Panos Theofilas1, Alexander J Ehrenberg1, Sara Dunlop1, Ana T Di Lorenzo Alho2, Austin Nguy1, Renata Elaine Paraizo Leite3, Roberta Diehl Rodriguez3, Maria B Mejia1, Claudia K Suemoto4, Renata Eloah De Lucena Ferretti-Rebustini5, Livia Polichiso3, Camila F Nascimento3, William W Seeley1, Ricardo Nitrini6, Carlos Augusto Pasqualucci3, Wilson Jacob Filho4, Udo Rueb7, John Neuhaus8, Helmut Heinsen9, Lea T Grinberg10. 1. Department of Neurology, University of California, San Francisco, San Francisco, CA, USA. 2. Hospital Albert Einstein, São Paulo, Brazil; Department of Pathology, LIM-22, University of São Paulo Medical School, São Paulo, Brazil. 3. Department of Pathology, LIM-22, University of São Paulo Medical School, São Paulo, Brazil. 4. Division of Geriatrics, University of Sao Paulo Medical School, São Paulo, Brazil. 5. University of São Paulo, School of Nursing, São Paulo, Brazil. 6. Department of Neurology, University of Sao Paulo Medical School, São Paulo, Brazil. 7. University of Frankfurt, Frankfurt, Germany. 8. Department of Biostatistics, University of California, San Francisco, CA, USA. 9. Department of Pathology, LIM-22, University of São Paulo Medical School, São Paulo, Brazil; University of Wuerzburg, Wuerzburg, Germany. 10. 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.
Abstract
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.
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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