APOE4 impairs the microglial response in Alzheimer's disease by inducing TGFß-mediated checkpoints.

The APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). The contribution of microglial APOE4 to AD pathogenesis is unknown, although APOE has the most enriched gene expression in neurodegenerative microglia (MGnD). Here, we show in mice and humans a negative role of microglial APOE4 in the induction of the MGnD response to neurodegeneration. Deletion of microglial APOE4 restores the MGnD phenotype associated with neuroprotection in P301S tau transgenic mice and decreases pathology in APP/PS1 mice. MGnD-astrocyte cross-talk associated with ß-amyloid (Aß) plaque encapsulation and clearance are mediated via LGALS3 signaling following microglial APOE4 deletion. In the brains of AD donors carrying the APOE4 allele, we found a sex-dependent reciprocal induction of AD risk factors associated with suppression of MGnD genes in females, including LGALS3, compared to individuals homozygous for the APOE3 allele. Mechanistically, APOE4-mediated induction of ITGB8-transforming growth factor-ß (TGFß) signaling impairs the MGnD response via upregulation of microglial homeostatic checkpoints, including Inpp5d, in mice. Deletion of Inpp5d in microglia restores MGnD-astrocyte cross-talk and facilitates plaque clearance in APP/PS1 mice. We identify the microglial APOE4-ITGB8-TGFß pathway as a negative regulator of microglial response to AD pathology, and restoring the MGnD phenotype via blocking ITGB8-TGFß signaling provides a promising therapeutic intervention for AD.

Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma.

The apolipoprotein E4 (APOE4) allele is associated with an increased risk of Alzheimer disease and a decreased risk of glaucoma, but the underlying mechanisms remain poorly understood. Here, we found that in two mouse glaucoma models, microglia transitioned to a neurodegenerative phenotype characterized by upregulation of Apoe and Lgals3 (Galectin-3), which were also upregulated in human glaucomatous retinas. Mice with targeted deletion of Apoe in microglia or carrying the human APOE4 allele were protected from retinal ganglion cell (RGC) loss, despite elevated intraocular pressure (IOP). Similarly to Apoe-/- retinal microglia, APOE4-expressing microglia did not upregulate neurodegeneration-associated genes, including Lgals3, following IOP elevation. Genetic and pharmacologic targeting of Galectin-3 ameliorated RGC degeneration, and Galectin-3 expression was attenuated in human APOE4 glaucoma samples. These results demonstrate that impaired activation of APOE4 microglia is protective in glaucoma and that the APOE-Galectin-3 signaling can be targeted to treat this blinding disease.

CD163+ macrophages infiltrate axon bundles of postmortem optic nerves with glaucoma.

PURPOSE: Prior research in animal models has shown that macrophages and microglia play an important role in pathogenesis of glaucoma, but the phenotype and distribution of macrophages in human glaucomatous tissue have not been sufficiently characterized. METHODS: We analyzed H&E, CD68-, and CD163-immunostained slides from 25 formaldehyde-fixed, paraffin-embedded autopsy eyes: 12 control eyes and 13 eyes with glaucoma. The diagnosis of glaucoma was made based on a history of glaucoma as reported in the medical record and histological changes characteristic of glaucoma. Glaucoma cases and controls were matched in terms of age, sex, and race. RESULTS: Qualitative analysis of the conventional outflow pathway and the optic nerve revealed that all eyes contained CD163+ cells but a negligible number of CD68+ cells. CD163+ macrophages infiltrated the trabecular meshwork and surrounded Schlemm's canal of normal eyes and eyes with glaucoma, but the pattern was variable and qualitatively similar between groups. In optic nerves of control eyes, CD163+ macrophages were present at low levels and restricted to septa between axon bundles. In glaucomatous optic nerves, the number of CD163+ cells was increased both qualitatively and quantitatively (glaucoma 5.1 ± 0.6 CD163+ cells/mm2, control 2.5 ± 0.3 CD163+ cells/mm2, p < 0.001), with CD163+ cells infiltrating axon bundles in cases of both mild and severe diseases. CONCLUSIONS: The increase in CD163+ cell number in eyes with mild and severe glaucoma is the first demonstration of macrophage infiltration in glaucomatous human optic nerves. This finding supports a role for macrophages in glaucoma pathogenesis and progression.

