Y. Joyce Liao, MD, PhD

All Publications

• 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 DOI 10.1016/j.jneumeth.2018.10.038

  View details for PubMedID 30389488

• 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 DOI 10.1080/02713683.2018.1508726

  View details for PubMedID 30273053

• 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 DOI 10.1371/journal.pone.0191005

  View details for Web of Science ID 000423412500032

  View details for PubMedID 29364897

  View details for PubMedCentralID PMC5783375

• 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 DOI 10.1371/journal.pone.0203924

  View details for PubMedID 30403759

• 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

• 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

• 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

• Should Antiviral/Anti-Varicella Zoster Virus Treatment Be Used in Patients With Giant Cell Arteritis? Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society Liao, Y. J., Kedar, S. 2018

  View details for DOI 10.1097/WNO.0000000000000664

  View details for PubMedID 29877905

• 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 DOI 10.1016/j.ajoc.2018.02.009

  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 DOI 10.1038/s41433-018-0088-1

  View details for PubMedID 29695760

• Anti-interleukin-6 antibody as treatment for giant cell arteritis Journal of Neuro-Ophthalmology Liao, Y. J. 2018
• 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

• 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
• The microvascular niche instructs T cells in large vessel vasculitis via the VEGF-Jagged1-Notch pathway. Science translational medicine Wen, Z., Shen, Y., Berry, G., Shahram, F., Li, Y., Watanabe, R., 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 DOI 10.1126/scitranslmed.aal3322

  View details for PubMedID 28724574

• 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

  View details for PubMedCentralID PMC4902281

• 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

• 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

• 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

• 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
• 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
• 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

• 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

• 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 Web of Science ID 000179442400012

  View details for PubMedID 12016243

  View details for PubMedCentralID PMC1071711

• 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