Associations of Growth-Associated Protein 43 with Cerebral Microbleeds: A Longitudinal Study

Article type: Research Article

Authors: Li, Da^{a; 1} | Sun, Yan^{b; 1} | Ding, Lin^c | Fu, Yan^b | Zhou, Jie^a | Yu, Jin-Tai^{a; d; *} | Tan, Lan^{b; *} | for the Alzheimer’s Disease Neuroimaging Initiative

Affiliations: [a] Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Nanjing, China | [b] Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China | [c] Department of Neurosurgery, Rizhao People’s Hospital, Rizhao, China | [d] Department of Neurology and Institute of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China

Correspondence: [*] Correspondence to: Prof. Lan Tan, Department of Neurology, Qingdao Municipal Hospital, No. 5 Donghai Middle Road, Qingdao, China. E-mail: [email protected] and Prof. Jin-Tai Yu, Department of Neurology, Huashan Hospital, Fudan University, 12th Wulumuqi Zhong Road, Shanghai 200040, China. Tel.: +86 21 52888160; Fax: +86 21 62483421; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Note: [2] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

Abstract: Background:Cerebral microbleeds (CMB) play an important role in neurodegenerative pathology. Objective:The present study aims to test whether cerebrospinal fluid (CSF) growth-associated protein 43 (GAP-43) level is linked to CMBs in elderly people. Methods:A total of 750 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who had measurements of GAP-43 and CMBs were included in the study. According to the presence and extent of CMBs, participants were stratified into different groups. Regression analyses were used to assess cross-sectional and longitudinal associations between GAP-43 and CMBs. Results:Participants with CMB were slightly older and had higher concentrations of CSF GAP43. In multivariable adjusted analyses for age, gender, APOE ɛ4 status, and cognitive diagnoses, higher CSF GAP-43 concentrations were modestly associated with CMB presence (OR = 1.169, 95% CI = 1.001–1.365) and number (β= 0.020, SE = 0.009, p = 0.027). Similarly, higher CSF GAP43 concentrations were accrual of CMB lesions, associated with higher CMB progression (OR = 1.231, 95% CI = 1.044–1.448) and number (β= 0.017, SE = 0.005, p = 0.001) in the follow up scan. In stratified analyses, slightly stronger associations were noted in male participants, those 65 years and older, carriers of APOE ɛ4 alleles, and with more advanced cognitive disorders. Conclusions:CSF GAP-43 was cross-sectionally associated with the presence and extent of CMBs. GAP-43 might be used as a biomarker to track the dynamic changes of CMBs in elderly persons.

Keywords: Alzheimer’s disease, Alzheimer’s disease Neuroimaging Initiative, cerebral microbleeds, CSF biomarker, GAP-43, synaptic dysfunction

DOI: 10.3233/JAD-230508

Journal: Journal of Alzheimer's Disease, vol. 97, no. 4, pp. 1913-1922, 2024