Mesh-like Network Of Arteries Adjusts To Restore Blood Flow To Stroke-injured Brain

A grid of small arteries at the surface of the brain redirects flow and widens at critical points to restore blood supply to tissue starved of nutrients and oxygen following a stroke, a new study has found.

“This is optimistic news,” said David Kleinfeld, a physics professor at the University of California, San Diego, whose group studies blood flow in animal models of stroke.

Damage from stroke can continue for hours or even days as compromised brain tissue surrounding the core injury succumbs to deprivation of oxygen and nutrients.

“This is the area doctors are trying to protect after a stroke,” said Andy Shih, a postdoctoral fellow in Kleinfeld’s group who conducted the experiments. “Those neurons are teetering on the edge of death and survival.”

Previous work with animal models had found that blood flow can persistently slow in the aftermath of a stroke, which would hinder the delivery of drugs that might help recovery. But those studies only measured the speed of the blood.

By measuring both the speed of blood cells moving through individual small arteries and the diameters of the same vessels, the scientists found that the arteries dilate to maintain a constant delivery of blood cells.

“You find that the velocity has gone down, but that the diameter—on average—exactly compensates,” Kleinfeld said.

Patrick Drew and Philbert Tsai in Kleinfeld’s group, and Beth Friedman and Patrick Lyden, MD, of the neuroscience department at UC San Diego’s School of Medicine co-authored the paper. Lyden, whose contributions to a 1995 study proved that the drug tPA can reverse the course of stroke when administered promptly, also directs the UC San Diego Stroke Center. The Journal of Cerebral Blood Flow and Metabolism published their new finding online January 28.

Key to this resilience, it seems, is the structure of the vascular network overlying the brain.

“Vessels on the surface of the brain have a mesh-like architecture,” Kleinfeld said. “One consequence of that is that it operates like a grid system that redistributes “current flow as you need it.”

“City traffic freezes a lot less than you would think because once a street gets bogged down, you can move over to another street,” he said. “This seems to be what happens on the surface of the brain.”

Flows through the surface vessels reversed and stalled, as previously observed, but those changes helped to redistribute blood to ensure a steady supply though vessels that penetrate into the brain.

Shih focused his measurements on small arteries, called arterioles, at the point where they dive into the brain to supply a discrete patch of the cortex, a juncture that is vulnerable to occlusions that can cause microstrokes this group’s previous work has found.

“These are extremely important. A single penetrating arteriole will feed a column of tissue,” Shih said. “These are bottlenecks in flow.”

The penetrating vessels neither reversed nor stalled, even though many connected to loops and bridges in the vascular network that could have allowed that to happen. Even when the pressure dropped permanently as a result of stroke damage, wider lanes allowed the network to deliver red blood cells at the same rate.

“Diameter is the major determinant to how blood actually flows through vessels. Open up a blood vessel a little bit and you’ll have a huge change in the amount of blood that goes through,” Shih said. “Blood flow comes back, and it seems that these vessels are very resistant to the stroke. They function quite normally.”

The work was funded by the Canadian Institutes of Health Research, National Institutes of Health, National Science Foundation and Veterans Medical Research Foundation.

Alzheimer's Prevented And Reversed With Natural Protein In Animal Models

Memory loss, cognitive impairment, brain cell degeneration and cell death were prevented or reversed in several animal models after treatment with a naturally occurring protein called brain-derived neurotrophic factor (BDNF). The study by a University of California, San Diego-led team – published in the February 8, 2009 issue of Nature Medicine – shows that BDNF treatment can potentially provide long-lasting protection by slowing, or even stopping the progression of Alzheimer's disease in animal models.

"The effects of BDNF were potent," said Mark Tuszynski, MD, PhD, professor of neurosciences at the UC San Diego School of Medicine and neurologist at the Veterans Affairs San Diego Health System. "When we administered BDNF to memory circuits in the brain, we directly stimulated their activity and prevented cell death from the underlying disease."

BDNF is normally produced throughout life in the entorhinal cortex, a portion of the brain that supports memory. Its production decreases in the presence of Alzheimer's disease. For these experiments, the researchers injected the BDNF gene or protein in a series of cell culture and animal models, including transgenic mouse models of Alzheimer's disease; aged rats; rats with induced damage to the entorhinal cortex; aged rhesus monkeys, and monkeys with entorhinal cortex damage.

In each case, when compared with control groups not treated with BDNF, the treated animals demonstrated significant improvement in the performance of a variety of learning and memory tests. Notably, the brains of the treated animals also exhibited restored BDNF gene expression, enhanced cell size, improved cell signaling, and activation of function in neurons that would otherwise have degenerated, compared to untreated animals. These benefits extended to the degenerating hippocampus where short-term memory is processed, one of the first regions of the brain to suffer damage in Alzheimer's disease.

The demonstration of the effectiveness and safety of BDNF administration in animals provides "a rationale for exploring clinical translation" to humans, the team concludes, suggesting that the protective and restorative effects of BDNF on damaged neurons and neuronal signaling may offer a new approach to treating Alzheimer's disease.

