Gennady Landa

Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood

Neurogenesis is known to take place in the adult brain. This work identifies T lymphocytes and microglia as being important to the maintenance of hippocampal neurogenesis and spatial learning abilities in adulthood. Hippocampal neurogenesis induced by an enriched environment was associated with the recruitment of T cells and the activation of microglia. In immune-deficient mice, hippocampal neurogenesis was markedly impaired and could not be enhanced by environmental enrichment, but was restored and boosted by T cells recognizing a specific CNS antigen. CNS-specific T cells were also found to be required for spatial learning and memory and for the expression of brain-derived neurotrophic factor in the dentate gyrus, implying that a common immune-associated mechanism underlies different aspects of hippocampal plasticity and cell renewal in the adult brain.

Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis

The role of activated microglia (MG) in demyelinating neurodegenerative diseases such as multiple sclerosis is controversial. Here we show that high, but not low, levels of IFN-gamma (a cytokine associated with inflammatory autoimmune diseases) conferred on rodent MG a phenotype that impeded oligodendrogenesis from adult neural stem/progenitor cells. IL-4 reversed the impediment, attenuated TNF-alpha production, and overcame blockage of IGF-I production caused by IFN-gamma. In rodents with acute or chronic EAE, injection of IL-4-activated MG into the cerebrospinal fluid resulted in increased oligodendrogenesis in the spinal cord and improved clinical symptoms. The newly formed oligodendrocytes were spatially associated with MG expressing MHC class II proteins and IGF-I. These results point to what we believe to be a novel role for MG in oligodendrogenesis from the endogenous stem cell pool.

Inner segment-outer segment junctional layer integrity and corresponding retinal sensitivity in dry and wet forms of age-related macular degeneration.

Purpose: To investigate a relationship between the inner segment-outer segment (IS-OS) junctional layer integrity and the overlying retinal sensitivity assessed by Spectral OCT/SLO (spectral-domain optical coherence tomography) and microperimetry testing in patients with dry and wet forms of age-related macular degeneration (AMD). Methods: Spectral-domain optical coherence tomography examination and microperimetry testing were performed in 55 eyes of 43 consecutive patients with AMD. Microperimetry maps were registered onto three-dimensional retinal topography maps, and point-to-point analysis of correlation between microperimetric retinal sensitivities and corresponding status of the underlying IS-OS junctional layer was performed. In addition, the analysis of correlation between the best-corrected visual acuity and the integrity of IS-OS layer in the center of the fovea also was performed. Results: Retinal sensitivity was inversely and strongly correlated with the integrity of IS-OS layer in both dry and wet forms of AMD (correlation coefficient [r] = −0.75 [95% confidence interval, 0.49−0.88], P < 0.001, and −0.79 [95% confidence interval, 0.61−0.89], P < 0.001, respectively). The correlation between the best-corrected visual acuity and the integrity of IS-OS layer in the center of fovea was less significant (r = −0.58 [95% confidence interval, 0.19−0.79], P = 0.02, for dry AMD, and r = −0.6 [95% confidence interval, 0.32−0.78], P = 0.015, for wet AMD). Conclusion: Retinal sensitivity consistently correlated with the status of underlying IS-OS junctional layer in both dry and wet forms of AMD. Loss of IS-OS layer is significantly associated with poor retinal sensitivity, assessed by microperimetry. Compared with visual acuity, functional testing with microperimetry appears to more consistently correlate with changes in the outer retina, such as IS-OS junctional integrity, especially, in patients with wet AMD.

Correlation between Spectral Domain Optical Coherence Tomography Findings and Fluorescein Angiography Patterns in Diabetic Macular Edema

OBJECTIVE To study the relationship between spectral domain optical coherence tomography (SD-OCT) findings and fluorescein angiography (FA) patterns in patients with diabetic macular edema (DME). DESIGN Retrospective, observational, cross-sectional study. PARTICIPANTS We included 59 eyes from 59 patients with DME that had SD-OCT/scanning laser ophthalmoscope (SLO) and FA performed on the same day. Eyes with macular edema owing to other ocular diseases were excluded. METHODS The relationship between SD-OCT and FA findings was evaluated by superimposing and aligning the SLO images onto the FA photos. The SLO image of the OPKO/OTI Spectral OCT/SLO (OPKO-OTI, Miami, FL) corresponds with the exact origin and orientation of the SD-OCT scan, which was then correlated with the FA image. Foveal and extrafoveal regions were studied separately. Leakage on FA and pathologic changes on OCT were graded by using standard photographs. Pathologic changes studied in the OCT images included edema and cystic spaces in the inner and outer retina, loss of retinal layers, and foveal cysts. MAIN OUTCOME MEASURES Correlation between SD-OCT changes and corresponding FA patterns. RESULTS The outer retina was the predominant location of fluid in DME. The severity of the outer retinal edema on OCT was positively correlated with the severity of leakage on FA (r = 0.735; P<0.001). Cystic changes in the inner and outer retina were also correlated with the severity of fluorescein leakage (r = 0.507 and P<0.001; r = 0.561 and P<0.001, respectively). Loss of inner retinal layers on OCT was highly correlated with capillary nonperfusion on FA (r = 0.953; P<0.001). Large foveal cysts on SD-OCT corresponded to cystoid leakage patterns on FA. CONCLUSIONS Pathologic changes on SD-OCT correlated well with FA findings. Loss of inner retinal layers was specifically correlated with capillary nonperfusion and severe ischemia. Judgment of whether management of DME based on fine retinal structural changes influences clinical outcomes must be reserved pending further investigation with prospective trials. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Comparative Study of Intravitreal Bevacizumab (Avastin) versus Ranibizumab (Lucentis) in the Treatment of Neovascular Age-Related Macular Degeneration

Aims: To compare the safety and efficacy of 2 anti-vascular-endothelial-growth-factor agents – bevacizumab (Avastin) versus ranibizumab (Lucentis) – in the treatment of patients with neovascular age-related macular degeneration (AMD). Methods: Retrospective analysis of patients who received intravitreal injections of bevacizumab or ranibizumab for neovascular AMD. Primary outcome measures were best-corrected visual acuity (BCVA) and central foveal thickness (CFT) assessed by Spectral Domain scanning laser ophthalmoscope-optical coherence tomography (SD-OCT). A secondary outcome measure was the report of any adverse events in the 2 groups. Results: The number of injections in the bevacizumab group was 184 (average of 4.7 per eye) compared to 187 in the ranibizumab group (average of 5.5 per eye). The mean logMAR equivalent of BCVA at 1 month after the injection improved by 0.18 in the bevacizumab group (p = 0.009) and by 0.13 in the ranibizumab group (p = 0.004). The average SD-OCT CFT decreased from 325 ± 72 to 300 ± 69 μm in the bevacizumab group (p = 0.016) and from 307 ± 57 to 289 ± 56 μm in the ranibizumab group (p = 0.017). In the bevacizumab group, there was 1 event of lower extremity pain (0.54%) and 1 event of increased arterial blood pressure (0.54%). In the ranibizumab group, there were 2 events of transiently increased intraocular pressure (1.1%) and 1 event (0.53%) of intraocular inflammation following injection. Conclusions: Bevacizumab and ranibizumab treatments resulted in similar gains in visual acuity and reduction in macular thickness, documented each month following injection. Intravitreal bevacizumab appears to be as safe and effective as intravitreal ranibizumab in the treatment of exudative AMD.

Combined Three-Dimensional Spectral OCT/SLO Topography and Microperimetry: Steps toward Achieving Functional Spectral OCT/SLO

Aims: To investigate the combination of 3D optical coherence tomography (OCT) retinal thickness measurements and superimposed scanning laser ophthalmoscopy (SLO) microperimetry obtained using a Spectral OCT/SLO and to test the correlation between retinal thickness and retinal sensitivity in retinal diseases grouped according to anatomic locations. Methods: Patients with various retinal diseases and subjects with normal fundi underwent microperimetry testing and imaging with the Spectral OCT/SLO. Based on the Spectral OCT/SLO findings, the participants were divided into 4 groups: patients with retinal thickening due to the outer retina pathology (group I); patients with retinal thickening due to the cystic changes observed in the inner retina (group II); patients with macular neurosensory retina thinning associated with geographic atrophy or underlying subretinal cicatricial changes (group III), and subjects with unremarkable fundus appearance and normal appearing retina on Spectral OCT/SLO (group IV). The primary outcome was the correlation coefficient (r) between Spectral OCT/SLO-measured macular thickness and microperimetry values. Results: Correlations between retinal thickness and psychophysical thresholds were calculated for each patient, and these values were averaged within groups. The mean correlation values (Pearson product movement) were as follows: for group I (n = 21 eyes) r = 0.04; for group II (n = 24 eyes) r = –0.53; for group III (n = 16 eyes) r = 0.41, and for group IV (n = 15 eyes) r = 0.04. Conclusions: The combination of 3D OCT images and superimposed SLO microperimetry obtained by Spectral OCT/SLO demonstrated that thickening due to cystic changes of the inner retinal layers or thinning of the neurosensory retina on OCT correlated most significantly with decreases in psychophysical threshold sensitivities.

Weekly Vaccination with Copaxone (Glatiramer Acetate) as a Potential Therapy for Dry Age-Related Macular Degeneration

Purpose: Drusen formation in age-related macular degeneration (AMD) shares some similarities with Alzheimers disease (AD), which is associated with amyloid deposits. Aggregated beta-amyloid induces microglia to become cytotoxic and block neurogenesis. Recent evidence showed that T cell-based vaccination with Copaxone in AD mice model resulted in modulation of microglia into neuroprotective phenotype and as a result in reduction of cognitive decline, elimination of plaque formation, and induction of neuronal survival and neurogenesis. The aim was to investigate whether the effect of Copaxone on drusen in dry AMD is similar to that on deposits of other age-related chronic neurodegenerative diseases such as Alzheimer disease (AD). Materials and Methods: Patients over 50 years of age with intermediate dry AMD in both eyes were randomized to receive Copaxone or sham injections and were weekly treated by subcutaneous injections of Copaxone (dose of 20 mg) or sham injections for 12 weeks. At baseline, 6-week, and 12-week visits, visual acuity, contrast sensitivity, fundus examination and photography, fluorescein angiography, and ocular coherent tomography were performed. Main outcome measure was a change in total drusen area (TDA) measured by Image-Pro software and presented in arbitrary units (AU). Results: Eight studied eyes of four treated patients showed a decrease in TDA from 48130 to 16205 AU at 12 weeks as compared to baseline. In contrast, four control eyes (two patients) demonstrated almost no change in TDA (from 32294 to 32781 AU). Conclusion: These preliminary results show that Copaxone reduces drusen area.

