title: Association of pituitary adenylate cyclase-activating polypeptide with cognitive decline in mild cognitive impairment due to Alzheimer disease.
abstract: OBJECTIVE
  There is a deficit of pituitary adenylate cyclase-activating polypeptide (PACAP) in patients with neuropathologically confirmed Alzheimer dementia. However, whether this deficit is associated with the earlier stages of Alzheimer disease (AD) is unknown. This study was conducted to clarify the association between PACAP biomarkers and preclinical, mild cognitive impairment (MCI), and dementia stages of AD in postmortem brain tissue.
  
  
  OBJECTIVE
  To examine PACAP and PACAP receptor levels in postmortem brain tissues and cerebrospinal fluid from cognitively and neuropathologically normal control individuals, patients with MCI due to AD (MCI-AD), and individuals with AD; analyze the relationship between PACAP, cognitive, and pathologic features; and propose a model to assess these relationships.
  
  
  METHODS
  We measured PACAP and its receptor (PAC1) levels using enzyme-linked immunoassay. A total of 35 cases were included. All the brain tissue and cerebrospinal fluid samples were selected from Banner Sun Health Research Institute Brain and Body Donation Program. All cognitive test results were in record with the Arizona Alzheimer's Consortium.
  
  
  METHODS
  A comparison of PACAP and PAC1 levels among the healthy controls, MCI-AD, and AD dementia groups, as well as a systematic correlation analysis between PACAP level, cognitive performance, and pathologic severity.
  
  
  RESULTS
  The PACAP levels in cerebrospinal fluid, the superior frontal gyrus, and the middle temporal gyrus were inversely related to dementia severity. The PACAP levels in cerebrospinal fluid correlated with the Mattis Dementia Rating Scale score (Pearson r = 0.50; P = .03) and inversely correlated with total amyloid plaques (Pearson r = -0.48; P < .01) and tangles (Pearson r = -0.55; P = .01) in the brain. The PACAP in the superior frontal gyrus and middle temporal gyrus correlated with the Stroop Color-Word Interference Test (Pearson r = 0.58; P < .01) and the Auditory Verbal Learning Test-Total Learning (Pearson r = 0.33; P = .02), respectively. The PACAP in the primary visual cortex did not correlate with the Judgment of Line orientation test (P = .14). Furthermore, the PAC1 level in the superior frontal gyrus showed an upregulation in MCI-AD but not in AD. The pharmacodynamic model of the PACAP-PAC1 interaction best predicted cognitive function in the superior frontal gyrus, but it was less predictive in the middle temporal gyrus and failed to be predictive in the primary visual cortex.
  
  
  CONCLUSIONS
  Deficits in PACAP are associated with clinical severity in the MCI and dementia stages of AD. Additional studies are needed to clarify the role of PACAP deficits in the predisposition to, pathogenesis of, and treatment of AD.
authors.affiliation: Barrow Neurological Institute, Dignity Health Organization, St Joseph's Hospital and Medical Center, Phoenix, Arizona.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Han
authors.affiliation: Department of Neurology, Mayo Clinic, Scottsdale, Arizona.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Caselli
authors.affiliation: Barrow Neurological Institute, Dignity Health Organization, St Joseph's Hospital and Medical Center, Phoenix, Arizona.
authors.forename: Leslie
authors.initials: L
authors.lastname: Baxter
authors.affiliation: Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, Arizona.
authors.forename: Geidy
authors.initials: G
authors.lastname: Serrano
authors.affiliation: Barrow Neurological Institute, Dignity Health Organization, St Joseph's Hospital and Medical Center, Phoenix, Arizona.
authors.forename: Junxiang
authors.initials: J
authors.lastname: Yin
authors.affiliation: Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, Arizona.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Beach
authors.affiliation: Banner Alzheimer's Institute, Phoenix, Arizona.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Reiman
authors.affiliation: Barrow Neurological Institute, Dignity Health Organization, St Joseph's Hospital and Medical Center, Phoenix, Arizona.
authors.forename: Jiong
authors.initials: J
authors.lastname: Shi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis / Q000378:metabolism; D015415:Biomarkers / Q000134:cerebrospinal fluid / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid* / Q000175:diagnosis / Q000378:metabolism; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D008297:Male; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000134:cerebrospinal fluid* / Q000378:metabolism
chemical_list: C495401:ADCYAP1 protein, human; D015415:Biomarkers; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide