William W. Seeley - US grants

DESCRIPTION (provided by applicant): This is an application for a K08-Alzheimer's Disease Clinical Scientist Development Award, entitled "FMRI and Pathology of Anterior Cingulate and Frontoinsular Cortex in FTLD and AD." The primary goal of the proposed research is to use novel functional imaging and pathological techniques to probe a neural circuit rooted in anterior cingulate (ACC), anterior insular (Al), and orbital frontoinsular (Fl) regions known to be selectively vulnerable in frontotemporal dementia (FTD) compared with Alzheimer's Disease (AD). Degenerative dementias target specific, functionally-linked neuronal networks. AD begins in medial temporal areas, producing memory dysfunction, while FTD involves the ACC, Al, and Fl, leading to disordered social conduct. The forces that determine these contrasting anatomic patterns remain unknown. The specific aims of the proposed research are (1) To assess resting state fMRI connectivity within the ACCAI- FI network in FTD, AD, and healthy age-matched controls, (2) To explore connectivity of the ACC-AI-FI network to peripheral autonomic markers in FTD and AD, and (3) To determine the relative susceptibility of a recently evolved cellular population-the spindle neurons-within the ACC and Fl in FTD, AD, and nonneurological controls at autopsy. The overarching hypotheses of this research are that FTD patients alone will have diminished, aberrant ACC-AI-FI network connectivity that is uncoupled from autonomic responses, and that FTD patients will exhibit greater absolute and relative spindle neuron losses than those seen in AD. As part of the proposed research, the applicant seeks training in (1) fMRI, including functional connectivity techniques, (2) basic autonomic physiology recording, (3) neuropathology, including methods for quantifying loss of neuronal subtypes within specific brain regions, (4) clinical care of dementia, (5) manuscript preparation and grant writing and (6) the responsible conduct of research. The proposed research plan, didactic courses, and tutorial instruction from mentors and advisors will promote the applicant's development into an independent investigator in the neuroscience of dementia. Degenerative dementias cause immeasurable human suffering and impose a growing strain on health care resources. The proposed research seeks to benefit the public health by clarifying the biological basis of dementia, ultimately promoting earlier diagnosis and better treatments for dementia patients.

This project, entitled "Mapping Early Network Dysfunction in FTD and AD" will develop novel network connectivity analyses with the goal of improving early detection and diagnosis of frontotemporal dementia (FTD) and Alzheimer's disease (AD). Normal cognitive and behavioral functions require coordinated activity, within large-scale, distributed networks. Emerging data from human studies and animal disease models suggest that specific networks may develop early, tell-tale aberrations during incipient neurodegenerative disease. To explore this possibility, we will use functional connectivity MRI (fcMRI) and diffusion spectral imaging (DSI) to study 60 patients with FTD, 20 asymptomatic FTD gene mutation carriers, 15 patients with AD, and 30 healthy controls. We hypothesize that network connectivity mapping will link each clinical syndrome to a specific intrinsic brain network, will prove capable of detecting early disease, and will provide new insights into symptom pathogenesis. Our aims are (1) to detect network alterations in early stage FTD and AD, (2) to compare the ability of fcMRI, DSI, and conventional structural MRI to detect network-level dysfunction in presymptomatic FTD gene mutation carriers, and (3) to correlate FTD and AD symptoms with network connectivity disruption. The knowledge gained could provide a first step toward a novel, non- invasive imaging biomarker for early FTD and AD and clarify the network basis for FTD, AD, and other neuropsychiatric disorders that target the brain at the network level. RELEVANCE (See instructions): This project will investigate the specific brain networks disrupted in frontemporal dementia and Alzheimer's disease. The goal of the research is to use neuroimaging to clarify where in the brain these diseases begin and how network dysfunction leads to symptoms. Further developed, these methods could improve early detection and diagnosis and provide a sensitive biomarker for following the effects of treatment.

