2011 — 2015 |
Grinberg, Lea Tenenholz |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Brainstem as An Early Site in Ad and Ftld: Closing the Etiopathogenic Gap @ University of California, San Francisco
DESCRIPTION (provided by applicant): Features shared by all neurodegenerative diseases represent critical research targets. All follow a characteristic, anatomical sequence, with lesions that spread along functional neuronal network pathways. Despite these commonalities, each disease features a distinct anatomical pattern of early regional vulnerability. These disease-specific anatomical patterns guide translational research by focusing attention on the most relevant targets in humans and model organisms and emphasize the need to identify which brain areas degenerate first in each disease. Strong evidences suggest that specific brainstem (BS) nuclei develop neurofibrillary changes before the cortex in AD. In FTLD, early reports suggest BS neurodegeneration, but few studies have addressed this issue using TDP-43. This information may prove relevant for deciphering early regional vulnerability, anatomical progression and possible non- cognitive symptomatology. Our long-term goal is to provide an integrated picture of BS vulnerability in AD and FTLD-TDP and to incorporate this understanding into the etiopathogenesis of these diseases. The overall objective of this application is to identify the BS histopathological and cytoarchitectonic changes in AD and FTLD-TDP by using a comprehensive network-based approach in well characterized human brains. We will study how often and early these nuclei are involved, whether the changes are symmetric and have a topographical gradient, and which clinical manifestations are associated. This proposal is based on the hypothesis that selected BS nuclei are interdependently and constantly involved in very early stages of AD and FTLD-TDP. Clarifying BS involvement in these diseases will facilitate development of biomarkers, improve diagnostic clinical criteria, and suggest therapeutic targets. The hypothesis will be tested by pursuing two specific aims: To determine the chronology, severity, interdependence, and symptom-relevance of neuropathological changes in the isodendritic core in AD vs. healthy elderly controls and in FTLD vs. healthy elderly controls. This approach is innovative because it utilizes brains processed into thick histological slides and 3D reconstructed. This method is superior in quality, quicker and more economical than the traditional methods and renders excellent stereological and immunohistochemical studies. In addition, the control groups will be composed of a large number of difficult-to-get healthy elderly. This proposal is significant because it is expected to that the knowledge gained will highlight unrecognized early symptoms and suggest new biomarkers and potential therapies. Integrative histopathological and cytoarchitectonic studies remain critical to understanding AD and FTLD and will serve as a foundation for ongoing and future translational research. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public heath because the high economic and social costs associated with neurodegenerative dementias may soon become an unbearable burden to society and effective disease- modifying treatments remain elusive. For this reason, closing important gaps in the understanding of dementia etiopathogenesis as proposed in this proposal by clarifying the involvement of BS nuclei in AD and FTLD-TDP and proposing novel targets for prevention and treatment of these devastating diseases are relevant to the NIH's mission of reducing burdens of illness and disability.
|
1.009 |
2016 — 2020 |
Grinberg, Lea Tenenholz |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Core B: Human Biology Validation Core @ J. David Gladstone Institutes
Project summary/abstract Human Core ? Grinberg U54 CWOW The Human Biology Validation core will provide vital research support to the CWOW. 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 Human Core will be led by Dr. Lea T. Grinberg and Dr. Bruce L. Miller. Dr. Anne Fagan will lead a CSF array sub-core The Human Core goals are to: (1) directly supporting this CWOW?s Projects (P) with well-characterized and carefully treated human tissue, bio-fluids, and cells from tauopathy patients and controls; (2) validating the relevance results from P 1-3 in human specimens; (3) developing enhanced tools for boosting the amount of information retrieved for each single biospecimen samples. These core functions will support the aims of Projects 1 (PI: Gan) and 3 (PI: Cuervo) by providing well-characterized human brain and bio fluid specimens from tauopathies. Moreover, the Human Core will help to validate the findings from the CWOW?s projects to accelerate translation from bench to clinical use.
