James C. Torner - US grants

This is a comparison of the effect of raloxifene hydrochloride, placebo and hormone replacement therapy on lumbar spine and femoral neck bone mineral density and endometrial thickness in early postmenopausal women.

This study will determine if subjects who participated in the Fracture Intervention Trial and received alendronate for 3 to 6 years have preserved or increased total hip bone mineral density with an additional 5 years of therapy.

DESCRIPTION (provided by applicant): Osteoarthritis (OA) is the most common form of arthritis and disease in the knee is a leading cause of disability. Most epidemiologic studies of knee OA have focused on radiographic disease, but symptomatic OA should be a major focus of studies on preventing OA, because symptomatic disease causes disability and has formidable societal and public health impacts. OA is potentially preventable, but only a limited number of mostly nonmodifiable risk factors has been identified, even though modifiable risk factors such as particular activities, muscle weakness, proprioceptive deficits, micronutrient deficiencies and structural factors have been proposed and may affect substantially the risk of disease. Prevention opportunities are most relevant and are most likely to be used by those who already have disease or who are at highest risk of getting it. This proposal introduces four new approaches into the epidemiologic study of knee osteoarthritis: l.a focus on symptomatic disease, 2. a comprehensive evaluation of risk factors including modifiable ones, 3. a focus on those who would really benefit from prevention opportunities, those who already have disease or those who are at high risk of getting it and 4. the incorporation of more comprehensive and reproducible imaging than has previously been used including, state of the art radiographic techniques and MRI. MRI provides rich information on structural factors in which abnormalities may affect the risk of disease. The overall objective of this study is to evaluate longitudinally the effects of three groups of factors: biomechanical factors (squatting,kneeling, stair climbing, quadriceps weakness and proprioceptive deficits), bone and structural factors (bone density,bone marrow and meniscal lesions on MRI) and micronutrient deficiencies (vitamin C, E and D) on the occurrence and progression of symptomatic and radiographic knee OA in a population-based sample of men and women aged 50 to 79. We propose to recruit a community-based sample of 3,000 men and women likely to either have knee OA or be at high risk of OA. High-risk groups will include those who are overweight, those with knee symptoms or those with a history of knee injuries or operations. Subjects will be evaluated with symptom questionnaires, radiographs and MRI?s and will be followed 36 months for the development or progression of symptomatic or radiographic OA. Analyses will focus on the relation of these important risk factors and OA outcomes. This large, multifaceted and comprehensive study of persons with knee OA, or at high risk of disease, offers to address definitively the relation of potentially important risk factors to the development or progression of a major disabling disease and to provide new insights into disease biology and potential opportunities for prevention.

[unreadable] DESCRIPTION (provided by applicant): Knee OA is a leading cause of chronic disability in older Americans. Few strategies to prevent knee OA development, progression, or disability exist, due to limited knowledge of the responsible factors. There has been increasing recognition of the role of knee laxity and malalignment, two potentially modifiable factors that are the focus of the current application. These factors are being examined in the ongoing 300-subject MAK study (Mechanical Factors in Arthritis of the Knee) at Northwestern University, in which extensive experience has been gained with them, and evidence of their importance has accumulated. [unreadable] [unreadable] Now proposed is a comprehensive examination of the effect of laxity and malalignment in subjects with or at high risk to develop knee OA, as an ancillary study to the recently funded Multicenter OA Study (MOST). MOST is a study of 3000 men and women, with the primary goal of examining the effect of a panel of risk factors on OA outcomes over 3 years. MOST involves 4 sites: the Coordinating and MRI Reading Center (UCSF), Data Analysis and X-ray Reading Center (BU), and 2 Clinical Centers (UAB and UI). [unreadable] [unreadable] Hypotheses of this application focus on whether laxity and malalignment are each associated with: a higher risk of incident OA than non-lax knees and more neutrally aligned knees; a decline in physical function; risk of OA progression. Primary hypotheses focus on symptom and x-ray outcomes; MRI-based assessment of cartilage morphology is also proposed as a means of examining the compartment-specific effects of each of these factors in a subset of the MOST cohort. [unreadable] [unreadable] Support is requested: to replicate in MOST the measurement systems and protocols (for laxity and alignment) currently in use in the MAK study; to assess laxity and alignment at the baseline exam of MOST; in a subset of the cohort, to obtain MRI at baseline and at 3 year follow-up using a high-field scanner to examine change in cartilage volume and thickness as outcomes of laxity and malalignment; and to test the relationship of laxity and malalignment with risk of important OA outcomes.

