Alzheimer’s and Low Blood Sugar in Diabetes May Trigger a Vicious Cycle

A new UC San Francisco-led study looks at the close link between diabetes and dementia, which can create a vicious cycle.

Diabetes-associated episodes of low blood sugar may increase the risk of developing dementia, while having dementia or even milder forms of cognitive impairment may increase the risk of experiencing low blood sugar, according to the study published online Monday in JAMA Internal Medicine.

Researchers analyzed data from 783 diabetic participants and found that hospitalization for severe hypoglycemia among the diabetic, elderly participants in the study was associated with a doubled risk of developing dementia later. Similarly, study participants with dementia were twice as likely to experience a severe hypoglycemic event.

The study results suggest some patients risk entering a downward spiral in which hypoglycemia and cognitive impairment fuel one another, leading to worse health, said Kristine Yaffe, MD, senior author and principal investigator for the study, and a UCSF professor of psychiatry, neurology and epidemiology based at the San Francisco Veterans Affair Medical Center.

“Older patients with diabetes may be especially vulnerable to a vicious cycle in which poor diabetes management may lead to cognitive decline and then to even worse diabetes management,” she said.

Cognitive Function a Factor in Managing Diabetes

The researchers analyzed hospital records of patients from Memphis and Pittsburgh, ages 70 to 79 at the time of enrollment, who participated in the federally funded Health, Aging and Body Composition (Health ABC) study, begun in 1997. The UCSF results are based on an average of 12 years of follow-up study. Participants in the Health ABC study periodically underwent tests to measure cognitive function.

Nearly half of participants included in the newly published analysis were black, and the rest were white. None had dementia at the start of the study, and all either had diabetes at the beginning of the study or were diagnosed during the course of the study.

“Individuals with dementia or even those with milder forms of cognitive impairment may be less able to effectively manage complex treatment regimens for diabetes and less able to recognize the symptoms of hypoglycemia and to respond appropriately, increasing their risk of severe hypoglycemia,” Yaffe said. “Physicians should take cognitive function into account in managing diabetes in elderly individuals.”

Certain medications known to carry a higher risk for hypoglycemia — such as insulin secretagogues and certain sulfonylureas — may be inappropriate for older adults with dementia or who are at risk for cognitive impairment, according to Yaffe.

Previous studies in which researchers investigated hypoglycemia and cognitive function have had inconsistent findings. A strength of the current study is that individuals were tracked from baseline over a relatively long time, and the older age of participants may also have been a factor in the highly statistically significant outcome, Yaffe said.

Mice Give New Clues to Origins of OCD

Columbia Psychiatry researchers have identified what they think may be a mechanism underlying the development of compulsive behaviors. The finding suggests possible approaches to treating or preventing certain characteristics of OCD.

OCD consists of obsessions, which are recurrent intrusive thoughts, and compulsions, which are repetitive behaviors that patients perform to reduce the severe anxiety associated with the obsessions. The disorder affects 2–3 percent of people worldwide and is an important cause of illness-related disability, according to the World Health Organization.

Using a new technology in a mouse model, the researchers found that repeated stimulation of specific circuits linking the brain’s cortex and striatum produces progressive repetitive behavior. By targeting this region, it may be possible to stop abnormal circuit changes before they become pathological behaviors in people at risk for obsessive-compulsive disorder (OCD). The study, which was led by Susanne Ahmari, MD, PhD, assistant professor of clinical psychiatry at Columbia Psychiatry and the New York State Psychiatric Institute, was published in the June 7 issue of Science.

While the obsessions and compulsions that are the hallmarks of OCD are thought to be centered in the cortex, which controls thoughts, and the striatum, which controls movements, little is known about how abnormalities in these brain regions lead to compulsive behaviors in patients.

To simulate the increased activity that takes place in the brains of OCD patients, Dr. Ahmari and her colleagues used a new technology called optogenetics, in which light-activated ion channels are expressed in subsets of neurons in mice, and neural circuits are then selectively activated using light delivered through fiberoptic probes.

“What we found was really surprising,” said Dr. Ahmari. “That activation of cortico-striatal circuits did not lead directly to repetitive behaviors in the mice. But if we repeatedly stimulated for multiple days in a row for only five minutes a day, we saw a progressive development of repetitive behaviors—in this case, repetitive grooming behavior—that persisted up to two weeks after the stimulation was stopped.”

She added, “And not only that, when we treated the mice with fluoxetine, one of the most common medications used for OCD, their behavior went back to normal.” The current study, as well as others currently being performed by Dr. Ahmari and her team, may ultimately provide clues for new treatment targets in terms of both novel drug development and direct stimulation techniques, including deep brain stimulation (DBS).

Reduced brain volume in kids with low birth-weight tied to academic struggles

An analysis of recent data from magnetic resonance imaging (MRI) of 97 adolescents who were part of study begun with very low birth weight babies born in 1982-1986 in a Cleveland neonatal intensive care unit has tied smaller brain volumes to poor academic achievement.

More than half of the babies that weighed less than 1.66 pounds and more than 30 percent of those less than 3.31 pounds at birth later had academic deficits. (Less than 1.66 pounds is considered extremely low birth weight; less than 3.31 pounds is labeled very low birth weight.) Lower birth weight was associated to smaller brain volumes in some of these children, and smaller brain volume, in turn, was tied to academic deficits.

Researchers also found that 65.6 percent of very low birth weight and 41.2 percent of extremely preterm children had experienced academic achievement similar to normal weight peers.

The research team — led by Caron A.C. Clark, a scientist in the Department of Psychology and Child and Family Center at the University of Oregon — detected an overall reduced volume of mid-brain structures, the caudate and corpus callosum, which are involved in connectivity, executive attention and motor control.

The findings, based a logistic regression analyses of the MRIs done approximately five years ago, were published in the May issue of the journal Neuropsychology. The longitudinal study originally was launched in the 1980s with a grant from the National Institute of Child Health and Human Development (National Institutes of Health, grant HD 26554) to H. Gerry Taylor of Case Western University, who was the senior author and principal investigator on the new paper.

"Our new study shows that pre-term births do not necessarily mean academic difficulties are ahead," Clark said. "We had this group of children that did have academic difficulties, but there were a lot of kids in this data set who didn’t and, in fact, displayed the same trajectories as their normal birth-weight peers."

Academic progress of the 201 original participants had been assessed early in their school years, again four years later and then annually until they were almost 17 years old. “We had the opportunity to explore this very rich data set,” Clark said. “There are very few studies that follow this population of children over time, where their trajectories of growth at school are tracked. We were interested in seeing how development unfolds over time.”

The findings, Clark added, provide new insights but also raise questions such as why some low-birth-weight babies develop normally and others do not? “It is very difficult to pick up which kids will need the most intensive interventions really early, which we know can be really important.”

The findings also provide a snapshot of children of very low birth weights who were born in NICU 30 years ago. Since then, technologies and care have improved, she said, meaning that underweight babies born prematurely today might have an advantage over those followed in the study. However, she added, improving NICUs also are allowing yet smaller babies to survive.

Clark now is exploring these findings for early warning clues that might help drive informed interventions. “Pre-term birth does mean that you are much more likely to experience brain abnormalities that seem to put you at risk for these outcomes,” she said. “They seem to be a pretty strong predictor of poor cognitive development as children age. We really need to find ways to prevent these brain abnormalities and subsequent academic difficulties in these kids who are born so small.”

Motor neurons like this one, found in the crab Cancer borealis, underlie the walking, swimming, breathing, flying and other rhythmic behaviors found in most creatures, including humans.

Eve Marder wins 2013 Gruber Neuroscience Prize

Award recognizes ‘the best neuroscience research being done anywhere’

The Gruber Foundation today awarded its 2013 neuroscience prize to Eve Marder ’69, a pioneering researcher who has dedicated her career to understanding the nervous system’s basic functions. The Victor and Gwendolyn Beinfield Professor of Neuroscience at Brandeis, Marder studies a relatively simple network of some 30 large neurons found in the gut of lobsters and crabs — a small yet elegant window into humans’ unfathomably rich nervous system, home to billions of neurons and trillions of interconnections.

The $500,000 prize recognizes and rewards “the best [neuroscience] work being done anywhere in the world,” according to the Gruber Foundation website. 

"Eve Marder has made a number of remarkable and groundbreaking discoveries that have fundamentally changed our understanding of how neural circuits operate and produce behavior," says Carol Barnes, chair of the selection advisory board to the Neuroscience Prize. "She has also been an exceptional leader outside the laboratory, working tirelessly to bring people together to improve scientific research, policy, and education."

