Sex differences contribute to vision damage in NF1

12/13/16 • 0 min

BioMed Radio - Washington University School of Medicine in St. Louis

Vision problems can be caused by neurofibromatosis. Kids with mutations in the NF1 gene that causes neurofibromatosis often develop tumors on the optic nerve, but not all of them develop vision problems. Interestingly, Washington University researchers previously had learned that girls with tumors on the nerve were five to 10 times more likely to lose vision than boys with tumors of about the same size. Now those same researchers have found, in mice, that estrogen is the reason that females with these tumors are more likely to lose vision. Further study showed that cells called microglia are more common and more active in the tumors females develop. Those cells make substances that are more toxic to nerve cells and, therefore, damage vision. The researchers say strategies to temporarily lower estrogen levels in children with tumors on the optic nerve may make it possible to preserve vision without the need for chemotherapy to shrink such tumors. TUMORS ON THE OPTIC NERVE ARE A COMMON FEATURE OF A GENETIC CONDITION CALLED NEUROFIBROMATOSIS TYPE 1 (NF1). ABOUT 15 TO 20 PERCENT OF YOUNG BOYS AND GIRLS WHO HAVE NF1 WILL DEVELOP THOSE TUMORS, CALLED OPTIC GLIOMAS. BUT LESS THAN HALF WILL EVER DEVELOP VISION PROBLEMS AS A RESULT. THAT’S IMPORTANT TO KNOW BECAUSE DAVID GUTMANN, DIRECTOR OF THE WASHINGTON UNIVERSITY NF CENTER, SAYS YOU DON’T WANT TO TREAT THE TUMOR WITH CHEMOTHERAPY IF IT’S NOT GOING TO THREATEN VISION. (act) :14 o/c same size When we looked at our kids with NF1 who have these optic gliomas, girls whose tumors were in the nerve were 5 to 10 times more likely to lose vision than boys with tumors of about the same size. IT TURNS OUT THAT FEMALE SEX HORMONES ARE PARTLY TO BLAME FOR THAT DIFFERENCE. GUTMANN AND HIS TEAM LOOKED AT MOUSE MODELS OF NF1 AND FOUND THAT ONLY FEMALE MICE WERE LOSING VISION FROM THE TUMORS. SO, THEY WORKED TO GET RID OF THE ESTROGEN IN THE FEMALE MICE TO SEE WHAT WOULD HAPPEN. (act) :15 o/c vision loss If you either chemically ablate the ovaries, or remove the ovaries, in these female mice with optic gliomas, they were not experiencing the damage to the optic nerve that leads to vision loss. NEXT, GUTMANN’S TEAM FOUND THAT ESTROGEN WAS ASSOCIATED WITH LARGER NUMBERS OF IMMUNE SYSTEM CELLS CALLED MICROGLIA, AND THOSE MICROGLIA WERE MORE ACTIVE. (act) :27 o/c to die And because they were numerous, and because they were changed in a way that makes them more active, they were making compounds, chemicals, that were damaging the nerve. And while identifying those neurotoxins, we were able to establish a cause-and-effect relationship between estrogen, the microglia and the “death signals” that eventually cause the nerves to die. GUTMANN SAYS ALTHOUGH THE COMPARISON FROM MOUSE TO HUMAN ISN’T PERFECT, IT IS CLEAR THAT BOYS AND GIRLS, EVEN AT VERY YOUNG AGES, HAVE HIGH ENOUGH LEVELS OF SEX HORMONES IN THEIR BRAINS TO EXPLAIN THESE DIFFERENCES IN MICROGLIA. AND GUTMANN SAYS UNDERSTANDING THE ROLE THAT SEX HORMONES PLAY IN THE DAMAGE TO VISION THAT THESE TUMORS CAN CAUSE ALSO WILL PROVIDE THE RESEARCHERS WITH NEW IDEAS ABOUT HOW TO TREAT OPTIC GLIOMAS IN KIDS WHO HAVE NF1. (act) :26 o/c vision loss We can treat them with conventional therapies, but what I’d like to see us start moving towards is not focusing on treating the tumor, but focusing on treating those immune system cells that are damaging the nerve itself. Because we can “win the battle,” that is, we can stop the tumor from growing, but over the past 30 years, we haven’t “won the war.” And the war is really to prevent further vision loss. GUTMANN’S TEAM REPORTS ITS FINDINGS IN THE JOURNAL OF EXPERIMENTAL MEDICINE. I’M JIM DRYDEN… RUNS 2:51

Previous Episode

Brain changes in Tourette syndrome

Using MRIs, researchers at Washington University School of Medicine in St. Louis have identified areas in the brains of children with Tourettes syndrome that appear markedly different from the same areas in the brains of children who dont have the neuropsychiatric disorder.