This work builds on previous studies by Tuszynski and others, demonstrating the therapeutic affects of nerve growth factor (NGF) administered to patients with Alzheimer's disease. In 2001, Tuszynski and his team at UC San Diego Medical Center performed the first surgical implants of NGF genes into the brains of Alzheimer's patients, with follow-up results showing these patients experienced a possible slowing in cognitive decline and increased metabolic function in the brain. The NGF studies continue today, with Phase 2, multi-center studies currently underway.

"NGF therapy aims to stimulate the function of specific cholinergic neurons, which are like the air traffic controllers of the brain, helping to direct the activities of cells in broad regions of the brain," Tuszynski explained. However, he added that the benefits of NGF therapy, if validated in ongoing trials, will not be curative. Eventually, the effect of the NGF "boost" will be countered by the widespread death of neurons in the cerebral cortex as a result of advancing Alzheimer's disease.

"In contrast, BDNF acts directly on dying cells in specific memory circuits of the brain," Tuszynski said. "In this series of studies, we have shown that BDNF targets the cortical cells themselves, preventing their death, stimulating their function, and improving learning and memory. Thus, BDNF treatment can potentially provide long-lasting protection by slowing, or even stopping disease progression in the cortical regions that receive treatment."

The protective and restorative effects of BDNF occurred independently of the build-up of amyloid, a protein that accumulates in the brain to form plaques in Alzheimer's disease. Many current experimental treatments for Alzheimer's disease target amyloid production, so the potential role of BDNF as an alternative protective intervention is of great potential interest, said Tuszynski. Because BDNF targets a different set of disease mechanisms than amyloid modulation, there is also potential to combine BDNF and amyloid-based treatments, theoretically providing a two-pronged attack on the disease.

The study was supported by the National Institutes of Health, the California Regional Primate Research Center, the Veterans Administration, the Alzheimer's Association, the State of California, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the Shiley Family Foundation. Tuszynski is scientific founder of Trophin Therapeutics, a company that may potentially benefit from the research results.

Study co-authors are Alan H. Nagahura, David A. Merrill, Shingo Tsukada, Brock E. Schroeder, Gideon M. Shaked, Ling Want, Armin Blesch, James M. Conner, Edward Rockenstein, Edward H. Koo, and Eliezer Masliah of the UC San Diego Department of Neurosciences, and Andrea A. Chiba of the UC San Diego Departments of Neurosciences and Cognitive Science. Giovanni Coppola and Daniel Geschwind of the Program in Neurogenetics, Department of Neurology at UCLA, and Albert Kim and Moses V. Chao, Skirball Institute of Biomolecular Medicine at New York University School of Medicine.

Scientists Develop 'Crystal Ball' For Personalized Cancer Treatment

For many cancer patients, chemotherapy can be worse than cancer itself. A patient may respond to one drug but not another -- or the tumor may mutate and stop responding to the drug -- resulting in months of wasted time, ineffective treatment and toxic side effects.Now UCLA scientists have tested a non-invasive approach that may one day allow doctors to evaluate a tumor's response to a drug before prescribing therapy, enabling physicians to quickly pinpoint the most effective treatment and personalize it to the patient's unique biochemistry. The Proceedings of the National Academy of Sciences publishes the UCLA findings in its Feb. 2 advance online edition.

"For the first time, we can watch a chemotherapy drug working inside the living body in real time," explained Dr. Caius Radu, a researcher at the Crump Institute for Molecular Imaging and assistant professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA. "We plan to test this method in healthy volunteers within the year to determine whether we can replicate our current results in humans."

In an earlier study, Radu and his colleagues created a small probe by slightly altering the molecular structure of gemcitabine, one of the most commonly used chemotherapy drugs. They labeled the probe with a special tag that enabled them to watch its movement throughout the body during imaging.

In this study, the UCLA team injected the probe into mice that had developed leukemia and lymphoma tumors. After an hour, the researchers imaged the animals' bodies with positron emission tomography (PET), a non-invasive scan often used on cancer patients to identify whether a tumor has spread from its original site or returned after remission.

"The PET scanner operates like a molecular camera, enabling us to watch biological processes in living animals and people," said Radu, who is also a member of the Jonsson Comprehensive Cancer Center at UCLA. "Because we tag the probe with positron-emitting particles, the cells that absorb it glow brighter under the PET scan."

"The PET scan offers a preview for how the tumor will react to a specific therapy," added first author Rachel Laing, a UCLA graduate researcher in molecular and medical pharmacology. "We believe that the tumor cells that absorb the probe will also take up the drug. If the cells do not absorb the probe, it suggests that the tumor might respond better to another medication."

The UCLA researchers plan to expand the scope of their research by examining whether the probe can predict cellular response to several other widely used chemotherapy drugs. Their goal is to determine whether the probe can provide a diagnostic test of clinical value.

"The beauty of this approach is that it is completely non-invasive and without side effects," said Radu. "If we are successful in transporting this test to a clinical setting, patients will be able to go home immediately and resume their daily activities."

If testing in healthy subjects proves safe and effective, UCLA researchers will begin recruiting volunteers for a larger clinical study of the probe in cancer patients.

The study was funded by The Dana Foundation, National Cancer Institute, Department of Energy and Howard Hughes Medical Institute. Radu and Laing's coauthors included Martin Walter, Dean Campbell, Harvey Herschman, Nagichettiar Satyamurthy, Michael Phelps, Johannes Czernin and Owen Witte, all of UCLA.