Raffaele Mancino

Epidemiology of primary glaucoma: prevalence, incidence, and blinding effects.

Certain general conclusions can be drawn from a series of 56 studies on glaucoma prevalence. Even in the most recently published studies the rate of undiagnosed glaucoma is particularly high. Another fairly constant finding is the discrepancy between the clinical and epidemiologic diagnoses of glaucoma. The prevalence of primary open-angle glaucoma (POAG) has been increasing, and this trend is undoubtedly due at least in part to advances in diagnostic technology. The decreasing prevalence of primary angle-closure glaucoma (PACG) is due to the adoption of more stringent criteria for the diagnosis of this form of glaucoma. Prevalence increases proportionately with age for each racial group. African or African origin populations had the highest POAG prevalence at all ages but the increase in prevalence of POAG is steeper for white populations. PACG is commonest in Asian ethnic groups, with the exception of the Japanese. Low-tension glaucoma (LTG) is quite common in the Japanese population. Over 80% of those with PACG live in Asia, while POAG disproportionately affects those of African derivation. Women are more affected by glaucoma. Very few incidence studies have been completed, because the cost of examining large samples is high. There are only two recent studies conducted on persons of African descent in Barbados (West Indies) and on white inhabitants of Rotterdam (Netherlands). Risk of incident glaucoma was highest among persons classified as having suspect POAG at baseline, followed by those with ocular hypertension. No difference in incidence of POAG between men and women was found. The more recent studies which included routine visual-field testing reveal rates of blinding glaucoma <10% in many countries, including those that are developing.

Retinal damage caused by high intraocular pressure-induced transient ischemia is prevented by coenzyme Q10 in rat.

Recent studies support a role for excitotoxicity in the development of retinal ganglion cell (RGC) damage in subjects suffering from glaucoma. Coenzyme Q10 (CoQ10), an essential cofactor of the electron transport chain, has been reported to afford neuroprotection, preventing the formation of the mitochondrial permeability transition pore. Using an established animal model of retinal ischemia/reperfusion here, we show that synaptic glutamate increases at 130min from beginning of reperfusion and delayed apoptosis in the RGC layer is seen at 24h. Intraocular administration of CoQ10 minimizes glutamate increase and affords neuroprotection, suggesting that oxidative stress and energy failure might be implicated in the mechanisms of RGC death.

Incidence of blindness and low vision in a sample population ☆: The Priverno Eye Study, Italy

PURPOSE To study the incidence of blindness and low vision over a 7-year period. DESIGN Population-based cohort study. PARTICIPANTS The survivors of the original cohort of 860 persons from Priverno, Italy, aged 45 to 69 years, were reexamined. Of the 760 eligible survivors, 619 (81.4%) had a 7-year follow-up visit. METHODS Baseline and follow-up examinations included the collection of anamnestic and ophthalmologic data by the same observers using the same methods and classification criteria to minimize sources of variability. MAIN OUTCOME MEASURES Best-corrected visual acuity (VA) measured at 4 m by standardized logarithmic chart was expressed as the logarithm of the minimum angle of resolution (logMAR). World Health Organization definitions of blindness and low vision were adopted (respectively, VA > 1.3 logMar and VA > 0.6 to 1.3 logMar in the better eye or in either eye). Participants at risk for visual impairment were those without blindness or low vision in one or both eyes at baseline; participants at risk for one-eye visual impairment were those without blindness or low vision in both eyes at baseline. RESULTS A total of 33 participants were defined as incident cases of visual impairment. The overall incidence figures for blindness, low vision, one-eye blindness, and one-eye low vision were respectively 0.2% (95% confidence interval [CI], 0.0-0.9), 1.3% (95% CI, 0.7-2.6), 1.2% (95% CI, 0.6-2.4), and 2.9% (95% CI, 1.8-4.6). CONCLUSIONS This study provides population-based estimates of the incidence of visual impairment in an adult, free-living European population. With respect to the younger participants, older subjects at baseline were at higher risk for incident visual impairment, the main causes of which were cataract, myopia, and diabetic retinopathy. The incidence of visual impairment in the subgroup aged 55 to 64 years at baseline was significantly higher than that found in Beaver Dam 5-year study and similar to that found in Beaver Dam 10-year Study, when the same definitions were adopted. This difference may be partially explained by social and cultural habits of the female samples, but many other factors may play a role.

3-T Diffusion tensor imaging of the optic nerve in subjects with glaucoma: correlation with GDx-VCC, HRT-III and Stratus optical coherence tomography findings

Objectives To correlate diffusion-tensor imaging (DTI) of the optic nerve with morphological indices obtained by scanning laser polarimetry (GDx-VCC); confocal scanning laser ophthalmoscopy (Heidelberg III retinal tomograph; HRT-III) and optical coherence tomography (Stratus OCT). Methods Thirty-six subjects (12 with no eye disease and 24 with perimetrically diagnosed glaucoma) were examined. One eye for each participant was studied with 3-Tesla DTI (with automatic generation of mean diffusivity (MD) and fractional anisotropy (FA) values); GDx-VCC, HRT-III and OCT. Single and multiple regression analyses of all variables studied were performed. Results MD displayed the strongest correlation with linear cup/disc ratio (LCDR) from HTR-III (r=0.662), retinal nerve fibre layer (RNFL) thickness (avThickn) from OCT (r=−0.644), and nerve fibre index (NFI) from GDx (r=0.642); FA was strongly correlated with the LCDR (r=−0.499). In multiple regression analyses, MD correlated with LCDR (p=0.02) when all variables were considered; with avThickn (p<0.01) (analysis of all RNFL parameters); with NFI (p<0.01) (analysis of all GDx parameters); with avThickn (p<0.01) (analysis of OCT parameters); with LCDR (p=0.01) (analysis of HRT-III morphometric parameters) and with linear discriminant function (RB) (p=0.02) (analysis of HRT-III indices). As for FA, it correlated with avThickn (p=0.02) when we analysed the OCT parameters and with RB (p=0.01) (analysis of HRT-III indices). Conclusions DTI parameters of the axonal architecture of the optic nerve show good correlation with morphological features of the optic nerve head and RNFL documented with GDx-VCC, HRT-III and OCT.

Differences between Proximal versus Distal Intraorbital Optic Nerve Diffusion Tensor Magnetic Resonance Imaging Properties in Glaucoma Patients

PURPOSE To analyze in vivo the diffusion tensor magnetic resonance imaging (DT-MRI) properties of the intraorbital optic nerve at two different levels: Proximal to the optic nerve head (ONH) and distal to the ONH at the level of the orbital apex in glaucoma patients. METHODS Twenty-four patients with primary open-angle glaucoma were examined. The categorization into early and severe glaucoma was performed by Hodapps classification. Fifteen healthy individuals served as controls. DT-MRI was performed with a 3T-MR unit. RESULTS At early stage mean diffusivity (MD) values were higher at the proximal site with respect to the distal site. On the contrary, a decrease in fractional anisotropy (FA) was observed only relative to patient stage, independent of optic nerve site. Moreover, at early disease stage an increase in overall diffusivities, was evident at the proximal site, whereas at the distal site a decrease of the largest diffusivity and an increase in both the intermediate and smallest diffusivities were observed. FA and MD measured at the proximal site, had, respectively, the highest sensitivity and specificity in discriminating between healthy and glaucomatous eyes. CONCLUSIONS Our study represents the first attempt to evaluate in vivo fiber integrity changes along the optic nerve with DT-MRI. Optic nerve degeneration appears to be a process that affects differently the proximal and the distal segments of the optic nerve. The complementary high sensitivity of FA with the high specificity of MD at the proximal site may provide reliable indexes for the identification of glaucomatous patients at early stages.

