Dr. Gideon Rothschild
Assistant Professor
Department of Psychology
University of Michigan

Project Narrative: Studies in recent years have found that sleep disturbances, which are highly prevalent in the adult population, are a risk factor for the development of cognitive decline and Alzheimer’s disease (AD). However, the brain mechanisms by which sleep disturbances could promote cognitive decline remain unresolved. In this proposal, we aim to directly address this knowledge gap in mouse animal models by recording and manipulating neural activity in the hippocampus-a critical brain region for memory- as mice experience chronic sleep disturbances that model the human condition. Our overarching goal is to elucidate the neural mechanisms linking sleep disturbances, aberrant hippocampal activity and development of AD, with the hope of promoting novel therapeutic and prevention approaches for AD, which are in dire need.

Norman Scheel
Dr. rer. nat. (Ph.D.), Dipl.-Inf.
Department of Radiology
College of Human Medicine
Michigan State University

Narrative description: Even though functional resting-state MRI was first introduced more than two decades ago, it is still difficult to derive the global complexity of brain function from these recordings. In our early-stage research, introducing dimensional complexity measures to resting-state fMRI, we found significant changes in the complexity of brain function due to healthy aging. In this development project, we aim to lay the groundwork to establish dimensional complexity as a marker for cognitive elasticity, as it might prove to be valuable in diagnostics and the prediction of cognitive decline in dementia and Alzheimer’s Disease.

Weichen Zhou, PhD
Research Investigator
Department of Computational Medicine and Bioinformatics
University of Michigan

Project Narrative: This project, entitled ‘Explore the functional impact of transposable elements in Alzheimer’s disease and related dementias’, is proposed by Weichen Zhou (Research Investigator) and Ryan E. Mills (Associate Professor) at the Department of Computational Medicine and Bioinformatics, University of Michigan Medical School. It seeks to explore the connection between the somatic transposable elements in the human genome and Alzheimer’s disease and related dementias. It will leverage large-scale datasets to extensively explore the genome-wide transposable elements and then stratify Alzheimer’s disease-relevant ones by using the rich clinical information from the cohorts. Further analysis pipelines and a predictive model will be built to investigate the functional impact of these transposable elements on Alzheimer’s disease and would improve the understanding of genetic causes of Alzheimer’s disease and related dementias.

Hala Darwish, PhD
Associate Professor
School of Nursing
University of Michigan

Andrew Bender, PhD (Michigan State University)

Goal: The maintenance of cognitive abilities in older age despite neural decrements appears to reflect one’s capacity for cognitive and neural plasticity. Such resilience to neuropathological processes appears moderated by educational attainment and life course enrichment, but there are no established markers of resilience. The proposed pilot study seeks to establish feasibility for studying new markers of resilience against early neurocognitive decline in mild cognitive impairment (MCI) by leveraging existing data and resources from the MADRC longitudinal clinical cohort. We propose evaluating the potential of novel markers from existing diffusion MRI neuroimaging and neuropsychological test data to classify early declines in MCI. Specifically, we will investigate novel measures of white matter crossing fiber complexity and cognitive plasticity (i.e., practice effects), as potential markers of neurocognitive resilience against declines in MCI. We will evaluate differences in baseline level and 1–2 year longitudinal change to test whether short-term changes in practice effects and crossing fiber populations are attenuated or absent in MCI. We will examine whether these markers are less biased by race and ethnicity than other neuropsychological measures of cognitive decline. The proposed pilot study will lead to development of a collaborative R01 proposal to investigate new markers of neurocognitive resilience.

DeAnnah Byrd, PhD (Wayne State University)

Goal: Cognitive decline is a substantial and growing public health concern. The older U.S. population is expected to increase dramatically by 2030, growing from 35 to 72 million, and becoming significantly more racially and ethnically diverse. Most concerning are reports suggesting that Blacks have a higher risk of cognitive disease than Whites. In particular, Blacks have more chronic conditions such as high blood pressure (HBP), diabetes, and stroke, which can affect the brain and cognition. Likewise, Blacks are further disproportionately exposed to stress. Although, social support and coping resources have been shown to positively impact health outcomes and buffer against stress; few studies have examined whether health status, stress, and coping factors account for differences in cognitive decline in Blacks. The goal of this project is to explore innovative approaches to address individual variation in risk and protective factors contributing to cognitive changes and decline in Blacks. This project uses secondary data taken from the Baltimore Study of Black Aging—Patterns of Cognitive Aging to examine whether health and psychosocial factors that differ by race (e.g., HBP and perceived stress as risks and social support and coping as protective factors) underlie racial inequalities in cognitive decline in older U.S. adults.

