Robert A. Stern, PhD - US grants

Electroconvulsive therapy (ECT) is an important and effective antidepressant treatment. However, temporary confusion and memory impairments remain significant side effects. There are numerous interactions among ECT, homeostasis of the hypothalamic-pituitary- thyroid axis, depressive symptomatology, and neurocognitive functioning. The findings of previous pre-clinical and clinical investigations led to the principal investigator to conduct a double-blind, placebo- controlled, pilot study of combined ECT and thyroid hormone treatment in a series of 20 male inpatients. Result indicated that a nightly dose of 50 micro g of triiodothyronine (T3) significantly accelerated the antidepressant action of ECT, diminished the amnestic sequelae, and increased seizure durations. The proposed investigation will expand on the preliminary work to include a larger, more representative group of patients, and test the study hypotheses with a more rigorous research design. Four major hypotheses will be tested: 1) The adjunctive administration of T3 during the course of ECT will enhance the clinical efficacy of ECT. Specifically, it is expected that patients receiving T3 plus ECT will be more likely to achieve an adequate antidepressant response and have an accelerated antidepressant response, compared to patients receiving ECT and placebo. 2) The combined treatment will diminish the neurocognitive side effects associated with ECT. Specifically, it is expected that patients receiving T3 plus ECT will have less disorientation and attentional deficits following individual ECT treatments, and will have less overall post-treatment impairment in anterograde and retrograde memory, less subjective memory complaints, and greater satisfaction with their treatment, compared to patients receiving ECT and placebo. 3) It is also expected that T3 will lower seizure threshold and enhance seizure duration in patients receiving ECT. 4) Finally, it is expected that patients receiving the combined treatment will exhibit a significant decrease in circulating T4 from pre- to post-treatment, and that the degree of clinical improvement will be directly associated with diminished T4 levels. The proposed study will test these hypotheses in 60 men and women, hospitalized at the UNC Neuropsychiatric Hospital. Patients will be randomly assigned, in a double-blind manner, to receive ECT with or without adjunctive T3. Neuropsychological and clinical assessments will be obtained at baseline, at regular intervals throughout treatment, 3-5 days following treatment, and at a one month post-treatment follow-up. Results of this study may have important clinical and economic ramifications by accelerating the antidepressant effects of ECT and diminishing the morbidity associated with this treatment.

Electroconvulsive therapy (ECT) is an important and effective antidepressant treatment. However, temporary confusion and memory impairments remain significant side effects. There are numerous interactions among ECT, homeostasis of the hypothalamic-pituitary- thyroid axis, depressive symptomatology, and neurocognitive functioning. The findings of previous pre-clinical and clinical investigations led to the principal investigator to conduct a double-blind, placebo- controlled, pilot study of combined ECT and thyroid hormone treatment in a series of 20 male inpatients. Result indicated that a nightly dose of 50 micro g of triiodothyronine (T3) significantly accelerated the antidepressant action of ECT, diminished the amnestic sequelae, and increased seizure durations. The proposed investigation will expand on the preliminary work to include a larger, more representative group of patients, and test the study hypotheses with a more rigorous research design. Four major hypotheses will be tested: 1) The adjunctive administration of T3 during the course of ECT will enhance the clinical efficacy of ECT. Specifically, it is expected that patients receiving T3 plus ECT will be more likely to achieve an adequate antidepressant response and have an accelerated antidepressant response, compared to patients receiving ECT and placebo. 2) The combined treatment will diminish the neurocognitive side effects associated with ECT. Specifically, it is expected that patients receiving T3 plus ECT will have less disorientation and attentional deficits following individual ECT treatments, and will have less overall post-treatment impairment in anterograde and retrograde memory, less subjective memory complaints, and greater satisfaction with their treatment, compared to patients receiving ECT and placebo. 3) It is also expected that T3 will lower seizure threshold and enhance seizure duration in patients receiving ECT. 4) Finally, it is expected that patients receiving the combined treatment will exhibit a significant decrease in circulating T4 from pre- to post-treatment, and that the degree of clinical improvement will be directly associated with diminished T4 levels. The proposed study will test these hypotheses in 60 men and women, hospitalized at the UNC Neuropsychiatric Hospital. Patients will be randomly assigned, in a double-blind manner, to receive ECT with or without adjunctive T3. Neuropsychological and clinical assessments will be obtained at baseline, at regular intervals throughout treatment, 3-5 days following treatment, and at a one month post-treatment follow-up. Results of this study may have important clinical and economic ramifications by accelerating the antidepressant effects of ECT and diminishing the morbidity associated with this treatment.

DESCRIPTION (provided by applicant): Subclinical hypothyroidism is a biochemical diagnosis characterized by elevated thyrotropin (TSH) levels with normal circulating thyroxine (T4) and triiodothyronine (T3) levels. Although SCH does not present with symptoms of clinical hypothyroidism it may be associated with mood, cognitive, and physical symptoms, and increased risk for hyperlipidemia and ischemic heart disease. SCH may also increase vulnerability to depression, cognitive impairment, and dementia. SCH is relatively common and occurs in approximately five to ten percent of the population, with higher prevalence (up to 20%) in women over age 60. To date, there have been no well designed, controlled studies that have evaluated the neuropsychiatric effects of SCH on the most vulnerable population (i.e., elderly individuals), and the impact of thyroid hormone treatment in this group, despite the well documented association between thyroid dysfunction and mood and cognitive disturbance. The purpose of this proposal is to evaluate depression and neuropsychological function in non-demented, elderly individuals with SCH and the efficacy of T4 treatment in improving mood and cognition in these subjects. There are two phases to the proposed study. In phase I, we will employ a cross- sectional design to evaluate the specific nature, severity and pattern of mood, cognitive, and physical symptoms in elderly, non-demented participants with SCH compared with euthyroid controls. In the second phase, we will carry out a double-blind, placebo- controlled, sixteen week study of the effect of T4 in improving these measures in the SCH subjects. Mood, cognition, quality of life, physical symptoms of hypothyroidism and thyroid status (T4, T3, TSH and antithyroperoxidase (anti-TPO) antibodies) will be measured. This study will yield important information about the neuropsychiatric effects of SCH on a vulnerable population and the effect of thyroid hormone treatment in reducing symptoms and improving overall functioning. Public Health Relevance: This project aims to determine whether there are specific alterations of mood and cognition with mild thyroid failure, also known as subclinical hypothyroidism. Furthermore, this research will also address whether alterations of mood and cognition associated with subclinical hypothyroidism are improved with thyroid hormone treatment.

ABSTRACT Women 65 and older (older women) account for nearly half of all new cases of breast cancer. With the graying of America the absolute number of older women diagnosed and undergoing breast cancer treatment will almost double by the year 2030. Treatment guidelines for these older patients include systemic therapy and older women are interested in chemotherapy for even small returns in survival extension. But systemic therapy is not without side effects, and numerous studies have documented cognitive decline after receipt of these agents. Imaging and animal studies confirm that cancer chemotherapy affects brain structure and function. However, very little is actually known about cognitive decline in older patients, because virtually all of the existing research has been conducted in younger patients. Since aging itself is associated with cognitive decline, older patients are likely to be particularly vulnerable to the adverse cognitive effects of systemic therapy. Our preliminary work suggests that this is the case, but this has never been empirically tested. This study will be the first large scale, prospective, controlled investigation to evaluate cognitive changes in older cancer patients. We use the vulnerability model of cancer survivorship to describe systemic therapy effects on cognition over a 12 month period, test associations between cognition and quality of life and to evaluate whether APOE polymorphisms moderate cognitive outcomes. We have assembled a team of oncologists, geriatricians, neurologists, neuro-, cognitive and behavioral psychologists and consumers from Lombardi Comprehensive Cancer Center, Memorial Sloan-Kettering Cancer Center, Boston University and Y- Me (a national consumer advocacy organization). We will enroll 325 newly diagnosed older breast cancer patients and an equal number of non-cancer friend controls. Participants will undergo baseline (pre-systemic therapy) neuropsychological testing and telephone interviews; clinical data will be abstracted from records. Participants will repeat cognitive testing and QOL measures 12 months after baseline. The primary outcome is change in the summary score on tests in the Attention, Working Memory, and Psychomotor Speed Domain. Four additional domains are included as secondary outcomes to assess broader cognitive function and examine differential impact: Language; Executive Functioning; Learning and Memory; Visuospatial. The results of this study will contribute to designing appropriate regimens for older women, developing preventive interventions, informing clinical decision-making about treatment, and guiding second generation studies. Overall, this topic has high research, clinical and public health importance, given the projected growth in the older population, rising incidence with advancing age, trends towards increasing use of systemic therapy in older patients, use of more aggressive dosing regimens, high survival rates, and increasing life expectancy.

