Bradford C. Dickerson, MD - US grants

DESCRIPTION (provided by applicant): This is an application for a K23-Mentored Patient-Oriented Research Career Development Award entitled "Structural-functional MRI studies of memory in MCI & AD." The primary goal of the proposed research is to use an integrated set of structural and functional MRI measures to define the anatomic and physiologic abnormalities underlying memory dysfunction in normal aging, mild cognitive impairment (MCI), and very mild Alzheimer's disease (AD). Quantitative volumetric MRI methods are capable of detecting neuroanatomic abnormalities in aging, MCI and AD some of which are useful as predictors of cognitive decline. Functional MRI (fMRI) tools have begun revealing specific regional brain activity associated with learning and memory. Despite the fact that memory deficits are a hallmark initial symptom of AD, very few fMRi studies have attempted to explore specific abnormalities associated with memory loss in aging, MCI, or AD, and relationships between neurodegenerative structural changes and brain activation patterns are only beginning to be investigated. Therefore, the primary goals of the proposed research are to 1) study regional brain activation patterns associated with encoding of word lists in young and elderly controls, and in patients with MC! and very mild AD, using an event-related "subsequent-memory" fMRI paradigm, and 2) study the relationships between these activation patterns and regional brain atrophy, measured using quantitative volumetric MRI techniques. The overarching hypotheses of this research are that elderly, MCI, and AD subject groups will show different abnormal fMRI activation patterns during word list learning, and that these abnormalities will not merely reflect atrophy but will indicate attempted compensatory responses, some of which will predict subsequent recall and some of which will not. As part of the proposed research, the candidate seeks training in: 1) fMRI techniques and methods for integrating structural and fMRI data; 2) the cognitive neuroscience of learning and memory and psychometrics of age-related cognitive decline; and 3) ethical clinical research methods. The proposed research plan, didactic courses, and tutorial instruction from mentors and advisors will foster the candidate's development into an independent clinician-scientist using neuroimaging and cognitive methods to study the anatomy and physiology of memory deficits in aging, MCI, and AD.

functional magnetic resonance imaging; learning stimulant; neural plasticity; cholinesterase inhibitors; visual perception; learning; drug screening /evaluation; psychophysics; bioimaging /biomedical imaging; behavioral /social science research tag; human subject; clinical research;

DESCRIPTION (provided by applicant): Our previous work has demonstrated that quantitative in vivo magnetic resonance imaging (MRI) techniques can identify structural and functional alterations within the medial temporal lobe (MIL) in individuals with mild cognitive impairment (MCI), who manifest clinical symptoms of AD prior to dementia. Compared to cognitively intact persons of similar age, persons with MCI demonstrate abnormalities in both MIL function and structure. For example, changes in hippocampal activation may precede (and possibly initially serve a compensatory role for) hippocampal atrophy (which correlates with AD neuropathology). Yet the specificity of these changes to particular MIL subregions is not yet clear, primarily due to limitations in the resolution of imaging techniques. Histological investigations suggest that aging is associated with changes in the dentate gyrus and subiculum, while AD affects the entorhinal cortex and cornu ammonis (CA) hippocampal fields. Recent advances in MRI methods have begun to produce in vivo data of unprecedented resolution (e.g., 500 micrometer resolution-at least twice the resolution of typical research scans), enabling the development of novel methods for the in vivo visualization and quantification of MRI data from MIL subregions. We propose to use these novel high-resolution in vivo MRI methods to investigate the specificity of memory- related functional and structural substrates within MIL subregions in cognitively intact older individuals and in those with MCI, including very mildly symptomatic individuals who do not yet have significant memory impairment ("preMCI"). The primary goal of this research is to determine whether MTL-subregion-specific functional changes can be found in PreMCI before structural changes are detected. Since histologic studies indicate that distinct cellular and pathologic changes within MIL subregions are present in AD and not in normal aging, high-resolution imaging data may enable more precise differentiation of individuals with mild age-related memory changes vs. those with the earliest clinical signs of AD. In addition, high-resolution MIL imaging could begin to bridge the gap between in vivo and histologic data. Ultimately, we hope that these tools will enable earlier identification of minimally symptomatic individuals with AD-related brain changes who could be enrolled in clinical trials of drugs to slow the progression of this devastating disease.

