Stephen M. Rao - US grants

Relatively little is known regarding the neuropsychological changes associated with multiple sclerosis (MS). It is the intent of the five year project to define the cognitive and affective disturbance observed in patients with this demyelinating disease. Two groups of patients, MS (N=156) and neurological controls (N=60), will be randomly selected from a large representative patient pool and matched on the basis of age, education, occupation, sex and race. All subjects will be administered a battery of cognitive and affective psychometric tests, and will undergo a neurological examination (including measures of disability), magnetic resonance (MR) imaging, an examination of activities of daily living (ADL), and an assessment of educational/vocational activities. Sixty MS patients and all control patients will be re-evaluated after a three year interval. The objective of this project are: (1) to determine the prevalence, type and severity of cognitive and affective disturbance in a large representative sample of patients with MS, (2) to examine the natural history of cognitive and affective disturbances in MS over a three year retest interval, (3) to identify the behavioral correlates of cerebral plaques and ventricular dilatation, as identified by MR imaging, (4) to assess the effects of cognitive and affective disturbance on ADL and educational/vocational activities, (5) to develop and validate a brief screening instrument to identify MS patients with cognitive disturbance, and (6) to study the relationship between cognitive and affective disturbance in MS.

The long range goal of Project III is to develop and apply the technology of functional magnetic resonance imaging (FMRI) to the study of human motor control and learning. FMRI will be used to elucidate the neural mechanisms that support movement in neurologically intact subjects. Four specific aims will be addressed in the proposed five-year project. The first aim will determine the parametric relationships between the force, velocity, and duration of repetitive, single joint movements of the upper and lower extremities and the magnitude of MR signal change observed in the primary and secondary cortical motor systems. The information derived from these studies will provide important information for designing and interpreting subsequent experiments. The second aim will examine the somatotopic organization of the primary motor cortex, lateral premotor cortex, supplementary motor area, cingulate sulcus, and cerebellum by examining the spatial extent of the signal change from repetitive, single joint movements of the upper and lower extremities. The three experiments proposed for the third aim are derived from human cognitive theory and will map the neural systems associated with specific aspects of cognitive- motor processing, including (1) motor programming and control operations supporting heterogeneous and repetitive sequential movements, (2) the utilization of hierarchical representations of sequential movements, and (3) timing operations associated with movement. The fourth aim will map the changes in brain activation patterns associated with the acquisition and the retention of motor skills by mapping the early and late functional changes associated with motor sequence learning. The fourth aim will also investigate two key aspects of skill acquisition, perceptual-motor and visual-pattern processing, to determine how the brain implements these processes throughout the course of learning. The experiments in this project seek to explore fundamental questions of human brain organization using a new technology that has the potential to become an extremely powerful neuroscience tool. The ultimate goals of this project are to construct a detailed map of functional specialization within the brain systems involved in motor control and to achieve a more comprehensive understanding of the neural systems that regulate the performance, learning, and retention of motor skills. Results of these studies may eventually lead to novel experimental procedures for understanding the abnormal brain organization patterns associated with human movement disorders.

