Howard J. Aizenstein, M.D., Ph.D. - US grants

This proposal is for a K23 Mentored Patient-Oriented Research Career Development Award. The applicant is a geriatric psychiatrist at the University of Pittsburgh who proposes to develop the skills necessary to bridge intervention research in geriatric psychiatry with cognitive neuroscience. Career development activities will focus on functional MRI methods and data analysis, with an emphasis on the challenges of conducting and interpreting functional imaging studies in the psychiatrically ill elderly. These skills will be applied to intervention research in late-life depression (LLD), which will be conducted under the auspices of the Mental Health Intervention Research Center for Late-Life Mood Disorders (MHIRC/LLMD). The applicant will develop expertise and a program of research to investigate the functional neuroanatomy of late-life depression using functional MRI and computational modeling. Initial efforts will focus on identifying in individuals with LLD functional interactions among brain areas associated with depression i.e., the anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), caudate nucleus, and hippocampus. This methodology will permit the testing of hypotheses about the functioning of specific brain regions in LLD versus healthy elderly populations, and further understanding of cognitive changes known to be associated with LLD. During the second phase of the career development plan, the fMRI results obtained in the first phase will be used to refine a computational model of how changes to these specific brain regions (such as through Alzheimer's disease and cerebrovascular disease) interact with LLD. The model will be used to generate hypotheses about how pre-treatment fMRI scans predict the course of LLD treatment response. The hypotheses will be tested using longitudinal follow-up data (i.e., post-treatment), obtained in association with an ongoing MHIRC/LLMD protocol. Repeat fMRI will also be performed post-treatment to investigate the neural basis of treatment response. This award will support the applicant in obtaining the training necessary to undertake this direction of research and to develop as an independent scientist.

[unreadable] DESCRIPTION (provided by applicant): Depression in the elderly is complicated by both cerebrovascular disease and neurodegeneration, both of which are believed to contribute to the limited efficacy of antidepressant treatment in the elderly. However, the neurobiologic basis of the depressive syndrome and treatment response in late-life depression have not been established. The primary aim of this R01 application is to characterize the functional neuroanatomy of geriatric major depression, which we believe is characterized by altered functional connectivity, and use this to explain treatment response variability. The proposed study will identify in elderly individuals the changes in regional brain activity associated with being depressed, being treated for depression, and responding to depression treatment. To this end we will investigate, with fMRI, eighty elderly depressed subjects and 40 elderly controls. Subjects will undergo fMRI scanning on two occasions 12 weeks apart. For the depressed subjects, the scanning will occur just before and 12 weeks after initiating treatment with escitalopram. The depressed subjects will be restricted to individuals aged 65 and older, whose first episode of depression started at age 60 or older. We limit our sample to these 'late-onset' elderly depression subjects because, by definition, these individuals did not have mid-life depression, and thus should be most likely to show late-life specific biological factors. Our fMRI tasks target three of the key cognitive and affective neural pathways associated with LLD: a) cognitive control, b) declarative memory, and c) affective reactivity. These are central to theories of LLD and are associated with specific brain regions that have been linked to the neurobiology of LLD: the lateral prefrontal cortex (LPFC), the dorsal anterior cingulate cortex (dACC); the medial temporal lobe (MTL), and the amygdala. In the specific tasks, subjects will inhibit a prepotent response (cognitive control), recognize previously seen words (declarative memory), and respond to faces expressing emotion (affective reactivity). Functional connectivity, as well regional activity, will be estimated using the BOLD fMRI signal. The results of this study will characterize the functional neuroanatomy of late- life depression, which will be used to explain why some patients do not respond well to anti-depressant treatment. These treatment response subgroups can then serve as targets for future prevention and treatment studies. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Depression in the elderly is complicated by both cerebrovascular disease and neurodegeneration, both of which are believed to contribute to the limited efficacy of antidepressant treatment in the elderly. However, the neurobiologic basis of the depressive syndrome and treatment response in late-life depression have not been established. The primary aim of this R01 application is to characterize the functional neuroanatomy of geriatric major depression, which we believe is characterized by altered functional connectivity, and use this to explain treatment response variability. The proposed study will identify in elderly individuals the changes in regional brain activity associated with being depressed, being treated for depression, and responding to depression treatment. To this end we will investigate, with fMRI, eighty elderly depressed subjects and 40 elderly controls. Subjects will undergo fMRI scanning on two occasions 12 weeks apart. For the depressed subjects, the scanning will occur just before and 12 weeks after initiating treatment with escitalopram. The depressed subjects will be restricted to individuals aged 65 and older, whose first episode of depression started at age 60 or older. We limit our sample to these 'late-onset'elderly depression subjects because, by definition, these individuals did not have mid-life depression, and thus should be most likely to show late-life specific biological factors. Our fMRI tasks target three of the key cognitive and affective neural pathways associated with LLD: a) cognitive control, b) declarative memory, and c) affective reactivity. These are central to theories of LLD and are associated with specific brain regions that have been linked to the neurobiology of LLD: the lateral prefrontal cortex (LPFC), the dorsal anterior cingulate cortex (dACC);the medial temporal lobe (MTL), and the amygdala. In the specific tasks, subjects will inhibit a prepotent response (cognitive control), recognize previously seen words (declarative memory), and respond to faces expressing emotion (affective reactivity). Functional connectivity, as well regional activity, will be estimated using the BOLD fMRI signal. The results of this study will characterize the functional neuroanatomy of late- life depression, which will be used to explain why some patients do not respond well to anti-depressant treatment. These treatment response subgroups can then serve as targets for future prevention and treatment studies.

DESCRIPTION (provided by applicant): Conventional treatment of late-life depression (LLD) often requires long trials of several antidepressants before an effective regimen can be found for an individual. This can take many months and is associated with persistent depressive symptoms, an increased risk of suicide, patients dropping out of care, and worsening of medical co-morbidities. This long response time in LLD is one of the most challenging clinical features of LLD. Thus, in the elderly it is particularly important to shorten this window, and to identify as early as possible what medication regimen will be the most effective for an individual. With the recent development of Pharmacologic Functional MRI (phMRI), it has become possible to track cerebral blood flow patterns (as proxies of regional brain activity) in response to a medication. The primary aims of the proposed LLD phMRI study are 1). To characterize the trajectories of the phMRI brain responses over the course of initiation and titration of an antidepressant, and 2). To use these trajectories to identify the earliest time-point when functional brain changes predict treatment response. As an exploratory aim, the phMRI trajectories will be related to other prominent markers of treatment response in LLD, cognition and structural brain changes. The proposed study is a continuation of R01MH076079, now in its 5th year, which has successfully achieved its aims of characterizing the functional neuroanatomy of LLD, using a model of altered connectivity. The hypotheses for this continuation follow from an observation in the current study that the 12-week change in functional MRI (fMRI) activity was more predictive of treatment response, than was baseline fMRI activity. The proposed study follows-up on this observation by measuring fMRI activity at 5 different time-points over the course of treatment to identify the earliest point at which brain activity in LLD can be used to predict treatment response. The fMRI paradigm includes affective reactivity and affective regulation tasks designed to highlight the ventral limbic affective processing circuits (including the rostral cingulate, anterior insula, and amygdala), which are implicated in LLD treatment. Novel image analysis methods, including resting-state calibration of task-related fMRI, will be used to optimize scan-rescan reliability. One hundred LLD subjects will participate. The proposed study leverages the resources of a recently funded large NIH clinical treatment trial of Venlafaxine XR to treat geriatric depression (IRLGREY, PI: Reynolds, R01MH083648). The imaging component of this study is integrated with the ongoing IRLGREY study, and thus initial subject recruitment, characterization, and treatment will be covered by IRLGREY. This study is designed to impact both ends of the translational research path, from characterizing the pharmacologic effects in the brain to the potential clinical use of MRI for personalized treatment of LLD. As far as we are aware, this will be the first study to systematically characterize the trajectory of fMRI limbic activity to an SRI. The study focuses on the elderly because the importance of predicting treatment response in that group has added urgency due to their prolonged response to treatment and high suicide risk.

