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Clinical Trials, Imaging, Neuroscience, Research, Stanford News, Women's Health

Estradiol – but not Premarin – prevents neurodegeneration in women at heightened dementia risk

Estradiol - but not Premarin - prevents neurodegeneration in women at heightened dementia risk

bottle of pillsWomen near the age of menopause and at elevated risk for dementia – owing, say, to a family history of Alzheimer’s disease, a personal history of major depression, or a genotype positive for the infamous Alzheimer’s-predisposing gene variant, ApoE4 – may want to consider talking to their doctor about estrogen-based hormone therapy.

In a brain-imaging study just published in PLOS ONE, hormone therapy protected key “early warning” brain regions from metabolic decline in women who fit that description – but only if they started therapy shortly after reaching menopause, and only if the pill they took contained just estradiol, the dominant female sex-steroid hormone. Premarin, a more widely used hormone-therapy formulation derived from the urine of pregnant mares, was far less protective.

Premarin contains more than 30 substances, with estradiol accounting for only about 17 percent. Other components exert various endocrinological effects on different tissues. In my release on the new study, I wrote:

More than 20 million women in the United States are between 45 and 55 years old – an age range at which many once were considered prime candidates for Premarin. Hormone therapy… was… widely heralded as protecting postmenopausal women from heart disease, osteoporosis and even cognitive decline.

Indeed, from 1992 through 2001 Premarin was the most widely prescribed drug in the United States. Then came the deluge. Here’s the backstory:

In July 2002, a large multicenter study of hormone therapy’s effects was abruptly halted when – contrary to expectations – woman assigned to PremPro (Premarin plus progestin, a synthetic version of progesterone, another important female steroid hormone) developed more cardiovascular disease than those getting a placebo. Within 18 months, about half of American women who’d been on hormone therapy abandoned it. Its use has since plunged considerably further.

Then in 2003, an ancillary study called WHIMS (“Women’s Health Initiative Memory Study”) reported that dementia incidence among 65- to 79-year-old women randomly assigned to PremPro was double  that of women on placebo. This disappointing finding was widely covered in the media.

But Rasgon and her colleagues’ findings are consistent with other analyses indicating that women initiating hormone therapy within five years of their last menstrual cycle experienced beneficial brain effects. In fact, major differences in trial design may explain the discrepancy between WHIMS’s decidedly negative results and the new study’s more nuanced ones.

The WHIMS women were older, on average, than those in Rasgon’s study and were beginning hormone therapy after a long hiatus during which their bodies were no longer producing substantial quantities of estrodiol. Moreover, the PremPro given to women in the active arms of WHIMS contained progestin – which, the new study shows, speeds metabolic deterioration in at least dementia-prone women’s brains.

Natalie Rasgon, MD, PhD, director of the Stanford Center for Neuroscience in Women’s Health and the study’s lead author, puts it plainly. “Hormone therapy’s neurological effect on women at risk for dementia depends critically on when they begin therapy and on whether they use estradiol or Premarin.”

Previously: Hormone therapy halts accelerated biological aging seen in women with Alzheimer’s genetic risk factor, Hormone therapy soon after menopause onset may reduce Alzheimer’s risk and Study shows common genetic risk factor for Alzheimer’s disrupts brain function in healthy older women, but not men
Photo by Canned Muffins

Imaging, Ophthalmology, Research, Stanford News, Technology

Instagram for eyes: Stanford ophthalmologists develop low-cost device to ease image sharing

Instagram for eyes: Stanford ophthalmologists develop low-cost device to ease image sharing

eye-phoneThis probably won’t grab as many headlines as the news of a smartphone that wakes you up with the sizzle and smell of bacon, but it should!

A team of Stanford scientists is using 3D printing to create inexpensive adapters that make it easy to use a smartphone and an ordinary examination lens to capture high-quality images of the front and back of the eye. And – what seems to me as just as important – providing a nearly effortless way to share those images.

“Think Instagram for the eyes,” said one of the developers, assistant professor of ophthalmology Robert Chang, MD.

This is a big deal because most primary-care doctors have no good way to see into patients’ eyes, and no easy way to share the images. The usual eye-imaging instruments are expensive and hard to use, and even ophthalmologists who have the equipment and know-how find capturing and sharing the images slow going.

