insights on pathophysiology of neuronal damage in glaucoma · pathogenesis of neuronal damage in...
TRANSCRIPT
3/16/2018
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COMTROVERSIES IN PATHOGENESIS OF NEURONAL DAMAGE IN GLAUCOMA
TAREK EID, MD
PROFESSOR OF OPHTHALMOLOGY
TANTA UNIVERSITY1
Topics of Controversy1. Which is damaged first?
• Apoptosis of RGC SOMA• Axonal transport blockade of RGC AXONS
2. What triggers damage?• A neuroinflammation• An ischemic insult• A biomechanical insult
3. CSF pressure & translaminar pressure difference• A real pathogenetic factor? or• An illusion?
4. CNS changes in glaucoma:• Come first (descending degeneration)?• Come second (ascending degeneration)?
5. Human genome & glaucoma inheritance• Where are we now?• Where are we going?
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WHICH IS DAMAGED FIRST?
OR
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Apoptosis of Retinal
ganglion cell
Soma
Axoplasmic flow blockade of
RGC axons
Apoptosis of Retinal ganglion cell bodies (soma)
The cell receives an order to die
DNA FRAGMENTATION
CHROMATIN CONDENSATION
Electron-dense Pyknotic nuclei
(Apoptotic bodies)
AUTOPHAGIC DEGENERAION\
• Neville N, et al Ganglion cell death in glaucoma: What do we really know. Br J Ophthalmol 1999;83:980)
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• RGC loss: 0.4%/yr with ageing• In glaucoma, up to 4% loss/yr• RGC death in glaucoma occurs predominantly through APOPTOSIS• A programmed cell death, autonomous process (cell suicide),
genetically controlled, requires energy
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What initiates RGC death in glaucoma?Loss of neurotrophic
support
• Block of transport of materials within the axons to RGC body neurotrophicdeprivation (especially Brain-derived neurotrophic factor, BDNF) loss of trophic substances from the brain to the RGC for normal survival induction of apoptosis “retrograde degeneration of RGC”
Overexcitation by excitatory amino acids
• Glutamate overstimulatesNMDA receptors and activate nitric oxide synthaseintracellular influx of Ca++ stimulate RGC death via activation of several apoptotic pathways Apoptosis subsequent RGC axonal degeneration
• Role of Ca channel blockers in glaucoma
• Calcins DJ. Prog Retin Eye Res 2012;31:702-9• Takida et al. Brain Res 2007;1184:306-15• Kuribayashi J et al. Brain Res 2010;1362:133-40
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RGC AXONAL TRANSPORT (AXOPLAZMIC FLOW)
• Intracellular movement of molecules and organelles along the axons in an energy-dependant manner
• Orthograde (antegrade) flow (eye to brain, RGC to LGN) • Carries mitochondria, proteins, lipids,
autophagosomes, and synaptic vesicles containing nurotransmitter
• Retrograde flow (brain to eye, LGN to RGC)• Recycles materials back to RGC
• Provides trophic substances from the brain to the RGC for normal survival
Anderson DR. Axonal transport in the retina and optic nerve. In Glasser JS. Ed: Neuroophthalmology Symposium. Bascom Palmer Eye Institute, vol IX, St Louis, CV Mosby, 1977, p 140
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The mechanism
driving axonal
transport may be
sensitive to
translamina pressure
gradient and may not
be able to overcome
increasing hydrostatic
pressure gradient
(high IOP or low CSFP)
(Downs JC, et al.. Optom Vis Sci 2008;85:425-35)
WHAT BLOCKS AXOPLASMIC TRANSPORT (FLOW)?