Goal: Hypertension is the most prevalent and pernicious vascular risk factor that exacerbates age-related neural cognitive declines. Adequate antihypertensive treatment does not rescue neurological health or cognitive function, which suggests that hypertension has secondary effects on antecedents of neural cognitive decline. Iron accumulation that drives oxidative stress and subsequent metabolic dysfunction is a plausible mechanism of hypertension effects on cognition, and brain iron via MRI is a promising biomarker of impending decline in aging, Alzheimer’s disease and related dementia (ADRD). Iron preferentially accumulates in age-sensitive brain regions—e.g., striatum, hippocampus—which may be exacerbated by hypertension to explain greater cognitive decline. Brain iron accumulation is a putative biomarker sensitive to early stages of neurodegeneration, yet its interaction with hypertension is unknown. This proposal uses the existing Michigan ADRC sample to evaluate the effect of hypertension and vascular risk on subcortical iron concentration, two-year cognitive decline, and ADRD diagnosis. A subset of the existing sample will be recruited to undergo a state-of-the-art high-resolution hippocampal subfield scan to evaluate the possible correlation between hippocampal iron concentration and entorhinal cortex and subiculum volumes as additional biomarkers of ADRD pathology. The study aims to evaluate pathways for hypertension effects on ADRD and its progression.

Peter Todd, PhD (University of Michigan)

Goal: Studies in diverse model organisms ranging from yeast to mice and across tissue types, including the brain, demonstrate decreases in global protein synthesis with chronological aging. Age-related changes in the abundance of specific components of the translational apparatus, namely initiation and elongation factors as well as specific ribosomal proteins, suggest that an element of this decline in protein synthesis may result from direct alterations in the translational machinery. Intriguingly, nucleolar size (the site of ribosomal biogenesis) also decreases with age. Interventions that enhance longevity, such as Rapamycin treatment, directly impact translation, suggesting that altered translational dynamics in aging are both important and potentially modifiable. The brain is particularly vulnerable to age-associated declines in cellular physiology since it is made up of a finite number of post-mitotic neurons that rely on localized protein synthesis for certain synaptic functions, suggesting that alterations in translation could contribute to problems in the aging brain.

Despite multiple lines of evidence demonstrating global decreases in translation, we know little about the molecular mechanisms underlying this conserved aging phenomenon. This proposal will use recent advances in transcript specific translational profiling and comparative proteomic approaches to define alterations in the global translational landscape with age and following an intervention (Rapamycin treatment) in UMHET3 mice. My central hypothesis is that age-related alterations in the translational machinery abundance directly impact translational dynamics, leading to age-associated decreases in both global and transcript-specific protein synthesis. This proposal will define the aging “translatome” and generate specific testable predictions as to the molecular mechanisms underlying global decreases in protein translation with age as well as the dynamic changes that occur after rapamycin treatment.

Omar Ahmed, PhD (University of Michigan) 

Goal: By understanding the relationship between retrosplenial ion channels, neuronal subtypes, brain rhythms and memory in both healthy and AD-model animals, the significance of this project spans both basic and translational neuroscience. Specifically, we will 1) elucidate the learning and memory correlates of a recently discovered, unique high frequency oscillation (HFO) localized to the retrosplenial cortex and understand how these retrosplenial HFOs are altered in both a rat and a mouse model of AD; 2) construct a detailed circuit connectivity map among major neuronal subtypes of the RSC and deduce the computations each of these subtypes is ideally suited to perform; 3) test the causal role of high Kv1.1 expression in RSC FS cells in impairing memory function. This work is likely to open up a novel line of research and potential therapies focused on the retrosplenial molecular/cellular underpinnings of AD, and is not directly focused on amyloid-β.