DESCRIPTION (provided by applicant): The integrity of the medial temporal lobe (MTL), which is composed of multiple interacting subregions, is critical for human memory function. Healthy aging appears to involve relatively minor alterations in some subregions of the MTL memory system, while Alzheimer's disease (AD) even at an early clinical stage arises from considerable abnormalities in multiple MTL subregions. Post-mortem studies imply that AD neuropathology accumulates sequentially, beginning in layer II cellular "islands" of the entorhinal cortex (ERC), disrupting the perforant pathway from ERC to hippocampus proper (HP), and ultimately affecting HP directly. Yet imaging techniques have not been available to study the fine structure of the MTL in living humans, so hypotheses related to this proposed sequential progression which has been inferred from cross-sectional analyses of post-mortem tissue have yet to be tested. We have recently made substantial progress developing ultra high-resolution MRI (uhrMRI) methods using a 3 Tesla system with a custom-built 32-channel head coil. We are now able to acquire in vivo structural MRI data of remarkable resolution (e.g., 0.30- 0.50mm, more than 3 times the resolution of typical research scans). Using these methods, we are beginning to visualize fine structural elements of MTL subregions, including the perforant pathway and layer II ERC cell islands. To our knowledge, these anatomical features have never been convincingly seen in living humans. We hypothesize that these uhrMRI methods can be used to visualize and quantify fine anatomical structural elements of MTL subregions, such as perforant pathway fibers and ERC layer II cell islands. The overall goal of this application is to further optimize uhrMRI methods to improve the visualization and quantification of MTL subregions, to validate these methods using ultra high-field (7 Tesla) ex vivo MRI of post-mortem tissue samples, and to begin to apply the in vivo methods to study changes in fine MTL structure with aging. Project Narrative: The identification and measurement of specific elements of the fine structure of the human medial temporal lobe would potentially be of great value for understanding normal human neuroanatomy as it relates to memory and aging, and how it is disrupted in the earliest stages of AD. The ultra high resolution MRI methods being developed to study the anatomy of this brain region in unprecedented detail will likely be applicable to other brain regions, which may be affected by other neurologic and psychiatric disorders. Thus, this work may have broad relevance to clinical neuroscience and the neurobiology of disease.

DESCRIPTION (provided by applicant): Primary progressive aphasia (PPA) is a devastating neurodegenerative syndrome that involves relentless development of aphasia with relative sparing of other cognitive functions, at least early in its course. There are several subtypes that appear to arise as a result of different underlying pathologies. PPA and its subtypes can be difficult to differentiate from other neurodegenerative disorders and from each other, particularly early in their course. Furthermore, there is very little data that would enable the prediction of progression in PPA. Improving our capacity to predict progression would be not only extremely useful for treatment development, but also very valuable for improving our understanding of the basic systems biology of this syndrome. The Principal Investigator of this proposal is a behavioral neurologist who directs the PPA Program at MGH, a multidisciplinary clinical-research program that currently sees approximately one new and two follow-up PPA patients per week. The co-investigator is a systems neuroanatomist who has worked for many years to develop and apply quantitative neuroimaging methods to characterize and measure the topography of large-scale language and other brain networks, and to apply this knowledge to neurologic and psychiatric disorders. We have recently collected preliminary data suggesting that PPA affects specific nodes of cortical language networks, and it progresses in a systematic fashion according to the topography of the network. We propose here to use advanced imaging techniques to refine knowledge of the functional and structural connectivity of the brain's language networks, and to use this knowledge to test the hypothesis that PPA progresses in a predictable fashion within these networks. In addition to adding to our fundamental knowledge of language networks of the brain, this work has the potential to lay a framework for the development of tools for prognostication and monitoring of PPA, which we hope will be useful for the testing of new therapeutic interventions in this devastating neurologic disorder. PUBLIC HEALTH RELEVANCE: Primary progressive aphasia (PPA), a devastating neurodegenerative syndrome that involves relentless development of language impairment. For reasons that are not yet clear, it targets language networks of the brain in a remarkably specific way. This project aims to better define the functional and structural connectivity of large-scale language systems of the brain in order to determine whether this knowledge can be used to predict the progression of the disorder.

DESCRIPTION (provided by applicant): Although social cognition dysfunction is a hallmark initial symptom of frontotemporal dementia (FTD) and schizophrenia, it has received relatively little systematic study in these disorders and the relationship between neurodegenerative and neuropsychiatric structural changes and brain activation patterns is only beginning to be explored. The primary goal of the proposed research is to use an integrated set of structural and functional MRI measures to define the anatomic and physiologic abnormalities underlying social cognition dysfunction in patients with frontotemporal dementia and schizophrenia with the further goal of improving the management and rehabilitation of these patients. In FTD and schizophrenia, quantitative volumetric MRI methods are capable of detecting differential neuroanatomic abnormality patters in relation to areas of cognitive dysfunction. Likewise, functional connectivity MRI (fcMRI) tools have revealed activity of specific regional brain networks associated with social cognition tasks. Therefore, our specific aims are (1) to develop an objective battery to assess social cognition in FTD and schizophrenia, (2) to investigate regional brain atrophy patterns associated with social cognitive impairment in patients with FTD and schizophrenia, and (3) to determine whether subtle social cognitive dysfunction is associated with functional abnormalities in brain networks associated with social cognition using resting-state functional MRI data and compare these findings to those related to regional atrophy patterns in FTD and schizophrenic patients. Across the neurodegenerative and neuropsychiatric diseases studied here, we hypothesize that social cognitive impairments will relate more to functional and structural abnormalities in networks subserving social cognition and less to diagnostic classification; that is, some patients with FTD or schizophrenia will have prominent social cognitive impairment and underlying brain abnormalities in networks subserving social cognition while some patients will have other types of symptoms with relative preservation of social cognition, supporting the recently conceived concept of common domains of cognitive-affective dysfunction across neuropsychiatric disorders.

