Bradley T. Christian - US grants

DESCRIPTION (provided by applicant): Prenatal exposure to alcohol has been shown to damage the serotonin (5-HT) system in the brain throughout the course of development. Early life impairment of this system has been linked to behavioral abnormalities including increased anxiety and aggression. The 5-HT1A receptor is of particular interest in fetal alcohol (FA) exposure because of its presence in early development and its role in regulation of the 5-HT system and the neuroendocrine stress axis. In this work, we propose to acquire pilot data to examine possible changes in 5-HT1A receptor binding caused by prenatal exposure to alcohol. To accomplish this, we will characterize and validate the use of a promising, novel PET radioligand, [F-18]mefway, in the nonhuman primate model. Compared with current 5-HT1A radioligands, [F-18]mefway demonstrates: i) superior imaging characteristics due to the [F-18] radiolabel, ii) improved target to background binding in the PET signal, and iii) a more favorable metabolite profile for yielding quantitative accuracy. Full characterization of the in vivo rate constants of [F-18]mefway will be performed in normal rhesus monkeys through a series of multiple injection studies, using arterial blood sampling and full compartmental kinetic analysis. The information from this first specific aim will be used to aid in the design of the experiments to measure 5-HT1A receptor binding potential in prenatally alcohol exposed rhesus monkeys which belong to a cohort of animals that have been used over the last decade at the University of Wisconsin-Madison for studying behavior, genetics and neurobiology in fetal alcohol exposure (PI-Schneider: AA12277). For the second specific aim, [F-18]mefway will be used to acquire pilot data in rhesus monkeys that received prenatal exposure to alcohol and matched controls to measure in vivo 5-HT1A binding. Comparisons will then be performed to evaluate the effects of prenatal alcohol exposure on the 5-HT1A receptor system. An understanding of FA-exposure on the 5-HT1A system holds great potential for examining the mediating mechanisms and processes for relationships between FA-exposure and neurobehavioral impairments. PUBLIC HEALTH RELEVANCE Prenatal exposure to alcohol has been shown to damage the serotonin (5-HT) system in the brain during the course of neural development. Early life impairment of this system has been linked to behavioral abnormalities including increased anxiety and aggression and may be related the maladaptive behaviors often displayed by individuals born with fetal alcohol exposure. PET neuroligand imaging is ideally suited to investigate in vivo changes in the serotonin system caused by fetal alcohol exposure. In this proposal, our goal is to conduct pilot studies of possible disruptions in the serotonin (5-HT1A receptor subtype) system in an animal model of prenatal alcohol exposure using a novel PET radioligand, [F-18]mefway. This work holds great potential for characterizing a biomarker that will aid in understanding the relationships between fetal alcohol exposure and neurochemical impairments.

DESCRIPTION (provided by applicant): A further understanding of the multiple genetic and environmental risk factors associated with anxiety and mood disorders is greatly needed to advance courses of treatment and provide relief for humans suffering from these devastating illnesses. Disruption of the serotonin (5-HT) system has been implicated in anxiety and depression and a 5-HT related genetic predisposition for these psychiatric illnesses has been identified in the length polymorphism of the 5-HT transporter promoter region (5-HTTLPR) for carriers of the short (s) allele, with s carriers displaying reduced gene 5-HTT transcription. Rhesus monkeys, also carry this genetic variant and provide an invaluable resource for studying gene x environment interactions. The overall goal of this proposal is to utilize a novel 5-HT1A radioligand and PET imaging methods in the rhesus monkey to examine the potential relationship between 5-HTTLPR polymorphisms, prenatal stress and 5-HT1A binding indices. PET scans will be acquired on a well characterized and tightly controlled cohort of 28 rhesus monkeys, from a colony originally supported by NIMH funding to study prenatal stress. [F-18]Mefway will be used to measure 5- HT1A autoreceptor and postsynaptic receptor density (Bmax) and apparent KD in single PET imaging experiments. We hypothesize that the largest reduction in 5-HT1A Bmax will be seen in the prenatally stressed group with the s allele polymorphism, suggesting the gene x environment interaction will be the dominant component of the variance. The work outlined in this project will provide the framework for extending this research of 5-HT1A PET imaging to investigate environmental variables that may play a vital role in psychopathology predisposition and genotype expression in larger cohorts of nonhuman primates and for eventual translation into human populations. PUBLIC HEALTH RELEVANCE: Stressful life experiences may render some individuals more vulnerable than others to anxiety-related or mood disorders. Disruption of the serotonin system has been implicated in anxiety and depression and a related genetic variation has been identified that may predispose individuals for these illnesses. In this proposal, our goal is to use PET imaging of the serotonin system in the nonhuman primate model to study the effects of prenatal stress on the serotonin 5HT1A receptor. Particularly, to examine if carriers with a short variation of the gene for encoding the serotonin transporter are more profoundly affected by prenatal stress than those with long gene variation. This work holds great potential for advancing our knowledge of how environmental experiences interact with genes in the development of anxiety-related illnesses.