DESCRIPTION (provided by applicant): The goal of this project is to examine the clinical presentation and biomarkers that accompany chronic traumatic encephalopathy (CTE; also known as dementia pugilistica), a preventable cause of dementia. Although concussive and/or subconcussive brain trauma appears to be a necessary factor in the development of CTE, it is not sufficient. The specific additional risk factors (e.g., genetics), and possible preventive strategies (e.g., concussion management, limiting overall subconcussive trauma) for this condition remain unknown. Moreover, although case studies have suggested that the pre-dementia clinical presentation includes cognitive deficits, depression, suicidal behavior, and problems with impulse control, there have been no systematic studies to support these observations. The research team has conducted neuropathological studies demonstrating that CTE is a tauopathy with a unique profile of neurodegeneration that is distinct from Alzheimer's and other neurodegenerative diseases of aging. To date, the only means of diagnosing CTE is post-mortem brain examination. In order to conduct prospective research into the epidemiology, early detection, risk factors, clinical course, and, ultimately, treatment and prevention of CTE, objective biomarkers for the disease must first be discovered. This project involves a cross-sectional examination of the biomarkers and clinical presentation of CTE. This initial study will focus on a sample of subjects who are at high risk of developing CTE: a randomly selected group of 150 retired NFL athletes, ages 40-69, all with high head trauma exposure (load) based on a combination of the total years played and positions played, incorporating helmet sensor data to determine the relative risk of various positions. We will also select a control group of same-age male athletes, with exclusion criteria based on a history of brain trauma or any participation in organized sports or military that may have caused exposure to even subconcussive brain trauma. In addition, APOE genotype will be examined as a potential moderating variable, based on our neuropathological findings and other data reported in the literature, both of which suggest that the APOE 54 allele may increase disease susceptibility. We will compare the high exposure group to the control group on several potential biomarkers, selected based on our previous neuropathological studies of CTE, our pilot neuroimaging data, and other findings by our team and in the literature regarding the long-term effects of repetitive brain trauma. We will then compare the groups on pertinent clinical variables, including neurologic, motor, neuropsychological, and psychiatric evaluations, and examine the relationship between the clinical variables and biomarkers in the high exposure group. Results of this initial investigation will help guide future longitudinal studies into the epidemiology, risk factors, and clinical presentation of CTE, and may provide additional knowledge relevant to the pathogenesis, detection, and eventual treatment of other neurodegenerative diseases such as AD.

? DESCRIPTION (provided by applicant): Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by a distinct deposition of an abnormal form of the tau protein in a pattern that is unique from other diseases, including Alzheimer's disease (AD). CTE has been found most often in professional contact sport athletes (e.g., boxing, football) who have been subjected to repetitive blows to the head resulting in concussive and subconcussive trauma. Neuropathologically-confirmed CTE has been reported in individuals as young as 17 and in athletes who only played sports through high school or college. It also has been found in non-athletes who experienced repetitive head impacts, including epileptics, victims of physical abuse, and military service members. In contrast to what may be inferred by the extensive media attention on CTE, the science of CTE remains in its infancy; critical questions remain, such as whether or not it is a common disease. Although the neuropathological features of CTE have become further clarified in recent years, the clinical presentation of CTE is still not well characterized, even though there have been case reports in the literature of dementia pugilistica in boxers since the early 1900's. Clinical diagnostic criteria have only recently been published and lack validation. Neuroimaging and fluid biomarkers developed for the diagnosis of other neurodegenerative diseases have only been used in preliminary studies. There is thus an urgent need to develop accurate methods for detecting and diagnosing CTE during life so that effective interventions for prevention and treatment can be developed. Moreover, though a history of repetitive head impacts is a necessary risk factor for CTE, it alone is not sufficient. There is a need to understand what specific aspects of the head impact exposure places an individual at increased risk for CTE and to examine potential genetic modifiers of that risk. To address these needs, we propose a multidisciplinary, multicenter, longitudinal study of former athletes with high exposure to repetitive head impacts (120 former NFL players with and without symptoms) or medium exposure to repetitive head impact (60 former college football players with and without symptoms) and a control group of 60 asymptomatic same-age men without any history of repetitive head impact exposure or traumatic brain injury. The aims of our proposal are: (1) to collect and analyze neuroimaging and fluid biomarkers for the detection of CTE during life, including the use of a novel PET tracer to measure the amount of abnormal brain tau; (2) to characterize the clinical presentation of CTE; (3) to examine the progression of CTE over a three year period; (4) to refine and validate diagnostic criteria for the clinical diagnosisof CTE; (5) to investigate genetic and head impact exposure risk factors for CTE; and (6) to share project data with researchers across the country and abroad in order to expedite growth in our understanding and treatment of this disease.

