Johns Hopkins research may improve early detection of dementia

Using scores obtained from cognitive tests, Johns Hopkins researchers think they have developed a model that could help determine whether memory loss in older adults is benign or a stop on the way to Alzheimer's disease. The risk of developing dementia increases markedly when a person is diagnosed with mild cognitive impairment, a noticeable and measurable decline in intellectual abilities that does not seriously interfere with daily life. But physicians have no reliable way to predict which people with mild cognitive impairment are likely to be in the 5 to 10 percent a year who progress to dementia. In a proof-of-concept study, the Johns Hopkins investigators analyzed records of 528 people age 60 and over, who were referred to the Johns Hopkins Medical Psychology Clinic for cognitive testing as part of a dementia work-up between 1996 and 2004. The results were compared to those of 135 healthy older adults who participated in a study of normal aging. Both groups completed tests of memory, language, attention, processing speed and drawing abilities from which 13 scores were recorded Nursing CEUs Since each person is naturally more skillful in some areas than in others, the scores of healthy adults showed a symmetrical, bell-shaped range: Most of their scores were high, a few were a bit lower, and a few were even lower. By grouping the patients into cohorts based on the severity of their dementia, the researchers found a trend in the test scores that is likely to mimic the deterioration of an individual's scores over time. At the outset, he says, Alzheimer's disease subtly disrupts some mental abilities, while leaving others intact. Thus, well before a person develops clear cognitive impairment, his or her performance declines slightly on a few measures. When shown on a graph, these changes cause the healthy symmetric, bell-shaped curve to shift and become asymmetrical. Regardless of how low a person's test scores were, the researchers determined that lopsidedness in their score distribution correlated with dementia. They predicted that people with low scores that were evenly distributed were not likely to develop dementia. But those with clearly lopsided test score distributions on the 13 measures administered were already experiencing varying levels of dementia. "Departures from the normal bell-shaped pattern of variability on cognitive tests might determine which people with low scores develop dementia," says David J. Schretlen, Ph.D., a professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and leader of a study published online Nov. 12 in the journal Neuropsychology. Since these declines can be subtle, the researchers also increased the precision of cognitive testing by accounting for the effects of age, sex, race and education on test performance. The challenge for doctors, Schretlen explains, is that most normal, healthy people will produce a few low scores on cognitive testing. That makes it nearly impossible to know at the outset whether a patient who reports forgetfulness and produces one or two low scores has a benign form of mild cognitive impairment, or is in the earliest stage of dementia. As a result, doctors often tell such patients to return for follow-up testing in a year or two. But if future research confirms it, this new statistical model could help doctors get the prognosis right earlier in the disease, at the first visit, and start treating patients accordingly. Mostly, Schretlen says, doctors could use the new model to reassure patients who are not at risk of dementia, while fast-tracking interventions for those who are. Because there currently are no effective treatments for Alzheimer's disease, those likely headed that way could be counseled to take the good time they have to organize their affairs, and do things they have always wanted to do. They also could be fast-tracked into clinical trials of medications to slow the progression of dementia. "If we are going to have any hope of helping patients with Alzheimer's disease, we need to do it as early as possible," Schretlen says. "Once the brain deteriorates, there's no coming back." Recent failures of drugs in late-stage clinical trials for Alzheimer's disease have been a real blow, he adds, but new treatments are being developed. The new way of reading existing test scores follows a 2008 study by the same researchers showing that one of every six healthy adults scored poorly on two or more of 10 tests in a brief cognitive battery — even though there was nothing wrong with them. The main reason it is difficult to tell whether older people have benign mild cognitive impairment or not is because they are not routinely screened for cognitive impairment, he says. A visit to a specialist comes only after someone has noticed symptoms, and then cognitive testing is interpreted without the benefit of a baseline assessment. What would solve this problem, he says, would be for everyone over the age of 55 to get routine neurocognitive testing every five years. ### The study was supported by the Therapeutic Cognitive Neuroscience Fund; the Benjamin and Adith Miller Family Endowment on Aging, Alzheimer's and Autism; the William and Mary Ann Wockenfuss Research Fund Endowment; and the National Institutes of Health's National Institute of Mental Health (MH60504). Under an agreement with Psychological Assessment Resources, Inc., Schretlen is entitled to a share of royalties on sales of a test and software used in the study. The terms of this arrangement are being managed by The Johns Hopkins University in accordance with its conflict-of-interest policies. Other Johns Hopkins researchers involved in the study include Gila Z. Reckess, Ph.D.; Mark Varvaris, B.A.; and Barry Gordon, M.D., Ph.D. For more information about Schretlen, click here. Johns Hopkins Medicine (JHM), headquartered in Baltimore, Maryland, is a $6.7 billion integrated global health enterprise and one of the leading health care systems in the United States. JHM unites physicians and scientists of the Johns Hopkins University School of Medicine with the organizations, health professionals and facilities of The Johns Hopkins Hospital and Health System. JHM's vision, "Together, we will deliver the promise of medicine," is supported by its mission to improve the health of the community and the world by setting the standard of excellence in medical education, research and clinical care. Diverse and inclusive, JHM educates medical students, scientists, health care professionals and the public; conducts biomedical research; and provides patient-centered medicine to prevent, diagnose and treat human illness. JHM operates six academic and community hospitals, four suburban health care and surgery centers, and more than 30 primary health care outpatient sites. The Johns Hopkins Hospital, opened in 1889, was ranked number one in the nation for 21 years in a row by U.S. News & World Report. For more information about Johns Hopkins Medicine, its research, education and clinical programs, and for the latest health, science and research news, visit http://www.hopkinsmedicine.org Aging and Long Term Care CE Course Johns Hopkins Medicine Media Relations and Public Affairs