DESCRIPTION (provided by applicant): Successful aging appears to relate in part to a variety of behaviors that require processing of motivated, goal- directed, and personally relevant (i.e., salient) information. For the most part, current research on salience has focused on the cognitive factors that allow attention to relevant information in the external environment. In our research, we focus on age-related changes in affective salience and their implications for social functioning. In our original grant, we examined age-related changes in the processing of novel and affectively potent stimuli, with a focus on the human amygdala [(R01 AG030311), Neural Mechanisms of Social Decision Making in Aging, August 1, 2006 - July 31, 2011)]. We found that amygdala responses to novelty, valence, and arousal are less robust and the functional connectivity between the amygdala and other affective brain structures is reduced in older individuals than in younger people. These findings indicate that information in the world is less affectively salient to older individuals. This is despite the fact that there appear to be few anatomical changes in the network that we have identified underlying affective salience (other than normal age-related reductions in amygdala volume). In the competing renewal, we will expand on these findings anatomically, functionally, and behaviorally. Using high resolution scanning, we will examine with more sophistication and precision, and in a larger sample, the extent to which both the structural integrity and intrinsic connectivity of brain regions within th affective salience network are maintained (or change) with age (Aim 1). In the context of spared anatomy and intrinsic connectivity within the affective salience network, task- related affective assemblies within this network are less robust with age, and we will examine the extent to which age-related reductions in sensory information from the body (in the form of reduced interceptive sensitivity) are responsible for task-related reductions in affective salience (Aim 2). Perhaps objects and events in the world are less salient because the bodily perturbations they produce are not detected and represented as efficiently in the aging brain. Furthermore, we will examine the extent to which these reductions in affective salience and interception underlie or contribute to normal age-related changes in memory for novel, neutral material (Aim 3) and in social engagement (Aim 4). Finally, using a longitudinal design, we will confirm that any age-related stability or decrements in affective salience can be disentangled from the substantial individual differences that exist, and also examine the extent to which strong affective reactivity is a protective factor, resulting in better memory for novel material and/or maintained social engagement as people age (Aim 5).

DESCRIPTION (provided by applicant): Research increasingly shows the links between frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS), both devastating neurodegenerative diseases. FTD, ALS, and their overlap subtypes can be difficult to differentiate from other neurodegenerative disorders and from each other, particularly early in their course. Furthermore, there is very little data that would enable the monitoring of progression. Improving our capacity to diagnose and monitor progression would be not only extremely useful for treatment development, but also very valuable for improving our understanding of the basic systems biology of these disorders. This project aims to better define the functional and structural measures of frontal and motor systems of the brain in order to determine whether this knowledge can be used to diagnose and monitor the progression of these disorders. The principal investigator of this proposal is a behavioral neurologist who directs the FTD Unit at MGH, a multidisciplinary clinical-research program with a cohort of more than 100 patients. A growing number of patients are being identified with elements of both FTD and ALS. The Co-PI is a systems neuroanatomist who has worked for many years to develop and apply quantitative neuroimaging methods to characterize and measure the topography of large-scale brain networks, and to apply this knowledge to neurologic and psychiatric disorders. We have collected preliminary data indicating that FTD and ALS affect specific nodes of partially overlapping brain networks. We propose here to use advanced imaging techniques to refine knowledge of the functional and structural connectivity of these networks in patients on the FTD-ALS spectrum. In addition to adding to our fundamental knowledge of brain networks, this work has the potential to lay a framework for the development of tools for diagnosis and monitoring of FTD-ALS, which we hope will be useful for the testing of new therapeutic interventions in these devastating neurologic disorders.

DESCRIPTION (provided by applicant): Frontotemporal dementia (FTD) is a spectrum of devastating neurodegenerative diseases characterized by progressive impairment in emotional and social behavior, language and executive function. There are no effective treatments at present, although clinical trials are being planned. Some forms of FTD are inherited in an autosomal dominant manner as a result of a mutation in one of several genes that have been identified. In this exploratory proposal, we aim to perform a preliminary investigation of individuals who carry one of these genetic mutations but who are not yet showing symptoms or who are showing questionable or very mild symptoms to try to determine whether MRI measures of brain structure or function or other kinds of biological markers might provide information about changes in the brain that precede symptoms. The ultimate goal of this research is to identify biological markers of the degenerative process of FTD that can be used to measure whether potential future treatments can ameliorate the process prior to the development of symptoms.

