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Alzheimer's Disease Administrative Supplements

We are providing the materials below to help grantees interested in NOT-AG-17-008: Alzheimer's Disease and its related Dementias (AD/ADRD) focused administrative supplements for NIH grants that are not focused on Alzheimer's disease (AD). The first section includes modified descriptions of how Alzheimer's and Alzheimer's-related dementias are identified for coding purposes at NIH.

The second section is a set of abstracts (also available in Reporter) that provide examples of existing grants that currently are recognized as focused on AD/ADRD for the purposes of coding. They illustrate something of the range of topics that are possible.

NIH Coding definitions for Alzheimer's disease and its related Dementias

Alzheimer's Disease: Includes Alzheimer's disease diagnosis, treatment, etiology, and prevention. Mild cognitive impairment research is perceived by experts as AD prevention research and should be included. Research using an AD population should be looked at closely and typically included.

Related Dementias: The National Plan to Address Alzheimer's Disease includes related dementias. It was decided at the category development session to include projects studying both Alzheimer's disease and other dementias. These include: Frontotemporal Dementia (FTD), Lewy Body Dementia, and Vascular Cognitive Impairment/Dementia. The dementias associated with Parkinson's disease and with Down syndrome are included too. Cognitive decline in aging is also relevant to the Alzheimer's Disease category.

Related Diseases: Other neurodegenerative diseases, such as Parkinson's Disease, are included when Alzheimer's disease is also being studied and when common pathways are described. Macular degeneration studies that describe a common pathway with Alzheimer's disease, such as amyloid beta, are included. Other neurologic diseases, such as Huntington's Disease, Major Depressive Disorder, Multiple Sclerosis, Parkinson's Disease, Batten Disease, Schizophrenia and AIDS Dementia, are not included unless also researching Alzheimer's.

Caregiving: Studies on family caregivers of Alzheimer's disease patients, as well as Alzheimer's care in nursing homes, are included. Research on caregiving should be included and treated broadly, even if Dementia-specific.

Basic Research: Basic research on neuropathology, cognitive decline, memory loss, amyloid, tau, Lewy Bodies, etc. is included, when a relationship to Alzheimer's disease is stated.

Abstracts of Current Active Grants

Project Number: 1RF1AG057264-01

Former Number: 1R01AG057264-01

Contact PI / Project Leader: LA SPADA, ALBERT R



Abstract: Proteostasis is essential for cell health and viability, and involves complex and highly conserved networks that regulate protein translation, protein folding, and protein degradation. A decline in proteostasis function is one of the features of aging tissues, particularly of the central nervous system (CNS). Indeed, the aging brain is particularly sensitive to proteotoxic stress, as demonstrated by the high number of age-associated neurodegenerative disorders characterized by protein misfolding and aggregation, including Alzheimer's disease (AD). The regulation of non-cell autonomous proteostasis has recently arisen as a novel mechanism for the modulation of systemic homeostasis in worms and flies, and is postulated to have important organismal effects on metabolism and aging. However, to date, there are no studies addressing the existence and activity of these pathways in mammals, and their potential effects on the aging brain. Transcription Factor E-B (TFEB) is a powerful master transcription factor regulator of proteostasis, integrating autophagy and bioenergetics. We recently derived transgenic mice that moderately over- express TFEB in skeletal muscle, and discovered that the resulting enhanced skeletal muscle proteostasis function can significantly ameliorate proteotoxicity in the CNS and also improve cognition and memory in aging mice. In this project, we will determine if enhanced skeletal muscle proteostasis is capable of promoting neuroprotection, uncover the mechanistic basis for this effect, develop powerful new models for testing mitophagy/autophagy activity in the aging CNS, and determine if soluble factors secreted by muscle ("myokines") mediate the beneficial CNS effects in conditional skeletal muscle- expressing TFEB transgenic mice. Identification of pathways regulating cross-talk between skeletal muscle and CNS may yield targets with high therapeutic potential for diseases of the aging CNS.

Public Health Relevance Statement: The importance of proteostasis to health and disease is well documented, yet how this process is regulated in a whole organism context remains poorly understood, especially in mammals. Individual organs in the body, particularly skeletal muscle, may play a pivotal role in regulating proteostasis in other tissues; hence, this project investigates the role of skeletal muscle-expressed Transcription factor E-B (TFEB), a master transcription factor regulator of autophagy and cellular clearance, in promoting CNS proteostasis during aging. These studies will address muscle-to-brain cell-non autonomous proteostasis signaling, determine if enhanced skeletal muscle proteostasis is capable of promoting neuroprotection, uncover the mechanistic basis for this effect, develop powerful new models for testing mitophagy/autophagy activity in the aging CNS, and establish if soluble factors secreted by muscle ("myokines") mediate beneficial CNS effects in conditional skeletal muscle-expressing TFEB transgenic mice, in the hope that such work may yield therapeutic opportunities for promoting CNS quality control pathways and function in age-related brain diseases.