Frequency of Agreement Between Structural and Functional Glaucoma Testing: A Longitudinal Study of 3D OCT and Current Clinical Tests.

PURPOSE: To evaluate how often tests of structure and function detect glaucoma progression at the same study visit. Tests include current glaucoma clinical tests and a new 3-dimensional (3D) optical coherence tomography (OCT) rim measurement. DESIGN: Prospective cohort study. METHODS: For 124 open-angle glaucoma patients at a single institution, one eye was randomly selected for each patient. Patients were included if they had open-angle glaucoma and if they had at least 4 yearly study visits. Study visits included a full dilated eye exam, disc photography (DP), Humphrey visual field (HVF 24-2) testing, 2D OCT retinal nerve fibre layer (RNFL) thickness measurements, and 3D OCT neuroretinal rim measurements (i.e., minimum distance band or MDB). For each test at each study visit, eyes were classified as progressors or non-progressors using event-based analysis. Agreement occurred if tests progressed in the same eye at the same study visit. Agreements between all compared tests were calculated as percentages of agreement. RESULTS: The study included 124 open-angle glaucoma eyes, which had an average follow-up period of 66.9 ± 16.4 months. Structural tests (i.e., DP, global RNFL thickness, and global MDB rim thickness) progressed at the same visit as the functional test (i.e., HVF testing) in only 5.0% (3/60) to 16.0% (13/81) of eyes. Global MDB thickness and global RNFL thickness showed similar agreement with functional HVF testing (i.e., 16.0% [13/81] and 8.3% [7/84], respectively), and global MDB thickness showed better structure-function agreement with HVF testing than between DP and HVF testing (i.e., 5.0% [3/60], P = 0.04). For all paired comparisons between testing methods, eyes with moderate glaucoma showed similar or better agreement than eyes with mild or severe glaucoma. CONCLUSIONS: Clinical tests of structure and function do not usually progress at the same clinic visit. Most of the time, glaucoma progression is only detected by one or two tests.

Myeloid masquerade: Microglial transcriptional signatures in retinal development and disease.

Microglia are dynamic guardians of neural tissue and the resident immune cells of the central nervous system (CNS). The disease-associated microglial signature (DAM), also known as the microglial neurodegenerative phenotype (MGnD), has gained significant attention in recent years as a fundamental microglial response common to various neurodegenerative disease pathologies. Interestingly, this signature shares many features in common with developmental microglia, suggesting the existence of recycled gene programs which play a role both in early neural circuit formation as well as in response to aging and disease. In addition, recent advances in single cell RNA sequencing have revealed significant heterogeneity within the original DAM signature, with contributions from both yolk sac-derived microglia as well as bone marrow-derived macrophages. In this review, we examine the role of the DAM signature in retinal development and disease, highlighting crosstalk between resident microglia and infiltrating monocytes which may critically contribute to the underlying mechanisms of age-related neurodegeneration.

Steroid Response Following Dropless Cataract Surgery Using Subconjunctival Triamcinolone.

Purpose: To assess the rates of postoperative steroid response following dropless cataract surgery using a subconjunctival depot of triamcinolone versus conventional cataract surgery using topical prednisolone. Patients and Methods: We reviewed consecutive cataract surgery cases performed by a single surgeon to determine the likelihood of steroid response, defined as intraocular pressure (IOP) 50% above baseline or IOP > 24 mmHg postoperatively, excluding the first 72 hours. Logistic regression models were performed including baseline characteristics as exposures in the model and steroid response as the outcome. Main outcome measures were the proportion of eyes developing steroid response, risk factors for developing steroid response, and duration of steroid response. Results: Of the 150 dropless and 218 conventional cases, 26 eyes developed steroid response (15 dropless and 11 conventional cases [10% vs 5%, P=0.096]). Risk factors for steroid response included dropless surgery (OR=2.43, 95% CI=1.03-6.02], P=0.046) and prior diagnosis of glaucoma (OR=7.18, 95% CI=2.66-19.22], P<0.001). Baseline IOP, age, sex, race, and axial length did not increase risk for steroid response. Of the eyes with steroid response, more dropless cases had an IOP elevation ≥30 days (9/15 eyes vs 1/11 eyes; P=0.008), including one patient with refractory IOP elevation in the dropless group who required urgent bilateral trabeculectomy for IOP control. Conclusion: Dropless cataract surgery increases the risk of prolonged steroid response postoperatively. Patients with glaucoma have an increased risk of steroid response and may not be good candidates for dropless cataract surgery with subconjunctival triamcinolone.

