Study Suggests New Human Genotype May Be Prone To Variant Creutzfeldt-Jakob Disease

A small study in this week's British Medical Journal suggests a new human genotype may be prone to variant Creutzfeldt-Jakob disease (vCJD).

Although this new evidence may rekindle fears of a larger epidemic, others warn that it is important to be cautious in interpreting these results.

Since the initial discovery of vCJD in the United Kingdom a decade ago, there has been concern about the ultimate extent of the epidemic. Fortunately the magnitude of the epidemic at present seems to match the lower limit of the early estimates, with 161 definite or probable cases in the UK.

Researchers at the University of Edinburgh analysed DNA from two tissue samples that harboured prion proteins (a marker for vCJD infection) to identify the genetic make-up (genotype) of the patients.

So far, all clinical cases of vCJD have occurred in individuals with the homozygous methionine (MM) genotype, and it was hoped that this was the only susceptible population group. But both these samples carried the homozygous valine (VV) genotype, suggesting that individuals with the VV genotype may also be susceptible to vCJD infection.

The fear is that individuals with this genotype may be at risk of developing the condition, possibly with longer incubation periods, say the authors. Alternatively, these people may be asymptomatic carriers who might transmit the condition to other susceptible individuals by blood transfusion or surgery.

Though they warn against over-interpreting data from only two positive cases, they conclude that these uncertainties further underline the need for continued surveillance of vCJD in the UK.

It is important to be cautious in interpreting the results of this study, warn experts from Canada in an accompanying editorial. The study shows the existence of the prion protein in two tissue samples, not clinical evidence of vCJD in two patients. The study also provides no evidence to suggest that tissue from these two people could transmit vCJD to others.

"Studies such as this are essential to the continuing effort to control the extent of the epidemic and highlight the urgent need for ongoing surveillance for vCJD," they add. "They also pose challenges to health officials who have to formulate policies comprising difficult trade-offs based on uncertain evidence."

Can Dementia Spread From Mother To Offspring?

Researchers have demonstrated spread of senile amyloidosis from affected mice to their nursing offspring. The paper by Korenaga et al., "Transmission of amyloidosis in offspring of mice with AApoAII amyloidosis," appears in the March issue of The American Journal of Pathology and is highlighted on the cover of the Journal.

Dementia can result from several disease mechanisms, including amyloidosis. Amyloidosis occurs when cellular proteins that normally float freely in the body form organized, nonfunctional aggregates, or fibrils, that cause cellular damage. This injury can lead to such disorders as Alzheimer's disease and Creutzfeld-Jakob disease, depending on the protein involved and where the fibrils accumulate.

Genetics are known to be involved in these disorders, but researchers have also shown that injecting fibrils into susceptible mice accelerates disease onset. That led researchers guided by Dr. Xiaoying Fu to ask whether pups born to affected mothers also display accelerated disease.

Using a mouse strain that carries a mutation for senile amyloidosis, Dr. Fu's group injected female mice with amyloid fibrils, to accelerate their disease, and then allowed the mice to mate and produce offspring. The mouse pups born to these mothers exhibited elevated levels of amyloid fibrils that increased with age. These fibrils were first seen in the intestines, spreading later to liver, spleen and other organs.

Interestingly, when mice born to injected mothers were nursed by control mothers (no fibrils injected), only one of nine pups had amyloid fibrils at 6 months. However, pups born to control mothers but nursed by injected mothers had amyloidosis at levels similar to that of pups born/nursed by injected mothers. The presence of fibrils in the milk of injected mothers was confirmed by protein assay and electron microscopy, and spread via the milk was demonstrated by injecting affected milk into naïve mice (fibrils were found at 3 months).

These authors use traditional "infectivity" concepts to show that ingestion of fibrils by nursing mouse pups, and not by events occurring in utero, transmits amyloid fibrils to their offspring, thus accelerating amyloidosis. Such events have not been observed in human amyloidosis but have been suggested in sheep scrapie, a prion disease related to Creutzfeld-Jakob disease.

Prion diseases, such as scrapie and bovine spongiform encephalopathy (mad cow), are known to be transmissible, with spread among susceptible hosts demonstrated in the laboratory and in the real world. Non-prion amyloidosis, however, has not been shown to spread in such a way until now.

Though provocative, the implications for such laboratory findings in human disease, such as Alzheimer's disease, are not clear. The study does, however, suggest interesting new areas for study of amyloidosis.