Project Number: 1R01AG057353-01

Contact PI / Project Leader: RAMANATHAN, ARVIND



Abstract: Age-related neurodegenerative diseases like Alzheimer's Disease exhibit a breakdown in neuronal protein homeostasis (proteostasis). The relationship between age-related metabolic dysfunctions and protein aggregation in such diseases remains poorly understood. Elucidating the molecular basis for the age-related loss of proteostasis is expected to inspire new therapeutic approaches, not only for diseases like Alzheimer's, but more broadly for a wide range of age-related diseases. Increasingly, this promise of "Geroscience" is being recognized as critical for extending our healthspan. Among the most productive experimental approaches in Geroscience is the use of genetically accessible model systems for the study of longevity. These models have allowed the identification of single gene mutations and of interventions that extend lifespan, highlighting the plasticity of the aging process and suggesting avenues to significantly alter its course. The cellular events impacted by such interventions and causing the lifespan extension, however, remain largely unclear. In many cases, the effect on longevity is associated with changes in proteostasis and metabolism. To understand the relationship between proteostasis and longevity in detail, however, requires an integrated approach that investigates the effects of lifespan extending perturbations on global protein homeostasis and metabolic flux in a well-defined genetic system. Here, the applicants propose such integration by combining the expertise of groups using genetic approaches (Jasper), proteomic and bioinformatic approaches (Schilling and Ghaemmaghami), and metabolomic approaches (Ramanathan) to develop models for protein and metabolic homeostasis in long-lived mutants of Drosophila. Recent technological advances in the field of mass spectrometry have enabled global analyses of protein turnover rates and metabolic flux in complex organisms. Combining these technologies with detailed analysis of lifespan-extending genetic perturbations is expected to provide transformative new insights into molecular changes required for longevity. The aims proposed by the applicants are to (i) assess age-related changes in global protein turnover and metabolic flux, (ii) determine if changes in energy metabolism downstream of the Jun-N-terminal Kinase and Insulin signaling pathways influence protein turnover, and (iii) perform genetic studies to explore the causes of aging and longevity. It is anticipated that combining the strengths of the Drosophila system with state-of-the-art proteomic and metabolomic approaches will significantly accelerate the discovery of fundamental mechanisms influencing physiology and cell function with age, providing new therapeutic avenues for age-related diseases.

Public Health Relevance Statement: Changes in protein homeostasis and metabolism accompany many lifespan-extending genetic interventions. The applicants propose an integrated approach to comprehensively characterize protein turnover rates and metabolic flux in the brain of long-lived mutants of Drosophila melanogaster. It is anticipated that this integrated approach will significantly accelerate the discovery of fundamental mechanisms influencing physiology and cell function with age, providing new avenues of therapy for age-related diseases like Alzheimer's Disease.

Project Number: 1R01AG055527-01A1

Contact PI / Project Leader: MOSSAVAR-RAHMANI, YASMIN



Abstract: Multicultural Healthy Diet to Reduce Cognitive Decline & Alzheimer Disease Risk We propose a randomized clinical trial to investigate whether the Multicultural Healthy Diet (MHD), an anti-Inflammatory diet based on the Dietary Inflammatory Index tailored to a multi- cultural population, can improve cognitive functioning in a middle aged (40-65 yr old) urban population in Bronx, New York compared to a usual diet. We propose this study starting in a middle-aged population because early indicators of cognitive aging may manifest long before old age. Many previous studies have also used global mental function tests and relied on designs with relatively few and widely spaced repeated measurements, both of which can compromise the ability to detect cognitive change. To overcome these limitations, we propose to assess dietary effects on cognition using a "measurement-burst" design, which will consist of administering 35 brief assessments of a broad range of cognitive functions using smartphones during week-long measurement-bursts at nine-month intervals and repeated three times. This intensive measurement approach allows assessment of cognitive function in "real-time" which can provide a more reliable index of function that is more sensitive to change. The aims of this proposal are to: A1. Show that the MHD can be adapted to a diverse middle-aged cohort in the Bronx. Evaluate pre- and post-intervention serum biomarkers indicative of a MHD diet pattern, specifically total folate & vitamers, tocopherols, carotenoids, vitamin B12 and fatty acid profile; and self-reported intake of food groups such as fruits and green leafy vegetables, to compare study arms. A2. Test whether a MHD intervention in a multi-ethnic urban setting can benefit cognitive function in a middle-aged population. Assess cognitive functions (spatial working memory, short term memory, self-reported mental sharpness, processing speed), using real-time ambulatory assessments over a 7-day period every 9 months to evaluate the time course over which positive impacts are detectable. A3. Identify components of the MHD diet that are associated with stable or improved measures of cognition. We will evaluate biomarkers indicative of a MHD diet pattern (see A1) and relate to cognitive function measures.

