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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

Anesthesiology, Neuroscience, Pain, Stanford News

When touch turns into torture: Researchers identify new drug target for chronic, touch-evoked pain

When touch turns into torture: Researchers identify new drug target for chronic, touch-evoked pain

I admit it: I’m a baby when it comes to the smallest bruises. But I do feel guilty about fussing over papercuts when I hear about people with tactile allodynia, a chronic pain condition where the slightest touch can cause searing pain.

Allodynia, meaning “other pain,” refers to pain from things that shouldn’t normally hurt. For people with tactile allodynia, or touch-evoked pain, simple needs like a hug or a soothing breeze can turn into nightmares. Everyday activities such as brushing their hair or putting on a shirt can hurt. They can certainly kiss their NFL dreams goodbye.

Treating such chronic pain is tricky, because the root cause is not a wound that can be patched up with a Band-Aid. The culprit is often a damaged nerve or nerve circuit, leading to a mix-up of pain and touch signals, and fooling the brain into misreading touch as being painful.

Painkillers such as morphine haven’t been very effective at quelling this particular type of pain so far. That’s because they may have been targeting the wrong nerve cells all along, researchers here reveal.

Their recent article in the journal Neuron describing the finding points out that the nerve cells, or neurons, that control this type of pain are different from the usual pain neurons that morphine-based drugs target.

In my Inside Stanford Medicine story, I describe how the finding can help drug companies develop the right drugs to treat this type of chronic pain. Senior author of the Neuron article, assistant professor of anesthesiology and of molecular and cellular physiology Gregory Scherrer, PhD, and colleagues, zero in on specific binding sites on these neurons that drugs can target in order to cut off their signal and numb the pain.

Because the underlying nerves spread through the skin, topical creams or skin patches carrying the right drug would work quite well to reduce the pain, the authors say.

In the story, Scherrer also explains why drug companies gave up on such drugs before, and how his research could now help these companies successfully develop drugs to help patients with this type of pain.

Previously: Do athletes feel pain differently than the rest of us?Toxins in newts lead to new way of locating pain and On being a parent with chronic pain 

Genetics, Neuroscience, Research, Stanford News

X marks the spot, and so does Y: Brain differences, missing or extra sex chromosomes, and gene dosage

X marks the spot, and so does Y: Brain differences, missing or extra sex chromosomes, and gene dosage

X and Ys - smallHow is a gene like a drug? The more there is of it, the bigger the effect. You have to be careful how you spoon it out. Of course, gene “doses” don’t come in teaspoons, they come in chromosomal copy numbers.

You typically have two copies of each gene – one on the chromosome dad gave you, and one on the chromosome you got from mom – although, it must be said, the “flavors” of these copies many not be identical (e.g., specifying blue versus brown eye color).

And sometimes – in fact, often – one copy of a gene is “turned off” altogether, its activation more or less blocked by biochemical stop-signs. That’s about the same as having only one copy, until and unless the light turns green at some point. A particularly pronounced case of single-dose-itis (my word) occurs on the sex chromosomes, designated either X (for female) or Y (for male) because if you view them under a microscope, that’s sort of what they look like. Unlike the other 22 pairs of paternally and maternally derived chromosomes contained in each human cell, X and Y chromosomes actually look noticeably different from one another even at the gross-inspection stage. “Viewed” closer up with the tools of molecular biology, the two versions of the sex chromosome turn out to have large numbers of lengthy stretches that really are different and indeed may be entirely absent on the Y chromosome. Those differences make every cell in a woman’s body different from every cell in a man’s, as UC-Berkeley biologist Art Arnold, PhD, once pointed out at a particularly lively Stanford symposium on gender differences last year.

Still, X and Y chromosomes share plenty of common regions. So a deviation from the usual double chromosome count, even when the extra or missing chromosome is an X or a Y, can make a big difference in the dosages for plenty of genes. One genetic defect called Klinefelter syndrome, characterized by the presence of a Y and two X chromosomes in each cell, leads to an excessive dose of many genes (three copies instead of two, to be specific). Another genetic defect, Turner syndrome, results in each cell containing only a solitary X chromosome – and only a single copy of numerous genes. Both Turner and Klinefelter syndromes are marked by characteristic cognitive deficits.

Allan Reiss, MD, PhD, director of Stanford’s Center for Interdisciplinary Brain Sciences Research, and his colleagues compared the brains of people with Klinefelter and Turner syndromes with those of individuals with normal sex-chromosome counts. They showed in this imaging study in the Journal of Neuroscience, that anatomical aberrations in particular brain regions among people with extra or absent copies of the sex chromosome closely track the neurological deviations associated with these syndromes – and, importantly, that these aberrations may be caused by the gene-dosage differences resulting from variant sex-chromosome counts.