DESCRIPTION (provided by applicant): This project will investigate selective vulnerability in frontotemporal dementia (FTD) and Alzheimer's disease (AD). Whereas AD begins with memory impairment, early FTD leads to social-emotional processing deficits. Some patients with FTD develop motor neuron disease (MND), which shortens the disease course and provides a window into early FTD anatomical deficits. In the behavioral variant of FTD (bvFTD), early atrophy and metabolic dysfunction focally affects the anterior cingulate (ACC) and frontoinsular (FI) cortices, especially in the right hemisphere. Recent work suggests selective vulnerability of a unique class of large projection neurons, von Economo neurons (VENs), found only in ACC and FI and restricted, among primates, to humans and great apes. The proposed studies will further examine the hypothesis that VENs are a central feature of the early bvFTD anatomic injury pattern. Our aims are to (1) Determine whether FI VENs are selectively vulnerable in bvFTD vs. AD and non-neurological controls (NNC) and explore laterality effects, (2) Examine histopathological correlates and antecedents of VEN cell death, and (3) explore the hypothesis that VEN vulnerability in bvFTD relates to specific neurodevelopmental signaling proteins alterations. We will study brain autopsy materials from 15 NNC, 15 AD, 20 bvFTD-MND, and 30 bvFTD subjects using quantitative neuroanatomical and immunohistochemical methods to assess neuron number and morphology, disease protein inclusion formation, synapse loss, astrogliosis, and neurodevelopmental/plasticity signals. The knowledge gained could help create a more comprehensive bvFTD pathogenesis model by determining the specific anatomical substrates of early disease and pathophysiological events that surround this targeted injury. PUBLIC HEALTH RELEVANCE: This project will investigate the specific brain regions and neurons that degenerate in frontemporal dementia, a neurological disease that causes changes in personality and behavior. The goal of the research is to clarify where in the brain the disease strikes and what biological properties render specific brain cells vulnerable. This information may provide clues regarding new potential treatments for the disorder.

Project 6, entitled Network biomarkers will develop novel network connectivity analyses for detecting and monitoring preclinical FTD and early clinical bvFTD. The overarching goal is to move beyond prevaling barriers to implementing intrinsic connectivity network (ICN) mapping as a neurodegenerative disease biomarker. Recent research suggests that each neurodegenerative syndrome targets a specific, large-scale distributed network that can be identified in the healthy brain using ICN methods. As a non-invasive, repeatable, dynamic functional imaging modality, ICN mapping has the potential to play a vital role in FTD drug discovery. How ICNs break down in presymptomatic FTD gene mutation carriers and patients with early bvFTD, however, remains unknown. Furthermore, no data are available regarding longitudinal ICN changes in FTD or how ICN integrity relates to clinical deficits. Existing barriers to addressing these questions and developing ICN biomarkers include lack of reliability data in patients and the need to build methodological consensus. In Project 6, we will seek to overcome these issues and address key questions about early sites, longitudinal progression, and symptom-relevance of ICN changes by studying subjects with preclinical FTD (asymptomatic FTD gene mutation carriers), early clinical bvFTD, early svPPA, and healthy controls recruited through Core A (Clinical), genotyped through Core D (Genetics), imaged through Core E (Imaging) and characterized in terms of emotion processing in Project 3 (Emotions). We will pursue the following specific aims: (1) To determine the most reliable and sensitive ICN analysis strategy for detecting preclinical FTD and early clinical bvFTD at first evaluation, (2) To identify longitudinal network connectivity changes in preclinical FTD and early clinical bvFTD over 6- and 12-month intervals, and (3) To link specific ICN changes to loss of emotional functioning in preclinical FTD, early bvFTD and svPPA (with Project 3). Successful completion of the proposed studies could help provide the field with a non-invasive diagnostic and disease monitoring neuroimaging biomarker for early FTD and, potentially, for related neurodegenerative diseases.

PROJECT SUMMARY (See instructions): Core B is a Neuropathology and Biomarker Core (NP Core) that plays a vital role in the UCSF FTD PPG. FTLD neuropathology has become increasingly exciting and complex in recent years, with major advances arising from w/ork accomplished through this PPG. During the past two cycles. Core B has been led by Dr. John Trojanowski at the University of Pennsylvania (PENN). In this renewal application, we propose to centralize Core B functions at UCSF through an NP Core led by Dr. William Seeley and to add a new cerebrospinal fluid (CSF) biomarker component led by Drs. Trojanowski and Leslie Shaw at PENN. The new NP Core aims to: (1) Obtain CNS tissue for NP characterization and banking by performing timely autopsies on patients and healthy controls ascertained through Core A; (2) Analyze specimens and document NP diagnoses by dissecting a standard set of 23 regions-of-interest for routine histological staining and systematic immunohistochemical characterization; (3) Enter NP findings into a comprehensive research oriented database; (4) Bank and distribute CNS tissues by reviewing tissue requests by committee and providing samples to qualified investigators for research; and (5) Store and analyze CSF for diagnostic biomarkers by receiving CSF samples from an average of 45 patients per year with FTD or AD clinical diagnoses and performing CSF total tau, phospho-tau and beta-amyloid levels on every sample. These core functions will support the aims of Projects 2 (Multi-modal imaging), 3 (Emotions), and 4 (Clinical criteria) by providing final neuropathological diagnoses that serve as primary outcomes or grouping variables. Moreover, the NP Core will help to futher develop a unique bank of specially handled CNS tissues (brain, spinal cord, and CSF) for ongoing and future FTLD molecular, translational, clinicopathological, and biomarker discovery research.