The BU ADC Clinical Core (CC) conducts and enhances cutting-edge Alzheimer?s disease (AD) research. CC registry data and subject participation support local and national clinical research studies. We have successfully maintained approximately 20% African American representation in the registry. The CC obtains research-quality MRI scans on registry participants and CC investigators are actively engaged in, and make major contributions to national and international AD research endeavors, including genetics and genomics, biomarker development, cognitive and functional assessment, and cognitive neuroscience. CC investigators have also made significant contributions to the clinical description, diagnosis, and risk factor analysis of chronic traumatic encephalopathy (CTE). We have fully integrated the examination of CTE, with an emphasis on the comparison of CTE and AD, and have included a cohort of former National Football League (NFL) players in the CC registry. We also have integrated CC activities and methods with those of several funded studies of CTE affiliated with the CC. During the next funding cycle, the CC will have the following specific aims: Aim 1: To evaluate and longitudinally examine a registry of approximately 425 participants, comprised of: 50 cognitively normal controls without subjective cognitive complaints (SCC); 125 controls with SCC; 100 subjects with mild cognitive impairment; 75 subjects with mild-moderate AD dementia; and 75 former NFL players with extensive repetitive head impact exposure. Aim 2: To provide data and a source for well-characterized participants for local and national research studies on brain aging, AD spectrum, and CTE research. Research-quality diagnoses will be made on all participants through multidisciplinary diagnostic consensus conferences. High quality data will be collected and submitted to the National Alzheimer?s Coordinating Center (NACC) for data sharing with qualified investigators. The Registry was designed to meet the recruitment needs of the local and national AD research community. Aim 3: To obtain brain donation consents for a minimum of 75% of registry participants and to work with the Neuropathology Core (NPC) to successfully obtain brain tissue from a minimum of 90% of consented participants upon death. The CC and the NPC will examine clinicopathological agreements, with a special emphasis on the comparison of AD and CTE. Aim 4. To collect blood and CSF products from registry participants. The CC will work closely with the NPC to integrate the collection of specimens with the analysis, banking, and distribution of specimens. We will extract DNA and genotype APOE and provide samples to qualified AD and CTE researchers, the National Cell Repository for Alzheimer?s Disease and the Alzheimer?s Disease Genetics Consortium. Aim 5: To conduct research-quality MRI scans on a minimum of 85% of the registry to support AD- and CTE-related research. We will upload MRI data to NACC. The Neuroimaging section of the CC will conduct post-processing of scans and will make the data available to CC investigators and to others in the AD and CTE research communities.

Exposure to repetitive head impacts (RHI) through participation in contact and collision sports (CCS) can result in symptomatic concussions and asymptomatic subconcussions and may increase risk for later-life cognitive decline and neuropsychiatric dysfunction, as well as dementia from neurodegenerative disease, including chronic traumatic encephalopathy. Despite many scientific advances in this area, critical knowledge gaps exist due to: small samples, cross-sectional designs, focus on male professional American football players, recruitment biases, and reliance on retrospective reports from informants. Many questions remain, such as: What aspects of RHI are most pertinent to these risks? Are there non-RHI factors that enhance or mitigate risk? Do the risks generalize to women and to soccer players? Our goal is to address these limitations and examine risk factors for, and characterize the frequency, severity, and profile of cognitive impairment, neurobehavioral dysregulation (e.g., explosiveness, impulsivity, ?short fuse?), and dementia, in female and male former soccer players and male former American football players. We will create the Head Impact and Trauma Surveillance Study (HITSS) by leveraging the Brain Health Registry (BHR) at the University of California, San Francisco. BHR is an online registry for the longitudinal study of people interested in participating in Alzheimer?s disease (AD) and related dementias (ADRD) research, with ~70,000 participants currently enrolled. BHR participants complete demographic and health questionnaires, medical and neurologic histories, depression scales, subjective cognitive complaint measures, and two validated online cognitive tests. They can also have a study partner complete additional online measures of the participant?s cognitive and functional status and neuropsychiatric symptoms. A HITSS Module will be developed and added to BHR to assess CCS history, RHI exposure (e.g., positions played, age of first exposure, duration of play, era of play, soccer heading), and standardized neuropsychiatric measures. Participants will be recruited into HITSS through an extensive national advertising and social media outreach. We will enroll 1800 former soccer (900 female, 900 male) and 1800 male former American football players into HITSS, across levels of play (high school, college, or elite/professional), ages 40- 75. Using the existing BHR dataset, two comparison groups (n = 1800 each) of current BHR participants without a CCS or TBI history will be propensity-matched to the former soccer and former American football players. We will test the hypothesis that greater cumulative RHI exposure from soccer and American football increases risk for cognitive impairment, neurobehavioral dysregulation, and dementia, and that non-RHI factors (e.g., TBI history, sex, race, vascular risk, cognitive reserve) will modify the effect. Data will be shared with researchers worldwide. Findings will advance research on risk of later-life cognitive decline, neurobehavioral dysregulation, and dementia from CCS involvement. Development of HITSS will also create: (1) a self-sustaining mechanism for follow-up of participants in other CCS studies; (2) a longitudinal, sharable dataset of thousands of female and male, active and former CCS athletes; and (3) a readiness registry of CCS athletes for future research.