TAG: "Imaging"

Research finds differences in brains, behavior of girls and boys with autism


UC Davis study uses imaging technique to neuroanatomically subdivide corpus callosum.

New research by the MIND Institute finds that the brains and behavior of girls with autism differs from that of boys with autism and typically developing girls.

By Phyllis Brown, UC Davis

New research conducted by the UC Davis MIND Institute on a large cohort of preschoolers with autism spectrum disorder has found differences in the underlying biology of their brains, and in their behavior, that may help explain how the condition affects a little-studied and poorly understood population of children: girls.

Autism spectrum disorder is diagnosed much more frequently in boys than girls, at a ratio of 4 to 1. Despite recent efforts, little research has been done on girls — there are fewer of them, so fewer are represented in autism research. An estimated 1 in 42 boys has autism; in girls the statistic is 1 in 189.

The U.S. Centers for Disease Control and Prevention currently estimates the overall incidence of autism at 1 in 68 children born today.

In a brain study, the researchers found differences in the corpus callosum, the region of the brain that connects the left and right hemispheres.

That study is published online today (May 12) in the journal Molecular Autism, as part of a special issue devoted to gender differences. It adds to the growing body of evidence that suggests that in autism, there are underlying biological differences between boys and girls.

In separate research presented at the International Meeting for Autism Research (IMFAR) in Salt Lake City May 13-16, the researchers find that the behavioral differences between girls who have autism and typically developing same-age girls are much greater than the differences between boys with autism and typically developing same-age males. The finding suggests that girls with autism have greater social impairments than do boys.

The research was led by Christine Wu Nordahl, assistant professor in the UC Davis Department of Psychiatry and Behavioral Sciences and principal investigator of the Girls with Autism Imaging of Neurodevelopment (GAIN) study.

“It’s important to identify differences in underlying biology in boys and girls, because this could help us determine whether there are different etiologies of autism, and that potentially could lead us to different treatments and interventions,” Nordahl said.

Brain study

The magnetic resonance imaging (MRI) study of brain structure was conducted in a large sample of 3- to 5-year-old children, 112 boys and 27 girls — a large number for girls with autism — and 53 boys and 29 girls who were developing typically and served as control subjects.

“Previous studies have found alterations in the corpus callosum in children and adults with autism, but most were focused on males only, or had very small female sample sizes,” Nordahl said.

The study used a technique called diffusion tensor imaging (DTI), a type of magnetic resonance imaging that allowed the researchers to neuroanatomically subdivide the corpus callosum, based on where in the cerebral cortex the fibers projected.

“We found that the organization of callosal fibers was different in boys and girls with autism, particularly those projecting into the frontal lobes,” she said. “The frontal lobes are involved in many aspects of functioning, including social behavior, goal-directed behavior and executive functioning. Differences in the patterns of callosal fibers projecting to these areas may lead to differences in how autism manifests in boys and girls.”

Behavioral study

For the preliminary research presented at IMFAR, Nordahl explored behavioral differences in boys and girls with autism. Research in the area previously has been inconsistent.

“Most behavioral studies of gender differences directly compare males and females with autism. Our approach was to evaluate social impairments in a large group of children that included girls and boys with both autism and typical development,” Nordahl said. “We were interested not only in directly comparing boys and girls with autism, but also in assessing how boys and girls with autism compare in relation to their typically developing peers.”

“We found that the behavioral differences between girls with autism and typically developing girls are much larger than differences between boys with autism and typically developing boys,” she said. “In other words, girls with autism deviate further from typically developing girls than boys with autism relative to typically developing males, suggesting that girls with autism have more severe social impairments than boys.”

Nordahl said that much more works needs to be done to understand the sex differences between male and female children with autism, and particularly, increasing the numbers of female children who participate in autism research.

Future studies in Nordahl’s laboratory will include targeted recruitment of girls with autism, in order to carry out a comprehensive evaluation of behavioral and neurobiological differences in boys and girls with autism in relation to each other, as well as to their typically developing peers.

“There definitely is a need to evaluate more girls with autism, to fully understand the differences between boys and girls,” she said.

Nordahl said that the GAIN Study hopes to evaluate an additional 100 preschool-aged girls with autism during the next three years.

For further information regarding enrollment in the study contact Study Coordinator Michelle Huynh, (916) 703-0410, mmhuynh@ucdavis.edu.

The study was funded by the National Institute of Mental Health R01 MH089626, U24 MH081810, R00 MH085099 and the UC Davis MIND Institute. Statistical support was provided by the MIND Institute Intellectual and Developmental Disabilities Research Center U54 HD079125.

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Seeing through Alzheimer’s disease


UC Berkeley’s William Jagust uses imaging to help find insights into Alzheimer’s.

William Jagust’s Alzheimer’s research has found evidence of neuron networks breaking down. (Photo by Peg Skorpinski, UC Berkeley)

By Wallace Ravven

A jury would have to acquit. Two tough guys are caught at the scene of a brutal beating, but no one witnessed the crime. No video cameras or cell phone captured the assault. Maybe both men arrived after the attack. Or one might have acted alone. They’re suspicious, but not guilty beyond a reasonable doubt.

The same might be said about our current understanding of how Alzheimer’s disease develops. Two proteins — called beta-amyloid and tau — definitely muck up neurons in Alzheimer’s victims.  Amyloid clumps into plaques that interfere with cell-to-cell communication. Tau proteins contort into tangled fibers inside the cells.

But until recently, neuroscientists have not been able to track the course of Alzheimer’s in the brain. Amyloid and tau might not destroy neurons directly, or perhaps amyloid works alone, wrecking the delicate integrity of neural networks and degrading memory.

Researchers have been limited to a single snapshot of the brain — one view of the battlefield provided by an autopsy. The course and chronology of the damage that steals memory are still up for grabs.

“We’ve been scratching our heads about how these two proteins are related to each other and to the cause of Alzheimer’s for literally 100 years,” says Berkeley neuroscientist William Jagust. “We don’t know the difference between ‘normal’ memory loss and the likely pathology associated with tau. We don’t know whether amyloid or tau is most important in Alzheimers, or if amyloid plaques between neurons affect the tau tangles inside cells.”

