title: The dorsal raphe nucleus shows phospho-tau neurofibrillary changes before the transentorhinal region in Alzheimer's disease. A precocious onset?
abstract: OBJECTIVE
  Alzheimer's disease (AD) is a progressive and irreversible disease. There is strong evidence that the progression of the phospho-tau neurofibrillary cytoskeletal changes, rather than the beta-amyloid burden, is crucial in determining the severity of the dementia in AD. The Braak and Braak staging system (BB) focuses mainly on the cortical cytoskeletal pathology and classifies this progressive pathology into six stages, spreading from the transentorhinal region to primary cortices. Although it is reported elsewhere that the midbrain's dorsal raphe nucleus (DR), which is connected with those areas of the cerebral cortex undergoing early changes during BB I and II, exhibits AD-related cytoskeletal pathology, this nucleus has not been considered by the BB.
  
  
  METHODS
  To determine during which BB stage and how frequently the DR is affected by AD-related neurofibrillary changes, we studied the DR of 118 well-characterized individuals of the Brain Bank of the Brazilian Aging Brain Study Group categorized according to the BB. Thirty-eight of these individuals were staged as BB = 0, and 80 as BB >or= 1.
  
  
  RESULTS
  In all of the BB >or= 1 individuals (cortical neurofibrillary changes were present at least in the transentorhinal region) and in more than 1/5 of the BB = 0 individuals neurofibrillary changes were detected in the supratrochlear subnucleus of the DR.
  
  
  CONCLUSIONS
  These observations: (i) support the hypothesis of transneuronal spread of neurofibrillary changes from the DR to its interconnected cortical brain areas; and (ii) indicate that the supratrochlear subnucleus of the DR is affected by neurofibrillary changes before the transentorhinal cortex during the disease process underlying AD.
authors.affiliation: Department of Pathology, Instituto Israelita de Ensino e Pesquisa Albert Einstein, São Paulo, Brazil.
authors.forename: L T
authors.initials: LT
authors.lastname: Grinberg
authors.forename: U
authors.initials: U
authors.lastname: Rüb
authors.forename: R E L
authors.initials: RE
authors.lastname: Ferretti
authors.forename: R
authors.initials: R
authors.lastname: Nitrini
authors.forename: J M
authors.initials: JM
authors.lastname: Farfel
authors.forename: L
authors.initials: L
authors.lastname: Polichiso
authors.forename: K
authors.initials: K
authors.lastname: Gierga
authors.forename: W
authors.initials: W
authors.lastname: Jacob-Filho
authors.forename: H
authors.initials: H
authors.lastname: Heinsen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000453:epidemiology / Q000378:metabolism / Q000473:pathology*; D003865:Major Depressive Disorder / Q000453:epidemiology; D018450:Disease Progression; D004493:Education; D018728:Entorhinal Cortex / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D011903:Raphe Nuclei / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D012720:Severity of Illness Index; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins