According to a recent study, children with autism were found to have elevated cortisol levels.
Researchers at the Institute for Autism Research at Canisius College have found that functional level appears to play a critical role in the stress levels of children with autism spectrum disorder (ASD). Specifically, lower-functioning children with ASD (LFASD) exhibited significantly higher levels of cortisol, the primary stress hormone in humans, than both high-functioning children with ASD (HFASD) and typical children.
Prior research has suggested that individuals with ASD experience elevated stress and related problems such as anxiety, however, many of the studies relied on informant rating scales and behavioral observations which have significant limitations for children with ASD. Attempts to more directly measure stress in this population using physiological measures such as cortisol have yielded mixed results. According to Susan K. Putnam PhD, chair and professor of psychology, the study's lead author, some of the inconsistent results may have been due to the prior studies not taking into account the significant differences in functional levels of individuals with ASD. "The inclusion of functionally-different individuals with ASD in studies has led to a need for studies of more precisely-defined subgroups with ASD, including subgroups based on functional level," said Putnam. This was the first study to assess cortisol (stress) levels in groups that were clearly differentiated based on functional level, specifically cognitive level.
Given the limitations in existing studies, the research team attempted to examine stress levels in ASD by examining the pattern of salivary cortisol across the day (morning, midday, and evening) and potential differences between lower-functioning children with ASD (LFASD IQ below 70), high-functioning children with ASD (HFASD IQ 85 or higher), and typical children. "It was important to determine whether the ASD groups exhibited the typical diurnal pattern of high cortisol in the morning, followed by a decrease at midday, and a further decline in the evening to determine if this typical pattern was present, and then examine the effect of functional level on stress level," said IAR co-director, Marcus Thomeer PhD, one of the study authors. Saliva samples were collected three times per day over four days on weekends from 13 children with LFASD, 16 children with HFASD, and 14 typical children. Results indicated that all three groups showed the typical pattern in which cortisol levels were highest at waking, followed by midday, and were lowest at bedtime. These findings are consistent with several prior studies of individuals with ASD.
The most significant finding, however, was that cortisol levels differed between the groups across the day. "Children with LFASD had significantly higher cortisol, the stress indicator, across the day than both the HFASD and typical children and, interestingly, children with HFASD did not significantly differ from the typical children across the day," said Putnam.
These findings have significant implications as they suggest that differences in cortisol levels and stress may be linked to the functional level, specifically IQ, of children with ASD. According to Putnam, this is an area in need of further study as it is unknown whether the elevated cortisol in the children with LFASD (compared to HFASD) is indicative of more significant neurological impairment and/or greater sensitivity to environmental stressors (associated with ASD symptoms), or whether a bi-directional relationship exists. IAR co-director Christopher Lopata PsyD, one of the study authors, noted that "identifying stress-level differences between functionally-differentiated groups with ASD has critical implications for how we assess and treat stress and stress-related reactions and conditions in children with ASD."
Findings from the study were recently published online first in the Journal of Developmental and Physical Disabilities.
A blood test is in development to detect autism, which can lead to earlier diagnosis and treatment.
In a potentially major advance in diagnosing autism spectrum disorder, San Diego's Pediatric Bioscience is preparing to sell a blood test later this year that would detect risk of one of its most common forms.
The company's test detects antibodies in a woman’s blood that can cause what it calls “maternal autoantibody-related” autism, which the company says, based on clinical studies, represents 23 percent of all autism cases.
The test delivers a false positive response just 1.3 percent of the time, said Jan D’Alvise, the company's president and chief executive.
If the test lives up to its billing, it could significantly improve care and prevention of autism spectrum disorder, which now occurs in 1 of 68 births. The disorder is treatable with therapy to encourage social skills. But therapy works best when started as early as possible, when the brain is still young and plastic.
"About 500,000 kids are born with developmental delays each year," she said. "Pediatricians say it can take six to 12 months to be referred to a specialist for diagnosis."