As one of Chang’s fellow developers, Stanford ophthalmology resident Dave Myung, MD, PhD, told me when I interviewed him for an article in Inside Stanford Medicine:

“A picture is truly worth a thousand words… Imagine a car accident victim arriving in the emergency department with an eye injury resulting in a hyphema – blood inside the front of her eye. Normally the physician would have to describe this finding in her electronic record with words alone. Smartphones today not only have the camera resolution to supplement those words with a high-resolution photo, but also the data-transfer capability to upload that photo securely to the medical record in a matter of seconds.”

The scientists describe the adapters, currently dubbed the EyeGo, in two articles in the new issue (volume 3, issue 1) of Journal of Mobile Technology in Medicine. And you can read my story to learn more about the development process, including how Myung pieced together the first prototype (with plastic bits he ordered from the Internet and a few Legos), how mechanical engineering graduate student Alex Jais created the first printed model on his own 3D printer, and how residents Lisa He, MD, and Brian Toy, MD, are leading studies to test them out.

Those interested in using an EyeGo adapter for research or beta-testing can e-mail the team at

Previously: Image of the Week: Sigmoid volvulus and Treating common forms of blindness using tissue generated with ink-jet printing technology
Photograph by Dave Myung

Imaging, Stanford News, Technology

Stanford researchers develop web-based tool to streamline interpretation of medical images

Stanford researchers develop web-based tool to streamline interpretation of medical images

A web-based tool created by researchers at Stanford enables physicians and researchers to better interpret the wealth of data contained in medical images by capturing information in a way that is explicit and computationally accessible.

The tool, called electronic Physician Annotation Device (ePAD), was developed by the Rubin Lab at the School of Medicine and is available to download for free. Daniel Rubin, MD, an assistant professor of radiology, and his team initially designed ePAD in response to an unmet need in cancer imaging, but he says the tool can be used more generally quantitatively evaluate images and characterize disease. He told me:

The 20,000-foot view here is about information about images is recorded. Currently, images are recorded in narrative text form. But a narrative is a very opaque picture if you’re a clinician, or a patient, trying to understand how the picture has changed over time and determine the response of a disease treatment. However, if a radiologist is looking at images and all the information from prior studies, such as dates and abnormalities, is contained in a table and a graph shows the changes in time, then its easier for referring clinicians to understand and for computers to process.

The other aspect that is unique is that ePAD runs in a web browser. The huge advantage of doing this is the platform can be run anywhere, without needing to install software locally, or require an expensive workstation (such as we use in Radiology).

Rubin is currently in the process of launching a pilot project of the system at the Stanford Cancer Institute. As part of the project, ePAD will be used to assess treatment success for patients who are matched to clinical trials using a smart database. Clinicians and researchers at other institutions have also begun using the tool, and Rubin hopes to expand its reach to create a vast, searchable medical image database. “We’re very excited about ePAD because we think it has far reaching implications,” he said.

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Imaging, Neuroscience, Pediatrics

Developing a Google-like search system to improve diagnosis, treatment of pediatric brain disorders

Developing a Google-like search system to improve diagnosis, treatment of pediatric brain disorders

What if doctors could consult a digital library of pediatric MRI scans to determine if an abnormal structure in a patient’s brain was cause for concern? That’s the goal of a group of Johns Hopkins researchers who are creating a Google-like search system to use in diagnosing and treating children’s brain disorders.

While the project is still in the early stages, and access is limited to physicians and patients within the Johns Hopkins medical system, developers hope to extend the database or replicate it elsewhere in coming years. A university release offers more details on the project:

[Researchers] have been working for more than four years to establish a clinical database of more than 5,000 whole-brain MRI scans of children treated at Johns Hopkins. The patients’ names and other identifying information were withheld, but details related to their medical conditions were included. The computer software indexed anatomical information involving up to 1,000 structural measurements in 250 regions of the brain. These images were also sorted into 22 brain disease categories, including chromosomal abnormalities, congenital malformations, vascular diseases, infections, epilepsy, and psychiatric disorders.

Database developers list several ways the system can enhance diagnosis and treatment of pediatric brain disorders, including facilitating identification and correct classification of pediatric brain disorders, providing a more objective image analysis than traditional methods, identifying unclassified diseases or new diseases and being able to treat patients earlier potentially preventing irreversible injury to the brain.