Retinal ganglion cell axons (green) in the optic nerve only partially transport dyes out of the retina (red) even at early stages in glaucoma
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High IOP► distortion of
laminar beams (esp at the
poles with large pores)
►mechanical injury to
axons► block orthograde
& retrograde flow
Ischemia of ONH & tissue
hypoxia ►mitochondrial
injury ►decrease energy
for axoplasmic flow ►
Axonal transport blockade
and accumulation of
organelles near lamina
WHAT TRIGGERS DAMAGE?8
OR
A neuroinfla-mmation
An ischemic
insult
A biomecha-nical insult
OR
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The Glial Tissue & Neuro-inflammation in Glaucoma
• Sato I, Howel GR. The complex role of neuroinflammation in glaucoma. Cold Spring Harb Percpect Med 2014;4:a017269
9May be a mediator of RGC & axon damage in
glaucoma
Inflammatory reaction & astrogliosis
Transendothelial migration of monocytes into the ONH
Up-regulation of adhesion molecules on endothelium
Activation of proinflammatory mediators (cytokines, complement pathway, tissue necrosis factor, …)
Receptor activation on astrocytes & microglia cells
A trigger (high IOP, injury)
Ocular Ischemia & Glaucoma
• Davis BM, et al. Glaucoma: the retina and beyond. Acta Neuropathol. 2016;132:807-26
Reduced Ocular nlood flow & Perfusion Pressure
Recurrent mild ischemic injury to RGCs
Tissue hypoxia
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Oxidative stress (release of H2O2 &
other reactive oxygen species)
Excitotoxicity (increased sensitivity
to glutamate & excessive stimulation
of NMDA receptors)
Mitochondrial dysfunction
Impede axonal transport with BDNF
depletion
Apoptosis of RGCs soma
Stimulate Ca+ dependent enzymes
Increased influx of intracellular Ca+
NMDA-induced Apoptosis of RGCs soma
Anterograde degeneration of RGC axons & higher visual
pathways
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ONH BIOMECHANICS: STRESS & STRAIN
Orbital (atmospheric) pressure
Retinal ganglion cells
RGC axons
Scleral canal & peripapillary sclera
ONH vasculature
Lamina cribrosaarchitecture & extracellular matrix
PRESSURE EFFECTS(STRESS/FORCES)
STRUCTURE GEOMETRY & MATERIAL PROPERTIES (STRAIN EFFECTS)
Tissue pressure in ON
• Burgoyne CF, Downs JC. Premise and prediction-How optic nerve head biomechanics underlies the susceptibility and clinical behavior of the aged optic nerve head?J Glaucoma 2008;17:318-28
ONH astrocytes & glial tissue
CSF pressure/ fluctuation(TLPD)
IOP magnitude/ fluctuation
Perfusion pressure/fluctuation
Retrobulbartissue pressure
GLAUCOMATOUS OPTIC NEUROPATHY
Neuronal damage (RGC axons and soma
Thinning of RNFL &
Ganglion cell complex
Atrophy of neuroretinal
rim and prelaminar
cupping
ONH Excavation
Posterior deformation of LC &
Laminar cupping
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FORCECSFP/TLPD
IOP
OPP
ONH & PP ScleraRGC axons
Astrocyte activation
ECM remodeling
Scleral canal expansion & laminar
beam tightening
Laminar Capillary blood flow
interruption
Reduced nutrient diffusion from laminar capillaries to RGC axons
Tissue hypoxia, oxidative stress & mitochondrial dysfunctionDecreased energy for axonal
transport
AXONAL TRANSPORT BLOCKADE
APOPTOSIS OF RGCs
BLOCK Neurotrophic
factors to RGCs
Anterograde axonal
degeneration
PRELAMINAR
CUPPING
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IOP-DRIVEN ALTERATIONS OF LC (REMODELING)
DURING EARLY STAGES DURING CHRONIC STAGES
Posterior deformation & outward migration of LC
(LAMINAR CUPPING)
IOP-related stress focused only on LC (the weak spot In sclera)
Increase ECM production & thickening of LC to maintain load-
bearing condition of laminar beams
More rigid sclera prevents scleral canal expansion
IOP elevation/fluctuation, (TLCP Gradient (IOP/CSF)
Less rigid sclera causes scleral canal expansion
Stretching & tightening of lamina cribrosa beams
Resist posterior deformation & Generate strain within laminar
beams
Load bearing capacity of LC is exceeded
Activation of LC cells & astrocytes
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THE CSF & TRANSLAMINAR PRESSURE DIFFERENCE
A real pathogenetic factor
Or
An illusion?
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CSF PRESSURE & TRANS-LAMINAR PRESSURE DIFFERENCE
• A pressure gradient across the LC between intraocular space with a higher IOP and retrobulbar tissue pressure including a lower CSF Pressure
• Abnormal TLPD influences axoplasmic flow of RGC axons
• Correlation of 3 pressures (IOP, CSFP, BP) may suggest a systematic mechanism simultaneously influencing all three of them
• Jonas JB. Role of cerebrospinal fluid pressure in the pathogenesis of glaucoma ActaOphthalmol 2011;89:505-514
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Translamina Pressure Difference: CLINICAL OBSERVATIONS
Diagnosis IOP CSFP TLPD PATHOLOGICAL FINDING
HT-POAG High Normal High Posterior laminar deformation
LT-POAG Normal Low High Posterior laminar deformation
Ocular hypertension
High High Low No change
Papilledema Normal Very high Very low Anterior laminardeformation
Arterial hypertension
High High No change No deformation
Arterial Hypotension
Normal Low High Posterior laminar deformation
• Jonas JB. Role of cerebrospinal fluid pressure in the pathogenesis of glaucoma ActaOphthalmol 2011;89:505-514
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TLPD: CLINICAL OBSERVATIONS
• Jonas JB. Role of cerebrospinal fluid pressure in the pathogenesis of glaucoma ActaOphthalmol 2011;89:505-514
• Limitations of CSF Studies in glaucoma
• Invasive nature of CSF pressure measurement (lumbar puncture)
• It is not clear that the lumber CSFP is directly related to CSFP around the ON in the orbit
• The role of retrolaminar tissue pressure within the ON which may act as a stable pillar of the LC against IOP even with low CSFP in the subarachnoid space around ON
• Hospital-based studies may carry the potential of bias of the diseased sample or the control group (nonglaucomatous neurological pts)
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CNS CHANGES IN GLAUCOMA
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Come second?
