University Times

New genetic risk factor for susceptibility to Alzheimer's identified

Alzheimer's disease (AD) researchers at Pitt have singled out a new genetic risk factor for the debilitating brain disease that affects four million Americans today and is expected to strike as many as 14 million during the next 50 years.

In a decade-long research study following more than 300 first-degree relatives of 189 Alzheimer's patients, Pitt researchers identified a small area of chromosome 10 that, when combined with the previously identified APOE E4 gene, significantly increases a person's risk of developing the disease.

This combination of genes produced a 16-fold increase in the risk of AD among first-degree relatives, researchers said. By comparison, this effect is greater than the increased risk of lung cancer caused by smoking. These new results are supported by independent studies of AD patients and control studies from Pittsburgh, Boston and Bonn, Germany.

Study results appear in the July issue of Molecular Psychiatry.

"Our findings may provide new opportunities for designing and evaluating treatments that prevent or delay the onset of AD," said George S. Zubenko, professor of psychiatry at Pitt's School of Medicine and adjunct professor of biological sciences at Carnegie Mellon University.

Zubenko and his colleagues studied normal individuals between the ages of 40 and 75 who were first-degree relatives of patients with AD. The subjects were given standard memory evaluation tests to be certain they had not suffered any cognitive decline prior to the start of the study, and then blood samples were drawn to identify genetic and biochemical risk factors for AD and related disorders.

Eighteen people developed AD after 11.5 years of regular follow-up evaluations. Ongoing assessments of the remainder of the group and the continuing search for new risk factors is being supported by research grants from the National Institutes of Health, for which Zubenko serves as the principal investigator.

According to Zubenko, these findings may provide new molecular targets for therapeutic drug development and will help researchers design trials involving subjects who have the greatest likelihood of responding to therapy and for whom successful therapy would have the greatest impact.

Furthermore, the newly discovered risk locus affects brain levels of dopamine, the neurotransmitter used by neurons that degenerate in Parkinson's disease. As a result, the new findings may have relevance for both of these common neurodegenerative disorders.

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Study looks at consequences of premature pubertal development

Timing of puberty is important in the healthy psychosocial development of adolescents. However, children with premature adrenarche (PA) experience puberty at an earlier age, putting them at risk for future problems. Lorah D. Dorn, an assistant professor in Pitt's School of Nursing, is studying the relationship of the changing endocrine makeup of these girls in early puberty with emotional/behavior problems or cognitive difficulties.

Dorn's research, funded by a $1.5 million, four-year grant from the National Institutes of Mental Health, will study 90 six-to-eight year old girls with PA, and 90 "on-time" adrenarche girls. The "Developmental Psychobiology of Premature Adrenarche" study will examine factors such as hormone concentrations, stage of puberty, cortisol reactivity, psychological variables, IQ and memory.

"If our earlier pilot study findings are confirmed showing more emotional/behavioral problems and cognitive difficulties, this information may lead to prevention/intervention efforts to reduce these difficulties affecting children with PA," Dorn said.

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Common prostate cancer treatment may cause severe bone loss

Men may be losing bone at an alarming rate as a result of a commonly used treatment for prostate cancer, according to researchers at the UPMC Health System and Beth Israel Deaconess Medical Center.

The findings, published in the June issue of the Journal of Clinical Endocrinology and Metabolism, suggest that gonadotropin-releasing hormone agonists (GnRH-a), a frequently used treatment for prostate cancer, causes severe drops in bone mass and results in an increased risk of fracture in men.

"We were surprised to find that men who were treated with GnRH-a for prostate cancer experienced up to a decade's worth of bone loss within the first year of therapy," said senior author Susan Greenspan, a professor in the Pitt medical school's Department of Medicine and director of UPMC's Osteoporosis Prevention and Treatment Center.

GnRH-a works by depriving the body of testosterone, an androgen hormone that increases the growth of prostate tumors. However, testosterone also is essential to maintaining bone mass in men. While doctors have been using GnRH-a for more than a decade in treating men with late-stage metastatic prostate cancer, they have begun using it more recently in men with earlier-stage disease and for longer periods of time.

