore Eye Research Institute, the Department of Ophthalmology and Memory Aging & Cognition Centre, at the National University of Singapore. “Retinal imaging is a non-invasive and cheap way of examining the blood vessels of the retina.”
Worldwide, high blood pressure is the single most important risk factor for stroke. However, it’s still not possible to predict which high blood pressure patients are most likely to develop a stroke.
Researchers tracked stroke occurrence for an average 13 years in 2,907 patients with high blood pressure who had not previously experienced a stroke. At baseline, each had photographs taken of the retina, the light-sensitive layer of cells at the back of the eyeball. Damage to the retinal blood vessels attributed to hypertension — called hypertensive retinopathy — evident on the photographs was scored as none, mild or moderate/severe.
During the follow-up, 146 participants experienced a stroke caused by a blood clot and 15 by bleeding in the brain.
Researchers adjusted for several stroke risk factors such as age, sex, race, cholesterol levels, blood sugar, body mass index, smoking and blood pressure readings. They found the risk of stroke was 35 percent higher in those with mild hypertensive retinopathy and 137 percent higher in those with moderate or severe hypertensive retinopathy.
Even in patients on medication and achieving good blood pressure control, the risk of a blood clot was 96 percent higher in those with mild hypertensive retinopathy and 198 percent higher in those with moderate or severe hypertensive retinopathy.
“It is too early to recommend changes in clinical practice,” Ikram said. “Other studies need to confirm our findings and examine whether retinal imaging can be useful in providing additional information about stroke risk in people with high blood pressure.”
Scientists develop ‘molecular flashlight’ that illuminates brain tumors in mice
In a breakthrough that could have wide-ranging applications in molecular medicine, Stanford University researchers have created a bioengineered peptide that enables imaging of medulloblastomas, among the most devastating of malignant childhood brain tumors, in lab mice.
The researchers altered the amino acid sequence of a cystine knot peptide — or knottin — derived from the seeds of the squirting cucumber, a plant native to Europe, North Africa and parts of Asia. Peptides are short chains of amino acids that are integral to cellular processes; knottin peptides are notable for their stability and resistance to breakdown.
The team used their invention as a “molecular flashlight” to distinguish tumors from surrounding healthy tissue. After injecting their bioengineered knottin into the bloodstreams of mice with medulloblastomas, the researchers found that the peptide stuck tightly to the tumors and could be detected using a high-sensitivity digital camera.
The findings are described in a study published online Aug. 12 in the Proceedings of the National Academy of Sciences.
“Researchers have been interested in this class of peptides for some time,” said Jennifer Cochran, PhD, an associate professor of bioengineering and a senior author of the study. “They’re extremely stable. For example, you can boil some of these peptides or expose them to harsh chemicals, and they’ll remain intact.”
That makes them potentially valuable in molecular medicine. Knottins could be used to deliver drugs to specific sites in the body or, as Cochran and her colleagues have demonstrated, as a means of illuminating tumors.
For treatment purposes, it’s critical to obtain accurate images of medulloblastomas. In conjunction with chemotherapy and radiation therapy, the tumors are often treated by surgical resection, and it can be difficult to remove them while leaving healthy tissue intact because their margins are often indistinct.
“With brain tumors, you really need to get the entire tumor and leave as much unaffected tissue as possible,” Cochran said. “These tumors can come back very aggressively if not completely removed, and their location makes cognitive impairment a possibility if healthy tissue is taken.”
The researchers’ molecular flashlight works by recognizing a biomarker on human tumors. The bioengineered knottin is conjugated to a near-infrared imaging dye. When injected into the bloodstreams of a strain of mice that develop tumors similar to human medullublastomas, the peptide attaches to the brain tumors’ integrin receptors — sticky molecules that aid in adhesion to other cells.
But while the knottins stuck like glue to tumors, they were rapidly expelled from healthy tissue. “So the mouse brain tumors are readily apparent,” Cochran said. “They differentiate beautifully from the surrounding brain tissue.”
The new peptide represents a major advance in tumor-imaging technology, said Melanie Hayden Gephart, MD, neurosurgery chief resident at the Stanford Brain Tumor Center and a lead author of the paper.