Previously: Happy ending for migraine-plagued teen, Finding hope for rare pediatric brain tumorBig advance against a vicious pediatric brain tumorVideo profiles work of pediatric brain tumor researcher and New Stanford trial targets rare brain tumor

Imaging, In the News, Research, Stanford News

Process that creates transparent brain named one of year’s top scientific discoveries

Process that creates transparent brain named one of year's top scientific discoveries


Remember CLARITY? Earlier this year, Stanford psychiatrist and bioengineer Karl Deisseroth, MD, PhD, and colleagues announced the development of the method, which renders tissue transparent while leaving it structurally intact. The work, as outlined in a release, “ushers in an entirely new era of whole-organ imaging that stands to fundamentally change our scientific understanding of the most important but least understood of organs, the brain, and potentially other organs, as well.” Now, Wired Science has included it on their list of the top scientific discoveries of 2013.

Previously: Stanford-developed fertility treatment deemed a “top medical breakthrough” of the year, Lightning strikes twice: Optogenetics pioneer Karl Deisseroth’s newest technique renders tissues transparent, yet structurally intact, Peering deeply – and quite literally – into the intact brain: A video fly-through and Scientific community (and Twitter) buzzing over Stanford’s see-through brain
Image (a three-dimensional rendering of clarified brain imaged from below) courtesy of the Deisseroth lab

Imaging, Neuroscience, Research, Stanford News

A closer look at the way our brains process humor

A closer look at the way our brains process humor

We’re all familiar with the positive feeling of amusement we get when watching “America’s Funniest Home Videos” or when laughing about a good joke with friends at a party. What many people are less aware of, though, is the fact that humor actually is a prototypical human social emotional state that differentiates us from nearly all other animals.

With this knowledge, it’s tempting to ask how humor is processed on a neural basis by the human brain, and what function humor could play in humans in evolutionary terms. To stimulate future research on these and other questions, Jessica Black, PhD, Allan Reiss, MD, and I wrote a review paper, Neural Basis of Humor Processing in Humans,” that was recently published online by Nature Reviews Neuroscience.

We also found evidence for altered humor processing in adults suffering from psychological or psychiatric disorders… Such findings are of potential clinical relevance as they provide valuable information on [the] conditions…

The central part of our review paper consists of a summary of all functional magnetic resonance imaging (fMRI) papers on humor that have appeared during the last 13 years. In our eyes, the findings of those studies nicely converge with previously derived psychological humor models in suggesting that humor perception involves two core processes.

In a first step, also referred as to the cognitive humor component, an apparent discrepancy or incongruity between two or more elements of incoming information is detected and resolved. For example, incongruity can be introduced by the occurrence of an unexpected twist in successive events, which then has to be resolved by associating the new outcome with an alternative meaning. In terms of functional neuroanatomy, one area of the temporal parietal cortex, the temporo-occipito-parietal junction, appears to be particularly well-suited for such incongruity processing. In a second step, incongruity resolution is then linked to a positive feeling of amusement or mirth, also referred as to the emotional humor component. The latter appears to be mainly maintained by high activity in reward-related brain circuits, making us feel good about the successful resolution of incongruity.

Along with reviewing the fMRI literature on the core processes involved in humor, we  looked at the influence of sex, personality and brain disorder on humor processing. The available data indicates that there are sex differences in humor processing in the sense that girls and women more strongly activate brain regions sustaining both cognitive and emotional humor components than boys and men. One possible underlying mechanism might be relatively lower reward expectation in females, making them more susceptible to humor effects on reward processing circuits.

We also found evidence for altered humor processing as a function of personality traits in healthy children and adults (e.g., shyness or extraversion), as well as in adults suffering from psychological (e.g. depression and social anxiety disorder) or psychiatric (e.g. autism) disorders. By describing the potentially separable effects of these characteristics on cognitive versus emotional humor components, such findings are of potential clinical relevance as they provide valuable information on conditions involving altered experience of social reward.

Finally, we suggest that our review of the neural basis of humor in humans can also inform theories on the evolutionary significance of humor. In particular, this applies to a theory of humor associated with sexual selection. This theory states that humor may contribute to mate selection choices for women, allowing them to evaluate potential mates on otherwise difficult to discern characteristics like intelligence, social skills and resilience. (For more details, see my previous blog).

While our perspective paper provides valuable insights into the present knowledge of humor processing in humans, it clearly shows there are many outstanding questions that need to be addressed in the future. Our investigations will continue.