RESEARCHERS AT WASHINGTON UNIVERSITY SCHOOL OF MEDICINE IN ST. LOUIS HAVE IDENTIFIED A FEW AREAS IN THE BRAINS OF CHILDREN WITH TOURETTES SYNDROME THAT APPEAR TO BE DIFFERENT FROM THE SAME AREAS IN THE BRAINS OF KIDS WHO DONT HAVE THE NEUROLOGICAL DISORDER. AND THE REGIONS THAT THEY IDENTIFIED ARE ONES WHERE THEY HADNT REALLY EXPECTED TO SEE DIFFERENCES. JIM DRYDEN HAS THE STORY

THE RESEARCHERS USED MAGNIETIC RESONANCE IMAGING IN THE LARGEST STUDY OF ITS KIND EVER DONE ON PATIENTS WITH TOURETTES SYNDROME. IT INVOLVED RESEARCH TEAMS AT SEVERAL CENTERS AROUND THE UNITED STATES. PRINCIPAL INVESTIGATOR KEVIN BLACK, A PSYCHIATRIST AT WASHINGTON UNIVERSITY SCHOOL OF MEDICINE IN ST. LOUIS, SAYS THE RESEARCHERS ANALYZED MRI BRAIN SCANS CONDUCTED ON 103 KIDS WHO HAD TICS RELATED TO TOURETTES SYNDROME AND ANOTHER 103 KIDS OF THE SAME AGE AND GENDER WHO DIDNT. (act) :23 o/c template brain

The method that we picked is one that looks at the whole brain. Basically, it squishes and stretches a brain until its the same shape as a standard brain, and keeps track of how much its squished, or stretched, in each spot so that you can tell what the volume of the brain was that matches any given part of the template brain.

IN ADDITION TO THE SQUISHING AND STRETCHING OF THE IMAGE, THE METHOD ALSO CAN DIFFERENTIATE BETWEEN GRAY MATTER AND WHITE MATTER IN THE BRAIN.

(act) :09 o/c the MRI

The method also figures how much gray matter or white matter was in each spot based on the color, essentially, of the brain image, of the MRI.

BLACK SAYS WHEN THE STUDY BEGAN, THE RESEARCHERS WERE FOCUSED ON PARTS OF THE BRAIN THAT ARE RELATED TO MOVEMENT BECAUSE TOURETTES IS CHARACTERIZED BY MOVEMENTS CALLED TICS. BUT BLACK SAYS THE STUDY DIDNT FIND DIFFERENCES IN THOSE PARTS OF THE BRAIN. INSTEAD, THEY FOUND EXTRA GRAY MATTER IN SOME PARTS OF THE BRAIN AND REDUCED WHITE MATTER IN OTHER PARTS, AND MANY OF THOSE BRAIN REGIONS WERE RELATED TO THE PROCESSING OF SENSATION. THAT COULD MAKE SOME SENSE, BLACK SAYS, BECAUSE MANY PEOPLE WITH TOURETTES REPORT THAT THEY TEND TO TIC IN RESPONSE TO A SENSATION.

(act) :24 o/c own beast

Like, Well, Im only clearing my throat because it feels funny, that kind of thing. Or I only sniff because my nose feels itchy. Maybe the sensory features are really the most obvious ones. Like, if you have a cold, and somebody says, Well, why dont you stop coughing? Youre like, Well, Im only coughing because Ive got junk in my throat. You know, that kind of sense that, really, its the feelings inside that lead to the tics, rather than the tics being their own beast.

AS TO WHETHER THE DIFFERENCES IN THE BRAINS OF KIDS WITH TOURETTES ARE ACTUALLY CAUSING THEM TO TIC OR ARE THE RESULT OF THOSE CHILDREN TRYING TO ADJUST TO THEIR TICS, BLACK SAYS ITS TOO EARLY TO TELL.

(act) :23 o/c years now

Is this something that starts early in life? Does it start before people have tics, and that leads to their having tics? Or, is it a healthy response to tics that helps fight them off? Those are questions that we can best answer by trying to catch people very early on in the course of tic disorders. Thats a line of work that Ive been trying to do for several years now. HE SAYS THE SEARCH FOR A BETTER UNDERSTANDING OF WHAT TOURETTES IS AND HOW TO TREAT IT MORE EFFECTIVELY CAN BE A SLOW PROCESS BECAUSE THE DISEASE IS RELATIVELY RARE, AND STUDIES TAKE A LONG TIME. BUT BLACK SAYS COOPERATION BETWEEN SEVERAL CENTERS, AS OCCURRED IN THIS STUDY, COULD HELP SPEED THE PACE OF DISCOVERY. THE NEW STUDY IS PUBLISHED IN THE JOURNAL MOLECULAR PSYCHIATRY. IM JIM DRYDEN

RUNS 3:00

Next Episode

Blunted response to rewards in preschoolers with depression

Adults and teenagers with clinical depression don’t respond to rewards in a normal manner. Their moods are less enthusiastic, and their brains don’t act the same way as those in adults and adolescents who are not depressed. Although depression has been diagnosed in children as young as 3, it hasn’t been clear whether the responses of very young children to rewards also may be blunted. So Washington University researchers studied kids ages 4 to 7 and found that, like adults, when these young children were depressed, their brains were less likely to respond to rewards. The researchers say that could mean insensitivity to rewards may serve as a “red flag” for depression in young children.