A positive test in mothers of infants or young children could expedite referral for assessment, she said. Also, if given before a planned pregnancy, the test could help women decide whether they should turn to parenting alternatives such as surrogate pregnancy or adoption.
Children of those who test positive would be sent to a specialist for a final diagnosis, expediting therapy.
Pediatric Bioscience plans to start selling the test in the third quarter of this year, D'Alvise said at the Biotech Showcase conference in San Francisco, an annual meeting of biotech investors and companies held concurrently with the JP Morgan Healthcare Conference. The company is now raising funds for that launch.
The test will cost about $1,000, and the company will partially subsidize the test for the women who aren't able to pay. Insurers are expected to reimburse for the test once they're familiar with it and have received recommendations from clinicians.
The market for such a screening method could be worth $1.8 billion annually, D’Alvise said.
While the form of autism identified by the test represents less than a quarter of all cases, a positive response for a potential mother greatly increases the overall risk, D'Alvise said at the conference.
Women who have a child with a developmental delay already have a 12 percent chance of having an autistic child. But the chance rises to 64 percent chance for those who score positive on the test.
Women who already have an autistic child have an overall 17 percent risk of having another autistic child; that risk jumps to 72 percent for those who score positive.
Risk is also higher in general for women over the age of 35.
According to the U.S. Centers for Disease Control and Prevention, about 1.2 million Americans younger than 21 have autism. That’s 30 percent higher than what the CDC reported two years ago, and more than double what the agency calculated in 2002.
Behavioral tests
No test now exists that reliably links autism to biological markers, said Eric Courchesne, a top autism researcher at UC San Diego. Genetic variants have been found that correlate with autism, but these represent only a "very, very tiny subset" of all autism cases, Courchesne said.
"For some of those genes, defects are found in non-autistic individuals as well," he said. "So the search for genetic markers of autism is ongoing."
Tests for autism all look for behavioral clues, said Courchesne, who recently published research pointing to structural abnormalities in the brains of autistic children. These abnormalities were found by examining postmortem brain tissue from children with and without autism, all between the ages of 2 and 15.
But such analysis can't be performed on the living, so assessments look at behavior.
In 2010, UC San Diego autism researcher Karen Pierce co-authored a study in the Archives of General Psychiatry showing that an autism diagnosis was foreshadowed for infants as young as 14 months if they preferred seeing movies of geometric shapes to children dancing or doing yoga.
And abnormalities in eye-tracking in 2-to-6-month-old infants correlate to later autism diagnosis. Research on the correlation waspublished by Emory University researchers in November, 2013 in the journal Nature.
These tests indicate that the attention of autistic children is fixated on objects instead of other people.
Immune research
Pediatric Bioscience chief executive D'Alvise said the company started developing its test several years ago, based on studies led by UC Davis researcher Judy Van de Water, an immunologist who has long been investigating how the immune system is involved with autism.
Pediatric Bioscience's blood test for autism is based on studies led by UC Davis researcher Judy Van de Water.
Scientists traditionally assumed that immune activity was reduced in pregnant women to allow the mother to tolerate the developing baby. However, recent research has found that the immune system becomes hyperactive.
For example, a study by Stanford University researchers found that the immune cells of pregnant women over-react to flu viruses. The research, led by Dr. Catherine Blish, was published Sept. 22, 2014in the Proceedings of the National Academy of Sciences.
Because of this hyperactivity, the test isn't appropriate for pregnant women, D'Alvise said.
In autism, the theory is that in some women, antibodies attack certain proteins important to the fetal brain, impairing its normal development.
Van de Water and colleagues have so far identified seven antibodies involved in autism. They expect to find more as research continues.
In their most recent study, published in the journal Cerebral Cortex, the scientists tested the effect of human maternal autoantibodies on fetal mice. They found that the antibodies affect glial brain cells in the ventricular zone of the developing mouse brain. This provides a mechanism to explain development of autism, the study concluded.