Previously: Tomayto, tomahto: Separate genes exert control over differential male and female behaviors, Humor as a mate-selection strategy for women? and Brain imaging, and the image-management cells that make it possible
Photo by Naberacka

Neuroscience, Research, Stanford News

Elastic for floppy nerves

Elastic for floppy nerves

13545-touch_shutterstockHere’s something that was news to me: scientists don’t actually know how we sense touch. They know a lot about the neurons that send signals to the brain when you, say, touch your keyboard. But that initial sensation as the finger hits a key, when the skin is lightly depressed, what triggers the nerve to know the finger has touched something? That’s not known.

I wrote about some work this week from the Stanford Bio-X team of Miriam Goodman, PhD, and Alex Dunn, PhD, who work on this problem. A post doctoral fellow working in their labs, Michael Krieg, PhD, was looking into mechanical properties of the nerves that sense touch. One thing led to another, scientifically speaking, and eventually he found a matrix of proteins in these nerves that are not only involved in transmitting the signal of touch, but also seem to keep nerves resilient.

Dunn used socks to describe the difference between nerves that had this protein matrix, called spectrin, and those that didn’t. “When we looked at bending we realized that this looked a lot like an old sock. It looked loose and floppy,” he said. “We thought maybe what’s going on is the spectrin is acting like elastic.”

There’s more in the story about some cool measurements Krieg made into just how much tension the spectrin matrix puts on the cell. (How do you measure 1/1,000,000,000,000 of an apple anyway?)

Neuroscience, Parenting, Pediatrics, Research

Talk to her (or him): Study shows adult talk to preemies aids development

Talk to her (or him): Study shows adult talk to preemies aids development

preemie sleeping

When my little niece was born at 25 weeks’ gestation, she lived in a clear plastic incubator for the first several months out of the womb. Walled off in her own world, she grew and stabilized her health seemingly by the force of her own strong will, which still powers her as a 6-year-old. Unlike healthy full-term babies who can be snuggled, sung to and incorporated into the fold of a family’s daily life, preemies in the NICU may have less direct contact with their parents and other loved ones initially. But a recent study (subscription required) published in the journal Pediatrics has found that when adults spent more time talking to premature infants in the NICU, those babies score better on development tests at ages 7 and 18 months corrected age (actual age in weeks minus weeks premature).

Reuters Health article reports:

For the new study, the researchers recruited families of 36 babies that were medically stable but born before 32 weeks of pregnancy and kept in the NICU.

….

The babies in the study wore vests equipped with devices that record and analyze the conversations and background noises near the baby over 16 hours. The recordings were taken at 32 and 36 weeks of gestational age.

Overall, the babies were exposed to more talking at 36 weeks than at 32 weeks, but the actual amount of talk each baby was exposed to during the study periods varied from 144 words to over 26,000 words.

The study found an increased amount of parent talk in the NICU was linked to higher language and thinking scores when the babies were older. “I think we should pay attention to it, and try to understand it a little bit better and figure out what the causal mechanisms are,” Heidi Feldman, MD, PhD, a Lucile Packard Children’s Hospital Stanford physician who was not involved in the study, said of the findings.

Previously: The year in the life of a preemie – and his parentsUsing the iPad to connect ill newborns, parents and The emotional struggles of parents of preemies
Photo by singingbeagle

Neuroscience, Stanford News, Videos

Middle school students get brainy

Middle school students get brainy

You know it’s going to be a good week when Monday morning starts with a bucket of whole human brains. I got to attend Brain Day, in which Stanford graduate students take a collection of human brains as well as a zoo full of animal brains into local middle schools to give students a lesson in biology they won’t soon forget. I describe the kids’ excitement in a story today, but this video by my colleague Kurt Hickman says it all.

Previously: Study shows “exploration first” model is a better way for students to learn, A day at med school for Bay Area teens, Image of the Week: Studying brains at Stanford’s Med School 101 and This is your brain on science: NIH funds eight K-12 neuroscience education programs

Cancer, Neuroscience, Patient Care, Stanford News

A Stanford physician’s take on cancer prognoses – including his own

In a New York Times SundayReview piece, Paul Kalanithi, MD, a chief resident in neurological surgery at Stanford, describes cancer prognoses from two perspectives, both his own. The 36-year-old doctor writes about reading scans to help colleagues decide if surgery is the right course of treatment for certain brain-cancer cases. He details the important and difficult job of facing patients who ask questions about their chance of survival. Kalanithi also reveals what he learned about the question and answer processes since he was diagnosed with cancer eight months ago, and how he’s learned to live with conviction despite a prognosis of uncertainty.

From the piece:

For a few months, I’d suspected I had cancer. I had seen a lot of young patients with cancer. So I wasn’t taken aback. In fact, there was a certain relief. The next steps were clear: Prepare to die. Cry. Tell my wife that she should remarry, and refinance the mortgage. Write overdue letters to dear friends. Yes, there were lots of things I had meant to do in life, but sometimes this happens: Nothing could be more obvious when your day’s work includes treating head trauma and brain cancer.