|
0.938 |
2016 — 2021 |
Grinberg, Lea Tenenholz |
K24Activity Code Description: To provide support for the clinicians to allow them protected time to devote to patient-oriented research and to act as mentors for beginning clinical investigators. |
Neuropathological Changes Underlying Clinical Heterogeneity in Alzheimer Disease @ University of California, San Francisco
ABSTRACT This is an application for a K24 award for Dr. Lea T. Grinberg, a neuropathologist at the University of California, San Francisco (UCSF). Dr. Grinberg is an Associate Professor in Residence and co-lead the UCSF/Memory and Aging Center's Neuropathology Core. She is an established researcher in the patient- oriented clinical research of dementia. A distinctive hallmark of her research is her direct involvement in creating, managing and analyzing well-characterized postmortem collections of brains belonging to people at- risk or already with dementia. Dr. Grinberg proposes to use K24 dedicated time to mentor USCF as well as international investigators in patient-oriented dementia research. Her mentees will gain hands-on research experience, expertise in age-related human neuropathology, training in data analysis, manuscript preparation, and grant writing, as well as career, mentoring. Mentee training will leverage the infrastructure and resources of the UCSF/Memory and Aging Center Autopsy program, which is part of ongoing longitudinal cohort studies (P50AG02350 and P01AG019724), and her collaborations with multidisciplinary researchers in the areas of dementia domestically and worldwide. To increase her mentoring skills, she proposes to participate in the UCSF Mentor Development Program. Dr. Grinberg intends to conduct K24-supported Alzheimer's disease research studies that will serve as training vehicles for mentees and expand her research. These studies, using clinical, genetic and neuropathological data, will be conducted using data from ongoing UCSF/Memory and Aging Center's NIH-funded cohort studies of persons with Alzheimer's disease(AD) . She will examine the role of recently described neurodegenerative changes in modifying the clinical phenotype of AD. In summary, this K24 will enhance Dr. Ginberg's active research program with extensive infrastructure at UCSF to support her goal to remain a leader in neurodegenerative diseases, especially in the field of neuropathology, and to develop a program of excellence for training medical students, trainees, and junior faculty in POR related to age-related neuropathology that is also intended to close the gaps caused by interruption of neuropathology training for neurologists and neurodegenerative disease training for neuropathologists.
|
1.009 |
2020 — 2021 |
Grinberg, Lea Tenenholz Neylan, Thomas C |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Clinical Features and Neuropathological Basis of Sleep Wake Behavior in Alzheimer's and Psp @ University of California, San Francisco
PROJECT SUMMARY / ABSTRACT Sleep disturbances occur frequently in neurodegenerative disease and constitute the most common reason for institutionalization. Sleep disruption has also been proposed to contribute causally to increasing amyloid beta (A?) deposition, which has fueled interest in bidirectional relationships of sleep and Alzheimer's Disease (AD), but its relationship to the other major AD neuropathology ? accumulation of pathogenic tau-related neurofibrillary tangles ? is unknown. In AD, sleep dysfunction includes sleep fragmentation, sundowning, and daytime sleepiness, measured by short sleep latencies on the multiple sleep latency test (MSLT). In contrast, we found that Progressive Supranuclear Palsy (PSP), a different tauopathy not associated with A? deposition, features marked reductions in duration of both Rapid Eye Movement (REM) sleep and Non-REM (NREM) sleep, and prolonged sleep latencies seen by MSLT. The tau neuropathologies of AD and PSP both begin subcortically, in brainstem and hypothalamus. Their divergent sleep-wake behavior profiles ? in PSP, dramatically decreased total sleep time, absent daytime sleep, vs. in AD, sleep redistributed across night & day periods, with little reduction of total sleep time ? along with contrasting tau burden in sleep- and wake-related brainstem nuclei (Prelim. Res.), provides a novel opportunity to discover the neurobiological basis of their disturbed sleep-wake rhythms. We will test the novel hypothesis that differential vulnerabilities of nuclei in wake-promoting (loss in AD > PSP) and sleep-promoting (loss in PSP > AD) neurons determines the different pattern of sleep-wake disturbances in these 2 contrasting tauopathies. The premise of this proposal is that: 1) sleep-wake disturbances are common to both of these tauopathies; 2) leveraging the subcortical anatomically distinct neurodegeneration foci seen early in PSP & AD, that segregate functionally as wake-predominant in AD and sleep-predominant nuclei in PSP, as natural lesions, will uncover mechanisms of their differential profiles of disturbed sleep and wakefulness; and 3) future design of efficient, specific treatments for sleep in PSP and AD will require understanding of their respective mechanisms. We will test our idea by determining if differences in sleep-wake behavior in PSP and AD subjects vs. healthy controls (HC) are quantitatively attributable to corresponding altered pathoanatomical measures (including total numbers of neurons and of specific neuronal subpopulations, and hp-tau burden) in nuclei involved in wake and NREM sleep regulation. We will assess quantitative clinical neurohistopathological correlates in respective subsamples of PSP, AD, and control subjects who completed sleep measures prior to death and autopsy. The project represents a unique collaborative/interdisciplinary opportunity with highly specialized brain collections and sleep analysis, whose results may yield an unprecedented disease-specific mechanistic rationale for therapeutically targeting pro-sleep circuits vs. a wakefulness-inhibition approach in AD and PSP.
