Gil Rabinovici - US grants

[unreadable] DESCRIPTION (provided by applicant): This is an application for a K-23 Mentored Career Development Award entitled "Amyloid PET in AD, FTLD & PPA: Diagnosis, Functional & Structural Correlations." The primary goal of the proposed research is to apply PET imaging with the amyloid-beta (AP) ligand Pittsburgh Compound-B (PIB) towards the differential diagnosis of dementia, while simultaneously studying the relationships between amyloid deposition, clinical presentation, and brain structure and function. Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) are two leading causes of dementia with distinct histopathologies. Primary progressive aphasia (PPA) is a clinical syndrome that can be caused by FTLD or (less commonly) AD pathology. PIB is a novel PET tracer that specifically binds Ap amyloid, a pathologic hallmark of AD that is not part of the FTLD spectrum. The specific aims of this study are: (1) To measure the utility of PIB-PET in distinguishing AD and FTLD; (2) To identify clinical features that predict the presence of Ap amyloid in PPA and FTLD, and thereby refine diagnostic criteria; (3) To study the relationships between clinical presentation, regional Ap amyloid deposition and neuronal functional and structural integrity using PIB-PET, FDG-PET, and MRI-based cortical thickness measurements. Overall, the proposal seeks to establish PIB-PET as an important clinical tool for improving diagnostic accuracy in dementia, and an important scientific tool for studying the role of Ap amyloid in the pathogenesis of AD. The applicant's long-term goal is to become an independent translational investigator in dementia with expertise in structural, functional and molecular neuroimaging. The applicant seeks training in: (1) neuroimaging, (2) neuropathology and neurobiology of -disease, (S)-biomarker analysis,. (4.) .biostatistics and. data analysis, (5) cognitive and systems neuroscience, (6) clinical dementia care, (7) presentation, Dublication and grant writing and (8) responsible conduct of research. The training program includes mplementing the proposed research plan, didactic courses and instruction from mentors and consultants. Dementia is a leading cause of age-related morbidity and mortality, and a growing strain on health-care resources. The proposed research studies the potential of a new brain imaging technique to improve diagnostic accuracy in dementia, and to study the biology of Alzheimer's disease. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): This is an application for a K-23 Mentored Career Development Award entitled Amyloid PET in AD, FTLD & PPA: Diagnosis, Functional & Structural Correlations. The primary goal of the proposed research is to apply PET imaging with the amyloid-beta (AP) ligand Pittsburgh Compound-B (PIB) towards the differential diagnosis of dementia, while simultaneously studying the relationships between amyloid deposition, clinical presentation, and brain structure and function. Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) are two leading causes of dementia with distinct histopathologies. Primary progressive aphasia (PPA) is a clinical syndrome that can be caused by FTLD or (less commonly) AD pathology. PIB is a novel PET tracer that specifically binds Ap amyloid, a pathologic hallmark of AD that is not part of the FTLD spectrum. The specific aims of this study are: (1) To measure the utility of PIB-PET in distinguishing AD and FTLD; (2) To identify clinical features that predict the presence of Ap amyloid in PPA and FTLD, and thereby refine diagnostic criteria; (3) To study the relationships between clinical presentation, regional Ap amyloid deposition and neuronal functional and structural integrity using PIB-PET, FDG-PET, and MRI-based cortical thickness measurements. Overall, the proposal seeks to establish PIB-PET as an important clinical tool for improving diagnostic accuracy in dementia, and an important scientific tool for studying the role of Ap amyloid in the pathogenesis of AD. The applicant's long-term goal is to become an independent translational investigator in dementia with expertise in structural, functional and molecular neuroimaging. The applicant seeks training in: (1) neuroimaging, (2) neuropathology and neurobiology of -disease, (S)-biomarker analysis,. (4.) .biostatistics and. data analysis, (5) cognitive and systems neuroscience, (6) clinical dementia care, (7) presentation, Dublication and grant writing and (8) responsible conduct of research. The training program includes mplementing the proposed research plan, didactic courses and instruction from mentors and consultants. Dementia is a leading cause of age-related morbidity and mortality, and a growing strain on health-care resources. The proposed research studies the potential of a new brain imaging technique to improve diagnostic accuracy in dementia, and to study the biology of Alzheimer's disease.