DESCRIPTION (provided by applicant): Slowing gait and difficulty walking are major and common problems of older adults, they worsen with age and they are associated with greater risk of disability, hospitalization and death. There is strong emergent evidence that structural brain abnormalities, such as white matter hyperintensities (WMH), are associated with lower- extremity mobility limitations. Our preliminary data suggest there is a striking high prevalence of 'resilient' elderly, who have preserved mobility and function despite substantial WMH. In two of our independent studies, more than 40% of individuals with substantial WMH have faster than expected mean gait, normal physical function and greater 10-year survival rate. These adults also have normal information-processing speed, a cognitive domain strongly related to mobility. We propose that this apparent resilience is related to unique neural activation patterns and to slower accrual of micro-structural abnormalities within critical mobility-related regions (Aim 1). These features are not visible on standard structural MRI obtained at one time point and require advanced longitudinal MRI methodology. Based on previous work and our pilot work we hypothesize that higher neural activation offsets the adverse impact of overall WMH on function (Aim 2). Aim 3 will explore the relationship of risk factors and resilience. In particular, we will test whether slower longitudinal worsening of risk factors (blood pressure, interleukine-6 and glucose) can enhance resilience, by slowing down the accrual of micro-structural abnormalities. Although it is known that greater cross-sectional levels of these risk factors are associated with WMH the impact of their longitudinal trajectories on brain functional and micro-structural characteristics has not been examined in large groups of older adults. In this dual-PI project, Drs. Rosano and Aizenstein propose to acquire a repeat brain MRI in older adult participants of a parent longitudinal NIA epidemiologic study - the Health ABC study (Health, Aging and Body Composition Study) ongoing since 1996. Participants have received a 1st brain MRI in 2007-08 with measures of micro-structure (PI: Dr. Rosano, K23AG028966-01, R01 AG029232). The proposed 2nd MRI will measure brain function (neural activation) in addition to micro-structure. This study cost-effectively leverages longitudinal data on cardiometabolic and inflammatory risk factors, as well as hospitalization and strokes ascertained for 14 years. While Dr. Rosano's MRI study is ongoing, it is absolutely critical to obtain a 2nd MRI to measure longitudinal microstructural changes, maximize participants' retention and minimize costs. This proposal differs from Dr. Rosano's current study of cross-sectional structural brain measures, because it will focus on functional (neural activation) and longitudinal micro-structural changes. Results from this research project may shed light on the mechanisms underlying physical disability and may help us prepare prevention and intervention studies.

? DESCRIPTION (provided by applicant): The goal of this revision application (competing supplement) is to integrate the assessment of brain tau deposition as a unique marker of neurodegeneration (ND). Our guiding concept is that isolated medial temporal tau (MT-tau) in the hippocampus and entorhinal cortex (i.e., Braak stages I-III) is more a factor of aging than Alzheimer's disease (AD) pathology, but neocortical tau (NC-tau; Braak IV-VI) is typically amyloid-beta (A?)-dependent and part of the AD pathophysiological process and is thus a marker of ND. The central goal of the project as a whole remains further understanding the association of asymptomatic A? deposition and ND markers (NC-tau, hippocampal volume and cerebral metabolism) with progression to clinical cognitive impairment - as A? deposition alone cannot fully explain cognitive variability. In addition to the A? and ND markers we currently collect using Pittsburgh Compound-B (PiB) positron emission tomography (PET), structural MRI and [F-18]fluorodeoxyglucose (FDG) PET, in this revision, we now propose to collect [F-18]AV-1451 (formerly T807) PET data on tau deposition to more fully understand the biomarker correlates of cognitive decline. Our cohort has now matured to the point that the occurrence of incident MCI and incident A?-positivity [incident-A?(+)] is sufficient to address other hypothese that could not be properly addressed until sufficient follow-up was in place - as is the case now. One critical hypothesis that we can now test is that A?(+) cognitively normal older adults are at high risk to develop clinically-significant cognitive impairment (i.e., MCI) (Aim 1). In addition, ur growing cohort of incident-A?(+) subjects allows us to observe the transition from being A?-negative to the earliest A?-positive [A?(+)] state (Aim 2.2). Also, our longitudinal fMRI data in incident-A?(+) individuals will allow us to test for the first time the assumption that higher functional activity/connectivity in A?(+) individuals reflects a true increase from baseline, and ot a maintenance of lifelong high activity/connectivity and will aid us in predicting when A?(+) individuals will develop cognitive decline (Aim 3). Finally, we propose to enhance our cohort to more effectively address the relationship between A? deposition and cognition by broadening the cognitive range of our cohort (Aim 2.1). We will interpret all of these data in the context of neurodegeneration markers (tau PET, atrophy and hypometabolism) as well as A? PET. The overall impact and significance of this study will be to further our understanding of: 1) the incidence of asymptomatic A?and tau deposition; 2) the relationships between early A? and tau deposition and other neurodegeneration markers, functional activity/connectivity and cognition; and ultimately, 3) the relationship of asymptomatic A? and tau deposition and clinical MCI (and the timing of that association). Innovative aspects of this project include: 1) the study of incidet MCI in A?(+) individuals; 2) the study of incident-A?(+) cases; 3) the longitudinal study of the natural history of functional activity/connectivity in incident-A?(+) individuals and its relationhip to progression to MCI; and 4) the integration of tau PET.