DESCRIPTION (provided by applicant): Unruptured Intracranial Aneurysms (UIA) constitute a significant public health problem in the United States, which is growing in magnitude. The economic and social implications of optimizing clinical practice in this area are striking, given the considerable and escalating frequency with which UIAs are now detected in the population. The prevention of unnecessary death and disability related to UIA depends to a large degree upon a better understanding of the natural history of these lesions, as well as the short- and long-term benefits and risks associated with their repair. The current proposal represents a continuation of the prospective component of the International Study of Unruptured Intracranial Aneurysms (ISUIA). Its primary objectives center around defining the long-term risks of UIA rupture and other UIA natural history outcomes, risk factors associated with these natural history outcomes, long-term outcomes associated with endovascular and surgical repair of these lesions, and predictors of good and poor treatment outcomes. The first two phases of ISUIA have provided substantial and unique information regarding short-term prospective natural history and treatment outcomes, and have established that short-term prospective natural history rupture rates are different than retrospective natural history rupture rates. The current proposal utilizes the large ISUIA cohort of patients established over the past ten years to provide vital long-term clinical information, which would otherwise be unobtainable. The current proposal involves the follow-up of living cases with UIA among the 4,060 cases in the prospective cohort, including 1,692 cases in the unoperated cohort and 2,368 cases in the cohort, which had UIA repair. The additional follow-up will allow the estimation of ten-year hemorrhage rates, and other outcome measures beyond the currently available five-year rates. It will also provide critical information on the long-term durability and effectiveness of endovascular and surgical treatment procedures, which are important in making clinical decisions regarding optimal management. Primary analyses will examine neurologic outcome, specifically fatal and non-fatal intracranial hemorrhagic strokes, secondary to aneurismal rupture and morbidity/mortality following UIA treatment. Secondary analyses will examine other aneurismal complications, such as ischemic stroke and death from all causes, including retreatment, durability of treatment, and functional endpoints, including Rankin, Barthel, and SF36 scores.

DESCRIPTION (provided by applicant): Osteoarthritis (OA) is the most common form of arthritis and remains one of the few chronic diseases of aging for which there is little if any effective treatment and few preventive strategies. Symptomatic knee osteoarthritis affects 12% of elders and despite medical advances, remains, for many affected, a major source of pain and function limitation. The MOST study is the first large scale observational study to focus on persons with or at high risk of knee osteoarthritis. The central goal of MOST is to identify modifiable risk factors. To accomplish this, we recruited and have followed 3026 persons who either had knee osteoarthritis at baseline or were at high risk of developing disease because they had one or more disease risk factors. We are proposing a renewal of MOST. In continuing to follow this unique cohort, we will address a series of new questions representing three investigative themes: mechanical risk factors, causes of knee symptoms and long term disease trajectory. The focus on risk factors which affect knees on the basis of loading reflects the view of MOST investigators that OA is a mechanically driven disease. Mechanical risk factors are likely to be both strongly associated with disease risk and modifiable. Pain is the cardinal symptom of OA and the main cause of its clinical and public health impact. An investigation of pain sensitivity seeks to better understand the neurological mechanisms that sustain or magnify OA symptoms. Another symptom associated with knee OA is knee buckling, whose frequency and impact has only recently been described and whose association with falls and fractures in older adults is unknown. Lastly, we will take advantage of two grant cycles of comprehensive information on functional loss and repeated MRI's to address the long term trajectory of this chronic disease. In this renewal of the MOST study we will re-examine a group of persons who already have disease or are at high risk of getting it, to evaluate the risk factors for disease. Those factors that prove to be related to disease development or progression could then be targeted for risk factor modification offering unique opportunities for disease prevention. Risk factors to be studied include many which are practical to modify, including strength, ways of walking, and balance. Also, MOST will provide the best understanding yet of the relation between changes in knee structures and their effects on pain and function, providing structural targets for treatment.