"The most common technique to identify brain tumors relies on preoperative, intravenous injection of a contrast agent, enabling most tumors to be visualized on a magnetic resonance imaging scan," Gephart said. These MRI scans are used like in a computer program much like an intraoperative GPS system to locate and resect the tumors.
“But that has limitations,” she added. “When you’re using the contrast in an MRI scan to define the tumor margins, you’re basically working off a preoperative snapshot. The brain can sometimes shift during an operation, so there’s always the possibility you may not be as precise or accurate as you want to be. The great potential advantage of this new approach would be to illuminate the tumor in real time — you could see it directly under your microscope instead of relying on an image that was taken before surgery.”
Though the team’s research focused on medulloblastomas, Gephart said it’s likely the new knottins could prove useful in addressing other cancers.
“We know that integrins exist on many types of tumors,” she said. “The blood vessels that tumors develop to sustain themselves also contain integrins. So this has the potential for providing very detailed, real-time imaging for a wide variety of tumors.”
And imaging may not be the only application for the team’s engineered peptide.
“We’re very interested in related opportunities,” Cochran said. “We envision options we didn’t have before for getting molecules into the brain.” In other words, by substituting drugs for dye, the knottins might allow the delivery of therapeutic compounds directly to cranial tumors — something that has proved extremely difficult to date because of the blood/brain barrier, the mechanism that makes it difficult for pathogens, as well as medicines, to traverse from the bloodstream to the brain.
“We’re looking into it now,” Cochran said.
A little serendipity was involved in the peptide’s development, said Sarah Moore, a recently graduated bioengineering PhD student and another lead author of the study. Indeed, the propinquity of Cochran’s laboratory to co-author Matthew Scott’s lab at Stanford’s James H. Clark Center catalyzed the project. “Our labs are next to each other,” Moore said. “We had the peptide, and Matt had ideal models of pediatric brain tumors —mice that develop tumors in a similar manner to human medulloblastomas. Our partnership grew out of that.”
Scott, PhD, professor of bioengineering and of developmental biology, credits the design of the Clark Center as a contributor to the project. The building is home to Stanford’s Bioengineering Department, a collaboration between the School of Engineering and the School of Medicine, and Stanford Bio-X, an initiative that encourages communication among researchers in diverse scientific disciplines.
“So in a very real sense, our project wasn’t an accident,” Scott said. “In fact, it’s exactly the kind of work the Clark Center was meant to foster. The lab spaces are wide and open, with very few walls and lots of glass. We have a restaurant that only has large tables — no tables for two, so people have to sit together. Everything is designed to increase the odds that people will meet and talk. It’s a form of social engineering that really works.”
Scott said he is gratified by the collaboration that led to the team’s breakthrough, and observed that the peptide has proved a direct boon to his own work. About 15 percent of Scott’s mice develop the tumors requisite for medulloblastoma research. The problem, he said, is that the cancers are cryptic in their early stages.
“By the time you know the mice have them, many of the things you want to study — the genesis and development of the tumors — are past,” Scott said. “We needed ways to detect these tumors early, and we needed methods for following the steps of tumor genesis.”
Ultimately, Scott concluded, the development of the new peptide can be attributed to Stanford’s long-established traditions of openness and relentless inquiry.
“You find not just a willingness, but an eagerness to exchange ideas and information here,” Scott said. “It transcends any competitive instinct, any impulse toward proprietary thinking. It is what makes Stanford — well, Stanford.”
(Source: med.stanford.edu)
Accidentally cut your ear off? Just 3D print a new one
It’s way too late for Vincent van Gogh, but cutting off your ear is a much less impressive gesture now you can get a new one printed.
This week, researchers at Hangzhou Dianzi University in China unveiled their Regenovo 3D printer. Unlike more familiar 3D printers, which work with plastic or metal dust, Regenovo prints living tissue – such as these little ears.
The Hangzhou team aren’t the only ones 3D-printing spare parts for people. Earlier this year, a team at Cornell University in Ithaca, New York, also demonstrated an ear printer, and Organovo in San Diego, California, are on the way to building fresh human livers.
