The Sequential Blood-based Biomarkers in Longitudinal Study of Alzheimer’s Disease and Mild Cognitive Impairment

• Main Authors: Wei-Ju Lee, 李威儒
• Other Authors: Shing-Jong Lin
• Format: Others
• Language: en_US
• Published: 2018
• Online Access: http://ndltd.ncl.edu.tw/handle/75dgyr

博士 === 國立陽明大學 === 臨床醫學研究所 === 106 === Alzheimer’s disease (AD) is the most common neurodegenerative dementia. It is characterized by a progressive decline of cognition, behaviors and psychological symptoms (BPSD), and ultimately leads to total dependence. Mild cognitive impairment (MCI) is believed to be a pre-dementia state and to increase the risk of later developing dementia. Neurodegeneration in AD patients is characterized by amyloid beta protein (Aβ) deposits, aggregated hyperphosphorylated tau, neuroinflammation, and many aging-related changes. Aβ, clusterin, and monocyte chemoattractant protein-1 (MCP-1) are three important biomarkers involving AD pathogenesis. Aβ is the core pathological hallmark of AD. Clusterin is a multifunctional lipoprotein involved in Aβ fibrillation, clearance, and complement inhibition. MCP-1, also known as chemokine CCL2, is the most potent chemokine in the regulation of migration and infiltration of monocytes/macrophages in AD through interactions with CC-chemokine receptor 2 (CCR2). The associations among the baseline biomarker levels, the longitudinal cognitive and behavioral changes, and the genetic effects of selected single nucleotide polymorphisms were analyzed. AD and MCI patients were recruited and evaluated annually with the Mini-Mental Status Examination (MMSE) and Neuropsychiatric Inventory (NPI) for 2 years. Healthy controls were recruited at baseline for comparison. AD Patients in the highest tertile of plasma clusterin levels showed significantly lower MMSE scores (p = 0.04) and more MMSE changes in the 1-year follow-up (p = 0.008) than those in the lowest tertile, but the baseline clusterin level could not predict the MMSE changes in the 2-year follow-up. In apolipoprotein E (APOE) ε4 carrier AD patients, the baseline ratio of plasma Aβ1–42/Aβ1–40 in the highest tertile predicted an increase in NPI agitation/aggression scores in the 2-year follow-up (p = 0.02). In AD and MCI patients, after adjusting for covariates, AD patients had higher plasma MCP-1 levels compared with MCI patients and controls, and severe AD patients had the highest levels. The baseline MCP-1 level was significantly correlated with the MMSE changes in the two-year follow-up (p = 0.046) and the A allele of CCR2 rs1799864 was associated with a higher MCP-1 level in AD and MCI patients. In conclusion, plasma Aβ, clusterin, and MCP-1 might predict specific long-term BPSD, reflect the cognitive status, and be associated with the rate of cognitive decline of AD, respectively. A higher ratio of plasma Aβ1–42/Aβ1–40 could predict agitation/aggression in APOE ε4 carrier AD patients. Plasma clusterin could serve as a biomarker for the severity of cognitive decline. A higher plasma MCP-1 level is associated with greater severity and faster cognitive decline. Additionally, the CCR2 polymorphism may play a role in the regulation of MCP-1/CCR2 signaling in AD.