PurposeTo determine the sex and age-related effects of C1qa ablation on retinal ganglion cell (RGC) and optic nerve (ON) axonal loss in a mouse model of glaucomatous neurodegeneration.MethodsCongenic C1qa mice were generated in the DBA/2NNia background. Female and male knockout (-/-), heterozygous (+/-), and wild type (+/+) mice were aged up to 14 months and IOPs were recorded in a subset of animals. Retinas of mice from all three groups at 5–6, 9–10 and 11–13 months of age were flat-mounted after retrograde labeling with Fluorogold. Imaged retinas were scored (RGC score) semi-quantitatively on a 10 point scale by two independent observers. A subset of retinas and optic nerves were also used for measurement of total number of RGCs. Semi-thin sections of ON were imaged and graded (ON score) for the amount of axonal damage semi-quantitatively, by two masked observers. Analysis of covariance (ANCOVA) was used for statistical comparisons. Microglial cells in flat-mounted retinas of 5–6 month old C1qa -/- and C1qa +/+ mice were used for assessment of microglial activation utilizing morphological criteria.ResultsFemale C1qa -/- mice had significantly higher IOP (p<0.000001, ANOVA) between 8 and 13 months of age compared to C1qa +/+ animals. No differences in IOPs between animals of the three genotypes were observed in males. At 5–6 months of age, there was no difference in RGC or ON scores between the three genotypes in animals of either sex. At 9–10 months of age, female mice didn’t show significant differences in RGC or ON scores between the three genotypes. However, male C1qa -/- and C1qa +/- mice of the same age had better RGC and ON scores (p<0.003 and p<0.05, ANCOVA, for RGC and ON scores, respectively) compared with C1qa +/+ mice. At 11–13 months of age, female C1qa -/- mice had better RGC scores (p<0.006, ANCOVA) compared to C1qa +/+ and C1qa +/- animals. Accordingly, C1qa -/- mice had higher RGC counts (p<0.03, t-test) compared to C1qa +/+ animals. In male mice, there was a tendency for 12 month old C1qa -/- animals to have better RGC scores and higher RGC counts, but this didn't reach statistical significance. ON scores in 11–13 month old animals of either sex were not different between all three genotype. Microglial activation in male 5–6 month old C1qa -/- mice was decreased compared to C1qa +/+ animals; no such effect was seen in females.ConclusionsAbsence of C1qa ameliorates RGC and ON loss in the DBA/2NNia strain, but this effect differs between the two sexes. C1q-mediated RGC damage seems to be more potent than IOP-mediated RGC loss. In contrast, C1qa absence provides axonal protection early on, but this protection cannot overcome the effects of significant IOP elevation.

type of comorbidity (non-cardiovascular, cardiovascular and mixed). Descriptive statistics were used to describe the relationship between comorbidity and variables of interest. Age-stratified multivariate Cox Proportional Hazards models were used to assess the association of comorbidity with all-cause mortality overall and by age strata (#60, 61-70,71-80, and .80 years old). Results: The study included 926 HF subjects: mean age was 68 years, and 42% died during follow-up. The age-specific allcause mortality rates of subjects #60, 61 -70, 71 -80, and . 80 years of age, were 20%, 28%, 48% and 82% respectively. In the overall cohort, subjects with non-cardiovascular and mixed comorbidities had a higher risk of all-cause mortality than those with cardiovascular comorbidities (HR=2.0,95%CI=1.2-3.2 and HR=1.6, 95% CI=1.1-2.2 respectively). The risk of all-cause mortality for mixed comorbidities compared to cardiovascular comorbidities was higher for subjects 61-70 years of age (HR=5.4, 95% CI=1.4-19.7), but lower for subjects .80 years of age (HR=0.5,95% CI=0.4-0.8). Conclusions: We found an association of higher risk of all-cause mortality with mixed and non-cardiovascular comorbidities compared to cardiovascular comorbidities in different age-groups. These findings may help to inform clinicians and health care providers on the management of HF patients with comorbidities and of different age groups.