arvo 2015 - a pinhas
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Macular Mitochondrial
Flavoprotein Autofluorescence
in Eyes with
Primary Open Angle Glaucoma
Alexander Pinhas1, 2, Moataz Razeen MD1, Theodora Danias1,3, Nikhil
Menon1,2, Nadim Choudhury1,2, Matthew Field4, Joseph Panarelli MD1, Richard B
Rosen MD1
1. New York Eye and Ear Infirmary of Mount Sinai, New York, NY, USA 2. Icahn School of Medicine at Mount Sinai, New York, NY, USA3. Staten Island Technical High School, Staten Island, NY, USA
4. University of Michigan, Ann Arbor, MI, USA
2
Marrus Family Foundation, Bendheim‐Lowenstein Family Foundation, Wise Family Foundation, RD & Linda Peters Foundation, Edith C. Blum Foundation, Chairman's Research Fund of the New York Eye and Ear Infirmary, and an Unrestricted Grant from Research to Prevent Blindness
Acknowledgments
Commercial Relationship DisclosureA Pinhas: NoneM Razeen: NoneT Danias: NoneN Menon: NoneN Choudhury: NoneM Field: OcuSciences: Code E (Employment)J Panarelli: NoneR Rosen: Clarity: Code C (Consultant); Opticology: Code I (Personal Financial Interest); OD-OS: Code C (Consultant); Carl Zeiss Meditech: Code C (Consultant); Optovue: Code C (Consultant); Advanced Cellular Technologies: Code C (Consultant)
Primary Open Angle Glaucoma (POAG): Screening and Assessment
In POAG, intra-ocular pressure (IOP) and structural and functional indices of disease1 are often not sensitive enough to detect its earliest onset, or short-term response to treatment.2
3
1. Preferred Practice Pattern, Primary Open-Angle Glaucoma, American Academy of Ophthalmology 2010.2. Bettin & Matteo. Ophthalmic Res. 2013;50(4):197-208.
Thus, the search for more sensitiveassessment tools continues!
Mitochondrial Metabolic Dysfunction1-3
▶ In retinal ganglion cell (RGC) somas and axons, reactive oxygen species (ROS) cause damage to the mitochondrial oxidative phosphorylation machinery (OxPhos) over time
4
1. Osborne. Exp Eye Res. 2010.2. Munemasa et al. J Neurochem. 2010.3. Zhang et al. J Biol Chem. 1990.
Image borrowed from the Medical Research Council<www.mrc-mbu.cam.ac.uk>
▶ Accumulated damage causes a hypo-metabolic state with decreased ATP production, and with secondary insults leads to RGC dysfunction and eventual death
5
Can We Non-Invasively Measure Mitochondrial Metabolic Dysfunction?
Flavoprotein Fluorescence (FPF)
6
Image borrowed from <www.pixgood.com>
Oxidized (e-1 poor)
Reduced (e-1 rich)
▶ Flavoproteins are redox cofactors serving as temporary place holders for electrons
Flavoprotein Fluorescence (FPF)
7
Image borrowed from <www.pixgood.com>
Oxidized (e-1 poor)
Reduced (e-1 rich)
▶ Exhibit autofluorescence, but only in the oxidized state
▶ Flavoproteins are redox cofactors serving as temporary place holders for electrons
Flavoprotein Fluorescence (FPF)
8
Image borrowed from <www.pixgood.com>
▶ Thus, in POAG, FPF should be observed to increase
▶ Oxidized:reduced ratio of metabolically-active flavoproteins increases with decreased OxPhos activity1
Oxidized (e-1 poor)
Reduced (e-1 rich)
1. Field et al. Exp Eye Res. 2011.
OcuSciencesTM OcuMet BeaconTM:
9
RMA is coupled with a standard slit lamp chin rest
▶ Retinal Metabolic Analysis (RMA) Machine Measures Retinal FPF in Vivo
10
▶ 5 consecutive images using blue excitation light
▶ Shone onto ~15°-circular region of the retina
11
▶ Flavoproteins fluoresce in the green after excitation
▶ Narrow bandpass filter (± 2-3nm) to maximize and optimize FPF signal and minimize other fluorescent signals
12
Intensity (Gray Scale Units)
Num
ber
of P
ixel
s
▶ RMA output is number of pixels versus intensity
▶ FPF score is the mean of the histogram
▶ FPF scores from 5 consecutive images are averaged
The RMA has shown that macular FPF increases with…
13
▶ Oxidative stress and apoptosis1
▶ Age2
▶ Diseases such as diabetes mellitus and age-related macular degeneration2-6
1. Field et al. Exp Eye Res. 2011.2. Elner et al. Trans Am Ophthalmol Soc. 2008.3. Elner et al. Arch Ophthalmol. 2008.4. Field et al. Arch Ophthalmol. 2008.5. Field et al. Retina. 2009 Sep. 6. Field et al. Ophthalmic Surg Lasers Imaging.