DESCRIPTION (provided by applicant): The aging brain maintains the ability to learn while being affected by neuronal death, vascular abnormalities and connectivity loss. A possible explanation for this preserved function is the maintenance of neuroregenerative potential even in late-life. Strong emerging human in-vivo evidence indicates that the hippocampal formation becomes larger in response to physical activity (PA) interventions in well-functioning elderly in their late sixties. However, it is not known whether very old and frail individuals also respond to PA with hippocampal expansion and -if they do- whether changes remain beyond one year. Moreover, it is unknown whether hippocampal changes are specific for areas with neuroregenerative potential (the dentate gyrus), and the effects of PA on related cerebrovascular and functional brain measures. Addressing these gaps in knowledge in very old adults will expand our understanding of brain plasticity in very old age, specifically in response to intervention. We propose to address this gap in knowledge by examining whether the PA-related effects previously reported in the hippocampal formation of younger elderly exist in very old and frail adults for periods of time beyond 1 year, whether these effects are significant for the dentate gyrus, microcirculature and functional connectivity. To date, there have been two major barriers to answer these questions: 1) conventional non- invasive imaging cannot precisely measure the dentate gyrus; 2) very old adults are likely to be physically frail and unlikely to participate and adhere to a PA program for long period of times. This proposal addresses these barriers by applying non-invasive Ultra High-Field neuroimaging at 7Tesla in frail older adults who are already participating in an existing long-term randomized clinical trialof walking compared to health education (Successful Aging: SA). We have already acquired Ultra High-Field brain images at the time of randomization in 2010 in 65 ptc and have funds to acquire all brain MRI at the 2nd yr follow-up, for an estimated sample size of n=50 with MRIs pre and post-intervention and an additional n=30 with MRI at the post-intervention only. This is an application to process and analyze these data to: 1) Quantify the relationship of PA with Ultra High-Field brain markers (AIM1); 2) identify the localization of the PA-related changes in Ultra High-Field brain markers (AIM2); 3) Explore the role of Ultra High Field markers in explaining brain response to PA (AIM3).This proposal has a high chance of success because it applies previously validated neuroimaging protocols in response to a type of PA intervention that has also been previously validated in this special population. This is a unique opportunity to conduct this transformative study in a highly cost-effective design, leveraging existing data on Ultra High field brain MRIs, existing operational infrastructure for recruitment, retention, intervention, and clinical assessment of the ongoing LIFE study and the expertise of the LIFE leadership team, Co-I's of this proposal. Because of the high costs of RCTs, it is highly unlikely that this combination of highly advanced neuroimaging and type of intervention study will occur again.