Potential new class of drugs blocks nerve cell death

Potential new class of drugs protects nerve cells in models of Parkinson's disease and amyotrophic lateral sclerosis Diseases that progressively destroy nerve cells in the brain or spinal cord, such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), are devastating conditions with no cures. Now, a team that includes a University of Iowa researcher has identified a new class of small molecules, called the P7C3 series, which block cell death in animal models of these forms of neurodegenerative disease. The P7C3 series could be a starting point for developing drugs that might help treat patients with these diseases. These findings are reported in two new studies published the week of Oct. 1 in PNAS Early Edition. "We believe that our strategy for identifying and testing these molecules in animal models of disease gives us a rational way to develop a new class of neuroprotective drugs, for which there is a great, unmet need," says Andrew Pieper, M.D., Ph.D., associate professor of psychiatry at the UI Carver College of Medicine, and senior author of the two studies. About six years ago, Pieper, then at the University of Texas Southwestern Medical Center, and his colleagues screened thousands of compounds in living mice in search of small, drug-like molecules that could boost production of neurons in a region of the brain called the hippocampus. They found one compound that appeared to be particularly successful and called it P7C3. "We were interested in the hippocampus because new neurons are born there every day. But, this neurogenesis is dampened by certain diseases and also by normal aging," Pieper explains. "We were looking for small drug-like molecules that might enhance production of new neurons and help maintain proper functioning in the hippocampus." However, when the researchers looked more closely at P7C3, they found that it worked by protecting the newborn neurons from cell death. That finding prompted them to ask whether P7C3 might also protect existing, mature neurons in other regions of the nervous system from dying as well, as occurs in neurodegenerative disease. Using mouse and worm models of PD and a mouse model of ALS, the research team has now shown that P7C3 and a related, more active compound, P7C3A20, do in fact potently protect the neurons that normally are destroyed by these diseases. Their studies also showed that protection of the neurons correlates with improvement of some disease symptoms, including maintaining normal movement in PD worms, and coordination and strength in ALS mice. Of mice and worms In the ALS mouse model, a highly active variant of the original P7C3 molecule, known as P7C3A20, which the investigators synthesized, largely prevented death of the nerve cells within the spinal cord that are normally destroyed by this disease. The P7C3 molecule also worked, but was not as effective at protecting neurons in this model. As cell survival increased in the ALS model, coordination and strength of the mice improved as well. Mice that were given P7C3A20 were able to stay on a rotating rod much longer than untreated animals or animals that received the less active compounds. Animals receiving P7C3A20 also performed better in analysis of their walking gait, which typically worsens in these animals as the disease progresses. In PD, dopamine-producing neurons necessary for normal movement are gradually destroyed. In patients, loss of these brain cells leads to tremors, stiffness, and difficulty walking. The study again showed that P7C3 protects these neurons from cell death and the more active analogue, P7C3A20, provided even greater protection. The two compounds also potently blocked cell death of dopaminergic neurons in a C. elegans worm model of PD. Moreover, reduced cell death in this model was associated with improved movement in the worms. Healthy C. elegans worms have a very characteristic swimming motion. This movement is disrupted in the PD worm. Hector De Jesus-Cortes, a graduate student of neuroscience at UT Southwestern Medical Center and lead author of the Parkinson's study, videotaped and analyzed the PD worms' mobility with and without treatment. Normal swimming was almost completely preserved with P7C3A20, and was also fairly well preserved with P7C3. Tweaking the molecule The research team compared the activity of several new P7C3-related compounds that they synthesized, in both the hippocampal neurogenesis screen and the mouse model of PD. "Every variation of our P7C3 molecule that works in the neurogenesis assay also works in the PD model," Pieper says. "As we continue to refine the molecule, our hope is that the results from the neurogenesis assay will accurately predict the neuroprotective potency of the compound, and thus aid in more rapidly optimizing a new neuroprotective agent." Nursing CEUs The team plans to continue tweaking the structure of the P7C3 molecule to improve its neuroprotective ability while eliminating potential side effects. "Our hope is that this work will form the basis for designing a neuroprotective drug that could eventually help patients," Pieper says. ### Pieper and De Jesus-Cortes conducted the study with colleagues at UT Southwestern Medical Center, including Steven McKnight, Ph.D., chairman of biochemistry, and Joseph Ready, Ph.D., professor of biochemistry. The work was funded in part by grants from the National Institute for Mental Health.