Neurofilament Light Chain in Aqueous Humor as a Marker of Neurodegeneration in Glaucoma.

Purpose: Neurofilament light chain (NfL) is a neuronal cytoskeletal protein that has been identified as a marker of neurodegeneration in diseases of the central nervous system. In this study, we investigated whether NfL in the aqueous humor (AH) can serve as a marker of neurodegeneration in glaucoma in a racially diverse North American population. Design: Single-center, case-control study. Participants: We enrolled patients with various types and stages of glaucoma undergoing planned ophthalmic surgery as part of their routine care and compared them with patients without glaucoma undergoing phacoemulsification for age-related cataract. Methods: We collected AH from 39 glaucoma patients and 10 patients without glaucoma. AH NfL was quantified using the Single-Molecule Array (Simoa)® NF-light assay (Quanterix). Demographic information, such as age, body mass index, sex, and self-reported race, as well as clinical information, such as pre-operative intraocular pressure (IOP), maximum IOP, and number of pre-operative glaucoma medications, was obtained by reviewing the medical record. Main Outcome Measures: Levels of AH NfL. Results: In a model controlling for age and body mass index (BMI), NfL was significantly elevated in AH from glaucoma patients (mean: 429 pg/mL; standard deviation [SD]: 1136 pg/mL) compared to AH from patients without glaucoma (mean: 3.1 pg/mL; SD: 1.9 pg/mg): P = 0.002. Higher AH NfL was associated with higher maximum IOP (R = 0.44, P = 0.005), higher pre-operative IOP (R = 0.46, P = 0.003), and more pre-operative glaucoma medications (Rs = 0.61, P < 0.001). There was no association between AH NfL and Humphrey visual field mean deviation (R = -0.20, P = 0.220), retinal nerve fiber layer thickness as measured with optical coherence tomography (R = 0.07, P = 0.694), or glaucoma stage (Rs = 0.015, P = 0.935). Conclusion: Our findings suggest that AH NfL may have clinical utility as a marker of glaucomatous neurodegeneration.

Identification of a protective microglial state mediated by miR-155 and interferon-γ signaling in a mouse model of Alzheimer's disease.

Microglia play a critical role in brain homeostasis and disease progression. In neurodegenerative conditions, microglia acquire the neurodegenerative phenotype (MGnD), whose function is poorly understood. MicroRNA-155 (miR-155), enriched in immune cells, critically regulates MGnD. However, its role in Alzheimer's disease (AD) pathogenesis remains unclear. Here, we report that microglial deletion of miR-155 induces a pre-MGnD activation state via interferon-γ (IFN-γ) signaling, and blocking IFN-γ signaling attenuates MGnD induction and microglial phagocytosis. Single-cell RNA-sequencing analysis of microglia from an AD mouse model identifies Stat1 and Clec2d as pre-MGnD markers. This phenotypic transition enhances amyloid plaque compaction, reduces dystrophic neurites, attenuates plaque-associated synaptic degradation and improves cognition. Our study demonstrates a miR-155-mediated regulatory mechanism of MGnD and the beneficial role of IFN-γ-responsive pre-MGnD in restricting neurodegenerative pathology and preserving cognitive function in an AD mouse model, highlighting miR-155 and IFN-γ as potential therapeutic targets for AD.

Clathrin adaptor AP-1 complex excludes multiple postsynaptic receptors from axons in C. elegans.

Neurons are highly polarized cells with morphologically and molecularly distinct axonal and dendritic compartments. It is not well understood how postsynaptic receptors are selectively enriched in dendrites in vivo. We investigated the molecular mechanisms of dendritically polarized localization of a glutamate receptor, an acetylcholine receptor, and a ROR-type receptor tyrosine kinase in the interneuron RIA in C. elegans. We found that the clathrin adaptor AP-1 complex mu1 subunit UNC-101 functions cell autonomously to maintain the correct localization of these receptors in a dynamin-dependent manner. In unc-101 mutants, instead of being dendritically enriched, all 3 receptors are evenly distributed in the axonal and dendritic compartments. Surprisingly, UNC-101 predominantly localizes to the axonal compartment, suggesting a possible transcytosis model for the dendritic targeting of neurotransmitter receptors.