This work involved collaborators at the Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Matsumoto; the Institute for Frontier Medical Science, Kyoto University, Kyoto; Fukui Medical University, Matsuoka; the Institute for Developmental Research, Aichi Human Service Center, Kasugai; and The Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Tokyo, Japan.

Korenaga T, Yan J, Sawashita J, Matsushita T, Naiki H, Hosokawa M, Mori M, Higuchi K, Fu X: Transmission of amyloidosis in offspring of mice with AApoAII amyloidosis. Am J Pathol 2006 168:898-906

New Mechanism Found For Neurodegenerative Effects Of Amphetamines In Mice

University of Toronto researchers have discovered a new mechanism for the neurodegenerative effects of amphetamines. These drugs are converted in the brain into free radicals, highly reactive molecules that cause neurodegenerative brain damage and whose effects manifest and linger long after the amphetamine has left the body.

"The question of whether amphetamines like ecstasy (MDMA) or methamphetamine (METH) cause neurodegeneration in humans is one of the most controversial areas in science today," says Professor Peter Wells of the Leslie Dan Faculty of Pharmacy, lead author of the study that appears in the April issue of the Journal of the Federation of American Societies for Experimental Biology (FASEB Journal). "The short-term effects of these drugs — hypothermia, electrolyte imbalances and an elevated risk of heart attack — are well understood, but not their long-term consequences."

Wells and doctoral students Winnie Jeng, Annmarie Ramkissoon and Toufan Parman theorized that prostaglandin H synthase (PHS) — an enzyme that synthesizes a range of hormones throughout mammalian life — is the catalyst that transforms amphetamines into free radical products that react with oxygen in the body to enhance the formation of highly toxic reactive oxygen species. These toxic forms of oxygen are implicated in neurodegenerative diseases such as Alzheimer's and Parkinson's because of the increased oxidative stress they place on the body, resulting in irreversible damage to DNA, proteins and lipid membranes. Organs such as the brain, which lack abundant antioxidant protection, are particularly vulnerable to oxidative stress.

To approximate an acute human exposure, the researchers administered four doses of either MDA (the major metabolite of ecstasy) or METH at two-hour intervals to young adult mice. In the case of MDA, before the first drug injection an additional group of mice was given a single dose of aspirin (acetylsalicylic acid), which is known to inhibit PHS and block its ability to convert drugs to free radical products. Over a six-month period, following the single day's treatment of MDA or METH, the mice were observed and had their motor co-ordination tested by walking on a rotating rod. Normally, mice balance easily on the rods for extended periods. Within two weeks of the last treatment, all the mice given MDA or METH without aspirin had trouble with this task and remained disabled for at least six months. These mice also exhibited enhanced molecular damage to the DNA in their brains and a loss of nerve terminals that remained for at least one week after exposure to MDA or METH. The mice pretreated with aspirin had less molecular damage to their DNA and fewer motor disabilities, suggesting that the neurodegenerative effects of MDA are dependent upon its conversion by PHS into a reactive free radical product.

"Our findings reveal how exquisitely susceptible brains are to this kind of damage, at least in mice," Wells says. "The long-term negative effects in the mice treated with MDA or METH all resulted from a single day's dosage that approximated the higher range of human exposures."

Although the team's findings cannot be extrapolated to humans without further study, Wells believes they do suggest a novel mechanism through which amphetamines may contribute to neurodegeneration.

"Our hypothesis about PHS-catalyzed conversation may also be relevant to the neurodegenerative risks associated with aging," he says. "Preliminary results from other studies suggest that PHS may convert other compounds in our brains into free radicals, and there is some evidence in the clinical literature that suggests patients who take high doses of PHS-inhibiting drugs such as aspirin may experience less neurodegeneration. The potential of substances like aspirin to prevent neurodegenerative damage merits more examination, particularly among people who take it chronically for pain."

This study was funded by the Canadian Institutes of Health Research, with support from the National Institute on Drug Abuse (U.S.A) and Health Canada's Healthy Environments and Consumer Safety Branch.

Extreme Personality Poses Risk Of ADHD, Conduct Disorder

Children with personalities marked by aggressiveness, mood swings, a sense of alienation and a need for excitement may be at greater risk for attention deficit hyperactivity disorder or conduct disorder, according to a new Florida State University study.

FSU psychology professors Jeanette Taylor and Chris Schatschneider, FSU doctoral student Kelly Cukrowicz and University of Minnesota Professor William Iacono found that children with ADHD or conduct disorder had more negative emotions – aggressiveness, tension and feelings of being exploited, unlucky or poorly treated – and lower constraints – a tendency to break rules and engage in thrill-seeking behavior – than children with neither of the disorders. Not surprisingly, those children who have both ADHD and conduct disorder had the most extreme personality profiles.

"This helps us to understand that personality is part of the bigger picture of these disorders," Taylor said. "That could help with initial assessments or lead to unexpected discoveries or potential interventions. We're saying to researchers and clinicians, 'Think about personality when you look at these issues.' "

The study, published in the Journal of Child Psychology and Psychiatry, is the first to investigate personality trait patterns among children who have ADHD, conduct disorder or a combination of both. It is important to learn more about the co-occurrence of ADHD and conduct disorder because the consequences are so severe, Taylor said.

"It's more than the sum of its parts," she said, explaining that children and adolescents with a combination of the two disorders are at much higher risk of school failure, criminal activity, substance abuse and depression. Previous studies have indicated that between 15 to 35 percent of children with ADHD also have conduct disorder.

Between 3 percent and 5 percent of U.S. school age children are estimated to have ADHD, a disorder that encompasses symptoms of hyperactivity, inattention or impulsivity. Conduct disorder affects about 13 percent of children and adolescents and is characterized by severe misbehavior including chronic lying, setting fires, destroying property or hurting animals.

The researchers analyzed personality data from 1,438 sets of same-sex, reared-together 11-year-old and 17-year-old male and female twins who participated in the Minnesota Twin Family Study. The rate of ADHD, conduct disorder and the co-occurrence of both was about the same as is found in the general population, Taylor said. Those who did not have symptoms of the disorders served as the control group.

The connection between personality and the disorders is clear, but more research will have to be done to determine whether the personality traits are shaped by the psychological disorders or vice versa.

"Developmentally, it makes sense that the personality comes first," she said. "But to say that one causes the other is too simplistic. I think they become intertwined."

Loud Music Worsens Effects Of Taking Ecstasy

Loud music prolongs the effects of taking ecstasy for up to five days. A study published today in the open access journal BMC Neuroscience shows that the reduction in rats' brain activity induced by 3,4 -Methylenedioxymethamphetamine (MDMA or ecstasy) lasts long after administration of the drug — up to five days — if loud music is played to them simultaneously. The effects wear off within a day when no music is played.

Michelangelo Iannone from the Institute of Neurological Science, Italy, and colleagues from University Magna Graecia in Catanzaro, Italy, injected rats with a low dose (3mg/kg) or a high dose (6mg/kg) of MDMA or, in the control group, with saline. The rats were either left without acoustic stimulation or exposed to white noise – sound at a stable frequency that is used in many types of electronic music. The sound was played at 95dB, the maximum noise intensity permitted in nightclubs by Italian law. The electrocortical activity (EcoG spectrum) of the rats was monitored, using electrodes placed on their skull, from 60 minutes before administration of the drug and start of the music, to up to five days after the music was stopped.

Iannone et al.'s results show that low-dose MDMA did not modify the brain activity of the rats compared with saline, as long as no music was played. However, the EcoG total spectrum of the rats given a low dose of MDMA significantly decreased once loud music was played. The EcoG spectrum of rats in the control group was not modified by loud music. High-dose MDMA induced a reduction in brain activity, compared with both saline and low-dose MDMA. This reduction was enhanced once the loud music was turned on and lasted for up to five days after administration of the drug. In rats that had been given a high dose of MDMA but had not been exposed to music, brain activity returned to normal one day after administration of the drug.

Article:
Electrocortical effects of MDMA are potentiated by acoustic stimulation in rats
Michelangelo Iannone, Immacolata Vecchio, Stefania Bulotta, Donatella Paolino, Maria Cristina Zito, Santo Gratteri, Francesco S Costanzo and Domenicantonio Rotiroti
BMC Neuroscience 2006, 7:12 (16 February 2006) doi:10.1186/1471-2202-7-12

Team Discovers Possible 'Universal Strategy' To Combat Addiction

 An international research team led by the University of Saskatchewan has discovered a signaling pathway in the brain involved in drug addiction, together with a method for blocking its action, that may point to a single treatment strategy for most addictions.

Their findings appear in the March issue of the prestigious journal Nature Medicine.