But there’s a sense of anticipation in the air, buoyed by researchers’ increasing ability to peer into the brains of people struggling with Alzheimer’s as well as  seniors free of its grip. In the past decade, PET scans and other powerful new imaging tools have begun to fill in the story of how healthy and damaged brains change throughout life.

“We still have many questions and few answers,” Jagust says. “But brain PET scanning in both diseased and healthy people is sort of blowing that wide open. We now have the tools to study the progression of plaque formation from its earliest stages and to determine how amyloid and tau affect cognitive decline over time.

Before PET scanning, Jagust says, researchers already knew from autopsies that about a third of older people with amyloid plaques had no symptoms of cognitive decline.

“This created the argument: ‘If they have no symptoms, how can it be that amyloid causes Alzheimer’s?’ You can’t answer that with an autopsy.” But if periodic PET scans show increasing plaque deposition over time as cognitive loss becomes severe, then the plaque argument becomes much stronger.

Research in his lab supports the hypotheses that plaques interfere with the formation or maintenance of synaptic connections. Using the metabolic imaging technique of functional MRI, he focused on plaque-ridden brains of healthy older people, and found indirect, but strong evidence that connections within networks of neurons were breaking down.

“Parts of the brain that should be connected strongly are becoming weakly connected, and parts that are normally not strongly connected become so. It’s almost like the brain is becoming rewired.”

But the rewiring evidence cuts both ways. In another study, Jagust found that some people with amyloid plaques performed as well on memory tests as those who were plaque-free. In some of them, novel connections appeared between neurons in their brains, suggesting new networks were in play.

“There is evidence of ‘rewiring’ that appears to be detrimental, but also evidence of ‘rewiring’ that may serve a compensatory role  — providing a cognitive reserve,” he says. “The balance between these in individuals may explain why some decline and others do not.” The research was published in 2013 in the Journal of Neuroscience and in 2014 in Nature Neuroscience.

Several large clinical trials have shown that experimental immunotherapeutic drugs can at least moderately slow Alzheimer’s amyloid plaque deposition. So far, the decline in plaque buildup has not slowed memory loss. But Jagust is confident that the tremendous boost in brain imaging will lead to effective therapies.

One ambitious study, just launched at Harvard and UC San Diego neuroscientists, combines refined imaging and drug trial, focusing on 1,000 people in their 70s and 80s. Study participants do not have Alzheimer’s, though some have amyloid plaques. Researchers hope that by intervening early enough with drugs to slow plaque accumulation, they can prevent or at least delay severe cognitive loss. If early intervention is key, then so is the ability to detect even the slightest sign of neurological damage. The Jagust Lab is using statistical and computational approaches to refine PET scan sensitivity.

In images of people’s brains with significant amyloid deposits, the protein shows up clearly as fiery orange bands across the cerebral cortex, or gray matter areas of the brain. Jagust suspects that improved scanning will allow researchers to spot mere traces that hint at possible trouble to come. The lab is also beginning studies that will image accumulations of tau, allowing the researchers to understand the relationships between tau and amyloid, and provide another target for drug development.

“If the images can tease apart the different roles of beta-amyloid and tau, and if we can detect damage in its very earliest stages, we would have strong reason to hope that new drugs can spare or significantly slow cognitive damage. I don’t think this is being overly optimistic.”

In recognition of his research on brain aging and dementia, Jagust received the 2013 Potamkin Prize for Research in Pick’s, Alzheimer’s and Related Diseases by the American Academy of Neurology and the American Brain Foundation.

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Spinal cord axon injury location determines neuron’s regenerative fate


Imaging advances revealing insights into body’s ability to respond to spinal cord injuries.

Injury to a spinal cord axon after a major branch point.

By Heather Buschman, UC San Diego

Researchers at the UC San Diego School of Medicine report a previously unappreciated phenomenon in which the location of injury to a neuron’s communication wire in the spinal cord — the axon — determines whether the neuron simply stabilizes or attempts to regenerate. The study, published today (April 30) by Neuron, demonstrates how advances in live-imaging techniques are revealing new insights into the body’s ability to respond to spinal cord injuries.

While the body of a neuron is small, its axon can extend far up or down the spinal cord, which is about one and half feet long in humans. Along that distance, the axon branches out to make hundreds of connections with other cells, sending out signals that allow us to sense and respond to the world around us. Unless something happens to disrupt the axon’s reach, that is. Adult human axons in the brain and spinal cord are very limited in their ability to regenerate after injury — a hurdle that many researchers are trying to overcome in the treatment of spinal cord injuries and neurodegenerative diseases of the brain.

In this study, senior author Binhai Zheng, Ph.D., associate professor of neurosciences, first author Ariana O. Lorenzana, Ph.D., and colleagues used a sophisticated optical imaging technique that allows them to directly visualize the spinal cord in living mouse models. With this approach, the researchers were able to systematically examine the effects of axon injury location on degeneration and regeneration of the injured branch. The injury locations they compared were just before an axon’s major branch point (where a single axon branches into two) and just after it. The injuries just after the branch point cut off one branch, leaving the other intact, or cut both branches.

The researchers found that injury to the main axon, before a branch point, resulted in regeneration in 89 percent of the cases. Axons with both branches cut after a branch point regenerated in 67 percent of cases. Regeneration occurred in the form of axon elongation, branching or both for at least five days after injury. In contrast, regeneration occurred only 12 percent of cases following cuts to just one of two axon branches after a major branch point. In this case, the injured branch trims itself all the way back to the base, preserving the function of the other, uninjured branch.

“What we think is happening is that if an axon is injured in such a way that it still has some kind of connection, is still transmitting signals, the neuron can justify stabilization, but not the energy it would take to either regenerate axon length or just kill the whole thing off,” Zheng said. “On the other hand, once both branches of an axon are cut and there’s no longer any connection or output, the neuron can justify the energy and resources to regenerate, even though that effort is largely futile in the central nervous system of an adult mammal.”

This is a new, yet very fundamental, understanding of neuron behavior — one that will be important to keep in mind as new therapeutic approaches are proposed for spinal cord injuries, the researchers say.

Co-authors of this study include Jae K. Lee, Matthew Mui, and Amy Chang, all of UC San Diego.

This research was funded, in part, by the National Institutes of Health (grants R01NS054734, R21NS088536, F31NS074867 and F32NS056697), Dana Foundation and Roman Reed Foundation.

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Federal funding boosts breast CT scanning research and development


National Cancer Institute awards $2.9M grant to John Boone of UC Davis.

By Dorsey Griffith, UC Davis

John M. Boone, a UC Davis medical physicist and professor of radiology, has been awarded a $2.88 million grant from the National Cancer Institute to further develop and research computed tomography (CT) to detect breast cancer.

Boone is a pioneer in breast CT, working with a team of scientists and physicians for more than 15 years to develop the technology. His team has built four breast CT scanners, each with successive improvements in spatial resolution.

The project, “Breast CT: Final Steps to Translation,” will involve 400 women who have been identified through standard-of-practice methods to have suspicious lesions that require breast biopsy.

The study will make two comparisons. In the first, mammography will be compared to breast CT to determine which modality is better at detecting breast lesions that are ultimately proven to be cancerous. The study also will compare contrast-enhanced breast CT with contrast-enhanced magnetic resonance imaging (MRI). In contrast-enhanced imaging, the patient is injected with a contrast agent, which helps distinguish vascular tumors, such as those in the breast.

Boone said the goal of the first comparison is to evaluate if breast CT better is a better screening method for detecting lesions that turn out to be malignant.

“Because breast cancer can present as both soft tissue masses and as micro-calcifications, this means that our newest scanner needs to detect both better than digital mammography,” he said. “Only then will breast CT technology be able to improve breast cancer detection rates in women at normal risk for breast cancer.”

The second comparison aims to demonstrate that breast CT with contrast is more efficient to examine the breast than MRI, taking less time for both the patient and for diagnostic evaluation by the radiologist.

“If shown to be equivalent to contrast-enhanced breast MRI, contrast-enhanced breast CT would be a viable and far more cost-effective tool for imaging women with suspicious lesions,” Boone said. “This would likely reduce the negative biopsy rate and increase the positive predictive value of breast imaging in general.”

More than 300 patients already have undergone breast CT at UC Davis. Through a collaborative arrangement with the University of Pittsburgh, a UC Davis-designed breast CT machine has been used to scan an additional 300 patients. The research team has published nearly 50 papers on breast CT in the past 15 years.

“Our long-term goals are to show with our newest scanner that we can improve cancer detection rates in the screening population over that of mammography and tomosynthesis,” Boone said. “By increasing the performance of breast cancer screening in a practical and cost-efficient manner, we hope to move the standard-of-care to true 3-D breast imaging in order to improve care and increase survival in women with breast cancer, and importantly to also reduce over-treatment of women with benign findings.”

In addition to Boone, co-investigators include Karen Lindfors, Shadi Aminololama-Shakeri and Tony Seibert, all of UC Davis, and Craig Abbey of UC Santa Barbara.

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Brain imaging explains reason for language outcomes in autistic toddlers


Findings could help determine how and why treatments are effective for some, but not all.

By Scott LaFee, UC San Diego

Using functional magnetic resonance imaging (fMRI), UC San Diego School of Medicine researchers say it may be possible to predict future language development outcomes in toddlers with autistic spectrum disorder (ASD), even before they’ve been formally diagnosed with the condition.

The findings are published in today’s (April 9) online issue of the journal Neuron.

A major challenge of ASD diagnosis and treatment is that the neurological condition – which affects 1 in 68 children in the United States, mostly boys – is considerably heterogeneous. Early symptoms differ between each ASD toddler, as does progression of the condition. No uniform clinical phenotype exists, in part because the underlying causes for different subtypes of autism are diverse and not well-understood.

“There is no better example than early language development,” said senior author Eric Courchesne, Ph.D., professor of neurosciences and co-director of the Autism Center of Excellence at UC San Diego. “Some individuals are minimally verbal throughout life. They display high levels of symptom severity and may have poor clinical outcomes. Others display delayed early language development, but then progressively acquire language skills and have relatively more positive clinical outcomes.”

In other words, said Courchesne, in some children with ASD language improves substantially with age; but in some it may progress too slowly or even diminish. The neurodevelopmental bases for this variability are unknown, he said. Differences in treatment quantity do not fully account for it. But numerous studies have shown that early, accurate diagnoses of ASD can improve treatment benefits in many affected children.

“It’s important to develop more and new biological ways to identify and stratify the ASD population into clinical subtypes so that we can create better, more individualized treatments,” said co-author Karen Pierce, Ph.D., associate professor of neurosciences and co-director of the Autism Center of Excellence.

In the Neuron paper, Courchesne, first author Michael V. Lombardo, Ph.D., a senior researcher at the University of Cambridge and assistant professor at the University of Cyprus, Pierce and colleagues describe the first effort to create a process capable of detecting different brain subtypes within ASD that underlie and help explain varying development language trajectories and outcomes. “We wanted to see if patterns of brain activity in response to language can explain and predict how well language skills would develop in a toddler with ASD before that toddler actually began talking,” said Courchesne.

The researchers combined prospective fMRI measurements of neural systems’ response to speech in children at the earliest ages at which risk of ASD can be clinically detected in a general pediatric population (at approximately ages 1-2 years) with comprehensive longitudinal diagnostic and clinical assessments of language skills at 3-4 years of age.

They found that pre-diagnosis fMRI response to speech in ASD toddlers with relatively good language outcomes was highly similar to non-ASD comparison groups with robust responses to language in superior temporal cortices, a region of the brain responsible for processing sounds so that they can be understood as language.

In contrast, ASD toddlers with poor language outcomes had superior temporal cortices that showed diminished or abnormal inactivity to speech.

In sum, the study found entirely different neural substrates at initial clinical detection that precede and underlie later good versus poor language outcome in autism. These findings, said researchers, will open new avenues of progress towards identifying the causes and best treatment for these two very different types of autism.

“For the first time, our study shows a strong relationship between irregularities in speech-activation in the language-critical superior temporal cortex and actual, real-world language ability in ASD toddlers,” said Lombardo.

The scientists said fMRI imaging also showed that the brains of ASD toddlers with poor language development processed speech differently, including how neural regions governing emotion, memory and motor skills were involved.

“Our work represents one of the first attempts using fMRI to define a neurofunctional biomarker of a subtype in very young ASD toddlers,” said Pierce. “Such subtypes help us understand the differences between persons with ASD. More importantly, they can help us determine how and why treatments are effective for some, but not all, on the autism spectrum.”

Co-authors include Lisa Eyler, UCSD and Veterans Affairs San Diego Healthcare System; Cindy Carter Barnes, Clelia Ahrens-Barbeau, Stephanie Solso, and Kathleen Campbell, UCSD.

Funding for this research came, in part, from National Institute of Mental Health grants P50-MH081755, R01-MH080134 and R01-MH036840, the National Foundation for Autism Research and Jesus College, Cambridge and the British Academy.

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Retired NFL players who suffered concussions show pattern of protein deposits


New test may lead to better identification of brain disorders like CTE.

PET scan of a brain with suspected CTE. More red and yellow indicates more abnormal brain proteins.

By Rachel Champeau, UCLA

A new UCLA study takes another step toward the early understanding of a degenerative brain condition called chronic traumatic encephalopathy, or CTE, which affects athletes in contact sports who are exposed to repetitive brain injuries. Using a new imaging tool, researchers found a strikingly similar pattern of abnormal protein deposits in the brains of retired NFL players who suffered from concussions.

The innovative imaging technique uses a chemical marker combined with positron emission tomography, or PET scan, and was initially tested in five retired NFL players and described in an article published in 2013. Now, building on their previous work, the UCLA researchers found the same characteristic pattern in a larger number of retired players who had sustained concussions.

The latest study also shows that the brain imaging pattern of people who have suffered concussions is markedly different from the scans of healthy people and from those with Alzheimer’s disease. Researchers say the findings could help lead to better identification of brain disorders in athletes and would allow doctors and scientists to test treatments that might help delay the progression of the disease before significant brain damage and symptoms emerge.

The study appears in today’s (April 6) online edition of the Proceedings of the National Academy of Science.

CTE is thought to cause memory loss, confusion, progressive dementia, depression, suicidal behavior, personality changes and abnormal gaits and tremor.

Common factor in CTE and Alzheimer’s

Currently, CTE can only be diagnosed definitively following autopsy. To help identify the disease, doctors look for an accumulation of a protein called tau in the regions of the brain that control mood, cognition and motor function. Tau is also one of the abnormal protein deposits found in the brains of people with Alzheimer’s, although in a distribution pattern that is different from that found in CTE.

“The distribution pattern of the abnormal brain proteins, primarily tau, observed in these PET scans, presents a ‘fingerprint’ characteristic of CTE,” said Dr. Jorge Barrio, senior author of the study and a professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA.

The team identified four stages of deposits that could signify early to advanced levels of CTE.

“These different stages reflected by the brain marker may give us more insight into how CTE develops and allow us to track the disease over time,” said Dr. Vladimir Kepe, an author of the study and a research pharmacologist in molecular and medical pharmacology at the Geffen School of Medicine.

The new, larger study included 14 retired NFL players (including the five subjects from the earlier study), all of whom had sustained at least one concussion. Their results were compared with those of 19 men and nine women with healthy brains and 12 men and 12 women with Alzheimer’s disease of similar ages.

Participants received a scan using the UCLA-developed technique, which previously was used for assessing neurological changes associated with Alzheimer’s disease. The test involves injecting a chemical marker called FDDNP, which binds to deposits of neurofibrillary tau “tangles” and amyloid beta “plaques” — the hallmarks of Alzheimer’s. Then, using PET scans, the researchers were able to pinpoint where in the brain these abnormal proteins accumulated.

Participants also underwent MRI scans, neuropsychological testing, and neurological and physical exams to determine whether they had symptoms consistent with CTE, Alzheimer’s dementia or normal aging.

“We found that the imaging pattern in people with suspected CTE differs significantly from healthy volunteers and those with Alzheimer’s dementia,” said Dr. Julian Bailes, an author of the study and director of the Brain Injury Research Institute and the Bennett Tarkington Chairman of the Department of Neurosurgery at NorthShore University HealthSystem in Evanston, Illinois. “These results suggest that this brain scan may also be helpful as a test to differentiate trauma-related cognitive issues from those caused by Alzheimer’s disease.”

Tau and CTE

The PET scans revealed that the imaging patterns of the retired football players showed tau deposit patterns consistent with those that have been observed in autopsy studies of people with CTE.

In addition, the areas in the brain where the patterns occurred were also consistent with the types of symptoms experienced by some of the study participants.

Compared with healthy people and those with Alzheimer’s, the former athletes had higher levels of FDDNP in the amygdala and subcortical regions of the brain, which are areas that control learning, memory, behavior, emotions, and other mental and physical functions.

People with Alzheimer’s, on the other hand, had higher levels of FDDNP in areas of the cerebral cortex that control memory, thinking, attention and other cognitive abilities. And the athletes who had experienced more concussions also had higher FDDNP levels.

The next stage of the research will include multisite studies and will follow subjects over time to determine how effectively FDDNP can detect possible CTE and predict future symptoms. Researchers also will expand the studies to include other groups of people affected by brain injury, such as military personnel.

Previous brain autopsy studies have shown that amyloid plaques are present in less than 45 percent of retired football players, most typically in those with advanced CTE. Most of the retired players in the new study did not have advanced CTE, which suggests that their FDDNP signal represents mostly tau deposits in the brain.

The scans of people with the highest levels of FDDNP binding in areas where tau accumulates in CTE, also show binding in areas of the brain affected by amyloid plaques, which is consistent with autopsy findings indicating that this abnormal protein also plays a role in more serious cases of CTE.

The team also reported initial results of scans of two military veterans. Researchers note that more expanded studies will help them better understand how different causes of head injury may contribute to chronic brain disorders.