Meanwhile a team at Heriot-Watt University in Edinburgh, UK, has turned human embryonic stem cells into 3D-printer ink. Things are more advanced when it comes to making new bones, as a woman with a 3D-printed titanium jawbone could tell you.
High Blood Sugar Linked to Dementia
People with diabetes face an increased risk of Alzheimer’s disease and other forms of dementia, a connection scientists and physicians have worried about for years. They still can’t explain it.
Now comes a novel observational study of patients at a large health care system in Washington State showing that higher blood glucose levels are associated with a greater risk of dementia — even among people who don’t have diabetes. The results, published Thursday in The New England Journal of Medicine, “may have influence on the way we think about blood sugar and the brain,” said Dr. Paul Crane, the lead author and associate professor of medicine at the University of Washington.
The researchers tracked the blood glucose levels of 2,067 members of Group Health, a nonprofit HMO, for nearly seven years on average. Some patients had Type 2 diabetes when the study began, but most didn’t. None had dementia.
Over the years, as they saw doctors at Group Health, the participants received blood glucose tests. “It’s a common test in routine clinical practice,” Dr. Crane said. “We had an amazing opportunity with all this data. All the lab results since 1988 were available to us.”
The participants (average age at the start: 76) also reported to Group Health every other year for cognitive screening and, if their results were below normal, further testing and evaluation. Over the course of the study, about a quarter developed dementia of some kind, primarily Alzheimer’s disease or vascular dementia.
To measure blood sugar levels, the researchers combined glucose measurements, both fasting and nonfasting, with the HbA1c glycated hemoglobin assay, which provides a more accurate long-term picture. They also adjusted the data for other cardiovascular factors already linked to dementia, like high blood pressure and smoking.
“We found a steadily increasing risk associated with ever-higher blood glucose levels, even in people who didn’t have diabetes,” Dr. Crane said. Of particular interest: “There’s no threshold, no place where the risk doesn’t go up any further or down any further.” The association with dementia kept climbing with higher blood sugar levels and, at the other end of the spectrum, continued to decrease with lower levels.
This held true even at glucose levels considered normal. Among those whose blood sugar averaged 115 milligrams per deciliter, the risk of dementia was 18 percent higher than among those at 100 mg/dL, just slightly lower. The effects were also pronounced among those with diabetes: patients with average glucose levels of 190 mg/dL had a 40 percent higher risk of dementia than those whose levels averaged 160 mg/dL.
Though a longitudinal study like this one provides insight into the differences between people, it can’t explain why higher blood glucose might be connected to dementia, or tell individuals whether lower blood glucose is protective.
“People shouldn’t run for the hills or try crazy diets,” Dr. Crane cautioned. While an epidemiological study like this one can guide further exploration, he said, “This doesn’t show that changes in behavior that lower your individual blood sugar would decrease your individual risk of dementia.”
As for the blood glucose levels the study recorded, “clinically, they’re not big differences,” said Dr. Medha Munshi, a geriatrician and endocrinologist who directs the geriatric diabetes program at the Joslin Diabetes Center in Boston, who was not involved in the study. “I wouldn’t change my goals for diabetes management based on this study.” Nor would she warn someone whose blood glucose hits 115 mg/dL that he or she faces a greater risk of dementia.
But because diabetes itself can pose such a threat to health and quality of life, she still urges patients to adopt healthy practices like exercising regularly and maintaining a normal weight to try to avoid the disease. If by doing so they also lower their dementia risk — and knowing that would require a different study, focused on interventions — that would be a bonus.
This research “offers more evidence that the brain is a target organ for damage by high blood sugar,” said Dr. Munshi. “And everyone is still working on the ‘why’.
Hidden Beauty: Exploring the Aesthetics of Medical Science
This collaborative project by a scientist and artist asks the reader to consider the aesthetics of human disease, both within and beyond the context of our preconceived social systems. Disease is a dynamically powerful force of nature that acts without regard to race, religion or culture. These forces create visually stunning patterns with a remarkable ability to evoke human emotion in isolation that differs when viewed in the context of the disease that produced the image. We see beauty in the delicate lacework of fungal hyphae invading a blood vessel, the structure of the normal cerebellum, and the desperate drive of metastasizing cancer cells. However, the appreciation of the imagery produced by disease is bittersweet; we simultaneously experience the beauty of the natural world and the pain of those living with these disease processes. Ultimately, this series of images will leave the viewer with an appreciation of visual beauty inherent within the medical sciences.