NiAD Summary/Abstract: Individuals with Down syndrome (DS) have been largely neglected in therapeutic and biomarker studies of Alzheimer's disease (AD). Adults with DS are uniformly affected by AD pathology by their 30's and have a 70-80% chance of clinical dementia by their 60's. In 95% of cases, DS is associated with three copies of chromosome 21, each containing of copy of the Amyloid-beta (A?) Precursor Protein gene (leading to a 1.5-fold increase in A? protein). Yet, nowhere is it clearer than in DS that A? deposition is not sufficient to produce dementia, as individuals harbor this pathology for over a decade before cognitive decline is apparent. DS can be seen as a setting of amplified sensitivity to risk and protective factors that moderate the relationship between A?, neurodegeneration and clinical dementia. Understanding the factors that moderate this relationship in DS and biomarkers for those factors is critically important in the design of therapeutic trials for AD in DS and in general. Thus, this longitudinal study of Neurodegeneration in Aging DS (NiAD) and its relationship to cognition has the potential to: 1) identify critical factors that link A? deposition to neurodegeneration and, ultimately, dementia; 2) define biomarkers for these factors; and, most importantly, 3) set a foundation for an efficient transition from this biomarker study to a therapeutic trial to combat AD in DS augmented by biomarker outcomes. For the past 5 years, the three independent research groups included in this application have been studying the course of A? deposition and other imaging biomarkers and their impact on cognitive/functional measures in adults with DS [(a) the combined Pittsburgh/Madison study; (b) the Banner Alzheimer's Institute study; and (c) the Cambridge study]. In their ongoing work, 140 adults with DS (including 23 with DS/AD-dementia) have undergone magnetic resonance imaging (MRI) and amyloid-positron emission tomography (PET) scans and neuropsychological/ functional assessments. These three research groups now propose to combine resources and harmonize all protocols in response to the request from NIA/NICHD to develop a large AD biomarker study in DS. This study will be further strengthened by aligning NiAD with the three largest ongoing longitudinal studies of AD biomarkers in the general population: the Alzheimer Disease Neuroimaging Initiative (ADNI), the Dominantly Inherited Alzheimer Network (DIAN) and the Alzheimer Prevention Initiative (API). All data will be made available in an open-access format using a model similar to ADNI. The established DS cohort is a significant advantage that will shorten the recruitment phase, maximize longitudinal data that can be acquired and allow for addition of new biomarkers to be compared to longitudinal clinical and imaging measures. The proposed 5-year longitudinal study will examine progression of AD related biomarkers (A?-, tau- and fluorodeoxyglucose-PET, structural and functional MRI, cerebrospinal fluid A? and tau, plasma A? and proteomics, genetics, neuropathology) and cognitive/functional measures in 180 adults with DS (>25 yrs. of age) and 40 biomarker-controls. Subjects will be re-evaluated every 15 months to assess changes in cognition/adaptive functioning and every 30 months to detect biomarker changes.

Abstract The goal of this High-End Instrumentation proposal is to enhance the molecular imaging capabilities of the University of Wisconsin Waisman Brain Imaging Laboratory (WBIL) and update our positron emission tomography (PET) imaging system. We are requesting funds to purchase the Siemens Biograph Horizon PET/CT scanner to replace our existing 17 year old scanner that is no longer vendor-supported. This commercially available system was selected based upon its state-of-the-art PET component and a more economical CT component (used exclusively for attenuation correction for our neuroimaging research). This system has an extended axial field of view (22cm) which provides an overall increased detection sensitivity, along with a more uniform sensitivity over the volume of the brain. This will result in dramatically improved SNR compared to our existing system. There are currently 9 major NIH-funded projects by University of Wisconsin investigators utilizing PET imaging as a primary outcome measure. These are heavily focused on measuring changes in amyloid and tau burden as presymptomatic biomarkers for Alzheimer?s disease using longitudinal study designs. Detecting these subtle changes (<10%) in amyloid and tau binding over the course of several years requires a stable, reliable and quantitatively accurate PET system over a long term. The Horizon PET/CT system will be 100% dedicated to research applications to overcome the challenge of integrating these multi-scan protocols into the schedule of a clinical scanner. UW researchers have directed a tremendous amount of resources into creating invaluable subject populations and we are now well-positioned to fully exploit the powerful PET molecular imaging measures in our investigations of neurodevelopment and neuropathology. This new PET/CT will ensure our future for uninterrupted acquisition of high quality data for this important research.

