Association of Pituitary Adenylate Cyclase–Activating Polypeptide With Cognitive Decline in Mild Cognitive Impairment Due to Alzheimer Disease

Abstract

IMPORTANCE 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.OBJECTIVES 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. DESIGN, SETTING, AND PARTICIPANTSWe 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. MAIN OUTCOMES AND MEASURESA 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. RESULTSThe 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 AND RELEVANCE 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.

PACAP as a Potential Biomarker: Alterations of PACAP Levels in Human Physiological and Pathological Conditions

“…In a subsequent study, the same research group showed that PACAP decline was associated with mild cognitive impairment preceding Alzheimer's disease in the above described brain areas [ 18 ]. It was found that PACAP levels were lower not only in the superior frontal gyrus and middle temporal gyrus but also in the CSF [ 18 ], although to a lesser extent than in fully developed Alzheimer's disease.…”

“…These results show that PACAP does not only play a role in the pathological mechanisms of different types of primary headaches, but its plasma levels are associated with the disease and show correlation with the migraine phases [ 40 , 41 ]. Another recent study has further confi rmed the signifi cance of PACAP in the pathogenesis of migraine, rather than in tension-type headaches [ 18 ]. The authors confi rmed significantly lower interictal levels of PACAP in migraineurs than in healthy controls or in tension-type headache patients.…”

“…It was found that PACAP levels were lower not only in the superior frontal gyrus and middle temporal gyrus but also in the CSF [ 18 ], although to a lesser extent than in fully developed Alzheimer's disease. Values were inversely correlated with the dementia rating score.…”

“…These data suggest a progressive decline of PACAP levels in Alzheimer-related dementias. The expression level of the PAC1 receptor was also evaluated and it was shown to be upregulated in mild cognitive impairment, but not in fully developed Alzheimer's disease in the superior frontal gyrus [ 18 ]. This implies a transient, possibly compensatory upregulation of PAC1 receptor in mild impairment, which is lost at more progressed states [ 18 ].…”

“…The expression level of the PAC1 receptor was also evaluated and it was shown to be upregulated in mild cognitive impairment, but not in fully developed Alzheimer's disease in the superior frontal gyrus [ 18 ]. This implies a transient, possibly compensatory upregulation of PAC1 receptor in mild impairment, which is lost at more progressed states [ 18 ]. The authors suggest that CSF PACAP could be a good candidate of disease progression marker given the close correlation with disease scores and the specifi city, since no reduction was observed in other types of dementia (see below).…”