The team, led by Xia Zhang, associate professor in the U of S department of psychiatry, found that a naturally occurring enzyme known as PTEN acts on the part of the brain where many drugs of abuse exert their rewarding effects – the ventral tegmental area (VTA).

"Our results suggest a potential universal strategy for treating drug addiction," Zhang says. "Most drugs of abuse act on the neurons in this area."

He cautions that much work remains to be done before a treatment based on the discovery could be developed to help drug addicts. This includes several years of further testing, including animal and, finally, human trials.

"We have our peptide, but there's a long way to go before a clinical application," he says.

"Dr. Zhang's research is important to our understanding of drug addiction. His work epitomizes how health research holds the key to improved health and quality of life for Canadians and people throughout the world," said Dr. Rémi Quirion, Scientific Director of the Canadian Institutes of Health Research Institute of Neurosciences, Mental Health and Addiction.

Zhang, who worked with colleagues at the U of S, University of Toronto, and Vanderbilt University in Tennessee on the project, explains that VTA brain cells are sensitive to serotonin, a hormone associated with learning, sleep and mood. The team discovered that PTEN acts on these serotonin receptors, increasing brain cell activity. This is the same "reward" process sparked by drugs of abuse.

Armed with this knowledge, the team designed a molecule called a peptide, tailored to fit the serotonin receptors and block PTEN. When rats were treated with this PTEN-blocker, it shut down the drug reward process — including the process that induces craving and withdrawal.

The study, funded by the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council, looked at nicotine and THC (the active ingredient in marijuana). However, Zhang says the results could also hold true for other drugs such as cocaine, heroin, and even methamphetamine.

Zhang's U of S research team is part of the Neural Systems and Plasticity Research Group, one of several interdisciplinary health sciences research groups at the University.

The group, dedicated to the study of brain systems and how they change with experience, draws expertise from numerous departments across six colleges on campus.

Genetics Plays Role In Relapse Of Illicit Drug-seeking Behavior

 Inbred strains of rats differ in how aggressively they seek cocaine after a few weeks of use, researchers say.

The finding, posted online Jan. 18 by Psychopharmacology, is another piece of evidence that genetics plays a role in the relapse of drug-seeking behavior in humans, says Dr. Paul J. Kruzich, behavioral neuroscientist at the Medical College of Georgia and lead study author.

It also fingers glutamate, a neurotransmitter involved in learning and memory, as an accomplice in stirring the cravings and uncontrollable urges that drive some drug users to use again, he says.

“Given the right environmental stimuli, all persons addicted to psychostimulants can relapse, but potentially some people are a little more susceptible than others … it’s all about gene-environment interaction,” says Dr. Kruzich.

He took two strains of inbred rats – Fischer 344 and Lewis – with known genetic differences, enabled each to self-adminster cocaine for 14 days, then took the drug away for a week but not the levers the animals used to access it.

During that hiatus, he adminstered a drug that stimulates glutamate receptors, possible targets for drugs of abuse.

He found that the F344 strain worked harder to get cocaine than the Lewis rats following treatment with the glutamate drug, suggesting they were more susceptible to relapse.

“Maybe 12-step programs and faith-based programs will be enough to keep some people from relapsing,” says Dr. Kruzich. “For others we may have to come up with medical treatments we can use on top of those to keep them from taking drugs again.”

He says there are many different versions of the hundreds of genes that may play a role in increasing the risk of relapse.

It’s known that some people become addicted more quickly than others, some literally with their first use, he says. The hardest part is not getting people to stop taking drugs: that happens when they are checked in a clinic or put in jail. The real work is keeping them from relapsing when they are out of such restricted environs, he says.

“Something happens, either they see an old colleague they have used with, they go into an old environment, they have a huge stressor in life and they start to want the drug. They have drug hunger, what we call drug craving,” says Dr. Kruzich. “When it gets bad enough, they engage in drug-seeking behavior.”

His lab is working to identify the relapse trigger to use as a target for developing ways to curb craving and subsequent relapse.

His studies focus on an area of the brain called the nucleus accumbens core, a target for drugs of abuse long considered a pleasure center, Dr. Kruzich says. Drugs such as cocaine and methamphetamine stimulate release of dopamine in the nucleus accumbens. Dopamine is a neurotransmitter believed responsible for the euphoria that come with drug use. In fact, animals given dopamine blockers won’t self-adminster drugs of abuse, and dopamine has long been a focus of drug-abuse studies.

“These drugs impinge upon the reward centers of the brain that normally food, sex, survival and adaptation impinge upon,” says Dr. Kruzich. “When you are having that great piece of cheesecake and thinking, ‘Oh man,’ that is the kind of response these drug of abuse are evoking but much more so than that cheesecake could ever do.”

Glutamate, also released in the nucleus accumbens core, may play an equally important role in drug relapse, he says. Drugs such as cocaine appear to alter glutamate neurotransmission in the core, which may contribute to the rewiring of the brain that occurs with drug use. “It’s not that these drugs just damage neurons, which they can, but they rewire the circuitry of the brain so no longer is your spouse or your job or other things in your life important to you. Your brain is tricked into thinking that drugs are the most important thing for your survival,” Dr. Kruzich says.

Unfortunately, drugs that restore glutamate function also produce seizures, so scientists are looking for an indirect approach to restore the misdirected rewiring.

First Human Tests Of Antidepressant Bupropion As Methamphetamine Addiction Treatment Hold Promise

 A new study led by researchers at UCLA's Semel Institute suggests the antidepressant bupropion may help treat methamphetamine addiction. No medications presently are approved for treating methamphetamine addicts.

Appearing Nov. 23 as an advance online publication of the peer-reviewed journal Neuropsychopharmacology, the study finds bupropion blunts the methamphetamine "high" and reduces cravings prompted by visual cues such as ambient drug use.

The research team hypothesizes that bupropion reduces the effects of methamphetamine by preventing the drug from entering brain cells, where methamphetamine can produce release of neurotransmitters that cause feelings of euphoria.

The study is the first to examine the effectiveness of bupropion for treating methamphetamine addiction in humans. A multisite Phase II clinical trial led by UCLA researchers is in progress.

"Finding new, effective ways to treat methamphetamine addiction is a key component of bringing the ongoing epidemic of abuse under control," said Dr. Thomas F. Newton, the study's principal investigator and professor at the Semel Institute for Neuroscience and Human Behavior.

"Bupropion's novel effect on the brain is what makes this line of research so promising," added Newton, who also is a professor of psychiatry and biobehavioral sciences at the David Geffen School of Medicine at UCLA. "These findings may point the way toward medications with even greater potential to be helpful."

Twenty of 26 participants enrolled in the project completed the study. Participants were active methamphetamine users between ages 18 and 45. Researchers randomly assigned each participant to receive treatment either with a placebo — an inactive ingredient such as a sugar pill — or bupropion.

Each participant received a series of three intravenous doses of methamphetamine as the study began and a second, identical series of doses six days after treatment with placebo or bupropion began.

Using a variety of subjective rating scales and questionnaires, participants reported on the subjective effects of the methamphetamine use at baseline and again after treatment with placebo or bupropion. Subjects who took the medication reported a lesser high after treatment.

Each set of research subjects reported similarly on cravings, both at baseline and after treatment, after watching a video with actors portraying methamphetamine use. Subjects who took bupropion reported less intense craving.

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The study was funded by the National Institute on Drug Abuse. Other members of the research team included Richard De La Garza II and Timothy Fong of UCLA's Semel Institute and Geffen School of Medicine; John D. Roache and Christopher L. Wallace of the University of Texas Health Science Center at San Antonio; and Shou-Hua Li, Ahmed Elkashef, Nora Chiang and Roberta Kahn at the National Institute on Drug Abuse in Bethesda, Md.

Online resources:
* Semel Institute: http://www.npi.ucla.edu/.
* Geffen School of Medicine: http://www.medsch.ucla.edu/.
* National Institute on Drug Abuse: http://www.nida.nih.gov/.
* University of Texas Health Science Center at San Antonio: http://www.uthscsa.edu/.

LSD Finds New Respectability

Hamilton, ON – It was the drug of choice on university campuses, the drug that spawned psychedelic culture as well as countless jail sentences and fines, but LSD actually has respectable roots—roots that a McMaster University researcher is uncovering.

"Far from being fringe medical research, trials of LSD were once a legitimate branch of psychiatric research," explains Erika Dyck, a doctoral researcher in the Department of History at McMaster. "LSD produced a "model psychosis," meaning people who took the drug exhibited symptoms of illnesses such as schizophrenia. Doctors used this as a new method for studying mental illness."

In a recent issue of the Canadian Journal of Psychiatry, Dyck traces the history of LSD—and its eventual withdrawal from medical research. LSD, or d-lysergic acid diethylamide, first appeared in scientific literature in 1943. For nearly a decade, it gave psychiatrists insight into the experi-ences of schizophrenic patients and showed potential as a cure for alcoholism.

In the 1960s, as the media increasingly associated the drug with love-ins, anti-war demonstrations and the counterculture, governments intervened to criminalize LSD, restricting and then terminating medical research into its potential therapeutic effects.

Now, therapeutic uses of psychedelic drugs are resurfacing. Research groups in the United States are currently examining the usefulness of MDMA, or "ecstasy," in treating pain in medical conditions such as Parkinson's disease and cancer.

This makes Dyck optimistic that LSD may become a valid area of research again. "Many illegal drugs are used in medical settings. Scientists who studied LSD made important contributions to psychiatry, and found it helped many people cope with mental illness."

Dyck discovered another interesting fact while researching LSD: The term "psychedelic", it turns out, was a Canadian invention – coined in Weyburn, Sask. in the 1950s.

The paper is available online at www.cpa-apc.org/Publications/Archives/CJP/2005/june/InRevDyck.asp.

McMaster University, named Canada's Research University of the Year by Research InfoSource, has world-renowned faculty, and state-of-the-art research facilities. McMaster's culture of innovation fosters a commitment to discovery and learning in teaching, research and scholarship. Based in Hamilton, the University has a student population of more than 23,000, and an alumni population of more than 115,000 in 128 countries.

New Lab Research May Help Those Deafened By Immune System Attack

ANN ARBOR, Mich. — Our immune system protects us from disease, destroying invading microbes with a swarm of attacking cells. But it can also go haywire for no apparent reason, ganging up on normal tissues in our body and wreaking havoc.

In thousands of people each year, the immune system attacks the inner ear, home to the tiny, delicate structures that allow us to hear. Without warning, in days or weeks, patients lose the ability to hear in one or both ears. Some might get part or all of their hearing back if they take steroid medicines, but many are left to cope with partial or total deafness without knowing what caused it. And no one knows why it happens.

Now, new research based at the University of Michigan's Kresge Hearing Research Institute may help more patients find out quickly if steroids could help them, or if they can be spared the drugs' harsh side effects. It may also expand the definition of the condition, known as autoimmune sensorineural hearing loss or AISNHL, and help more people get a firm diagnosis of what's causing their mysterious hearing loss.

In the August issue of the Archives of Otolaryngology — Head and Neck Surgery, researchers reports results from a study of 63 people with rapidly progressing hearing loss in Michigan, Pennsylvania and Indiana, and 20 people with normal hearing. The patients were suspected of having an auto-immune cause for their hearing loss, and all received steroids, but they hadn't been formally diagnosed.

The researchers found that more than half of the hearing-loss patients had antibodies against a protein found in the inner ear, called IESCA for inner-ear supporting cell antigen. This is a sign their immune systems recognized it as foreign.

"In all, 28 of the 63 patients experienced improvement in their hearing after steroid treatment, and 35 did not. But the vast majority, 89 percent, of those who improved had a positive immunofluorescence test for an antibody to IESCA that we have studied at U-M for years," says senior author Thomas Carey, Ph.D., a professor and distinguished research scientist at the U-M Medical School and department chair in the School of Dentistry. "The results strongly suggest that a direct test for antibodies could accurately predict which patients will regain hearing with steroid treatment." Such a test, he notes, is still several years away from being available to patients.

The new findings also may be important to people with systemic autoimmune disorders such as lupus or rheumatoid arthritis. Such people may be prone to losing all or part of their hearing due to an overzealous autoimmune reaction. All eight study participants who had systemic autoimmune diseases showed signs of antibodies against IESCA. Six of them regained hearing after steroid treatment.

U-M researchers have been studying IESCA for several years in animals and have found that it may be a main target of the immune system's deafening attack on the inner ear. IESCA is found in the supporting cells that help make up the organ of Corti, a tiny but crucial structure inside the cochlea, or inner ear.

Inside the organ of Corti are the ultra-sensitive hair cells, whose movement in response to vibrations creates the nerve signals that are fed to the brain and interpreted as sounds and speech. Damage to the organ of Corti and hair cells, whether due to immune system attack, loud noise, trauma or medications, can diminish or destroy hearing.