Greenspan said: "With close to 200,000 men being diagnosed with prostate cancer each year, we could be facing an enormous increase in the incidence of debilitating bone fractures in men."

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Prof hopes to expand skills of stroke survivors' caregivers

Many people are suddenly thrust into a caregiving role when someone in their family suffers a stroke. Family members must rapidly assimilate a tremendous amount of information and acquire new skills to meet the needs of the stroke survivor. At the same time, they must adhere to healthy habits that preserve their own health and well-being.

With a three-year grant from the National Institutes of Health/National Institute of Nursing Research, Judith T. Matthews, assistant professor at the School of Nursing, hopes to expand the repertoire of problem-solving skills for family caregivers of stroke survivors and persuade them to maintain optimal health.

Matthews, who has an extensive background in community health nursing, says her study, "Use of Technology With Caregivers of Stroke Survivors," is geared toward promoting competencies in the family caregiver — often a spouse or an adult child.

"Because shorter hospitalizations severely reduce the opportunity for in-hospital preparation for the caregiving role, family caregivers often view themselves as lacking requisite knowledge, skill and support to handle this new responsibility," Matthews said. "Not only must they grapple with learning new competencies, family caregivers must also deal with their feelings about how these changes affect their lives."

Matthews plans to offer family caregivers an intervention that will include telephone counseling and web-based information, health promotion, and peer and professional support.

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Brain studies show children from alcoholic families more prone to drink

Pitt researchers have discovered that adolescents from families with a history of alcohol dependence have differences in their brains that make them prone to alcohol abuse before they ever touch a drink.

The research team, headed by Shirley Y. Hill, professor of psychiatry, psychology and human genetics at Pitt's School of Medicine, studied adolescents who averaged 17 years of age from families with multigenerational alcohol dependence to see if they had morphological changes in their brains that could make them susceptible to alcohol abuse. Through brain imaging, Hill found changes in the amygdala, a walnut-sized structure in the brain that helps control basic emotions. Children from families with a history of alcohol abuse had reduced right amygdala volume compared with children from families with no abuse.

"The effect on the amygdala is significant because the amygdala is part of an important reward circuit that has been implicated in addictive behavior including cocaine use, gambling and, now, familial alcohol dependence. This circuit is one of the fundamental components of the brain's reward systems and appears to be important in the reinforcing actions of repeated drug and alcohol abuse," Hill explained.

Why the right amygdala in particular is affected is not known, but perhaps a faster rate of growth in the right brain versus left brain during childhood and adolescence makes it more likely that developmental lags in growth in this area may show up more prominently on the right side.

"We suspect that brain development for some of the adolescents catches up by adulthood. Nevertheless, they are more vulnerable as teens. We have found in our studies that teens from families with a history of alcohol dependence begin drinking earlier. This pattern in such a vulnerable group of teens can set up a pathway toward alcohol dependence lasting into or even through adulthood," Hill said.

"Additionally, there is evidence that the brains of teenagers may be more susceptible to the negative consequences of heavy alcohol consumption," she said. "Our research shows that, in kids from families with a history of alcohol dependence, some of these changes actually appear before they start drinking, which points to a strong genetic influence."

Hill's research was supported by the National Institute of Alcohol Abuse and Alcoholism. Study results were published in the June 5 issue of Biological Psychiatry.

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Researchers use stem cells to treat incontinence in animal models

Pitt researchers have successfully used stem cell tissue engineering to restore deficient urethral sphincter muscles in animal models, according to a study presented this month at the 96th Annual Meeting of the American Urological Association (AUA). Researchers successfully regenerated viable muscle using muscle derived stem cells.

"These findings are exciting on many levels. First, this is the first time that stem cell tissue engineering has been used to regenerate and restore function in deficient sphincter muscles. Secondly, it lays the foundation for further investigation into methods of using stem cells to treat stress urinary incontinence," said Michael Chancellor, professor of urology and gynecology at Pitt.