DESCRIPTION (Adapted from applicant's abstract): Attention Deficit Disorder (ADHD) is a common neurodevelopmental disorder that defines a group of individuals with developmentally inappropriate levels of inattention and hyperactivity-impulsivity. Long-term follow-up studies indicate that ADHD persists into adulthood in 30-66 percent of cases. Neuropsychological studies have identified a wide range of cognitive deficits in ADHD, including impairments on measures of response inhibition, sustained attention/working memory, timing perception/reproduction, and conceptual reasoning, prompting the suggesting that ADHD is associated with abnormal functioning of the prefrontal cortex and its subcortical connections. As a result of significant technological advances in human brain imaging, it is now possible to identify functional brain abnormalities that may underlie the cognitive deficits in ADHD. The long-range goal of this project, therefore, is to apply whole-brain fMRI to better understand the brain- mediated neurocognitive deficits in ADHD adults and to elucidate the mechanisms of action of psychostimulants commonly used to treat this disorder. The first hypothesis to be tested is that, relative to healthy individuals, unmedicated ADHD subjects will evidence minimal or no task- induced regional brain activation in frontostriatal circuitry. The second hypothesis is that methylphenidate (M)P will produce increases in task- induced functional activity in frontostriatal circuity in both ADHD and normal subjects. Third, the investigator hypothesizes that MP will "normalize" task-induced functional specificity in ADHD individuals relative to normal subjects. Three specific aims will be addressed: 1) to determine the regional changes in functional brain activation in unmedicated ADHD adults in response to performing cognitive tasks involving response inhibition, working memory, timing perception/reproduction, and conceptual reasoning, 2) to determine the effects of MP on task-activated brain activation patterns in normal subjects using a double-blind, placebo-controlled, cross-over design, and 3) to determine the effects of MP on task-activated brain activation patterns in ADHD subjects using a double-blind, placebo-controlled, cross- over design. The proposed fMRI experiments, therefore, should not only enhance our understanding of the brain abnormalities associated with ADHD, but should also provide a general blueprint for evaluating the neurocognitive effects of drugs in normal and abnormal populations.

Along with normal subjects, four patient populations are being studied: MS, Alzheimer's disease, stroke, and despressed subjects. The aim of this investigation is to develop a neuroanatomic brain map of cognitive functions in healthy adults and apply this knowledge to the study of the four groups listed above.

DESCRIPTION (provided by applicant): The person-identity network (PIN), which underlies the recognition and identification of familiar people, is considered within the domain of the long-term semantic memory system. Knowledge of its neural underpinnings, derived primarily from studies of brain-lesioned patients, suggest that the PIN may have important and unique features in comparison to the general object semantic system. This five-year proposal consists of seven event-related functional MRI experiments designed to better understand the neurobiological substrates of the PIN, effects of healthy aging on the PIN, and the identification of PIN-related brain activation patterns that may identify the earliest stages of abnormality in individuals at-risk for developing Alzheimer's disease (AD). In Aim 1, two experiments in healthy young participants will: (1) identify common and unique neural systems associated with distinct modes of access (faces versus names) to the PIN, and (2) compare retrieval from the PIN with retrieval from other semantic categories (familiar landmarks). In Aim 2, we will examine the effect of healthy aging and low genetic risk for developing AD on retrieval from the PIN by: (1) contrasting activation patterns produced by younger and older participants for name and face recognition, and (2) comparing activation patterns for recent and remote famous people to examine the neural substrates of a possible temporal gradient in remote memory. In Aim 3, the neural representation of the PIN will be examined in older healthy participants with a genetic susceptibility toward developing AD by virtue of having a sibling with AD and possessing at least one apolipoprotein E e4 (APOE e4) allele. The neural significance of being at-risk for developing AD will be examined in two PIN experiments involving: (1) famous face/name recognition, and (2) temporal gradient. These PIN studies will determine whether the presence of the APOE e4 allele is associated with a unique activation pattern that may serve as an early marker for subsequent cognitive decline. In Aim 4, older participants will undergo a second neuroimaging study after three years to assess longitudinal changes in brain activation patterns associated with the PIN as a function of AD at-risk status. Results of this project are expected to provide novel insights into our understanding of the neural systems that mediate retrieval from the PIN, and the neurobiological substrates of memory pathology that may presage abnormal age-related memory functioning.

functional magnetic resonance imaging; cognition disorders; cognition; brain mapping; neural information processing; depression; multiple sclerosis; basal ganglia; Alzheimer's disease; stroke; neuroanatomy; bioimaging /biomedical imaging; human subject; clinical research;

fear; conditioning; neuroanatomy; memory; learning; functional magnetic resonance imaging; behavioral /social science research tag; human subject; clinical research;

memory; neural information processing; brain imaging /visualization /scanning; temporal lobe /cortex; dopamine; neuroanatomy; basal ganglia; acetylcholine; functional magnetic resonance imaging; clinical research; human subject;

