Y. Joyce Liao, MD, PhD

All Publications

• High Altitude as a Risk Factor for the Development of Nonarteritic Anterior Ischemic Optic Neuropathy. Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society Liu, Y. A., Mesentier-Louro, L. A., Shariati, M. A., Moss, H. E., Beres, S. J., Liao, Y. J. 2022

  Abstract

  Episodic high-altitude exposure leads to optic disc edema and retinopathy. It is uncertain whether high-altitude exposure is a risk factor for nonarteritic anterior ischemic optic neuropathy (NAION).We performed a single-center, retrospective, cross-sectional case study of 5 patients with high-altitude-associated NAION (HA-NAION) from April 2014 to April 2019. Main study parameters included known vascular risk factors for NAION, evolution of visual acuity, visual field, optic disc, and macula measurements.We studied 5 eyes of 5 patients with HA-NAION that occurred at 7,000-9,000 ft above sea level, 28 patients with classic NAION that developed at sea level (normal altitude NAION or NA-NAION), and 40 controls. All 5 patients with HA-NAION had clinically confirmed NAION by a neuro-ophthalmologist within 3-21 days of onset and comprehensive follow-up evaluations (average follow-up of 23 months). Other than high-altitude exposure, 4 of 5 patients had undiagnosed obstructive sleep apnea (OSA, apnea-hypopnea index 5.4-22.2) and 1 had systemic vascular risk factors. All patients had disc-at-risk in the contralateral eye. The best-corrected distance visual acuity was 20/20 to 20/70 (median logMAR 0) at presentation and 20/70 to counting finger (median logMAR 0) at ≥6 months. Automated static perimetry revealed average mean deviation of -18.6 dB at presentation and -22.1 dB at ≥6 months. The average retinal nerve fiber layer was 244 µm (80-348 µm) at onset and 59 µm (55-80 µm) at ≥6 months. The average ganglion cell complex thickness was 50 µm (43-54 µm) at onset and 52 µm (50-55 µm) at ≥6 months. The patients with OSA were started on home continuous positive airway pressure treatment. Visual outcomes were similar in patients with HA-NAION and NA-NAION. - After addressing all NAION risk factors, no new events occurred in the HA-NAION group within 2-8 years with or without repeat high-altitude exposure.NAION can occur under high-altitude conditions. HA-NAION is associated with relatively younger age at onset, disc-at-risk, and OSA. These patients exhibit a relatively progressive course of vision loss after initial onset and severe thinning of optic nerves on optical coherence tomography. Treatment for OSA is recommended, especially with repeated high-altitude exposure.

  View details for DOI 10.1097/WNO.0000000000001629

  View details for PubMedID 36166787

• Immunoprofiling of Nonarteritic Anterior Ischemic Optic Neuropathy. Translational vision science & technology Mesentier-Louro, L. A., Stell, L., Yan, Y., Montague, A. A., de Jesus Perez, V., Liao, Y. J. 2021; 10 (8): 17

  Abstract

  Purpose: Nonarteritic anterior ischemic optic neuropathy (NAION) is a common acute optic neuropathy in those older than 50 years. There is no blood diagnostic test or efficient treatment for NAION. We investigated the suitability of blood inflammatory proteins as biomarkers and therapeutic targets of NAION.Methods: We conducted an exploratory, cross-sectional case-control study including 18 patients with NAION (n = 5 acute, and n = 13 chronic) and 9 controls. NAION was confirmed by clinical examination and optical coherence tomography. Subjects underwent peripheral blood collection; plasma was isolated within 2 hours and analyzed using a 76-plex array of cytokines, chemokines, and growth factors.Results: In acute NAION, there was increased peripapillary retinal thickness on optical coherence tomography consistent with optic disc edema. Plasma profiling revealed dramatic changes in inflammatory proteins in NAION. Statistical analysis generated a list of 20 top-ranked molecules in NAION, with 15% overlap in acute and chronic NAION. Principal component analysis, hierarchical clustering, and Spearman correlation generally segregated controls, acute and chronic NAION, with some overlap. Longitudinal data from one patient demonstrated an evolving inflammatory pattern from acute to chronic NAION. In acute NAION, Eotaxin-3, MCP-2, TPO, and TRAIL were the top biomarker candidates. In chronic NAION, IL-1alpha and CXCL10 emerged as the strongest therapeutic targets.Conclusions: Post-NAION inflammation occurs in both acute and chronic NAION. Statistical analysis of plasma profile changes generated a list of 20 potential biomarker and therapeutic targets of NAION.Translational Relevance: We identified blood molecular targets to improve NAION diagnosis and treatment.

  View details for DOI 10.1167/tvst.10.8.17

  View details for PubMedID 34264294

• Multimodal Imaging Features of Optic Disc Drusen. American journal of ophthalmology Yan, Y., Ludwig, C. A., Liao, Y. J. 2021

  Abstract

  PURPOSE: Identify key en face multimodal imaging features of optic disc drusen (ODD).DESIGN: Retrospective cross-sectional study.METHODS: .SETTING: Single academic center.PATIENT OR STUDY POPULATION: 786 patients (age 10-82 years) with diagnostic codes for ODD or the term "optic disc drusen" in clinical notes extracted using natural language processing.INTERVENTION OR OBSERVATION PROCEDURES: Color fundus image, green-light and blue-light fundus autofluorescence (FAF), near-infrared reflectance (NIR), and enhanced-depth imaging optical coherence tomography (EDI-OCT).MAIN OUTCOME MEASURES: Ophthalmic imaging characteristics and sensitivity of en face imaging compared with EDI-OCT.RESULTS: 38 (61 eyes) of 786 patients had high-quality EDI-OCT and en face multimodal imaging. Green-light FAF had the highest sensitivity (96.8%) and showed homogeneously hyperautofluorescence while blue-light FAF differentiated superficial and deep ODD by the heterogeneous brightness of FAF. Blue-light FAF (93.5%) and NIR (91.8%) were also sensitive and provided important features including the location, size, and depth of ODD and morphology of the optic disc and ODD-associated features such as horizontal hyperreflective lines and peripapillary hyperreflective ovoid mass-like structures (PHOMS), respectively. Color fundus imaging had the lowest sensitivity (82%). There was good inter-rater reliability for all en face imaging modalities (P < .0001 for all).CONCLUSIONS: Green-light FAF had the highest sensitivity in diagnosis of ODD, while blue-light FAF and NIR provided more information regarding the severity, location, depth, and size of ODD. In eyes that are negative on green-light FAF, EDI-OCT can be performed and provides the highest-resolution characterization of the entire optic disc to rule out ODD.

  View details for DOI 10.1016/j.ajo.2020.12.023

  View details for PubMedID 33485838

• The Project Baseline Health Study: a step towards a broader mission to map human health NPJ DIGITAL MEDICINE Arges, K., Assimes, T., Bajaj, V., Balu, S., Bashir, M. R., Beskow, L., Blanco, R., Califf, R., Campbell, P., Carin, L., Christian, V., Cousins, S., Das, M., Dockery, M., Douglas, P. S., Dunham, A., Eckstrand, J., Fleischmann, D., Ford, E., Fraulo, E., French, J., Gambhir, S. S., Ginsburg, G. S., Green, R. C., Haddad, F., Hernandez, A., Hernandez, J., Huang, E. S., Jaffe, G., King, D., Koweek, L. H., Langlotz, C., Liao, Y. J., Mahaffey, K. W., Marcom, K., Marks, W. J., Maron, D., McCabe, R., McCall, S., McCue, R., Mega, J., Miller, D., Muhlbaier, L. H., Munshi, R., Newby, L., Pak-Harvey, E., Patrick-Lake, B., Pencina, M., Peterson, E. D., Rodriguez, F., Shore, S., Shah, S., Shipes, S., Sledge, G., Spielman, S., Spitler, R., Schaack, T., Swamy, G., Willemink, M. J., Wong, C. A. 2020; 3 (1): 84

  Abstract

  The Project Baseline Health Study (PBHS) was launched to map human health through a comprehensive understanding of both the health of an individual and how it relates to the broader population. The study will contribute to the creation of a biomedical information system that accounts for the highly complex interplay of biological, behavioral, environmental, and social systems. The PBHS is a prospective, multicenter, longitudinal cohort study that aims to enroll thousands of participants with diverse backgrounds who are representative of the entire health spectrum. Enrolled participants will be evaluated serially using clinical, molecular, imaging, sensor, self-reported, behavioral, psychological, environmental, and other health-related measurements. An initial deeply phenotyped cohort will inform the development of a large, expanded virtual cohort. The PBHS will contribute to precision health and medicine by integrating state of the art testing, longitudinal monitoring and participant engagement, and by contributing to the development of an improved platform for data sharing and analysis.

  View details for DOI 10.1038/s41746-020-0290-y

  View details for Web of Science ID 000538242900001

  View details for PubMedID 32550652

  View details for PubMedCentralID PMC7275087

• Vision loss in optic disc drusen correlates with increased macular vessel diameter and flux and reduced peripapillary vascular density American Journal of Ophthalmology Yan, Y., Zhou, X., Chu, Z., Stell, L., Shariati, M. A., Wang, R. K., Liao, Y. J. 2020
• The Project Baseline Health Study: A Step Towards a Broader Mission to Map Human Health npj Digital Medicine Gambhir, S., ..., Liao, Y. J., et al., et al 2020
• Vision loss in optic disc drusen correlates with increased macular vessel diameter and flux and reduced peripapillary vascular density. American journal of ophthalmology Yan, Y. n., Zhou, X. n., Chu, Z. n., Stell, L. n., Shariati, M. A., Wang, R. K., Liao, Y. J. 2020

  Abstract

  To determine the key optical coherence tomography (OCT) and OCT angiography (OCTA) parameters that correlate with visual field loss in optic disc drusen (ODD).Retrospective cross-sectional study..Single academic center.17 patients with ODD (29 eyes) and 35 age-matched controls (53 eyes) INTERVENTION OR OBSERVATION PROCEDURES: Static perimetry, OCT and OCTA imaging of optic disc and macula.static perimetry, OCT, and OCTA measurements.We investigated the relationship between static perimetry and 14 OCT/OCTA measurements in patients with ODD vs. age-matched controls and found 5 key measurements that most correlated with visual field loss included: peripapillary retinal nerve fiber layer (RNFL), macular ganglion cell complex (GCC), peripapillary vessel area density (VAD), macular vessel diameter (VD) and flux. Hierarchical clustering of these 5 measurements vs. all clinical characteristics revealed 3 distinct clusters. ODD and control eyes with no visual field loss (mean deviation (MD) > -2.0 dB) had high RNFL, GCC, and low macular VD and flux. ODD eyes with mild visual field loss (MD -2.0 to -5.0 dB) had high RNFL, GCC, and increased macular VD and flux. ODD eyes with moderate/severe visual field loss (MD < -5.0 dB) had decreased RNFL, GCC, peripapillary VAD, and increased macular VD and flux.OCT and OCTA provided objective measurements that can help predict visual field loss in ODD. Our data suggest that increased macular flow may be an early biomarker of visual field loss in ODD, while decreased peripapillary vessel density and RNFL thickness are late biomarkers of visual field loss in ODD.

  View details for DOI 10.1016/j.ajo.2020.04.019

  View details for PubMedID 32360344

• Increased ER Stress After Experimental Ischemic Optic Neuropathy and Improved RGC and Oligodendrocyte Survival After Treatment With Chemical Chaperon. Investigative ophthalmology & visual science Kumar, V., Mesentier-Louro, L. A., Oh, A. J., Heng, K., Shariati, M. A., Huang, H., Hu, Y., Liao, Y. J. 2019; 60 (6): 1953–66

  Abstract

  Purpose: Increased endoplasmic reticulum (ER) stress is one of the earliest subcellular changes in neuro-ophthalmic diseases. In this study, we investigated the expression of key molecules in the ER stress pathways following nonarteritic anterior ischemic optic neuropathy (AION), the most common acute optic neuropathy in adults over 50, and assessed the impact of chemical chaperon 4-phenylbutyric acid (4-PBA) in vivo.Methods: We induced AION using photochemical thrombosis in adult mice and performed histologic analyses of key molecules in the ER stress pathway in the retina and optic nerve. We also assessed the effects of daily intraperitoneal injections of 4-PBA after AION.Results: In the retina at baseline, there was low proapoptotic transcriptional regulator C/EBP homologous protein (CHOP) and high prosurvival chaperon glucose-regulated protein 78 (GRP78) expression in retinal ganglion cells (RGCs). One day after AION, there was significantly increased CHOP and reduced GRP78 expressions in the ganglion cell layer. In the optic nerve at baseline, there was little CHOP and high GRP78 expression. One day after AION, there was significantly increased CHOP and no change in GRP78 expression. Treatment immediately after AION using daily intraperitoneal injection of chemical chaperone 4-PBA for 19 days significantly rescued Brn3A+ RGCs and Olig2+ optic nerve oligodendrocytes.Conclusions: We showed for the first time that acute AION resulted in increased ER stress and differential expression of ER stress markers CHOP and GRP78 in the retina and optic nerve. Rescue of RGCs and oligodendrocytes with 4-PBA provides support for ER stress reduction as possible treatment for AION.

  View details for PubMedID 31060051

• Direct targeting of the mouse optic nerve for therapeutic delivery. Journal of neuroscience methods Mesentier-Louro, L. A., Dodd, R., Domizi, P., Nobuta, H., Wernig, M., Wernig, G., Liao, Y. J. 2018

  Abstract

  BACKGROUND: Animal models of optic nerve injury are often used to study central nervous system (CNS) degeneration and regeneration, and targeting the optic nerve is a powerful approach for axon-protective or remyelination therapy. However, the experimental delivery of drugs or cells to the optic nerve is rarely performed because injections into this structure are difficult in small animals, especially in mice.NEW METHOD: We investigated and developed methods to deliver drugs or cells to the mouse optic nerve through 3 different routes: a) intraorbital, b) through the optic foramen and c) transcranial.RESULTS: The methods targeted different parts of the mouse optic nerve: intraorbital proximal (intraorbital), intracranial middle (optic-foramen) or intracranial distal (transcranial) portion.COMPARISON WITH EXISTING METHODS: Most existing methods target the optic nerve indirectly. For instance, intravitreally delivered cells often cannot cross the inner limiting membrane to reach retinal neurons and optic nerve axons. Systemic delivery, eye drops and intraventricular injections do not always successfully target the optic nerve. Intraorbital and transcranial injections into the optic nerve or chiasm have been performed but these methods have not been well described. We approached the optic nerve with more selective and precise targeting than existing methods.CONCLUSIONS: We successfully targeted the murine optic nerve intraorbitally, through the optic foramen, and transcranially. Of all methods, the injection through the optic foramen is likely the most innovative and fastest. These methods offer additional approaches for therapeutic intervention to be used by those studying white matter damage and axonal regeneration in the CNS.

