title: 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.
abstract: BACKGROUND
  Alzheimer's disease (AD) progression follows a specific spreading pattern, emphasizing the need to characterize those brain areas that degenerate first. The brainstem's locus coeruleus (LC) is the first area to develop neurofibrillary changes (neurofibrillary tangles [NFTs]).
  
  
  METHODS
  The methods include unbiased stereological analyses in human brainstems to estimate LC volume and neuronal population in controls and individuals across all AD stages.
  
  
  RESULTS
  As the Braak stage increases by 1 unit, the LC volume decreases by 8.4%. Neuronal loss started only midway through AD progression. Age-related changes spare the LC.
  
  
  CONCLUSIONS
  The long gap between NFT accumulation and neuronal loss suggests that a second trigger may be necessary to induce neuronal death in AD. Imaging studies should determine whether LC volumetry can replicate the stage-wise atrophy observed here and how these changes are specific to AD. LC volumetry may develop into a screening biomarker for selecting high-yield candidates to undergo expensive and less accessible positron emission tomography scans and to monitor AD progression from presymptomatic stages.
authors: Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors: Panos
authors: P
authors: Theofilas
authors: Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors: Alexander J
authors: AJ
authors: Ehrenberg
authors: Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors: Sara
authors: S
authors: Dunlop
authors: Hospital Albert Einstein, São Paulo, Brazil; Department of Pathology, LIM-22, University of São Paulo Medical School, São Paulo, Brazil.
authors: Ana T
authors: AT
authors: Di Lorenzo Alho
authors: Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors: Austin
authors: A
authors: Nguy
authors: Department of Pathology, LIM-22, University of São Paulo Medical School, São Paulo, Brazil.
authors: Renata Elaine Paraizo
authors: REP
authors: Leite
authors: Department of Pathology, LIM-22, University of São Paulo Medical School, São Paulo, Brazil.
authors: Roberta Diehl
authors: RD
authors: Rodriguez
authors: Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors: Maria B
authors: MB
authors: Mejia
authors: Division of Geriatrics, University of Sao Paulo Medical School, São Paulo, Brazil.
authors: Claudia K
authors: CK
authors: Suemoto
authors: University of São Paulo, School of Nursing, São Paulo, Brazil.
authors: Renata Eloah De Lucena
authors: REL
authors: Ferretti-Rebustini
authors: Department of Pathology, LIM-22, University of São Paulo Medical School, São Paulo, Brazil.
authors: Livia
authors: L
authors: Polichiso
authors: Department of Pathology, LIM-22, University of São Paulo Medical School, São Paulo, Brazil.
authors: Camila F
authors: CF
authors: Nascimento
authors: Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
authors: William W
authors: WW
authors: Seeley
authors: Department of Neurology, University of Sao Paulo Medical School, São Paulo, Brazil.
authors: Ricardo
authors: R
authors: Nitrini
authors: Department of Pathology, LIM-22, University of São Paulo Medical School, São Paulo, Brazil.
authors: Carlos Augusto
authors: CA
authors: Pasqualucci
authors: Division of Geriatrics, University of Sao Paulo Medical School, São Paulo, Brazil.
authors: Wilson
authors: W
authors: Jacob Filho
authors: University of Frankfurt, Frankfurt, Germany.
authors: Udo
authors: U
authors: Rueb
authors: Department of Biostatistics, University of California, San Francisco, CA, USA.
authors: John
authors: J
authors: Neuhaus
authors: Department of Pathology, LIM-22, University of São Paulo Medical School, São Paulo, Brazil; University of Wuerzburg, Wuerzburg, Germany.
authors: Helmut
authors: H
authors: Heinsen
authors: Department of Neurology, University of California, San Francisco, San Francisco, CA, USA; Department of Pathology, LIM-22, University of São Paulo Medical School, São Paulo, Brazil. Electronic address: lea.grinberg@ucsf.edu.
authors: Lea T
authors: LT
authors: Grinberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D001344:Autopsy; D015415:Biomarkers / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008125:Locus Coeruleus / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000473:pathology*; D013238:Stereotaxic Techniques
chemical_list: D015415:Biomarkers
keywords: Alzheimer's disease; Brainstem; Human; Locus coeruleus; Neurofibrillary tangles; Neuron counts; Postmortem; Unbiased stereology; Volumetry