Potential role of IL-13 in neuroprotection and cortical excitability regulation in multiple sclerosis

Background: Inflammation triggers secondary neurodegeneration in multiple sclerosis (MS). Objectives: It is unclear whether classical anti-inflammatory cytokines have the potential to interfere with synaptic transmission and neuronal survival in MS. Methods: Correlation analyses between cerebrospinal fluid (CSF) contents of anti-inflammatory cytokines and molecular, imaging, clinical, and neurophysiological measures of neuronal alterations were performed. Results: Our data suggest that interleukin-13 (IL-13) plays a neuroprotective role in MS brains. We found, in fact, that the levels of IL-13 in the CSF of MS patients were correlated with the contents of amyloid-β1-42. Correlations were also found between IL-13 and imaging indexes of axonal and neuronal integrity, such as the retinal nerve fibre layer thickness and the macular volume evaluated by optical coherence tomography. Furthermore, the levels of IL-13 were related to better performance in the low-contrast acuity test and Multiple Sclerosis Functional Composite scoring. Finally, by means of transcranial magnetic stimulation, we have shown that GABAA-mediated cortical inhibition was more pronounced in patients with high IL-13 levels in the CSF, as expected for a neuroprotective, anti-excitotoxic effect. Conclusions: The present correlation study provides some evidence for the involvement of IL-13 in the modulation of neuronal integrity and synaptic function in patients with MS.

Interleukin-1β causes excitotoxic neurodegeneration and multiple sclerosis disease progression by activating the apoptotic protein p53

BackgroundUnderstanding how inflammation causes neuronal damage is of paramount importance in multiple sclerosis (MS) and in other neurodegenerative diseases. Here we addressed the role of the apoptotic cascade in the synaptic abnormalities and neuronal loss caused by the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor (TNF-α) in brain tissues, and disease progression caused by inflammation in relapsing-remitting MS (RRMS) patients.ResultsThe effect of IL-1β, but not of TNF-α, on glutamate-mediated excitatory postsynaptic currents was blocked by pifithrin-α (PFT), inhibitor of p53. The protein kinase C (PKC)/transient receptor potential vanilloid 1 (TRPV1) pathway was involved in IL-1β-p53 interaction at glutamatergic synapses, as pharmacological modulation of this inflammation-relevant molecular pathway affected PFT effects on the synaptic action of IL-1β. IL-1β-induced neuronal swelling was also blocked by PFT, and IL-1β increased the expression of p21, a canonical downstream target of activated p53.Consistent with these in vitro results, the Pro/Pro genotype of p53, associated with low efficiency of transcription of p53-regulated genes, abrogated the association between IL-1β cerebrospinal fluid (CSF) levels and disability progression in RRMS patients. The interaction between p53 and CSF IL-1β was also evaluated at the optical coherence tomography (OCT), showing that IL-1β-driven neurodegenerative damage, causing alterations of macular volume and of retinal nerve fibre layer thickness, was modulated by the p53 genotype.ConclusionsInflammatory synaptopathy and neurodegeneration caused by IL-1β in RRMS patients involve the apoptotic cascade. Targeting IL-1β-p53 interaction might result in significant neuroprotection in MS.

The 12-year incidence of glaucoma and glaucoma-related visual field loss in Italy: the Ponza eye study.

PurposeTo assess the 12-year incidence of glaucoma and glaucoma-related visual field loss in a population-based cohort study. PatientsIn 2000, we reexamined 411 of the 581 survivors from the original Ponza eye study conducted in 1988. MethodsPrimary open-angle (POAG), primary angle-closure (PACG), and secondary [pseudoexfoliative (PEX)] glaucoma were diagnosed according to the 3-tiered system of evidence developed by the International Society of Geographical and Epidemiological Ophthalmology. Severity of glaucoma was classified according to the Bascom-Palmer system. Visual loss was defined according to World Health Organization guidelines. Relative risk ratios were calculated for several variables. ResultsThe 12-year incidence of definite POAG was 3.8% (95% confidence intervals (CI), 2.3-6.2), that is, an average annual rate of 0.32%. Corresponding rates for PACG and PEX glaucoma were 0.5% (95% CI, 0.1-1.8) and 0.8% (95% CI, 0.3-2.2), respectively. Half the incident glaucoma cases (45%) had not been diagnosed earlier. Fifty-five percent of the incident POAG eyes had Bascom-Palmer stage 1 or 2 disease and 40% of the incident PACG or PEX glaucoma eyes had stage 3 or 4 disease. Seven of 20 incident glaucoma cases presented with monocular or binocular visual loss because of advanced visual field loss. Significant risk factors for POAG included high myopia (>6.0 D), intraocular pressure ≥22 mm Hg, and glaucoma family history. ConclusionThe average annual incidence of definite POAG in Ponzas lower than that reported in persons of African ancestry and higher than that observed in certain other white populations.

