title: A novel approach for integrative studies on neurodegenerative diseases in human brains.
abstract: Despite a massive research effort to elucidate Alzheimer's disease (AD) in recent decades, effective treatment remains elusive. This failure may relate to an oversimplification of the pathogenic processes underlying AD and also lack of understanding of AD progression during its long latent stages. Although evidence shows that the two specific neuropathological hallmarks in AD (neuronal loss and protein accumulation), which are opposite in nature, do not progress in parallel, the great majority of studies have focused on only one of these aspects. Furthermore, research focusing on single structures is likely to render an incomplete picture of AD pathogenesis because as AD involves complete brain networks, potential compensatory mechanisms within the network may ameliorate impairment of the system to a certain extent. Here, we describe an approach for enabling integrative analysis of the dual-nature lesions, simultaneously, in all components of one of the brain networks most vulnerable to AD. This approach is based on significant development of methods previously described mainly by our group that were optimized and complemented for this study. It combines unbiased stereology with immunohistochemistry and immunofluorescence, making use of advanced graphics computing for three-dimensional (3D) volume reconstructions. Although this study was performed in human brainstem and focused in AD, it may be applied to the study of any neurological disease characterized by dual-nature lesions, in humans and animal models. This approach does not require a high level of investment in new equipment and a significant number of specimens can be processed and analyzed within a funding cycle.
authors: Memory and Aging Center, Department of Neurology, University of California, San Francisco Nelson Rising Lane, P.O. Box 1207, San Francisco, CA 94143, USA.
authors: Panos
authors: P
authors: Theofilas
authors: Memory and Aging Center, Department of Neurology, University of California, San Francisco Nelson Rising Lane, P.O. Box 1207, San Francisco, CA 94143, USA; Discipline of Pathophysiology, University of Sao Paulo Medical School, Av. Dr. Arnaldo 455, Sao Paulo, CEP 01246903, SP, Brazil.
authors: Livia
authors: L
authors: Polichiso
authors: Memory and Aging Center, Department of Neurology, University of California, San Francisco Nelson Rising Lane, P.O. Box 1207, San Francisco, CA 94143, USA.
authors: Xuehua
authors: X
authors: Wang
authors: Discipline of Pathophysiology, University of Sao Paulo Medical School, Av. Dr. Arnaldo 455, Sao Paulo, CEP 01246903, SP, Brazil; Hospital Israelita Brasileiro Albert Einstein, Av. Albert Einstein 627/701, Sao Paulo, SP, Brazil.
authors: Luzia C
authors: LC
authors: Lima
authors: Discipline of Pathophysiology, University of Sao Paulo Medical School, Av. Dr. Arnaldo 455, Sao Paulo, CEP 01246903, SP, Brazil; Hospital Israelita Brasileiro Albert Einstein, Av. Albert Einstein 627/701, Sao Paulo, SP, Brazil.
authors: Ana T L
authors: ATL
authors: Alho
authors: Department of Pathology, LIM-22, University of Sao Paulo Medical School, Av. Dr. Arnaldo 455, sala 1353, Sao Paulo, CEP 01246903, SP, Brazil.
authors: Renata E P
authors: REP
authors: Leite
authors: Division of Geriatrics, University of Sao Paulo Medical School, Av. Dr. Arnaldo 455, sala 1151, Sao Paulo, SP, Brazil.
authors: Claudia K
authors: CK
authors: Suemoto
authors: Department of Pathology, LIM-22, University of Sao Paulo Medical School, Av. Dr. Arnaldo 455, sala 1353, Sao Paulo, CEP 01246903, SP, Brazil.
authors: Carlos A
authors: CA
authors: Pasqualucci
authors: Division of Geriatrics, University of Sao Paulo Medical School, Av. Dr. Arnaldo 455, sala 1151, Sao Paulo, SP, Brazil.
authors: Wilson
authors: W
authors: Jacob-Filho
authors: Laboratory of Morphological Brain Research, Department of Psychiatry, University of Wuerzburg, Oberdürrbacher Str. 6, 97080 Würzburg, Germany.
authors: Helmut
authors: H
authors: Heinsen
authors: Department of Pathology, LIM-22, University of Sao Paulo Medical School, Av. Dr. Arnaldo 455, sala 1353, Sao Paulo, CEP 01246903, SP, Brazil.
authors: Memory and Aging Center, Department of Neurology, University of California, San Francisco Nelson Rising Lane, P.O. Box 1207, San Francisco, CA 94143, USA; Discipline of Pathophysiology, University of Sao Paulo Medical School, Av. Dr. Arnaldo 455, Sao Paulo, CEP 01246903, SP, Brazil. Electronic address: Lea.Grinberg@ucsf.edu.
authors: Lea T
authors: LT
authors: Grinberg
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001927:Brain Diseases / Q000378:metabolism / Q000473:pathology; D001933:Brain Stem / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique / Q000191:economics / Q000379:methods*; D006801:Humans; D021621:Imaging, Three-Dimensional / Q000191:economics / Q000379:methods*; D007150:Immunohistochemistry / Q000191:economics / Q000379:methods*; D008125:Locus Coeruleus / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009434:Neural Pathways / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology; D011903:Raphe Nuclei / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
keywords: 3D reconstruction; Alzheimer's disease; Brain network; Brainstem; Human; Immunohistochemistry; Neurodegenerative diseases; Neuropathology; Stereology