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- Zhou, XP, et al.
(författare)
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Non-coding variability at the APOE locus contributes to the Alzheimer's risk
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3310-
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
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| 2. |
- Sanford, R., et al.
(författare)
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Longitudinal Trajectories of Brain Volume and Cortical Thickness in Treated and Untreated Primary Human Immunodeficiency Virus Infection
- 2018
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Ingår i: Clinical Infectious Diseases. - : Oxford University Press (OUP). - 1058-4838 .- 1537-6591. ; 67:11, s. 1697-1704
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Tidskriftsartikel (refereegranskat)abstract
- Background. Human immunodeficiency virus (HIV) penetrates the brain in early infection. We used neuroimaging to longitudinally examine the impact of HIV and combination antiretroviral therapy (cART) on the brain in treated and untreated HIV-infected participants, starting in primary HIV infection (PHI). Methods. Sixty-five participants, enrolled during PHI, underwent longitudinal magnetic resonance imaging, 30 of whom commenced cART during follow-up. Cross-sectional data from 16 patients with chronic HIV infection (CHI) and 19 HIV-uninfected participants were included for comparison. Brain volume and cortical thickness were estimated using tensor-based morphometry and cortical modeling, respectively. Mixed-effects models longitudinally mapped structural brain changes before and after cART. The relationship between brain morphometry estimates and blood and cerebrospinal fluid (CSF) biomarkers were also tested. Region-of-interest analyses were performed to compare brain morphometry estimates between the groups. Results. Prior to cART, longer duration of untreated infection in PHI correlated with volume loss in the thalamus, caudate, and cerebellum, and with cortical thinning in the frontal and temporal lobes and cingulate cortex. After cART, no further volume loss was observed. However, small increases of cortical thickness in the frontal and temporal lobe correlated with longer cART duration. No correlations were observed with blood or CSF measures. The PHI group did not have different brain morphometric measures compared to the HIV-uninfected group, but had larger volumes in the thalamus, caudate, putamen, and cortical gray matter compared with CHI participants. Conclusions. Subcortical atrophy and cortical thinning occur during untreated infection but may be arrested by cART. These findings emphasize the importance of early cART.
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