Social Brain Circuits Disrupted in Autism

In a study of high-functioning adolescents with an autism spectrum disorder, scientists using functional brain imaging have found reduced connectivity selectively affecting parts of the brain that form circuits supporting social behavior. The findings sharpen the focus of previous reports suggesting disruptions in connectivity across the brain in autism, and offer a target for future studies to search for the genes that shape the development of these circuits and how they become disrupted in the disorder. Background Difficulties with communication and social interactions are central features of autism spectrum disorders (ASD), and are universally present in those with an ASD. In an effort to determine how brain function is disrupted in autism, scientists have used noninvasive functional brain imaging to explore connectivity in the brain—the extent to which patterns of activity in functionally related parts of the brain correlate with each other. Scientists increasingly see the brain and its disorders in terms of circuits, with a given behavior engaging multiple centers across the brain, functioning in tandem. Functional imaging of people with an ASD has suggested that there are disruptions in connectivity across the brain. Narrowing the search to determine if losses in connectivity affect only specific circuits has been difficult, however. Mapping which centers of the brain are tightly connected in most people but disrupted in illness potentially involves comparisons in activity between thousands of points in different brain regions. Accordingly, previous studies have focused on a predetermined, small handful of regions to evaluate connectivity differences in ASD. This Study Stephen Gotts, Alex Martin and colleagues at the National Institute of Mental Health developed an approach to identify regions throughout the entire brain for which connectivity was reduced in ASD, and measure the magnitude of the reductions. The scans were done on 31 adolescents with ASD and 29 without the disorder, while they were at rest, not engaged in any task. Scan results revealed decreases in connectivity among those with ASD compared to individuals without ASD, concentrated in areas of the brain involved in social functions. In particular, the greatest decreases occurred between a cluster of brain regions involved in the emotional aspects of social behavior (the limbic brain) and two other clusters: one involved in language and communication and the other in the interplay between visual perception and movement. Moreover, participants in the study who had the greatest difficulties with social interactions were those in whom the decreases in connectivity were the most marked. Significance These data offer evidence in terms of brain activity to confirm what scientists have suspected but have been unable to examine systematically, that disruptions in connectivity in autism are concentrated in social centers of the brain. According to Dr. Gotts, what they found was not that this circuit was inactive, but that, among participants with ASD, patterns of activity in the three clusters of brain centers did not correlate with each other. “So a circuit that is normally in sync with the rest of the social brain has become decoupled. The limbic brain is composed of areas and structures that mediate emotional and affective components of our social interactions, so you can understand the social rules about how other people are behaving and acting. These brain regions are active in autism spectrum disorders and are coordinated amongst themselves, but they are not interacting appropriately with the rest of the social brain.” The clusters of brain centers identified in the study as functionally connected are also anatomically connected circuits. One of the most exciting aspects of the research, says Gotts, is that in humans, this brain circuit shows a different developmental growth trajectory relative to the rest of the brain's cortex during typical development. Since genes are responsible for guiding growth during development, these findings provide a target for searching for genes that drive abnormal growth and limbic circuit functioning in ASD. The differences in connectivity also offer the possibility of a “systems-level” marker—an indicator reflecting function across the brain—to use in developing and testing possible treatment. Local abnormalities in cell signaling or, alternatively, loss of longer range neuronal connections could explain the differences reported. If the differences can be traced to more local dynamics, it may be possible to identify new medications or behavioral therapies; variations in circuit activity as shown by functional brain imaging could be used as markers of whether therapy was effective.

Brain regions showing decreases in connectivity in high functioning adolescents with an autism spectrum disorder (ASD) are shown to the left: Limbic-related regions involved in emotional/affective aspects of social behavior (shown in red), regions involved in social communication and comprehension (shown in blue), and regions involved in visual, somatosensory and motor aspects of social behavior (shown in green). In typically developing adolescents, these circuits are interactive and coordinated, exhibiting correlated patterns of brain activity over time (traces of neural activity would appear as illustrated in upper right plot). In adolescents with an ASD, the activity in the limbic circuit has become decoupled from the other social brain regions (see red activity trace in lower right plot). Activity within the limbic circuit itself remains coordinated but no longer interacts appropriately with the other two circuits nursing ceus Reference Gotts, S.J., Simmons, W.K., Milbury, L.A., Wallace, G.L., Cox, R.W., and Martin, A. Fractionation of Social Brain Circuits in Autism Spectrum Disorders. Brain 2012 doi:10.1093/brain/aws160.

Possible Causes of Sudden Onset OCD in Kids Broadened

NIH Immune-Based Treatment Study Underway

Criteria for a broadened syndrome of acute onset obsessive compulsive disorder (OCD) have been proposed by a National Institutes of Health scientist and her colleagues. The syndrome, Pediatric Acute-onset Neuropsychiatric Syndrome (PANS), includes children and teens that suddenly develop on-again/off-again OCD symptoms or abnormal eating behaviors, along with other psychiatric symptoms – without any known cause nursing ceus

PANS expands on Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus (PANDAS), which is limited to a subset of cases traceable to an autoimmune process triggered by a strep infection. A clinical trial testing an immune-based treatment for PANDAS is currently underway at NIH and Yale University (see below).

“Parents will describe children with PANS as overcome by a ‘ferocious’ onset of obsessive thoughts, compulsive rituals and overwhelming fears,” said Susan Swedo, M.D., of the NIH’s National Institute of Mental Health (NIMH), who first characterized PANDAS two decades ago. “Clinicians should consider PANS when children or adolescents present with such acute-onset of OCD or eating restrictions in the absence of a clear link to strep.”

Swedo, James Leckman, M.D., of Yale University, and Noel Rose, M.D., Ph.D. of Johns Hopkins University, propose working criteria for PANS in February 2012 in the open source journal Pediatrics & Therapeutics.

