Arjun V. Masurkar, MD, PhD - US grants

PROJECT SUMMARY/ABSTRACT CLINICAL CORE There is now abundant evidence that the pathology of Alzheimer's disease and related disorders (collectively referred to as AD) begins decades before the onset of clinical symptoms. This prodromal, preclinical period, while appearing cognitively and functionally silent is in fact associated with robust changes that may be detected by biomarkers and presents an ideal opportunity for early detection and intervention. To do this, we have taken the lead in developing and validating novel and innovative clinical-cognitive-behavioral measurements to identify individuals at-risk and combine these findings with state-of-art biomarker studies. The NYU ADC current research focus is on individuals with NIA-AA Stages 1 to 3 (particular focus on subjective memory complaints, CSF and imaging biomarkers, and physical functionality): preclinical disease, MCI, and mild AD compared with healthy aging (NIA-AA preclinical stage 0). The overall goal of the Clinical Core is to provide accurate research diagnoses for a cohort of longitudinally followed older adults to autopsy to provide appropriate subjects and subject-derived materials for research projects conducted by ADC investigators and collaborating scientists. This focus directly serves the primary research theme of the NYU ADC: the characterization of preclinical AD and its transition to MCI and early AD. We propose 8 Specific Aims: (1) Maintain and characterize an active UDS cohort of ~400 individuals (Clinical Dementia Rating [CDR] 0 50% of cohort), MCI (CDR 0.5 30% of cohort), or mild AD (CDR 0.5 or 1 20% of cohort); (2) Recruit, assess, and retain new participants (~45) from diverse backgrounds to replenish the cohort in proportion to attritional losses; (3) Provide culturally-sensitive recruitment strategies and longitudinal research assessments; (4) Collect, store, and distribute CSF, blood, and DNA biospecimens; (5) Obtain consent for brain donations; (6) Provide appropriate subjects, data, and biospecimens for research studies; (7) Integrate data collection and quality control procedures; and (8) provide infrastructure, resources, and coordinate contribution to NACC and other national and international collaborations. By providing a wealth of standardized longitudinal clinical, cognitive, biomarker, and neuroimaging data to investigators, the NYU ADC Clinical Core is poised to play a significant role in providing the infrastructure and resources necessary to advance our understanding of preclinical AD and its transition to the symptomatic stages of MCI and mild AD.

ABSTRACT- CLINICAL CORE The Clinical Core (CC) is central to the function of the NYU ADRC by providing comprehensive evaluations and accurate research diagnoses for participants engaged in its long-standing longitudinal study of normal versus pathologic cognitive aging. The CC has made significant advances in the characterization of preclinical to dementia stages: establishing subjective cognitive decline as a prodromal stage, developing widely used scales for clinical phenotyping, and helping establish important imaging biomarkers of early stage disease. We continue our goal to understand mechanisms that influence transitions towards dementia. We emphasize the study of critical, early transitions (normal->preclinical/prodromal->MCI) and how they relate to state-of-the-art biomarkers of the ATN framework and AD/ADRD heterogeneity. Our approach will combine standard UDS 3 assessments with an innovative NYU-specific protocol that uses advanced MR and PET neuroimaging, robust clinical phenotyping schemes, and new biofluid/disease monitoring strategies. We propose 4 specific aims. Aim 1 is to comprehensively characterize a cohort of ~500 community-dwelling older adults [70% normal, 20-25% MCI, 40% from Black/African-American and Latino groups] with (a) a unique protocol for longitudinal clinical phenotyping and biomarker analysis to evaluate preclinical/prodromal disease and AD/ADRD heterogeneity, (b) timely data reporting to participants and national repositories, and, (c) brain donation consenting to establish clinical- biomarker-pathological correlations. Aim 2 is to support a large network of interventional AD/ADRD trials and in- house affiliated studies on multi-etiology dementia by maintaining a dynamic registry of ?study-ready? participants. Aim 3 is to improve the clinical phenotyping of at-risk/early stage subjects by (a) developing novel characterization schemes for neuropsychiatric symptoms and SCD and (b) leveraging emerging technology to investigate digital biomarkers related to cognition, sleep, and motor function. Aim 4 is to improve clinical skills of dementia practitioners, promote the use of CC data for AD/ADRD research among early career investigators, and educate the public about AD/ADRD and the value of normal controls and brain/biospecimen donation. These aims allow the CC to advance its state-of-the-art program that is well poised to answer critical questions within the current AD/ADRD research framework and contribute to NAPA research implementation milestones.