DESCRIPTION (provided by applicant): Patients who develop sporadic Alzheimer's disease (AD) before age 65 (~5% of all AD patients) pose a clinical challenge and a scientific enigma. From a clinical perspective, early-onset (EO) patients often present with primary executive, language or visuospatial symptoms (with relative sparing of memory), and accurate diagnosis is challenging due to overlap with non-AD dementia and non-degenerative conditions. Emerging AD biomarkers could facilitate accurate diagnosis but have rarely been studied in this population. The performance of biomarkers in studies of typical late-onset (LO) AD cannot be generalized to EO patients because of differences in degenerative patterns and reference ranges. From a scientific perspective, EO syndromes show a striking dissociation between amyloid-beta (A?) pathology, which is diffuse and symmetric in all syndromes, and brain degeneration, which parallels symptoms and can be asymmetric or focal. This raises fundamental questions about the mechanisms that drive clinical and anatomic diversity in AD. This proposal applies detailed clinical phenotyping and multi-modal neuroimaging to optimize the diagnosis of EO syndromes, and to study mechanisms of heterogeneity in AD. Leveraging the specialization of the UCSF ADRC in early-onset dementia, the study will include 150 mildly impaired (CDR 0.5-1) EO AD patients, 50 each with a predominant executive/memory, language and visuospatial clinical phenotype, and 40 patients with LO-AD. A positive amyloid (PIB) PET scan will be required for inclusion. Patients will undergo structural MRI, functional connectivity (resting state) MRI (fcMRI), FDG-PET and CSF analysis. Comparative data from matched normal controls (NC) and non-AD dementia patients will be obtained from other ongoing studies. The central hypothesis of the proposal is that neurodegeneration in all AD variants converges in temporoparietal regions that comprise the posterior portion of the default mode network (DMN), a core, selectively vulnerable network in AD. Aim 1 tests the diagnostic applications of this hypothesis by comparing the sensitivity and specificity of temporoparietal versus hippocampal MRI/FDG measures in discriminating EO-AD versus NC and non-AD dementia, and compares the performance of imaging biomarkers in EO vs. LO-AD. Aim 2 applies fcMRI to test the hypothesis that the posterior DMN is affected across EO syndromes and in LO-AD, while the relative involvement of other functional networks drives the clinical phenotype in each AD variant. Aim 3 investigates how functional connectivity in healthy adults relates to the patterns of amyloid deposition and neurodegeneration in AD variants, in order to test a model in which A? deposition is driven by nodal stress in cortical hubs, while neurodegeneration originates in syndrome-specific epicenters within the DMN that initiate the trans-neuronal spread of disease and drive the clinical phenotype. These investigations will facilitate the early and accurate diagnosis of EO AD variants, and will further our understanding of the relationships between clinical phenotype, structural and functional brain changes and molecular pathology in AD.

PROJECT 1: SUMMARY/ABSTRACT Approximately 5% of patients of with Alzheimer's Disease (AD) develop symptoms before age 65 in the absence of a known autosomal dominant mutation. Patients with non-familial early-onset AD (EO-AD) show greater deficits in executive function, attention, language and visuospatial abilities and relatively spared episodic memory compared to patients with late-onset AD (LO-AD). Non-amnestic and hippocampal-sparing AD phenotypes are far more common in patients with EO disease. Accurately diagnosing AD in EO patients is challenging due to the atypical clinical presentations and overlap with non-AD dementia, and misdiagnosis rates are high even at expert centers. Molecular and neurodegenerative biomarkers are likely to facilitate early and accurate diagnosis, but few studies have addressed their performance in patients with EO disease - results from LO-AD studies may not generalize to EO populations because of differences in degenerative patterns and reference ranges. Furthermore, patients with EO-AD may harbor unrecognized susceptibility factors that lead to disease onset at such a young age. While the apolipoprotein E ¿4 allele is strongly correlated with young age-of-onset, it is present in only ~50% of EO patients, suggesting that additional mechanisms of vulnerability have yet to be discovered. Leveraging on the strength of the UCSF ADRC in recruiting and characterizing patients with early-onset AD, this study will apply detailed clinical phenotyping, multi-modal neuroimaging and novel genetic approaches to optimize early-stage diagnosis and to elucidate mechanisms of vulnerability in EO-AD. We will evaluate 100 mildly impaired (CDR 0.5-1) early-onset (estimated age of onset d65) patients recruited from the Clinical core. All patients will meet NIA-AA criteria for MCI or probable AD and demonstrate evidence of AD pathology based on a positive amyloid (florbetapir) PET scan. Comparative data from 100 matched normal controls (NC) and 75 non-AD dementia patients will be acquired via the Clinical and Imaging cores. Aim 1 will test the diagnostic performance of (1) CSF and (2) hippocampal versus cortically-based MRI biomarkers in distinguishing EO-AD from NC and non-AD dementia. Aim 2 will build on preliminary data suggesting that ApoE4 modifies the phenotype of EO-AD, testing the hypothesis that ApoE4 carriers will show greater memory impairment and hippocampal atrophy and lower amyloid compared to E4 non-carriers. A hypothesis-generating Aim 3 will apply novel genetic tools to study vulnerability factors in EO-AD, hypothesizing that: (1) ApoE4-positive and E4-negative patients will show differential gene expression patterns in peripheral blood, reflecting involvement of distinct biological pathways; and (2) by screening EO-AD patients with a gene chip that includes ~250,000 rare, protein-altering genetic markers, we will identify novel risk variants in genes implicated in AD pathogenic pathways. Overall, this project will facilitate the early and accurate diagnosis of EO-AD, and will further our understanding of susceptibility factors associated with pre-senile disease onset.

