Amyloid beta, the plaque that accumulates in the brains of people with Alzheimer’s disease, may also contribute to Alzheimer’s by interfering with normal blood flow in the brain, according to investigators at the University of Alabama at Birmingham.

In findings published Nov. 23 in the journal Brain, the team shows that when amyloid beta accumulates around blood vessels — where it is known as vascular amyloid — it appears to prevent the brain from properly regulating blood flow, which is essential to normal brain function.

“We have increasingly become aware that the disruption of blood flow in the brain can increase the risk of Alzheimer’s disease,” said Erik Roberson, M.D., Ph.D., associate professor in the UAB Department of Neurology. “While we have known that vascular amyloid built up around blood vessels, we did not fully understand its effects, and new technology now allows us to visualize how it affects the function of those vessels.”

Increased brain activity — remembering the lyrics to a song, for example — requires an increase in energy to the neurons responsible for memory. Neurons draw energy from glucose, which is transported by the blood stream. Cells called astrocytes regulate the diameter of blood vessels to increase or decrease blood flow and the corresponding glucose transportation. Astrocytes also tell the blood vessel to return to normal when the need has passed.

Astrocytes accomplish this signaling by means of projections called astrocytic endfeet, which wrap around the smooth muscle cells of the blood vessel wall. When a neuron calls for more glucose, the message is passed via the astrocytic endfeet, and the blood vessel expands and boosts blood volume.

The fate of astrocytic endfeet in a brain tumor study published last year at UAB led the research team to look more closely at vascular amyloid. UAB researchers led by Harald Sontheimer, Ph.D., then a professor in the Department of Neurobiology, published a paper in Nature Communications in June 2014 which showed that, in brain tumors, malignant astrocytes called glioma cells could travel along blood vessels and push astrocytic endfeet away, severing their connection to the vessel and interfering with their ability to regulate blood flow.

“We know vascular amyloid accumulates around the outside of blood vessels, and after seeing those research findings from the Sontheimer group, we wondered if these plaques could be doing the same thing,” Roberson said. “Working with Dr. Sontheimer and his laboratory, we used advanced imaging techniques — including high-resolution, 3-D image reconstructions from multiphoton laser scanning microscopes, and sophisticated labeling and experimental techniques — and were able to determine that, yes, vascular amyloid did push the astrocytic endfeet away and interfered with normal regulation of blood vessels.”

vascular slime3-D microscope image of blood vessels (in red) with surrounding vascular amyloid plaques (in green). Courtesy Ian Kimbrough.“In a live animal model of Alzheimer’s disease, we then activated the vascular smooth muscle cells with a pulsed laser, allowing us to mimic neuron-induced astrocyte-vascular signaling,” said Ian Kimbrough, a graduate research assistant in Neurobiology and a collaborator on the original brain tumor study. “In locations where no vascular amyloid was present, we saw a very dramatic and robust vessel response; however, on blood vessels that were surrounded by plaque, we saw a much diminished response.”

Kimbrough says that UAB is one of the few research centers in the Southeast with multiphoton laser-scanning microscopes, instruments capable of capturing images deep into a living brain. These images can then be used to create three-dimensional, volumetric representations of brain morphology.

“Using this 3-D model, which we can rotate and manipulate,” he said, “we can see the exact spatial relationship between the vasculature, the astrocytic endfeet and the vascular amyloid. This allows us to analyze how these elements interplay in a normal, healthy brain compared to an Alzheimer’s disease brain.”

Roberson and Kimbrough say that, as the plaque buildup worsens, the vascular amyloid forms rings around the blood vessels, with bridges eventually linking one ring to the next. These rings form a rigid exoskeleton on the vessels, restricting their ability to change in diameter when increased blood flow is demanded by neurons.

“The vessel has to be able to expand and contract, to dilate and constrict, if it’s going to regulate blood flow,” Roberson said. “If they have become rigid like a pipe, instead of having a flexible wall that can go back and forth, then they cannot do their job of regulating blood flow to the brain properly.”

“This was among the first studies to really attempt to understand the relationship between vascular amyloid and blood flow in the brain,” he said. “For the first time, using the amazing technology at our disposal, we can see what is happening in the vessel walls in real time, to better understand how the presence of vascular amyloid effects the function of that vessel.”