The U-M team has developed a monoclonal antibody, called KHRI-3, that attaches to IESCA in the inner ear, and can be detected in living animal systems and cell cultures. It has allowed them to study IESCA's role in hearing loss in animal models, and show that damage to the inner ear caused by antibodies to IESCA can destroy hearing. The KHRI-3 antibody creates a staining pattern that resembles a line of tiny wine glasses when it binds to IESCA in the organs of Corti of guinea pigs.

The U-M has patent applications pending in the U.S. and abroad pertaining to KHRI-3, IESCA and AISNHL. The University, Carey and several colleagues stand to profit if tests or treatments based on these patents are developed. The development of a clinical test for patient antibody to IESCA will take time, Carey says.

In previous papers, Carey and his colleagues have shown that IESCA has about the same molecular weight as — but is distinct from — a protein that serves as the basis for a currently available commercial AISNHL test. That test, based on a protein-separation test known as Western blot, is known to give accurate results only some of the time. The U-M team reported in previous paper in the Journal of Neuroscience that IESCA is identical to a protein called CTL2, or choline transport-like protein 2.

In the new study, the researchers tested blood from the 63 patients and 20 normal controls with two tests: a Western blot test and an immunofluorescence (IF) test based on KHRI-3. They correlated the results of those two tests with patients' response to steroid treatment, based on standard criteria and the results of hearing tests performed before and after treatment. They also considered patients' other autoimmune diseases, the length and pace of hearing loss progression before treatment, and age and gender.

Thirty of the patients were female, and 33 male; their average age was 47, reflecting the young age at which AISNHL typically begins. Twenty-six had lost hearing in both ears, the rest in the left or right ear. They had no known cause for hearing loss, and most had lost their hearing gradually over weeks, though eight had lost it over hours or days. Many also had dizziness, ringing or a sensation of fullness in their ears. In all, half regained some or all of their hearing after steroid treatment.

Seventy-five percent of the patients had "wine glass" staining with IF testing, and 68 percent had positive Western blot results for the same size protein as is used in the commercial test.

The two different blood tests weren't always consistent – – results were the same in 47 patients (both positive or both negative) but different in 16. But the IF test appeared give a more specific response to steroid treatment: patients who had a positive IF test result were three times more likely to improve after steroid treatment than those with negative IF results.

The two tests combined were even more predictive: 54 percent of those who had positive results on both tests improved after steroid, compared with 10 percent of those who had two negative results.

Interestingly, Carey notes, nearly all of the patients who had sudden hearing loss over hours or days had antibodies, and nearly all improved with steroids.

Since this kind of rapid-onset hearing loss has historically been excluded from the formal definition of AISNHL, Carey suggests the definition may need re-examining in light of this strong evidence for an immune-system cause in these patients.

In addition to Carey, who is associate chair for research of the Department of Otolaryngology at the U-M Medical School, the paper's other U-M authors are Otolaryngology/Kresge members Hisham Zeitoun, MPhil., FRCS, the lead author; H. Alexander Arts, M.D.; Dawn E. Denny; Michael J. Disher, M.D.; Hussam El-Kashlan, M.D.; David S. Lee, M.D.; Thankam S. Nair, M.S.; Anna Ramakrishnan, M.S.; and Steven Telian, M.D. Co-authors from outside U-M are Jennifer Gray Beckman, JD; Christopher D. Lansford, M.D.; Robert Sataloff, M.D.; and Susan G. Fisher, Ph.D.

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The research was funded by the Autoimmune Sensorineural Hearing Loss Research Fund, the Ruth and Lynn Townsend Fund, a gift from the Holden Foundation, the Deafness Research Foundation and the National Institutes of Health.

Special note for hearing-loss patients: The new findings, while exciting, are laboratory results and cannot be immediately applied to human treatment. It will take several years to develop a test that could be used in patients who have recently developed hearing loss. If you have recently begun to experience hearing loss that is progressing, seek immediate attention from an otolaryngologist, sometimes called an ear, nose and throat (ENT) doctor. He or she can advise you on immediate and long-term treatment options.

If you would like to help support U-M research into autoimmune sensorineural hearing loss, visit https://cgi.www.umich.edu/cents-bin/cents-open/mcado2 to make a secure on-line donation; please note that you would like the donation to go to the Autoimmune Hearing Loss Research Fund of the Kresge Hearing Research Institute.