“As the field moves toward agreement on this broadened syndrome, affected youth will be more likely to receive appropriate care, regardless of whether they are seen by a neurologist, pediatrician or child psychiatrist,” said NIMH Director Thomas R. Insel, M.D.

Differing causes sharing a “common presentation”

The PANS criteria grew out of a PANDAS workshop convened at NIH in July 2010, by the NIMH Pediatric and Developmental Neuroscience Branch, which Swedo heads. It brought together a broad range of researchers, clinicians and advocates. The participants considered all cases of acute-onset OCD, regardless of potential cause.

Clinicians reported that evaluations of more than 400 youth diagnosed with PANDAS confirmed that affected boys outnumbered girls 2:1, with psychiatric symptoms, always including OCD, usually beginning before 8 years.

Although debate continues about the fine points, the field is now of one mind on the core concept of “acute and dramatic” onset of a constellation of psychiatric symptoms. There is also broad agreement on the need for a “centralized registry” that will enable the research community to analyze evidence from studies that will eventually pinpoint causes and treatments. Such a registry is currently under development by members of the International Obsessive Compulsive Foundation (IOCDF).

Since a diagnosis of PANS implies no specific cause, clinicians will have to evaluate and treat each affected youth on a case-by-case basis.

“PANS will likely turn out to include a number of related disorders with different causes that share a common presentation,” explained Swedo.

The authors propose that a patient must meet 3 diagnostic criteria for a diagnosis of PANS:
1.Abrupt, dramatic onset of OCD or anorexia.
2.Concurrent presence of at least two additional neuropsychiatric symptoms with similarly severe and acute onset. These include: anxiety; mood swings and depression; aggression, irritability and oppositional behaviors; developmental regression; sudden deterioration in school performance or learning abilities; sensory and motor abnormalities; somatic signs and symptoms.
3.Symptoms are unexplainable by a known neurologic or medical disorder.

Among the wide range of accompanying symptoms, children may appear terror stricken or suffer extreme separation anxiety, shift from laughter to tears for no apparent reason, or regress to temper tantrums, “baby talk” or bedwetting. In some cases, their handwriting and other fine motor skills worsen dramatically. Leckman’s team at the Yale Child Study Center is in the process of developing assessment tools for diagnosing the syndrome.

PANDAS treatment study targets errant antibodies

Meanwhile, Swedo, Leckman, and Madeleine Cunningham of the University of Oklahoma, and colleagues, are collaborating on a new, multi-site placebo-controlled study, testing the effectiveness of intravenous immunoglobulin (IVIG) for reducing OCD symptoms in children with PANDAS.

Previous human and animal research suggested mechanisms by which strep-triggered antibodies mistakenly attack specific brain circuitry, resulting in obsessional thoughts and compulsive behaviors.

“Strep bacteria has evolved a kind of camouflage to evade detection by the immune system,” Swedo explained. “It does this by displaying molecules on its cell wall that look nearly identical to molecules found in different tissues of the body, including the brain. Eventually, the immune system gets wise to this ‘molecular mimicry,’ recognizes strep as foreign, and produces antibodies against it; but because of the similarities, the antibodies sometimes react not only with the strep, but also with the mimicked molecules in the human host. Such cross-reactive ‘anti-brain’ antibodies can cause OCD, tics, and the other neuropsychiatric symptoms of PANDAS.”

IVIG, a medication derived from normal antibodies, neutralizes such harmful antibodies, restoring normal immune function. It is used to treat other autoimmune illnesses and showed promise in a pilot study with PANDAS patients.

“We predict that IVIG will have striking benefits for OCD and other psychiatric symptoms, and will prove most effective for children who show high levels of anti-brain antibodies when they enter the study,” said Swedo.

Prospective study participants are first screened by phone by investigators at the NIH or the Yale Child Study Center. Those who meet eligibility requirements are then randomized to receive either active IVIG or a placebo procedure during a brief inpatient stay at the NIH Clinical Center. The researchers remain blind to which children received the active medication; after 6 weeks of placebo control, they give any children whose symptoms fail to improve the option to receive open-label active treatment.