Correlation between retina blood flow velocity assessed by retinal function imager and retina thickness estimated by scanning laser ophthalmoscopy/optical coherence tomography.

Purpose: The purpose of this study was to evaluate the correlation between the retinal blood flow (RBF) assessed by the retinal functional imager (RFI) and central macular thickness/volume assessed by a spectral scanning laser ophthalmoscopy/optical coherence tomography (SLO-OCT) system. Methods: Seventeen eyes of 14 consecutive patients with various ocular diseases were examined. Retinal blood circulation characteristics were measured using the RFI. Retinal thickness/volume parameters were obtained by SLO-OCT. Analysis of correlation between RBF velocity and SLO-OCT findings was performed. Results: The analysis of the correlation between RBF and central retinal thickness/volume (5 × 5 mm grid pattern) showed a strong correlation between the average venous RBF velocity and central retinal volume. A linear relationship between the retinal blood velocity in veins and center, middle ring, outer ring and total central squares of macular volume [correlation coefficient 0.86 (p = 0.00001); 0.89 (p = 0.000001); 0.82 (p = 0.0004); 0.85 (p = 0.00001), respectively] has been observed. Arterial blood flow velocity did not correlate with thickness and with central retinal volume. Conclusions: Venous RBF, analyzed by the RFI, significantly correlated with the volume of the central retina, measured by SLO-OCT. Venous blood velocity increased linearly with the increase in the central retinal volume. In this small study, assessment using the RFI provides useful information and may contribute to the further understanding of hemodynamics in the retina blood vessels. The RFI shows promise of being able to analyze retinal hemodynamics noninvasively and may contribute to the further understanding of the relationship between retinal thickening and function.

Update on current and future novel therapies for dry age-related macular degeneration.

Age-related macular degeneration (ARMD) is the leading cause of irreversible blindness in developed countries. There are currently no cures, but there are promising potential therapies that target the underlying disease mechanisms of dry ARMD. Stem cells, ciliary neurotrophic factor, rheopheresis, ozonated autohemotherapy and prostaglandins show promise in stabilizing or improving visual acuity. Age-Related Eye Disease Study vitamins may reduce progression to severe ARMD. Adjuvant therapy like low vision rehabilitation and implantable miniature telescopes may help patients adjust to the sequelae of their disease, and herbal supplementation with saffron, zinc monocysteine and phototrop may be helpful. Therapies that are currently in clinical trials include brimonidine, doxycycline, anti-amyloid antibodies (GSK933776 and RN6G), RPE65 inhibitor (ACU-4429), complement inhibitors (ARC1905, FCFD4514S), hydroxychloroquine, intravitreal fluocinolone acetate and vasodilators like sildenafil, moxaverine and MC-1101. Therapies that have not been shown to be effective include POT-4, eculizumab, tandospirone, anecortave acetate, the antioxidant OT-551, sirolimus and vitamin E.

New patterns of retinal collateral circulation are exposed by a retinal functional imager (RFI)

Aims: To describe different patterns of retinal collateral circulation observed in normal subjects and in patients with a variety of ocular diseases during studies with the retinal functional imager (RFI). Methods: Normal subjects and patients with various ocular diseases underwent retinal blood flow imaging using the retinal functional imager. Results: Twenty-eight eyes of 21 patients constituted the study population (eight eyes of six normal subjects and 20 eyes of 15 patients with different ocular diseases). Four patterns of retinal collateral circulation have been recognised: (1) looped collateral pattern—this arterovenous anastomotic vessel is characterised by a link between the endings of the adjacent artery and vein, and has an appearance of a loop; (2) vertical collateral pattern—this anastomotic vessel is characterised by a connection between superior and inferior vascular systems (arterial or venous), and in its course this collateral vessel crosses the horizontal raphe; (3) H-shaped collateral pattern—this arterovenous anastomotic vessel is characterised by a connection between two adjacent vessels (artery and vein), but, unlike anastomotic vessel of the “looped” pattern, this vessel connects the middle parts of the vessels and not the endings of these vessels; (4) cilioretinal–retinal collateral pattern. This anastomotic vessel is characterised by a link between the cilioretinal artery and retinal arterial circulation. Conclusions: The findings of this study shed a different light on the retinal circulation and have demonstrated new patterns of retinal collateral circulation evident from RFI imaging. These patterns appear to be present in normal subjects as well as in patients with various ocular diseases.