Premium
IC‐P‐030: In Vivo Nadh Fluorescence Imaging of Double Transgenic Ad Mice Reveals Chronic Tissue Hypoxia
Author(s) -
Iordanova Bistra,
Murphy Matthew C.,
Klunk William E.,
Vazquez Alberto L.
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.040
Subject(s) - hyperoxia , in vivo , biology , genetically modified mouse , nicotinamide adenine dinucleotide , hypoxia (environmental) , pathology , nad+ kinase , transgene , chemistry , biochemistry , oxygen , medicine , organic chemistry , gene , microbiology and biotechnology , enzyme
terol, and participate in neuroinflammatory processes. CYP activity is also implicated in Alzheimer’s disease (AD), particularly in amyloid-b (Ab) accumulation in CSF. We examined whether genetic polymorphisms of CYP are associated with AD pathology. Methods: [18F]florbetapir-PET imaging was employed to assess brain Ab levels in 256 subjects from a discovery cohort (ADNI: 186CN, 105 lMCI, 47AD). Linear regression models examined the association of 30 SNPs from four genes of CYP (CYP3A4, CYP2C9, CYP2C19 and CYP1A1) with global [18F]florbetapirSUVR, adjusting for age, sex, and ApoE-e4carriage status. Significant signals were interrogated at the voxel level using RMINCtool, and, separately, tested for associations with CSF Ab and Ab/p-tau ratio. Neuropathologic data from the Rush ROS and MAP cohorts were used to generalize the findings to Ab load and PHFtau tangle density by immunocytochemistry in post-mortem brains (302 CN, 180 aMCI, 259 AD). Results: The analysis of [18F]florbetapir identified an intronic variant in the CYP2C19 gene (rs4388808; P1⁄40.0005), in which carriers of the minor-allele (G) had lower global SUVR (Figure 1). The voxel-wise analysis showed a significant effect of the SNP in the frontal and posterior cingulate cortices, as well as in the inferior parietal cortex (Figure 2). Carriers of the minor-allele were also associated with higher CSF Ab (P1⁄40.003) and higher Ab/p-tau ratio (P1⁄40.01). In postmortem brains, minor-allele carriers had a lower Ab load (P1⁄40.04), lower PHFtau tangle density (P1⁄40.03) as well as better episodic memory (P1⁄40.008). Conclusions: The rs4388808, an intronic variant of the CYP2C19 gene is implicated in Ab load, tau pathology and episodic memory, where the minor-allele protects against AD pathology.