DESCRIPTION (provided by applicant): This application addresses the broad Challenge Area (05) Comparative Effectiveness Research and the specific Challenge Topic: 05-NS-104* Intervention vs. Best Medical Therapy in Asymptomatic Persons With Identified Vascular Abnormalities. The International Study of Unruptured Intracranial Aneurysms (ISUIA) study group undertook an initial epidemiological project on September 1, 1991, to determine the natural history of unruptured intracranial aneurysms (UIAs) and the morbidity and mortality associated with repair of these lesions to help define the optimal management of patients with UIAs. Over the past 17 years, 5,500 patients at 61 medical centers were entered and followed as called for in the study protocol. The hypotheses and specific aims for ISUIA were to determine the long-term risk of hemorrhage, risk factors for hemorrhage, the long-term disability rates and factors related to disability, and risk of death. The average follow-up of the prospective cohort was 8.6 years with a total of 34,800 person-years. The proposed continuation of secondary analysis will address key questions that became evident through the conduct and results of Phase III of ISUIA. Aim 1: In addition to size and location, aneurysm shape and morphology may be predictive of hemorrhage and adverse outcome of surgery or endovascular treatment. We propose to analyze the existing ISUIA data to determine the shape of intracranial aneurysms and impact on occurrence of hemorrhage and treatment outcome. We will validate the variation in shape through direct digitization of the angiograms. We will determine the role of size, morphology and shape in predicting aneurismal hemorrhage. We will determine the role of size, morphology and shape in surgical and endovascular morbidity and mortality. Aim 2: Analysis of the long-term outcome of patients in ISUIA showed that aneurismal hemorrhage accounted for 10% of deaths. This aim will determine risk factors for overall morbidity and mortality. In order to accomplish this aim we will conduct competing risk analysis of mortality, determine risk factors for aneurismal and non-aneurismal outcomes, and will compare overall outcome of the retrospective and prospective cohorts. Aim 3: ISUIA included a prospective non-randomized cohort of 4059 patients. The analysis based upon the aims of the prior grants to date has been within the unoperated, surgical and endovascular subgroups. We propose to compare long-term hemorrhage and outcome by treatment resulting in a decision analysis. First we will perform an analysis of the prospective cohort of the decision for treatment. Second, using propensity score adjustment, we will compare the long-term risk of hemorrhage and outcome between treatment groups. Third, we will utilize the comparisons and subgroups to perform a decision analysis. This meets the aims of the Challenge Grant topic 05-NS-104: Intervention vs. Best Medical Therapy in Asymptomatic Persons With Identified Vascular Abnormalities by identifying patients who are at risk of aneurismal hemorrhage by examining shape and morphology of the aneurysm, by identifying patients who are at risk of hemorrhage versus other causes of morbidity and mortality to increase the efficiency of clinical trials, and to use data from ISUIA to assess the long-term effectiveness in comparable patients, estimating short-term and long-term results to identify appropriate risk strata for ongoing study and for clinical trials. The proposed analysis of the ISUIA cohort will further define the risk of aneurysm rupture, the competing causes of death and the effectiveness of hemorrhage prevention through surgical and endovascular treatment.