Opposite Roles of NMDA Receptors in Relapsing and Primary Progressive Multiple Sclerosis

Synaptic transmission and plasticity mediated by NMDA receptors (NMDARs) could modulate the severity of multiple sclerosis (MS). Here the role of NMDARs in MS was first explored in 691 subjects carrying specific allelic variants of the NR1 subunit gene or of the NR2B subunit gene of this glutamate receptor. The analysis was replicated for significant SNPs in an independent sample of 1548 MS subjects. The C allele of rs4880213 was found to be associated with reduced NMDAR-mediated cortical excitability, and with increased probability of having more disability than the CT/TT MS subjects. MS severity was higher in the CC group among relapsing-remitting MS (RR-MS) patients, while primary progressive MS (PP-MS) subjects homozygous for the T allele had more pronounced clinical worsening. Mean time to first relapse, but not to an active MRI scan, was lower in the CC group of RR-MS patients, and the number of subjects with two or more clinical relapses in the first two years of the disease was higher in CC compared to CT/TT group. Furthermore, the percentage of relapses associated with residual disability was lower in subjects carrying the T allele. Lesion load at the MRI was conversely unaffected by the C or T allele of this SNP in RR-MS patients. Axonal and neuronal degeneration at the optical coherence tomography was more severe in the TT group of PP-MS patients, while reduced retinal nerve fiber thickness had less consequences on visual acuity in RR-MS patients bearing the T allele. Finally, the T allele was associated with preserved cognitive abilities at the Rao’s brief repeatable neuropsychological battery in RR-MS. Signaling through glutamate NMDARs enhances both compensatory synaptic plasticity and excitotoxic neurodegeneration, impacting in opposite ways on RR-MS and PP-MS pathophysiological mechanisms.

Association between a Genetic Variant of Type-1 Cannabinoid Receptor and Inflammatory Neurodegeneration in Multiple Sclerosis

Genetic ablation of type-1 cannabinoid receptors (CB1Rs) exacerbates the neurodegenerative damage of experimental autoimmune encephalomyelitis, the rodent model of multiple sclerosis (MS). To address the role on CB1Rs in the pathophysiology of human MS, we first investigated the impact of AAT trinucleotide short tandem repeat polymorphism of CNR1 gene on CB1R cell expression, and secondly on the inflammatory neurodegeneration process responsible for irreversible disability in MS patients. We found that MS patients with long AAT repeats within the CNR1 gene (≥12 in both alleles) had more pronounced neuronal degeneration in response to inflammatory white matter damage both in the optic nerve and in the cortex. Optical Coherence Tomography (OCT), in fact, showed more severe alterations of the retinal nerve fiber layer (RNFL) thickness and of the macular volume (MV) after an episode of optic neuritis in MS patients carrying the long AAT genotype of CNR1. MS patients with long AAT repeats also had magnetic resonance imaging (MRI) evidence of increased gray matter damage in response to inflammatory lesions of the white matter, especially in areas with a major role in cognition. In parallel, visual abilities evaluated at the low contrast acuity test, and cognitive performances were negatively influenced by the long AAT CNR1 genotype in our sample of MS patients. Our results demonstrate the biological relevance of the (AAT)n CNR1 repeats in the inflammatory neurodegenerative damage of MS.