In the paper, the researchers note that the FDDNP PET scan is one of several methods — including blood-based biomarkers, diffusion tensor imaging MRI and resting state functional MRI — that are being studied by scientists across the country to help diagnose CTE early.

With more than 500 neuroscientists throughout campus, UCLA is a leader in research to understand the human brain, including efforts to treat, cure and prevent traumatic brain injury and brain disorders such as Alzheimer’s disease.

This study was supported by grants from the NIH (P01-AG025831 and M01-RR00865) and gifts to UCLA from the Toulmin Foundation and Robert and Marion Wilson. No company provided research funding for this study.

The FDDNP marker used with brain PET scans to identify abnormal proteins is intellectual property owned by UCLA and licensed to TauMark, LLC. UCLA authors Dr. Jorge Barrio, Dr. Gary Small and Dr. Sung-Cheng Huang are co-inventors of the PET marker. Barrio and Small have a financial interest in the company. Other disclosures are available in the manuscript.

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UC Davis: Study finds characteristic pattern of protein deposits in retired NFL players’ brains

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‘Gold standard’ method created for measuring key early sign of Alzheimer’s


UCLA helps validate first standardized protocol for measuring an early sign of Alzheimer’s.

Liana Apostolova, UCLA

By Mark Wheeler, UCLA

After six years of painstaking research, a UCLA-led team has validated the first standardized protocol for measuring one of the earliest signs of Alzheimer’s disease — the atrophy of the part of the brain known as the hippocampus.

The finding marks the final step in an international consortium’s successful effort to develop a unified and reliable approach to assessing signs of Alzheimer’s-related neurodegeneration through structural imaging tests, a staple in the diagnosis and monitoring of the disease. The study is published in the journal Alzheimer’s and Dementia.

Using brain tissue of deceased Alzheimer’s disease patients, a group headed by Dr. Liana Apostolova, director of the neuroimaging laboratory at the Mary S. Easton Center for Alzheimer’s Disease Research at UCLA, confirmed that the newly agreed-upon method for measuring hippocampal atrophy in structural MRI tests correlates with the pathologic changes that are known to be hallmarks of the disease — the progressive development of amyloid plaques and neurofibrillary tangles in the brain.

“This hippocampal protocol will now become the gold standard in the field, adopted by many if not all research groups across the globe in their study of Alzheimer’s disease,” said Apostolova, who was invited to play a key role in the consortium because of her reputation as one of the world’s leading experts in hippocampal structural anatomy and atrophy. “It will serve as a powerful tool in clinical trials for measuring the efficacy of new drugs in slowing or halting disease progression.”

The brain is the least accessible and most challenging organ to study in the human body; as a result, Alzheimer’s disease can be diagnosed definitively only by examining brain tissue after death. In living patients, physicians diagnose Alzheimer’s by evaluating other health factors, known as biomarkers, in combination with memory loss and other cognitive symptoms.

The hippocampus is a small region of the brain that is associated with memory formation, and memory loss is the earliest clinical feature of Alzheimer’s disease. Its shrinkage or atrophy, as determined by a structural MRI exam, is a well-established biomarker for the disease and is commonly used in both clinical and research settings to diagnose the disease and monitor its progression.

But until now, the effectiveness of structural MRI has been limited because of the widely different approaches being used to identify the hippocampus and measure its volume — which has called into question the validity of this approach. A typical hippocampus is about 3,000 to 4,000 cubic millimeters in volume. But, Apostolova notes, two scientists analyzing the same structure can come up with a difference of as much as 2,000 cubic millimeters.

In addition, no previous study had verified whether estimates for the volume of the hippocampus using MRI corresponded to actual tissue loss.

To address these deficiencies, the European Alzheimer’s Disease Consortium–Alzheimer’s Disease Neuroimaging Initiative was established to develop a Harmonized Protocol for Hippocampal Segmentation, or HarP — an effort to establish a definitive method for measuring hippocampal shrinkage through structural MRI in a way that best corresponds to the Alzheimer’s disease process.

Once the HarP was established, Apostolova and four other experts were invited to develop the gold standard for measuring the hippocampus to be used by anyone employing the HarP protocol. The UCLA-led team then validated the technique and ensured the changes in the hippocampus corresponded to the hallmark pathologic changes associated with Alzheimer’s disease.

“The technique is meant to be used on scans of living human subjects, so it’s important that we are absolutely certain that this methodology measures what it is supposed to and captures disease presence accurately,” Apostolova said.

To do that, her group used a powerful 7 Tesla MRI scanner to take images of the brain specimens of 16 deceased individuals — nine who had Alzheimer’s disease and seven who were cognitively normal — each for 60 hours. This provided unprecedented visualization of the hippocampal tissue, Apostolova said.

After applying the protocol to measure the hippocampal structures, the researchers analyzed the tissues for two changes that signify the disease: a buildup of amyloid tau protein and loss of neurons. The team found a significant correlation between hippocampal volume and the Alzheimer’s disease indicators.

“As a result of the years of scientifically rigorous work of this consortium, hippocampal atrophy can finally be reliably and reproducibly established from structural MRI scans,” Apostolova said.

Although the technique can be used immediately in research settings such as clinical trials, the next step, Apostolova noted, will be to use the standardized protocol to validate automated techniques available for measuring the hippocampus so the approach could be used more widely — including for the diagnosis of the disease in doctor’s offices and other patient care settings.

Funding for the study was provided by the National Institute on Aging (P50 AG16570), the Jim Easton Consortium for Alzheimer’s Drug Discovery and Biomarker Development, the National Institutes of Health (R01 AG040770), and the Alzheimer’s Association (IIRG 10-174022). Please see the paper for a complete list of the study’s authors.

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New clues about risk of cancer from low-dose radiation


Berkeley Lab research could lead to ways to ID people particularly susceptible to cancer.

By Dan Krotz, Berkeley Lab

Scientists from the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) have uncovered new clues about the risk of cancer from low-dose radiation, which in this research they define as equivalent to 100 millisieverts or roughly the dose received from ten full-body CT scans.