DESCRIPTION (provided by applicant): Biomarkers for early detection of Alzheimer's disease (AD) and for monitoring treatment response are becoming critically important as novel pharmacotherapeutics emerge. Several candidate biochemical, anatomical, and functional biomarkers have shown promise for identifying disease risk or treatment response potential, but vary in their efficacy and invasiveness. Among these candidate biomarkers, task-activated functional magnetic resonance imaging (fMRI) is a promising approach that is noninvasive, carries little risk, and offers a high potential for identifying persons who may eventually develop AD. The purpose of this investigation is to examine the value of task-activated fMRI in the identification and prediction of disease course in populations at-risk for the development of mild cognitive impairment (MCI) or AD. In specific Aim 1, we propose to examine the 7.0 year longitudinal course of 108 asymptomatic individuals with varying risk for conversion to MCI/AD based on the presence/absence of one or two apolipoprotein-E (APOE) e4 alleles and/or a family history of dementia, and of 24 patients with amnestic MCI (aMCI), a condition strongly associated with conversion to AD. Primary measures include fMRI using a semantic memory activation task involving famous name recognition, neurobehavioral testing, and brain morphometry. We hypothesize that baseline levels of brain activation and longitudinal changes in activation will be the strongest predictor of cognitive decline. In Specific Aim 2, we propose to conduct a 24-week, randomized, double-blind, placebo-controlled, parallel group study of the Exelon(R) [rivastigmine] transdermal patch in 120 aMCI patients who have one or both APOE e4 alleles. Task-activated fMRI will serve as the primary biomarker of treatment efficacy along with neuropsychological testing and brain morphometry as secondary endpoints. We hypothesize that the treatment group will demonstrate a normalization (i.e. reduction) in the task-related neural activation pattern relative to the placebo group. In addition, we predict that change in task-activated fMRI magnitude will demonstrate greater sensitivity to cholinergic modulation than changes in neuropsychological testing and structural MRI. These studies offer the opportunity to determine the role of fMRI as a biomarker for predicting future decline in the latent and prodromal phase of AD as well as for monitoring therapeutic outcome in clinical trials.