Project Summary/Abstract: Depression (target disease of this proposal) affects 34 million Americans including 2 million seniors per year. It is a leading cause of morbidity and mortality in older adults (target population of this proposal). The vascular depression hypothesis (proposed in 1998) remains the most salient theory explaining the onset and perpetuation of depression in older adults. This model is based on the observation that in older adults, white matter hyperintensities (a hallmark of small vessel disease, SVD) are associated with depression onset and perpetuation. Progress in understanding the relationship of small vessel disease with late-life depression has been stymied in part by lack of specificity of white matter hyperintensities which can represent components of edema, gliosis, ischemia, and inflammation. Traditional MR imaging is unable to distinguish between these components, and thus the specific mechanisms that contribute to depression remain unclear. The emergence of ultrahigh field MR imaging allows for greater specificity of the WMH lesions, and other components of small vessel disease. Bringing 7 tesla (T) imaging into mainstream clinical use will be accomplished through 1) having exclusive (over 1.5/3T) application(s) and 2) achieving robust, safe, consistent, and homogenous high-quality images. Through a consortium consisting of experts at University of Pittsburgh combined with collaboration at FDA, University of Minnesota, and Quality Electrodynamics Inc., our goal is to enhance our understanding of the neuropathophysiology, treatment, and management of depression in older adults. We will achieve this goal through the development of robust radiofrequency methodology, as well as pulse sequences that produce 7T images with the aforementioned necessary attributes. This will be paired with complementary 3T MRI at baseline. We will use our recently developed (as well as a proposed) custom designed 7T radiofrequency coil system and pulse sequences that are already being used in disease/patient studies. Based on our preliminary results, the proposed RF solution will provide unprecedented homogeneity and consistency among different subjects/patients, and therefore excellent signal to noise ratio and contrast to noise ratio for detection of components of small vessel disease. The study will examine two cohorts 1) a group of 30 older adults recruited through the Alzheimer's Disease Research Center (ADRC) for developing an MRI to histopathology statistical model of SVD and 2) 60 older adults with late-life depression who will undergo scanning at baseline and after 2 years. The longitudinal 7T MRI and SVD model will be used to help characterize the small vessel changes associated with depression in older adults. In summary, this study develops an emerging and timely technology (high-performance ultrahigh field MRI) to study a critical pathophysiological process (cerebral small vessel disease) in a clinically relevant population (Late-Life Depression). This project will further advance all of these three domains.

ABSTRACT This proposal requests support for the five-year continuation of our NIMH-funded institutional training grant, ?Clinical and Translational Research Training in Late-Life Mood Disorders? (T32 MH019986), Years 21-25. The primary goal of this two-year fellowship (three years in selected case) is to provide rigorous training in the basic foundations and methodologic tools necessary for successful clinical and translational investigation in geriatric mental health and psychiatry. The fellowship is designed for post-residency psychiatrists and PhDs in the behavioral sciences (four post-doctoral fellows annually). Consistent with NIMH priorities, the focus of training in the new funding period will continue to be translational and treatment development research, as well as interventions and mental health services research. Research training is designed to be broadly multi disciplinary. The most important components of the training program are apprenticeship with an academically successful mentor and a structured training plan facilitated by a network of committed faculty. In most cases, this leads to faculty appointments and successful competition for extramural funding. Trainees develop core skills and knowledge in grant writing and research project management by participating in a weekly career and research development seminar, and focus on issues specific to geriatric mental health research in twice monthly meetings with the program directors. A wide range of didactic offerings is available and is prescribed on an individual basis. All fellows participate in ongoing training in the responsible conduct of research. The proposed training activities take place within the Geriatric Psychiatry Program at the University of Pittsburgh. The second goal of the program is to provide research training opportunities, in the form of a summer research elective, to rising second-year medical students, in order to attract a diverse and talented group of medical students into psychiatric research careers. We propose to continue funding two summer research elective slots annually through this training program, as well as a one year-long medical student fellowship to the most promising student in each summer's program. Both components of the program, pre- and post-doctoral, are part of a broad research training strategy at the University of Pittsburgh Department of Psychiatry, to respond to a national shortage of researchers in geriatric mental health. The Department fosters many research career development activities for students and faculty at all levels. This training grant both contributes to and benefits from this developmental strategy.