Given the proper stimulus, stem cells have the ability to divide for indefinite periods and differentiate into a variety of different cells, including muscle. Researchers have been using this information to investigate the theory that it is possible to regenerate injured tissue through the injection of stem cells.

Urinary incontinence affects 13 million Americans. Those with stress urinary incontinence involuntarily lose urine while doing activities that put stress on the abdomen, such as laughing, sneezing, coughing, lifting or walking. A result of damage to the urethral sphincter, stress incontinence is most often caused by childbirth, menopause or pelvic surgery.

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Stents may improve outcomes of patients with symptoms of stroke

Stent-assisted angioplasty may alleviate symptoms, increase blood flow to the brain and improve the typically poor prognosis of patients with stroke symptoms from arterial blockages that occur in the rear of the brain, according to a study published in the June issue of Neurosurgery.

The findings suggest that stents, small metallic cages inserted into the basilar or vertebral arteries (located in the back of the neck), of these patients after they have undergone angioplasty to clear away blockage (stenosis), may be an alternative treatment to bypass surgery or angioplasty alone.

"These strokes are difficult to treat. Blockage of these arteries portends a poor prognosis for patients, with 5 to 11 percent experiencing irreversible neurological deterioration or death," said Michael Horowitz, associate professor in Pitt's Department of Neurological Surgery. "Our study results demonstrate that stent-assisted angioplasty is an option for high-risk surgical patients."

For surgical management of basilar or vertebral artery stenosis, the combined mortality and morbidity rate is 34 percent, while angioplasty of these arteries without stenting leads to restenosis in 20 to 30 percent of patients.

The retrospective study, by Pitt and the University of Texas Southwestern Medical Center, examined the outcomes of 11 patients with stroke symptoms who underwent angioplasty and stenting of either the vertebral or basilar arteries. All of the patients in the study had transient ischemic attacks, or fixed deficits that failed to respond to medical treatment. Their symptoms included headache, facial droop, loss of coordination, vertigo and depressed mental status.

After a follow-up period of four months, seven of the patients no longer had recurrent symptoms, lived at home and resumed activities at the same or better levels compared with before the procedure.

The remaining four patients died either from complications during the procedure or several months after the procedure. Two of the four patients experienced a fatal rupture of the vertebral or basilar artery, the third had a stroke and died three months later, and the procedure on the fourth patient resulted in brain death.

"Although this study demonstrates the potential for stent-assisted angioplasty, it also demonstrates the risks associated with dilation of stenotic, often fragile, diseased vessels," said Horowitz. "Long-term follow-up is needed to determine whether this treatment will improve on the natural history of the disease with medical management alone."

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Older women more likely to get breast cancer if they have high bone density, study shows

Investigators from Pitt's Graduate School of Public Health have found that older women with high bone mineral density (BMD) are nearly three times as likely to develop breast cancer as are older women with low BMD, and that their tumors tend to be at an advanced stage at diagnosis.

Results of the study are published in the June 20 issue of the Journal of the National Cancer Institute. This study confirms a smaller Pitt study that was published in the Journal of the American Medical Association in 1996.

"This study shows that there is an inverse relationship between osteoporosis and invasive breast cancer, two of the most common and important conditions affecting an older woman's health," said Jane Cauley, associate professor of epidemiology and study co-author. "The results suggest that bone mineral density is one of the most powerful predictors of breast cancer, especially advanced breast cancer, among elderly women."

Investigators stress that high BMD itself is not the cause of breast cancer, but a marker for hormone levels, and that women should not discontinue their efforts to maintain bone mass through diet or medication.

"Sex steroid hormones, like testosterone and estrogen, or other growth promoting hormones, may be the link to breast cancer," said Cauley, "and BMD may reflect a woman's long-term exposure to these hormones. Further studies are needed to identify the common denominator."

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Researcher receives MERIT award

Linda Jen-Jacobson of Pitt's biological sciences department has received a MERIT award from the National Institute of General Medical Sciences.

The award extends the term of her National Institutes of Health-funded project, "Sequence-specific DNA-protein interactions," from the current four years (start date April 1, 2001) to 8-10 years.