PAST RESEARCH HAS FOUND THAT THE BRAINS OF DEPRESSED ADULTS AND ADOLESCENTS OFTEN DON’T RESPOND AS MUCH TO REWARDS AS THE BRAINS OF PEOPLE WHO DON’T HAVE DEPRESSION. NOW, CHILD PSYCHIATRY RESEARCHERS AT WASHINGTON UNIVERSITY SCHOOL OF MEDICINE IN ST. LOUIS HAVE FOUND THE SAME THING IS TRUE IN VERY YOUNG CHILDREN. JIM DRYDEN HAS MORE… IT’S GETTING TO BE THE SEASON FOR PRESENTS, AND IF YOUR FOUR-YEAR-OLD DOESN’T SEEM EXCITED ABOUT THAT, IT COULD BE A PROBLEM ACCORDING TO RESEARCHERS AT WASHINGTON UNIVERSITY SCHOOL OF MEDICINE IN ST. LOUIS. IN OLDER ADOLESCENTS AND ADULTS, RESEARCH HAS FOUND THAT WHEN A PERSON IS DEPRESSED, THE BRAIN’S RESPONSE TO REWARDS CAN BE BLUNTED. NOW, THE FIRST AUTHOR OF A NEW STUDY OF PRESCHOOLERS SAYS THEY’VE FOUND THE SAME THING IS TRUE IN KIDS AS YOUNG AS FOUR. ANDREW BELDEN SAYS THIS IS… (act) :14 o/c age-appropriate tasks …frequently found in adults and adolescents, so what we were interested in doing was to see, do, in fact, the depressed preschoolers show this blunted response to reward doing slightly modified, but age-appropriate tasks? AGE-APPROPRIATE TASKS BECAUSE THE CHILDREN WERE PLAYING FOR TOYS. ADULTS AND ADOLESCENTS WERE STUDIED USING MONEY AS A REWARD. BELDEN SAYS FOR THIS STUDY, KIDS WERE SHOWN A COUPLE OF SETS OF TOYS THAT THEY COULD WIN. THEN THEY SAT AT A COMPUTER AND WERE ASKED TO PICK ONE OF TWO DOORS, WHICH THEN RANDOMLY GAVE THEM POINTS TOWARD A GOOD TOY OR SUBTRACTED POINTS FROM THEM, KIND OF LIKE A SLOT MACHINE FOR PRESCHOOLERS. (act) :08 o/c adolescents, adults The depressed preschoolers show a neural response very similar to what is seen in older children, adolescents, adults. THE RESEARCHERS MEASURED BRAIN ACTIVITY BY HAVING THE KIDS WEAR A SHOWER CAP-LOOKING DEVICE THAT WAS HOOKED TO ELECTRODES THAT MONITORED THEIR BRAIN ACTIVITY AS THE CHILDREN MADE CHOICES AND LEARNED WHETHER THOSE CHOICES WERE GETTING THEM CLOSER TO A TOY THEY LIKED, OR FARTHER AWAY. SENIOR INVESTIGATOR JOAN LUBY SAYS HER RESEARCH PREVIOUSLY HAD IDENTIFIED ANHEDONIA, THAT IS AN INABILITY TO EXPERIENCE JOY, FOR EXAMPLE IN ACTIVITIES AND PLAY, AS AN IMPORTANT MARKER OF DEPRESSION IN PRESCHOOLERS. AND THESE NEW FINDINGS APPEAR TO FIT WITH THOSE OLDER ONES. (act) :17 o/c rewarding tasks So this just gave us the neural validator of the behavior. An alteration in this process this early in development is a serious concern because it sort of sets the stage for how people approach their interaction with rewarding tasks. AND BELDEN SAYS THE DIFFERENCES WEREN’T APPARENT WHEN THE CHILDREN MADE A CHOICE THAT COST THEM POINTS. IN OTHER WORDS, IT WASN’T THAT THE BRAIN REACTED MORE NEGATIVELY TO FAILURE. IT WAS THAT IT REACTED LESS POSITIVELY TO SUCCESS AND REWARD. (act) :06 o/c or reward The difference was specific to their reactivity, their neural reaction, to winning, or reward. LUBY AND BELDEN ARE CONTINUING TO STUDY PRESCHOOLERS WITH AND WITHOUT DEPRESSION. THEY SAY THEY PLAN TO USE MRI IMAGING TO LOOK MORE CLOSELY AT SPECIFIC BRAIN REGIONS THAT MAY BE RESPONSIBLE FOR THE DIFFERENCES THEY SAW IN THIS STUDY, AND LUBY SAYS THE RESEARCHERS ALSO PLAN TO SEE WHETHER THERAPY MIGHT CHANGE THESE PATTERNS. (act) :06 o/c the treatment With the expectation that they will have a greater response to reward after undergoing the treatment. LUBY, BELDEN AND THEIR COLLEAGUES REPORT THEIR FINDINGS IN THE JOURNAL OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATRY. I’M JIM DRYDEN… RUNS 3:00