  View details for PubMedID 30389488

• Slower saccadic reading in Parkinson's disease PLOS ONE Jehangir, N., Yu, C., Song, J., Shariati, M., Binder, S., Beyer, J., Santini, V., Poston, K., Liao, Y. 2018; 13 (1): e0191005

  Abstract

  Idiopathic Parkinson's Disease (PD) is characterized by degeneration of dopaminergic and other neurons, leading to motor and non-motor deficits. Abnormal eye movements in PD, including fixations, saccades, and convergence, are well described. However, saccadic reading, which requires serial and alternating saccades and fixations, is not well studied, despite its obvious impact on the quality of life. In this study, we assessed saccadic reading using variations of the King-Devick (KD) test, a rapid single digit number naming test, as a way to assess the ability to make serial left-to-right ocular motor movements necessary for reading. We recruited 42 treated PD patients and 80 age-matched controls and compared their reading times with a variety of measures, including age, duration of disease, Unified Parkinson's Disease Rating Scale (UPDRS), the National Eye Institute 25-Item Visual Functioning Questionnaire 25 (VFQ-25), and Montreal Cognitive assessment (MoCA) test. The subjects performed 4 trials of reading 120 single digit numbers aloud as fast as possible without making errors. In each trial, they read 3 pages (KD1, KD2, and KD3), and each page contained 40 numbers per page in 8 lines with 5 numbers/line. We found that PD patients read about 20% slower than controls on all tests (KD1, 2, and 3 tests) (p < 0.02), and both groups read irregularly spaced numbers slower than regularly spaced numbers. Having lines between numbers to guide reading (KD1 tests) did not impact reading time in both PD and controls, but increased visual crowding as a result of decreased spacing between numbers (KD3 tests) was associated with significantly slower reading times in both PD and control groups. Our study revealed that saccadic reading is slower in PD, but controls and PD patients are both impacted by visuospatial planning challenges posed by increased visual crowding and irregularity of number spacing. Reading time did not correlate with UPDRS or MoCA scores in PD patients but significantly correlated with age, duration of disease, and VFQ-25 scores. The presence of convergence insufficiency did not significantly correlate with reading time in PD patients, although on average there was slower reading time in those with convergence insufficiency by 8 s (p = 0.2613). We propose that a simple reading task using 120 single-digit numbers can be used as a screening tool in the clinical setting to assess functional ocular motor difficulties in Parkinson's disease that can have a profound impact on quality of life.

  View details for PubMedID 29364897

• Report on the National Eye Institute Audacious Goals Initiative: Regenerating the Optic Nerve. Investigative ophthalmology & visual science Goldberg, J. L., Guido, W., For The Agi Workshop Participants 2016; 57 (3): 1271-1275

  Abstract

  The National Eye Institute (NEI) hosted a workshop on November 19, 2014, as part of the Audacious Goals Initiative (AGI), an NEI-led effort to rapidly expand therapies for eye diseases through coordinated research funding. The central audacious goal aims to demonstrate by 2025 the restoration of usable vision in humans through the regeneration of neurons and neural connections in the eye and visual system. This workshop focused on identifying promising strategies for optic nerve regeneration. Its principal objective was to solicit input on future AGI-related funding announcements, and specifically to ask, where are we now in our scientific progress, and what progress should we reach for in the coming years? A full report was generated as a white paper posted on the NEI Web site; this report summarizes the discussion and outcomes from the meeting and serves as guidance for future funding of research that focuses on optic nerve regeneration.

  View details for DOI 10.1167/iovs.15-18500

  View details for PubMedID 26990163

• Association of left ventricular diastolic function with coronary artery calcium score: A Project Baseline Health Study. Journal of cardiovascular computed tomography Haddad, F., Cauwenberghs, N., Daubert, M. A., Kobayashi, Y., Bloomfield, G. S., Fleischman, D., Koweek, L., Maron, D. J., Rodriguez, F., Liao, Y. J., Moneghetti, K., Amsallem, M., Mega, J., Hernandez, A., Califf, R., Mahaffey, K. W., Shah, S. H., Kuznetsova, T., Douglas, P. S., Project Baseline Health Study Investigators 2022

  Abstract

  BACKGROUND: Coronary artery calcium (CAC) and left ventricular diastolic dysfunction (LVDD) are strong predictors of cardiovascular events and share common risk factors. However, their independent association remains unclear.METHODS: In the Project Baseline Health Study (PBHS), 2082 participants underwent cardiac-gated, non-contrast chest computed tomography (CT) and echocardiography. The association between left ventricular (LV) diastolic function and CAC was assessed using multidimensional network and multivariable-adjusted regression analyses. Multivariable analysis was conducted on continuous LV diastolic parameters and categorical classification of LVDD and adjusted for traditional cardiometabolic risk factors. LVDD was defined using reference limits from a low-risk reference group without established cardiovascular disease, cardiovascular risk factors or evidence of CAC, (n​=​560). We also classified LVDD using the American Society of Echocardiography recommendations.RESULTS: The mean age of the participants was 51​±​17 years with 56.6% female and 62.6% non-Hispanic White. Overall, 38.1% had hypertension; 13.7% had diabetes; and 39.9% had CAC >0. An intertwined network was observed between diastolic parameters, CAC score, age, LV mass index, and pulse pressure. In the multivariable-adjusted analysis, e', E/e', and LV mass index were independently associated with CAC after adjustment for traditional risk factors. For both e' and E/e', the effect size and statistical significance were higher across increasing CAC tertiles. Other independent correlates of e' and E/e' included age, female sex, Black race, height, weight, pulse pressure, hemoglobin A1C, and HDL cholesterol. The independent association with CAC was confirmed using categorical analysis of LVDD, which occurred in 554 participants (26.6%) using population-derived thresholds.CONCLUSION: In the PBHS study, the subclinical coronary atherosclerotic disease burden detected using CAC scoring was independently associated with diastolic function.CLINICALTRIALS: GOV IDENTIFIER: NCT03154346.

  View details for DOI 10.1016/j.jcct.2022.06.003

  View details for PubMedID 35872137

• Upregulation of retinal VEGF and connexin 43 in murine nonarteritic anterior ischemic optic neuropathy (NAION) induced with 577 nm laser. Experimental eye research Rangel, B., Mesentier-Louro, L. A., Lowe, L. L., Shariati, M. A., Dalal, R., Imventarza, J. A., Liao, Y. J. 2022: 109139

  Abstract

  Nonarteritic anterior ischemic optic neuropathy (NAION) is a common acute optic neuropathy and cause of irreversible vision loss in those older than 50 years of age. There is currently no effective treatment for NAION and yet the biological mechanisms leading to neuronal loss are not fully understood. Glial cells activation and intercommunication mediated by molecules such as gap junction protein Connexin 43 (Cx43) is thought to modulate neuronal fate in central nervous system disorders. In this study, we investigated retinal glial changes and neuronal loss following a novel NAION animal model using a 577 nm laser. We induced unilateral photochemical thrombosis using rose bengal at the optic nerve head vasculature in adult C57BL/6 mice using a 577 nm laser and performed morphometric analysis of the retinal structure using serial in vivo optical coherence tomography (OCT) and histology for glial and neuronal markers. OCT imaging revealed peripapillary thickening of the retinal ganglion cell complex (GCC, baseline: 79.5 ± 1.0 mum, n = 8; NAION: 93.0 ± 2.5 mum, n = 8, P < 0.01) and total retina (baseline: 202.9 ± 2.4 mum, n = 8; NAION: 228.1 ± 6.8 mum, n = 8, P < 0.01) at day 1 after NAION, and significant GCC thinning (baseline 78.3 ± 2.1 mum, n = 6; NAION: 72.2 ± 1.9 mum, n = 5, P < 0.05) at day 21. NAION induced a significant increase in retinal VEGF levels at day 1 (control: 2319 ± 195, n = 5; NAION: 4549 ± 683 gray mean value, n = 5, P < 0.05), which correlated with retinal thickness (r = 0.89, P < 0.05). NAION led to increased mRNA levels for Cx43 (Gj1a) at day 1 (control: 1.291 ± 0.38; NAION: 3.360 ± 0.58 puncta/mm2, n = 5, P < 0.05), which was not associated with changes in mRNA levels of glial fibrillary acidic protein (Gfap) at the same time (control: 2800 ± 0.59; NAION: 4690 ± 0.90 puncta/mm2 n = 5, P = 0.19). Retinal ganglion cell loss at day 21 was confirmed by a 30% decrease in Brn3a+ cells (control: 2844 ± 235; NAION: 2001 ± 264 cells/mm2, n=4, P<0.05). We described a novel protocol of NAION induction by photochemical thrombosis using a 577nm laser, leading to retinal edema and VEGF increase at day 1 and RGCs loss at day 21 after injury, consistent with the pathophysiology of human NAION. Early changes in glial cells intercommunication revealed by increased Cx43+ gap junctions are consistent with a retinal glial role in mediating cell-to-cell signaling after an ischemic insult. Our study demonstrates an early glial response in a novel NAION animal model and reveals glial intercommunication molecules such as Cx43 as a promising therapeutic target in acute NAION.

  View details for DOI 10.1016/j.exer.2022.109139

  View details for PubMedID 35691373

• Visuo-motor assessments of eye-brain diseases using infrared oculography Yu, M., Shariati, M., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2022

  View details for Web of Science ID 000844437001158

• Development of a Skin Biopsy-Based Calcification Assay for Detection of Optic Disc Drusen: A Pilot Study Imventarza, J., Kumar, A., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2022

  View details for Web of Science ID 000844401303201

• Increased ciliary length of oligodendrocytes in anterior optic nerve with ageing Tran, M., Ning, K., Kowal, T., Majumder, R., Wang, Q., Hu, Y., Liao, Y., Sun, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2022

  View details for Web of Science ID 000844401302306

• Age-Associated Changes in Astrocytes Cilia of Mouse Retina and Optic Nerve Majumder, R., Ning, K., Kowal, T., Wang, Q., Tran, M., Wang, B., Hu, Y., Liao, Y., Sun, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2022

  View details for Web of Science ID 000844401302309

• Optical Coherence Tomography Angiography Features of Optic Nerve Ischemia Pugazhendhi, S., Yu, M., Shariati, M., Zhou, X., Cheng, Y., Wang, R. K., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2022

  View details for Web of Science ID 000844401300135

• Multicolor Imaging of Optic Disc Drusen. Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society Yan, Y., Pugazhendhi, S., Beres, S. J., Liao, Y. J. 2022

  Abstract

  ABSTRACT: Optic disc drusen (ODD) are calcified deposits at the anterior optic nerve that are often detectable by ophthalmic imaging, including optical coherence tomography and fundus autofluorescence imaging. Multicolor (MC) imaging is a novel modality that captures reflectance of blue, green, and near-infrared laser lights with confocal scanning laser ophthalmoscopy to rapidly acquire high-resolution reflectance images of the optic disc and retina. Here, we show an eye with 3 MC imaging features of ODD, including prominent green hyperreflectance of the optic disc, green sheathing of the papillary and peripapillary vasculature (arterioles > venules), and presence of orange superficial ODD. MC imaging can provide rapid high-resolution assessment of eyes with optic nerve head elevation to help distinguish pseudopapilledema vs papilledema in children and adults without dilation, and future large studies incorporating MC imaging will help determine its contribution in the diagnosis and monitoring of ODD and assessment of other causes of optic nerve head elevation.

  View details for DOI 10.1097/WNO.0000000000001470

  View details for PubMedID 35482433

• Multimodal Ophthalmic Imaging of Nonarteritic Anterior Ischemic Optic Neuropathy With and Without Optic Disc Drusen JOURNAL OF NEURO-OPHTHALMOLOGY Pugazhendhi, S., Yan, Y., Liao, Y. 2022; 42 (1): E349-E351

  View details for Web of Science ID 000760427000080

• Predicting Visuo-Motor Diseases From Eye Tracking Data. Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing Vodrahalli, K., Filipkowski, M., Chen, T., Zou, J., Liao, Y. J. 2022; 27: 242-253

  Abstract

  Eye tracking, or oculography, provides insight into where a person is looking. Recent advances in camera technology and machine learning have enabled prevalent devices like smart-phones to track gaze and visuo-motor behavior at near clinical-quality resolution. A critical gap in using oculography to diagnose visuo-motor dysfunction on a large scale is in the design of visual task paradigms, algorithms for diagnosis, and sufficiently large datasets. In this study, we used a 500 Hz infrared oculography dataset in healthy controls and patients with various neurological diseases causing visuo-motor abnormality due to eye movement disorder or vision loss. We used novel visuo-motor tasks involving rapid reading of 40 single-digit numbers per page and developed a machine learning algorithm for predicting disease state. We show that oculography data acquired while a person reads one page of 40 single-digit numbers (15-30 seconds duration) is predictive of of visuo-motor dysfunction (ROC-AUC = 0:973). Remarkably, we also find that short recordings of about 2.5 seconds (6-12* reduction in time) are sufficient for disease detection (ROC-AUC = 0:831). We identify which tasks are most informative for identifying visuo-motor dysfunction (those with the most visual crowding), and more specifically, which aspects of the task are most predictive (the recording segments where gaze moves vertically across lines). In addition to segregating disease and controls, our novel visuo-motor paradigms can discriminate among diseases impacting eye movement, diseases associated with vision loss, and healthy controls (81% accuracy compared with baseline of 33%).

  View details for PubMedID 34890153

• Peripapillary and macular microvasculature features of non-arteritic anterior ischemic optic neuropathy. Frontiers in medicine Pugazhendhi, S., Yu, M., Zhou, G., Chen, Y., Wang, R., Liao, Y. J. 2022; 9: 1033838

  Abstract

  Purpose: The hallmark of non-arteritic anterior ischemic optic neuropathy (NAION) is vascular compromise to the anterior optic nerve and thinning of the retinal nerve fiber layer (RNFL) and secondary degeneration of the retinal ganglion cell body or thinning of the ganglion cell complex (GCC). This study investigates optical coherence tomography (OCT) and OCT Angiography (OCTA) changes in chronic NAION and identifies imaging biomarkers that best predict disease.Methods: We performed a retrospective case-control study of 24 chronic NAION eyes (18 patients) and 70 control eyes (45 patients) to compare both whole-eye and regional OCT, OCTA, static perimetry measurements. OCT measurements were quantified automatically using commercial software, and OCTA was analyzed using custom MATLAB script with large vessel removal to measure 154 total parameters per eye.Results: We confirmed that static perimetry mean deviation (MD) was significantly worse in chronic NAION (-13.53 ± 2.36) than control (-0.47 ± 0.72; P < 0.001) eyes, and NAION eyes had 31 mum thinner RNFL (control: 95.9 ± 25.8 mum; NAION: 64.5 ± 18.0, P < 0.001), and 21.8 mum thinner GCC compared with controls (control: 81.5 ± 4.4 mum; NAION: 59.7 ± 10.5, P < 0.001). Spearman correlation analysis of OCTA parameters reveal that vessel area density (VAD) and flux are highly correlated with visual field MD and OCT measurements. Hierarchical clustering two distinct groups (NAION and control), where standardized measurements of NAION eyes were generally lower than controls. Two-way mixed ANOVAs showed significant interaction between patient status (control and chronic NAION) and structure (optic disk and macula) for annulus VAD and flux values and mean RNFL and GCC thickness. Post-hoc tests showed this effect stems from lower peripapillary values in NAION compared to controls. Separate logistic regression models with LASSO regularization identified VAD and flux are one of the best OCTA parameters for predicting NAION.Conclusion: Ischemic insult to the optic disk is more severe likely from primary degeneration of the affected peripapillary region while macula is affected by secondary retrograde degeneration and loss of retinal ganglion cells. In addition to OCT measurements, peripapillary and macular vascular parameters such as VAD and flux are good predictors of optic nerve and retinal changes in NAION.

