title: Neural reserve, neuronal density in the locus ceruleus, and cognitive decline.
abstract: OBJECTIVE
  To test the hypothesis that higher neuronal density in brainstem aminergic nuclei contributes to neural reserve.
  
  
  METHODS
  Participants are 165 individuals from the Rush Memory and Aging Project, a longitudinal clinical-pathologic cohort study. They completed a mean of 5.8 years of annual evaluations that included a battery of 19 cognitive tests from which a previously established composite measure of global cognition was derived. Upon death, they had a brain autopsy and uniform neuropathologic examination that provided estimates of the density of aminergic neurons in the locus ceruleus, dorsal raphe nucleus, substantia nigra, and ventral tegmental area plus summary measures of neuronal neurofibrillary tangles and Lewy bodies from these nuclei and medial temporal lobe and neocortex.
  
  
  RESULTS
  Neuronal densities in each nucleus were approximately normally distributed. In separate analyses, higher neuronal density in each nucleus except the ventral tegmental area was associated with slower rate of cognitive decline, but when modeled together only locus ceruleus neuronal density was related to cognitive decline (estimate = 0.003, SE = 0.001, p < 0.001). Higher densities of tangles and Lewy bodies in these brainstem nuclei were associated with faster cognitive decline even after controlling for pathologic burden elsewhere in the brain. Locus ceruleus neuronal density, brainstem tangles, and brainstem Lewy bodies had independent associations with rate of cognitive decline. In addition, at higher levels of locus ceruleus neuronal density, the association of Lewy bodies with cognitive decline was diminished.
  
  
  CONCLUSIONS
  Density of noradrenergic neurons in the locus ceruleus may be a structural component of neural reserve.
authors.affiliation: Rush Alzheimer's Disease Center and Departments of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA. rwilson@rush.edu
authors.forename: Robert S
authors.initials: RS
authors.lastname: Wilson
authors.forename: Sukriti
authors.initials: S
authors.lastname: Nag
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Boyle
authors.forename: Loren P
authors.initials: LP
authors.lastname: Hizel
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.forename: Aron S
authors.initials: AS
authors.lastname: Buchman
authors.forename: Julie A
authors.initials: JA
authors.lastname: Schneider
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology; D001344:Autopsy / Q000379:methods; D001933:Brain Stem / Q000473:pathology*; D003071:Cognition / Q000502:physiology*; D003072:Cognition Disorders / Q000473:pathology*; D015331:Cohort Studies; D006801:Humans; D008125:Locus Coeruleus / Q000473:pathology*; D008137:Longitudinal Studies / Q000379:methods; D008568:Memory / Q000502:physiology; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000473:pathology; D009474:Neurons / Q000473:pathology*