Disc Hemorrhages Are Associated With Localized Three-Dimensional Neuroretinal Rim Thickness Progression in Open-Angle Glaucoma.

PURPOSE: To evaluate the relationship between the occurrence of optic disc hemorrhages (DH) and glaucoma progression as determined by multiple glaucoma testing modalities. DESIGN: Prospective cohort study. METHODS: A longitudinal study was undertaken of 124 open-angle glaucoma patients who had yearly disc photography, visual fields (VFs), spectral-domain optical coherence tomography (SD-OCT), retinal nerve fiber layer (RNFL) thickness scans, and optic nerve volume scans (Spectralis), all performed on the same day over a 5-year period. The minimum distance band (MDB) thickness, a 3-dimensional (3D) neuroretinal rim parameter, was calculated from optic nerve volume scans. Patients were classified as glaucoma progressors or glaucoma nonprogressors using event-based analysis. RESULTS: Of 124 open-angle glaucoma patients, 19 (15.3%) had 1 or more DHs on yearly disc photographs. Presence of a DH was associated with localized 3D neuroretinal rim thickness progression (superior MDB progression; odds ratio: 3.96; P = .04) but not with global or inferior MDB progression (P = .14 and .81, respectively), DP progression (P = .08), VF progression (P = .45), or RNFL global, inferior, or superior progression (P = .17, .26, and .76, respectively). In the majority of patients with MDB progression (14/17 or 82%), the progression was noted before or concurrently with the first instance of DH. CONCLUSIONS: Glaucoma progression detected by high-density 3D SD-OCT neuroretinal rim measurements preceded DH occurrence in the majority of patients. These findings support the hypothesis that DHs are indicators of ongoing glaucoma progression rather than discrete events that cause subsequent progression.

Neurodegeneration Markers Galectin-3 and Apolipoprotein E Are Elevated in the Aqueous Humor of Eyes With Glaucoma.

Purpose: Galectin-3 (Gal-3) and apolipoprotein E (APOE) are markers of activated microglia in neurodegenerative diseases of the central nervous system, whose targeting is protective in mouse models of glaucoma. In this study, we examined levels of Gal-3 and APOE in human aqueous humor (AH) and defined their clinical associations with glaucoma. Methods: We collected AH from 59 glaucoma patients and 15 controls at the start of planned ophthalmic surgery. Gal-3 and APOE levels were quantified by enzyme-linked immunosorbent assay. Total protein in AH was quantified by bicinchoninic acid assay. Significant associations between Gal-3, APOE, and clinical covariates were defined using univariate and multivariate linear regression models. Results: Gal-3 and APOE levels were significantly elevated in the AH of glaucoma patients compared to controls (P = 0.004 and P < 0.001, respectively). Gal-3 and APOE were positively correlated across the entire cohort (r = 0.65, P = 6.2E-9). No association was observed between Gal-3 and total protein or APOE and total protein (P = 0.35 and P = 0.50, respectively), indicating that their levels were not increased in glaucomatous AH due to nonspecific protein accumulation. Multivariate linear regression modeling revealed significant associations between Gal-3 and maximum recorded intraocular pressure (P = 0.009) and between APOE and number of past ophthalmic surgeries (P = 0.031). Conclusions: We demonstrate that Gal-3 and APOE are significantly elevated in the AH of eyes with glaucoma and are associated with a history of poorly controlled disease. Translational Relevance: Gal-3 and APOE in AH may inform clinical decision-making as quantifiable readouts of microglial activation in eyes with glaucoma.

The Prevalence of Autoimmune Diseases in Patients with Primary Open-Angle Glaucoma Undergoing Ophthalmic Surgeries.

