title: Quantifying the accretion of hyperphosphorylated tau in the locus coeruleus and dorsal raphe nucleus: the pathological building blocks of early Alzheimer's disease.
abstract: OBJECTIVE
  Hyperphosphorylated tau neuronal cytoplasmic inclusions (ht-NCI) are the best protein correlate of clinical decline in Alzheimer's disease (AD). Qualitative evidence identifies ht-NCI accumulating in the isodendritic core before the entorhinal cortex. Here, we used unbiased stereology to quantify ht-NCI burden in the locus coeruleus (LC) and dorsal raphe nucleus (DRN), aiming to characterize the impact of AD pathology in these nuclei with a focus on early stages.
  
  
  METHODS
  We utilized unbiased stereology in a sample of 48 well-characterized subjects enriched for controls and early AD stages. ht-NCI counts were estimated in 60-μm-thick sections immunostained for p-tau throughout LC and DRN. Data were integrated with unbiased estimates of LC and DRN neuronal population for a subset of cases.
  
  
  RESULTS
  In Braak stage 0, 7.9% and 2.6% of neurons in LC and DRN, respectively, harbour ht-NCIs. Although the number of ht-NCI+ neurons significantly increased by about 1.9× between Braak stages 0 to I in LC (P = 0.02), we failed to detect any significant difference between Braak stage I and II. Also, the number of ht-NCI+ neurons remained stable in DRN between all stages 0 and II. Finally, the differential susceptibility to tau inclusions among nuclear subdivisions was more notable in LC than in DRN.
  
  
  CONCLUSIONS
  LC and DRN neurons exhibited ht-NCI during AD precortical stages. The ht-NCI increases along AD progression on both nuclei, but quantitative changes in LC precede DRN changes.
authors.affiliation: University of California, San Francisco, California, USA.|University of California, Berkeley, California, USA.
authors.forename: A J
authors.identifier: http://orcid.org/0000-0003-4334-9424
authors.initials: AJ
authors.lastname: Ehrenberg
authors.affiliation: University of California, San Francisco, California, USA.|University of California, Berkeley, California, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Nguy
authors.affiliation: University of California, San Francisco, California, USA.
authors.forename: P
authors.initials: P
authors.lastname: Theofilas
authors.affiliation: University of California, San Francisco, California, USA.
authors.forename: S
authors.initials: S
authors.lastname: Dunlop
authors.affiliation: University of São Paulo Medical School, São Paulo, Brazil.
authors.forename: C K
authors.initials: CK
authors.lastname: Suemoto
authors.affiliation: University of São Paulo Medical School, São Paulo, Brazil.|Hospital Israelita Albert Einstein, São Paulo, Brazil.
authors.forename: A T
authors.initials: AT
authors.lastname: Di Lorenzo Alho
authors.affiliation: University of São Paulo Medical School, São Paulo, Brazil.
authors.forename: R P
authors.initials: RP
authors.lastname: Leite
authors.affiliation: University of São Paulo Medical School, São Paulo, Brazil.
authors.forename: R
authors.initials: R
authors.lastname: Diehl Rodriguez
authors.affiliation: University of California, San Francisco, California, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Mejia
authors.affiliation: University of Frankfurt, Frankfurt, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Rüb
authors.affiliation: University of São Paulo Medical School, São Paulo, Brazil.
authors.forename: J M
authors.initials: JM
authors.lastname: Farfel
authors.affiliation: University of São Paulo, School of Nursing, São Paulo, Brazil.
authors.forename: R E
authors.identifier: http://orcid.org/0000-0002-6159-5787
authors.initials: RE
authors.lastname: de Lucena Ferretti-Rebustini
authors.affiliation: University of São Paulo Medical School, São Paulo, Brazil.
authors.forename: C F
authors.initials: CF
authors.lastname: Nascimento
authors.affiliation: University of São Paulo Medical School, São Paulo, Brazil.
authors.forename: R
authors.initials: R
authors.lastname: Nitrini
authors.affiliation: University of São Paulo Medical School, São Paulo, Brazil.
authors.forename: C A
authors.initials: CA
authors.lastname: Pasquallucci
authors.affiliation: University of São Paulo Medical School, São Paulo, Brazil.
authors.forename: W
authors.initials: W
authors.lastname: Jacob-Filho
authors.affiliation: University of California, San Francisco, California, USA.
authors.forename: B
authors.initials: B
authors.lastname: Miller
authors.affiliation: University of California, San Francisco, California, USA.
authors.forename: W W
authors.initials: WW
authors.lastname: Seeley
authors.affiliation: University of São Paulo Medical School, São Paulo, Brazil.|University of Wüerzburg, Wüerzburg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Heinsen
authors.affiliation: University of California, San Francisco, California, USA.|University of São Paulo Medical School, São Paulo, Brazil.
authors.forename: L T
authors.initials: LT
authors.lastname: Grinberg
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D065847:Dorsal Raphe Nucleus / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000473:pathology; D008125:Locus Coeruleus / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins
keywords: Alzheimer disease; Human; brain stem; dorsal raphe nucleus; locus coeruleus; unbiased stereology