They studied mice and found their risk of mammary cancer from low-dose radiation depends a great deal on their genetic makeup. They also learned key details about how genes and the cells immediately surrounding a tumor (also called the tumor microenvironment) affect cancer risk.

In mice that are susceptible to mammary cancer from low-dose radiation, the scientists identified more than a dozen regions in their genomes that contribute to an individual’s sensitivity to low-dose radiation. These genome-environment interactions only become significantly pronounced when the mouse is challenged by low-dose radiation.

The interactions also have a big impact at the cellular level. They change how the tumor microenvironment responds to cancer. Some of these changes can increase the risk of cancer development, the scientists found.

They report their research March 9 in the journal Scientific Reports.

Because mice and humans share many genes, the research could shed light on the effects of low-dose radiation on people. The current model for predicting cancer risk from ionizing radiation holds that risk is directly proportional to dose. But there’s a growing understanding that this linear relationship may not be appropriate at lower doses, since both beneficial and detrimental effects have been reported.

“Our research reinforces this view. We found that cancer susceptibility is related to the complex interplay between exposure to low-dose radiation, an individual mouse’s genes, and their tumor microenvironment,” says Jian-Hua Mao of Berkeley Lab’s Life Sciences Division.

Mao led the research in close collaboration with fellow Life Science Division researchers Gary Karpen, Eleanor Blakely, Mina Bissell and Antoine Snijders, and Mary Helen Barcellos-Hoff of New York University School of Medicine.

The identification of these genetic risk factors could help scientists determine whether some people have a higher cancer risk after exposure to low-dose radiation. It could lead to genetic screening tests that identify people who may be better served by non-radiation therapies and imaging methods.

The scientists used a comprehensive systems biology approach to explore the relationship between genes, low-dose radiation, and cancer. To start, Mao and colleagues developed a genetically diverse mouse population that mimics the diversity of people. They crossed a mouse strain that is highly resistant to cancer with a strain that is highly susceptible. This yielded 350 genetically unique mice. Some were resistant to cancer, some were susceptible, and many were in between.

Next, Mao and colleagues developed a way to study how genes and the tumor microenvironment influence cancer development. They removed epithelial cells from the fourth mammary gland of each mouse, leaving behind the stromal tissue. Half of the mice were then exposed to a single, whole-body, low dose of radiation. They then implanted genetically identical epithelial cells, which were prone to cancer, into the fourth mammary glands that were previously cleared of their epithelial cells.

“We have genetically different mice, but we implanted the same epithelial cells into all of them,” says Mao. “This enabled us to study how genes and the tumor microenvironment — not the tumor itself — affect tumor growth.”

The scientists then tracked each mouse for 18 months. They monitored their tumor development, the function of their immune systems, and the production of cell-signaling proteins called cytokines. The researchers also removed cancerous tissue and examined it under a microscope.

They found that low-dose radiation didn’t change the risk of cancer in most mice. A small minority of mice was actually protected from cancer development by low-dose radiation. And a small minority became more susceptible.

In this latter group, they found thirteen gene-environment interactions, also called “genetic loci,” which contribute to the tumor susceptibility when the mouse is exposed to low-dose radiation. How exactly these genetic loci affect the tumor microenvironment and cancer development is not yet entirely understood.

“In mice that were susceptible to cancer, we found that their genes strongly regulate the contribution of the tumor microenvironment to cancer development following exposure to low-dose radiation,” says Mao.

“If we can identify similar genetic loci in people, and if we could find biomarkers for these gene-environment interactions, then perhaps we could develop a simple blood test that identifies people who are at high risk of cancer from low-dose radiation,” says Mao.

The research was supported by the Department of Energy’s Office of Science.

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Wearable electronics device makes it easier to image infants


Flexible, lightweight and wearable electronics strategy has led to plans for clinical trials.

New wearable electronics will allow an infant to be swaddled in a blanket laced with a network of nearly weightless, printed “coils” for more comfortable, less expensive MRI scanning.

By Wallace Ravven

An infant born three months prematurely fails to flush pink at birth and has an alarmingly low blood pressure. Ultrasound identifies a heart abnormality and doctors rush the newborn to an MRI suite to confirm the diagnosis. But the scanning itself can cause physical agitation that interferes with clear imaging. In some cases, it can make it harder for the baby to breathe.

When scans require high sensitivity on a small area of the body, a hard, heavy vest of metal coils must press down on the baby. The bulky burden weighs more than the newborn. Infants squirm under the pressure, but anesthesia to calm them down adds an unwanted risk. Lightening the load by securing the weighty apparatus off the baby leads to degraded resolution, prompting a need for longer MRI exposures.

The hardware is part of the radio frequency (RF) coil assembly that receives the MRI’s electromagnetic signals. Besides being awkward and heavy, the coils are expensive to manufacture and must be reused for years. Sanitizing the bulky assembly is difficult.

Cut to a faculty lunch in 2011. UC Berkeley MRI expert Miki Lustig hears his colleague Ana Claudia Arias describe her lab’s progress adapting a technique similar to conventional ink jet printing to fabricate electronic devices.

It was a technology, Lustig says, that was “well beyond my comfort zone.” But he wondered if Arias’ printable electronics techniques could fabricate ultra-lightweight, “two-dimensional” RF coils to ease the trauma to tiny tots and improve image quality.

Lustig and Arias, both faculty members in the electrical engineering and computer sciences department, walked back to their offices together.

“I asked her if she thought RF coils could be printed. It just seemed like a good idea. She said ‘let me think about it.’ A few days later — almost immediately — she said we should give it a try. She started ordering materials to test different substrates and putting a team together.”

Printing electronic circuits and devices based on metals and semiconductors from solution is a very young field that Arias first entered in 2003 at the near-legendary Xerox PARC in Palo Alto. She came to PARC from Plastic Logic Limited, where she worked after finishing her Ph.D. in physics at the Cavendish Laboratory at Cambridge University, U.K.

While at Xerox, Arias began to explore fabrication of wearable sensors. Her group developed several components of a flexible sensor that targeted the prevention of brain injuries by monitoring pressure, acoustic and light levels in the battlefield.