DESCRIPTION (provided by applicant): Frontotemporal dementia (FTD) is a spectrum of devastating neurodegenerative diseases characterized by progressive impairment in emotional and social behavior, language and executive function. There are no effective treatments at present, although clinical trials are being planned. Some forms of FTD are inherited in an autosomal dominant manner as a result of a mutation in one of several genes that have been identified. Despite this genetic information, we currently understand very little about the pathways altered in human neurons leading to neurodegeneration. To address this gap in our knowledge, the overall goal of the proposed study is to apply state-of-the-art methods for deriving human induced pluripotent cells (iPSCs) from FTD patients to model aspects of the underlying disease mechanisms and to investigate the step-by-step progression and development of pathophysiology in living human neurons cultured in the laboratory. In this exploratory proposal, we aim to perform a preliminary investigation of individuals who carry one of these genetic mutations. We will obtain skin biopsies and transform the fibroblasts into induced pluripotent cells and then into neurons in culture in order to study abnormalities in cellular metabolic pathways that are specific to each individual's genetic mutation and context. The ultimate goal of this research is to generate neuronal cellular models of FTD to provide a platform for the development of high-content, cell-based assays to be used in chemical and genetic screens for modifiers of tau toxicity, and potential therapeutics that can reverse or prevent disease phenotypes.

? DESCRIPTION (provided by applicant): Normal aging is accompanied by slow declines in neural structural integrity and cognitive function. Recently there has been great interest in developing programs to help promote cognitive functioning in older adults with the goal of slowing the rate of normal decline and/or delaying the onset of dementia. A growing body of literature suggests that regular practice of meditation may provide a novel method to both promote cognitive functioning and slow normal age-related decline of neural structure and function. However, most of this existing data is cross-sectional or lacks assessments of long-term outcome following an initial meditation training period. Further, many of the studies demonstrating cognitive benefits have been restricted to behavioral assessment and have not included neuroimaging, so little is known about the neural mechanisms underlying the observed cognitive differences. The overarching goal of this project is to evaluate the utility of an 8-week meditation-based program to promote successful cognitive aging. We will assess changes in neural structure and cognitive function in a cohort of cognitively normal older adults (65-80 years old) randomized to mindfulness training or a control condition. We will assess the stability of these changes at four time-points following program completion (6, 12, 18 and 24 months).

Project Summary/Abstract Alzheimer disease (AD) is a devastating neurodegenerative diseases with a variety of distinct clinical phenotypes, including typical amnesic dementia as well as atypical language, visual and behavioral/dysexecutive presentations. Our ability to be confident in a diagnosis of atypical AD has been greatly improved by technology to image brain beta-amyloid (A?) in living patients using PET scans. We have known for years that the other major protein involved in AD- paired helical filament (PHF) tau- appears more closely correlated with brain atrophy and neurodegeneration, the lesions most closely associated with symptoms and clinical phenotype. In the past this has only been possible to measure in post-mortem brain tissue after death. In this proposal, we aim to perform an investigation of a new PET imaging ligand that binds to brain PHF tau in order to try to measure this protein in living individuals with typical AD and PCA-AD. We will scan individuals who have one of two major clinical phenotypes (typical amnestic AD, and posterior cortical atrophy and a known biomarker of AD pathobiology (CSF tau/ A? or amyloid PET imaging). We will compare 18F-T807 tau and 11C-PiB amyloid PET images within and between the clinical phenotypes, and examine them in relation to regional brain atrophy. We will focus particular attention to the posterior cingulate/precuneus as a region of potential overlap between typical AD and PCA-AD to determine whether topographical differences in the underlying molecular pathologies and/or neurodegeneration in this region correlate with differences in clinical phenotype. The ultimate goal of this research is to begin to determine whether 18F-T807 PET will be a useful tool for the design of clinical trials aiming to treat both typical and atypical clinical forms of AD.

Abstract Primary progressive aphasia (PPA) is a devastating neurodegenerative syndrome that involves relentless development of aphasia with relative sparing of other cognitive functions, at least early in its course. There are multiple subtypes as well as multiple underlying pathologies. PPA and its subtypes can be difficult to differentiate from other neurodegenerative disorders and from each other, particularly early in their course. There are currently few clinical tools to assist in the early specific diagnosis of PPA and its subtypes. We have recently made substantial preliminary progress toward the development of novel imaging techniques that could be extremely valuable in early specific diagnosis of the molecular basis of specific pathologies underlying PPA. We propose to use tau and amyloid imaging tracers to attempt to discriminate these underlying molecular pathologies, and FDG-PET, functional connectivity MRI, and morphometric structural MRI to measure and longitudinally monitor markers of neurodegeneration in the language network(s) and other brain regions. In addition to more accurate diagnosis, these measures will likely be important for prognostication and monitoring of decline and the effects of putative therapies. The overall goal of this proposal is to translate these methods from new scientific technologies into clinically useful tools that can be used by clinicians around the country and internationally to improve the diagnostic specificity and assessment capabilities for PPA and its subtypes.