Pascal Vrticka, PhD, is a postdoctoral scholar in Stanford’s Center for Interdisciplinary Brain Sciences Research.

Previously: Humor as a mate selection strategy for women?, Making kids laugh for science: Study shows how humor activates children’s brains and How sense of humor develops in the brain

Aging, Imaging, Neuroscience, Stanford News

Teaching an old dog new tricks: New faster and more accurate MRI technique quantifies brain matter

Teaching an old dog new tricks: New faster and more accurate MRI technique quantifies brain matter

DOG TRICKWhen it comes to neurodegenerative diseases that erode the brain, such as multiple sclerosis, or processes that build up brain tissue, such as the formation of neural connections, the volume of our brains’ white matter matters. Yet, until recently, it was difficult to assess how much white matter a brain had lost or gained, or how it compared to that of other brains, because brain scan techniques had limited speed and accuracy.

Now, a team of researchers led by Stanford postdoctoral scholar Aviv Mezer, PhD, and psychology professor Brian Wandell, PhD, have found a faster and more reliable way to apply a commonly used brain scan technique, called magnetic resonance imaging (MRI), to quantify the volume of different areas of the brain.

The results were recently published (subscription required) in the journal Nature Medicine; a Stanford News story provides more details.

The researchers have already applied this new brain scan technique to patients with multiple sclerosis. Next, they’ll use it to measure changes in the developing brains of children.

Holly MacCormick is a writing intern in the medical school’s Office of Communication & Public Affairs. She is a graduate student in ecology and evolutionary biology at University of California-Santa Cruz. 

Previously: Can a single concussion cause lasting brain damage?Found: Potential new way to predict some multiple-sclerosis patients’ disease course, drug responseTwo different types of MS, one big step toward personalized medicineDeveloping a computer model to better diagnose brain damage, concussionsStanford neuroimmunologist discusses recent advances in MS research and Study shows practicing tai chi may increase brain volume in healthy older adults
Photo by pbump

Emergency Medicine, Health Policy, Imaging, Pregnancy, Research, Stanford News

Studying the best approach to diagnosing appendicitis in pregnant women

Studying the best approach to diagnosing appendicitis in pregnant women

OLYMPUS DIGITAL CAMERAWhen it comes to pregnant women, managing abdominal pain and diagnosing appendicitis can be a tricky proposition for doctors. Current practice includes an ultrasound followed by further imaging if the diagnosis remains unclear, but some providers and patients are hesitant to use one common imaging tool – a CT scan. That’s because of its use of radiation, and its possible risk to the fetus.

Zachary Kastenberg, MD, is a general surgery resident at Stanford and reports that he and his colleagues encounter this issue relatively frequently in the emergency department. “We often find ourselves guiding expecting mothers and fathers through difficult, anxiety-provoking decisions with minimal evidence to support differing practitioner perspectives,” he recently told me, noting that acute appendicitis is the most common cause of non-obstetric surgery in pregnant women.

Kastenberg said he wanted to help “influence the management and diagnosis of abdominal pain in pregnant women and to inform practitioners regarding the relative risks of abdominal imaging and fetal radiation during pregnancy.” And so he and colleagues performed a comprehensive cost-effectiveness analysis of the diagnostic strategies for appendicitis during pregnancy. Using a computer-based model, the researchers examined the costs and short- and long-term risks of the interventions, and various quality-of-life measures across the lifetime of a cohort of 25-year-old mothers-to-be and their fetuses.

What the researchers found was that in the vast majority of cases, preoperative imaging is the most prudent choice for managing pregnant women with suspected appendicitis. They also determined that magnetic resonance imaging (MRI) – which doesn’t involve radiation – is the most cost-effective diagnostic strategy, and that CT – even when taking into consideration the potential risks of radiation-associated childhood cancer – is a cost-effective option when MRI isn’t available. The latter finding is particularly important for those hospitals (usually smaller or rural ones) that don’t have an MRI machine or access to skilled MRI interpretation at night or on weekends.

Kastenberg acknowledged that patients may still experience anxiety associated with radiation exposure. But he says he hopes the analysis “will give physicians the confidence to guide patients through an educated discussion of the risks and benefits of preoperative imaging, including CT, when confronted with this difficult clinical situation.”

Kastenberg is a post-doctoral fellow in Stanford’s Center for Health Policy and the Center for Primary Care and Outcomes Research. The research appears in the October issue of the Journal of Obstetrics and Gynecology.

