Endoscopic Palliation in Patients With Incurable Malignant Colorectal Obstruction by Means of Self-expanding Metal Stent

Abstract

In humans, apolipoprotein E (apoE) has 3 isoforms: apoE2, apoE3, and apoE4. APOE4 is a major genetic risk factor for Alz-heimer disease (AD). 1 Apolipoprotein E4 has direct effects on the cerebrovascular system, resulting in microvascular lesions and blood-brain barrier (BBB) damage, as recently reviewed. 2 Neurovascular dysfunction is also present in cognitively nor-mal APOE4 carriers and individuals with APOE4-associated dis-orders including AD. 1-3 Moreover, postmortem brain tissue analy-sis has indicated that BBB breakdown in patients with AD is more pronounced in APOE4 carriers compared with APOE3 or APOE2. 4-6 Our recent studies in transgenic mice have demon-strated that apoE4 leads to BBB breakdown by activating the pro-inflammatory cyclophilin A (CypA)–matrix metalloproteinase 9 (MMP-9) pathway in brain pericytes, which in turn results in degradation of the BBB tight junctions and basement mem-brane proteins. 7 It has also been shown that apoE4-mediated BBB breakdown leads to secondary neuronal injury and cogni-tive decline in transgenic mice. 7 Apolipoprotein E2 and apoE3 maintained normal BBB integrity in transgenic mice by sup-pressing the CypA–MMP-9 pathway. 7 Here, we studied the ce-rebrospinal fluid (CSF)/plasma albumin quotient (Q Alb), an es-tablished marker of BBB breakdown, 8 and CypA and active MMP-9 levels in the CSF of cognitively normal individuals with different APOE genotypes to determine whether apoE4-dependent changes in BBB permeability and CypA–MMP-9 path-way as shown in APOE4, but not APOE3 and APOE2 transgenic mice, also occur in humans. We studied a total of 49 cognitively normal individuals as indicated by the Clinical Dementia Rating score of 0 and Mini-Mental State Ex-amination score of approximately 30. This study did not ex-clude participants meeting criteria for major depressive dis-order because there were no differences in the studied markers of BBB damage in this group compared with controls. The stud-ied individuals represented 3 different APOE genotypes: APOE2/E3 (n = 11), APOE3/E3 (n = 28) and APOE3/E4 (n = 10). Within each genotype, individuals were stratified into 2 age groups—40 through 65 years old and 66 through 85 years old—to control for age-dependent effects (Table). Cerebrospinal fluid and plasma collection and APOE genotyping were performed as described. 9 Enzyme-linked immunosorbent assays were used to determine levels of CypA (catalog no. sE90979Hu; USCN Life Science), active MMP-9 (catalog no. 72017; AnaSpec), and albumin (catalog no. E-80AL; Immunology Consultant Labo-ratories). Data were analyzed by multifactorial analysis of vari-ance with 2 factors (age and APOE genotype), with Bonfer-roni post hoc tests to adjust for multiple comparisons, and Pearson correlation analysis using Graphpad Prism version 5.0. Analyses were performed by an investigator blinded to the ex-perimental conditions. A P value of less than .05 was consid-ered statistically significant. Results | Older cognitively normal individuals carrying 1 APOE4 allele compared with younger cognitively normal APOE4 car-riers or age-matched APOE4 noncarriers had increased Q Alb by approximately 77% and 67%, respectively (P < .01; Figure, A). No age-dependent increase in Q Alb was associated with APOE2 or APOE3 alleles. Compared with cognitively normal younger APOE4 carriers or age-matched APOE4 noncarriers, older cognitively normal APOE4 carriers had increased CSF levels of CypA by approximately 190% and 95%, respectively