CORE D - ABSTRACT The UCSF ADRC Neuropathology, Biospecimens, and Genetics core (NP core, Core D) provides vital research support to the UCSF ADRC and to the neurodegenerative disease research community at UCSF and beyond. Neurodegenerative disease pathology and genetics have become increasingly exciting and complex in recent years, with major advances arising from work accomplished through this ADRC. In this renewal application, the NP Core will continue to be led by Dr. William Seeley. Dr. Lea Grinberg will found a new Biospecimens sub-core, and Drs. Dan Geschwind and Giovanni Coppola will continue to lead the Genetics sub-core at UCLA. The NP Core aims to: (1) Obtain and bank human biomaterial for neuropathological, biochemical, and genetic charaterization; (2) Analyze specimens and document results, including NP diagnoses rendered using current diagnostic consensus criteria, and (3) Enter NP, bioassay, and genetics results into research-oriented databases and distribute specimens. These core functions will support the aims of Projects 1 (EOAD variants), 2 (PPA heterogeneity), and 3 (iPSC models) by providing final neuropathological diagnoses, organizing and conducting biochemical analyses, and providing genotyping and gene expression analysis. Moreover, the NP Core will help to further develop a unique bank of specially handled materials (brain, spinal cord, CSF, plasma, urine, RNA/DNA) for ongoing and future molecular, translational, clinicopathological, and biomarker discovery research.

ABSTRACT Core B is a Neuropathology and Biomarker Core (NP Core) that plays a vital role in the UCSF FTD PPG. FTLD neuropathology has become increasingly exciting and complex in recent years, with major advances arising from work accomplished through this PPG. In this renewal application, we propose to continue to cultivate a world-class FTLD-oriented neurodegenerative disease brain bank at UCSF. The NP Core aims to: (1) Obtain CNS tissue for NP characterization and banking by performing timely autopsies on patients and healthy controls ascertained through the Clinical Core; (2) Analyze specimens and document NP diagnoses by dissecting a standard set of 23 tissue blocks for routine histological staining and systematic immunohistochemical characterization, resulting in semi-quantitative and quantitative assessments; (3) Enter NP findings into a comprehensive research-oriented database; (4) Bank CNS tissues, blood, plasma, and CSF, analyze CSF for putative diagnostic biomarkers, and distribute biospecimens to qualified investigators; (5) Engage with PPG collaborators in conducting FTLD clinico-pathological research by meeting regularly with PPG Project leaders who rely on NP Core data; and (6) Train the next generation of neuropathology leaders and clinical scientists grounded in neuropathology principles and methods by holding consensus and clinico- pathological conferencesThese core functions will support the aims of Projects 3 (Emotions), 4 (Clinical criteria), and 7 (Language) by providing final neuropathological diagnoses that serve as primary outcomes or grouping variables as well as semi-quantitative and/or quantitative regional pathological data. Moreover, the NP Core will help to further develop a unique bank of specially handled CNS tissues (brain, spinal cord, and CSF) for ongoing and future FTLD molecular, translational, clinicopathological, and biomarker discovery research.