DESCRIPTION (provided by applicant): This ARRA Challenge Grant application addresses Broad Challenge Area (05) - Comparative Effectiveness Research and Specific Challenge Topic 05-AG-105 - Comparative Intervention Trials for Diseases and Syndromes of Aging Including Neurodegenerative Diseases. Cognitive decline in older age is associated with loss of independence, functional decline in activities of daily living, nursing home placement, and mortality. Whether cognitive declines occur universally as part of the normal aging process or are the result of subclinical disease activity in a subgroup of elders at-risk for developing Alzheimer's disease (AD) is a matter of scientific debate. At present, older age, family history (FH) of AD, and the presence of the APOE e4 allele are the best, if imperfect, predictors of future cognitive decline in non-demented individuals. Our preliminary studies indicate that functional MRI (fMRI), using a semantic activation task, differentiates cognitively intact elders at-risk for AD from those not at-risk and can predict future cognitive decline in otherwise healthy older individuals. Published trials have demonstrated positive effects of short-term cognitive training (CT) and aerobic exercise training (ET) interventions on cognitive abilities in healthy elders. Despite these positive results, (1) there exist no published studies directly comparing the efficacy of CT to ET in improving cognitive function, (2) no study examining whether a combined treatment (CT+ET) would be superior to a single intervention (CT or ET alone), (3) neuropsychological testing, the primary outcome measure of intervention trials, does not provide information pertaining to the underlying neural changes that mediate cognitive improvement, and (4) interventions have been aimed at non-specific groups of elders rather than targeting elders at-risk for developing AD. To address these gaps in our knowledge, we propose a single specific aim, namely to conduct a 12-week, four-arm, randomized, controlled, clinical trial to compare the efficacy of CT, ET, and Combined Training (CT+ET) relative to an Active Control (AC), consisting of educational and flexibility training. The primary outcome measure is task-activated fMRI, with secondary outcomes assessed with cognitive, ADL, and fitness assessments. The target intervention population will consist of cognitively intact, but physically inactive, older adults at-risk for developing AD based on a positive FH and APOE e4 status. This project will be the first to (1) compare the relative efficacy of CT, ET, and a combined intervention;(2) use functional neuroimaging to assess intervention efficacy;and (3) intervene in older individuals at risk for developing AD. The long-range goal is to evaluate effective, low-risk, and relatively inexpensive interventions for addressing cognitive decline, with enormous implications for containing costs associated with health-care delivery to the ever increasing aging population of the United States. PUBLIC HEALTH RELEVANCE: Published trials have demonstrated positive effects of short-term cognitive training (CT) and aerobic exercise training (ET) interventions on cognitive abilities in healthy elders. Despite these positive results, we do not know the relative efficacy of CT and ET in improving cognitive function or whether a combined treatment (CT+ET) would be superior to a single intervention. We also do not understand the brain changes that mediate cognitive improvement or whether the treatments would work in healthy elders at-risk for developing Alzheimer's disease (AD). In this 12-week, randomized, clinical trial, we will compare the efficacy of CT, ET, and Combined Training (CT+ET) relative to an Active Control, consisting of educational and flexibility training. The primary outcome measure is task-activated fMRI, with secondary outcomes assessed with cognitive, activities of daily living, and fitness assessments. The target intervention population will consist of cognitively intact, but physically inactive, older adults at-risk for developing AD. The overall goal is to evaluate the efficacy of low-risk and relatively inexpensive interventions for addressing cognitive decline in older age.

DESCRIPTION (provided by applicant): Brain mechanisms underlying subtle cognitive changes in the premanifest stage of Huntington disease (prHD) are not understood due to a relative dearth of functional imaging studies. Preliminary evidence suggests that alterations in regional brain activation may be sensitive to very early changes in prHD. However, as cognition depends on communication among brain regions, functional connectivity of brain networks may be a more important intermediate phenotype of early pathology. The proposed longitudinal investigation of prHD will examine functional connectivity MRI (fcMRI) measured from a resting state. Resting state fcMRI correlates with cognitive abilities and has advantages as a biomarker for longitudinal studies, yet has received scant attention in prHD. The primary goal of this projec is to use fcMRI connectivity to identify the earliest changes in brain networks in prHD and to track them longitudinally. The proposed study will employ two different, but complimentary analytic approaches to study fcMRI, as some approaches may be more sensitive to disease-relevant changes. Connectivity strength in networks will be compared between a control group and prHD individuals who are stratified into three groups based on their genetic signature of disease progression. Participants will have been studied annually for three or four consecutive years. Aim 1 will identify sensitive fcMRI markers of prHD using a region-of-interest (ROI) method. The selection of seed ROI will be informed by task-activated fMRI on tests that probe for functioning in different frontostriatal networks. The main hypothesis is that connectivity strength of seeds will be progressively weakened as prHD individuals approach diagnosis. Aim 2 will identify sensitive fcMRI markers of prHD from complex network analysis, which characterizes organizational features and information- processing capabilities of whole-brain networks. The main hypothesis is that the organization, processing efficiency, and/or functional interactions between regions will progressively weaken as prHD individuals approach diagnosis. Aim 3 will determine if fcMRI markers identified at baseline are sensitive to longitudinal decline across a three to four year period. The main hypothesis is that longitudinal changes in connectivity markers will emerge prior to changes in brain morphometry and cognitive functioning. The present proposal will also examine if fcMRI partially depends on the structural integrity of brain tissue. Each aim will include a sub-aim wherein high angular diffusion weighted imaging and structural MRI will determine if a loss in fiber-tract connectivity and volume/thinning correlate with altered connectivity in specific networks at baseline. The relative sensitivity of fcMRI and structural markers of longitudinal change will be evaluated. We will also determine if fcMRI connectivity markers selectively correlate with cognitive abilities at baseline and longitudinal changes in cognition. Altogether, the proposed multipronged approach is expected to promote a new understanding of brain networks in prHD.

Abstract The APOE ?4 allele is the most important genetic risk factor for late onset Alzheimer's disease (AD). APOE ?4 may contribute to AD risk by altering inflammation, lipid homeostasis and/or amyloid clearance. Recent genetics studies have implicated multiple pathways in innate immunity in late-onset AD, including the triggering receptor expressed on the myeloid cells 2 (TREM2) gene. In contrast, exercise and physical activity (PA) produce anti-inflammatory changes in the periphery and neurogenic, angiogenic, and anti-inflammatory brain changes in animals. The mechanistic relationships between APOE, innate immunity, and AD, and the potential moderating influence of PA, remain to be established. Our published data on cognitively intact, healthy elders followed for 18 months indicate that sedentary ?4 carriers demonstrate significantly lower fMRI activation, poorer episodic memory performance, smaller hippocampal volumes, and abnormal white matter diffusion compared to ?4 carriers who engage in regular PA. Most importantly, these group differences were not observed between low and high PA non-carriers, suggesting that the neuroprotective effects of PA are especially potent for persons at genetic risk for AD. Additional preliminary studies demonstrate that TREM2+ innate immune cells play a direct role in regulating AD pathologies in both animal models of AD and potentially in human AD patients. For the proposed interdisciplinary project, our overall hypothesis posits that PA counteracts the negative inflammatory effects of the ?4 allele, affecting TREM2 and other innate immune pathways implicated in AD, thereby reducing the risk of cognitive decline and AD in ?4 carriers. This project has two specific aims. Aim 1 will recruit 150 cognitively intact, healthy elders (ages 65-80): 75 APOE ?4 carriers (?3/?4) and 75 ?4 non-carriers (?3/?3). Participants will undergo state-of-the-art measurements of PA and fitness; structural and functional 3T MRI; amyloid PET imaging; CSF/blood biomarkers related to AD, inflammation, and exercise; and comprehensive memory/cognition testing on two occasions separated by 24- months. Aim 2 is analogous to the human project and will determine the impact of voluntary wheel running PA across age (3 months, 6 months, and 9 months) in novel transgenic mouse models of AD humanized for ?3 and ?4 and crossed with APPPS1 (APPPS1; APOE3/3 and APPPS1; APOE4/4) and control strains. Key indices include: TREM2+ cells, expression of proinflammatory markers, brain A?42, and spatial memory performance. Together, these complementary human and animal studies will provide key insights into potential mechanisms linking APOE genotype, exercise, inflammation, AD brain pathology, and cognition that could ultimately be targeted therapeutically.

