Yuri Agrawal, M.D. - US grants

DESCRIPTION (provided by applicant): This project aims to characterize age-related changes in vestibular function, and explore their influence on important gait outcomes that increase fall risk and mortality in older individuals. These aims will be carried out within the Baltimore Longitudinal Study of Aging (BLSA), a rigorous, comprehensive longitudinal study of >1000 individuals age 20-103. Specifically, Aim 1 is to characterize SCC and otolith functional status and age- related variation in the BLSA population, and evaluate these for associations with demographic and comorbid medical factors. We will estimate population means and heterogeneity (variance) in AVOR gain in each SCC plane and cervical and ocular VEMP amplitudes as a function of age. We will evaluate differences in age- related SCC and otolith function by demographic factors (gender, race) and comorbidities (diabetes). In Aim 2, we plan to evaluate longitudinal changes in SCC and otolith function within BLSA participants over 5 years and investigate differences by demographic and comorbid medical factors. In 5 years, ~600 BLSA participants will be evaluated at 3-5 repeated visits. We will estimate mean and heterogeneity in rate of change of AVOR gain in each SCC plane and cervical and ocular VEMP amplitudes as a function of time. We will assess whether rates of change differ by demographic and comorbidity subgroups. In Aim 3, we will investigate the association of SCC and otolith function with age-related gait impairment. We will also evaluate whether a compensatory strategy that improves gaze stabilization modifies the association between SCC function and age-related gait impairment. We will evaluate associations between SCC and otolith function and two important age-related gait impairments - slow gait speed and increased gait variability (e.g. in step length, width, velocity), controlling for potential confounders including ankle proprioception, vision, lower extremity strength and neurocognitive function. A well-characterized compensatory strategy for SCC function loss is the gaze-stabilizing compensatory saccade. Importantly, this saccade can be induced and improved through vestibular rehabilitation. We will evaluate the frequency and timing of this compensatory saccade in the BLSA cohort as a function of age and AVOR gain, and investigate whether early timing of this saccade reduces the impact of low AVOR gain on gait speed and variability. This work represents an interdisciplinary approach to characterize the changes in vestibular physiologic function that occur with aging, and to explore the impact of these changes on clinically-significant outcomes including gait speed and variability and the role of vestibular adaptation in modifying these associations. The proposed work will fill fundamental knowledge gaps about how vestibular physiologic function changes with age. Moreover, findings from this study will inform clinical practice by establishing the range of predicted values for SCC and otolith function by age, by providing expected trajectories for SCC and otolith function according to baseline patient characteristics for individual- level patient counseling, and by identifying specific deficts (e.g. delay of compensatory saccades) that can be targeted clinically to improve functional outcomes and ultimately reduce fall risk in older individuals.

Project summary This project investigates whether vestibular loss in aging adults predicts hippocampal atrophy. The proposed research will be carried out within the Baltimore Longitudinal Study of Aging (BLSA), a rigorous, comprehensive longitudinal study of >800 individuals age ?60. Specifically, Aim 1 is to determine whether vestibular loss predicts hippocampal atrophy. We hypothesize that vestibular loss predicts subsequent atrophy of the CA1 subfield in the posterior hippocampus where the place cells and head direction cells are predominantly located and most modulated by vestibular input. Aim 2 is to determine whether vestibular loss predicts atrophy of the major pathways that carry vestibular input to the hippocampus. We hypothesize that vestibular loss predicts atrophy of white matter tracts between the thalamus and hippocampus (e.g. fornix), and between the vestibular cortex and hippocampus (e.g. cingulum). Moreover, our exploratory hypothesis is that vestibular loss predicts atrophy of the main thalamic nuclei that relay vestibular information from the vestibular end-organs and nuclei to the hippocampus (e.g. ventroposterior complex, ventrolateral nucleus, anterior dorsal nucleus). To accomplish these aims, we will use data from the Baltimore Longitudinal Study of Aging (BLSA). BLSA participants undergo vestibular physiologic testing and repeated brain MRI evaluations every 1-2 years. We will evaluate whether changes in vestibular function predict structural hippocampal changes over a 6-year follow-up period (2013-2019) in 80 participants. The BLSA has validated advanced approaches to measure longitudinal changes in gray matter volume and white matter tract integrity. We will also collaborate with colleagues in Computational Anatomy to apply novel methods to measure hippocampal and thalamic shape (i.e. differential atrophy) and sub-field atrophy. These methods can identify the structural basis for neurodegenerative disease with remarkable precision, such as pinpointing the earliest foci of Alzheimer?s disease pathology years before the disease manifests. At the end of this grant, we will gain knowledge about the specific hippocampal sub-fields and potentially the vestibulo-hippocampal circuits that are affected by vestibular loss in aging adults. Future studies will be directed at determining whether hippocampal changes induced by vestibular loss contribute to the onset of Alzheimer?s disease. Because effective vestibular therapies exist, results of these studies will help to determine whether vestibular treatment holds promise for Alzheimer?s disease mitigation.

Project summary This project investigates whether vestibular loss predicts falls in patients with Alzheimer?s disease (AD). The proposed research is an observational study of 150 patients with AD to evaluate the association between baseline vestibular function and 2-year incidence of falls. We will also explore whether vestibular function is associated with balance and gait function, as well as spatial cognitive function, as potential mechanisms by which vestibular function contributes to fall risk. Specifically, Aim 1 is to determine whether vestibular loss predicts falls in patients with mild-moderate AD. We hypothesize that poorer vestibular function at baseline predicts a higher 2-year incidence of falls. Additionally, we hypothesize that the attributable risk of falls associated with vestibular loss will be substantial enough (>~10%) to warrant further investigation of vestibular therapy as a clinically significant modifier of fall risk. Aim 2 is to evaluate whether vestibular loss in AD predicts impaired static and dynamic balance, measured using the Berg Balance Scale (BBS) and the Timed-Up-and-Go (TUG) test. We hypothesize that greater reduction in vestibular function over the 2-year follow-up period predicts greater decline in BBS and TUG performance. Aim 3 is to evaluate whether vestibular loss in AD predicts impaired spatial cognitive skills. We will administer cognitive tests of spatial cognition (including the Money Road Map test, the Card Rotations test, the Visual Form Discrimination test and the Clock Drawing test), and we will also query participants and caregivers about difficulty with driving, losing objects, getting lost and wandering behaviors as functional manifestations of impaired spatial cognition in AD patients. We hypothesize that greater reduction in vestibular function over the 2-year follow-up period predicts greater decline in spatial cognitive test scores, and a higher incidence of functional spatial cognitive impairment. Moreover, we hypothesize that impaired balance measures (from Aim 2) and impaired spatial cognitive skills will both be independent mediators of the association between vestibular loss and incident falls. To accomplish these aims, we will leverage well-established resources at Johns Hopkins including the Johns Hopkins Alzheimer?s Disease Research Center and the Memory and Alzheimer?s Treatment Center. Falls are a major source of morbidity in AD and current interventions are not uniformly effective. If our observational studies demonstrate that vestibular loss is associated with poorer balance and spatial cognition and incident falls, these results will inform the design of interventional trials to prevent falls in AD patients.

PROJECT SUMMARY Alzheimer's disease (AD) is the most common cause of dementia. Underlying pathological and physiological changes related to the onset and progression of AD are believed to emerge several years prior to clinical manifestations. Sensory impairments, gait abnormalities, and motor slowing may precede the diagnosis of AD by a decade or more, presenting the exciting possibility that changes in sensorimotor functioning may act as early noninvasive biomarkers for AD. Previous work by our group has identified links between cognitive performance and sensory impairment and gait speed and variability, making them potential preclinical markers of early AD pathology. We propose to use up to 10 years of existing longitudinal data, and ongoing/new data collection in approximately 1,000 older adults in the Baltimore Longitudinal Study of Aging (BLSA), to examine the roles of sensory function, gait speed and variability, and free-living measures of daily physical activity (PA) as precursors to cognitive impairment. We will also determine the link between sensorimotor measures and biomarkers of AD pathology, including A? deposition using [11C]-Pittsburgh compound B positron emission tomography, brain atrophy using structural magnetic resonance imaging (MRI), Tau and pTau from cerebrospinal fluid, and cognitive performance. We will further utilize the rich data resources of the BLSA to develop a parsimonius prediction model for risk of progression to MCI/AD, and validate its performance in the Atherosclerosis Risk in Communities (ARIC) study. A better understanding of the associations among sensorimotor changes, subclinical AD pathology, and cognitive performance may elucidate a high-risk phenotype that is associated with increased risk of poor cognitive outcomes over time and increase our understanding of the complex associations among declines in sensory, physical, and cognitive functioning with age. To this end, future intervention studies of AD prevention might screen for sensorimotor impairments as a high-risk phenotype reflective of increased risk for developing AD, which could serve as surrogate outcomes in clinical trials. Moreover, sensorimotor impairments may present feasible and modifiable targets for AD prevention by identifying critical threshold(s) for implementation of assistive and rehabilitative technologies such as hearing aids, corrective lenses, surgical or pharmacologic procedures to correct hearing and/or vision impairment (e.g., cataract surgery, cochlear implants), and physical therapy/timing and coordination of movement training to correct gait abnormalities.

Project summary Patients with Alzheimer?s disease (AD) are known to have greater balance and gait impairment and double the rate of falls relative to healthy older adults (60-70% vs ~30%). Currently, few effective interventions exist to manage and mitigate falls in AD, and unfortunately, falls continue to be one of the primary drivers of morbidity, institutionalization, and mortality among AD patients. Recent studies have shown that AD patients have a two-fold higher prevalence of vestibular impairment (~50%) relative to age-matched controls (~25% prevalence). Additionally, in pilot data from an ongoing observational study, we have shown that vestibular loss is associated with an increased rate of falls in AD patients. Vestibular therapy (VT) is a well-established treatment for vestibular loss, and consists of physical therapy-based exercises designed to foster compensation for reduced vestibular function. VT is effective in improving balance and reducing fall risk in cognitively-intact patients with vestibular impairment. However, whether VT could be effective in improving balance and reducing falls in AD patients with vestibular loss has never been explored. In this study, we propose a randomized controlled trial of VT in 100 patients with mild-moderate AD who have vestibular impairment. We will randomize patients 1:1 to a standard course of VT (1 session per week for 8 weeks) or to an active control matched for effort and duration. We will compare the efficacy of VT vs. active control primarily on 1-year incident fall rate. We will also investigate potential intermediate outcomes between VT and falls ? specifically balance outcomes (a predicted target of VT) and spatial cognitive outcomes (a novel target of VT) ? to understand potential mechanisms by which VT may influence fall rates. We hypothesize that VT will have preliminary efficacy in reducing 1-year incident fall rates relative to an active control intervention in a convenience sample of 100 patients with mild-moderate AD. We will also explore whether VT has preliminary efficacy in improving balance and cognition relative to the active control intervention. To accomplish the proposed study, we will recruit 100 patients from the Memory and Alzheimer?s Treatment Center, a well-established AD clinical research resource at Johns Hopkins. Falls are a disastrous outcome in patients with AD. If this pilot trial followed by a Phase III multi-center trial provide strong evidence for the benefit of VT in reducing falls, this low-risk intervention could be widely disseminated and implemented by an existing workforce and infrastructure, and produce substantial, sustained change in AD clinical practice.