Elizabeth Thomas, a scientist who studies autism and other neurological disorders at The Scripps Research Institute, commended Van de Water and colleagues as "pioneers in this provocative area of research." However, Thomas, who was sent the Cerebral Cortex study for review, said the research isn't quite at the stage where an autism spectrum disorder test should be marketed.
"While these studies are compelling to provide a pathogenic mechanism for how maternal antibodies may cause ASD symptoms, it is still not clear that the implicated proteins are the most relevant ones for ASD; hence it seems a bit premature to be marketing a diagnostic test for ASD based on these proteins," Thomas said by email.
"Antibodies often bind to many possible targets. A more convincing study would employ the use of individual antibodies purified against each of the proteins making up the diagnostic screen, and studying their effects on mouse neurodevelopment and behavior," Thomas wrote.
D'Alvise replied that she is aware of the criticism among researchers, but is confident the test will pass regulatory muster and be clinically useful. The test is now being examined for certification for use in a lab certified under CLIA standards.
"We have a team who has done this so many times, who have launched literally hundreds of clinical diagnostic tests," D'Alvise said. "We know what is required, and we all wouldn't be so dedicated and committed to this if we didn't believe that this test is going to meet all the standards with flying colors."
While more research is needed and ongoing, D'Alvise said the set of autoantibodies used in the test functions as a "very specific set of biomarkers for a major subtype of ASD."
The test will go through a large, blinded clinical validation study, which the company plans to complete this spring, D'Alvise said. The results will then be presented to CLIA. The company expects CLIA will then certify the Pediatric Bioscience testing laboratory, allowing it to market the test.
Van de Water also replied in an emailed response, stating that the research on the maternal autoantibodies extends far beyond the Cerebral Cortex article and even autism itself.
"The notion that an autoantibody can be a useful biomarker of disease risk, even when the role of those autoantibodies in disease pathogenies remains unclear, has precedence in several autoimmune disorders including those associated with SLE (anti-Ro/SSA, anti-La/SSB, anti-snRNP, and anti-Sm, and anti-double stranded DNA (anti-dsDNA))," van de Water wrote.
"While detection of autoantibodies to these nuclear antigens have been used for the diagnosis and monitoring of SLE for decades, their specific role in the pathology of this disorder are still largely unknown. This is the case for several, but not all, autoantibody associated autoimmune disordersm" Van de Water wrote.
"While it is hoped that in the future we might be able to use our knowledge regarding the identity of these autoantigens to explore possible therapeutic avenues, there is still a great deal of research to be done regarding which of the autoantibodies are most relevant to the changes in brain development."
From research to test
As one part of getting the findings from research to clinical use, Pediatric Bioscience had to calibrate how to interpret the presence or absence of the maternal antibodies to make the test reliable, with a special emphasis on reducing false positives. This is important to avoid providing false alarms.
At the same time, a positive result must predict a significant enough increase in risk to make it worthwhile.
The test was originally scheduled to launch late last year. During that time, the company changed how it performs the screening — from a complicated manual process that takes highly trained personnel to run -- to a more automated system that can scale to to the volume expected. D'Alvise said the automated system provides results as good or probably better than the original method.
“That gave us the confidence to move into full-stage development,” she added.
The company, which now has about 7 full-time employees, is preparing to expand with the introduction of the test. The company expects to have about 18 employees by the end of 2015, D'Alvise said.
We also have news regarding how concussions are diagnosed. Researchers are developing a test that could be a game changer.
Quarterback Taylor Kelly of the Arizona State Sun Devils understands the mindset of college football players when it comes to injuries: They are going to want to keep playing.
"Guys just want to go out and play it, you know? They don't care if their heads are a little banged up," Kelly said.
Neurologist Dr. Javier Cardenas specializes in brain injury. He says overcoming the reluctance of athletes to admit symptoms is only one of the problems in diagnosing concussions.