PROJECT ABSTRACT Exposure to repetitive head impacts (RHI) through participation in contact sports can result in symptomatic concussions and asymptomatic sub-concussions and may increase risk for the neurodegenerative disease chronic traumatic encephalopathy (CTE). The pathognomonic lesion of CTE is phosphorylated tau (p-tau) deposition in neurons and other cell processes around small blood vessels, at the depths of the cortical sulci. CTE can only be diagnosed at autopsy, severely limiting research on risk and resilience factors, mechanisms, epidemiology and treatment. There is an urgent need for in vivo biomarkers that can accurately detect CTE and differentiate it from other neurological disorders in living people. Tau positron emission tomography (PET) imaging is a promising tool for detecting p-tau aggregates in Alzheimer?s disease (AD). Initial human imaging studies using the tau PET ligand 18F-flortaucipir (18F-FTP) in individuals at high risk for CTE show low intensity binding and modest correlations between antemortem imaging and post-mortem tau. 18F-MK-6240 is a second- generation tau PET ligand that has improved in vivo imaging properties and reduced ?off-target? (non-tau related) binding compared to 18F-FTP. Our goal is to test the premise that the tau-PET ligand MK-6240 can detect p-tau pathology in living people at high risk for CTE. We will compare MK-6240 standard uptake value ratios (SUVR) in 30 male former National Football League (NFL) players with cognitive symptoms, ages 45-74, and 10 matched male cognitively normal individuals without a TBI history (i.e., ?controls?). We will leverage the infrastructure of the NIA-funded Univ. of California, San Francisco AD Research Center (UCSF ADRC) and the NIA-funded Boston University AD Research Center (BU ADRC) and the experience these centers have in the evaluation of symptomatic former NFL players and with PET imaging. Former NFL players and controls will enroll in the UCSF or BU ADRC, depending on their geographical location, and complete harmonized exams, including neurological, neuropsychological, and self-report mood/behavior measures; MRI exams; and brain donation consent. The resources from this proposal will supplement the Center visits with tau-PET (MK-6240) and amyloid (18F-florbetapir) imaging. We will test the hypothesis that that compared to controls, former NFL players at-risk for CTE will show increased MK-6240 retention in a distribution consistent with CTE neuropathological staging, and tracer retention will correlate with worse cognitive and neuropsychiatric function and greater exposure to RHI. This will be the first study to examine the usefulness of tau-PET MK-6240 in the detection of CTE p-tau. If successful, it will provide preliminary data for larger proposals to examine MK-6240 as an accurate and reliable biomarker to support a clinical diagnosis of probable CTE and differentiate it from other neurological disorders. The ability to accurately detect and diagnose CTE during life is a critical next step in clinical research on the risk factors, mechanisms, and treatment of this brain disease.

PROJECT SUMMARY Despite advances in biomarkers, the accuracy of the diagnosis of ADRD in everyday clinical practice remains inadequate, particularly for health disparities populations. This research program addresses this challenge by validating promising, widely accessible and inexpensive clinical and plasma-based biomarkers in diverse populations in an academic setting and in real-world clinical practice. Our over-arching goal is to reimagine approaches to the diagnosis of ADRD using scalable precision medicine tools. The proposal synergizes the research programs of co-PIs Dr. Gil Rabinovici, a behavioral neurologist and leader in brain imaging and biomarkers, and Dr. Kate Possin, a neuropsychologist and leader in innovation of tablet-based cognitive assessments and dementia care models. We will recruit 400 participants from the UCSF Alzheimer?s Disease Research Center (ADRC), which includes large, heterogeneous, deeply phenotyped clinical cohorts (ranging from cognitively unimpaired to dementia) with a large Latino/Hispanic component; and 750 participants from the New IDEAS study, which is evaluating the clinical utility of amyloid PET in Medicare beneficiaries with MCI or dementia and emphasizes recruitment of Black/African American and Latino/Hispanic patients. With Collaborator Dr. Peggye Dilworth-Anderson, novel enrollment approaches that attend to cultural nuances, provider workflows, and meaningful incentives will help set the standard for inclusive research. All participants will undergo a brief battery of domain-specific cognitive tests, and surveys of social determinants of health (SDH), cognitive and functional symptoms, and caregiver factors. Blood based biomarkers of amyloid, tau and neurodegeneration will be measured in 1,000 participants with co-investigator Dr. Sid O?Bryant. We will identify vulnerability factors and care needs that will inform future diagnostic care models. All participants will undergo amyloid PET, and UCSF ADRC participants will additionally undergo tau PET and MRI. We will identify the clinical measures and blood-based biomarkers that best predict molecular pathology. We will develop classifiers that consider patient factors, SDH, cognition, caregiver factors, and blood-based biomarkers to predict amyloid and tau PET findings, necessity for PET imaging and health outcomes. We will mentor and support junior and early stage-investigators throughout the project. This project will address ADRD Research Implementation Milestone 9.L ?Improving differential diagnosis of symptomatic cognitive impairment,? while also advancing additional key Milestones related to racial/ethnic diversity and blood-based biomarkers. This work will ready the field for inclusive identification of appropriate candidates for disease modifying therapies.