In this competing renewal (Year 11) of our R01 using fMRI to study late-life depression (LLD) pharmacotherapy (R01MH076079), the primary aim is to characterize functional connectivity changes associated with initial medication exposure (12-hour challenge). Our preliminary data suggests that these initial fMRI changes reflect monoaminergic engagement, regardless of monoaminergic class (serotonergic or noradrenergic), and predict later treatment response. In the proposed study we test a neural systems level model that response in LLD is mediated by acute pharmacologically-induced changes in cognitive and affective large scale network. Depression in older adults is frequently disabling and is often resistant to first-line treatments, requiring more prolonged treatment trials than in younger adults, mainly due to its heterogeneous pathophysiology (e.g. vascular and degenerative brain changes). Currently, there is little neurobiological data to guide changing or augmenting antidepressant medications. Thus, there has been a heightened focus on tailoring treatment to optimize outcome as described in the 2015 NIMH draft strategic plan (strategy 3.2). While antidepressant clinical response may take up to 8 weeks, recent studies suggest that physiologic changes, as measured with pharmacologic fMRI (phMRI) are seen within 24 hours of starting a new monoaminergic antidepressant1. For this proposal, we focus on three major Cognitive and Affective Networks (CAN): the Default Mode Network (DMN), the Salience Network (SN) and the Executive Control Network (ECN). The proposed model suggests that monoaminergic engagement leads to core CAN changes, changes that subsequently are related to overall clinical response as well as response in specific symptom clusters such as negative bias, somatizations/ anxiety and cognitive control. The same networks that are functionally connected while individuals are at rest, are also selectively engaged during tasks. Our prior work shows that pharmacotherapy ? regardless of type of antidepressant used - engages these specific networks at rest and during standard cognitive and affective tasks. Given the role of cerebrovascular disease in LLD treatment response, we will also explore the moderating role of vascular burden on the proposed association between CAN engagement and treatment response. We will recruit 100 older adults with LLD who will be randomized to receive treatment with either a very specific serotonin reuptake inhibitor (escitalopram) or a norepinephrine reuptake inhibitor (levomilnacipram). A pair of fMRI scans one day apart will be used to measure FC associated with medication titration. We propose to use a very early (12 hours after initiation of treatment) biomarker of treatment response, which, when validated, would decrease substantially the waiting time between medication changes. Additionally, our study will further our understanding of the acute neural system changes associated with monoaminergic antidepressants; this knowledge of mechanism is essential for both guiding LLD treatment research, and serving as an engagement target in LLD treatment research.

ABSTRACT Through the mechanism of a pre-doctoral T32 interdisciplinary training program, the Departments of Bioengineering (BIOE) and Psychiatry at the University of Pittsburgh (UPitt) are seeking NIH support for bioengineering pre-docs to train as mental health researchers. The program is aimed at educating talented students with engineering and other quantitative sciences background for careers in mental health research. Consistent with the NIMH strategic, we envision an increasing role for quantitative and computational science in psychiatric research. The trainees (6 per year) of this program will be uniquely qualified to help lead development and use new technical bioengineering approaches to address mental health research challenges. This training program capitalizes on the breadth of bioengineering in psychiatry research at UPitt and provides students with access to the clinical presentation and treatment of psychiatric disorders. PhD trainees will take foundational courses in bioengineering, cognitive and computational neuroscience, psychopathology, and ethics and will be complemented by electives. Students are exposed to clinical environments via a longitudinal clinical experience and two 1-week intensive clinical observerships. A diverse group of research-active mentors (16 in Psychiatry and 16 in Bioengineering) comprised of basic scientists, clinicians, and engineers, serve as advisors to guide students in their doctoral research efforts where each mentee will have 2 principle co-mentors (1 in BIOE and 1 in Psychiatry). Finally, students participate in several program-specific activities throughout their graduate school years, designed to enhance interactions and exchange of information (student-student and student-faculty) and to facilitate professional and career development. Each student receives extensive research training in the laboratories of the training faculty. There are three integrated focus areas of this pre-doctoral training program: (1) Neuroimaging, (2) Neurostimulation, and (3) Neural Engineering. All of these tracks are heavily utilized in a wide variety of mental health research including mood disorder, anxiety disorder, psychotic disorder, suicide, and cognitive impairment where currently there is a critical mass of researchers at UPitt addressing these disorders. This training program will provide a unique educational and research experience aimed at training bioengineering scientists to develop careers in mental health research.

