RESUMEN
Neovascular age-related macular degeneration (nAMD) is the leading cause of vision loss in the elderly. The gold standard of nAMD treatment is intravitreal injections of vascular endothelial growth factor (VEGF) inhibitors. Genetic factors may influence the response to anti-VEGF therapy and result in a high degree of response variability. The aim of the study was to evaluate the association of the polymorphisms in genes related to the complement system (rs2285714-CFI, rs10490924-ARMS2, rs2230199-C3, rs800292-CFH, and rs6677604-CFH) with nAMD its clinical features and optical coherent tomography (OCT) biomarkers of treatment response to anti-VEGF therapy. Genotyping by allele-specific PCR was performed in 193 AMD patients and 147 age-matched controls. A prospective study of the dynamics of changes in OCT biomarkers during aflibercept treatment included 110 treatment-naive patients. Allele T rs10490924 was associated with the increased risk of nAMD. For both rs800292 and rs6677604, carriage of the A allele was protective and decreased the nAMD risk. Associations of rs2230199 with central retinal thickness (CRT) and intraretinal cysts were revealed. The height of pigment epithelium detachment and the height of neuroretinal detachment were significantly higher in carriers of the minor allele of rs2285714, both at baseline and during treatment. The reduction of CRT was associated with higher CRT at baseline and the presence of the T allele of rs2285714. By the end of one-year follow-up the patients homozygous for the minor allele rs2285714 had significantly higher odds of the presence of anastomoses and loops and active neovascular membrane. Furthermore, minor allele carriers had decreased levels of complement factor I level in aqueous humor but not in the plasma, which may be due to the influence of rs2285714 on tissue-specific splicing. Our results suggest that the severity of AMD macular lesions is associated with rs2285714 and rs2230199 polymorphisms, which could be explained by their high regulatory potential. Patients with the minor allele of rs2285714 respond worse to antiangiogenic therapy.
RESUMEN
This study was aimed to systematize magnetic resonance imaging (MRI) presentation of toxic leukoencephalopathy, to find the correlation between method of central nervous system (CNS) leukemia prevention and changes on MRI, to find relationship between existence leukoencephalopathy on imaging and neurocognitive deficits in pediatric patients after anti-leukemic therapy. Brain MRI data of 48 children, who underwent a therapy course according to the ALL-MB intermediate risk protocol, was evaluated. In accordance with two arms of this protocol, they received either radiation therapy, or additional intrathecal administration of chemotherapeutic agents as a prevention of CNS leukemia. Also, neurocognitive tests were performed. According to the results of the performed investigation, 10 (50%) out of 20 children, who received cranial irradiation and 18 (66.6%) out of 27 patients, who received only intrathecal therapy demonstrated abnormal brain changes (leukoencephalopathy) according to MRI data. Leukoencephalopathy was mostly presented by diffuse zones and localized predominantly in the frontal and temporal lobes. There was no correlation between method of CNS prevention and the existence of leukoencephalopathy on MRI. The analysis of our data did not show significant differences in brain damage and severity of cognitive impairment depending on the type of prevention of CNS leukemia. Moreover, in this study no statistical correlation was found between leukoencephalopathy on MRI and neurocognitive impairment according to clinical tests data. Further long-term prospective studies and examinations should be performed to assess late neurotoxic effects.
RESUMEN
Growing evidence suggests that mitochondrial dysfunction is an early event in sporadic Alzheimer's disease (AD), but the impact of mitochondrial dysfunction on the transition from healthy aging to AD remains elusive. Here we estimated the influence of mitochondrial dysfunction on the initiation of AD signs in OXYS rats, which simulate key characteristics of sporadic AD. We assessed the mitochondrial ultrastructure of pyramidal neurons of the hippocampus at the age preceding the development (age 20 days), during manifestation (4-5 months), and at the well-pronounced stages (18-24 months) of the AD-like pathology in OXYS rats. Ultrastructural alterations were collated with the amounts of proteins mediating mitochondrial dynamics [mitofusins (MFN1 and MFN2) and dynamin-1-like protein (DRP1)]; with activity of respiratory chain complexes I, IV, and V in the hippocampal mitochondria; with reactive oxygen species (ROS) production; and with expression of uncoupling protein 2 (UCP2) regulating ROS production. Already at the preclinical stage, OXYS rats showed some characteristic changes in hippocampal mitochondria, which increased in size with the manifestation and progression of AD-like pathology, including decreased activity of respiratory complexes against the background of greater fusion and formation of larger mitochondria. Signs of AD developed simultaneously with increasing dysfunction of mitochondria, with a dramatic decrease in their number, and with increased fission but without upregulation of ROS production (observed only in 20-day-old OXYS rats). Summarizing the data from our present and previous studies, we conclude that mitochondrial dysfunction appears to mediate or possibly even initiate pathological molecular cascades of AD-like pathology in OXYS rats and can be considered a predictor of the early development of the late-onset form of AD in humans.