(Image: Alzheimer’s research, Phillip Wong PhD)
New drugs to find the right target to fight Alzheimer’s disease
Next-generation drugs designed to fight Alzheimer’s disease look very promising. Scientists have unveiled the mechanisms behind two classes of compound currently being tested in clinical trials. They have also identified a likely cause of early-onset hereditary forms of the disease.
The future is looking good for drugs designed to combat Alzheimer’s disease. EPFL scientists have unveiled how two classes of drug compounds currently in clinical trials work to fight the disease. Their research suggests that these compounds target the disease-causing peptides with high precision and with minimal side-effects. At the same time, the scientists offer a molecular explanation for early-onset hereditary forms of Alzheimer’s, which can strike as early as thirty years of age. The conclusions of their research, which has been published in the journal Nature Communications, are very encouraging regarding the future of therapeutic means that could keep Alzheimer’s disease in check.
Alzheimer’s disease is characterized by an aggregation of small biological molecules known as amyloid peptides. We all produce these molecules; they play an essential antioxidant role. But in people with Alzheimer’s disease, these peptides aggregate in the brain into toxic plaques – called “amyloid plaques” – that destroy the surrounding neurons.
The process starts with a long protein, “APP”, which is located across the neuron’s membrane. This protein is cut into several pieces by an enzyme, much like a ribbon is cut by scissors. The initial cut generates a smaller intracellular protein that plays a useful role in the neuron. Another cut releases the rest of APP outside the cell – this part is the amyloid peptide.
For reasons not yet well understood, APP protein can be cut in several different places, producing amyloid peptides that are of varying lengths. Only the longer forms of the amyloid peptide carry the risk of aggregating into plaques, and people with Alzheimer’s disease produce an abnormally high number of these.
A favorite Alzheimer’s target: gamma secretase
The two next-generation classes of compound that are currently in clinical trials target an enzyme that cuts APP, known as gamma secretase. Until now, our understanding of the mechanism involved has been lacking. But with this work, the EPFL researchers were able to shed some more light on it by determining how the drug compounds affect gamma secretase and its cutting activity.
In most forms of Alzheimer’s, abnormally large quantities of the long amyloid peptide 42 – named like that because it contains 42 amino acids – are formed. The drug compounds change the location where gamma secretase cuts the APP protein, thus producing amyloid peptide 38 instead of 42, which is shorter and does not aggregate into neurotoxic plaques.
Compared to previous therapeutic efforts, this is considerable progress. In 2010, Phase III clinical trials had to be abandoned, because the compound being tested inhibited gamma-secretase’s function across the board, meaning that the enzyme was also deactivated in essential cellular differentiation processes, resulting to side-effects like in gastrointestinal bleeding and skin cancer.
“Scientists have been trying to target gamma secretase to treat Alzheimer’s for over a decade,” explains Patrick Fraering, senior author on the study and Merck Serono Chair of Neurosciences at EPFL. “Our work suggests that next-generation molecules, by modulating rather than inhibiting the enzyme, could have few, if any, side-effects. It is tremendously encouraging.”
New insights into hereditary forms of the disease
During their investigation, the scientists also identified possible causes behind some hereditary forms of Alzheimer’s disease. Early-onset Alzheimer’s can appear as early as thirty years of age, with a life expectancy of only a few years. In vitro experiments and numerical simulations show that in early-onset patients, mutations in the APP protein gene modify the way by which APP is cut by the gamma-secretase enzyme. This results in overproduction of amyloid peptide 42, which then aggregates into amyloid plaques.
This research illuminates much that is unknown about Alzheimer’s disease. “We have obtained extraordinary knowledge about how gamma secretase can be modulated,” explains co-author Dirk Beher, scientific chief officer of Asceneuron, a spin-off of Merck Serono, the biopharmaceutical division of Merck KGaA, Darmstadt, Germany. “This knowledge will be invaluable for developing even better targeted drugs to fight the disease.”
(Source: actu.epfl.ch)