Marder’s singular contributions to neuroscience through her use of crustaceans — in a field heavily dominated by scientists using vertebrate model organisms, chiefly rodents — have helped define how we think about neurons and their astounding capabilities. 

Despite not practicing “consensus” science — Marder avoids the well-trodden path of established modes of inquiry, such as working in vertebrates — she has received numerous accolades, including election to the National Academy of Sciences and to the helm of the Society for Neuroscience, both in 2007.

“I’m a maverick within a conservative framework — I obey carefully the rules of scientific rigor and discipline,” says Marder, who began her freshman year at Brandeis thinking she would major in politics. By her senior year, enthralled with the emerging field of neuroscience, she applied to graduate school while some of her friends made their plans to join the counterculture.

As a graduate student at the University of California, San Diego, in the early 1970s, Marder began studying the stomatogastric nervous system of the West Coast spiny lobster, Panulirus interruptus. The stomatogastric nervous system, which controls the motion of the gut, is an example of a central pattern generator. These circuits generate organized and repetitive motor patterns that also underlie walking, swimming, flying, breathing and many other rhythmic behaviors that creatures from earthworms to humans take for granted. 

The big questions Marder has asked throughout her career attempt to understand the fundamental nature of neuronal circuit operation. In a Brandeis lab staffed by post-docs, graduate students and undergraduates, she’s helped advance basic tenets of neuroscience while continuing to refine several related lines of inquiry. 

Early in Marder’s Brandeis career, her lab demonstrated that neuromodulatory substances such as dopamine, serotonin and neuropeptides can alter circuit performance so that the same group of neurons can produce a variety of behaviors. Her research has helped reshape the way scientists think about conditions like depression, now believed to stem from imbalances in neuromodulation. 

Later, her lab studied how neurons and networks maintain stable network performance despite the ongoing turnover of the membrane proteins that give neurons their characteristic electrical properties. Most recently, her lab is studying animal-to-animal variability in neuronal properties. How much variability in circuit function is there between animals even as they respond similarly to changes in hormones or temperature?

“I’m always looking for the things we can study more effectively than someone working in a large nervous system,” explains Marder. “I don’t want to work on problems that someone else can do better.”

Awarded by a distinguished panel of experts following an international nomination process, the Gruber Foundation neuroscience prize is a humbling honor, Marder says. It is also recognition that great science requires both intellectual risk-taking and persistence. 

Marder plans to celebrate, just not over a fancy lobster dinner. She gave up eating crustaceans long ago.

New Scientific Analysis Shines a Light on Ötzi the Iceman’s Dark Secrets

Protein investigation supports brain injury theory and opens up new research possibilities for mummies

After decoding the Iceman’s genetic make-up, a research team from the European Academy of Bolzano/Bozen (EURAC), Saarland University, Kiel University and other partners has now made another major breakthrough in mummy research: using just a pinhead-sized sample of brain tissue from the world-famous glacier corpse, the team was able to extract and analyse proteins to further support the theory that Ötzi suffered some form of brain damage in the final moments of his life.

Two dark coloured areas at the back of the Iceman’s cerebrum had first been mentioned back in 2007 during a discussion about the fracture to his skull. Scientists surmised from a CAT scan of his brain that he had received a blow to the forehead during his deadly attack that caused his brain to knock against the back of his head, creating dark spots from the bruising. Till now, this hypothesis had been left unexplored.

In 2010, with the help of computer-controlled endoscopy, two samples of brain tissue the size of a pinhead were extracted from the glacier mummy. This procedure was carried out via two tiny (previously existing) access holes and was thus minimally invasive. Microbiologist Frank Maixner (EURAC, Institute for Mummies and the Iceman) and his fellow scientist Andreas Tholey (Institute for Experimental Medicine, Kiel University) conducted two parallel, independent studies on the tiny bundles of cells. Tholey’s team provided the latest technology used in the study of complex protein mixtures known as “proteomes”. The various analyses were coordinated by Frank Maixner and Andreas Keller.

The protein research revealed a surprising amount of information. Scientists were able to identify numerous brain proteins, as well as proteins from blood cells. Microscopic investigation also confirmed the presence of astonishingly well-preserved neural cell structures and clotted blood cells. On the one hand, this led the scientists to conclude that the recovered samples did indeed come from brain tissue in remarkably good condition (the proteins contained amino acid sequence features specific to Ötzi). On the other hand, these blood clots in a corpse almost devoid of blood provided further evidence that Ötzi’s brain had possibly suffered bruising shortly before his death. Whether this was due to a blow to the forehead or a fall after being injured by the arrow remains unclear.

