By Jenny C Leary
In a genome-wide association (GWA) study, researchers from Boston University Schools of Medicine (BUSM) and Public Health (BUSPH) have identified several genes which influence degeneration of the hippocampus, the part of the brain most associated with Alzheimer disease (AD). The study, which currently appears online as a Rapid Communication in the Annals of Neurology, demonstrates the efficacy of endophenotypes for broadening the understanding of the genetic basis of and pathways leading to AD.
AD is a progressive neurodegenerative disorder for which there are no prevention methods. Available drugs only marginally affect disease severity and progression, making AD effectively untreatable.
GWA studies using very large samples have increased the number of robust associations to 10 genes, including APOE. However, these genes account for no more than 35 percent of the inherited risk of AD and most of the genetic underpinning of the disorder remains unexplained. According to the researchers, magnetic resonance imaging (MRI) of the brain provides in vivo quantitative measures of neurodegenerative and cerebrovascular brain injury that may represent AD-related changes long before clinical symptoms appear. These measures are more powerful than comparisons of individuals with AD with cognitively healthy persons because they avoid misclassification of normal persons who will develop disease in the future.
BUSM researchers conducted a two-stage GWA study for quantitative measures of hippocampal volume (HV), total cerebral volume (TCV) and white matter hyperintensities (WMH). Brain MRI measures of HV, TCV and WMH were obtained from 981 Caucasian and 419 African-American AD cases and their cognitively normal siblings in the MIRAGE (Multi Institutional Research in Alzheimer’s Genetic Epidemiology) Study. In addition, similar MRI measures were obtained from 168 AD cases, 336 individuals with mild cognitive impairment and 188 controls (all Caucasian) in the AD Neuroimaging Initiative (ADNI) Study. The MIRAGE Caucasian families and ADNI subjects were included in the first stage and the MIRAGE African American families were added in stage two. Results from the two Caucasians data sets were combined by meta-analysis.
In stage two, one genetic marker (i.e. single nucleotide polymorphism or SNP) from each of the gene regions that were most significantly associated with AD in the Caucasian data sets was evaluated in the African-American data set.
Novel genome-wide significant associations were observed for HV with SNPs in the APOE, F5/SELP, LHFP, and GCFC2 gene regions. All of these associations were supported by evidence in each data set.
“Our two-stage GWAS identified highly significant associations between a measure of degeneration in the brain region most strongly correlated with AD and several genes in both Caucasian and African American samples containing AD, cognitively impaired and cognitively healthy subjects. One of these associations was with the ε4 variant of APOE which is the most well-established genetic risk factor for AD. Other associations were demonstrated with markers in F5/SELP, LHFP, and GCFC2, genes not previously implicated in this disease” explained senior author Lindsay Farrer, PhD, chief of biomedical genetics at BUSM. He also noted, “previous studies showed that blood level of P-selectin (the protein encoded by SELP) has been correlated with rate of cognitive decline in AD patients.”
Farrer believes it is very likely that the number and specificity of these associations will increase in future studies using larger samples and focused on additional precise structural and functional MRI measures. “These findings will inform experiments designed to increase our understanding of disease-causing mechanism and may lead to new therapeutics targets,” added Farrer.
Researchers from Massachusetts General Hospital, Indiana University School of Medicine and University of California at Davis also collaborated on this study.
This study was supported by the National Institute on Aging (NIA), the Dana Foundation and the National Institutes of Health Clinical and Translational Science Institute. ADNI is funded by the NIA and the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson and Johnson, Eli Lilly and Co., Medpace, Merck and Co., Novartis AG, Pfizer, F. Hoffman-La Roche, Schering-Plough, Synarc, and Wyeth, as well as nonprofit partners the Alzheimer’s Association and Alzheimer’s Drug Discovery Foundation, with participation from the US Food and Drug Administration. Private sector contributions to ADNI are facilitated by the Foundation for the National Institutes of Health (www.fnih.org).
Boston University School of Medicine (BUSM) researchers have found that the incidence of gout and hyperuricemia (high uric acid levels) in the U.S. has risen significantly over the last 20 years and is associated with major medical disorders like hypertension and chronic kidney disease. The study, which is published in the American Journal of Medicine, was led by Hyon Choi, MD, DrPH, professor of medicine in the section of rheumatology and the clinical epidemiology unit at BUSM and rheumatologist at Boston Medical Center (BMC).
Gout is a common inflammatory arthritis triggered by crystallization of uric acid within the joints, causing severe pain and swelling.
Using data from the latest U.S. National Health and Nutrition Examination Survey (NHANES) conducted in 2007 and 2008, which included data from 5,707 participants, the researchers found that gout now affects 8.3 million Americans, or four percent of the population. They also found that hyperuricemia affects 43.3 million U.S. adults, or 21 percent of the population.
The study results demonstrated that participants with gout have remarkably high rates of hypertension (74 percent) and chronic kidney disease (71 percent). More than half of this patient population was obese (53 percent) and a significant number had diabetes (26 percent) and kidney stones (24 percent). These participants also showed high rates of heart attack (14 percent), heart failure (11 percent) and stroke (10 percent).
Additionally, study results showed that among individuals with the highest uric acid levels, rates of kidney disease (86 percent), hypertension (66 percent) and obesity (65 percent) were high. Approximately one third of the survey participants had heart failure and diabetes, and the prevalence of heart attack (23 percent) and stroke (12 percent) also were high.
“These findings highlight the remarkable prevalences and population estimates of medical disorders associated with gout and hyperuricemia in the U.S.,” said Choi, the study’s senior author. “Appropriate preventive and management measures of these associated conditions should be implemented in gout management, and when considering treatment strategies in gout, the lifestyle and pharmacologic measures that can concurrently improve serum uric acid and reduce associated disorders should be preferred.”