PURPOSE: To assess the prevalence of autoimmune disease (AiD) in patients with primary open-angle glaucoma (POAG) undergoing ophthalmic surgery. DESIGN: Retrospective, cross-sectional study. PARTICIPANTS: Patients with POAG undergoing any ophthalmic surgery and control subjects undergoing cataract surgery at the Massachusetts Eye and Ear from March 2019 to April 2020. METHODS: All available medical records with patient demographics, ocular, and medical conditions were reviewed. Differences in AiD prevalence were assessed and adjusted for covariates using multiple logistic regression. Additionally, a subgroup analysis comparing the POAG patients with and without AiD was performed. MAIN OUTCOME MEASURES: To assess the prevalence of AiD based on the American Autoimmune Related Diseases Association list. RESULTS: A total of 172 patients with POAG and 179 controls were included. The overall prevalence of AiD was 17.4% in the POAG group and 10.1% in the controls (P = 0.044); 6.4% of POAG patients and 3.4% of controls had more than 1 AiD (P = 0.18). The most prevalent AiDs in POAG group were rheumatoid arthritis (4.6%) and psoriasis (4.1%), which were also the most common in controls (2.8% each). In a fully adjusted multiple logistic regression analysis accounting for steroid use, having an AiD was associated with 2.62-fold increased odds of POAG relative to controls (95% confidence interval, 1.27-5.36, P = 0.009); other risk factors for POAG derived from the analysis included age (odds ratio [OR], 1.04, P = 0.006), diabetes mellitus (OR, 2.31, P = 0.008), and non-White ethnicity (OR, 4.75, P < 0.001). In a case-only analysis involving the eye with worse glaucoma, there was no statistical difference in visual field mean deviation or retinal nerve fiber layer (RNFL) thickness in POAG patients with AiD (n = 30) and without AiD (n = 142, P > 0.13, for both). CONCLUSIONS: A higher prevalence of AiD was found in POAG patients compared with control patients undergoing ophthalmic surgery. The presence of AiD was associated with increased risk for POAG after adjusting for covariates. Additional factors may have prevented a difference in RNFL thickness in POAG patients with and without AiD. Autoimmunity should be explored further in the pathogenesis of POAG.

Regulating microglial miR-155 transcriptional phenotype alleviates Alzheimer's-induced retinal vasculopathy by limiting Clec7a/Galectin-3+ neurodegenerative microglia.

Single cell RNA sequencing studies identified novel neurodegeneration-associated microglial (MGnD/DAM) subtypes activated around cerebral amyloid plaques. Micro-RNA (miR)-155 of the TREM2-APOE pathway was shown to be a key transcriptional regulator of MGnD microglial phenotype. Despite growing interest in studying manifestations of Alzheimer's disease (AD) in the retina, a CNS organ accessible to noninvasive high-resolution imaging, to date MGnD microglia have not been studied in the AD retina. Here, we discovered the presence and increased populations of Clec7a+ and Galectin-3+ MGnD microglia in retinas of transgenic APPSWE/PS1L166P AD-model mice. Conditionally targeting MGnD microglia by miR-155 ablation via the tamoxifen-inducible CreERT2 system in APPSWE/PS1L166P mice diminished retinal Clec7a+ and Galectin-3+ microglial populations while increasing homeostatic P2ry12+ microglia. Retinal MGnD microglia were often adhering to microvessels; their depletion protected the inner blood-retina barrier and reduced vascular amyloidosis. Microglial miR-155 depletion further limits retinal inflammation. Mass spectrometry analysis revealed enhanced retinal PI3K-Akt signaling and predicted IL-8 and Spp1 decreases in mice with microglia-specific miR-155 knockout. Overall, this study identified MGnD microglia in APPSWE/PS1L166P mouse retina. Transcriptional regulation of these dysfunctional microglia mitigated retinal inflammation and vasculopathy. The protective effects of microglial miR-155 ablation should shed light on potential treatments for retinal inflammation and vascular damage during AD and other ocular diseases.

Molecular mechanisms of synaptic specificity.

Synapses are specialized junctions that mediate information flow between neurons and their targets. A striking feature of the nervous system is the specificity of its synaptic connections: an individual neuron will form synapses only with a small subset of available presynaptic and postsynaptic partners. Synaptic specificity has been classically thought to arise from homophilic or heterophilic interactions between adhesive molecules acting across the synaptic cleft. Over the past decade, many new mechanisms giving rise to synaptic specificity have been identified. Synapses can be specified by secreted molecules that promote or inhibit synaptogenesis, and their source can be a neighboring guidepost cell, not just presynaptic and postsynaptic neurons. Furthermore, lineage, fate, and timing of development can also play critical roles in shaping neural circuits. Future work utilizing large-scale screens will aim to elucidate the full scope of cellular mechanisms and molecular players that can give rise to synaptic specificity.