Photo by Daquella Manera

Imaging, Pediatrics, Research, Stanford News

Neural networks show impairment from fragile X syndrome

Neural networks show impairment from fragile X syndrome

Fragile X syndrome – caused by a gene mutation on the X chromosome – doesn’t get a lot of press, but it’s the most common form of inherited intellectual disability.

Approximately 1 in 4,000 males and 1 in 8,000 females have it. According to my quick back-of-the-envelope calculation, based on 2010 data from the U.S. Census Bureau, that works out to roughly 56,000 afflicted people in the U.S.

The findings could aid in developing different kinds of treatment for fragile X

Researchers have known that certain regions of the brain are structurally altered in people with the condition, but now some researchers at Stanford and Lucile Packard Children’s Hospital have identified several large-scale neural networks that appear to be impaired by the condition. The findings could help in devising treatments for the disorder.

The researchers conducted a magnetic resonance imaging study of some children and young adults with fragile X syndrome, which, combined with some recently developed methods of quantifying brain activity, revealed the impairments. The neural network that showed the greatest impairment was the salience network, which is thought to be involved in evaluating emotional stimuli and generating appropriate responses.

According to researcher Scott Hall, PhD, an assistant professor of psychiatry and behavioral sciences here and a member of the Child Health Research Institute at Packard Children’s who worked on the study:

The findings could aid in developing different kinds of treatment for fragile X, both by helping researchers understand where the processing problems or deficits lie in the brain and also in potentially giving them a way to assess the effectiveness of a particular treatment, either by comparing brain scans from before and after a behavioral therapy session or observing scans during a course of medication.

The outward symptoms of fragile X syndrome are similar to those of people with autism – pronounced social awkwardness, language impairment and repetitive actions. Although autism is diagnosed solely on behavioral criteria, the researchers are hopeful the technique they employed might also be useful in diagnosing subgroups of children with autism, which could aid in developing new therapies.

You can read a more detailed account of the study, which was published online today in JAMA Psychiatry, and its possible ramifications in our press release.

Previously: How better understanding Williams syndrome could advance autism research and Two robust fragile X syndrome findings intersect

Cancer, Imaging, Research, Stanford News

Dynamic duo: Nanoparticle/prodrug combination finds and fights tumors, files reports

Dynamic duo: Nanoparticle/prodrug combination finds and fights tumors, files reports

Hazard_Journal of Small_COVER_v04Routine chemotherapy is a somewhat sloppy way of combating cancer, because the drugs employed work by killing rapidly dividing cells, not just cancerous ones. Hair cells, skin cells, the immune system, cells lining the intestine, and even a small but critical set of cells in the brain necessary for forging new memories – all these can be adversely affected.

But a Stanford team under the direction of radiologist/physician Heike Daldrup-Link, MD, and chemist Jianghong Rao, PhD, has produced a seek-and-destroy cancer therapy that could sharpen the attack while simultaneously making it easier to noninvasively visualize the therapy’s progress. In a study just published in the nanotechnology journal Small, the team describes the linking of an easily imaged, FDA-approved iron-rich nanoparticle, ferumoxytol, to a prodrug (a compound that, while lacking activity on its own, can get converted in the body into a potent drug).

The key to the success of this so-called theranostic is the pummeling it gets from matrix metalloproteinases, a family of enzymes that make their living by breaking down the molecular latticework that positions cells within  tissues. Most tumors are particularly rife with one of this family’s members, MMP-14, whose activities help tumors invade other, healthy tissues. Conveniently, MMP-14 is precisely the enzyme best equipped to carve up the prodrug,  releasing its active component. MMP-14 is found not only on tumor cells but, importantly, on the tiny blood vessels that pervade and feed them. When the theranostic particles, circulating in the bloodstream upon intravenous administration, reach those blood vessels, the drug is released, causing the vessels to cave in and starving the tumor mass that so depends on them.

The nanoparticles tend to stick around inside the collapsed microvasculature, allowing radiologists to see just where the drug has done its job (and, by extension, where cancerous lesions, including previously unknown ones, are in the body). Meanwhile healthy tissues are spared, tests in mice suggest.

Previously: Iron-supplement-slurping stem cells can be transplanted, then tracked to make sure they’re making new knees and Nano-hitchhikers ride stem cells into heart, let researchers watch in real time and weeks later
Image provided by Kim Gray Hazard

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