Public Health Relevance Statement: This proposal is designed to test whether an anti-inflammatory diet can improve cognitive function in a diverse middle-aged population in the Bronx before the onset of cognitive decline related to aging using novel measurement approaches of diet and cognition that measure both in real-time. This study will be conducted in the Bronx where chronic diseases and cognitive function challenges fall disproportionately among minorities. If this project is successful, the anti- inflammatory diet can be disseminated as a low cost strategy to prevent or delay cognitive decline and reduce Alzheimer's disease risk, a huge savings compared to the estimated $236 billion to care for seniors with Alzheimer's disease in the US.

Project Number: 1R15AG052935-01A1

Contact PI / Project Leader: KOHMAN, RACHEL A.



Abstract: Normal aging is associated with the development of low-grade chronic neuroinflammation that contributes to cognitive decline and several age-related pathologies. Presently, there is a gap in the knowledge about what factors initiate and sustain neuroinflammation. Until these mechanisms are elucidated, the ability to develop effective therapies to treat and/or prevent age-associated disorders that have an inflammatory component will likely be unattainable. The long-term goal is to identify the physiological mechanisms and functional consequences of neuroinflammation in aged subjects. The objective of the current application is to identify the immune receptor(s) that triggers the development and maintenance of chronic inflammation in the aged brain. The central hypothesis is that activation of a Toll-like receptor (TLR), an immune pattern recognition receptor, initiates and sustains the neuroinflammatory state that develops with aging. The rationale for this work is that discovering the immune receptor that mediates the development of the chronic neuroinflammation will facilitate the identification of the activating ligand(s) and provide novel therapeutic targets to treat persistent neuroinflammation. Guided by preliminary data, this hypothesis will be tested through completion of the following specific aims: 1) Identify the immune receptor that promotes the development and maintenance of age-related neuroinflammation. 2) Determine the therapeutic potential of TLR-4 inhibition to alleviate age- related deficits in cognitive function and neural plasticity. The objective for Aim 1 is to directly test whether eliminating TLR-4 activation in a region- and cell-specific manner prevents the onset and maintenance of age- related neuroinflammation. To accomplish this objective, the approach is to employ global and conditional knockout (KO) models and selective TLR-4 inhibitory antibodies to test whether a complete, peripheral, or microglia-specific deficiency in TLR-4 reduces neuroinflammation. For Aim 2, the approach is to assess alterations in memory and neural plasticity in aged mice following pharmacological inhibition of TLR-4. Further, immunofluorescence will be used to assess hippocampal neurogenesis in global and microglia-specific KO mice. Completion of Aim 2 will determine the role of TLR activation in mediating age-related cognitive and neural plasticity deficits as well as the cell-specific function of TLR-4 on microglia in regulating neurogenesis. The proposal is innovative because it is the first to determine whether TLR activation mediates the development of neuroinflammation in the aged and employs a novel cell-specific conditional KO model that will determine the contribution of TLR-4 on microglial cells to the progression of neuroinflammation. The proposed research is significant because it is expected to facilitate development of novel preventative and therapeutic treatments as well as expedite the identification of the ligand(s) that activate the immune system in aged individuals. Ultimately, such knowledge is expected to accelerate the development of efficacious treatments for neuroinflammation that will likely improve general health and decrease the risk of neurodegeneration.

Public Health Relevance Statement: The proposed research is relevant to public health as uncovering the mechanisms that mediate the development of chronic inflammation in the aged brain is ultimately expected to lead to novel preventative treatments. Reducing neuroinflammation is expected to improve cognitive function and decrease the incidence of neuropathology. Thus, the research is relevant to the part of NIH's mission that emphasizes gaining knowledge to reduce the burden of illness through disease prevention and improving general health.

Project Number: 1R44AG057364-01

Contact PI / Project Leader: HAVEY, GARY D



Abstract: This fast track SBIR application submitted by Advanced Medical Electronics Corp. requests funds to develop a software system that helps people living with mild cognitive impairment, Alzheimer's disease, and other dementia to age in place and give them the choice whether and when to move. Staying at home is both preferred and less expensive, but there are a number of challenges to overcome. The proposed social interactive interface (SII), which uses augmented intelligence to both converse with the target demographic in natural language and analyze data from "Internet of Things" devices, will address these challenges by relieving problem behaviors and caregiver burden; increasing medication adherence; and reducing depression, social isolation, hospitalizations due to dehydration and urinary tract infections, thereby reducing the overall cost of care. The SII will learn behavioral trends and determine whether activities of daily living are completed. When unusual behavior is detected, it will alert the caregiver. If the SII determines a behavior problem may occur, then it will provide a just-in-time psychosocial intervention (e.g., reminisce therapy). Finally, the SII will keep schedules, provide reminders of upcoming events, and alerts when events are missed. AME will partner with SimpleC. In phase 1, we will prototype the social interactive interface and evaluate its feasibility. In phase 2, we will develop the social interactive interface, integrate it with the SimpleC platform, and evaluate its efficacy.

Public Health Relevance Statement: Alzheimer's Disease and related dementias is one of the costliest chronic diseases, and they cannot be prevented, cured, or slowed. Exploiting aspects of Cloud-based computing, SimpleC has developed an assistive technology tool based on the evidence from tested, personalized psychosocial approaches to deliver a non-drug intervention to improve everyday behavior, function, and QOL in persons living with mild cognitive impairment, Alzheimer's, and other dementia. To help these people age in place, AME is partnering with SimpleC to create a software solution that will address the needs of those aging in place.

Project Number: 1R01AG056287-01

Contact PI / Project Leader: BENDALL, SEAN CURTIS


Awardee Organization: STANFORD UNIVERSITY

Abstract: Alzheimer's disease (AD) is a leading cause of disability and death in the US and a major global public health problem. Time is running short if we wish to avert a global public health disaster with untold suffering, disruption of families, and severe challenges to health care systems and economies. Solutions will come only from innovative research. Genomic studies for late-onset AD (LOAD) have identified over 20 risk loci; however, translating the relevant molecules identified by genomics to AD-specific mechanistic pathways has been challenging. Our application, entitled "The Phenotypic Landscape of Cognitive Decline Revealed by Next- Generation Multiplexed Ion Beam Imaging," is highly responsive to this urgent scientific need by proposing a uniquely innovative molecular imaging platform called multiplexed ion beam imaging (MIBI) that will determine high dimensional protein interactions for AD-relevant molecules identified by genomics studies in normal and pathological states. Our proposal has three Specific Aims. In Aim 1, we propose to analyze four regions in healthy aged brains: two sectors of the hippocampal pyramidal layer and from two isocortical regions. Next- generation MIBI instrumentation will be used to image simultaneously 30+ proteins that mark subtypes of neurons, synapses, and non-neuronal cells, while covering regulatory signaling, neuro-inflammatory components, and AD risk gene protein products with subcellular resolution. In Aim 2, we propose to use the same multiplexed imaging methods in AD brain stratified by APOE genotype. We will analyze these data with statistical machine learning methods already established in our laboratory, similar to what we have done previously with different cancers and the immune system. In Aim 3, using infrastructure we have already have established, we will create a web-based portal where all of the images from this study can be accessed, multi- color overlays generated ad hoc, and all the features we derive shared freely. We propose a transformative, collaborative approach to AD that leverages a long-standing NIA-funded longitudinal cohort and is highly responsive to the National Alzheimer's Plan. These novel insights will illuminate pathways that hold potential for new therapeutic targets and will create a shared research resource and analysis platform for the community of scientists committed to developing solutions for AD.

Public Health Relevance Statement: AD is an age- and neurodegenerative related disease estimated to affect five million or more of the ageing American population by 2050. There is thus an urgent need to identify unique predictive signatures that correlate with developing AD. The overarching goal of this proposal is to generate a phenotypic landscape of cognitive decline, to understand modulation of cognitive decline during compensation and relate genetic predisposition to changes in phenotypic landscape defined by muti-parametric measurements using enabling technologies like multiplexed ion beam imaging (MIBI).