|
1.009 |
2020 — 2021 |
Grinberg, Lea Tenenholz Neylan, Thomas C |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Linking Sleep Dysfunction to Tau-Related Degeneration Across Ad Progression @ University of California, San Francisco
PROJECT SUMMARY / ABSTRACT Wake, sleep and circadian disturbances are common occurrences in Alzheimer' disease (AD), often times preceding amnestic symptoms. Such disturbances affect the quality of life of patients and caregivers alike and boost institutionalization. A bidirectional correlation between amyloid-beta (A?) deposition and disturbed sleep contributes to slow wave sleep (SWS) deficits and sleep fragmentation. We discovered converging evidence in human sleep and neuropathological studies suggesting that individuals with progressive supranuclear palsy (PSP), a primary tauopathy, show an extreme sleep phenotype featuring a much shorter sleep duration. This point for a role of tau-related degeneration as an underlying cause of sleep disfunction, independent of A? deposition. Interestingly, brainstem, hypothalamic and basal forebrain nuclei involved in circandian-sleep-wake regulation develop AD- tau-based neurofibrillary tangles preceding tangles in cortical areas and often, before A? plaques appear. Our working hypothesis is that tau-induced degeneration of key brainstem, hypothalamic and basal forebrain nuclei controlling 1) SWS; 2) waking-arousal; and 3) circadian timing underlie sleep-wake behavior in AD, preceding both cognitive decline and later emergence of the feedforward cycle of sleep disturbance and accelerated A? deposition. We will test our hypothesis contrasting sleep-wake behavior in progressive AD stages versus healthy controls by analyzing differences in objective sleep measurements, clinical and molecular imaging profiles and quantitative pathoanatomical measures in nuclei involved in wake, NREM sleep regulation and circadian rhythm. Moreover, we will add a PSP as a positive control group. We are uniquely poised to succeed due to our group expertise, track record of working together and our access to uniquely well characterized clinicopathological cohort. This combination of factors creates a unique opportunity to exploit novel human findings that will inform and complement mechanistic hypotheses and testing in model systems. This is critical because animals' sleep-wake patterns and AD-like models diverge from those of humans and experimental models rather mimic non-AD tauopathies than tau-related AD patterns. We anticipate our findings will inform critical information on the temporal sequence of disrupted sleep and/or circadian rhythms and the accumulation and spreading of protein aggregates such as phospho-tau and A? in AD. Beyond this, results from this study will inform rational therapies for treating disturbed sleep in AD.