In the United States, nearly 100,000 patients receive general anesthesia and sedation daily to safely undergo surgical and non-surgical procedures. A high proportion of the patients receiving anesthesia care are elderly, and in addition may have pre-existing conditions such as Alzheimer's disease or cerebrovascular disease. As such, elderly patients have a higher risk of post-operative delirium and cognitive dysfunction. Anesthesiologists know that management of older patients requires different approaches compared with that of younger patients. For example, the dose required to achieve the same anesthetic state in elderly patients can be 50% lower than that for younger patients. Unfortunately, at present we know little about the fundamental neurophysiology of how anesthetic drugs influence the aging brain. This represents a major knowledge gap that prevents us from developing novel approaches to more safely administer anesthesia and sedation in elderly patients. In recent years, aided largely by non-invasive imaging methods, significant progress has been made in understanding systems-level neurophysiology of anesthetic effects in humans. In parallel, imaging biomarkers have advanced to enable the identification of two of the most common ?silent? pathologies that may put older adults at higher risk for poor post-anesthesia/surgical outcomes: Alzheimer's disease (AD) and cerebrovascular disease (CVD). We propose here to bring these two lines of research together with a study employing imaging markers of preclinical AD (amyloid PET, cortical atrophy) and CVD (FLAIR MRI, DTI) alongside sophisticated computational analysis of intra-operative EEG, with the goal of using these measures to better understand variability in response to anesthesia and post-operative outcomes. As we accomplish the aims of this grant, the data generated should lead to fundamental new insights into the neurophysiology of anesthesia in aging patients. These insights will advance knowledge about how to assess patients for risks of anesthesia and reduce those risks through improved brain monitoring, improved drug dosing, and a precision- medicine approach to tailoring anesthesia to the individual's brain.

Our goal is to assess how affect regulation strategies are protective of cognitive and affective functioning in those who are at risk of suffering age-related disorders of mood and cognition. According to RFA MH-17-405, studies of maturational shifts in affect regulation often yield inconsistent findings and the neurobiological systems that support affect regulation remain largely untested. In this application, we propose to closely investigate the dynamics and mechanisms of two maturational trajectories that impact affect regulation: increasing age and beta-amyloid plaques within the brain. To date, most efforts have focused on age-related changes in valence regulation (e.g., the age-related positivity effect). Arousal is acknowledged as important, but very little is known about how older adults actively regulate their arousal states, or the proximal and longer- term consequences of such regulation attempts for risk of suffering age-related changes in mood and cognition. Recent findings from our team suggest that those who optimize for momentary comfort cultivate arousal-avoidance affect regulation trajectories, whereas those who optimize for mastery in memory and attention cultivate grit trajectories (the ability to tolerate momentary unpleasantness in the service of some goal that requires effort, which is often transiently experienced as an unpleasant aroused state). Our work also suggests that affect regulation is associated with both the structure and connectivity within two of the brain's core networks: the salience and default mode networks. In older adults, beta-amyloid (A?) plaques within these two networks are a key pathology?one of the two major molecular hallmarks of Alzheimer's disease (AD)? associated with elevated risk of cognitive decline, symptoms of depression, and dementia. With these observations in mind, our team will combine (a) innovative theory and methods from the study of normal maturational changes in situation-focused affect regulation, (b) structural, functional, and molecular brain imaging, and (c) innovative computational modeling of spatial and temporal dynamics in one large five year study designed to examine how arousal-regulation is associated with changing age and A? status. We will characterize situation-focused arousal regulation strategies and cognitive effort at various levels of difficulty using behavioral, experiential, and neurobiological levels of analysis, both in the behavioral lab and during brain scanning. Data analysis will involve constructing dynamic temporal trajectories across performance in each task to characterize arousal-avoidance and grit (i.e., tolerance of high arousal in the service of effort). We will characterize and compare arousal-avoiding and grit regulation trajectories in individuals who vary in age (from 40 to 90 years old), A? status, cognitive impairment, and mood symptomatology (distinguishing two types of symptoms: distress (negativity) and apathy (lack of effort or engagement). The findings from the proposed research will be used to develop a longer-term project to determine how the temporal dynamics of affect regulation predict developmental/maturational trajectories for mood disorders and cognitive impairment.