Earlier Detection of Glaucoma Progression Using High-Density 3-Dimensional Spectral-Domain OCT Optic Nerve Volume Scans.

PURPOSE: To compare onset times of glaucoma progression among different glaucoma tests: disc photography (DP), visual field (VF) testing, 2-dimensional (2D) retinal nerve fiber layer (RNFL) thickness, and 3-dimensional (3D) spectral-domain (SD) OCT neuroretinal rim measurements. DESIGN: Prospective, longitudinal cohort study. PARTICIPANTS: One hundred twenty-four eyes of 124 patients with open-angle glaucoma. METHODS: Over a 5-year period, 124 patients with open-angle glaucoma underwent yearly DP, VF testing, SD OCT RNFL thickness scans, and optic nerve volume scans (Spectralis; Heidelberg Engineering), all performed on the same day. From high-density optic nerve volume scans, custom-built software calculated the minimum distance band (MDB) thickness, a 3D neuroretinal rim parameter. Patients were classified as glaucoma progressors or nonglaucoma progressors using event-based analysis. Progression by DP and VF testing occurred when 3 masked glaucoma specialists unanimously concurred. Progression by RNFL and MDB thickness occurred if change of more than test-retest variability was observed. Kaplan-Meier curves were constructed to analyze time-to-progression data. Kappa Coefficients were used to measure agreement of progressing eyes among methods. MAIN OUTCOME MEASURES: Time to glaucoma progression among all 4 methods. RESULTS: Global MDB thickness detected glaucoma progression in the highest percentage of eyes (52.4%) compared with DP (16.1%; P < 0.001) and global RNFL thickness (15.3%; P < 0.001). Global MDB thickness detected glaucoma progression earlier than either DP (23 months vs. 44 months; P < 0.001) or global RNFL thickness (23 months vs. 33 months; P < 0.001). Among MDB progressing eyes, 46.2% were confirmed simultaneously or later by other conventional methods. Agreement of glaucoma-progressing eyes for all 4 methods in paired fashion were slight to fair (κ = 0.095-0.300). CONCLUSIONS: High-density 3D SD OCT neuroretinal rim measurements detected glaucoma progression approximately 1 to 2 years earlier compared with current clinically available structural tests (i.e., DP and 2D RNFL thickness measurements).

Building a synapse: lessons on synaptic specificity and presynaptic assembly from the nematode C. elegans.

Synapses are specialized sites of cell contact that mediate information flow between neurons and their targets. Genetic screens in the nematode C. elegans have led to the discovery of a number of molecules required for synapse patterning and assembly. Recent studies have demonstrated the importance of guidepost cells in the positioning of presynaptic sites at specific locations along the axon. Interestingly, these guideposts can promote or inhibit synapse formation, and do so by utilizing transmembrane adhesion molecules or secreted factors that act over relatively larger distances. Once the decision of where to build a presynaptic terminal has been made, key molecules are recruited to assemble synaptic vesicles and active zone proteins at that site. Multiple steps of this process are regulated by ubiquitin ligase complexes. Interestingly, some of the molecules involved in presynaptic assembly also play roles in regulating axon polarity and outgrowth, suggesting that different neurodevelopmental processes are molecularly integrated.

Association of APOE With Primary Open-Angle Glaucoma Suggests a Protective Effect for APOE ε4.