Project Summary Cholinergic pathway deficits in Alzheimer?s disease (AD) have been associated with cognitive impairment. The ?4?2* nicotinic acetylcholine receptor (nAChR) is involved in cognitive functions such as attention, learning and memory. PET imaging of ?4?2* nAChR may be sensitive to detect abnormalities in the early stages of mild cognitive impairment (MCI) and AD. At University of California-Irvine (UCI) and University of Wisconsin-Madison (UWM), we are involved in imaging ?4?2* nAChR in aging, Alzheimer?s disease (AD) and neurobiology of learning and memory. During the previous 3-year funding period we have successfully completed initial human PET studies (test-retest and radiation dosimetry) with [18F]Nifene with the following major outcomes: 1) [18F]Nifene requires a 40 min dynamic scan for quantitation; 2) [18F]Nifene is able to detect thalamic radiations (white matter tracts); 3) Females show greater [18F]Nifene binding than males; and 4) No aging effect on [18F]Nifene binding was observed. Since the initial study included only 8 subjects, a larger group of subjects is required in order to confirm the findings of male-female differences and aging using [18F]Nifene. In this 3-year renewal application our goals are: 1) Confirm male-female differences using 32 healthy subjects (16M, 16F) and examine aging effects by grouping 16 (8M, 8F) in their 20?s and 16 (8M, 8F) in their 70?s in all brain regions. This is critical for designing our PET study in AD human subjects and to evaluate males and females separately; 2) In the second goal, in pursuit of translation of [18F]Nifene PET to study AD, we propose to study postmortem brains of AD. Two brain areas have been chosen based on previous findings of their significance, anterior cingulate (with corpus callosum) and hippocampus (containing CA1/subiculum). The latter brain region is known to be an early marker for neurofibrillary tangles (NFT). Thus, it will be important to confirm if there is a correlation between the loss of nicotinic receptors (measured by [18F]Nifene) and the increase in NFT (measured by [18F]MK-6240, currently being used in our human AD PET studies) in this brain region. The AD subjects will be compared with controls and Parkinson?s disease subjects (32 subjects in each group, 16M, 16F). This will help ascertain clinical relevance of [18F]Nifene PET imaging in AD. 3) The third goal is to evaluate degree of binding of [18F]Nifene to the receptor subtypes using knock-out (KO) mice. Both ?2 and ?4 KO will be studied using [18F]Nifene PET and autoradiography and a male-female and aging effect will be evaluated in wild-type (WT) mice. These findings will help design transgenic AD mice model studies in order to study the role of the ?4?2* receptors. This renewal application will help to ascertain that females have greater levels of [18F]Nifene binding, there is no aging effect on [18F]Nifene binding and to measure the extent of change in ?4?2* receptors in postmortem AD brains. This information will be used in the design of [18F]Nifene PET studies in our ongoing imaging PET studies of [18F]MK-6240 NFT in MCI and AD subjects.

ABSTRACT Synaptic loss is a major feature of symptomatic Alzheimer?s disease (AD). New positron emission tomography (PET) radioligands have been developed which bind to synaptic vesicle glycoprotein 2A (SV2A), a synaptic vesicle protein found in presynaptic nerve terminals throughout the brain. While development of these tracers is a major advance for the field of AD, very little is yet known about synapse loss across the clinical and pathological spectrum of AD, and longitudinal studies in large cohorts are lacking. In order to address this gap in knowledge, we propose to perform longitudinal SV2A PET imaging with [C-11]UCB-J in participants recruited from the Wisconsin Alzheimer?s Disease Research Center. The sample will include cognitively unimpaired AD biomarker negative participants, cognitively unimpaired biomarker positive participants, individuals with mild cognitive impairment (MCI), and participants with dementia due to AD. Participants will be imaged at baseline and at two- year follow-up. The hypothesis is that regional synaptic loss will serve as a sensitive marker of neurodegeneration in the context of plaque and tangle accumulation and will explain cognitive decline. In order to address this hypothesis, we propose the following three specific aims: 1) determine the extent to which [C- 11]UCB-J provides unique information from MRI regarding neurodegeneration; 2) determine the rate of synapse loss as reflected by [C-11]UCB-J signal; and 3) determine the extent to which [C-11]UCB-J associates with cognitive decline. In addition to [C-11]UCB-J PET, we will acquire [C-11]PIB PET to determine spatial amyloid plaque burden, as well as [F-18]MK6240 PET to determine tau tangle burden. This study will be the first to obtain these three markers in tandem, which will allow?for the first time?the ability to determine how these pathologies evolve in AD, and determine how they are spatially and temporally related to one another. The National Institute on Aging has called SV2A PET imaging a ?potentially game-changing biomarker in AD and AD-related dementias?. Synapse loss is expected to be the most closely associated with cognitive decline, yet no large human studies have yet been undertaken to examine regional synapse loss across the spectrum of AD. The proposed project addresses this gap in knowledge. This program of research is expected to improve early detection of AD, improve prediction of cognitive decline, and inform the development of new treatment strategies.