In addition to assaying for antibodies that attack brain cells, the researchers use magnetic resonance imaging to see if the treatment reduces inflammation in an area of the brain known as the basal ganglia, which is thought to be the target of the errant antibodies. They also analyze levels of immune system chemical messengers (cytokines) in cerebrospinal fluid and blood – with an eye to identifying biomarkers of disease activity and potential predictors of treatment response.

The study was launched with support from the NIH Clinical Center’s Bench to Bedside program, which encourages such intramural-extramural collaborations in translational science.


Children with PANS and PANDAS sometimes experience sudden loss of fine motor skills.
Source: Susan Swedo, M.D., NIMH Pediatric and Developmental Neuroscience Branch

Reference:

Swedo, SE, Leckman JF, Rose, NR. From Research Subgroup to Clinical Syndrome: Modifying the PANDAS criteria to describe PANS (Pediatric Acute-onset Neuropsychiatric Syndrome). Feb 2012, Pediatrics & Therapeutics.

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The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

Ethnic Disparities Persist in Depression Diagnosis and Treatment Among Older Americans

Older racial and ethnic minorities living in the community are less likely to be diagnosed with depression than their white counterparts, but are also less likely to get treated, according to a recent NIMH-funded analysis published online ahead of print December 15, 2011, in the American Journal of Public Health.


Source: iStock Photo

Background

Depression is a significant health concern for older adults, regardless of ethnic or racial status. Previous studies have found racial and ethnic differences in the diagnosis and treatment of depression among the general population.

Using 2001-2005 data from the nationally representative Medicare Current Beneficiary Survey (MCBS), Ayse Akincigil Ph.D., of Rutgers University and colleagues examined rates of depression diagnosis and treatment among older adults living in the community. The survey asked questions about health care use and costs, insurance coverage beyond Medicare, access to care, and use of services.

Results

The survey found that about 6.4 percent of whites, 4.2 percent of African Americans, and 7.2 percent of Hispanics were diagnosed with depression. Among those diagnosed, 73 percent of whites received treatment (either with antidepressants, psychotherapy or both), while 60 percent of African Americans received treatment and 63.4 percent of Hispanics received treatment. These kinds of diagnosis and treatment differences are consistent with previous studies, the researchers noted. They also noted pronounced differences in socioeconomic status and quality of insurance coverage across ethnicities. Fewer whites reported having low incomes than ethnic minorities. However, these differences did not appear to account for the disparities in diagnosis or treatment rates.

Significance

The findings are consistent with the notion that depression continues to be under-recognized and undertreated among older minorities. According to the researchers, future research should investigate cultural factors such as help-seeking patterns, stigma, and patient attitudes and knowledge about depression as potential factors contributing to the disparities. For instance, ethnic minorities may be less likely to seek help for a mood disorder, and those with lower incomes may have more difficulty gaining access to specialized health care. In addition, they may be more likely to seek help from nonmedical providers, such as pastors or lay counselors, according to the researchers. Other research has suggested that minorities tend to cite stigma or shame associated with having a mental disorder as a reason for not seeking help for depression.

Differences in diagnosis rates may also reflect the notion that African Americans tend to have a greater sense of distrust of doctors in general compared to white patients, said the researchers. In addition, minority patients also may be more likely to present with more physical aspects of depression such as sleep problems or pain, rather than mood or cognitive symptoms, which can complicate detection and diagnosis of depression.

What’s Next

The researchers suggest possible ways to minimize the disparities in depression diagnosis and treatment among older minorities. For instance, psychiatrists and other health care workers could be offered public financial incentives for practicing in poorer communities where depressed older people may go untreated. In addition, adding cross-cultural education into professional training opportunities for health care workers could further reduce disparities. In the meantime, promising approaches such as universal depression screening programs could be implemented, the researchers concluded Nursing CEUs

Citation

Akincigil A, Olfson M, Siegel M, Zurlo K, Walkup J, Crystal S. Racial and ethnic disparities in depression care in community-dwelling elderly in the United States. American Journal of Public Health. Online ahead of print Dec. 15, 2011.