  View details for DOI 10.3389/fmed.2022.1033838

  View details for PubMedID 36714135

• Biological and clinical correlates of the patient health questionnaire-9: exploratory cross-sectional analyses of the baseline health study. BMJ open Califf, R. M., Wong, C., Doraiswamy, P. M., Hong, D. S., Miller, D. P., Mega, J. L. 2022; 12 (1): e054741

  Abstract

  We assessed the relationship between the Patient Health Questionnaire-9 (PHQ-9) at intake and other measurements intended to assess biological factors, markers of disease and health status.We performed a cross-sectional analysis of 2365 participants from the Baseline Health Study, a prospective cohort of adults selected to represent major demographic groups in the USA. Participants underwent deep phenotyping on demographic, clinical, laboratory, functional and imaging findings.Despite extensive research on the clinical implications of the PHQ-9, data are limited on the relationship between PHQ-9 scores and other measures of health and disease; we sought to better understand this relationship.None.Cross-sectional measures of medical illnesses, gait, balance strength, activities of daily living, imaging and laboratory tests.Compared with lower PHQ-9 scores, higher scores were associated with female sex (46.9%-66.7%), younger participants (53.6-42.4 years) and compromised physical status (higher resting heart rates (65 vs 75 bpm), larger body mass index (26.5-30 kg/m2), greater waist circumference (91-96.5 cm)) and chronic conditions, including gastro-oesophageal reflux disease (13.2%-24.7%) and asthma (9.5%-20.4%) (p<0.0001). Increasing PHQ-9 score was associated with a higher frequency of comorbidities (migraines (6%-20.4%)) and active symptoms (leg cramps (6.4%-24.7%), mood change (1.2%-47.3%), lack of energy (1.2%-57%)) (p<0.0001). After adjustment for relevant demographic, socioeconomic, behavioural and medical characteristics, we found that memory change, tension, shortness of breath and indicators of musculoskeletal symptoms (backache and neck pain) are related to higher PHQ-9 scores (p<0.0001).Our study highlights how: (1) even subthreshold depressive symptoms (measured by PHQ-9) may be indicative of several individual- and population-level concerns that demand more attention; and (2) depression should be considered a comorbidity in common disease.NCT03154346.

  View details for DOI 10.1136/bmjopen-2021-054741

  View details for PubMedID 34983769

• Freezing of saccades in dopa-responsive parkinsonian syndrome. American journal of ophthalmology case reports Likitgorn, T., Yan, Y., Liao, Y. J. 2021; 23: 101124

  Abstract

  Purpose: Ocular motor abnormalities such as abnormal saccades are common in idiopathic Parkinson's disease (PD) and atypical parkinsonian syndrome, such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). In this study, we describe a case of patient with PD and show a video illustrating severe delay of reflexive saccades.Observations: A 68-year-old Caucasian woman with diagnosis of PD presented for evaluation of diplopia. Neuro-ophthalmic examination revealed good visual acuity in both eyes and normal optic nerves but prominent ocular motor abnormalities, including hypometric saccades, impaired smooth pursuit, and convergence insufficiency causing diplopia at near. Despite treatment with carbidopa-levodopa three times per day, she exhibited episodic, severe delay of reflexive saccades. During these episodes, the patient appeared frozen and unable to initiate reflexive saccades for 20 s or longer. This freezing of reflexive saccades was variable and occurred suddenly during exam but could be interrupted by smooth pursuit. There was no gait freezing, eyelid apraxia, or prominent exacerbation of other motor symptoms. Freezing of saccades dramatically resolved after increasing dosage of carbidopa-levodopa.Conclusions and Importance: We describe a patient with dopa-responsive parkinsonian syndrome with intermittent difficulty initiating reflexive saccades mimicking ocular motor apraxia. Resolution of saccadic freezing with higher carbidopa-levodopa is consistent with ocular motor impairment as a result of degeneration and dysfunction of the dopaminergic pathways in supranuclear ocular motor control.

  View details for DOI 10.1016/j.ajoc.2021.101124

  View details for PubMedID 34169178

• Variation in Evolving Optic Neuritis. Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society Bouffard, M. A., Mallery, R. M., Liao, Y. J., Torun, N. 2021

  Abstract

  BACKGROUND: The typical natural history of optic neuritis is subjected to important exceptions. Recognition of these exceptions has led to valuable insights regarding specific etiologies of optic neuritis. Exceptions to the natural history of recovering optic neuritis are well-defined (e.g., chronic relapsing inflammatory optic neuropathy), but exceptions to the natural history of evolving optic neuritis are less so.METHODS: Medical records of patients illustrating an atypical course of evolving optic neuritis were reviewed in a retrospective manner. Each patient was treated by at least one of the authors.RESULTS: Four patients were identified who illustrated an atypical natural history of incipient optic neuritis. Diagnoses included idiopathic optic neuritis, seropositive neuromyelitis optica spectrum disease, anti-myelin oligodendrocyte glycoprotein antibody disease, and multiple sclerosis in 1 patient each. Features of interest included an atypical temporal relationship between development of pain and onset of clinical optic neuropathy, an unusually protracted duration of pain, and an unusually long duration of worsening optic neuropathy before stabilization.CONCLUSIONS: This case series illustrates the substantial clinical heterogeneity which may be observed in the evolution of optic neuritis. The temporal relationship between development of pain and onset of clinical optic neuropathy, the duration of pain, and duration of worsening optic neuropathy before stabilization are all subjected to significant variability. Although most patients with optic neuritis present with painful vision loss which progresses over 1 week or less, careful attention to the exceptions described herein may facilitate earlier recognition of diagnostically challenging cases.

  View details for DOI 10.1097/WNO.0000000000001310

  View details for PubMedID 34310458

• Immunoprofiling of Nonarteritic Anterior Ischemic Optic Neuropathy Mesentier-Louro, L., Stell, L., Yan, Y., Montague, A., Perez, V., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2021

  View details for Web of Science ID 000690761400568

• Increased Cx43 and VEGF expression in acute nonarteritic anterior ischemic optic neuropathy induced with 577nm laser Rangel, B., Mesentier-Louro, L., Shariati, A., Dalal, R., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2021

  View details for Web of Science ID 000690760500625

• Topographic Quadrant Analysis of Peripapillary Superficial Microvasculature in Optic Disc Drusen FRONTIERS IN NEUROLOGY Yan, Y., Zhou, X., Chu, Z., Stell, L., Shariati, M., Wang, R. K., Liao, Y. 2021; 12: 666359

  Abstract

  Background: Limited information is known about the topographic effect of optic disc drusen (ODD) on peripapillary retinal nerve fibers and microvasculature. Objective: This study aims to understand the structural and functional impact of ODD in different quadrants of the optic disc. Methods: We performed a retrospective case-control study of 22 ODD patients (34 eyes) and 26 controls (33 eyes) to compare optical coherence tomography (OCT) retinal nerve fiber layer (RNFL), OCT angiography (OCTA), and corresponding static perimetry mean deviation (MD) calculated using the modified Garway-Heath map in different quadrants of the optic disc. OCTA was analyzed using custom MATLAB script to measure six parameters in a peripapillary annulus with large vessel removal: vessel area density (VAD), vessel skeleton density (VSD), vessel perimeter index (VPI), vessel complexity index (VCI), flux, and vessel diameter index (VDI). Results: Quadrant analysis revealed that OCTA VAD and VCI were significantly decreased in superior, nasal, and inferior but not temporal quadrant. RNFL, VSD, and VPI were significantly impacted only in the superior and nasal quadrants. Corresponding visual field MDs in all ODD eyes were not different in the four quadrants, although eyes with MD equal or worse than -5 dB (32%) had worst visual field corresponding to the superior quadrant of the optic disc (inferior arcuate visual field). Structure-structure comparison of OCT and OCTA showed high correlation of RNFL with multiple OCTA measurements in the superior, nasal, and inferior quadrants but not temporal quadrant. Structure-function analysis revealed significant correlation of VAD and VCI and visual field MD in every quadrant, but RNFL was only significantly correlated in the superior and inferior quadrants. Conclusions: Peripapillary VAD and VCI are decreased in more quadrants than RNFL, supporting the clinical utility of performing OCTA in addition to OCT. Consistent with the most common locations of ODD, five OCT/OCTA measurements (VAD, VCI, RNFL, VSD, VPI) are decreased in the superior and nasal quadrants. OCT/OCTA measurements were significantly impacted in contrast to the relatively mild effect on corresponding visual field MD, consistent with the idea that a decrease in objective structural and vascular measurements occurs without parallel change in subjective visual function in ODD.

  View details for DOI 10.3389/fneur.2021.666359

  View details for Web of Science ID 000656846300001

  View details for PubMedID 34093412

  View details for PubMedCentralID PMC8170317

• Multimodal Ophthalmic Imaging of Nonarteritic Anterior Ischemic Optic Neuropathy With and Without Optic Disc Drusen. Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society Pugazhendhi, S., Yan, Y., Liao, Y. J. 2021

  View details for DOI 10.1097/WNO.0000000000001242

  View details for PubMedID 33870937

• Multimodal ophthalmic imaging of nonarteritic anterior ischemic optic neuropathy with and without optic disc drusen Journal of Neuro-Ophthalmology Pugazhendhi, S., et al 2021
• Hypoxia-induced inflammation: Profiling the first 24-hour posthypoxic plasma and central nervous system changes. PloS one Mesentier-Louro, L. A., Rangel, B. n., Stell, L. n., Shariati, M. A., Dalal, R. n., Nathan, A. n., Yuan, K. n., de Jesus Perez, V. n., Liao, Y. J. 2021; 16 (3): e0246681

  Abstract

  Central nervous system and visual dysfunction is an unfortunate consequence of systemic hypoxia in the setting of cardiopulmonary disease, including infection with SARS-CoV-2, high-altitude cerebral edema and retinopathy and other conditions. Hypoxia-induced inflammatory signaling may lead to retinal inflammation, gliosis and visual disturbances. We investigated the consequences of systemic hypoxia using serial retinal optical coherence tomography and by assessing the earliest changes within 24h after hypoxia by measuring a proteomics panel of 39 cytokines, chemokines and growth factors in the plasma and retina, as well as using retinal histology. We induced severe systemic hypoxia in adult C57BL/6 mice using a hypoxia chamber (10% O2) for 1 week and rapidly assessed measurements within 1h compared with 18h after hypoxia. Optical coherence tomography revealed retinal tissue edema at 18h after hypoxia. Hierarchical clustering of plasma and retinal immune molecules revealed obvious segregation of the 1h posthypoxia group away from that of controls. One hour after hypoxia, there were 10 significantly increased molecules in plasma and 4 in retina. Interleukin-1β and vascular endothelial growth factor were increased in both tissues. Concomitantly, there was significantly increased aquaporin-4, decreased Kir4.1, and increased gliosis in retinal histology. In summary, the immediate posthypoxic period is characterized by molecular changes consistent with systemic and retinal inflammation and retinal glial changes important in water transport, leading to tissue edema. This posthypoxic inflammation rapidly improves within 24h, consistent with the typically mild and transient visual disturbance in hypoxia, such as in high-altitude retinopathy. Given hypoxia increases risk of vision loss, more studies in at-risk patients, such as plasma immune profiling and in vivo retinal imaging, are needed in order to identify novel diagnostic or prognostic biomarkers of visual impairment in systemic hypoxia.

  View details for DOI 10.1371/journal.pone.0246681

  View details for PubMedID 33661927

• Ocular motility and cranial nerves Massachusetts Eye and Ear Infirmary Illustrated Manual of Ophthalmology Friedman, N. K., et al 2021; 5th
• Diagnosing Optic Disc Drusen in the Modern Imaging Era: A Practical Approach Neuro-Ophthalmology Costello, F., et al 2021
• Updates on ophthalmic imaging features of optic disc drusen, papilledema, and optic disc edema. Current opinion in neurology Yan, Y., Liao, Y. J. 2020

  Abstract

  PURPOSE OF REVIEW: Optic nerve head elevation can be associated with vision loss. This review provides an update regarding key features of optic disc drusen (ODD) compared with papilledema from increased intracranial pressure and optic disc edema from other causes.RECENT FINDINGS: Clinical history and funduscopic examination are not sufficient to correctly diagnose different causes of optic nerve head elevation. Multimodal ophthalmic imaging is noninvasive and should be used as first-line diagnostic testing to distinguish optic disc edema or papilledema from pseudoedema. Advanced ophthalmic imaging, including enhanced depth imaging optical coherence tomography (EDI-OCT) and autofluorescence imaging, can visualize ODD at high resolution and determine whether there is optic disc edema. OCT angiography does not require contrast and can rapidly visualize papillary, peripapillary, and macular microvasculature and identify important vascular biomarker of ischemia and, potentially, visual prognosis.SUMMARY: Multimodal ophthalmic imaging can help in the diagnosis of ODD and optic disc edema and identify patients at high risk of vision loss and neurological issues in order to ensure appropriate diagnosis and treatment.

  View details for DOI 10.1097/WCO.0000000000000881

  View details for PubMedID 33278141

• SECOND GENERATION BRAF/MEK INHIBITION IN ANAPLASTIC PLEOMORPHIC XANTHROASTROCYTOMA Stocksdale, B., Liao, Y., Coffey, G., Nagpal, S. OXFORD UNIV PRESS INC. 2020: 117–18

  View details for Web of Science ID 000590061300491

• Dual Specific Phosphatase 14 Deletion Rescues Retinal Ganglion Cells and Optic Nerve Axons after Experimental Anterior Ischemic Optic Neuropathy. Current eye research Kumar, V., Ali Shariati, M., Mesentier-Louro, L., Jinsook Oh, A., Russano, K., Goldberg, J. L., Liao, Y. J. 2020: 1–9

  Abstract

  PURPOSE: Understanding molecular changes is essential for designing effective treatments for nonarteritic anterior ischemic optic neuropathy (AION), the most common acute optic neuropathy in adults older than 50years. We investigated changes in the mitogen-activated protein kinase (MAPK) pathway after experimental AION and focused on dual specificity phosphatase 14 (Dusp14), an atypical MAPK phosphatase that is downstream of Kruppel-like transcription factor (KLF) 9-mediated inhibition of retinal ganglion cell (RGC) survival and axonal regeneration.MATERIALS AND METHODS: We induced severe AION in a photochemical thrombosis model in adult C57BL/6 wild-type and Dusp14 knockout mice. For comparison, some studies were performed using an optic nerve crush model. We assessed changes in MAPK pathway molecules using Western blot and immunohistochemistry, measured retinal thickness using optical coherence tomography (OCT), and quantified RGCs and axons using histologic methods.RESULTS: Three days after severe AION, there was no change in the retinal protein levels of MAPK ERK1/2, phosphorylated-ERK1/2 (pERK1/2), downstream effector Elk-1 and phosphatase Dusp14 on Western blot. Western blot analysis of purified RGCs after a more severe model using optic nerve crush also showed no change in Dusp14 protein expression. Because of the known importance of the Dusp14 and MAPK pathway in RGCs, we examined changes after AION in Dusp14 knockout mice. Three days after AION, Dusp14 knockout mice had significantly increased pERK1/2+, Brn3A+ RGCs on immunohistochemistry. Three weeks after AION, Dusp14 knockout mice had significantly greater preservation of retinal thickness, increased number of Brn3A+ RGCs on whole mount preparation, and increased number of optic nerve axons compared with wild-type mice.CONCLUSIONS: Genetic deletion of Dusp14, a MAPK phosphatase important in KFL9-mediated inhibition of RGC survival, led to increased activation of MAPK ERK1/2 and greater RGC and axonal survival after experimental AION. Inhibiting Dusp14 or activating the MAPK pathway should be examined further as a potential therapeutic approach to treatment of AION.Abbreviations: AION: anterior ischemic optic neuropathy; Dusp14: dual specific phosphatase 14; ERK1/2: extracellular signal-regulated kinases 1/2; Elk-1: ETS Like-1 protein; GCC: ganglion cell complex; GCL: ganglion cell layer; inner nuclear layer; KO: knockout; MAPK: mitogen-activated phosphokinase; OCT: optical coherence tomography; RGC: retinal ganglion cell; RNFL: retinal nerve fiber layer.