PROJECT SUMMARY/ABSTRACT Anxiety is a highly prevalent and burdensome symptom of Alzheimer disease (AD), especially at early stages, and is linked to faster decline. Further mechanistic understanding would improve current treatments, which are suboptimal and/or carry significant side effects. Yet, the pathophysiology of anxiety in AD is unclear. The CA1 region of ventral hippocampus (vCA1), and specifically its deep pyramidal neurons (dPNs), may play a significant role in anxiogenesis in AD. The vCA1 dPNs are known to increase their activity during anxious behavior and project to other areas of the broad anxiogenic network, including amygdala, prefrontal cortex, and hypothalamus. In addition, compared to dorsal CA1, vCA1 features more intrinsic and synaptic excitability at baseline and appears to be more vulnerable to early AD. Here, our objective is to obtain a cell type-specific understanding of how AD affects ventral CA1 in order to better understand anxiogenesis in AD. Specifically, we test the hypothesis that anxiety in AD relates to hyperexcitability of the vCA1 dPNs. This hypothesis is bolstered by the above, and published and preliminary work suggesting vulnerability of vCA1 in AD-related anxiety and that, in AD, dPNs are prone to intrinsic hyperexcitability and excitatory-inhibitory imbalance. Using the 3xTg-AD mouse model, we test our central hypothesis with the following aims. In Aim 1, we use in vitro electrophysiology and retrograde labeling to elucidate AD-related alterations in synaptic and intrinsic excitability in vCA1 dPNs defined by their projection area. In Aim 2, we use implantable microendoscope imaging of GCaMP calcium signals, c-fos immunohistochemistry, and retrograde labeling to determine the in vivo activity of vCA1 dPNs and projection-defined dPN subpopulations during anxious behavior in AD mice. This work will provide two major results that will significantly add to the understanding of anxiety in AD, at the level of circuit architecture and population coding. Our strategy is conceptually and technically innovative by leveraging cell type-specific circuit knowledge and state-of-the-art approaches to address disease pathophysiology at a cellular level. In supporting our hypothesis, these experiments will determine which vCA1 dPN subpopulations and what excitability mechanisms would be the focus of future work. More generally, these results will further a cell type-specific understanding of AD changes in ventral hippocampus, a structure that has received less attention in mechanistic studies, is highly vulnerable to AD, and is important for not only anxiety but also social and motivational behaviors.

PROJECT SUMMARY/ABSTRACT Memory loss in early Alzheimer disease (AD) appears when pathophysiology extends from entorhinal cortex (EC) into hippocampal area CA1. CA1 processes EC input to generate hippocampal output, and bears the brunt of hippocampal AD pathology. AD studies on CA1 have treated its pyramidal neurons (PNs) as a homogeneous population. However, work from our and other groups established that CA1 PNs are diverse, comprised of superficial (sPN) and deep (dPN) layers with unique roles in memory. The two layers show differential changes in ischemia and epilepsy, but our knowledge of AD pathophysiology at this level is incomplete. This limits our understanding of memory deficits in AD and our ability to correct dysfunction. This knowledge can also advance our understanding of activity-dependent spread of AD and neurodegeneration risk factors. Our published and preliminary data, and the literature, support a working hypothesis that dorsal CA1 sPNs and dPNs exhibit contrasting pathophysiological and functional compromise due to amyloid and tau pathology. The sPNs develop pathologic signs of aging, and show intrinsic and synaptic hypoexcitability in aged and 3xTg-AD mice. The dPNs do not show these signs and become hyperexcitable. In human AD, the sPN layer is more prone to plaques and tangles, and the two layers show proteomic differences related to disease pathways and excitability. We test our hypothesis using amyloid (5xFAD) and tau (PS19) models to separately address the effects of these pathologies on sPNs/dPNs at three levels. In Aim 1, we use in vitro opto-electrophysiology to evaluate the impact of AD pathology on dorsal sPN- versus dPN-associated circuits. This will relate cell and synaptic identity to the directionality and extent of physiologic change. We expect that amyloid/tau induce hypoexcitability in sPN circuits and hyperexcitability in dPN circuits. In Aim 2, we use miniscope GCaMP calcium imaging to determine the influence of AD pathology on dorsal sPN versus dPN activity during hippocampal-dependent behavior. This will test the in vivo dominance of differential local circuit changes in CA1 over globally reduced efferent input in the setting of memory deficits. We expect that sPNs are more vulnerable to reductions in their in vivo activity during memory-guided behaviors. In Aim 3, we compare proteomic changes in dorsal sPNs versus dPNs in the setting of AD pathology. This will link cell identity, molecular markers of AD severity, and the degree/directionality of physiologic change. We expect that sPN proteomes will show more severe changes in pathologic AD pathways. This work is significant by providing new, cell-type specific, mechanistic knowledge about memory dysfunction in AD. This will also help link physiologic change to development of pathology and neurodegeneration. These are critical steps towards better treatments. Our strategy is innovative by combining multiple, state-of-the-art approaches to address disease pathophysiology in distinct cell types at multiple biological levels: circuit, behavior, and molecular.