The discoveries represent a major breakthrough for the scientists. The research team emphasised that “the use of new protein-analysis methods has enabled us to pioneer this type of protein investigation on the soft tissue of a mummified human, extracting from the tiniest sample a vast quantity of data which in the future may well answer many further questions.” While many DNA samples from mummies are difficult or impossible to analyse because of natural biological decay, one can often still find proteins in tissue samples which allow a closer analysis and provide valuable information, explained Andreas Tholey: “Proteins are the decisive players in tissues and cells, and they conduct most of the processes which take place in cells. Identification of the proteins is therefore key to understanding the functional potential of a particular tissue. DNA is always constant, regardless of from where it originates in the body, whereas proteins provide precise information about what is happening in specific regions within the body.” Protein analysis of mummified tissue makes an especially valuable contribution to DNA research, Maixner added: “Investigating mummified tissue can be very frustrating. The samples are often damaged or contaminated and do not necessarily yield results, even after several attempts and using a variety of investigative methods. When you think that we have succeeded in identifying actual tissue changes in a human who lived over 5,000 years ago, you can begin to understand how pleased we are as scientists that we persisted with our research after many unsuccessful attempts. It has definitely proved worthwhile!”

The results of this joint study are published in the renowned journal “Cellular and Molecular Life Sciences”. Along with a sample taken from the Iceman´s stomach content, more than a dozen tissue samples from less well preserved mummies from all over the world will be submitted to this new protein-based research method and should provide insights which previously had not been possible.

3-D map of blood vessels in cerebral cortex holds suprises

Blood vessels within a sensory area of the mammalian brain loop and connect in unexpected ways, a new map has revealed.

The study, published June 9 in the early online edition of Nature Neuroscience, describes vascular architecture within a well-known region of the cerebral cortex and explores what that structure means for functional imaging of the brain and the onset of a kind of dementia.

David Kleinfeld, professor of physics and neurobiology at the University of California, San Diego, and colleagues mapped blood vessels in an area of the mouse brain that receives sensory signals from the whiskers.

The organization of neural cells in this brain region is well-understood, as was a pattern of blood vessels that plunge from the surface of the brain and return from the depths, but the network in between was uncharted. Yet these tiny arterioles and venules deliver oxygen and nutrients to energy-hungry brain cells and carry away wastes.

The team traced this fine network by filling the vessels with a fluorescent gel. Then, using an automated system, developed by co-author Philbert Tsai, that removes thin layers of tissue with a laser while capturing a series of images to reconstructed the three-dimensional network of tiny vessels.

The project focused on a region of the cerebral cortex in which the nerve cells are so well known that they can be traced to individual whiskers. These neurons cluster in “barrels,” one per whisker, a pattern of organization seen in other sensory areas as well.

The scientists expected each whisker barrel to match up with its own blood supply, but that was not the case. The blood vessels don’t line up with the functional structure of the neurons they feed.

"This was a surprise, because the blood vessels develop in tandem with neural tissue," Kleinfeld said. Instead, microvessels beneath the surface loop and connect in patterns that don’t obviously correspond to the barrels.

To search for patterns, they turned to a branch of mathematics called graph theory, which describes systems as interconnected nodes. Using this approach, no hidden subunits emerged, demonstrating that the mesh indeed forms a continous network they call the “angiome.”

The vascular maps traced in this study raise a question of what we’re actually seeing in a widely used kind of brain imaging called functional MRI, which in one form measures brain activity by recording changes in oxygen levels in the blood. The idea is that activity will locally deplete oxygen. So they wiggled whiskers on individual mice and found that optical signals associated with depleted oxygen centered on the barrels, where electrical recordings confirmed neural activity. Thus brain mapping does not depend on a modular arrangement of blood vessels.

The researchers also went a step further to calculate patterns of blood flow based on the diameters and connections of the vessels and asked how this would change if a feeder arteriole were blocked. The map allowed them to identify “perfusion domains,” which predict the volumes of lesions that result when a clot occludes a vessel. Critically, they were able to build a physical model of how these lesions form, as may occur in cases of human dementia.

(Image: Andreas Weil)