The research was supported by Takeda Pharmaceuticals International, Inc.
Researchers from Boston University School of Medicine (BUSM) have demonstrated in experimental models that blocking the Sigma-1 receptor, a cellular protein, reduced binge eating and caused binge eaters to eat more slowly. The research, which is published online in Neuropsychopharmacology, was led by Pietro Cottone, PhD, and Valentina Sabino, PhD, both assistant professors in the pharmacology and psychiatry departments at BUSM.
Binge eating disorder, which affects approximately 15 million Americans, is believed to be the eating disorder that most closely resembles substance dependence. In binge eating subjects, normal regulatory mechanisms that control hunger do not function properly. Binge eaters typically gorge on “junk” foods excessively and compulsively despite knowing the adverse consequences, which are physical, emotional and social in nature. In addition, binge eaters typically experience distress and withdrawal when they abstain from junk food.
The researchers developed an experimental model of compulsive binge eating by providing a sugary, chocolate diet only for one hour a day while the control group was given a standard laboratory diet. Within two weeks, the group exposed to the sugary diet exhibited binge eating behavior and ate four times as much as the controls. In addition, the experimental binge eaters exhibited compulsive behavior by putting themselves in a potentially risky situation in order to get to the sugary food while the control group avoided the risk.
The researchers then tested whether a drug that blocks the Sigma-1 receptor could reduce binge eating of the sugary diet. The experimental data showed the drug successfully reduced binge eating by 40 percent, caused the binge eaters to eat more slowly and blocked the risky behavior.
The abnormal, risky behavior exhibited by the binge eating experimental group suggested to the researchers that there could be something wrong with how decisions were made. Because evaluation of risks and decision making are functions executed in the prefronto-cortical regions of the brain, the researchers tested whether the abundance of Sigma-1 receptors in those regions was abnormal in the binge eaters. They found that Sigma-1 receptor expression was unusually high in those areas, which could explain why blocking its function could decrease both compulsive binge eating and risky behavior.
“These findings suggest that the Sigma-1 receptor may contribute to the neurobiological adaptations that cause compulsive-like eating, opening up a new potential therapeutic treatment target for binge eating disorder,” said Cottone, who also co-directs the Laboratory of Addictive Disorders at BUSM with Sabino.
This research was funded by the National Institute on Drug Abuse under award numbers 5R00DA023680-05 and 5R01DA030425-02; the National Institute of Mental Health under award numbers 1R01MH093650-01A1 and 5R01MH091945-03; the National Institute on Alcohol Abuse and Alcoholism under award number 5R00AA016731-05; and the Boston University Peter Paul Career Development Professorship and Boston University Undergraduate Research Opportunities Program. The study’s other co-authors include Xiaofan Wang, MD, PhD; Jin Won Park, MA; Marta Valenza, MS; Angelo Blasio, PhD; Jina Kwak; Malliga R. Iyer, PhD; Luca Steardo, MD; Kenner C. Rice, PhD; and Teruo Hayashi, MD, PhD.
Douglas V. Faller, MD, director of the Boston University/Boston Medical Center Cancer Research Center, has been awarded a research grant from the Melanoma Research Alliance (MRA). The grant will help Faller, professor of medicine, biochemistry, pediatrics, microbiology, pathology and laboratory medicine at Boston University School of Medicine (BUSM), continue his research focused on uncovering novel, targeted approaches to treat melanoma.
Faller is one of 22 researchers from leading academic research institutions around the world receiving a grant from the MRA to develop improved means to prevent, detect and treat deadly skin cancer.
Previous research by others has shown that activating mutations of a protein called N-RAS, or RAS-related pathways, are found in more than 90 percent of melanoma cases. Mutated, activated N-RAS is an attractive therapeutic target for melanoma, but approaches aimed directly at RAS or its critical signaling pathways, which are required for the viability of normal cells, have had very limited success.
The “synthetic lethality” approach being explored by Faller and his colleagues exploits an Achilles’ heel of melanoma cells containing a mutated, activated N-RAS – the absolute requirement for a survival pathway mediated by PKC-delta. Normal cells and tissues do not require PKC-delta for growth and development. This tactic hijacks the RAS-signaling pathway, which normally promotes melanoma and tumor cell growth.
“Our approach could have broad potential in treating many forms of melanoma,” said Faller, who also is a physician in hematology/oncology at BMC. “This grant will help us better understand the molecular forces involved with melanoma progression, which could help lead to novel treatments against the disease.”
Faller received his MD from Harvard Medical School and PhD from Massachusetts Institute of Technology. Other research focus areas include the development of novel therapeutics for the treatment of cancers caused by viruses, and for the treatment of genetic diseases such as sickle cell disease, thalassemia, and cystic fibrosis.
”The disturbing increase in incidence of melanoma, especially among young people, lends even greater urgency to finding new tools and treatments for a disease that every year is diagnosed among almost 80,000 people and is responsible for more than 9,000 deaths in the US alone,” said Wendy K.D. Selig, President and CEO of MRA. “We are inspired by the exciting progress that is finally occurring in the field and delighted by the exceptional caliber of proposals, investigators, and institutions we are able to support through our 2012 grants.”
About the Boston University/Boston Medical Center Cancer Research Center
The BU/BMC Cancer Center comprises 101 faculty members from the Medical and Charles River Campuses. The research of Cancer Center members ranges from basic laboratory science to early translational and clinical research to population and environmental studies and spans the continuum from cancer prevention, screening, and diagnosis through treatment and survivorship. Scientific strengths include epidemiology, behavioral science, cancer prevention and control, environmental health, cancer disparities research, cancer cellular and molecular biology, genomics, hormone-responsive cancers, environmental toxins, airways cancers and the development of novel therapeutics.