  View details for DOI 10.1080/02713683.2020.1826976

  View details for PubMedID 33107352

• Increased astrogliosis and aquaporin 4 in retinal hypoxia da Silva, B., Mesentier-Louro, L., Shariati, A., Dalal, R., Nathan, A., Perez, V., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2020

  View details for Web of Science ID 000554495702240

• Prediction of Disease Status and Visual Dysfunction in Optic Disc Drusen Using Peripapillary and Macular Microvasculature Yan, Y., Zhou, X., Chu, Z., Stell, L., Wang, R. K., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2020

  View details for Web of Science ID 000554528302183

• Optic chiasm compression leads to global loss of macular vessel density and regional thinning of macular ganglion cell complex Likitgorn, T., Liao, Y., Yan, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2020

  View details for Web of Science ID 000554528304123

• Impact of neuro-ophthalmic diseases on driving and psychosocial well-being Patel, P., Shariati, A., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2020

  View details for Web of Science ID 000554495701322

• Identification of Novel Biomarkers of Nonarteritic Anterior Ischemic Optic Neuropathy Using Cytokine Profiling Mesentier-Louro, L., Shariati, A., da Silva, B., Stell, L., Dalal, R., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2020

  View details for Web of Science ID 000554528303289

• Neuroprotection of experimental anterior ischemic optic neuropathy using adenovirus-mediated enhancement of cAMP signaling in the perinuclear compartment Zhu, Y., Mesentier-Louro, L., Xia, X., Shariati, A., Liao, Y., Kapiloff, M. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2020

  View details for Web of Science ID 000554528303288

• Systemic hypoxia led to little retinal neuronal loss and dramatic optic nerve glial response. Experimental eye research Mesentier Louro, L. A., Shariati, M. A., Dalal, R. n., Camargo, A. n., Kumar, V. n., Shamskhou, E. A., de Jesus Perez, V. n., Liao, Y. J. 2020: 107957

  Abstract

  Vision loss is a devastating consequence of systemic hypoxia, but the cellular mechanisms are unclear. We investigated the impact of acute hypoxia in the retina and optic nerve. We induced systemic hypoxia (10% O2) in 6-8w mice for 48 h and performed in vivo imaging using optical coherence tomography (OCT) at baseline and after 48 h to analyze structural changes in the retina and optic nerve. We analyzed glial cellular and molecular changes by histology and immunofluorescence and the impact of pretreatment with 4-phenylbutyric acid (4-PBA) in oligodendroglia survival. After 48 h hypoxia, we found no change in ganglion cell complex thickness and no loss of retinal ganglion cells. Despite this, there was significantly increased expression of CCAAT-enhancer-binding protein homologous protein (CHOP), a marker of endoplasmic reticulum stress, in the retina and optic nerve. In addition, hypoxia induced obvious increase of GFAP expression in the anterior optic nerve, where it co-localized with CHOP, and significant loss of Olig2+ oligodendrocytes. Pretreatment with 4-PBA, which has been shown to reduce endoplasmic reticulum stress, rescued total Olig2+ oligodendrocytes and increased the pool of mature (CC-1+) but not of immature (PDGFRa+) oligodendrocytes. Consistent with a selective vulnerability of the retina and optic nerve in hypoxia, the most striking changes in the 48 h murine model of hypoxia were in glial cells in the optic nerve, including increased CHOP expression in the astrocytes and loss of oligodendrocytes. Our data support a model where glial dysfunction is among the earliest events in systemic hypoxia - suggesting that glia may be a novel target in treatment of hypoxia.

  View details for DOI 10.1016/j.exer.2020.107957

  View details for PubMedID 32032627

• Rapid Fluctuation of Subretinal Fluid on Encorafenib and Binimetinib. Retina (Philadelphia, Pa.) Li, A. S., Leng, T. n., Nagpal, S. n., Liao, Y. J. 2020

  View details for DOI 10.1097/IAE.0000000000002965

  View details for PubMedID 32833784

• ANATOMIC, GENETIC AND FUNCTIONAL PROPERTIES OF THE RETINAL CIRCULATION IN PULMONARY HYPERTENSION Pulmonary Circulation Nickel, N. P., Shamskhou, E. A., Razeen, M., Condon, D., Messentier, L., Dubra, A., Liao, Y., Zamanian, R. T., Yuan, K., de Jesus Perez, V. A. 2020

  View details for DOI 10.1177/2045894020905508

• Geographical variations in ocular and extra-ocular manifestations in Behcet's disease. European journal of rheumatology Shahram, F., Mahlen, M. T., Akhlaghi, M., Davatchi, F., Liao, Y. J., Weyand, C. M. 2019: 1–8

  Abstract

  OBJECTIVE: Behcet's disease (BD) is a rare vasculitis that results in multi-organ inflammatory disease. At-risk populations are most prevalent in the Middle East and East Asia. Clinical data on BD in Western countries, especially in the United States, are scarce. We have compared clinical patterning of BD vasculitis in two geographically defined patient cohorts in the Western United States and Iran.METHODS: Comparative analysis of a retrospective cohort of 56 patients with BD evaluated at Stanford University Hospital between 2000 and 2016 and a cohort of 163 patients from the BD Registry at Tehran University of Medical Sciences. Clinical, demographic, laboratory, and treatment data were available. Comparisons were performed using descriptive statistics, Student's t-test, and chi2-test.RESULTS: The Stanford patients with BD were significantly younger at disease onset, had a higher proportion of females, and had longer disease duration than Iranian patients with BD. Genital ulcers, skin, joint, neurological, vascular, cardiopulmonary manifestations were all significantly more common in the Stanford cohort and 38% of Stanford patients had four or more organ systems involved compared with approximately 10% of Iranian patients. In contrast, Stanford patients had fewer ocular lesions (Stanford 21.4% vs. Iran 53.4% p<0.05), with the biggest difference seen for retinal vasculitis.CONCLUSION: Patients with BD from the Western US have a more severe disease course when compared to Iranian patients with BD, as demonstrated by earlier onset and a higher rate of multi-organ involvement. The high risk of Iranian patients with BD developing vasculitis of ocular structures suggests distinct pathomechanisms driving ocular versus extra-ocular BD.

  View details for DOI 10.5152/eurjrheum.2019.18215

  View details for PubMedID 31329543

• The stressed optic nerve: gliopathy in hypoxic injury and potential for therapy Mesentier-Louro, L., Camargo, A., Shariati, A., Nathan, A., Dalal, R., Kumar, V., Dardet, M. E., Perez, V., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2019

  View details for Web of Science ID 000488800702167

• A Comparison: Structural optical coherence tomography and angiography in diabetic retinopathy and diabetic macular edema Huang, L. C., Shariati, A., Oh, A., Leng, T., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2019

  View details for Web of Science ID 000488628107153

• Should Antiviral/Anti-Varicella Zoster Virus Treatment Be Used in Patients With Giant Cell Arteritis? JOURNAL OF NEURO-OPHTHALMOLOGY Liao, Y., Kedar, S. 2019; 39 (1): 134–41

  View details for DOI 10.1097/WNO.0000000000000664

  View details for Web of Science ID 000480771000030

• Nonarteritic anterior ischaemic optic neuropathy and its association with obstructive sleep apnoea: a health insurance database study ACTA OPHTHALMOLOGICA Sun, M., Lee, C., Liao, Y., Su, C. 2019; 97 (1): E64–E70

  Abstract

  Nonarteritic anterior ischaemic optic neuropathy (NAION) is the most common acute optic neuropathy in old age. Although there are several known risk factors, the influence of obstructive sleep apnoea (OSA) has not been completely elucidated. The aim of this study was to evaluate the association between NAION and OSA.This retrospective, longitudinal cohort study used the national health insurance database of Taiwan covering the period 1996-2013. Patients without NAION at the diagnosis of OSA or who developed NAION 1 year after the diagnosis of OSA were enrolled. The patients were followed until death or the last day of the study. Cox proportional hazard regression was used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) to investigate the association between OSA and NAION.There were 8488 patients in the OSA group and 33 952 in the control group (without OSA), for a ratio of approximately 1:4. The percentages of NAION were 0.36% and 0.2% in the OSA and control groups, respectively, with a statistically significant difference (p < 0.01; chi-square test), and this significant difference remained in multivariate analysis (p = 0.019) with a significantly higher HR (1.66; 95% CI: 1.08-2.55). There was significant difference in the 30-39 years age group in multivariate analysis (p < 0.01, HR: 6.30; 95% CI: 2.28-17.40).There was a strong association between NAION and OSA, and the patients with OSA had a higher risk of NAION. Further large-scale, prospective studies are warranted to evaluate the effect of OSA on developing NAION.

  View details for PubMedID 30171667

• Direct targeting of the mouse optic nerve for therapeutic delivery JOURNAL OF NEUROSCIENCE METHODS Mesentier-Louro, L. A., Dodd, R., Domizi, P., Nobuta, H., Wernig, M., Wernig, G., Liao, Y. 2019; 313: 1–5

  View details for DOI 10.1016/j.jneumeth.2018.10.038

  View details for Web of Science ID 000458596100001

• Malignant optic glioma masked by suspected optic neuritis and central retinal vein occlusion. Radiology case reports Kalnins, A. n., Penta, M. n., El-Sawy, T. n., Liao, Y. J., Fischbein, N. n., Iv, M. n. 2019; 14 (2): 226–29

  Abstract

  Malignant optic glioma presents a clinical and diagnostic challenge, as early imaging findings overlap with other more common causes of optic nerve enhancement and enlargement, potentially leading to delay in diagnosis. This rare diagnosis carries an extremely poor prognosis, with death usually occurring within 1 year. We present a case of malignant optic glioma that was initially diagnosed as optic neuritis and central retinal vein occlusion, and we emphasize the importance of serial imaging and definitive biopsy to promote early diagnosis and treatment of this entity.

  View details for PubMedID 30450148

• A Small Molecule TrkB Neurotrophin Receptor Partial Agonist as Possible Treatment for Experimental Nonarteritic Anterior Ischemic Optic Neuropathy CURRENT EYE RESEARCH Shariati, M., Kumar, V., Yang, T., Chakraborty, C., Barres, B., Longo, F., Liao, Y. 2018; 43 (12): 1489-1499

  View details for DOI 10.1080/02713683.2018.1508726

  View details for Web of Science ID 000449997800011

• Anti-Interleukin-6 Antibody as Treatment for Giant Cell Arteritis JOURNAL OF NEURO-OPHTHALMOLOGY Liao, Y. 2018; 38 (4): 558–60

  View details for DOI 10.1097/WNO.0000000000000712

  View details for Web of Science ID 000451240600024

  View details for PubMedID 30199508

• A simple saccadic reading test to assess ocular motor function in cerebellar ataxia PLOS ONE Oh, A., Chen, T., Shariati, M., Jehangir, N., Hwang, T. N., Liao, Y. 2018; 13 (11)

  View details for DOI 10.1371/journal.pone.0203924

  View details for Web of Science ID 000449379500006

• A Small Molecule TrkB Neurotrophin Receptor Partial Agonist as Possible Treatment for Experimental Nonarteritic Anterior Ischemic Optic Neuropathy. Current eye research Ali Shariati, M., Kumar, V., Yang, T., Chakraborty, C., Barres, B. A., Longo, F. M., Liao, Y. J. 2018: 1–11

  Abstract

  PURPOSE: Brain-derived neurotrophic factor (BDNF) and activation of its high affinity receptor tropomyosin kinase (Trk) B promote retinal ganglion cells (RGCs) survival following injury. In this study, we tested the effects of LM22A-4, a small molecule TrkB receptor-specific partial agonist, on RGC survival in vitro and in experimental nonarteritic anterior ischemic optic neuropathy (AION), the most common acute optic neuropathy in those older than 50years.METHODS: We assessed drug effects on immunopanned, cultured RGCs and calculated RGC survival and assessed TrkB receptor activation by mitogen-activated protein (MAP) kinase translocation. To assess effects in vivo, we induced murine AION and treated the animals with one intravitreal injection and three-week systemic treatment. We measured drug effects using serial spectral-domain optical coherence tomography (OCT) and quantified retinal Brn3A+ RGC density three weeks after ischemia.RESULTS: In vitro, LM22A-4 significantly increased the survival of cultured RGCs at day 2 (95% CI control: 8.4-13.6; LM22A-4: 23.7-30.3; BDNF: 24.3-29.9; P≤0.0001), similar to the effect of the endogenous TrkB receptor ligand BDNF. There was also significant nuclear and cytoplasmic translocation of MAP kinase (95% CI control: 0.9-6.8; LM22A-4: 38.8-84.4; BDNF: 64.0-93.0; P=0.0002), a known downstream event of TrkB receptor activation. Following AION, LM22A-4 treatment led to significant preservation of the ganglion cell complex (95% CI: AION-PBS: 66.8-70.7%; AION-LM22A-4: 70.0-73.1; P=0.03) and total retinal thickness (95% CI: AION-PBS: 185-196%; AION-LM22A-4: 195-203; P=0.002) as measured by OCT compared with non-treated eyes. There was also significant rescue of the Brn3A+ RGC density on morphometric analysis of whole mount retinae (95% CI control: 2360-2629; AION-PBS: 1647-2008 cells/mm2; AION-LM22A-4: 1958-2216 cells/mm2; P=0.02).CONCLUSIONS: TrkB receptor partial agonist LM22A-4 promoted survival of cultured RGCs in vitro by TrkB receptor activation, and treatment in vivo led to increased survival of RGCs after optic nerve ischemia, providing support that LM22A-4 may be effective therapy to treat ischemic optic neuropathy.ABBREVIATIONS: AION: anterior ischemic optic neuropathy, BDNF: Brain-derived neurotrophic factor, GCC: ganglion cell complex, MAP: mitogen-activated protein, OCT: spectral-domain optical coherence tomography, OD: right eye, ON: optic nerve, ONH: optic nerve head, OS: left eye, RGC: retinal ganglion cell; Trk: tropomyosin kinase.

