Objective:To investigate the effects of blood pressure variability (BPV), serum reactive oxygen species (ROS) and superoxide dismutase (SOD) levels on cognitive function in patients with subcortical ischemic vascular disease (SIVD).Methods:A total of 133 patients with SIVD confirmed by craniocranial MRI admitted to Department of Neurology, Red Flag Hospital Affiliated to Mudanjiang Medical University from October 2021 to October 2022 were selected. According to Montreal Cognitive Assessment scores, they were divided into SIVD without cognitive impairment group (SIVD-NC group, n=39) and subcortical vascular cognitive impairment group (SVCI group, n=94); and 23 healthy volunteers with normal cognition who had normal brain MRI in the Physical Examination Center during the same period were chosen as control group. General data of all subjects and vascular risk factors in each group were collected, routine biochemical indexes of peripheral blood were detected, 24 h ambulatory blood pressure monitoring was performed, and serum ROS and SOD levels were detected by enzyme-linked immunosorbent assay. Statistical methods were used to analyze the risk factors for cognitive impairment, correlations of independent risk factors with cognitive function, and diagnostic value of risk factors in cognitive impairment in patients with SIVD. Results:(1) Compared with control group, SIVD-NC group had significantly increased percentages of patients with hypertension history or lacunar stroke history, and significantly increased hypersensitive C-reactive protein (hs-CRP) level ( P<0.05). Compared with control group and SIVD-NC group, patients in SVCI group had significantly older age, lower years of education, higher proportion of patients with lacunar stroke history, and increased hs-CRP level ( P<0.05). Compared with control group, SVCI group had significantly higher proportion of patients with hypertension history ( P<0.05). (2) SIVD-NC group had significantly higher ROS level than control group ( P<0.05); Compared with control group and SIVD-NC group, SVCI group had significantly increased ROS level ( P<0.05). (3) SIVD-NC group had significantly increased nighttime systolic blood pressure (nSBP) compared with control group ( P<0.05); SVCI group had significantly increased 24 h SBP, nSBP and nSBP-variable coefficient (CV) compared with control group and SIVD-NC group ( P<0.05). Compared with SIVD-NC group, SVCI group had significantly increased 24 h SBP-CV ( P<0.05). (4) The nSBP, nSBP-CV, serum hs-CRP and ROS, and lacunar stroke history were independent risk factors for cognitive impairment in SIVD patients ( OR=1.096, P<0.001, 95% CI: 1.042-1.154; OR=1.231, P=0.010, 95% CI: 1.050-1.443; OR=2.303, P=0.004, 95% CI: 1.311-4.039; OR=1.026, P<0.001, 95% CI: 1.014-1.039; OR=2.954, P=0.041, 95% CI: 1.045-8.348), and education level was a protective factor for that ( P<0.05). (5) Serum ROS and hs-CRP, nSBP, and nSBP-CV were negatively correlated with MoCA scores in SIVD patients ( r s=-0.336, P<0.001; r s=-0.503, P<0.001; r s=-0.204, P=0.018; r s=-0.309, P=0.001). (6) Serum ROS and hs-CRP, nSBP, and nSBP-CV had high diagnostic values in cognitive impairment in SIVD patients (areas under the curves: 0.874, 0.847, 0.804 and 0.702, P<0.05); combined diagnosis efficacy of multiple indexes was better (area under the curve: 0.948, P<0.05). Conclusion:Serum ROS and hs-CRP, nSBP and nSBP-CV are highly likely to be hemodynamic and serological monitoring indexes for screening of cognitive impairment in SIVD patients.

Approximately 140 million people worldwide are homozygous carriers of APOE4 (ε4), a strong genetic risk factor for late onset familial and sporadic Alzheimer's disease (AD), 91% of whom will develop AD at earlier age than heterozygous carriers and noncarriers. Susceptibility to AD could be reduced by targeted editing of APOE4, but a technical basis for controlling the off-target effects of base editors is necessary to develop low-risk personalized gene therapies. Here, we first screened eight cytosine base editor variants at four injection stages (from 1- to 8-cell stage), and found that FNLS-YE1 variant in 8-cell embryos achieved the comparable base conversion rate (up to 100%) with the lowest bystander effects. In particular, 80% of AD-susceptible ε4 allele copies were converted to the AD-neutral ε3 allele in human ε4-carrying embryos. Stringent control measures combined with targeted deep sequencing, whole genome sequencing, and RNA sequencing showed no DNA or RNA off-target events in FNLS-YE1-treated human embryos or their derived stem cells. Furthermore, base editing with FNLS-YE1 showed no effects on embryo development to the blastocyst stage. Finally, we also demonstrated FNLS-YE1 could introduce known protective variants in human embryos to potentially reduce human susceptivity to systemic lupus erythematosus and familial hypercholesterolemia. Our study therefore suggests that base editing with FNLS-YE1 can efficiently and safely introduce known preventive variants in 8-cell human embryos, a potential approach for reducing human susceptibility to AD or other genetic diseases.
Humans ; Apolipoprotein E4/genetics* ; Cytosine ; Mutation ; Blastocyst ; Heterozygote ; Gene Editing ; CRISPR-Cas Systems