NARRATIVE Project 6 entitled Multimodal Longitudinal Network Bioimaging? will combine task-free fMRI, longitudinal structural MRI and molecular imaging with the novel tau PET tracer [18F]AV1451 to determine how progressive regional brain atrophy and tau deposition in FTD relate to the healthy functional connectome. The overarching goal is to extend and refine a network-based neurodegeneration model developed in the previous cycle to predict regional progression of neurodegeneration and molecular pathology in patients with FTD. Converging data from in vitro experiments and animal models suggest that pathological tau spreads trans-synaptically across inter-connected networks, driving disease progression. We have previously shown that cross-sectional FTD-related atrophy patterns reflect the connectional architecture of the healthy brain, consistent with trans- neuronal spread of toxic misfolded proteins. However, the ability of the ?network-based neurodegeneration model? to predict longitudinal disease progression remains to be tested. In this project we will approach this question by using the healthy brain functional connectome to model longitudinal changes in structural MRI and [18F]AV1451 binding in patients with FTD syndromes strongly associated with underlying tau pathology: bvFTD due to MAPT mutations, PSP-S and CBS. Patients will be recruited through Core A (Clinical), genotyped through Core D (Genetics) and imaged through Core E (Imaging). Our connectivity models will incorporate node-level graph metrics that we have previously developed (shortest path to an epicenter) as well as a novel ?nodal hazard? score that incorporates a node's connectional proximity to its nearest network neighbors and the baseline involvement (atrophy or tau) of those neighbors. We will determine whether patient-tailored epicenters, reflecting each patient's anatomical profile, improve model fit and single-subject prediction of progression. Finally, we will begin to explore the temporal relationship between spread of tau and neurodegeneration. Our overarching hypothesis is that tau aggregation begins in vulnerable syndrome- and patient-specific epicenters and spreads trans-synaptically into neighboring nodes, which, in turn, disseminate tau along connections, driving neurodegeneration. To test this model, we will pursue the following specific aims: (1) To determine how the healthy brain functional connectome relates to FTD-related baseline AV1451 binding and longitudinal progression of AV1451 binding and atrophy, (2) To optimize methods for predicting longitudinal FTD-related AV1451 binding and atrophy progression in individual patients, (3) To compare the distribution of FTD-related AV1451 binding and brain atrophy at baseline and at 12 months follow-up. If successful, this project will provide initial in vivo evidence directly linking the spread of tau to brain connectivity and downstream neurodegeneration, advancing our understanding of disease mechanisms, and informing the development of tau-based therapies.

Abstract This project seeks to perform deep pathological phenotyping of frontotemporal dementia (FTD) and motor neuron disease (MND). The rationale for the proposal is that, despite the exploding basic biology of FTD and MND, limited information is available about the strongest biological predictors of neurodegeneration in the brains of patients. Even less is known about mechanisms underlying the striking selective vulnerability seen in FTD and MND or what drives the clinico-anatomical overlap of the two disorders. We will pursue these questions with a focus on TAR DNA-binding of 43 kDA (TDP-43) pathobiology, its relationship to other emerging FTD/MND mechanisms, and its targeting of specific neuronal subtypes within the FTD- and MND-related systems. We will further evaluate the complex neuropathological profile seen in C9ORF72 expansion-related FTD/MND and build datasets equipped to help determine which among the many pathological features in sporadic and C9-FTD/MND represent the strongest predictors of neurodegeneration. Our approach seeks to overcome existing methodological barriers by combining advanced histology, a novel tissue multiplexing platform that allows dozens of protein or RNA markers to be quantified in situ, and single nucleus transcriptomics. We will study patients across the FTD/MND- TDP-43 spectrum, including those with the C9ORF72 expansion, and control subjects. We aim to: (1) Relate TDP-43 pathobiology to nuclear transport defects, cryptic exon incorporation, and DNA damage, (2) Determine the pathological changes most prevalent in vulnerable neurons and regions and most strongly linked to neurodegeneration, and (3) Identify transcriptional signatures of neuronal vulnerability and TDP-43 pathobiology in FTD/MND. Successful completion of the proposed aims would resolve key questions about the human relevance of candidate pathogenic mechanisms in FTD/MND-TDP, enabling more informed prioritization of potential targets for human therapeutic development. The integrated multidimensional data produced would create a deep library for testing new hypotheses as they emerge and for generating new hypotheses. Finally, accomplishing our goals would advance a transformative new histopathological approach to studying neurodegenerative and other complex human diseases.

ABSTRACT ? ARTFL LEFFTDS Longitudinal FTLD: NEUROPATHOLOGY CORE Neurodegenerative disease pathology has become increasingly exciting and complex in recent years. This trend is particularly relevant to FTLD, with its many diverse and yet closely inter-related histopathological subtypes. The overarching goals of the ALLFTD Neuropathology Core will be to (1) enhance research within the ALLFTD consortium and (2) promote tissue-based FTLD research throughout the neurodegenerative disease research community. The core will be led by Drs. William Seeley, Dennis Dickson, and Ian Mackenzie, leading experts in FTLD anatomy and pathology. We aim to facilitate neuropathologic assessments and standardized data collection on ALLFTD participants, collect standardized data across sites, and bank fixed and frozen tissues for distribution to qualified investigators throughout the broader research community. We will perform a pilot study of inter-rater reliability of FTLD-TDP subtypes, and incorporate a novel FTLD-TDP module to enable standardized data collection. Finally, we will collaborate with ALLFTD researchers in the other Cores and Projects 1 and 2 to link clinical, genetic, imaging, and biomarker data to neuropathological data. Successful completion of these goals will have a major impact on the overall success of the ALLFTD consortium.