When she joined the Berkeley EECS faculty in 2011, she began to expand her collaborations to developed wearable medical devices that could track vital signs and give doctors feedback on their patients health.

“Printed electronics is an ideal technology for fabrication and integration of devices with different functionality, such as sensors, light sources and simple circuits. It is ideal for deposition of unique and customized designs. And when one adds flexible substrates to the equation you could start thinking about truly wearable — and comfortable — electronics”

To make “wearable electronics” for infant MRI patients, her team first tried to print directly onto cloth fabric.

“We wanted to make our coil feel like a swaddle blankie that fits snugly and softly around the babies,” she says.

But the cloth’s texture interfered with the ability to print high-quality capacitors, so the team turned to printing the “electronic inks” layer by layer onto plastic thin film, like what is used in photo transparencies. The lab succeeded in fabricating and demonstrating functioning RF coils with performance properties comparable to conventional RF coils.

Arias is supported by a Bakar Fellowship at Berkeley, support intended to help commercially promising research make the leap from the lab to the real world. She and Lustig plan to start a company to advance the technology into clinical use.

“We, researchers, don’t usually have experience and training with steps such as securing IP protection and developing a business plan to attract investment and ensure success. Mentors we met through the Bakar Program have been very helpful,” she says.

Their proof-in-principle of the flexible, lightweight and wearable electronics strategy has led to plans for clinical trials early next year. She and Lustig are collaborating with pediatrician Shreyas Vasanawala at Lucile Packard Children’s hospital to test the wearable RF coils on babies needing MRI scans. Vasanawala has been a key clinical consultant to the project from the beginning.

Arias sees the technology’s potential for adult MRI scanning as well — helping to make the MRI experience more comfortable and less scary to everyone, while getting better images of parts of the body that the bulky conventional RF coil assemblies don’t fit very well.

Meanwhile, she still has her eyes on developing that electronic blankie. “When you see kids in the hospital, it’s scary for them. When they’re in a blanket, it’s a much more comforting experience. We want to swaddle them.”

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UC Davis designated a lung cancer screening center


The only of its kind currently in the greater Sacramento area.

By Dorsey Griffith, UC Davis

UC Davis Health System has been endorsed by the American College of Radiology as a designated lung cancer screening center, the only of its kind currently in the greater Sacramento area.

The designation means that UC Davis has complied with stringent quality and safety requirements for its computed tomography (CT) scanning practices, and it confirms that UC Davis meets the required radiation-dose standards.

“This designation offers patients the security of an external review process to ensure that such exams are performed at the highest level of quality and safety,” said Friedrich D. Knollmann, professor of clinical radiology in the UC Davis Department of Radiology.

The designation follows a decision by the federal Centers for Medicare and Medicaid Services to recommend CT screening for individuals deemed at high risk for developing lung cancer. Those include men and women who have smoked more than a pack a day for 30 years or two packs a day for 15 years. The screening is limited to individuals over age 55 and up to 77 or 80 depending on the individual’s insurance.

Since Jan. 1, as set forth in the Affordable Care Act, private insurers must cover the screening for people who meet the criteria. The health care reform law stipulates that insurers must provide services recommended by the U.S. Preventive Services Task Force, an independent panel that analyzes data and makes recommendations about health screening.

The task force in December 2013 recommended low-dose CT screening for eligible individuals based on results of the groundbreaking National Lung Screening Trial, which determined that low-dose CT screening reduced the risk of dying from lung cancer in heavy smokers by 20 percent compared to screening with chest X-rays. Data from the trial were published in the New England Journal of Medicine in 2011.

Lung cancer is the third most common cancer and the leading cause of cancer death in the United States. Smoking is the leading cause of lung cancer; about 85 percent of all U.S. lung cancer cases are smoking related. Lung cancer is most commonly diagnosed in people 55 and older.

The American College of Radiology represents more than 37,000 diagnostic radiologists, radiation oncologists, interventional radiologists, nuclear medicine physicians and medical physicists. The organization works to improve, promote and protect the practice of radiology to ensure the quality and safety of patient care.

The UC Davis lung cancer screening program uses a multidisciplinary team of radiologists, thoracic surgeons, pulmonologists, pathologists, medical oncologists and radiation oncologists to develop a patient-centered plan for leading-edge lung cancer care. Individuals interested in lung cancer screening should discuss the pros and cons of the test with their primary care physician, who will, after a shared decision to participate has been reached, refer them to the UC Davis Department of Radiology.

Referrals can be faxed to (916) 703-2254, and screenings can be scheduled by calling (916) 734-0655.

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MRI technique developed for nonalcoholic fatty liver disease in children


UC San Diego study makes strides toward noninvasive diagnostic for pediatric liver disease.

By Heather Buschman, UC San Diego

Between 5 and 8 million children in the United States have nonalcoholic fatty liver disease (NAFLD), yet most cases go undiagnosed. To help address this issue, researchers at UC San Diego School of Medicine have developed a new magnetic resonance imaging (MRI)-based technique to help clinicians and researchers better detect and evaluate NAFLD in children. The study is published today (Feb. 5) in Hepatology.

“Currently, diagnosis of NAFLD requires a liver biopsy, which is not always available or performed. This leads to both misdiagnosis and missed diagnoses, hampering patient care and progress in clinical research,” said Jeffrey B. Schwimmer, M.D., professor of clinical pediatrics at UC San Diego, director of the Fatty Liver Clinic at Rady Children’s Hospital-San Diego and the first author of the study. “Thus, a noninvasive method for diagnosing and/or evaluating NAFLD has the potential to impact millions of children.”

NAFLD is characterized by large droplets of fat in at least 5 percent of a child’s liver cells. Obesity and diabetes are risk factors for NAFLD. Doctors are concerned about NAFLD in children because it can lead to hepatitis, liver scarring, cirrhosis and liver cancer.

Traditionally, NAFLD is diagnosed by a gastroenterologist in consultation with a pathologist, who examines the patient’s biopsied liver tissue under a microscope. The presence and severity of liver fat is graded by the pathologist as none, mild, moderate or severe, based on the percentage of liver cells that contain fat droplets.