PROJECT SUMMARY The objective of this research is to develop low-cost, non-invasive, electrophysiological biomarkers of brain amyloid and neurodegeneration in patients with Preclinical and Prodromal Alzheimer's disease (AD) using the sleep and resting state electroencephalogram (EEG). Diagnostic criteria recently developed for ?Preclinical? and ?Prodromal? AD hinge upon measurements of beta-amyloid (A?) and changes in brain structure and func- tion. Unfortunately, these ?gold standard? biomarkers are too expensive (~$3k/patient), invasive, or specialized for large-scale screening efforts. Thus, there is urgent need for novel cost-effective biomarkers that are rigor- ously linked to established criteria for Preclinical AD. There is a growing appreciation that brain oscillations ob- served in the sleep and resting state EEG are closely associated with underlying AD pathophysiology. It is well known that AD dementia is associated with disrupted sleep dynamics and altered sleep oscillations. Clearance of cerebral A? through the brain's glial lymphatic or ?glymphatic? system occurs specifically during non-rapid eye movement (NREM) sleep, and is dependent on EEG slow oscillation activity. The cortical generators of sleep and resting state EEG oscillations, which can be estimated using source localization, overlap with brain regions that display cortical thinning and loss of functional connectivity in AD. These relationships have not been extensively studied in preclinical nor prodromal AD. We therefore propose to 1) characterize the rela- tionship between quantitative measures of sleep and resting state EEG and neuroimaging AD bi- omarkers, 2) use these novel relationships alongside known AD-related changes in the EEG to develop EEG-based predictors of AD, and 3) develop a framework for translating these findings into low-cost (as little as $20), highly-scalable tools for screening and tracking of preclinical and prodromal AD.

Project Summary/Abstract The pathophysiology of Alzheimer's disease (AD) links amyloid plaques, neurofibrillary tangles, and neurodegeneration to neural network dysfunction, which ultimately manifests as symptoms of cognitive impairment. Patients with typical or atypical AD have dysfunction of brain networks that support cognitive functions that are impaired. Emerging evidence suggests that, in patients with the same degree of regional atrophy of these systems, hypometabolism or disrupted fcMRI connectivity may vary, offering the opportunity to intervene to improve network function and potentially symptoms, at least for a period of time. Preliminary evidence from studies with repetitive transcranial magnetic stimulation (rTMS) in humans demonstrate that these brain networks can be modulated in a manner that promotes improved behavioral task performance. However, most of this work has been done in cognitively normal young individuals, with many questions remaining regarding the potential application of rTMS to patients with prodromal AD. In this pilot project, we aim to investigate the selectivity of rTMS modulation of these two networks in patients with aMCI and lvPPA due to underlying AD based on amyloid and tau PET imaging collected as part of a separate project. We will examine the selectivity of rTMS modulation using simultaneous functional MRI and FDG-PET, and will investigate the effects on memory and language task performance The ultimate goal of this research is to begin to determine how TMS changes brain network function in patients with diseased brains and whether this could potentially support benefits in cognitive function in typical and atypical clinical forms of AD.

ABSTRACT Delirium, an acute state of inattention and confusion often precipitated by hospitalization and surgery, is a condition for which patients with neurodegenerative diseases such as dementia due to Alzheimer's disease (AD) are especially vulnerable. Evidence is mounting that people who do not have dementia at the time they experience delirium are at increased risk for long-term cognitive decline (LTCD) and future dementia; whether underlying AD pathology consistent with preclinical AD accounts for this heightened risk of delirium and adverse outcomes is not known. In the prior cycle of this Project, a number of findings from diffusion tensor imaging and fluid biomarkers associated with inflammation were identified as predisposing to delirium. However, it is not clear whether those biomarkers might have been associated with preclinical AD pathology, vulnerable aging, or other known pathologies. Using modern magnetic resonance imaging (MRI) techniques, we have identified an ?AD-Signature? of cortical atrophy and hippocampal hyperactivation as biomarkers of prodromal or preclinical AD. In addition, measures of changes in the brain that are associated with age-related cognitive decline in the absence of neurodegenerative or cerebrovascular disease can be detected as a ?Vulnerable Aging-Signature? of cortical atrophy and reduced frontoparietal functional connectivity. Therefore, the overarching goal of this proposal is to examine whether neuroimaging biomarkers of preclinical AD or vulnerable aging are predictive of delirium, delirium severity, and complicated delirium (i.e., delirium with LTCD), and to link these neuroimaging biomarkers to molecular biomarkers of pathology measured in the cerebrospinal fluid (CSF) and plasma. The Specific Aims are: 1) to determine in people with evidence of preclinical AD (i.e. patients with abnormal CSF AD biomarker levels of tau and beta-amyloid) whether AD- related brain atrophy or network dysfunction are associated with delirium, delirium severity, or LTCD; 2) to determine in people without evidence of preclinical AD (i.e. patients with normal CSF AD biomarkers) whether vulnerable aging-related brain atrophy or network dysfunction are associated with delirium, delirium severity, or LTCD; and 3) to investigate whether longitudinal cortical atrophy (measured pre-operatively and one year after surgery) due to preclinical AD or vulnerable aging is associated with postoperative LTCD or complicated delirium. To test these hypotheses, we will leverage the resources of P01AG031720 which generated the original SAGES I cohort (N=560 total, n=126 with longitudinal MRI), augmented by new CSF and MRI data collected in 128 SAGES I probability sampled patients (64 with delirium, 64 without) about four years after their surgery, and a new SAGES II cohort (N=400), of which 180 patients will have both CSF and MRI collected pre- operatively. The long-term objective of this Project is to improve the pathophysiological understanding of brain vulnerability to delirium in order to inform prevention strategies and, ultimately, pathophysiological-based treatments.