  View details for PubMedID 30273053

• Stem cell therapy for treatment of ischemic optic neuropathy Mesentier-Louro, L., Yang, N., Shariati, A., Domizi, P., Dodd, R., Wernig, G., Wernig, M., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2018

  View details for Web of Science ID 000442912501176

• Assessment of Endoplasmic Reticulum Stress Response after Diabetic Ischemic Optic Neuropathy Kumar, V., Shariati, A., Heng, K., Oh, A., Louro, L., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2018

  View details for Web of Science ID 000442932801095

• Ocular motor abnormalities during saccadic reading in different neuro-ophthalmic diseases Oh, A., Chen, T., Shariati, A., Jehangir, N., Yu, R., Yu, C., Mercado, C., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2018

  View details for Web of Science ID 000442912506170

• Vertical diplopia and oscillopsia due to midbrain keyhole aqueduct syndrome associated with severe cough. American journal of ophthalmology case reports Oh, A. J., Lanzman, B. A., Liao, Y. J. 2018; 10: 128–31

  Abstract

  Purpose: Midline structural defects in the neural axis can give rise to neuro-ophthalmic symptoms. We report a rare case of keyhole aqueduct syndrome presenting after two years of severe cough due to gastroesophageal reflux disease.Observations: A 58-year-old woman with a 2-year history of daily, severe cough presented to the neuro-ophthalmology clinic with progressive diplopia and oscillopsia. Examination revealed a 1-2 Hz down-beating nystagmus in primary gaze that worsened with left, right, and down gazes. Gaze evoked nystagmus and mild paresis were also seen with up gaze. There was an incomitant left hypertropia due to skew deviation that worsened with right and up gazes and improved with down gaze. She also had a right-sided ptosis and a 3 mm anisocoria not due to cranial nerve 3 paresis or Horner's syndrome. Brain magnetic resonance imaging showed a 1.5 mm * 11.7 mm * 6 mm midline cleft in the ventral midbrain communicating with the cerebral aqueduct, consistent with keyhole aqueduct syndrome. Her nystagmus and diplopia improved with oral acetazolamide treatment, at high doses of 2500-3000 mg per day.Conclusions and importance: We report the first case of midbrain keyhole aqueduct syndrome with ocular motor and other neuro-ophthalmic manifestations associated with severe cough. Although her cough was effectively treated and intracranial pressure measurement was normal, her ophthalmic symptoms continued to progress, which is common in previous cases reported. Treatment with acetazolamide led to significant improvement, supporting the use of acetazolamide in this rare condition.

  View details for PubMedID 29687086

• Association between obstructive sleep apnea and optic neuropathy: a Taiwanese population-based cohort study. Eye (London, England) Sun, M. H., Liao, Y. J., Lin, C. C., Chiang, R. P., Wei, J. C. 2018

  Abstract

  Obstructive sleep apnea (OSA) is associated with many systemic diseases including diabetes, hypertension, stroke, and cardiovascular disease. The aim of our study was to investigate the association between OSA and optic neuropathy (ON), and to evaluate the efficacy of treatment for OSA on the risk of ON.We used the data from the Longitudinal Health Insurance Database, which involved one million insurants from Taiwan National Health Insurance program (Taiwan NHI).OSA patients had a 1.95-fold higher risk of ON compared with non-OSA patients in all age group. The risk was significantly higher (adjusted hazard ratio: 4.21) in the group aged <45 years and male individuals (adjusted hazard ratio: 1.93). Meanwhile, sleep apnea was associated with ON regardless of the existence of comorbidity or not. OSA patients treated with continuous positive airway pressure (CPAP) had an adjusted 2.31-fold higher hazard of developing ON compared to controls, and those without any treatment had an adjusted 1.82-fold higher hazard of developing ON compared to controls. Moreover, ON patients had a 1.45-fold higher risk of OSA, and those aged between 45 and 64 years (hazard ratio: 1.76) and male individuals (hazard ratio: 1.55) had highest risk.Our study showed that OSA increased the risk of developing ON after controlling the comorbidities; however, treatment with CPAP did not reduce the risk of ON. Further large population study accessing to medical records about the severity of OSA and treatment for OSA is needed to clarify the efficacy of treatment for OSA in reducing the risk of ON.

  View details for PubMedID 29695760

• Visual function, digital behavior and the vision performance index. Clinical ophthalmology (Auckland, N.Z.) Ahmed, S. F., McDermott, K. C., Burge, W. K., Ahmed, I. I., Varma, D. K., Liao, Y. J., Crandall, A. S., Khaderi, S. K. 2018; 12: 2553–61

  Abstract

  Historically, visual acuity has been the benchmark for visual function. It is used to measure therapeutic outcomes for vision-related services, products and interventions. Quantitative measurement of suboptimal visual acuity can potentially be corrected optically with proper refraction in some cases, but in many cases of reduced vision there is something else more serious that can potentially impact other aspects of visual function such as contrast sensitivity, color discrimination, peripheral field of view and higher-order visual processing. The measurement of visual acuity typically requires stimuli subject to some degree of standardization or calibration and has thus often been limited to clinical settings. However, we are spending increasing amounts of time interacting with devices that present high-resolution, full color images and video (hereafter, digital media) and can record our responses. Most of these devices can be used to measure visual acuity and other aspects of visual function, not just with targeted testing experiences but from typical device interactions. There is growing evidence that prolonged exposure to digital media can lead to various vision-related issues (eg, computer vision syndrome, dry eye, etc.). Our regular, daily interactions (digital behavior) can also be used to assess our visual function, passively and continuously. This allows us to expand vision health assessment beyond the clinic, to collect vision-related data in the whole range of settings for typical digital behavior from practically any population(s) of interest and to further explore just how our increasingly virtual interactions are affecting our vision. We present a tool that can be easily integrated into digital media to provide insights into our digital behavior.

  View details for PubMedID 30573945

• A simple saccadic reading test to assess ocular motor function in cerebellar ataxia. PloS one Oh, A. J., Chen, T., Shariati, M. A., Jehangir, N., Hwang, T. N., Liao, Y. J. 2018; 13 (11): e0203924

  Abstract

  Cerebellar ataxia is a neurological disorder due to dysfunction of the cerebellum that affects coordination of fine movement, gait, and balance. Although ataxic patients commonly exhibit abnormal eye movement and have difficulties with saccadic reading, quantification of ocular motor abilities during reading in the clinical setting is rarely done. In this study, we assess visual performance with simple reading tests that can be used in the clinical setting and performed video infrared oculography in 11 patients with hereditary or acquired cerebellar ataxia and 11 age-matched controls. We found that compared with controls, ataxic patients read significantly slower on regularly and irregularly spaced 120 single-digit number reading tasks (read aloud) (p = 0.02 for both) but not on a word reading task (read silently), although there was large variability on the word reading task. Among the 3 reading tasks, the regularly spaced number reading task had the greatest difference (44%) between ataxic patients and controls. Analysis of oculography revealed that ataxic patients had slower reading speeds on the regularly spaced number reading task because of significantly higher saccade and fixation counts, impairment of small amplitude progressive saccades as well as large amplitude, line-changing saccades, greater fixation dispersion, and irregularity of scan paths and staircase gaze patterns. Our findings show that infrared oculography remains the gold standard in assessment of ocular motor difficulties during reading in ataxic patients. In the absence of this capability in the clinical setting, a simple 120 regularly spaced single-digit saccadic number reading test, which most patients can perform in less than 2 minutes, can be a possible biomarker for ocular motor abilities necessary for reading.

  View details for PubMedID 30403759

• Visual Disability and Reading Difficulty in Patients with Parkinson's Disease Yu, C., Shariati, A., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2017

  View details for Web of Science ID 000432170303173

• Association between obstructive sleep apnea and optic neuropathy: A Taiwanese Population-Based bidirectional cohort Study Sun, M., Liao, Y., Lin, C., Wei, J. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2017

  View details for Web of Science ID 000432176302020

• Gaze Changes During Visual Behavior in Hemianopia Liao, Y., Song, J., Shariati, A., Hwang, D. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2017

  View details for Web of Science ID 000432170303171

• High Correlation between OCTA and OCT Measurements in Patients with Optic Atrophy Shariati, A., Shen, Y., Chu, Z., Powers, M., Wang, R. K., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2017

  View details for Web of Science ID 000432170304192

• Structure-Function Analysis of Nonarteritic Anterior Ischemic Optic Neuropathy and Age-Related Differences in Outcome. Journal of neuro-ophthalmology Sun, M., Liao, Y. J. 2017

  Abstract

  The optic nerve head is vulnerable to ischemia leading to anterior ischemic optic neuropathy (AION), the most common acute optic neuropathy in those older than 50 years of age.We performed a cross-sectional study of 55 nonarteritic anterior ischemic optic neuropathy (NAION) eyes in 34 patients to assess clinical outcome and perform structure-function correlations.The peak age of NAION onset was between 50 and 55 years. Sixty-seven percent of patients presented with their first event between the ages of 40 and 60 years, and 32% presented at ≤50 years. Those with NAION onset at age ≤50 years did not have significantly better visual outcome per logMAR visual acuity, automated perimetric mean deviation (PMD) or optical coherence tomography (OCT) measurements. Kaplan-Meier survival curve and multivariate Cox proportional regression analysis showed that age >50 years at NAION onset was associated with greater risk of second eye involvement, with hazard ratio of 20. Older age at onset was significantly correlated with greater thinning of the ganglion cell complex (GCC) (P = 0.022) but not with logMAR visual acuity, PMD, or thinning of retinal nerve fiber layer (RNFL). Using area under receiver operating characteristic curve analyses, we found that thinning of RNFL and GCC was best able to predict visual outcome, and that mean RNFL thickness >65 μm or macular GCC thickness >55 μm significantly correlated with good visual field outcome.We showed that NAION onset at age >50 years had a greater risk of second eye involvement. Patients with OCT mean RNFL thickness >65 μm and mean macular ganglion cell complex thickness >55 μm had better visual outcomes.

  View details for DOI 10.1097/WNO.0000000000000521

  View details for PubMedID 28538035

• Experimental Anterior Ischemic Optic Neuropathy in Diabetic Mice Exhibited Severe Retinal Swelling Associated With VEGF Elevation INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Sun, M., Shariati, M. A., Liao, Y. J. 2017; 58 (4): 2296-2305

  Abstract

  Diabetes mellitus (DM) is one of the most important risk factors for nonarteritic anterior ischemic optic neuropathy (AION). In this study, we investigated for the first time the impact of experimental AION in a DM model.We induced a photochemical thrombosis model of AION after streptozotocin-induced DM and performed serial optical coherence tomography (OCT), morphometric analyses, and VEGF levels in the retina and sera.Compared with non-DM animals, experimental AION in DM mice led to significantly greater retinal swelling on day 1 and worse thinning at week 3 on OCT measurements. Greater retinal swelling on OCT in DM-AION eyes was associated with significantly increased loss of brain-specific homeobox/POU domain protein 3A (Brn3A+) retinal ganglion cells at week 3. In acute AION, there was greater inflammation as seen by an increase in ionized calcium-binding adapter molecule 1 (Iba1+)-activated microglia. On day 1, there was increase in vascular endothelial growth factor (VEGF) level in nondiabetic AION retinae and sera, but the VEGF level was the highest in the diabetic AION group, which decreased to nondiabetic levels after insulin treatment. The decrease in retinal and serum VEGF levels after insulin treatment correlated with a reduction in retinal swelling.In the setting of hyperglycemia, AION led to greater acute, postischemic microglial activation and elevation of VEGF levels, which likely contributed to greater retinal swelling acutely and worse retinal thinning and loss of retinal ganglion cells chronically. Treatment of hyperglycemia with insulin reduced VEGF levels and retinal swelling, consistent with the idea that VEGF is an important factor in postischemic swelling and that good glycemic control following AION may lead to better visual outcome.

  View details for DOI 10.1167/iovs.16-20308

  View details for Web of Science ID 000400649600042

  View details for PubMedID 28431433

• Immunoinhibitory checkpoint deficiency in medium and large vessel vasculitis PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Zhang, H., Watanabe, R., Berry, G. J., Vaglio, A., Liao, Y. J., Warrington, K. J., Goronzy, J. J., Weyand, C. M. 2017; 114 (6): E970-E979

  Abstract

  Giant cell arteritis (GCA) causes autoimmune inflammation of the aorta and its large branches, resulting in aortic arch syndrome, blindness, and stroke. CD4(+) T cells and macrophages form organized granulomatous lesions in the walls of affected arteries, destroy the tunica media, and induce ischemic organ damage through rapid intimal hyperplasia and luminal occlusion. Pathogenic mechanisms remain insufficiently understood; specifically, it is unknown whether the unopposed activation of the immune system is because of deficiency of immunoinhibitory checkpoints. Transcriptome analysis of GCA-affected temporal arteries revealed low expression of the coinhibitory ligand programmed death ligand-1 (PD-L1) concurrent with enrichment of the programmed death-1 (PD-1) receptor. Tissue-residing and ex vivo-generated dendritic cells (DC) from GCA patients were PD-L1(lo), whereas the majority of vasculitic T cells expressed PD-1, suggesting inefficiency of the immunoprotective PD-1/PD-L1 immune checkpoint. DC-PD-L1 expression correlated inversely with clinical disease activity. In human artery-SCID chimeras, PD-1 blockade exacerbated vascular inflammation, enriched for PD-1(+) effector T cells, and amplified tissue production of multiple T-cell effector cytokines, including IFN-γ, IL-17, and IL-21. Arteries infiltrated by PD-1(+) effector T cells developed microvascular neoangiogenesis as well as hyperplasia of the intimal layer, implicating T cells in the maladaptive behavior of vessel wall endogenous cells. Thus, in GCA, a breakdown of the tissue-protective PD1/PD-L1 checkpoint unleashes vasculitic immunity and regulates the pathogenic remodeling of the inflamed arterial wall.

  View details for DOI 10.1073/pnas.1616848114

  View details for Web of Science ID 000393422200011

  View details for PubMedID 28115719

  View details for PubMedCentralID PMC5307483

• Cardinal features of superior oblique myokymia: An infrared oculography study American Journal of Ophthalmology Case Report Thinda, S., Chen, Y., Liao, Y. J. 2017
• Cardinal features of superior oblique myokymia: An infrared oculography study. American journal of ophthalmology case reports Thinda, S. n., Chen, Y. R., Liao, Y. J. 2017; 7: 115–19

  Abstract

  Superior oblique myokymia (SOM) is a rare eye movement disorder characterized by unilateral oscillopsia and binocular diplopia. Our study aimed to better understand SOM using infrared oculography.We examined and recorded five patients with SOM.Binocular infrared oculography showed that in primary gaze, all patients exhibited torsional oscillations, which worsened in infraduction and abduction and improved in supraduction and adduction. Saccades showed increased downward saccade amplitudes but normal peak velocities. During fixation in primary gaze, removal of target led to extorsion and supraduction, unmasking underlying superior oblique weakness.Our data suggest both weakness and activity-dependent hyperactivity of the trochlear motor unit, supporting a model of injury followed by aberrant regeneration.

  View details for PubMedID 29260093

• The microvascular niche instructs T cells in large vessel vasculitis via the VEGF-Jagged1-Notch pathway. Science translational medicine Wen, Z. n., Shen, Y. n., Berry, G. n., Shahram, F. n., Li, Y. n., Watanabe, R. n., Liao, Y. J., Goronzy, J. J., Weyand, C. M. 2017; 9 (399)

  Abstract

  Microvascular networks in the adventitia of large arteries control access of inflammatory cells to the inner wall layers (media and intima) and thus protect the immune privilege of the aorta and its major branches. In autoimmune vasculitis giant cell arteritis (GCA), CD4 T helper 1 (TH1) and TH17 cells invade into the wall of the aorta and large elastic arteries to form tissue-destructive granulomas. Whether the disease microenvironment provides instructive cues for vasculitogenic T cells is unknown. We report that adventitial microvascular endothelial cells (mvECs) perform immunoregulatory functions by up-regulating the expression of the Notch ligand Jagged1. Vascular endothelial growth factor (VEGF), abundantly present in GCA patients' blood, induced Jagged1 expression, allowing mvECs to regulate effector T cell induction via the Notch-mTORC1 (mammalian target of rapamycin complex 1) pathway. We found that circulating CD4 T cells in GCA patients have left the quiescent state, actively signal through the Notch pathway, and differentiate into TH1 and TH17 effector cells. In an in vivo model of large vessel vasculitis, exogenous VEGF functioned as an effective amplifier to recruit and activate vasculitogenic T cells. Thus, systemic VEGF co-opts endothelial Jagged1 to trigger aberrant Notch signaling, biases responsiveness of CD4 T cells, and induces pathogenic effector functions. Adventitial microvascular networks function as an instructive tissue niche, which can be exploited to target vasculitogenic immunity in large vessel vasculitis.

  View details for PubMedID 28724574

• Abnormal Eye Movement Behavior during Reading in Parkinson's Disease Yu, C., Shariati, A., Lee, T., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2016

  View details for Web of Science ID 000394210602217

• Structure-Function Analysis in Chiasmal Compression Helps Predict Visual Prognosis Witthayaweerasak, J., Sun, M., Shariati, A., Li, J., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2016

  View details for Web of Science ID 000394210204072

• Experimental Anterior Ischemic Optic Neuropathy in Diabetic Mice Exhibited Severe Retinal Swelling and Subretinal Fluid Accumulation Acutely and More Severe Thinning Chronically Sun, M., Shariati, A., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2016

  View details for Web of Science ID 000394210601121

• Eye Fatigue During TV Watching: An Infrared Oculography Study of Linearly vs. Circularly Polarized LCD TV Shariati, A., Liao, K., Yu, C., Witthayaweerasak, J., Chang, R. T., Sun, M., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2016

  View details for Web of Science ID 000394210204362

• Giant Cell Arteritis: From Pathogenesis to Therapeutic Management. Current treatment options in rheumatology Watanabe, R., Goronzy, J. J., Berry, G., Liao, Y. J., Weyand, C. M. 2016; 2 (2): 126-137

  View details for PubMedID 27298757

• Dose-Response Modeling of the Visual Pathway Tolerance to Single-Fraction and Hypofractionated Stereotactic Radiosurgery SEMINARS IN RADIATION ONCOLOGY Hiniker, S. M., Modlin, L. A., Choi, C. Y., Atalar, B., Seiger, K., Binkley, M. S., Harris, J. P., Liao, Y. J., Fischbein, N., Wang, L., Ho, A., Lo, A., Chang, S. D., Harsh, G. R., Gibbs, I. C., Hancock, S. L., Li, G., Adler, J. R., Soltys, S. G. 2016; 26 (2): 97-104

  Abstract

  Patients with tumors adjacent to the optic nerves and chiasm are frequently not candidates for single-fraction stereotactic radiosurgery (SRS) due to concern for radiation-induced optic neuropathy. However, these patients have been successfully treated with hypofractionated SRS over 2-5 days, though dose constraints have not yet been well defined. We reviewed the literature on optic tolerance to radiation and constructed a dose-response model for visual pathway tolerance to SRS delivered in 1-5 fractions. We analyzed optic nerve and chiasm dose-volume histogram (DVH) data from perioptic tumors, defined as those within 3mm of the optic nerves or chiasm, treated with SRS from 2000-2013 at our institution. Tumors with subsequent local progression were excluded from the primary analysis of vision outcome. A total of 262 evaluable cases (26 with malignant and 236 with benign tumors) with visual field and clinical outcomes were analyzed. Median patient follow-up was 37 months (range: 2-142 months). The median number of fractions was 3 (1 fraction n = 47, 2 fraction n = 28, 3 fraction n = 111, 4 fraction n = 10, and 5 fraction n = 66); doses were converted to 3-fraction equivalent doses with the linear quadratic model using α/β = 2Gy prior to modeling. Optic structure dose parameters analyzed included Dmin, Dmedian, Dmean, Dmax, V30Gy, V25Gy, V20Gy, V15Gy, V10Gy, V5Gy, D50%, D10%, D5%, D1%, D1cc, D0.50cc, D0.25cc, D0.20cc, D0.10cc, D0.05cc, D0.03cc. From the plan DVHs, a maximum-likelihood parameter fitting of the probit dose-response model was performed using DVH Evaluator software. The 68% CIs, corresponding to one standard deviation, were calculated using the profile likelihood method. Of the 262 analyzed, 2 (0.8%) patients experienced common terminology criteria for adverse events grade 4 vision loss in one eye, defined as vision of 20/200 or worse in the affected eye. One of these patients had received 2 previous courses of radiotherapy to the optic structures. Both cases were meningiomas treated with 25Gy in 5 fractions, with a 3-fraction equivalent optic nerve Dmax of 19.2 and 22.2Gy. Fitting these data to a probit dose-response model enabled risk estimates to be made for these previously unvalidated optic pathway constraints: the Dmax limits of 12Gy in 1 fraction from QUANTEC, 19.5Gy in 3 fractions from Timmerman 2008, and 25Gy in 5 fractions from AAPM Task Group 101 all had less than 1% risk. In 262 patients with perioptic tumors treated with SRS, we found a risk of optic complications of less than 1%. These data support previously unvalidated estimates as safe guidelines, which may in fact underestimate the tolerance of the optic structures, particularly in patients without prior radiation. Further investigation would refine the estimated normal tissue complication probability for SRS near the optic apparatus.

  View details for DOI 10.1016/j.semradonc.2015.11.008

  View details for Web of Science ID 000373242700003

• Treatment of Nystagmus in Brainstem Cavernous Malformation with Botulinum Toxin CUREUS Chen, Y., Fredrick, D., Steinberg, G. K., Liao, Y. J. 2016; 8 (4)

  View details for DOI 10.7759/cureus.553

  View details for Web of Science ID 000453611400003

• Dose-Response Modeling of the Visual Pathway Tolerance to Single-Fraction and Hypofractionated Stereotactic Radiosurgery. Seminars in radiation oncology Hiniker, S. M., Modlin, L. A., Choi, C. Y., Atalar, B., Seiger, K., Binkley, M. S., Harris, J. P., Liao, Y. J., Fischbein, N., Wang, L., Ho, A., Lo, A., Chang, S. D., Harsh, G. R., Gibbs, I. C., Hancock, S. L., Li, G., Adler, J. R., Soltys, S. G. 2016; 26 (2): 97-104

  Abstract

  Patients with tumors adjacent to the optic nerves and chiasm are frequently not candidates for single-fraction stereotactic radiosurgery (SRS) due to concern for radiation-induced optic neuropathy. However, these patients have been successfully treated with hypofractionated SRS over 2-5 days, though dose constraints have not yet been well defined. We reviewed the literature on optic tolerance to radiation and constructed a dose-response model for visual pathway tolerance to SRS delivered in 1-5 fractions. We analyzed optic nerve and chiasm dose-volume histogram (DVH) data from perioptic tumors, defined as those within 3mm of the optic nerves or chiasm, treated with SRS from 2000-2013 at our institution. Tumors with subsequent local progression were excluded from the primary analysis of vision outcome. A total of 262 evaluable cases (26 with malignant and 236 with benign tumors) with visual field and clinical outcomes were analyzed. Median patient follow-up was 37 months (range: 2-142 months). The median number of fractions was 3 (1 fraction n = 47, 2 fraction n = 28, 3 fraction n = 111, 4 fraction n = 10, and 5 fraction n = 66); doses were converted to 3-fraction equivalent doses with the linear quadratic model using α/β = 2Gy prior to modeling. Optic structure dose parameters analyzed included Dmin, Dmedian, Dmean, Dmax, V30Gy, V25Gy, V20Gy, V15Gy, V10Gy, V5Gy, D50%, D10%, D5%, D1%, D1cc, D0.50cc, D0.25cc, D0.20cc, D0.10cc, D0.05cc, D0.03cc. From the plan DVHs, a maximum-likelihood parameter fitting of the probit dose-response model was performed using DVH Evaluator software. The 68% CIs, corresponding to one standard deviation, were calculated using the profile likelihood method. Of the 262 analyzed, 2 (0.8%) patients experienced common terminology criteria for adverse events grade 4 vision loss in one eye, defined as vision of 20/200 or worse in the affected eye. One of these patients had received 2 previous courses of radiotherapy to the optic structures. Both cases were meningiomas treated with 25Gy in 5 fractions, with a 3-fraction equivalent optic nerve Dmax of 19.2 and 22.2Gy. Fitting these data to a probit dose-response model enabled risk estimates to be made for these previously unvalidated optic pathway constraints: the Dmax limits of 12Gy in 1 fraction from QUANTEC, 19.5Gy in 3 fractions from Timmerman 2008, and 25Gy in 5 fractions from AAPM Task Group 101 all had less than 1% risk. In 262 patients with perioptic tumors treated with SRS, we found a risk of optic complications of less than 1%. These data support previously unvalidated estimates as safe guidelines, which may in fact underestimate the tolerance of the optic structures, particularly in patients without prior radiation. Further investigation would refine the estimated normal tissue complication probability for SRS near the optic apparatus.

  View details for DOI 10.1016/j.semradonc.2015.11.008

  View details for PubMedID 27000505

• Abnormal Eye Movement Behavior during Reading in Parkinson’s Disease Parkinsonism and Related Disorders Yu, C. Y., Lee, T., Shariati, M., Santini, V., Poston, K., Liao, Y. 2016; 32 (130): 130-132
• Treatment of Nystagmus in Brainstem Cavernous Malformation with Botulinum Toxin. Cure¯us Chen, Y., Fredrick, D., Steinberg, G. K., Liao, Y. J. 2016; 8 (4)

  Abstract

  We report a long-term eye movement study of a 68-year-old female with pontomedullary junction cavernous malformation whose dysconjugate nystagmus was treated with retrobulbar botulinum toxin A injections. Sequential, bilateral retrobulbar injections of botulinum toxin A were performed. Injections immediately decreased oscillopsia and nystagmus, and improved visual acuities. One to three months following injection, three-dimensional infrared oculography measured a significant 39-100% (P = 0.001) decrease in nystagmus amplitudes at multiple dimensions. This improvement diminished by six months in the right eye but sustained for about one year in the left eye. Over two years, botulinum toxin A injections were performed twice in the left eye and five times in the right eye. Our study supported the safe and effective use of repetitive retrobulbar botulinum toxin A injections in symptomatic nystagmus that failed medical therapy.

  View details for DOI 10.7759/cureus.553

  View details for PubMedID 27182467

  View details for PubMedCentralID PMC4852187

• Long Distance Homonymous Hemi-Macular Retrograde Degeneration of the Visual Pathway: A Comparison of Anterior and Posterior Visual Pathway Lesions Rajanala, A., Shariati, M., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2015

  View details for Web of Science ID 000362891106358

• Validation of the King-Devick Test Using 500-Hz Binocular Infrared Oculography Shariati, M., Sun, M., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2015

  View details for Web of Science ID 000362882207091

• Dramatic Fixation Instability in Peripheral Vestibulopathies without Visual Feedback Compared with Central Vestibulopathies Hwang, J., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2015

  View details for Web of Science ID 000362882207080

• The Presence of Calcium Significantly Enhanced Annexin-V-Labelling of Degenerating Axons after Experimental Anterior Ischemic Optic Neuropathy Lee, G., Shariati, M., Sun, M., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2015

  View details for Web of Science ID 000362891106038

• 50% of Non-Arteritic Anterior lschemic Optic Neuropathy Occurs between 40-55 Years Old Sun, M., Liao, Y., Shariati, M. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2015

  View details for Web of Science ID 000362891106044

• Optical Coherence Tomography Study of Retinal Changes in Normal Aging and After Ischemia INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Shariati, M. A., Park, J. H., Liao, Y. J. 2015; 56 (5): 2790-2797

  Abstract

  Age-related thinning of the retinal ganglion cell axons in the nerve fiber layer has been measured in humans using optical coherence tomography (OCT). In this study, we used OCT to measure inner retinal changes in 3-month-, 1-year-, and 2-year-old mice and after experimental anterior ischemic optic neuropathy (AION).We used OCT to quantify retinal thickness in over 200 eyes at different ages before and after a photochemical thrombosis model of AION. The scans were manually or automatically segmented.In normal aging, there was 1.3-μm thinning of the ganglion cell complex (GCC) between 3 months and 1 year (P < 0.0001) and no further thinning at 2 years. In studying age-related inner retinal changes, measurement of the GCC (circular scan) was superior to that of the total retinal thickness (posterior pole scan) despite the need for manual segmentation because it was not contaminated by outer retinal changes. Three weeks after AION, there was 8.9-μm thinning of the GCC (circular scan; P < 0.0001), 50-μm thinning of the optic disc (posterior pole scan; P < 0.0001), and 17-μm thinning of the retina (posterior pole scan; P < 0.0001) in the 3-month-old group. Changes in the older eyes after AION were similar to those of the 3-month-old group.Optical coherence tomography imaging of a large number of eyes showed that, like humans, mice exhibited small, age-related inner retinal thinning. Measurement of the GCC was superior to total retinal thickness in quantifying age-related changes, and both circular and posterior pole scans were useful to track short-term changes after AION.

  View details for DOI 10.1167/iovs.14-15145

  View details for Web of Science ID 000356439200002

  View details for PubMedID 25414186

• Subretinal fluid is common in experimental non-arteritic anterior ischemic optic neuropathy EYE Yu, C., Ho, J. K., Liao, Y. J. 2014; 28 (12): 1494-1501

  Abstract

  Anterior ischemic optic neuropathy (AION) is an important cause of acute vision loss for which several animal models exist. It has been associated with subretinal fluid in a previous study on patients but not yet so in animal models.A patient presented with acute non-arteritic AION (NAION) and underwent ophthalmic evaluation and testing including fluorescein angiography and spectral-domain optical coherence tomography (SD-OCT). On the basis of the patient's findings, we used SD-OCT circular and volume scans to analyze retinal changes in a murine model of NAION.One week after left eye vision loss, the patient had clinical and imaging findings consistent with NAION. On SD-OCT, there was prominent peripapillary retinal thickening consistent with intra-retinal edema and sub-foveolar fluid. Inspired by the findings in human AION, we looked for similar changes in murine NAION using SD-OCT. The circular scan did not adequately detect the presence of subretinal fluid. Using the 25-line scan, which covered a larger part of the posterior pole, we found that 100% of murine AION resulted in subretinal fluid at day 1. The subretinal fluid resolved by week 1.This study detailed a case of clinical NAION associated with intra-retinal and subretinal fluid. We also found that subretinal fluid was common in murine photochemical thrombosis model of AION and could be found far away from the optic disc.