Purpose: Prior studies have demonstrated that microglial activation is involved in the pathogenesis of primary open-angle glaucoma (POAG). Here we sought to identify genetic associations between POAG and variants in APOE and TREM2, genes associated with Alzheimer disease (AD) that critically regulate microglial neurodegeneration-associated molecular signature. Methods: APOE genotypes were called using imputed data from the NEIGHBOR consortium (2120 POAG cases, 2262 controls) and a second cohort from the Massachusetts Eye and Ear Infirmary (MEEI; 486 cases, 344 controls). TREM2 coding variants were genotyped by means of the Illumina HumanExome BeadArray. The data set was analyzed for association with POAG overall, as well as the high-tension glaucoma (HTG) and normal-tension glaucoma (NTG) subgroups, using logistic regression adjusting for age and sex. Results: In the combined NEIGHBOR-MEEI data set, significant association was observed for APOE ε4 in POAG overall (odds ratio [OR], 0.83; 95% confidence interval [CI], 0.74-0.94; P = 0.0022) and in both the HTG subgroup (OR, 0.81; 95% CI, 0.70-0.94; P = 0.0052) and NTG subgroup (OR, 0.71; 95% CI, 0.58-0.87; P = 0.0014). A rare TREM2 variant (A105V) was found only in HTG cases (3 of 2863 cases) and in none of the controls (P = 0.03). Three TREM2 rare variants associated with AD were not significantly associated with POAG (P > 0.05). Conclusions: We have found that the APOE ε4 allele is associated with a reduced risk of POAG. Interestingly, the same allele is adversely associated with AD, suggesting a mechanistic difference between neurodegenerative diseases of the eye and the brain. TREM2 variants associated with AD did not significantly contribute to POAG risk.

Staying away from the optic nerve: a formula for modifying glaucoma drainage device surgery in pediatric and other small eyes.

PURPOSE: To provide guidelines for safe implantation of glaucoma drainage devices (GDDs) in small and pediatric eyes to avoid contact between the optic nerve (ON) and the posterior edge of the GDD plate. METHODS: We developed a formula for calculating limbus-to-ON distance to estimate the available "real estate" for GDD placement in small eyes. The formula was validated using eyes of pediatric decedents undergoing clinical autopsy, with axial lengths (AL) of 15-24 mm. For each autopsy eye, we measured AL, anterior chamber depth, corneal diameter, and limbus-to-ON distances for the four eye quadrants. The main outcome measure was the degree of agreement between measured and calculated limbus-to-ON distances. RESULTS: A total of 15 autopsy eyes were divided into derivation (n = 10) and validation (n = 5) groups. A formula was derived to estimate superotemporal limbus-to-ON distance (DST) using AL and corneal diameter data. Linear regression showed excellent correlation between the measured DST and AL (R2 = 0.98). There was excellent agreement between measured and calculated limbus-to-ON values for all four eye quadrants (R2 range, 0.92-0.98). CONCLUSIONS: Our formula accurately predicts limbus-to-ON distances across a wide range of clinically relevant ALs. Based on this information, GDD surgery in small eyes can be adjusted by positioning the GDD closer to the limbus or by trimming the posterior edge of the GDD plate. To our knowledge, this is the first set of guidelines developed to promote safe implantation of GDDs in small eyes.

Low cerebrospinal fluid protein in prepubertal children with idiopathic intracranial hypertension.

PURPOSE: To evaluate a clinical observation that prepubertal children with idiopathic intracranial hypertension (IIH) have low cerebrospinal fluid (CSF) protein levels compared to healthy children and pubertal patients with IIH. METHODS: The medical records of prepubertal and pubertal IIH patients and controls seen in the pediatric neuro-ophthalmology clinic at Duke between 2003 and 2013 were retrospectively reviewed. The control group consisted of children who had normal intracranial pressure on lumbar puncture performed to evaluate for headaches or anomalous-looking optic nerves. The records were analyzed with attention to demographic characteristics, clinical presentation, course, and lumbar puncture results. RESULTS: A total of 23 prepubertal children with IIH (age range, 0.75-13 years), 16 pubertal patients with IIH (age range, 13-21 years), and 12 controls (age range 3-14 years) were included. CSF analysis revealed that prepubertal children with IIH had significantly lower CSF protein levels (17.3 ± 5.7 mg/dL) compared to pubertal subjects with IIH (23.4 ± 8.4 mg/dL; P = 0.019) or healthy controls (23.5 ± 6.4 mg/dL; P = 0.011). Furthermore, 9 of 23 prepubertal IIH patients (39%) had abnormally low CSF protein level (<15 mg/dL), compared to zero pubertal IIH patients (P = 0.005) and zero controls (P = 0.015). Acetazolamide increased CSF protein level in 100% of patients who underwent repeat lumbar puncture after starting the medication (average increase, 10.3 ± 6.6 mg/dL). CONCLUSIONS: Low CSF protein level may have diagnostic utility as a biomarker for prepubertal IIH. Furthermore, this finding suggests that some cases of prepubertal IIH may be caused by CSF overproduction rather than decreased CSF resorption.