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. 2020;73(1):217-227.
doi: 10.3233/JAD-191016.

A New Serum Biomarker Set to Detect Mild Cognitive Impairment and Alzheimer's Disease by Peptidome Technology

Koji Abe  1 , Jingwei Shang  1 , Xiaowen Shi  1 , Toru Yamashita  1 , Nozomi Hishikawa  1 , Mami Takemoto  1 , Ryuta Morihara  1 , Yumiko Nakano  1 , Yasuyuki Ohta  1 , Kentaro Deguchi  2 , Masaki Ikeda  3 , Yoshio Ikeda  3 , Koichi Okamoto  4 , Mikio Shoji  4 , Masamitsu Takatama  4 , Motohisa Kojo  5 , Takeshi Kuroda  6 , Kenjiro Ono  6 , Noriyuki Kimura  7 , Etsuro Matsubara  7 , Yosuke Osakada  8 , Yosuke Wakutani  8 , Yoshiki Takao  8 , Yasuto Higashi  9 , Kyoichi Asada  10 , Takehito Senga  10 , Lyang-Ja Lee  10 , Kenji Tanaka  10
Affiliations

A New Serum Biomarker Set to Detect Mild Cognitive Impairment and Alzheimer's Disease by Peptidome Technology

Koji Abe et al. J Alzheimers Dis. 2020.

Abstract

Background: Because dementia is an emerging problem in the world, biochemical markers of cerebrospinal fluid (CSF) and radio-isotopic analyses are helpful for diagnosing Alzheimer's disease (AD). Although blood sample is more feasible and plausible than CSF or radiological biomarkers for screening potential AD, measurements of serum amyloid- β (Aβ), plasma tau, and serum antibodies for Aβ1 - 42 are not yet well established.

Objective: We aimed to identify a new serum biomarker to detect mild cognitive impairment (MCI) and AD in comparison to cognitively healthy control by a new peptidome technology.

Methods: With only 1.5μl of serum, we examined a new _target plate "BLOTCHIP®" plus a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS) to discriminate control (n = 100), MCI (n = 60), and AD (n = 99). In some subjects, cognitive Mini-Mental State Examination (MMSE) were compared to positron emission tomography (PET) with Pittsburgh compound B (PiB) and the serum probability of dementia (SPD). The mother proteins of candidate serum peptides were examined in autopsied AD brains.

Results: Apart from Aβ or tau, the present study discovered a new diagnostic 4-peptides-set biomarker for discriminating control, MCI, and AD with 87% of sensitivity and 65% of specificity between control and AD (***p < 0.001). MMSE score was well correlated to brain Aβ deposition and to SPD of AD. The mother proteins of the four peptides were upregulated for coagulation, complement, and plasticity (three proteins), and was downregulated for anti-inflammation (one protein) in AD brains.

Conclusion: The present serum biomarker set provides a new, rapid, non-invasive, highly quantitative and low-cost clinical application for dementia screening, and also suggests an alternative pathomechanism of AD for neuroinflammation and neurovascular unit damage.

Keywords: Alzheimer’s disease; MALDI-TOF; biomarker; coagulation; complement; mild cognitive impairment; neuroinflammation; peptidome; plasticity.

PubMed Disclaimer

Conflict of interest statement

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/19-1016r1).

Figures

Fig.1
Fig.1
Serum probability of dementia (SPD, boxes) and MMSE (circles) in 100 normal control (NC) subjects, 60 MCI due to AD subjects, and 99 AD patients. Note serial increase of SPD and decrease of MMSE from NC, MCI to AD. Open circle represent NC, grey MCI, and black AD.
Fig.2
Fig.2
Amyloid PET and SPD with MMSE in 11 PET subjects for 1 NC, 3 MCI, and 7 AD. Panels A and B shows Aβ negative- and positive-example, (C) MMSE versus relative PET value of negative with 1 or less and positive with more than 1, and (D) MMSE versus SPD. Note the cortical Aβ deposit in PET-positive example (B), the strong correlation of relative PET value with MMSE in all 11 subjects (r = –0.75, p = 0.0070, panel C, oblique dotted line), and a significant correlation of SPD with MMSE in 7 AD patients (r = –0.67, p = 0.0908, panel D, oblique dotted line). Correlation coefficient of SPD versus MMSE was r = –0.03, p = 0.9198 for all 11 subjects (D, dotted line). Open circle represents NC, grey MCI, and black AD. + or – of grey MCI and control are Aβ-PET positive or negative, respectively.
Fig.3
Fig.3
Immunohistochemical pathology of four mother proteins in AD brain. In comparison to control brains, note significant increases of three proteins (FBC, FAC, and PPC1l) and a decrease of AHSG in AD brain. Scale bar = 50μm (*p < 0.05 and **p < 0.01 versus Control).
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