Young-onset (age < 65) dementias, especially the Frontotemporal Dementia and young-onset Alzheimer's disease, are a group of AD related dementias (ADRD) that are often rapidly progressive. These dementias also have a high morbidity and mortality rate (average survival is 7 years) and exceptionally high caregiving demands. Caregivers of patients with these diseases have unique needs since these dementias have a shorter period of time from diagnosis to before patients lose decision-making capacity, and they occur in patients who are typically younger and have usually not had end-of-life conversations with their caregivers. Caregivers of these patients often suffer a great deal of distress attempting to develop a comprehensive care plan for the advanced stages of dementia. Medical decision-making needs for patients and caregivers with young-onset dementia are complex, since many people living with these illnesses have not yet engaged in discussions about end-of-life care, many patients may not have expressed their preferences before they lose decision-making capacity, and caregivers are often unfamiliar with the stages of dementia and the different medical decisions required in each stage. Furthermore, discussions between clinicians and caregivers about medical care is often inadequate; traditional discussions rely on ad hoc verbal descriptions of hypothetical health states (advanced dementia) and treatments (CPR, intubation, feeding tubes). This approach is limited because these scenarios are hard for caregivers to envision, information is inconsistent, and verbal explanations are hindered by literacy barriers. To address these shortcomings, we have developed video decision aids for this population. We have shown the efficacy of these decision aids in healthy adults making hypothetical decisions, but not in caregivers of people with young-onset dementia. The overall objectives of this proposal is to collect additional data on caregiver views regarding informational needs, to refine these tools for the needs of caregivers of patients in the different stages of dementia (mild, moderate, severe), to create a user-manual to train community-based clinicians on the skills required to carry out this facet of care, and to conduct a randomized controlled trial of the decision aid (vs. enhanced usual care) in 150 caregivers. This study meets the specific requests of RFA-AG-18-030 by: 1. refining an existing intervention and pilot-testing the tool; 2. elucidating the underlying principle of the intervention; and, 3. creating a user-friendly, easily delivered intervention to train clinical care providers in the community. This proposal is designed to improve decision making for caregivers of patients with ADRD and lays the groundwork for a pragmatic trial of a caregiving intervention by supporting an early-Stage (Stage 1) behavioral intervention.

Massachusetts Alzheimer's Disease Research Center: Imaging Core The Imaging Core of the Massachusetts Alzheimer's Disease Research Center (MADRC) supports and performs imaging research to understand a variety of types of heterogeneity in Alzheimer's disease and Alzheimer's disease related disorders (AD/ADRD) and accelerate progress towards a cure. We carry out core functions in Aims 1, 2, and 3 marshaling resources to enhance the research mission through the support and contributions to imaging components of MADRC-affiliated local and national research projects and the development of uniform imaging protocols that contribute to novel efforts to understand heterogeneity, such as the classification of MADRC Research Cohort participants into the ATVN (amyloid, tau, vascular, neurodegeneration) biological research framework. In Aims 4, 5, and 6, we develop and implement new strategies and accelerate progress towards a cure in our refinement and validation of novel PET and structural and functional MRI methods. These innovative imaging methods are evaluated in the MADRC Research Cohort, leveraging this deeply phenotyped cohort of participants spanning diverse AD/ADRD diagnoses to make the process of innovation cost-effective (many participants have already been imaged and so these measures can be used to facilitate strategic recruitment; e.g., of amyloid ?positive? subjects) and value-added (by comparing novel imaging measures with those we understand well already). In Aims 7 and 8 we build the future by providing expertise, education, training and data and software tools to faculty, trainees and students for best practices in imaging research and by providing education to researchers, clinicians and the public on the advances, utility and responsible interpretation of imaging data in AD and ADRD research and ultimately clinical practice.