Project Number: 2R01EY002858-40

Contact PI / Project Leader: SHATZ, CARLA J


Awardee Organization: STANFORD UNIVERSITY

Abstract: What enables a baby's brain to learn so rapidly during early developmental critical periods? Is it possible to re- engage in adult the enhanced learning capacity present in the child's brain for repair or restoration of function? We have discovered that a neuronal receptor called PirB (Paired Immunoglobulin-like receptor B; human LilrB2/3) regulates synapse pruning and plasticity in cerebral cortex. Blocking PirB function in visual cortex rapidly leads to new dendritic spines and functional synapses even in adult. These observations have clinical relevance. A hallmark of Alzheimer's disease (AD) is loss of plasticity and excessive synapse pruning. But when PirB is knocked out in a mouse model of AD, mice are protected from memory loss. Moreover, new synapses generated by PirB blockade can be captured to facilitate recovery from severe vision loss in Amblyopia. A major goal of this research proposal is to save or regenerate synapses by understanding cell and molecular mechanisms of how PirB regulates synapse pruning. Three specific aims are proposed. 1) Assess effects of PirB deletion on dendritic spine density and stability in visual cortex. We have generated mice with a conditional allele of PirB (PirB flox/flox). We have also made a soluble PirB function- blocking recombinant protein: sPirB. These mice and reagents permit cell-type specific and temporal disruption of PirB and will be used in 2 photon imaging and physiological studies of synapse pruning and spine turnover in cortical pyramidal neurons. Results from these experiments should illuminate further how PirB regulates plasticity and synapse pruning in juvenile and adult visual cortex. 2) Investigate how PirB functions by using expression profiling to identify PirB signaling pathways. Preliminary experiments suggest that cofilin signaling contributes to PirB dependent regulation of dendritic spine density, and is hyperactivated in a mouse model of AD. Here an unbiased approach to identify PirB-driven alterations in mRNA expression is proposed. RiboTag mice will be used to isolate neuronal transcripts from PirB+/+ vs PirB-/- visual cortex. Using microarrays and RNAseq, the transcriptomes of the 2 genotypes will be analyzed and compared. This approach should facilitate identification of candidate signaling pathways regulated by PirB. 3) PirB and Alzheimer's disease- Engineer high affinity, specific blockers of the PirB-Abeta interaction. We have measured a direct interaction between PirB and soluble oligomers of beta amyloid (Abeta), the pathogenic 42 amino acid peptide in AD. The PirB-Abeta interaction represents a novel and potentially pivotal signaling axis. Protein engineering techniques including yeast display and affinity maturation will be used to create molecular entities able to block the Abeta-PirB (or Abeta-LilrB2 in human) interaction, potentially yielding new drug targets to treat AD. In sum, this proposal seeks to extend understanding of PirB function and dysfunction towards the ultimate goal of designing novel therapies that can regenerate lost synapses, thereby restoring function to neural circuits whose connections have been altered by abnormal experience or disease.

Public Health Relevance Statement: This research is centered on the theme of synapse pruning during normal developmental critical periods and when the pruning process is altered, as in Amblyopia, Alzheimer's disease or other neurodegenerative disorders. By studying visual system plasticity, we have discovered an unexpected and pivotal role for neuronal PirB in pruning and synaptic plasticity. This proposal seeks to extend our understanding of PirB function and dysfunction towards the ultimate goal of designing novel therapies that can regenerate lost synapses, thereby restoring function to neural circuits whose connections have been altered by abnormal experience or disease.