|
1.009 |
2021 |
Grinberg, Lea Tenenholz Resende, Elisa |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Better Memory With Literacy Acquisition Later in Life: a Randomized Controlled Trial @ University of California, San Francisco
Abstract Dementia is epidemic with a projected cost of $1.2 trillion by 2050. Currently, 2/3 of people with dementia live in low and middle-income countries (LMIC). 30% of dementia cases are preventable by modifying risk factors such as low education. Formal education acquired early in life protects against dementia, but whether acquiring education later in life can decrease dementia risk is less clear. Our previous cross-sectional work conducted in Brazil/UFMG in partnership with the USA/UCSF suggests that even few years of education might improve brain resilience by strengthening the relationship between episodic memory and medial temporal lobe structures, including the hippocampus (HC) and its connections. Whether acquiring education in adulthood could also strengthen those relationships and increase hippocampal efficiency is unknown. We started a pilot one-arm longitudinal study to determine whether a late-life literacy improves episodic memory measured by hippocampal functional and structural connectivity. Despite the historical challenges of enrolling illiterate adults in research, we devised a successful strategy and met the target enrollment and acquired baseline structural and functional MRIs, demonstrating feasibility of our approach. This proposal will build on and expand the collaboration between UFMG and UCSF to implement a two-arm, randomized controlled trial investigating the role of adult education in improving episodic memory and enhancing hippocampal connectivity. This partnership represents a unique opportunity to test this hypothesis given the combined expertise and resources from both centers. If successful in showing a benefit of adult education into memory, brain structure and function, this proposal will be critical for developing strategies to improve brain resilience and subsequently decrease dementia risk using a low-cost intervention. Noteworthy, The proposal will also contribute to build sustainable research capacity in Brazil by transferring the knowledge on advanced longitudinal neuroimaging analysis to UFMG. The learned techniques will be applied in further studies about neurological conditions conducted not only in UFMG but other Brazilian institutions.
|
1.009 |
2021 |
Grinberg, Lea Tenenholz |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Core C: Human Tissue Validation @ Icahn School of Medicine At Mount Sinai
PROJECT SUMMARY (CORE C: HUMAN TISSUE VALIDATION) The Human Tissue Validation Core will provide vital research support to the CWOW. Neurodegenerative disease pathology and genetics have become increasingly exciting and complex in recent years, with major advances arising from work accomplished using human postmortem tissue. In this application, Dr. Lea T. Grinberg will lead the Human Tissue Validation Core (Core C). The Human Core goals are to (1) directly supporting this CWOW?s Projects with well-characterized and carefully treated human tissue from tauopathy patients and controls; (2) validating the relevance results from Projects 1 and 2 in human specimens and assembloids; (3) developing enhanced tools for boosting the amount of information retrieved for each single biospecimen samples.
|
0.922 |
2021 |
Grinberg, Lea Tenenholz Liu, Chunlei [⬀] Otaduy, Maria Concepcion Garcia |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Imaging Brain Iron and Protein Aggregation With Mri For Assessing Alzheimer's Disease Pathology and Progression @ University of California Berkeley
Abstract Alzheimer?s disease (AD) affects over 5 million Americans and is expected to affect 2-3-fold more in the next few decades. AD is associated with aggregation of amyloid-beta (Ab) and phosphorylated tau proteins. Curiously, burden of A?, classically considered the most important AD pathological hallmark is not enough to indicate clinical decline or progression. For example, cognitive-normal elders may also carry high levels of A? and recent clinical trials aiming to reduce A? have generally failed to improve patients? conditions. Therefore, developing biomarkers that can better predict clinical outcome and progression are needed. Confluent evidence shows that regional brain magnetic susceptibility measured by MRI differs between AD patients and healthy controls, and importantly such changes may predict cognitive decline. However, it is unclear what causes these susceptibility changes in AD. While iron deposition has been widely suspected as the underlying cause, our recent study has discovered that aggregation of Ab and tau by itself produces strong diamagnetic susceptibility, opposite of the paramagnetic susceptibility generated by iron deposition. The opposing magnetic susceptibility of iron and aggregated pathological proteins poses a significant challenge as current MRI-based magnetic susceptibility mapping algorithms cannot differentiate iron from other colocalizing diamagnetic susceptibility sources within the same voxel. Our goal is to develop a novel technique that can differentially quantify molecular sources of magnetic susceptibility and test whether the resulting susceptibility components can serve as markers of progressive AD pathology. We will test our techniques and hypothesis utilizing a unique capability that combines in cranio MRI at autopsy with histological examinations. We have developed innovative histological processing methods that allow voxel-to-voxel matching between MRI and histology in 3D, thus permitting the examination of the relationship between magnetic susceptibility components and the neuropathology underlying AD. If successful, our techniques and findings might ultimately allow the detection of AD-related neuropathology at much earlier stages, permit intervention before neurons become irretrievably damaged and non-invasively assess disease progression. These techniques, once standardized, will be highly cost-effective, widely accessible and readily implementable in non-specialized clinical imaging centers, thus better serving the growing population of AD patients.
|
0.985 |