An ascending degeneration
Come first?
A descending degeneration
OR
CNS & GLAUCOMA: A Real Change?
• Experimental studies: trans-synaptic degeneration of LGN & V1 after IOP elevation and ON damage
• Postmortem analysis for a glaucoma patient revealed correlation of ON damage, VF defects, and pathological changes in ON, LGB, & VC
• MRI studies in glaucoma patients revealed reduction in ON diameter, optic chiasm height, height & volume of LGN, optic radiation & visual cortex,
• Aditya T et al. Automated morphometry of the visual pathway in primary open-angle glaucoma. Invest Ophthalmol Vis Sci 2011;52:2758-66
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GLAUCOMA AS A NEURODEGENERATIVE DISEASE
• Similarities between glaucoma & ND diseases (Alzheimer & Parkinson’s):
• Selective loss of specific neuron population:
• Alzheimer: loss of hippocampal & cortical neurons memory & cognitive
disorder
• Parkinson’s: loss of nigrostriatal dopaminergic neurons movement
disorder
• Glaucoma: loss of RGC neurons & axons loss of visual functions
• Mode of disease spread by trans-synaptic degeneration in both ND disorders & glaucoma
• Common mechanism of cell injury & death (apoptosis)
•Gupta & Yucel. Glaucoma as a neurodegenrative disease. Cur Opin Ophthalmol 2007;18:110•Tatton W, et al. Hypothesis for a common basis for neuroprotection in glaucoma and Alzheimer disease. Surv Ophthalmol SurvOphthalmol 2003;48:S25•Lin I-C, et al. Glaucoma, Alzheimer’s disease, and Parkinson’s disease: an 8-year population-based follow-up study. PLoS One 7 2014:e108938
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Are brain changes in glaucoma precede or follow RGC degeneration?
•Davis BM, et al. Glaucoma: the retina and beyond. Acta Neuropathol 2016;132:807-827
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HUMAN GENOME & GLAUCOMA INHERITANCE
Where are we now?
And
Where are we going?
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IS GLAUCOMA AN INHERITED DISORDER?
• Strong familial association in many types of glaucoma
• High prevalence of certain types of glaucoma among certain ethnic groups:
• POAG in black population
• PACG in East Asian , Alaska
• PDS & PG in white cuacasian
• Congenital glaucoma in Middle East
• Evident heritability of some parameters associated with glaucoma: high IOP, large cup/disc ratio, steroid responsiveness
• Some forms inherited as mendelian dominant or recessive traits (JOAG)
• Mapping of glaucoma associated genes: JOAG, POAG, PCG, Rieger’ssyndrome
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Advantages of molecular genetic studies
• Understanding disease pathophysiology from its rootcause
• Development of diagnostic tests of the disease based on genetic mutations
• Development of pharmacologic or gene therapy treatment that target the affected gene
• Prevention of disease development may be possible through gene replacement therapy
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Gene Therapy for Glaucoma
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FDA Approves the first true GENE
therapy, LUXTURNA for an inherited
retinal disorder of RPE 65 gene (Jan
2018)
Gene Editing For POAG Proves Successful in Mice
It has implications for persons with mutations in the myocilin
gene which have been reported in 4% of POAG
patients, most notably juvenile
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Conclusions
• Glaucoma is a multifactorial disease with multiple contributing factors to its pathogenesis
• Glaucomatous optic neuropathy at optic nerve head is the hallmark of the disease
• Optic nerve head excavation and retinal ganglion cell and axon atrophy are the main characteristic features of glaucomatous optic neuropathy
• Excavation (cupping) comprises two components: prelaminarcupping (loss of neural tissues) and laminar cupping (posterior deformation of lamina cribrosa)
• All mechanisms of glaucomatous injury of ONH are inseparably intertwined 29
Thank You for your kind attention
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TAREK EID, MD