"Right now when we identify a concussion it is purely subjective. We look at symptoms. Do they have headaches? Do they have dizziness? There is no objective information. Having something objective is the holy grail of concussion," said Cardenas.
This season, Kelly and his teammates took part in a study trying to find a better way to detect concussion. Riddell, the athletic equipment company, supplied the team with helmets that measure all head impacts during practices and games. Then, after every game, the players gave samples of their blood, saliva and urine.
These are now being analyzed at the Translational Genomics Research Institute in Phoenix to see whether evidence of head trauma shows up in body fluids as a so-called biomarker.
Brain cells contain generic material call microRNA. Normally, tiny spheres containing that material break off and make their way into the spinal fluid, then the bloodstream. During a concussion, the bran actually bounces against the skull, and researchers believe the impact can cause changes in the microRNA, changes they hope can be detected in blood tests.
TGen scientists are comparing the RNA in each player's body fluids with the impact data from his helmet to see if they match up.
"It might be that we can actually protect players. So identify players who are at risk but have them take it easy, sit out more, based how their biomarkers are rising over time," said Kendall Van Keuren-Jenses, a member of the research team.
The scientists have data illustrating how the technology might have helped one of the players in the study.
The graphic shows the head impacts recorded in his helmet over several weeks. One hit was the equivalent of four times the punch b a heavyweight boxer – the hardest impact received by any player in the study. He continued to play, and was diagnosed with a concussion 10 days later.
According to a recent study, narcolepsy might be caused by an immune system attack, meaning it could be tested for by a blood test, and treatment may center around the immune system.
A new study has uncovered evidence that most cases of narcolepsy are caused by a misguided immune system attack -- something that has been long suspected but unproven.
Experts said the finding, reported Dec. 18 in Science Translational Medicine, could lead to a blood test for the sleep disorder, which can be difficult to diagnose.
It also lays out the possibility that treatments that focus on the immune system could be used against the disease.
"That would be a long way out," said Thomas Roth, director of the Sleep Disorders and Research Center at Henry Ford Hospital, in Detroit.
"If you're a narcolepsy patient now, this isn't going to change your clinical care tomorrow," added Roth, who was not involved in the study.
Still, he said, the findings are "exciting," and advance the understanding of narcolepsy.
Narcolepsy causes a range of symptoms, the most common being excessive sleepiness during the day. But it may be best known for triggering potentially dangerous "sleep attacks." In these, people fall asleep without warning, for anywhere from a few seconds to a few minutes.
About 70 percent of people with narcolepsy have a symptom called cataplexy -- sudden bouts of muscle weakness. That's known as type 1 narcolepsy, and it affects roughly one in 3,000 people, according to the U.S. National Institute of Neurological Disorders and Stroke.
Research shows that those people have low levels of a brain chemical called hypocretin, which helps you stay awake. And experts have believed the deficiency is probably caused by an abnormal immune system attack on the brain cells that produce hypocretin.
"Narcolepsy has been suspected of being an autoimmune disease," said Dr. Elizabeth Mellins, a senior author of the study and an immunology researcher at Stanford University School of Medicine, in California.
"But," she said, "there's never really been proof of immune system activity that's any different from normal activity."
Mellins thinks her team has uncovered "very strong evidence" of just such an underlying problem.
The researchers found that people with narcolepsy have a subgroup of T cells in their blood that react to particular portions of the hypocretin protein -- but narcolepsy-free people do not. T cells are a key part of immune system defenses against infection.
That finding was based on 39 people with type 1 narcolepsy, and 35 people without the disorder -- including four sets of twins in which one twin was affected and the other was not.
It's known that genetic susceptibility plays a role in narcolepsy. And the theory, Mellins explained, is that in people with that inherent risk, certain environmental triggers may cause an autoimmune reaction against the body's own hypocretin.
Infections are the main culprit, and there is already evidence that the H1N1 "swine" flu is one trigger. In China, Mellins noted, there was an upswing in childhood narcolepsy cases after the H1N1 flu pandemic of 2009.