But on my first visit with my oncologist, she mentioned my going back to work someday. Wasn’t I a ghost? No. But then how long did I have? Silence.

The path forward would seem obvious, if only I knew how many months or years I had left. Tell me three months, I’d just spend time with family. Tell me just one year, I’d have a plan (write that book). Give me 10 years, I’d get back to treating diseases. The pedestrian truth that you live one day at a time didn’t help: What was I supposed to do with that day? My oncologist would say only: “I can’t tell you a time. You’ve got to find what matters most to you.”

Previously: Both a doctor and a patient: Stanford physician talks about his hemophilia, A patient’s journey with lung cancerBig data = big finds: Clinical trial for deadly lung cancer launched by Stanford study, Red Sunshine: One doctor’s journey surviving stage 3 breast cancer, Cancer survivor: The disease isn’t a “one-off, one-shot deal” and When the journalist becomes the patient

Behavioral Science, Neuroscience, Parenting, Pediatrics, Research

Study finds age at which early-childhood memories fade

Study finds age at which early-childhood memories fade

baby with balloonI have a clear memory of standing near a crêpe-paper-lined wall of my fourth-grade classroom and deciding that age 9 was the time kids got a grip on how things worked and became fully initiated into the world of adult-level thinking. (I had recently turned 9.) That hypothesis wasn’t confirmed but, let’s say, wouldn’t be struck down by the results of a recent study on childhood amnesia that suggests that 7 is the age that the earliest childhood memories – of events that happened before age 3 – fall away.

Researchers from Emory University recorded 83 3-year-olds being interviewed by their mothers about unique autobiographical events. From the study:

Different subgroups of children were tested for recall of the events at ages 5, 6, 7, 8, and 9 years. At the later session they were interviewed by an experimenter about the events discussed 2 to 6 years previously with their mothers (early-life events). Children aged 5, 6, and 7 remembered 60% or more of the early-life events. In contrast, children aged 8 and 9 years remembered fewer than 40% of the early-life events.

The authors found that children whose parents allowed them to direct the conversation, even to switch topics, recalled more than children whose parents kept them on topic.

A release describes more on the findings:

“One surprising finding was that, although the five-and-six year-old children remembered a higher percentage of the events, their narratives of these events were less complete,” [Emory University psychologist Patricia Bauer, PhD, the study's lead author] says. “The older children remembered fewer events, but the ones they remembered had more detail.”

Some reasons for this difference may be that memories that stick around longer may have richer detail associated with them and increasing language skills enable an older child to better elaborate the memory, further cementing it in their minds, Bauer says.

Young children tend to forget events more rapidly than adults do because they lack the strong neural processes required to bring together all the pieces of information that go into a complex autobiographical memory, she explains.

The study was published in the journal Memory.

Previously: We’ve got your number: Exact spot in brain where numeral recognition takes place revealedIndividuals’ extraordinary talent to never forget could offer insights into memory and Childhood-cancer survivors face increased risk of PTSD
Photo by Charlotte Morrall

Neuroscience, Research, Stanford News

Dinners spark neuroscience conversation, collaboration

Dinners spark neuroscience conversation, collaboration

Sometimes big discoveries start with small conversations.

That was the idea at least when Stanford’s Bio-X program placed scientists from different backgrounds in adjoining labs of the Clark Center. Ten years later, that’s a proven success. Scientists bumped into each other and shared coffee, and now interdisciplinary projects are flourishing.

What I found interesting was how much big ideas grew when people from across disciplines – many meeting for the first time that evening – started dreaming together.

Our most recently formed interdisciplinary institutes, the Stanford Neurosciences Institute and the Institute for Chemical Biology, don’t yet have their own building and can’t spark conversation by proximity. Instead, they’re taking a time-honored approach to bringing people together:  food.

I got to attend one of these conversation starters at a dinner held by William Newsome, PhD, professor of neurobiology and director of the newly formed Neurosciences Institute.

Newsome asked the attending crowd of biologists, engineers, radiologists, neurobiologists and bioengineers to dream big about what they’d want to achieve if money were no object and they could collaborate with anyone on campus.

What ensued was an hour-long discussion about decision-making networks, a new generation of brain-inspired computing, devices to stimulate miniscule brain regions, and ever more complex ways of peering into and understanding the brain.

What I found interesting was how much those big ideas grew when people from across disciplines – many meeting for the first time that evening – started dreaming together.

Brian Rutt, PhD, professor of radiology, saw his original idea for improved brain imaging take on new life when engineers and neurobiologists jumped in with their own thoughts about how those techniques could be employed in human diseases. Rutt told Newsome that getting scientists to talk across disciplines is going to be critical for generating the kinds of projects that are critical for the Institute’s success. “I think one of your challenges is to find a way of getting your members to both speak the same language and also appreciate each other’s science,” 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

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