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Open Access Publications from the University of California

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.

  • Author(s): Theofilas, Panos
  • Ehrenberg, Alexander J
  • Dunlop, Sara
  • Di Lorenzo Alho, Ana T
  • Nguy, Austin
  • Leite, Renata Elaine Paraizo
  • Rodriguez, Roberta Diehl
  • Mejia, Maria B
  • Suemoto, Claudia K
  • Ferretti-Rebustini, Renata Eloah De Lucena
  • Polichiso, Livia
  • Nascimento, Camila F
  • Seeley, William W
  • Nitrini, Ricardo
  • Pasqualucci, Carlos Augusto
  • Jacob Filho, Wilson
  • Rueb, Udo
  • Neuhaus, John
  • Heinsen, Helmut
  • Grinberg, Lea T
  • et al.

INTRODUCTION: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. DISCUSSION: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.

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