Norman Cheng, PhD (Wayne State University) and Scott Counts, PhD (Michigan State University) 

Goal: The goal of this pilot proposal is to establish proof of concept that magnetic properties of cerebral microbleeds and microinfarcts can be biomarkers for incipient dementia. Currently, these MRI micro-objects are known to be strongly associated with vascular cognitive impairment (VCI) and AD, but they also appear in healthy older people at a lower prevalence. From MRI, counting the number of microbleeds and/or microinfarcts is the only reliable method used clinically. However, the number of these putative lesions is subject to imaging parameters and it does not correlate well with the rate of cognitive decline in AD. As micro-objects with hemorrhagic components show magnetic susceptibility effects in MRI, here we propose to quantify the magnetic properties of these micro-objects from MR images of postmortem samples, validate the hemorrhagic components in those micro-objects from histological studies, and calculate the Cox hazard ratio between demented and control samples. We will request a total of 40 postmortem samples from MADC, all of which will be from subjects with vascular problems. Each of the demented and control groups will contain at least 10 samples. The samples among the two groups will be gender balanced and age matched, as well as be blinded to us.

Matthias Truttman, PhD (University of Michigan)

Goal: Alzheimer’s disease (AD) affects millions of patients worldwide. Despite concerted efforts, the precise cascade of molecular events underlying AD onset and progression remains elusive. Recently, we discovered that, along with histone proteins, the molecular chaperone Hsc70 is post-translationally modified by the attachment of an AMP nucleotide, a process called AMPylation. Intriguingly, the human AMPylase, Hype, accumulates in the nuclei of neocortex-derived neurons from AD patients (Fig. 1A), whereas Hype resides in the cytoplasm of control neurons. We hypothesize that nuclear accumulation of Hype alters the Hsc70 and histone AMPylation landscape, thereby affecting chromatin assembly and accessibility in AD. Our proposed research will address the impact of AMPylation on gene regulation in AD development.

Benjamin Combs, PhD (Michigan State University)

Goal: Inhibition of fast axonal transport (FAT) is closely linked to neurodegeneration of synapses and axons as well as pathological modifications of the tau protein observed early in Alzheimer’s diseases and related tauopathies. It is well established that several of these tau forms can disrupt FAT in multiple models of transport. We have previously identified a molecular mechanism by which tau can disrupt anterograde FAT but do not currently know the mechanism by which they can alter retrograde FAT (rFAT). Here, we propose to use the toxic P301L tau to test two of the major mechanistic pathways that tau could disrupt rFAT: alterations to kinase signaling pathways or direct interaction with the dynein motor complex and its regulatory subunits. We will express wild-type and P301L tau in primary rat hippocampal neurons and measure changes to kinases known to regulate rFAT, perform pulldown experiments to identify relevant protein-protein interactions, and characterize specific changes to rFAT that will inform our understanding of this toxic mechanism. Completion of this proposal will further our mechanistic understanding of non-amyloid toxic effects on rFAT and provide the basis for future grant proposals to further elucidate mechanistic details and explore potential therapeutic interventions.

Patrick Pruitt, PhD (Wayne State University)

Goal: Social isolation has been linked to late-life dementia incidence and, as a modifiable risk factor, represents a target for intervention studies to preserve or enhance cognitive function in older adults. The effects of social isolation on brain
function, through which it impacts cognition, have not been determined. Functional connectivity is an early indicator of neurodegeneration, marking it as a valuable measure for intervention trials, for which early identification of risk is
critical.

Here, we propose an investigation of the association between social isolation and functional connectivity of three core networks underlying cognition: default mode (DMN), frontoparietal (FPN), and salience (SN) networks. We hypothesize that social isolation will be associated with disrupted connectivity within the DMN and SN, as well as disrupted DMN/SN between-network connectivity. We further propose an exploratory analysis of associations between social isolation, network connectivity, and cognition.

We plan to test these hypotheses by analyzing resting-state fMRI scans, Lubben social engagement scores, and performance on neuropsychological testing, in 133 non-demented older adults across the pre-dementia cognitive continuum, for whom data has already been collected through the Michigan Alzheimer’s Disease Center.

Sheria Robinson-Lane, PhD (University of Michigan)

Goal: Family caregivers of Black older adults with Alzheimer's disease and/or related dementias (ADRD) have an elevated risk for developing dementia themselves. Stress-related risk factors likely contribute to this risk and may be reduced through targeted interventions that aim to improve overall cardiovascular health and self-management of chronic disease. Although evidence has demonstrated that culture plays an important role in caregiver outcomes, few interventions have been designed to meet the needs of underserved ethnic and racial populations, leaving a critical need for caregiver informed health interventions that promote effective self-management of chronic disease and the use of personally-relevant ways of coping to manage stress. In addition to reducing ADRD-related disability, culturally rooted and strength-based interventions can improve caregiver health, perceived ability to provide care for a person with ADRC (self-efficacy), and increases the likelihood that caregivers will experience benefits from caregiving. The overall objective of the proposed work is to test the feasibility of a descriptive study designed to identify a culturally responsive approach to caregiver support that will promote adaptive coping and optimize health for Black ADRD family caregivers. The proposed pilot work expands an active study by testing the utility of an electronically delivered questionnaire along with the addition of the Montreal Cognitive Assessment (MOCA) and a grip strength measure. It is anticipated that by integrating the additional cognitive assessment and grip strength measures described, and delivering the survey electronically, an exceptional study may be developed that will lead to a highly effective intervention. This work addresses a void in culturally responsive health interventions for Black ADRD family caregivers.

Laura Zahodne, PhD (University of Michigan)

Goal: To test the overarching hypothesis that racially-patterned social stress (discrimination) partially explains disparities in cognitive health through its effects on inflammation. In addition, this study will test whether associations among race, social stress, inflammation, and cognition differ according to socioeconomic status and quantify effects of examiner-examinee racial discordance on cognitive performance.

Dr. Laura Zahodne is a clinical neuropsychologist and an Assistant Professor of Psychology at the University of Michigan. Her research interests include psychosocial factors in aging and neurodegenerative disease, psychosocial factors and racial/ethnic diversity in cognitive aging, and statistical modeling of symptom trajectories in aging and neurodegenerative disease.

PI: Jessica Damoiseaux, PhD
Assistant Professor
Institute of Gerontology and the Department of Psychology
Wayne State University

Project Goal: To determine the difference in hippocampal functional and structural connectivity among older adults along the putative preclinical spectrum from healthy to subjective cognitive impairment (SCI) and mild cognitive impairment (MCI), and its association with objective cognitive performance.

PI: Irving Vega, PhD
Associate Professor
Translational Science & Molecular Medicine
Michigan State University

Magdalena Ivanova, PhD 
Research Assistant Professor of Neurology
Adjunct Assistant Professor of Biophysics
University of Michigan

Project Goal: To understand the role of EFhd2 as a putative modulator of tau oligomerization, in a collaborative effort between researchers at Michigan State University and University of Michigan.

PI: Jenna Wiens, PhD
Assistant Professor in Computer Science Engineering (CSE)
University of Michigan

Project Goal: The development of methods for leveraging University of Michigan Health System and VA Health Administration Electronic Health Record data for novel retrospective analyses of patient trajectories prior to and following a diagnosis with MCI and AD.

PI: Sami Barmada, MD, PhD
Associate Professor of Neurology
University of Michigan

Project Goal: To determine the importance of TDP43’s RNA binding domains to neurotoxicity, and to define the TDP43 targets that most closely associate with neurodegeneration in frontotemporal dementia models.

This project is funded by the Erb Family Foundation Grant.

Deborah A. Levine, MD, MPH
Assistant Professor of Internal Medicine
Assistant Professor of Neurology

Goal: to develop, test, and disseminate strategies to improve the care and clinical decision-making of older patients with MCI

Outcome: Data from this study was incorporated into an R01 grant application with Dr. Levine as PI which was funded. They are still in the data collection and analysis phase. There are no publications at this time.

Peter K Todd, MD, PhD
Harris Career Development Professor of Neurology

Goal: To identify novel hexanucleotide repeat expansions as a first step in establishing their roles in the biology of dementia

Outcome: They did not identify any novel repeat expansions as a cause of ALS or other disorders.

Publications: He F, Jones JM, Figueroa-Romero C, Zhang D, Feldman EL, Goutman SA, Meisler MH, Callaghan BC, Todd PK. Screening for novel hexanucleotide repeat expansions at ALS- and FTD-associated loci. Neurology Genetics. Volume 2, Issue 3, May 11th 2016, Page 71.

Vikas Kotagal, MD, MS
Assistant Professor of Neurology

Goal: To test the primary hypothesis that scalp cooling facilitates the glymphatic system and enhances clearance of soluble A-beta.

Outcome: Project is currently ongoing. Dr. Kotagal acquired a mentored VA grant this year.

Benjamin Hampstead, PhD
Associate Professor of Psychiatry, Neuropsychology Section

Goal: To examine whether tDCS can reduce the severity of SMCs and improve memory test performance in older adults with such complaints.

Outcome: Project is ongoing.