Autism may be linked to abnormal immune system characteristics and novel protein fragment

University of South Florida researchers made the discoveries using mouse models of autism

Tampa, FL (Jan 3, 2012) – Immune system abnormalities that mimic those seen with autism spectrum disorders have been linked to the amyloid precursor protein (APP), reports a research team from the University of South Florida's Department of Psychiatry and the Silver Child Development Center.

The study, conducted with mouse models of autism, suggests that elevated levels of an APP fragment circulating in the blood could explain the aberrations in immune cell populations and function – both observed in some autism patients. The findings were recently published online in the Journal of the Federation of American Societies for Experimental Biology nursing ceus.

The USF researchers concluded that the protein fragment might be both a biomarker for autism and a new research target for understanding the physiology of the disorder.

"Autism affects one in 110 children in the United States today," said research team leader Jun Tan, MD, PhD, professor of psychiatry and the Robert A. Silver Chair, Rashid Laboratory for Developmental Neurobiology at USF's Silver Child Development Center. "While there are reports of abnormal T-cell numbers and function in some persons affected with autism, no specific cause has been identified. The disorder is diagnosed by behavioral observation and to date no associated biomarkers have been identified."

"Not only are there no associated biomarkers, but the prognosis for autism is poor and the costs associated with care are climbing," said Francisco Fernandez, MD, department chair and head of the Silver Center. "The work of Dr. Tan and his team is a start that may lead to earlier diagnosis and more effective treatments."

The amyloid precursor protein is typically the focus of research related to Alzheimer's disease. However, recent scientific reports have identified elevated levels of the particular protein fragment, called, sAPP-α, in the blood of autistic children. The fragment is a well-known growth factor for nerves, and studies imply that it plays a role in T-cell immune responses as well.

To study the autism-related effects of this protein fragment on postnatal neurodevelopment and behavior, Dr. Tan and his team inserted the human DNA sequence coding for the sAPP-α fragment into the genome of a mouse model for autism. While the studies are ongoing, the researchers documented the protein fragment's effects on the immune system of the test mice.

"We used molecular biology and immunohistochemistry techniques to characterize T-cell development in the thymus and also function in the spleen of the test animals," Dr. Tan said. "Then we compared transgenic mice to their wild-type littermates."

The researchers found that increased levels of sAPP-α in the transgenic mice led to increased cytotoxic T-cell numbers. The investigators also discovered subsequent impairment in the recall function of memory T-cells in the test mice, suggesting that the adaptive immune response is negatively affected in the presence of high levels of the protein fragment.

"Our work suggests that the negative effects of elevated sAPP-α on the adaptive immune system is a novel mechanism underlying certain forms of autism," concluded Dr. Tan, who holds the Silver Chair in Developmental Neurobiology. "The findings also add support to the role of sAPP-α in the T-cell response."


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Other researchers involved in the study were Antoinette Bailey, Dr. Huayan Hou, Dr. Demian Obregon, Jun Tian, Dr. Yuyan Zhu, Dr. Qiang Zou, Dr. William Nikolic, Dr. Michael Bengston, Dr. Takashi Mori (Saitama Medical Center/Saitama Medical University, Japan) and Dr. Tanya Murphy.

The work was supported by the Silver Endowment and a grant from the National Institutes of Health/National Institute of Mental Health.

Citation: Aberrant T-lymphocyte development and function in mice overexpressing human secreted amyloid precursor protein-α: implications for autism; A. Bailey, H. Hou, D. Obregon, J. Tian, Y. Zhu, Q. Zou, W. Nikolic, M. Bengston, T. Mori, T. Murphy, J. Tan; The FASEB Journal; published online Nov. 15, 2011.

USF Health's mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Biomedical Sciences and the School of Physical Therapy and Rehabilitation Sciences; and the USF Physician's Group. The University of South Florida is a global research university ranked 34th in federal research expenditures for public universities.