In an effort known as the MRI Rosetta Stone Project, Schwimmer and colleagues used a special MRI technique known as magnitude-based MRI, which was previously developed by researchers in the UC San Diego Liver Imaging Group, to estimate liver proton density fat fraction (PDFF), a biomarker of liver fat content.

“Existing techniques for measuring liver fat are dependent upon the individual scanner and the center at which the measurements were made, so they cannot be compared directly,” said Claude B. Sirlin, M.D., professor of radiology at UC San Diego and senior author of the study. “By comparison, PDFF is a standardized marker that is reproducible on different scanners and at different imaging centers. Thus, the results of the current study can be generalized to the broader population.”

In this study, the researchers compared the new MRI technique to the standard liver biopsy method of assessing fat in the liver. To do this, the team enrolled 174 children who were having liver biopsies for clinical care. For each patient, the team performed both MRI-estimated PDFF and compared the results to the standard pathology method of measuring fat on a liver biopsy.

The team found a strong correlation between the amount of liver fat as measured by the new MRI technique and the grade of liver fat determined by pathology. This is an important step towards being able to use this technology for patients. Notably, the correlation was influenced by both the patient’s gender and the amount of scar tissue in the liver. The correlation between the two techniques was strongest in females and in children with minimal scar tissue.

Depending on how the new MRI technology is used, it could correctly classify between 65 and 90 percent of children as having or not having fatty liver tissue.

“Advanced magnitude MRI can be used to estimate PDFF in children, which correlates well with standard analysis of liver biopsies,” Schwimmer said. “We are especially excited about the promise of the technology for following children with NAFLD over time. However, further refinements will be needed before this or any other MRI technique can be used to diagnose NAFLD in an individual child.”

Study co-authors include Michael S. Middleton, Cynthia Behling, Kimberly P. Newton, Hannah I. Awai, Melissa N. Paiz, Jessica Lam, Jonathan C. Hooker, Gavin Hamilton and John Fontanesi, all at UC San Diego.

This research was funded, in part, by the National Institutes of Health (grants UL1RR031980, DK088925-02S1 and R56-DK090350-01A1) and the National Science Foundation (grant 414916).

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California breast density law slow to have an impact


UC Davis research demonstrates need for more physician education.

Jonathan Hargreaves, UC Davis

By Dorsey Griffith, UC Davis

Ten months after California legislators enacted a controversial law mandating that radiologists notify women if they have dense breast tissue, UC Davis researchers have found that half of primary care physicians are still unfamiliar with the law and many don’t feel comfortable answering breast density-related questions from patients. The findings, to be published in the March print edition of Journal of the American College of Radiology, suggest that if the law is going to have any significant impact on patient care, primary care providers need more education about breast density and secondary imaging options.

“Overall, the impact of the breast density legislation probably is not significant if  primary care physicians are not educated or aware of it,” said lead author Kathleen Khong, a UC Davis radiologist and staff physician. “We should put some emphasis on educating the primary care physicians so that when they get questions from patients, they can be comfortable in addressing the issues.”

The California law, which took effect in April 2013, requires that patients whose breast density is defined as “heterogeneously dense” or “extremely dense” (about 50 percent of women), receive the following notification:

“Your mammogram shows that your breast tissue is dense. Dense breast tissue is common and is not abnormal. However, dense breast tissue can make it harder to evaluate the results of your mammogram and may also be associated with an increased risk of breast cancer. This information about the results of your mammogram is given to you to raise your awareness and to inform your conversations with your doctor. Together, you can decide which screening options are right for you. A report of your results was sent to your physician.”

The researchers point out that breast density has long been a required part of any radiological report following mammography, but unless a patient asks to see the report, the information is shared only with the patient’s providers. Led by patient advocates, the legislation is intended to increase awareness of dense breasts and encourage patients to discuss the clinical issues with their doctors. According to published research, 28 states have passed, rejected or considered dense-breast notification legislation since 2009.

But the UC Davis study demonstrated that while women and their doctors are receiving the notifications, many of those physicians are unclear about what to do with the information. As a consequence, the researchers said, it appears that relatively few patients with dense breasts are asking questions about their breast density and its implications.

The UC Davis study surveyed 77 physicians about the new law.  Roughly half (49 percent) reported no knowledge of the legislation and only 32 percent of respondents noted an increase in patient levels of concern about breast density compared to prior years. In addition, a majority of primary care physicians were only “somewhat comfortable” (55 percent) or “not comfortable” (12 percent) with breast-density questions from their patients.

Khong said their survey results were surprising, but acknowledged that many primary care physicians may not feel they have sufficient training to make a clinical recommendation for a particular type of secondary screening. In fact, the study also found that 75 percent of respondents would like more education about the breast-density law and its implications for primary care.

“They are eager to learn and want to help their patients and be part of something positive as a result of this,” Khong said.

Jonathan Hargreaves, assistant professor of clinical radiology and a study co-author, said, for example,  that if a patient has dense breasts she should have a risk assessment, which takes into account her family history of breast cancer, biopsy history and other factors to determine whether a supplemental screening is warranted. Once  complete, the physician should then discuss the potential benefits and risks of supplemental imaging in determining the most appropriate approach for the patient. The use of ancillary screening in addition to mammography is a complex subject and still the subject of considerable debate, explained Hargreaves.

Tomosynthesis, known as 3-D mammography, is one supplemental test that breast radiologists generally agree provides a slight benefit for women with dense breasts over a standard mammogram and can be scheduled for the next annual mammographic screening appointment after receiving a notification. Breast magnetic resonance imaging (MRI) is another secondary imaging option, Hargreaves said, but is generally only used for screening in women who have a very strong family history of breast cancer or have a known high-risk gene, such as BRCA.

“The law has raised a lot of awareness about breast density,” Hargreaves said. “That being said, mammography screening is the primary thing patients need to do, and beyond that, the real benefits of other screening techniques are still the subject of ongoing medical debate.”

Khong and Hargreaves hope to validate their findings by expanding their research to include primary care physicians from other major university health care systems in California.

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