Association Between Cerebral Microbleeds and Circulating Levels of Mid-Regional Pro-Adrenomedullin

Article type: Research Article

Authors: Kuriyama, Nagato^{a; b; *} | Koyama, Teruhide^a | Ozaki, Etsuko^a | Saito, Satoshi^c | Ihara, Masafumi^c | Matsui, Daisuke^a | Watanabe, Isao^a | Kondo, Masaki^d | Marunaka, Yoshinori^{e; f} | Takada, Akihiro^e | Akazawa, Kentaro^g | Tomida, Satomi^a | Nagamitsu, Reo^a | Miyatani, Fumitaro^a | Miyake, Masahiro^h | Nakano, Eri^h | Kobayashi, Daikiⁱ | Watanabe, Yoshiyuki^j | Mizuno, Shigeto^k | Maekawa, Mizuho^a | Yoshida, Tamami^a | Nukaya, Yukiko^a | Mizuno, Toshiki^d | Yamada, Kei^g | Uehara, Ritei^a

Affiliations: [a] Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan | [b] Department of Social Health Medicine, Shizuoka Graduate University of Public Health, Shizuoka, Japan | [c] Department of Stroke and Cerebrovascular Diseases, Division of Neurology, National Cerebral and Cardiovascular Center, Osaka, Japan | [d] Department of Neurology, Kyoto Prefectural University of Medicine, Kyoto, Japan | [e] Medical Research Institute, Kyoto Industrial Health Association, Kyoto, Japan | [f] Research Center for Drug Discovery and Pharmaceutical Development Science, Research Organization of Science and Technology, Ritsumeikan University, Kusatsu, Japan | [g] Department of Radiology, Kyoto Prefectural University of Medicine, Kyoto, Japan | [h] Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan | [i] Division of General Internal Medicine, Department of Medicine, St. Luke’s International Hospital, Tokyo, Japan | [j] Faculty of Health and Medical Sciences, Kyoto University of Advanced Science | [k] Department of Endoscopy, Kindai University Nara Hospital, Nara Prefecture, Japan

Correspondence: [*] Correspondence to: Nagato Kuriyama, MD, PhD, Professor, Department of Social Health Medicine, Shizuoka Graduate University of Public Health, 4-27-2, Aoi-ku, Kita-ando, Shizuoka city, 420-0881, Japan. Tel.: +81 54 295 5400; Fax: +81 54 248 3520; E-mail: [email protected].

Abstract: Background:Mid-regional pro-adrenomedullin (MR-proADM) is a novel biomarker for cognitive decline based on its association with cerebral small vessel disease (SVD). Cerebral microbleeds (MBs) are characteristic of SVD; however, a direct association between MR-proADM and MBs has not been explored. Objective:We aimed to examine whether circulating levels of MR-proADM are associated with the identification of MBs by brain magnetic resonance imaging (MRI) and whether this association could be linked with cognitive impairment. Methods:In total, 214 participants (mean age: 75.9 years) without history of cerebral infarction or dementia were prospectively enrolled. All participants underwent brain MRI, higher cognitive function testing, blood biochemistry evaluation, lifestyle examination, and blood MR-proADM measurement using a time-resolved amplified cryptate emission technology assay. For between-group comparisons, the participants were divided into two groups according to whether their levels of MR-proADM were normal (< 0.65 nmol/L) or high (≥0.65 nmol/L). Results:The mean MR-proADM level was 0.515±0.127 nmol/L. There were significant between-group differences in age, hypertension, and HbA1c levels (p < 0.05). In the high MR-proADM group, the MR-proADM level was associated with the identification of MBs on brain MR images and indications of mild cognitive impairment (MCI). In participants with ≥3 MBs and MCI, high MR-proADM levels remained a risk factor after multivariate adjustment (OR: 2.94; p < 0.05). Conclusion:High levels of MR-proADM may be a surrogate marker for the early detection of cognitive decline associated with the formation of cerebral MBs. This marker would be valuable during routine clinical examinations of geriatric patients.

Keywords: Adrenomedullin, biomarkers, cerebral small vessel diseases, cognitive dysfunction, magnetic resonance imaging, peptides

DOI: 10.3233/JAD-220195

Journal: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 731-741, 2022