Abstract The APOE ?4 allele is the most important genetic risk factor for late onset Alzheimer's disease (AD). APOE ?4 may contribute to AD risk by altering inflammation, lipid homeostasis and/or amyloid clearance. Recent genetics studies have implicated multiple pathways in innate immunity in late-onset AD, including the triggering receptor expressed on the myeloid cells 2 (TREM2) gene. In contrast, exercise and physical activity (PA) produce anti-inflammatory changes in the periphery and neurogenic, angiogenic, and anti-inflammatory brain changes in animals. The mechanistic relationships between APOE, innate immunity, and AD, and the potential moderating influence of PA, remain to be established. Our published data on cognitively intact, healthy elders followed for 18 months indicate that sedentary ?4 carriers demonstrate significantly lower fMRI activation, poorer episodic memory performance, smaller hippocampal volumes, and abnormal white matter diffusion compared to ?4 carriers who engage in regular PA. Most importantly, these group differences were not observed between low and high PA non-carriers, suggesting that the neuroprotective effects of PA are especially potent for persons at genetic risk for AD. Additional preliminary studies demonstrate that TREM2+ innate immune cells play a direct role in regulating AD pathologies in both animal models of AD and potentially in human AD patients. For the proposed interdisciplinary project, our overall hypothesis posits that PA counteracts the negative inflammatory effects of the ?4 allele, affecting TREM2 and other innate immune pathways implicated in AD, thereby reducing the risk of cognitive decline and AD in ?4 carriers. This project has two specific aims. Aim 1 will recruit 150 cognitively intact, healthy elders (ages 65-80): 75 APOE ?4 carriers (?3/?4) and 75 ?4 non-carriers (?3/?3). Participants will undergo state-of-the-art measurements of PA and fitness; structural and functional 3T MRI; amyloid PET imaging; CSF/blood biomarkers related to AD, inflammation, and exercise; and comprehensive memory/cognition testing on two occasions separated by 24- months. Aim 2 is analogous to the human project and will determine the impact of voluntary wheel running PA across age (3 months, 6 months, and 9 months) in novel transgenic mouse models of AD humanized for ?3 and ?4 and crossed with APPPS1 (APPPS1; APOE3/3 and APPPS1; APOE4/4) and control strains. Key indices include: TREM2+ cells, expression of proinflammatory markers, brain A?42, and spatial memory performance. Together, these complementary human and animal studies will provide key insights into potential mechanisms linking APOE genotype, exercise, inflammation, AD brain pathology, and cognition that could ultimately be targeted therapeutically.

PROJECT SUMMARY/ABSTRACT The apolipoprotein E epsilon 4 (APOE ?4) allele is the most important genetic risk factor for late onset Alzheimer's disease (AD). A recent review by the World Health Organization highlighted the potential protective role of physical activity and exercise against cognitive decline, all-cause dementia, AD, and vascular dementia in healthy individuals. In an 18-month longitudinal observational study, we showed that sedentary ?4 carriers experience significant declines in episodic memory and hippocampal volume compared to ?4 carriers who engaged in moderate PA. Importantly, among ?4 non-carriers, no significant longitudinal changes in cognition and brain imaging were observed whether the non-carriers were sedentary or engaged in moderate PA, suggesting that PA has a specific neuroprotective role in delaying the progression of AD in ?4 carriers. Based on our results, a pragmatic, randomized controlled trial with blinded clinical and imaging outcomes is proposed to determine the impact of a home based, high intensity exercise intervention in healthy, cognitively intact ?4 carriers between the ages of 65 and 80 years. The CYCLE-AD (CYcling to Cease or Limit the Effects of Alzheimer's Disease) trial will recruit otherwise healthy sedentary carriers randomized to one of two groups (n=75 each): 1) an Indoor Cycling (IC) group that participates in high-intensity interval training (HIIT; 60-90% of heart rate reserve) in their home via the commercially available Peloton® cycling system or 2) a Usual and Customary Care (UCC) group, in which participants engage in their habitual level of PA. We hypothesize that an 18-month high-intensity aerobic exercise regimen will slow AD-related disease progression in sedentary elders at genetic risk for AD. Participants in the intervention group will engage in exercise 3x/week (minimum 90 minutes/week) for 18 months. Primary outcome measures, obtained at study entry and at 18 months, will include comprehensive cognitive testing and brain MR imaging to assess disease progression and a comprehensive PA/fitness assessment to measure the degree of change in physical fitness due to high intensity aerobic exercise. The overall goal of the CYCLE-AD trial is to determine the role of long-term, high intensity exercise in slowing or delaying the onset of cognitive and AD-related brain changes in ?4 carriers. Successful translation and demonstration of the effectiveness of a scalable home-based exercise intervention capable of slowing or delaying disease onset will transform AD treatment, improve patient outcomes and quality of life, and reduce health care costs.