MERIT awards, representing about 2.5 percent of NIH-funded projects, are made to investigators of "demonstrated superior competence and exceptional productivity" in order to present an opportunity to pursue avenues of research that might be considered risky.

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Therapy shows promise in preventing recurrence of head and neck cancer

Results from a study led by University of Pittsburgh Cancer Institute (UPCI) researcher Dong Moon Shin suggest that treating head and neck cancer patients with a combination of the biologic agents retinoid, interferon and vitamin E may lead to improved survival for patients with a locally advanced stage of the disease and result in few negative side effects.

Study results were published in the June 15 issue of the Journal of Clinical Oncology.

The phase II study focuses on patients with squamous cell carcinoma of the head and neck (SCCHN), which has a low five-year survival rate after standard treatment including surgery, radiation therapy or both surgery and radiation.

More than two-thirds of patients with SCCHN are diagnosed with stage III or IV cancer, which represent advanced stages of the disease, and are at high risk for disease recurrence or the development of second primary tumors (SPTs).

"Given the poor survival rates from head and neck cancer, the study's overall survival rates of 98 percent at one-year follow-up and 91 percent at two-year follow-up are very promising indications of the potential of this treatment for patients with locally-advanced head and neck cancer," said Shin, professor of medicine and otolaryngology at Pitt's School of Medicine and co-director of UPCI's Head and Neck Cancer Program.

Head and neck cancer occurs in the oral cavity, pharynx, larynx, paranasal sinuses, nasal cavity and the salivary glands, and accounts for 5 percent of all cancers diagnosed in the United States. Nearly 45,000 cases of head and neck cancer are diagnosed annually in the United States, and 13,000 die from causes related to this disease. Survival rates have not improved significantly over the past 20 years and are among the lowest compared to other major cancers.

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Pitt leads national study on treating patients with diabetes, heart disease

Recruitment has begun at 14 out of an expected 40 centers for a monumental study that will determine the best way to treat patients who have early coronary artery disease (CAD) and type 2 diabetes. CAD is the No. 1 killer of people with type 2 diabetes.

Pitt's Graduate School of Public Health (GSPH) is coordinating the study, which received a grant of more than $52.2 million from the National Heart, Lung and Blood Institute, $4.2 million from the National Institute of Diabetes and Digestive & Kidney Diseases and $15 million from Glaxo Smith Kline.

Known as the Bypass Angioplasty Revascularization Investigation 2D (BARI 2D), the study is comparing the effectiveness of various therapeutic regimens in reducing the number of deaths from CAD among type 2 diabetics. Investigators aim to determine whether aggressive drug therapy is more effective alone or in combination with surgery in reducing mortality in this population.

"The percentage of Americans who have been diagnosed with diabetes has doubled over the last 20 years, and that trend is expected to continue, partially due to the increase in obesity and sedentary lifestyles," said Katherine Detre, professor of epidemiology and director of the Epidemiology Data Center at GSPH, and principal investigator of the study. "The latest figures show that 6 to 10 percent of American adults ages 45 and older are diagnosed diabetic," she said. "However, it is believed that another 6 to 10 percent of American adults are diabetic but are unaware of it."

In type 2 diabetes, the body is unable to properly use insulin — a hormone needed to metabolize simple sugars. Such insulin resistance is a major risk factor for cardiovascular disease.

"Diabetics develop heart disease earlier than do non-diabetics and have lower survival rates," said David Kelley, professor of medicine in the Division of Endocrinology and Metabolism and study co-principal investigator. "Some 90 to 95 percent of the world's diabetic patients have type 2, and 80 percent of them are overweight. Obesity appears to trigger the onset of this form of the disease."

With the help of 2,800 volunteer participants, the study will answer two questions that are critical to type 2 diabetic patients with stable coronary artery disease: 1) Under what circumstances is it best to undergo revascularization in addition to drug therapy? 2) Which method of drug therapy is best at controlling glucose?

BARI 2D is a followup to BARI, a study involving patients with more severe CAD. Detre reported on the results of BARI in a recent issue of the New England Journal of Medicine.