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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Clinical Neuroscience and Neurodegeneration Study Section (CNN)
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Petanceska, Suzana
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Theofilas, Panos; Ehrenberg, Alexander J; Nguy, Austin et al. (2018) Probing the correlation of neuronal loss, neurofibrillary tangles, and cell death markers across the Alzheimer's disease Braak stages: a quantitative study in humans. Neurobiol Aging 61:1-12
Alho, Eduardo Joaquim Lopes; Alho, Ana Tereza Di Lorenzo; Grinberg, Lea et al. (2018) High thickness histological sections as alternative to study the three-dimensional microscopic human sub-cortical neuroanatomy. Brain Struct Funct 223:1121-1132
Alho, A T D L; Hamani, C; Alho, E J L et al. (2017) Magnetic resonance diffusion tensor imaging for the pedunculopontine nucleus: proof of concept and histological correlation. Brain Struct Funct 222:2547-2558
Theofilas, Panos; Ehrenberg, Alexander J; Dunlop, Sara et al. (2017) Locus coeruleus volume and cell population changes during Alzheimer's disease progression: A stereological study in human postmortem brains with potential implication for early-stage biomarker discovery. Alzheimers Dement 13:236-246
Ehrenberg, A J; Nguy, A K; Theofilas, P et al. (2017) Quantifying the accretion of hyperphosphorylated tau in the locus coeruleus and dorsal raphe nucleus: the pathological building blocks of early Alzheimer's disease. Neuropathol Appl Neurobiol 43:393-408
Dos Santos Matioli, Maria Niures Pimentel; Suemoto, Claudia Kimie; Rodriguez, Roberta Diehl et al. (2017) Diabetes is Not Associated with Alzheimer's Disease Neuropathology. J Alzheimers Dis 60:1035-1043
Alegro, Maryana; Theofilas, Panagiotis; Nguy, Austin et al. (2017) Automating cell detection and classification in human brain fluorescent microscopy images using dictionary learning and sparse coding. J Neurosci Methods 282:20-33
Takada, Leonel T; Bahia, Valeria S; GuimarĂ£es, Henrique C et al. (2016) GRN and MAPT Mutations in 2 Frontotemporal Dementia Research Centers in Brazil. Alzheimer Dis Assoc Disord 30:310-317
McAleese, Kirsty E; Alafuzoff, Irina; Charidimou, Andreas et al. (2016) Post-mortem assessment in vascular dementia: advances and aspirations. BMC Med 14:129
Stratmann, Katharina; Heinsen, Helmut; Korf, Horst-Werner et al. (2016) Precortical Phase of Alzheimer's Disease (AD)-Related Tau Cytoskeletal Pathology. Brain Pathol 26:371-86

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