Project Number: 1R01NS100849-01A1

Contact PI / Project Leader: NARAYANAN, NANDAKUMAR


Awardee Organization: UNIVERSITY OF IOWA

Abstract: Up to 80% of patients with Parkinson's disease (PD) will suffer from cognitive symptoms, including impaired attention, planning, reasoning and working memory as well as hallucinations, visuospatial dysfunction, and delusions. These impairments lead to mild cognitive impairment (PD-MCI) and dementia (PDD) in PD. Cognitive symptoms of PD are associated with enormous cost to our society. There are no clear biomarkers and few effective treatments for PD-MCI/PDD. Because risk for PD increases dramatically with age, this problem will surge as our population grows older. The mechanisms contributing to PD-MCI/PDD are unknown. Our group has found that low-frequency (1-8 Hz; or delta/theta bands) brain rhythms might be helpful in diagnosing cognitive dysfunction in PD. This delta/theta activity originates from areas of medial frontal cortex such as the anterior cingulate, and is detectable by mid-frontal scalp EEG electrodes. We have found that mid-frontal delta/theta brain rhythms are engaged when healthy individuals detect novelty, errors, and conflict, or make decisions. These rhythms are attenuated in PD patients. Our working model is that PD patients manifest diverse neuronal and network deficits that impair mid-frontal delta/theta activity, leading to failures in engaging cognitive control. These abnormalities contribute to PD-MCI and PDD. In this proposal we combine `big-data' machine learning tools, intraoperative neurophysiology in humans, and new brain-stimulation paradigms to investigate the role of mid-frontal delta/theta rhythms in PD. We will test the overall hypothesis that mid-frontal delta/theta impairments are a mechanism of cognitive dysfunction in PD. In Aim 1 we will determine if mid-frontal delta/theta activity predicts PD-MCI/PDD. In Aim 2 we will use unique intraoperative recordings to determine how delta/theta activity within medial frontal cortex influences neurons in the subthalamic nucleus, a key site of functional convergence that is targeted by current deep-brain stimulation for PD. Notably, the subthalamic nucleus is a compact structure that receives highly overlapping input from cognitive and motor cortical regions, making it likely that our recordings will capture cognitive processing within this nucleus. Finally, in Aim 3 we will determine if subthalamic nucleus deep-brain stimulation at delta/theta frequencies improves cognitive control in PD patients. Because these experiments involve recordings across several PD patient populations (Aim 1), from single subthalamic neurons (Aim 2), and brain stimulation (Aim 3), each of these aims will provide independent mechanistic insight into cognitive dysfunction in PD. PD is a complex disease, but if cortical EEG abnormalities are a consistent theme it might inspire new diagnostic tools or new brain-stimulation therapies for cognitive dysfunction in PD. Results from this proposal could also be important for other neurodegenerative diseases such as dementia with Lewy bodies and Alzheimer's disease.

Public Health Relevance Statement: Cognitive symptoms of Parkinson's disease are an enormous public health problem. Here, we will analyze brain rhythms that are involved in cognitive processing and also dysfunctional in Parkinson's dis- ease. We will use these brain rhythms to guide novel brain stimulation that has the potential to treat dementia and cognitive impairments in Parkinson's disease.

Project Number: 1R01NS097876-01A1

Contact PI / Project Leader: MARSHALL, RANDOLPH S



Abstract: Cerebral hemodynamic impairment due to high-grade carotid artery stenosis can impair cognition even in the absence of stroke, contributing to cognitive decline either directly, or as a consequence of a higher occurrence of silent infarction. Although there is good preliminary evidence from case series and physiological studies that hemodynamic impairment affects cognition in patients with carotid occlusive disease, treatment of this condition has never been tested in a randomized clinical trial. We propose to conduct an ancillary study to the NINDS-sponsored CREST-2 trial, a pair of outcome-blinded, Phase 3 clinical trials for patients with asymptomatic high-grade carotid artery stenosis which will compare carotid endarterectomy plus optimal medical therapy (OMT) versus OMT alone (n=1,240), and carotid artery stenting plus OMT versus OMT alone (n=1,240) to prevent stroke and death. . Our application addresses the intriguing question of whether cognitive impairment can be reversed when it arises from abnormal cerebral hemodynamic perfusion in a hemodynamically impaired subset of the CREST-2 –randomized patients. We will enroll 500 patients from CREST-2, all of whom receive cognitive assessments at baseline and yearly thereafter. We will identify 100 patients with hemodynamic impairment as measured by an inter- hemispheral MRI perfusion "time to peak" (TTP) delay on the side of stenosis. Among those who are found to be hemodynamically impaired and have baseline cognitive impairment, the cognitive batteries at baseline and at 1 year will determine if those with flow failure who are assigned to revascularization arm in CREST-2 will have better cognitive outcomes than those in the medical- only arm compared with this treatment difference for those who have no flow failure. We hypothesize that hemodynamically significant "asymptomatic" carotid disease may represent one of the few examples of treatable causes of cognitive impairment. If cognitive decline can be reversed in these patients, then we will have established a new indication for carotid revascularization independent of the risk of recurrent stroke.

Public Health Relevance Statement: The demonstration that some patients with carotid artery stenosis are living with reversible cognitive impairment would have compelling public-health impact. The estimated prevalence of asymptomatic, severe, carotid artery stenosis is 2% of the general population over age 60, or 124,000 in the US alone in 2010. If even 10% of these patients had cognitive dysfunction, annual societal costs could be up to $2.5 billion. Demonstrating a treatment for this population could lead to a major shift in the treatment algorithms of carotid artery disease, affecting tens of thousands of individuals in the US each year.

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