? DESCRIPTION (provided by applicant): Knee osteoarthritis (OA) is a common chronic painful disorder that is the most frequent cause of mobility disability in older people. The MOST study has been a major source of new knowledge about the course of this disease and factors that affect its course. Since the study began in 2003, it is increasingly recognized that by the time people develop chronic symptoms of knee OA, they usually have advanced structural findings of disease on MRI. Findings such as meniscal tears, malalignment and cartilage loss drive further structural deterioration and almost certainly limit prevention opportunities. We believe that prevention opportunities are likely to be greater if started in those who do not yet have severe continuous knee pain or advanced structural findings of disease. The functional impacts of knee OA occur in older people who experience multiple musculoskeletal comorbidities, and preventing disablement from OA requires a broader perspective than a focus on a single knee. For example, those with pain in one knee are at high risk of pain in other lower extremity musculoskeletal regions and, even if the knee is replaced, they may ultimately need treatment for pain in other joints developing as a consequence of the first joint affected. Also, in additionto functional loss, persons with OA experience buckling, falls and constraints in their involvement with the outside environment. We suggest there are opportunities to develop treatments and disease prevention strategies that have been unexplored and that by using new technologies and focusing on persons at a milder or earlier disease stage than previous studies, we can identify such opportunities. We propose to recruit a new mild disease cohort and continue to study the existing MOST cohort to identify new risk factors for disease and to study consequences of disease. Our goal is to find new strategies to prevent disease at an early stage and to limit the impact of disease once it has occurred.

Project Summary: Aneurysmal subarachnoid hemorrhage (aSAH) has a high mortality rate (~60%), with a large proportion of the survivors becoming functionally dependent. aSAH survivors have long term cognitive deficits and memory impairment in their productive years with major responsibilities with respect to work and family. In a 30-year nationwide population-based cohort study using data from Danish medical databases, the authors computed the absolute risks and hazard ratios (HR) of dementia up to 30 years after stroke. Compared with the general population, the HR (95% confidence interval) for dementia among ischemic stroke survivors was 1.72 (1.66?1.77), 2.70 (2.53?2.89) after intracerebral hemorrhage, and 2.74 (2.45?3.06) after aSAH. Why is that?? In aSAH subjects, accumulation of hemoglobulin (Hb) and non-heme iron (Fe) which are the natural byproduct lysis of red blood cells leads to significant neuronal cells death. Several preclinical studies in animals showed that both products lead to neuronal death and atrophy of any brain structures exposed to it and specifically the hippocampus and amygdala. These data were replicated in human, where authors found, the level of ferritin (Ft) in CSF, a reporter of the amount of Fe in brain, was found to strongly correlate with progression to Alzheimer's disease (AD). What is the mechanistic pathway of this process?? Our group showed that Hb is toxic to neuronal cells in vitro and adding deferiprone (De) attenuated and reversed this effect significantly. We then confirmed these results in a mouse model of intraventricular hemorrhage. Additionally, in a proof-of-concept study we showed that De significantly decreased Ft in CSF (p<0.0001) suggesting a potential therapeutic effect. Furthermore, others also showed in preclinical studies using different animal models, Fe chelating agents decrease Fe content both in the subarachnoid space and intraventricular improving the functional and cognitive outcome in these animals. Therefore, we propose this grant to test the hypothesis that deferiprone, a lipid soluble Fe chelating agent and therefore diffuse easily across the blood-brain barrier, will significantly decrease Ft (a reporter of total non-heme Fe content in CSF) in subjects with aSAH and hence improve cognitive function. To test this hypothesis, we propose a phase 1/2a single-center randomized double-blinded placebo vs. De trial that recruits and enrolls 66 subjects with aSAH who require placement of EVD as a standard of care. Subjects will be randomized equally into 2 groups: A) placebo & B) 15 mg/kg bid for 21 days. Ft will be collected daily from CSF. We will also test the cognitive changes using the Montreal Cognitive Assessment test along with a battery of well-standardized and widely used cognitive tests that measure various aspects of cognitive and behavioral functioning. We will also assess the volume of hippocampus and amygdala in this cohort and compare them to a matched, historic control cohort using specific MRI protocol. These tests will be correlated with the Ft content in CSF and the volume of hippocampus and amygdala on imaging studies obtained.