And in 2010, a cluster of narcolepsy cases in Europe was linked to a particular H1N1 vaccine that contained an "adjuvant" designed to induce a stronger immune system response. That vaccine, called Pandemrix, is no longer in use.
All of that led experts to speculate that in some genetically vulnerable people, the H1N1 virus could cause T cells to mistakenly attack hypocretin-producing brain cells.
And in the current study, Mellins's team found that segments of the H1N1 virus were similar to portions of the hypocretin protein -- the same portions that activated narcolepsy patients' T cells. They say that supports the idea that certain infections confuse T cells into attacking hypocretin-producing cells.
An expert on sleep welcomed the new study.
"They're providing more-compelling evidence that this is an autoimmune disease," said Dr. Nathaniel Watson, an associate professor of neurology at the University of Washington in Seattle, and a member of the board of directors for the American Academy of Sleep Medicine.
He and Mellins both said the results could have practical use, too. For one, researchers may be able to develop a blood test to help objectively diagnose narcolepsy.
Right now, Watson said, narcolepsy can be difficult to pinpoint, because the most common symptom -- daytime sleepiness -- has far more common causes. The most common, he noted, is simple: Not going to bed early enough.
So to diagnose narcolepsy, people may have to spend 24 hours in a sleep lab or, in some cases, have a lumbar puncture (spinal tap) to measure hypocretin in the spinal fluid.
Mellins said that if an autoimmune reaction is the cause of type 1 narcolepsy, it might be possible to treat with an immune-suppressing therapy.
The problem, though, is that once people develop full-blown symptoms, their hypocretin-producing cells have already been knocked off.
"We'd need some kind of pre-clinical marker of the disease to be able to intervene," said Watson at the University of Seattle.
Roth of Henry Ford Hospital agreed. "The big challenge is, how will you identify the people to treat?"
Three of the study authors reported they are inventors on a patent to use the hypocretin protein segments to diagnose narcolepsy. Stanford owns the intellectual property rights for this use.
Research has shown that measuring the level of adiponectin, a protein in your blood can predict the severity of migraines. Not clear about clinical use of this- JR
In a small, preliminary study of regular migraine sufferers, scientists have found that measuring a fat-derived protein called adiponectin (ADP) before and after migraine treatment can accurately reveal which headache victims felt pain relief.
A report on the study of people experiencing two to 12 migraine headaches per month, led by researchers at Johns Hopkins, is published in the March issue of the journalHeadache.
"This study takes the first steps in identifying a potential biomarker for migraine that predicts treatment response and, we hope, can one day be used as a target for developing new and better migraine therapies," says study leader B. Lee Peterlin, D.O., an associate professor of neurology and director of headache research at the Johns Hopkins University School of Medicine. She cautioned that larger, confirmatory studies are needed for that to happen.
Experts estimate that roughly 36 million Americans, or 12 percent of the population, suffer from debilitating migraine headaches that last four hours or longer. Migrainesare defined as headaches with at least two of four special characteristics: unilateral or one-side-of-the-head occurrence; moderately to severely painful; aggravated by routine activity and of a pounding or throbbing nature. Sufferers generally also feel nauseated or are sensitive to light and sound. Women are three times as likely to get migraines as men.
Such complicated diagnostic criteria mean that diagnosis is tricky, a fact driving efforts, Peterlin says, to find better diagnostic tools.
For the study, Peterlin and her colleagues collected blood from 20 women who visited three headache clinics between December 2009 and January 2012 during an acute migraine attack. Blood was taken before treatment with either sumatriptan/naproxen sodium (a drug routinely given to people with migraines) or a placebo. The investigators re-drew blood at 30, 60 and 120 minutes after the study drug was given. Eleven women received the drug and nine got the placebo.
The researchers measured blood levels of ADP, a protein hormone secreted from fat tissue and known to modulate several of the pain pathways implicated in migraine. The hormone is also implicated in sugar metabolism, insulin regulation, immunity and inflammation, as well as obesity, which is a risk factor for migraines.