Project Abstract / Summary Cognitive assessment is a key element of the diagnostic evaluation of patients suspected of having early symptomatic stages of neurodegenerative brain diseases, including Alzheimer?s disease (AD), Frontotemporal Lobar Degeneration (FTLD), and Lewy Body Disease (LBD). As biomarkers mature, the field is separating clinical syndromes arising from these diseases from the neuropathologic changes themselves, leading to concerns about classification systems for the illnesses these diseases produce. Many tests typically employed in cognitive assessment are verbal, often implemented by an examiner asking the patient a question and the patient answering. These tests are typically scored by hand, with the examiner counting correct or incorrect answers and a simple score being generated against normative scores. Many of the tests still in use were developed 30+ years ago. An exciting array of recent advances in artificial intelligence methods has begun to enable the measurement and classification of language and other cognitive characteristics captured in audio recordings. Here we introduce a new approach to accomplishing both of these possibilities. Recent developments in Natural Language Processing (NLP) and Machine Learning (ML) have now made possible the automated discovery and classification of features measurable in speech samples. Once established, these feature sets can be connected to distributions of cortical atrophy, thus enabling links between specific cognitive abnormalities and underlying neural networks. This approach to the analysis of clinical dementia syndromes can be achieved through a sufficiently large number of cognitive test measures recorded as speech samples. In addition, such analyses require the use of the latest generation of artificial intelligence models, called transformer-networks, to be able to learn the unique ways in which individuals with cognitive impairment or dementia respond to questions requiring memory, executive function, emotion, or language. In Aim 1, we will investigate the validity of an unsupervised artificial intelligence model for measuring cognitive abnormalities in patients with AD, FTLD, or DLB against traditional clinical measures and against MRI measures of regional brain atrophy. In Aim 2, we will investigate the performance of an unsupervised artificial intelligence model for classifying cognitive abnormalities in AD, FTLD, and DLB patients into clusters. In Aim 3, we will evaluate the reliability of these automated measures of cognitive abnormalities in AD, FTLD, and DLB. Through a finer-grained analysis of cognition in people with AD, FTLD, or DLB, it should be possible to develop better understanding of the overlapping and dissociable features of these dementias, aiming for improved diagnostic classification and better monitoring.

Project Summary/Abstract. Advanced biomarker mapping has led to the current understanding that Alzheimer?s disease (AD) is an extremely complex neurodegenerative disorder, with substantial heterogeneity in temporal and spatial characteristics of the classical amyloid and tau pathologies and resultant neurodegeneration among patients (as described by the amyloid-tau-neurodegeneration, ?A-T-N? biological framework that is the new standard for characterizing the neuropathology of AD). This complexity is a major barrier to clinical care and to the development of effective therapies, highlighting the importance of integrated biomarker neuromapping for understanding AD. However, substantial challenges remain in the neuropathologic characterization of patients. Current procedures for mapping the neurodegenerative component (N) of AD are limited in sensitivity to early pathology. Additionally, the specific biomarkers of the amyloid- and tau-based primary AD neuropathologies are only available through relatively invasive and/or expensive positron emission tomography (PET) and lumbar puncture (LP) cerebrospinal fluid (CSF) procedures in specialized laboratories and clinics. We aim here to advance AD neuropathology mapping on multiple levels: 1) we will implement a novel multi-scale structural mapping (MSSM) MRI procedure for sensitive quantification of the neurodegeneration component of AD; 2) we will use the MSSM procedure to differentially predict amyloid and/or tau positivity in symptomatic and asymptomatic individuals, providing a highly accessible method for pathology detection when advanced biomarkers are not available; 3) we will create individualized ?A-T-N? brainmaps through the integration of the MSSM metrics with existing PET amyloid and tau data; and 4) we will use MSSM features for the regional prediction of amyloid and tau pathology for use when PET data are not available. Our Specific Aims are: Aim 1. To test the accuracy of a novel MSSM procedure for probabilistic classification of symptomatic and asymptomatic individuals as being amyloid ?positive? or tau ?positive.? Hypothesis 1a (H1a). We hypothesize that MSSM ?N? metric can be used with a high level of sensitivity to predict whether an individual is A+ measured via PET using standard thresholds and/or T+ measured via PET using standard thresholds, or both. H1b. MSSM will provide better separation of individuals as N+ vs. N- than conventional MRI-based atrophy measures, validated through concordance with molecular pathology and clinical progression. Aim 2. To utilize the novel MSSM features for synthesis of PET-like maps of AD neuropathologic change. H2a. MSSM features will provide accurate spatial prediction of specific regional neuropathologic changes. Prediction accuracy will be measured against independent in vivo datasets including a subset with autopsy confirmation and regional quantification of plaques, tangles, and neuronal loss. Successful MSSM implementation would greatly advance the ability to screen for early and complex AD neuropathology. Successful MSSM implementation would greatly advance the ability to screen for AD neuropathology.