Project Summary/Abstract: There is a well-established association between small vessel disease (SVD, microangiopathy) and Alzheimer's disease (AD). The underlying mechanisms for associations between small vessels and the AD cascade remain unclear. Some of the association between SVD and AD is due to the cumulative cognitive burden from independent pathologies (AD and SVD) leading to early manifestation of the clinical syndrome of AD. It is becomingly recognized that another way in which SVD and AD are related is through bi-directional interaction at molecular and cellular levels: e.g., inflammatory factors associated with A? plaques contribute to SVD. Furthermore, an emerging hypothesis is that decreased pulsatility of small arterioles decreases cerebral spinal fluid (CSF) clearance of amyloid, putting someone at risk of AD. A better understanding of the underlying mechanisms relating SVD and AD is especially important as it can identify prevention and treatment targets. This proposed transdisciplinary (Multi-PI) proposal aims to develop advanced MRI methods (hardware, acquisition, and analysis) with 7T human imaging and study the pathways linking small vessel and CSF flow pathophysiology to AD. It will be achieved through a consortium consisting of expertise at 1) U. of Pittsburgh - MRI acquisition and analysis-, and AD; 2) FDA -RF-heating matters in relation guidelines-; 3) U. of Minnesota - MRI acquisition-; 4) Quality Electrodynamics Inc. (QED) -integration of patient friendly hardware-; and Montreal Neurological Institute -MRI analysis-. We will examine small vessel morphology, cerebrovascular reactivity (CVR), and CSF flow, all of which are inter-related components in AD pathophysiology. For instance, small vessel lesions (in part due to amyloid angiopathy) may disrupt CVR, and consequently interfere with A? clearance. The study is designed as a prospective observational study of older adults without dementia: 30 amyloid positive, and 30 amyloid negative (n = 60). We will leverage two ongoing studies (RF1AG025516 & R01AG052446) of AD pathology for recruitment, clinical characterization and PET imaging. Individuals are scanned at baseline (Aim 1) using current state of the art technology. Throughout we will work on MRI development (Aim 2). At 2-year follow up individuals will be scanned again with the same protocol as at baseline, and will also undergo scanning with the newly developed technology (Aim 3). In summary, this study develops, applies and validates advanced imaging of small vessel morphology, CVR, and CSF flow and other traditional MRI biomarkers to characterize pre-clinical AD, and potentially identify targets for prevention and/or treatment. The proposal takes advantage of recent and proposed advances in a timely and recently FDA-approved technology (7T human MRI) and collaborations between: a) scientists, engineers, and clinicians; b) leading 7T human MRI centers and a coil company; and c) a governmental regulatory agency.

? DESCRIPTION (provided by applicant): Hypothesis that systemic and cerebral vascular for the past five years, our group has been testing the disease (even at a subclinical level) modulates the onset of the cognitive syndrome of Alzheimer's disease (AD). We have found that there is an important, but complex, relationship between AD pathology and vascular disease. We have reported that A? deposition is linked to brain structure, markers of cholesterol transport and inflammation. Taken in combination, hippocampal atrophy, white matter lesions, and the extent of A? deposition provided powerful prediction of dementia after two years of follow-up. However, although half of cognitively normal subjects age 85+ were found to have A? deposition, two-thirds of these A?-positive subjects showed no clinical progression over two years. Conversely, one-third of the cognitively normal subjects who progressed to an AD syndrome over two years were A?-negative. These new findings indicate that vascular disease may act as: 1) as a moderating factor that alters brain compensation for AD pathology; 2) as a contributor to AD pathology; or 3) both. The implications of these are critically different and impact our understanding of the pathophysiology of dementia in old age, and by extension, its preventive treatments. The goal of this PPG is to gain further insight into the pre- symptomatic (or subclinical) dynamic processes of the two most common pathologies in old age, vascular disease and AD, in relationship to cognition. In order to longitudinally examine this dynamic process, we have assembled two cohorts: 1) the GEMS cohort of very elderly individuals (~90 yrs) who have been studied by us for 15 years and where the incidence of cognitive syndromes is very high and 2) the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) cohort that is younger (65-75 yrs) and where the expected incidence of cognitive syndromes is much lower. The value of extending our observation of the GEMS cohort through this late stage of frequent clinical change and coupling this to a postmortem study is clear. The importance of the Heart SCORE cohort is that it allows us to see significant changes at the subclinical level (i.e., cognitive decline without reaching the MCI/dementia state). If we observe an association between vascular disease, AD pathology, and cognitive decline in the Heart SCORE cohort, this will strongly support the hypotheses generated from the GEMS cohort. This design allows us to gather in-depth information on the association between vascular disease, AD pathology and cognition within a 5-year period that would otherwise take more than a decade to accumulate. These studies in the GEMS cohort (Project-1) and the Heart SCORE cohort (Project-2) are enriched by coupling them to the detailed neuropathological evaluations performed in Project-3 and the pharmacokinetic study of the newly applied tau positron emission tomography (PET) technology (Project-4) that aims to simultaneously add missing components to the characterization of tau-PET and improve the accuracy and value of the tau-PET data acquired in this PPG - and by the field in general.