Overall Abstract Alzheimer disease (AD) is the most common cause of dementia in the general population and the numbers of people living with the disease are rising exponentially. A similar event is occurring in the community of people with Down syndrome (DS) due, in part, to genetic risk (trisomy 21 and lifelong overexpression of APP) leading to overproduction of A?, combined with longer lifespans. The study of DS affords an opportunity to understand the timing and sequence of pathological changes associated with AD. An overarching theme of the Alzheimer?s Biomarkers Consortium ? Down Syndrome (ABC-DS) is to characterize AD in DS, an issue of major and growing significance. Data generated from ABC-DS are necessary to determine if the AD pathological cascade is the same between DS and late onset AD (LOAD) or whether the pathogenic staging has distinct features. Parallels between the two highlights the importance of research with people with DS for advancing our overall understanding of AD, which in turn can form the basis for clinical trials. To that end, ABC-DS assembles an exceptional and highly collaborative research team that will follow a cohort of people with DS to test hypotheses related to 1) how AD in DS may parallel sporadic AD within an amyloid, tau, neurodegeneration AT(N) framework and to identify modifiers of risk of conversion/progression (Project 1); 2) to identify genetic modifiers of the development of AD in DS (Project 2); and 3) to translate outcomes to a precision medicine framework and expedite clinical trials (Project 3). We will acquire harmonized clinical and neuropsychological outcomes (Clinical Core), neuroimaging outcomes (Neuroimaging Core), bio-fluids and genetics measures (Omics Core) and neuropathology data from autopsy (Neuropathology Core). To rapidly disseminate information to our DS communities and to engage underrepresented minorities, we have a Core dedicated to outreach, recruitment and retention (ADDORE Core). Lastly, to build upon nationwide efforts to identify targets for interventions to slow or prevent AD, our Biostatistics and Data Management Core will make high quality data from all aspects of our study available to qualified researchers by distributing outcomes through LONI and ATRI. Following the lead of outstanding established AD networks (ADNI, DIAN), ABC-DS will make a significant contribution to national efforts to improve the quality of life of our aging population through advancing progress toward effective prevention and treatment of AD.

Neuroimaging Core Abstract The ABC-DS Neuroimaging Core, led by Drs. Adam Brickman and Brad Christian, will apply state-of-the art positron emission tomography (PET) and magnetic resonance imaging (MRI) neuroimaging techniques to quantitate amyloid, tau, and neurodegeneration (AT(N)) in Down syndrome (DS) according to current pathophysiological models of Alzheimer?s disease (AD) together with related cerebrovascular, microstructural, and functional biomarkers. The specific aims of the Neuroimaging Core are to: (1) oversee the harmonized acquisition of PET and MRI data at each of the 8 clinical performance sites; (2) quantitate primary outcome measures for each neuroimaging modality; (3) integrate the processed neuroimaging data into a ABC-DS database to support the proposed projects; and (4) provide curated primary outcome variables and raw neuroimaging data to the wider scientific community. The overall scanning protocols will follow those developed by the Alzheimer?s Disease Neuroimaging Initiative (ADNI) for MRI (structural and functional) and PET (amyloid, tau, FDG). The outcome variables are derived by modality-specific analytic nodes, with each modality analyzed by a single laboratory with expertise in that neuroimaging biomarker. The Core will utilize NIA-sponsored resources that currently support ongoing large-scale AD neuroimaging initiatives (e.g. ADNI, Dominantly Inherited Alzheimer Network (DIAN)) to provide a fully developed data-access pipeline that encourages scientific investigation of neuroimaging biomarkers in DS.