  View details for DOI 10.1038/eye.2014.220

  View details for Web of Science ID 000346365600014

  View details for PubMedID 25257770

  View details for PubMedCentralID PMC4268460

• Severe, early axonal degeneration following experimental anterior ischemic optic neuropathy. Investigative ophthalmology & visual science Lee, G. H., Stanford, M. P., Shariati, M. A., Ma, J. H., Liao, Y. J. 2014; 55 (11): 7111-7118

  Abstract

  Anterior ischemic optic neuropathy (AION) is the most common acute optic neuropathy in adults older than 50 and leads to axonal degeneration, thinning of the retinal nerve fiber layer and loss of the retinal ganglion cells (RGCs). We used experimental AION model to study early axonal changes following ischemia.We induced optic nerve head ischemia in adult mice using photochemical thrombosis and analyzed retinal changes within 1 week. We used confocal scanning laser ophthalmoscopy (cSLO) and fluorescence microscopy of retinal whole mount preparations to analyze axonal degeneration in Thy1-YFP-H mice and those injected with annexin-V-A488 intravitreally.Three days after AION, morphometric analyses in Thy1-YFP-H mice revealed evidence of early axonal changes, including swollen or branched axonal stumps. There was also a beads-on-a-string appearance of YFP expression. The axonal enlargements occurred at an interval of 17 ± 1 μm or 6 ± 0 enlargements/100 μm. At day 7 after AION, the degenerating intraretinal RGC axons exhibited intense annexin-V-A488 staining (P = 0.002). The annexin-V staining pattern was fragmented, with intersegment interval of 20.1 ± 1.4 μm or 5.8 ± 0.4 annexin-V-A488(+) fragments/100 μm, which were similar to that of degenerating Thy1-YFP(+) axons.Following a photochemical thrombosis model of AION, RGC axons displayed severe degenerative changes within 1 week, suggesting that after ischemia, RGC axons may degenerate in a temporally and spatially distinct fashion from that of the soma. Our findings also further established annexin-V as a useful marker of retinal degeneration because it strongly labeled dying RGC axons.

  View details for DOI 10.1167/iovs.14-14603

  View details for PubMedID 25249599

• Accessory lateral rectus in a patient with normal ocular motor control. Journal of neuro-ophthalmology Liao, Y. J., Hwang, J. J. 2014; 34 (2): 153-154

  Abstract

  : Although supernumerary extraocular muscles are common in monkeys and other species, they are relatively rare in humans and typically are noted in the context of childhood strabismus. We present a case of an incidentally found unilateral accessory lateral rectus muscle in a 51-year-old woman with normal ocular motor control. In this patient, the accessory lateral rectus was approximately 10% the size of a normally sized lateral rectus muscle. It originated from the orbital apex, traveled between the optic nerve and the lateral rectus and attached to the superolateral aspect of the globe. This unique case demonstrates that accessory lateral rectus in humans may have no impact on eye movement and ocular alignment.

  View details for DOI 10.1097/WNO.0000000000000109

  View details for PubMedID 24796602

• Severe Impairment of Axonal Transport in Acute Experimental Anterior Ischemic Optic Neuropathy Ma, J., Shariati, M., Pisani, L., Pestilli, F., Dougherty, B., Perry, L., Lee, G., Contag, C., Wandell, B. A., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2014

  View details for Web of Science ID 000433205505248

• Intact extrastriate maps following V1 quarterfield lesion Horiguchi, H., Liao, Y., Wandell, B. A., Winawer, J. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2014

  View details for Web of Science ID 000433199700339

• Annexin-V Imaging of Degenerating Axons Following Experimental Anterior Ischemic Optic Neuropathy Lee, G., Shariati, M., Ma, J., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2014

  View details for Web of Science ID 000433203501277

• TrkB Neurotrophin Receptor Activation with Pharmacophore as Possible Treatment for Experimental Ischemic Optic Neuropathy Shariati, M., Ma, J., Longo, F., Yang, T., Barres, B., Chakraborty, C., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2014

  View details for Web of Science ID 000433205505245

• Non-Surgical Treatment for Racemic Neurocysticercosis with Compression of the Optic Nerve Journal of Spine and Neurosurgery Moreno, M., Bui, T., Agarwal, M., Nitta, R., Liao, Y. J., Li, G. 2014
• Responsive extrastriate maps despite a V1 lesion and quarterfield blindness Horiguchi, H., Wandell, B. A., Liao, Y., Winawer, J. PION LTD. 2014: 303

  View details for Web of Science ID 000342373600100

• Extreme Tolerance of the Optic Nerve to Ionizing Radiation: A Case Report Revealing the Role of the Dose-Volume Effect Cureus Adler, J. R., Murovic, J., Liao, Y. J., Shuer, L. M. 2014
• Severe Impairment of Axonal Transport in Acute Experimental Anterior Ischemic Optic Neuropathy Ma, J., Stanford, M., Shariati, A., Lee, G., Liao, Y. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2013

  View details for Web of Science ID 000436232703194

• Thinning of the Optic Nerve in Aging and after Ischemia: An Imaging Study Using Spectral-Domain Optical Coherence Tomography Shariati, M., Lee, G., Liao, Y., Stanford Sch Med ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2013

  View details for Web of Science ID 000436232707226

• TrkB Neurotrophin Receptor Activation with Pharmacophore as Possible Treatment for Anterior Ischemic Optic Neuropathy Liao, Y., Lee, G., Ma, J., Yang, T., Chakraborty, C., Barres, B., Longo, F., Shariati, M. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2013

  View details for Web of Science ID 000436232901104

• Optical coherence tomography study of experimental anterior ischemic optic neuropathy and histologic confirmation. Investigative ophthalmology & visual science Ho, J. K., Stanford, M. P., Shariati, M. A., Dalal, R., Liao, Y. J. 2013; 54 (9): 5981-5988

  Abstract

  The optic nerve is part of the central nervous system, and interruption of this pathway due to ischemia typically results in optic atrophy and loss of retinal ganglion cells (RGCs). In this study, we assessed in vivo retinal changes following murine anterior ischemic optic neuropathy (AION) using spectral-domain optical coherence tomography (SD-OCT) and compared these anatomic measurements to that of histology.We induced ischemia at the optic disc via laser-activated photochemical thrombosis, performed serial SD-OCT and manual segmentation of the retinal layers to measure the ganglion cell complex (GCC) and total retinal thickness, and correlated these measurements with that of histology.There was impaired perfusion and leakage at the optic disc on fluorescein angiography immediately after AION and severe swelling and distortion of the peri-papillary retina on day-1. We used SD-OCT to quantify the changes in retinal thickness following experimental AION, which revealed significant thickening of the GCC on day-1 after ischemia followed by gradual thinning that plateaued by week-3. Thickness of the peri-papillary sensory retina was also increased on day-1 and thinned chronically. This pattern of acute retinal swelling and chronic thinning on SD-OCT correlated well with changes seen in histology and corresponded to loss of retinal ganglion layer cells after ischemia.This is the first serial SD-OCT quantification of acute and chronic changes following experimental AION, which revealed changes in the ganglion cell complex similar to that of human AION, but over a time frame of weeks rather than months.

  View details for DOI 10.1167/iovs.13-12419

  View details for PubMedID 23887804

• Traumatic air bag maculopathy Archive of Ophthalmology Kung, J., Leung, L., Leng, T., Liao, Y. J. 2013; 131 (5)
• Treatment of Anterior Ischemic Optic Neuropathy: Clues from the Bench Taiwan Journal of Ophthalmology Liao, Y. J., Hwang, J. J. 2013
• The Immunopathology of Giant Cell Arteritis: Diagnostic and Therapeutic Implications JOURNAL OF NEURO-OPHTHALMOLOGY Weyand, C. M., Liao, Y. J., Goronzy, J. J. 2012; 32 (3): 259-265

  Abstract

  Giant cell arteritis (GCA) is an important cause of preventable blindness, most commonly due to anterior ischemic optic neuropathy. Ischemic tissue injury is the end result of a process that begins within the walls of susceptible arteries in which local dendritic cells (DCs) recruit and activate CD4 T cells that, in turn, direct the activity of effector macrophages. In response to the immune attack, the blood vessel forms lumen-stenosing intima. Multiple cascades of excessive T-cell reactivity contribute to the autoimmune features of giant cell arteritis with TH1 and TH17 immunity responsible for the early phase and TH1 immunity promoting chronic-smoldering inflammation. These cascades are only partially overlapping, supporting the concept that a multitude of instigators induce and sustain vascular inflammation. The artery actively participates in the abnormal immune response through endogenous immune sentinels, so-called vascular DCs embedded in the adventitia. Advancing age, the strongest of all risk factors for GCA, contributes to both, the dysfunction of the immune system and the vascular system. Expansion of the therapeutic armamentarium for GCA needs to focus on approaches that mitigate the impact of the aging artery and adapt to the needs of the immunosenescent host.

  View details for DOI 10.1097/WNO.0b013e318268aa9b

  View details for Web of Science ID 000308187800018

  View details for PubMedID 22914691

• Plasticity and Stability of the Visual System in Human Achiasma NEURON Hoffmann, M. B., Kaule, F. R., Levin, N., Masuda, Y., Kumar, A., Gottlob, I., Horiguchi, H., Dougherty, R. F., Stadler, J., Wolynski, B., Speck, O., Kanowski, M., Liao, Y. J., Wandell, B. A., Dumoulin, S. O. 2012; 75 (3): 393-401

  Abstract

  The absence of the optic chiasm is an extraordinary and extreme abnormality in the nervous system. The abnormality produces highly atypical functional responses in the cortex, including overlapping hemifield representations and bilateral population receptive fields in both striate and extrastriate visual cortex. Even in the presence of these large functional abnormalities, the effect on visual perception and daily life is not easily detected. Here, we demonstrate that in two achiasmic humans the gross topography of the geniculostriate and occipital callosal connections remains largely unaltered. We conclude that visual function is preserved by reorganization of intracortical connections instead of large-scale reorganizations of the visual cortex. Thus, developmental mechanisms of local wiring within cortical maps compensate for the improper gross wiring to preserve function in human achiasma.

  View details for DOI 10.1016/j.neuron.2012.05.026

  View details for Web of Science ID 000307417700007

  View details for PubMedID 22884323

  View details for PubMedCentralID PMC3427398

• Junctional Visual Field Loss in a Case of Wyburn-Mason Syndrome JOURNAL OF NEURO-OPHTHALMOLOGY Liu, A., Chen, Y., Chang, S., Liao, Y. J. 2012; 32 (1): 42-44

  Abstract

  A previously healthy girl failed a routine eye screening at the age of 6 years. Her visual fields showed generalized depression in the right eye and a superotemporal defect in the left eye, consistent with a junctional scotoma. Funduscopic examination and fluorescein angiography revealed markedly dilated tortuous vascular loops with arteriovenous communications consistent with retinal arteriovenous malformations (AVMs). MRI of the brain and cerebral angiography demonstrated right ophthalmic and right thalamic AVMs, with compression and atrophy of the right optic chiasm. This represents a case of Wyburn-Mason syndrome with a junctional scotoma.

  View details for DOI 10.1097/WNO.0b013e31821aeefb

  View details for Web of Science ID 000300607000009

  View details for PubMedID 21613961

• Functional rescue of experimental ischemic optic neuropathy with alpha B-crystallin EYE Pangratz-Fuehrer, S., Kaur, K., Ousman, S. S., Steinman, L., Liao, Y. J. 2011; 25 (6): 809-817

  Abstract

  Anterior ischemic optic neuropathy (AION) is an important cause of acute vision loss in adults, and there is no effective treatment. We studied early changes following experimental AION and tested the benefit of a potential treatment.Materials andWe induced experimental AION in adult mice and tested the effects of short-term (daily for 3 days) and long-term (every other day for 3 weeks) αB-crystallin (αBC) treatment using histological and serial intracranial flash visual evoked potential recordings.One day after experimental AION, there was swelling at the optic nerve (ON) head and increased expression of αBC, a small heat shock protein important in ischemia and inflammation. This upregulation coincided with microglial and astrocytic activation. Our hypothesis was that αBC may be part of the endogenous protective mechanism against injury, thus we tested the effects of αBC on experimental AION. Daily intraveneous or intravitreal αBC injections did not improve visual evoked potential amplitude or latency at days 1-2. However, αBC treatment decreased swelling and dampened the microglial and astrocytic activation on day 3. Longer treatment with intravenous αBC led to acceleration of visual evoked potential latency over 3 weeks, without improving amplitude. This latency acceleration did not correlate with increased retinal ganglion cell survival but did correlate with complete rescue of the ON oligodendrocytes, which are important for myelination.We identified αBC as an early marker following experimental AION. Treatment with αBC enhanced this endogenous, post-ischemic response by decreasing microglial activation and promoting ON oligodendrocyte survival.

  View details for DOI 10.1038/eye.2011.42

  View details for Web of Science ID 000291430100020

  View details for PubMedID 21475310

  View details for PubMedCentralID PMC3178147

• Dorsolateral Midbrain MRI Abnormalities and Ocular Motor Deficits Following Cytarabine-Based Chemotherapy for Acute Myelogenous Leukemia JOURNAL OF NEURO-OPHTHALMOLOGY Doan, T., Lacayo, N., Fisher, P. G., Liao, Y. J. 2011; 31 (1): 52-53

  View details for DOI 10.1097/WNO.0b013e3181e91174

  View details for Web of Science ID 000287238700013

  View details for PubMedID 20881617

• Giant cell arteritis: immune and vascular aging as disease risk factors ARTHRITIS RESEARCH & THERAPY Mohan, S. V., Liao, Y. J., Kim, J. W., Goronzy, J. J., Weyand, C. M. 2011; 13 (4)

  Abstract

  Susceptibility for giant cell arteritis increases with chronological age, in parallel with age-related restructuring of the immune system and age-induced remodeling of the vascular wall. Immunosenescence results in shrinkage of the naïve T-cell pool, contraction of T-cell diversity, and impairment of innate immunity. Aging of immunocompetent cells forces the host to take alternative routes for protective immunity and confers risk for pathogenic immunity that causes chronic inflammatory tissue damage. Dwindling immunocompetence is particularly relevant as the aging host is forced to cope with an ever growing infectious load. Immunosenescence coincides with vascular aging during which the arterial wall undergoes dramatic structural changes and medium and large arteries lose their pliability and elasticity. On the molecular level, elastic fibers deteriorate and matrix proteins accumulate biochemical modifications. Thus, the aging process impacts the two major biologic systems that liaise to promote giant cell arteritis; the immune system and the vessel wall niche.

  View details for DOI 10.1186/ar3358

  View details for Web of Science ID 000297150200044

  View details for PubMedID 21861860

  View details for PubMedCentralID PMC3239337

• Congenital Achiasma and See-Saw Nystagmus in VACTERL Syndrome JOURNAL OF NEURO-OPHTHALMOLOGY Prakash, S., Dumoulin, S. O., Fischbein, N., Wandell, B. A., Liao, Y. J. 2010; 30 (1): 45-48

  Abstract

  A 29-year-old man with vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal defects, and limb defects (VACTERL) presented with headache, photophobia, and worsening nystagmus. He had near-normal visual acuity and visual fields, absent stereopsis, and see-saw nystagmus. Brain MRI revealed a thin remnant of the optic chiasm but normal-sized optic nerves. Functional MRI during monocular visual stimulation demonstrated non-crossing of the visual evoked responses in the occipital cortex, confirming achiasma. These findings have not previously been reported in VACTERL.