Recruitment and Education Component: Summary/Abstract: The primary goal of the Research Education Component (REC) is to identify, attract, and promote the career development of ADRD investigators. The PITT-ADRC REC assumes primary responsibility for executing the Center?s bold vision for advancing the ADRD research workforce with a particular emphasis on cultivating the growth of our field?s future leaders. The inclusion and promotion of junior investigators in multiple areas of dementia research within our PITT- ADRC is an important responsibility of our senior faculty. With over a dozen federally funded training programs (T32s) in the neurosciences and/or aging, the University of Pittsburgh has the infrastructure for scientific mentoring and a critical mass of trainees ? both basic and clinical ? with an interest in ADRD research. Through participation in the aforementioned training programs and/or one-on-one mentorship by a senior investigator, early stage investigators at Pitt have many excellent opportunities to develop their skills in clinical and basic research methodology, grant writing, and manuscript preparation. We plan to leverage these existing resources for career development at the University of Pittsburgh by providing an additional centralized program of ADRD-specific research mentoring and an innovative pathway for the development ADRD research leadership through the Optimizing Scientific Careers in AD Research (OSCAR) scholars program. The REC is tightly integrated with the Center?s cores. We view research training through a primarily apprenticeship model, where the trainees develop through one on one work with their mentors, many of whom are participating faculty in other cores of the ADRC. The REC will enhance the research education occurring in the cores by coordinating trainee-wide activities, individualizing curriculum (especially in matching clinical research activities), and devoting administrative support to organizing events, matching mentees with mentors, and developing centralized resources for navigating the complex clinical research and regulatory environment of ADRD research. If successful, this REC will have a large and sustained impact on the field by training new leaders. This leadership is essential for meeting the expanding needs of the growing ADRD research work force. The innovative OSCAR ADRC core leader training program can become a model for research education and leadership training across the ADC network.

In this Yr16 renewal of our longitudinal study on the natural progression of AD biomarkers, the central goal remains to further understand the occurrence of asymptomatic amyloid-beta (A?) and tau deposition and the progression to clinical cognitive impairment. This cohort has now matured to the point that there is now sufficient longitudinal follow-up to address important hypotheses that were formulated from the beginning of this study but could not be properly addressed until 10-15 years of follow-up were in place - as is the case now. In this renewal period we aim to better characterize the different roles gray matter brain aging and small vessel disease have on AD progression. Chronological age is the most salient risk factor for late-onset AD. However, it remains unclear what components of the aging process account for this risk. In this proposal, we use gray matter brain age models to study the atrophy-related components of aging and 7T vascular imaging to characterize the SVD components of aging. Aim 1 uses this estimated gray matter brain age to explain individual differences in AD biomarkers and cognitive decline. Aim 2 uses fMRI and cerebrovascular imaging at 7T to examine the role of SVD in accelerating the amyloid-induced tauopathy and neurodegeneration. Aim 3 ties together brain aging and SVD to test components of a model that small vessel disease (SVD) accelerates Tau deposition and neurodegeneration (including accelerated gray matter brain aging). Over the last 2 years we have transitioned the MR imaging of this study to a 7T MR scanner to take advantage of its high field strength for 1) characterizing small vessel morphology (e.g., early markers of cerebrovascular disease) associated with AD risk and 2) characterizing functional neural systems (fMRI). Over the course of this study we have shown that many (~25%) of cognitively unimpaired older adults have significant cerebral amyloid deposition, subsequently defined as preclinical AD. We and others have shown that in this preclinical stage, cross-sectional Ab burden is only weakly associated with objective cognitive performance. At this early disease stage, Ab burden is more strongly associated with changes in the functional connectivity, which can be measured by fMRI. We and others have identified that regional medial temporal lobe functional connectivity (MTL_FC) during memory encoding is associated with increased Ab load. In recent preliminary work, we have found that traditional markers of SVD interact with amyloid burden in their relationship to MTL_FC. Those with high Ab and high White Matter Hyperintensity (WMH) burden have particularly high regional MTL_FC. In individuals with Ab burden, SVD accelerates tau deposition, neurodegeneration, and progression of cognitive and clinical decline. The current cohort of 70 active participants will be supplemented by recruitment of additional older adults to achieve 200 baseline assessments. Individuals will undergo 3 MRI scans and 2 Ab- and tau-PET scans over a 32-month interval.