Funding for the study came from the National Institutes of Health.

By: Bob Shepard
      UAB Media Relations
Engineers, physicians, computer scientists and statisticians will collaborate to research and apply big data in the health care, industrial and smart cities fields.

big data hub 2The lab is a joint initiative of the School of Engineering’s Department of Electrical and Computer Engineering, the Department of Neurology in the School of Medicine, and UAB IT Research Computing.The Big Data Research and Analytics Lab in the UAB School of Engineering, along with UAB Information Technology Research Computing and the School of Medicine’s Department of Neurology, will be part of a national effort to develop a Big Data Regional Innovation Hub serving 16 Southern states and the District of Columbia.

The South Big Data Regional Innovation Hub, or South BD Hub — to be managed jointly by Georgia Tech and the University of North Carolina — is part of the National Science Foundation’s four Big Data Regional Innovation Hubs announced today. The new initiative aims to build innovative public-private partnerships that address regional challenges through big data analysis.

“The award of the South Big Data Regional Innovation Hub to Georgia Tech and UNC-Chapel Hill provides the right context for collaboration among 116 stakeholders in academia, industry and the nonprofit sectors, which will enable us to — for the first time — address large-scale challenges facing many Southern states,” said Srinivas Aluru, co-principal investigator and professor in the School of Computational Science and Engineering at Georgia Tech.

Each of the NSF BD Hubs will engage businesses and research organizations in their region to develop common big data goals that would be impossible for individual members to achieve alone. The hubs will develop community-driven governance structures as well as “spoke projects” based on regional priorities and partnerships.

“Big data analysis is changing the way we see the world and is one of the more profound developments in science that we’ve seen in our lifetime,” said Iwan Alexander, Ph.D., dean of the UAB School of Engineering. “At UAB, we are uniquely positioned because of the wide range of expertise here in areas from engineering to medicine to business. Our Big Data Research and Analytics Lab has the potential to touch every part of campus, and as such, it can provide valuable input to this national network.”

In particular, UAB’s contributions to the South BD Hub are expected to be concentrated around the issues of health care, industrial big data and smart cities. UAB’s effort is being led by Thomas Anthony, director of the Big Data Research and Analytics Lab.

The lab is a joint initiative of the School of Engineering’s Department of Electrical and Computer Engineering, the Department of Neurology in the School of Medicine, and UAB IT Research Computing. The lab has been set up to bring together engineers, physicians, computer scientists and statisticians to develop novel ways to manage, analyze and visualize very large data sets.

big data hub 3UAB’s contributions to the South BD hub are expected to be concentrated around the issues of health care, industrial big data and smart cities.In addition to serving as a facility to process data generated at UAB and gathered through research of publicly available datasets, the lab is also working on emerging technologies and approaches to big data analytics that would be applicable to a large number of fields, which demonstrates the potential for big data to make a big impact on 21st century life.

“The important problems of our time — from solving disparities in health care to understanding the risks of coastal storms and floods — involve making sense of massive amounts of data,” said Ashok Krishnamurthy, deputy director at RENCI and co-PI with Aluru on the South BD Hub project. “The chance to lead this project with Georgia Tech means we will be at the forefront of using data for the public good.”

The South BD Hub will serve Alabama, Arkansas, Delaware, the District of Columbia, Florida, Georgia, Kentucky, Louisiana, Maryland, Mississippi, North Carolina, Oklahoma, South Carolina, Tennessee, Texas, Virginia and West Virginia. It will be developed in three phases — an initial bootstrap phase that will establish the basic governance structure, a transitional phase that will move toward an operational structure and a final operational phase.

Initial spokes of the South BD Hub will aim to apply big data analysis to scientific and social issues in five areas:

  • Health Care, including disparities in health, access to health care, health outcomes, precision medicine and health analytics.
  • Coastal Hazards, including understanding and mitigating the consequences of natural and manmade disasters.
  • Industrial Big Data, including cyberphysical systems, the Internet of Things, data-driven management of physical infrastructure, and power generation, transmission and distribution from a variety of sources.
  • Materials and Manufacturing, including data-driven contributions to the materials genome initiative and bridging the gap between materials science and manufacturing practice.
  • Habitat Planning, including urban infrastructure, smart cities efforts, transportation, rural-urban infrastructure, and wildlife habitat and conservation.
Initial NSF funding for the South BD Hub will be $1.5 million over three years. In addition to the South BD Hub, the NSF has funded Hubs in the Northeast, Midwest and Western U.S., which are managed by universities in those regions.





A multicenter study led by the University of Alabama at Birmingham
has found a biomarker identified via electroencephalography, or EEG,
that is 100 percent predictive for seizures in infants with tuberous
sclerosis complex. TSC is a genetic disorder that causes nonmalignant
tumors to form in many different organs, primarily in the brain, eyes,
heart, kidney, skin and lungs. The study is published online in Pediatric Neurology.

Approximately 80 percent of TSC patients develop seizures between
birth and age 3. The new EEG biomarker, the first of its kind in TSC
patients, presents as an abnormality in the EEG called an epileptiform
discharge. In the study, all infants with the biomarker developed
seizures within two to three months.

“The earlier seizures are recognized and treated, the better the
developmental outcomes for children with TS,” said E. Martina Bebin,
M.D., professor in the Department of Neurology
at UAB and the study’s senior author. “The development of this
predictive biomarker may provide a critical window of opportunity for
families and medical providers to initiate treatment at seizure onset,
with potentially a positive impact on the infant’s developmental
outcome.”

The study, conducted at five medical centers across the United States, examined 40 children with a diagnosis of TSC.

The presence of the biomarker means families will need to learn the
identifying signs of seizures and begin to involve a neurologist in
their child’s care prior to actual seizure onset. Bebin says the study
reinforces the idea that EEG should be done at time of diagnosis for
TSC, and repeated on a regular basis. The study conducted EEG every six
weeks.

“The results of this study not only support the importance of that
initial EEG but also the importance of subsequent EEGs in monitoring the
development of seizures and epileptiform discharges,” Bebin said. “Our
study demonstrates the feasibility and importance of close EEG
surveillance in infants with TSC for predicting those who will
subsequently develop epilepsy.”

“The results of this study not only support the importance of that
initial EEG but also the importance of subsequent EEGs in monitoring the
development of seizures and epileptiform discharges. Our study
demonstrates the feasibility and importance of close EEG surveillance in
infants with TSC for predicting those who will subsequently develop
epilepsy.”

Bebin says further studies are needed to better understand the
relationship between various therapeutic agents and the biomarker, along
with determination of the optimal timeframe in which to begin therapy.

Tuberous sclerosis complex is an autosomal dominant disease that
affects approximately one in 6,000 people and is one of the most common
genetic causes of epilepsy. Almost half of infants with TSC develop
epilepticspasms, which is associated with poor neurological prognosis.

The research team consisted of Bebin, Monisha Goyal, M.D., and Gary
Cutter, Ph.D., with UAB; Joyce Y. Wu, M.D., University of California at
Los Angeles; Jurriaan M. Peters, M.D., Ph.D., and Mustafa Sahin, M.D.,
Ph.D., Boston Children’s Hospital; Darcy Krueger, M.D., Ph.D.,
Cincinnati Children’s Hospital Medical Center; and Hope Northrup, M.D.,
and Kit Sing Au, M.D., University of Texas Medical School at Houston.

The multicenter study was funded by the National Institutes of Health and the Tuberous Sclerosis Alliance.
Pursuing links between inflammation and Parkinson’s, in lab and clinic

Pursuing links between inflammation and Parkinson’s, in lab and clinic



October 13, 2015

By Jeff Hansen



UAB's strengths in clinical care and research are powering an interdisciplinary expedition into largely uncharted territory: neuroinflammatory mechanisms in Parkinson's disease.



A group of UAB researchers have set themselves a two-year target — put an interdisciplinary team in place and have the necessary results in hand that will support the development of a Parkinson’s Disease Research Center of Excellence at UAB. Only nine such NIH-supported centers — also known as Morris K. Udall Centers — exist today, none in the Deep South.

UAB will focus on neuroinflammatory mechanisms in Parkinson’s disease, a gap in the research portfolio in the current centers. The team will probe how the body’s immune system may contribute to the pathology seen in the brains of Parkinson’s disease patients and to the development and progression of the disease.