  View details for DOI 10.1097/WNO.0b013e3181c28fc0

  View details for Web of Science ID 000275061500012

  View details for PubMedID 20182207

  View details for PubMedCentralID PMC3550004

• Cytomegalovirus Infection with MRI Signal Abnormalities Affecting the Optic Nerves, Optic Chiasm, and Optic Tracts JOURNAL OF NEURO-OPHTHALMOLOGY Pershing, S., Dunn, J., Khan, A., Liao, Y. J. 2009; 29 (3): 223-226

  Abstract

  A 49-year-old woman who had been immunosuppressed after a renal transplant developed bilateral severe visual loss. Visual acuities were finger counting and hand movements in the two eyes. Both optic nerves were pale. There were no other ophthalmic abnormalities. Brain MRI disclosed marked signal abnormalities involving the optic nerves, optic chiasm, and optic tracts. Cerebrospinal fluid polymerase chain reaction (PCR) was positive for cytomegalovirus. Treatment did not restore vision. Such extensive clinical and imaging involvement of the anterior visual pathway, which has been previously reported with other herpes viruses, illustrates the propensity for this family of viruses to track along axons.

  View details for Web of Science ID 000270048700011

  View details for PubMedID 19726946

• Genetic and acquired neural diseases involving voltage-gated calcium channels 62nd Annual Meeting of the Society-of-General-Physiologists Tsien, R. W., Barrett, C. F., Safa, P., Chen, Y., Boyden, E. S., Liao, Y. J. ROCKEFELLER UNIV PRESS. 2008: 22A–23A

  View details for Web of Science ID 000259634900054

• Anti-Ca2+ channel antibody attenuates Ca2+ currents and mimics cerebellar ataxia in vivo PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Liao, Y. J., Safa, P., Chen, Y., Sobel, R. A., Boyden, E. S., Tsien, R. W. 2008; 105 (7): 2705-2710

  Abstract

  Voltage-gated Ca(2+) channels (VGCCs) are membrane proteins that determine the activity and survival of neurons, and mutations in the P/Q-type VGCCs are known to cause cerebellar ataxia. VGCC dysfunction may also underlie acquired peripheral and central nervous system diseases associated with small-cell lung cancer, including Lambert-Eaton myasthenic syndrome (LEMS) and paraneoplastic cerebellar ataxia (PCA). The pathogenic role of anti-VGCC antibody in LEMS is well established. Although anti-VGCC antibody is also found in a significant fraction of PCA patients, its contribution to PCA is unclear. Using a polyclonal peptide antibody against a major immunogenic region in P/Q-type VGCCs (the extracellular Domain-III S5-S6 loop), we demonstrated that such antibody was sufficient to inhibit VGCC function in neuronal and recombinant VGCCs, alter cerebellar synaptic transmission, and confer the phenotype of cerebellar ataxia. Our data support the hypothesis that anti-VGCC antibody may play a significant role in the pathogenesis of cerebellar dysfunction in PCA.

  View details for DOI 10.1073/pnas.0710771105

  View details for Web of Science ID 000253469900081

  View details for PubMedID 18272482

  View details for PubMedCentralID PMC2268200

• Visual field maps in a subject without an optic chiasm Dumoulin, S. O., Masuda, Y., Horiguchi, H., Dougherty, R. F., Prakash, S., Liao, Y. J., WANDELL, A. PION LTD. 2008: 44–44

  View details for Web of Science ID 000263269900156

• Intracranial pressure returns to normal about a month after stopping tetracycline antibiotics ARCHIVES OF OPHTHALMOLOGY Winn, B. J., Liao, Y. J., Horton, J. C. 2007; 125 (8): 1137-1138

  View details for Web of Science ID 000248590600026

  View details for PubMedID 17698769

• Intracranial hypotension caused by leakage of cerebrospinal fluid from the thecal sac after lumboperitoneal shunt placement JOURNAL OF NEUROSURGERY Liao, Y. J., Dillon, W. P., Chin, C. T., Mcderimott, M. W., Horton, J. H. 2007; 107 (1): 173-177

  Abstract

  The authors describe a newly recognized complication of lumboperitoneal (LP) shunt placement, namely, intracranial hypotension from leakage of cerebrospinal fluid (CSF) through a defect in the lumbar dura created by the shunt catheter. They report on a 47-year-old obese woman with idiopathic intracranial hypertension who underwent routine placement of an LP shunt. Following surgery, her headache became worse. Two radionuclide shunt studies showed no anterograde tracer flow, suggesting either obstruction or a leak. After shunt reservoir manometry indicated low pressure, spinal magnetic resonance (MR) imaging was performed. The MR images revealed a CSF leak from the lumbar thecal sac. A computed tomography (CT) myelogram, performed by injection into the shunt reservoir, confirmed the presence of a leak by showing extravasation of contrast agent into the epidural space. The patient was treated by application of a CT-guided blood patch at the leak site. Catheter-associated CSF leak is an unusual cause of intracranial hypotension that can occur following LP shunt placement. This case report outlines the clinical features of this condition, documents the neuroradiological findings, and demonstrates successful treatment with a blood patch.

  View details for DOI 10.3171/JNS-07/07/0173

  View details for Web of Science ID 000247799900026

  View details for PubMedID 17639890

• Isolated sixth cranial nerve aplasia visualized with fast imaging employing steady-state acquisition (FIESTA) MRI JOURNAL OF NEURO-OPHTHALMOLOGY Pilyugina, S. A., Fischbein, N. J., Liao, Y. J., McCulley, T. J. 2007; 27 (2): 127-128

  Abstract

  An otherwise healthy 12-month-old girl presented for evaluation of reduced abduction of the left eye detected at 6 months of age. The remainder of the examination was unremarkable. A special MRI sequence-fast imaging employing steady-state acquisition (FIESTA)-visualized the right but not the left sixth nerve cisternal segment. This is the first reported use of the MRI FIESTA sequence to diagnose aplasia of the sixth cranial nerve.

  View details for Web of Science ID 000247021200011

  View details for PubMedID 17548999

• An approach to critically ill patients in coma WESTERN JOURNAL OF MEDICINE Liao, Y. J., So, Y. T. 2002; 176 (3): 184-187

  View details for PubMedID 12016243

• Normal cerebellar development but susceptibility to seizures in mice lacking G protein-coupled, inwardly rectifying K+ channel GIRK2 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Signorini, S., Liao, Y. J., Duncan, S. A., Jan, L. Y., Stoffel, M. 1997; 94 (3): 923-927

  Abstract

  G protein-gated, inwardly rectifying K+ channels (GIRK) are effectors of G protein-coupled receptors for neurotransmitters and hormones and may play an important role in the regulation of neuronal excitability. GIRK channels may be important in neurodevelopment, as suggested by the recent finding that a point mutation in the pore region of GIRK2 (G156S) is responsible for the weaver (wv) phenotype. The GIRK2 G156S gene gives rise to channels that exhibit a loss of K+ selectivity and may also exert dominant-negative effects on G(betagamma)-activated K+ currents. To investigate the physiological role of GIRK2, we generated mutant mice lacking GIRK2. Unlike wv/wv mutant mice, GIRK2 -/- mice are morphologically indistinguishable from wild-type mice, suggesting that the wv phenotype is likely due to abnormal GIRK2 function. Like wv/wv mice, GIRK2 -/- mice have much reduced GIRK1 expression in the brain. They also develop spontaneous seizures and are more susceptible to pharmacologically induced seizures using a gamma-aminobutyric acid antagonist. Moreover, wv/- mice exhibit much milder cerebellar abnormalities than wv/wv mice, indicating a dosage effect of the GIRK2 G156S mutation. Our results indicate that the weaver phenotypes arise from a gain-of-function mutation of GIRK2 and that GIRK1 and GIRK2 are important mediators of neuronal excitability in vivo.

  View details for Web of Science ID A1997WG23400028

  View details for PubMedID 9023358

• Heteromultimerization of G-protein-gated inwardly rectifying K+ channel proteins GIRK1 and GIRK2 and their altered expression in weaver brain JOURNAL OF NEUROSCIENCE Liao, Y. J., Jan, Y. N., Jan, L. Y. 1996; 16 (22): 7137-7150

  Abstract

  The weaver (wv) gene (GIRK2) is a member of the G-protein-gated inwardly rectifying potassium (GIRK) channel family, known effectors in the signal transduction pathway of neurotransmitters such as acetylcholine, dopamine, opioid peptides, and substance P in modulation of neurotransmitter release and neuronal excitability. GIRK2 immunoreactivity is found in but not limited to brain regions known to be affected in wv mice, such as the cerebellar granule cells and dopaminergic neurons in the substantia nigra pars compacta. It is also observed in the ventral tegmental area, hippocampus, cerebral cortex, and thalamus. GIRK2 and GIRK1, a related family member, have overlapping yet distinct distributions in rat and mouse brains. In regions where both channel proteins are expressed, such as the cerebral cortex, hippocampus, and cerebellum, they can be co-immunoprecipitated, indicating that they interact to form heteromeric channels in vivo. In the brain of the wv mouse, GIRK2 expression is decreased dramatically. In regions where GIRK1 and GIRK2 distributions overlap, both GIRK1 and GIRK2 expressions are severely disrupted, probably because of their co-assembly. The expression patterns of these GIRK channel subunits provide a basis for consideration of the machinery for neuronal signaling as well as the differential effects of the wv mutation in various neurons.

  View details for Web of Science ID A1996VR62100005

  View details for PubMedID 8929423

• Functional effects of the mouse weaver mutation on g protein-gated inwardly rectifying K+ channels NEURON Slesinger, P. A., Patil, N., Liao, Y. J., Jan, Y. N., Jan, L. Y., Cox, D. R. 1996; 16 (2): 321-331

  Abstract

  The weaver mutation corresponds to a substitution of glycine to serine in the H5 region of a G protein-gated inwardly rectifying K+ channel gene (GIRK2). By studying mutant GIRK2 weaver homomultimeric channels and heteromultimeric channels comprised of GIRK2 weaver and GIRK1 in Xenopus oocytes, we found that GIRK2 weaver homomultimeric channels lose their selectivity for K+ ions, giving rise to inappropriate receptor-activated and basally active Na+ currents, whereas heteromultimers of GIRK2 weaver and GIRK1 appeared to have reduced current. Immunohistochemical localization indicates that GIRK2 and GIRK1 proteins are expressed in the cerebellar neurons of mice at postnatal day 4, at a time when these neurons normally undergo differentiation. Thus, the aberrant behavior of mutant GIRK2 weaver channels could affect the development of weaver mice in at least two distinct ways.

  View details for Web of Science ID A1996TW95700012

  View details for PubMedID 8789947

• DISTINCT MORPHOGENETIC FUNCTIONS OF SIMILAR SMALL GTPASES - DROSOPHILA DRAC1 IS INVOLVED IN AXONAL OUTGROWTH AND MYOBLAST FUSION GENES & DEVELOPMENT Luo, L. Q., Liao, Y. J., Jan, L. Y., Jan, Y. N. 1994; 8 (15): 1787-1802

  Abstract

  The small GTPases of the Rac/Rho/Cdc42 subfamily are implicated in actin cytoskeleton-membrane interaction in mammalian cells and budding yeast. The in vivo functions of these GTPases in multicellular organisms are not known. We have cloned Drosophila homologs of rac and CDC42, Drac1, and Dcdc42. They share 70% amino acid sequence identity with each other, and both are highly expressed in the nervous system and mesoderm during neuronal and muscle differentiation, respectively. We expressed putative constitutively active and dominant-negative Drac1 proteins in these tissues. When expressed in neurons, Drac1 mutant proteins cause axon outgrowth defects in peripheral neurons without affecting dendrites. When expressed in muscle precursors, they cause complete failure of, or abnormality in, myoblast fusion. Expressions of analogous mutant Dcdc42 proteins cause qualitatively distinct morphological defects, suggesting that similar GTPases in the same subfamily have unique roles in morphogenesis.

  View details for Web of Science ID A1994PB10400005

  View details for PubMedID 7958857

• PRESYNAPTIC A-CURRENT BASED ON HETEROMULTIMERIC K+ CHANNELS DETECTED IN-VIVO NATURE Sheng, M., Liao, Y. J., Jan, Y. N., Jan, L. Y. 1993; 365 (6441): 72-75

  Abstract

  A wide variety of voltage-gated K+ channels are involved in the regulation of neuronal excitability and synaptic transmission. Their heterogeneity arises in part from the large number of genes encoding different K+ channel subunits (reviewed in ref. 1). In addition, heterologous expression studies indicate that assembly of distinct subunits into heteromultimeric channels may contribute further to K+ channel diversity. A question has been whether heteromeric K+ channels actually form in vivo, and if so, whether specific combinations of subunits could account for major K+ currents identified in neurons. We present here biochemical evidence that Kv1.4 and Kv1.2, two K+ channel subunits of the Shaker subfamily, co-assemble in rat brain. The Kv1.4/Kv1.2 heteromultimer combines features of both parent subunits, resulting in an A-type K+ channel. Immunocytochemical evidence suggests that the heteromultimers are localized in axons and nerve terminals. We propose that Kv1.4/Kv1.2 heteromultimers may form the molecular basis of a presynaptic A-type K+ channel involved in the regulation of neurotransmitter release.

  View details for Web of Science ID A1993LV64600057

  View details for PubMedID 8361540

• HUMAN FETAL LIVER GAMMA/DELTA T-CELLS PREDOMINANTLY USE UNUSUAL REARRANGEMENTS OF THE T-CELL RECEPTOR DELTA-LOCI AND GAMMA-LOCI EXPRESSED ON BOTH CD4+CD8- AND CD4-CD8- GAMMA/DELTA T-CELLS JOURNAL OF EXPERIMENTAL MEDICINE Wucherpfennig, K. W., Liao, Y. J., Prendergast, M., Prendergast, J., Hafler, D. A., STROMINGER, J. L. 1993; 177 (2): 425-432

  Abstract

  Substantial numbers of both alpha/beta and gamma/delta T cells are present in human fetal liver, which suggests a role of the fetal liver in T cell development. The diversity of fetal liver T cell receptor (TCR) gamma and delta chain rearrangements was examined among both CD4+CD8- and CD4-CD8- gamma/delta T cell clones. In addition, TCR delta chain transcripts from three fetal livers were sequenced after polymerase chain reaction amplification of TCR delta chains with V delta 1 or V delta 2 rearrangements. Five of six fetal liver gamma/delta T cell clones had a V delta 2-D delta 3-J delta 3 gene rearrangement with limited junctional diversity; three of these clones had an unusual CD4+CD8- phenotype. V delta 2-D delta 3-J delta 3 gene rearrangements were also common among both in-frame and out-of-frame transcripts from three fetal livers, indicating that they are the result of an ordered rearrangement process. TCR gamma chain sequences of the fetal liver gamma/delta T cell clones revealed V gamma 1-J gamma 2.3, V gamma 2-J gamma 1.2, and V gamma 3-J gamma 1.1 rearrangements with minimal incorporation of template-independent N region nucleotides. TCR gamma chain rearrangements found in these fetal liver T cell clones were different from those that have been observed among early thymic gamma/delta T cell populations, while similar TCR delta chain rearrangements are found among gamma/delta T cells from both sites. These data demonstrate that the fetal liver harbors gamma/delta T cell populations distinct from those found in the fetal thymus, suggesting that the fetal liver is a site of gamma/delta T cell development in humans. These unusual T cell populations may serve a specific function in the fetal immune system.

  View details for Web of Science ID A1993KJ44100019

  View details for PubMedID 8093893