Peterlin and her colleagues looked at total adiponectin levels and two subtypes or fragments of total ADP in circulation in the blood: low molecular weight (LMW)-adiponectin and high molecular weight (HMW)-adiponectin. LMW is comprised of small fragments of ADP and it is known to have anti-inflammatory properties, while HMW is made up of larger fragments of ADP and is known to have pro-inflammatory properties. Inflammatory pathways in blood vessels in the head are at work inmigraineheadache.
The researchers found that in all 20 participants when levels of LMW increased, the severity of pain decreased. When the ratio of HMW to LMW molecules increased, the pain severity increased.
"The blood tests could predict response to treatment," Peterlin says.
At onset of pain -- even before study drug was given - the researchers could identify who would be a responder to treatment and who would not, as there was a greater ratio of HMW to LMW in those who would be responders as compared to those who were not.
After study treatment changes in adiponectin were also seen. Interestingly, in those patients who reported less pain after receiving study drug to treat the migraine - whether they got the active migraine medication or a placebo -researchers were able to see a decrease in total levels of ADP in the blood.
Peterlin says the findings indicate it may be possible to develop a treatment that would reduce levels of ADP or parts of adiponectin such as HMW or LMW adiponectin. She says should ADP prove to be a biomarker for migraine, it could help physicians identify who has migraine and know who is likely to respond to which type of medication. It also may help doctors make better medication choices and try alternate drugs sooner.
Loyola University Medical Center researchers are reporting what could become the first reliable method to predict whether an antidepressant will work on a depressed patient.
The method would involve a blood test for a protein called vascular endothelial growth factor (VEGF). A Loyola study found that among depressed patients who had higher than normal blood levels of VEGF, more than 85 percent experienced partial or complete relief from depression after taking escitalopram (brand name Lexapro®). By comparison, fewer than 10 percent of depressed patients who had low levels of VEGF responded to the drug.
"This would be the first time we would have a predictor for how well a patient would respond to an antidepressant," said Angelos Halaris, MD, PhD, first author of the study. Halaris presented results during the 2011 annual meeting of the Society of Biological Psychiatry and the 4th Annual Illinois Brain, Behavior and Immunity Meeting.
About 60 percent of depressed patients do not respond fully to the first prescribed medication. Consequently, doctors often must prescribe a different medication again and again before finding one that works. "It would greatly benefit our patients if we could predict ahead of time whether a given medication would be effective for a certain patient," Halaris said.
The Loyola study involved 35 patients who took escitalopram for major depressive disorder. Escitalopram belongs to a class of antidepressants called selective serotonin reuptake inhibitors (SSRIs). Other common SSRIs are Prozac®, Paxil® and Zoloft®. Scientists aren't certain why SSRIs work in some patients but not in others. One possible mechanism is that SSRIs help restore a chemical balance in the brain. Some scientists recently have proposed a second possible mechanism, called neurogenesis -- SSRIs help to regenerate brain cells in specific parts of the brain that have atrophied in depressed patients.
The Loyola study supports the neurogenesis theory. It appears that escitalopram, the SSRI used in the Loyola study, jump-starts brain cells that have become inactive. This regeneration is fueled by VEGF. In the brain, VEGF stimulates the growth of blood vessels and works in other ways to keep brain cells healthy and active.
It appears that in patients with higher levels of VEGF, there was more regeneration, helping to reduce depression. Conversely, in patients with lower VEGF levels, there was less regeneration of brain cells and less relief from depression.
If the finding is confirmed by further studies, it could lead to a blood test that would help physicians tailor treatment. If, for example, a patient had low levels of VEGF, the physician might skip SSRIs and try alternative classes of antidepressants, such as bupropion, or alternative therapies, such as psychotherapy or Transcranial Magnetic Stimulation (TMG). These treatments are all available at Loyola University Medical Center.