Only recently have researchers begun to suspect an important role for inflammation in the disease, and that is still largely uncharted territory. Research in this area could lead to therapies that can slow the progression or stop the disease mechanisms of Parkinson’s. This is a vital need since no such therapies exist.

The research requires a mix of specialized expertise from both neuroimmunology and neurodegenerative diseases. UAB scientists David Standaert, M.D., Ph.D., Etty “Tika” Benveniste, Ph.D., and Andrew West, Ph.D., are leading that team, bolstered by a two-year exploratory, P20 grant that NIH recently awarded to support preparation for a subsequent Udall P50 grant application.

Seeking synergy

“With centers, the NIH always looks for synergy,” said Standaert, who is professor and chair of the UAB Department of Neurology and has deep knowledge of neurodegenerative disease medical care and research, particularly Parkinson’s. “The hallmark of a center is the openness and willingness to work together. You have to be willing to share your ideas and frustrations, and share your opinions, in a back and forth manner. Everyone has to give up something, but they will find that the whole is greater than each part taken alone.”

Standaert was previously director of the then-Massachusetts General Hospital/MIT Udall Center before coming to UAB. Benveniste, professor and chair of Cell, Developmental and Integrative Biology (CDIB) at UAB, investigates the connections between the immune system and the brain. West, associate professor of neurology at UAB and co-director of the UAB Center for Neurodegeneration and Experimental Therapeutics, focuses on research exploring genetic causes of Parkinson’s disease, and he has previously trained at the Mayo Clinic Udall Center for Excellence, the then-UCLA Udall Center for Excellence and the Johns Hopkins Udall Center for Excellence.

They are adding critical team members from outside the Parkinson’s disease research field to the existing core of expertise in the neurology department. These include researchers Hongwei Qin, Ph.D., M.D., an associate professor in CDIB who has studied the immune response in neurological diseases like multiple sclerosis; Chander Raman, Ph.D., an immunologist who is a professor of medicine; and Stephanie Guthrie, CRNP, a nurse practitioner who will be vital in obtaining blood samples from Kirklin Clinic patients who are newly diagnosed with Parkinson’s disease. Ashley Harms, Ph.D., an instructor in neurology who trained in neuroimmunology, will be the scientific coordinator for the P20 grant.

David Standaert

Immune residents, or infiltrators?

In addition to solidifying this core collaboration team, the researchers are testing key hypotheses in two pre-clinical model systems. Both of these systems have been engineered to have elevated levels of clumped α-synuclein in their brains to provoke innate immune responses. These model systems can differentiate between the activation of brain-resident immune cells and the infiltration of immune cells from outside the brain. This will lay the groundwork for targeting some of the control systems of these immune responses for therapeutic benefit in the mouse models.

Thirdly, the team will develop a pipeline to human subjects — so researchers can obtain blood from patients newly diagnosed with Parkinson’s.

“We see about one to three patients a month with newly diagnosed Parkinson’s disease at the Comprehensive Parkinson Disease and Movement Disorder Clinic, which has 11 physicians, four nurses, two nurse practitioners and about 6,000 patient visits a year,” Standaert said. “We need to catch them in that window when they are just diagnosed, before any treatment. This would be difficult to do at a smaller center, but we’re big enough to do that.”

Fresh blood is needed to isolate monocytes, which are innate immune system cells that reside outside of the brain. The monocytes will be purified the same day the blood is drawn and immediately tested to see if they have been activated for an immune response. “We get patient blood samples at the clinic, take them to the lab and study them that afternoon,” Standaert said. “The number of places that can do that is pretty few.”

Standaert has been building collaborations with Benveniste’s group for several years, but the appearance of an NIH request for applications for the P20 grant a year ago jump-started a greater push. “That galvanized the effort to bring together a team to ask, what are the critical questions in the field, and how can we build a team to address these problems?”

“This collaboration is what UAB does well,” Standaert said. “The project takes existing strengths — the great clinical operation at UAB and the fantastic scientists in UAB labs — and welds them together.”

The title of the P20 grant is “Innate and Adaptive Immunity in Parkinson Disease.”