2012.
Purpose of This Pilot Study
▶ To measure macular and optic disc FPF in eyes with POAG
▶ To compare macular FPF to healthy age-matched controls
▶ To correlate POAG FPF with clinical indicators of disease
14
Methods: Recruitment Criteria
15
▶ Inclusion criteria– Diagnosis of POAG*– BCVA of 20/60 or better, with good central fixation– Pupil dilation of at least 5 mm– Clear phakic lens and clear media
▶ Exclusion criteria– Pre-existing retinal or optic nerve disease other than
POAG– POAG surgery
*All POAG eyes imaged were using IOP-lowering medications.
Subjects Imaged
16
n # of eyes Mean Age (yrs)
Age Range (yrs)
Healthy Controls 45 90 54 40-66
POAG 15 25 59 42-68
▶ One eye per subject was used in data analysis▶ Both eyes were used only in determining signal
asymmetry between fellow eyes– Both eyes were imaged in 10/15 POAG patients and
in all 45 healthy controls
Clinical Indices of Disease
17
▶ From patient chart– Number of medications (#meds)– BCVA– IOP– Humphrey 24-2 visual fields (VF)
• mean deviation (MD)• pattern standard deviation (PSD)
▶ Spectralis SD-OCT before RMA imaging– Cup-to-disc ratio (CDR)– Circumferential peripapillary RNFL thickness– Macular thickness
Results: Macular FPF in POAGvs. Controls
18
Macular FPF of 15 POAG eyes was significantly higher than that of 45 age-matched healthy control eyes.Results are reported as group averages ± SD.
Healthy Controls (n=45) POAG (n=15)0
100
200
300
400
500
600M
acu
lar
FP
F480±134
403±94
t(58)=2.46, p=0.0170
40-49 50-59 60-690
100
200
300
400
500
600
700
Healthy ControlsPOAG
Decade of Life (yrs)
Mac
ula
r F
PF
Macular FPF By Decade of Life
19
When stratified by decade of life, significant difference* in FPF between POAG and healthy control eyes was observed only in the 60-69yo group (611±62.3 versus 489±70.8, t(19)=3.86, p=0.0010).
*
Macular FPF Between Fellow Eyes
20
There is greater variability in macular FPF signal asymmetry between fellow eyes of 10 POAG patients compared to 45 healthy controls.
Healthy Controls (n=45)
POAG (n=15)0
2
4
6
8
10
12
14%
Dif
fere
nce
13.1±10.6%
6.0±5.8%
t(53)=2.96, p=0.0046
Macular versus Optic Disc FPF
21
In POAG eyes, FPF was often greater at the optic disc compared to the macula, but not significantly. We do not have optic disc FPF data for healthy
age-matched controls for comparison
Macular FPF (n=15) Optic disc FPF (n=14)0
100
200
300
400
500
600F
PF
536±151480±134
t(27)=1.06, p=0.299
Correlating FPF WithClinical Indices of Disease
22
So far, we have not found statistically-significant correlation between clinical indices of disease and FPF signal in POAG (for either macular or optic disc FPF).
Case: A 61yo Male with POAG
23
#Meds :BCVA :
IOP :CDR :
Peripapillary RNFL :Macular FPF :
Optic Disc FPF :
2
20/40 15 mmHg 0.55 107 µm 550±7.69 569±21.1
#Meds :BCVA :
IOP :CDR :
Peripapillary RNFL :Macular FPF :
Optic Disc FPF :
2
20/100 13 mmHg 0.99 38.8 µm 695±15.1 828±3.21
MD: -4.74PSD: 5.64
MD: -30.8PSD: 3.37
325µm
OD OS
MacularThickness
: 295µmMacularThickness
:
Case: A 61yo Male with POAG
24
Macular FPF:550±7.69
Macular FPF:695±15.1
OD OS
#Meds :BCVA :
IOP :CDR :
Peripapillary RNFL :Macular FPF :
Optic Disc FPF :
2
20/40 15 mmHg 0.55 107 µm 550±7.69 569±21.1
#Meds :BCVA :
IOP :CDR :
Peripapillary RNFL :Macular FPF :
Optic Disc FPF :
2
20/100 13 mmHg 0.99 38.8 µm 695±15.1 828±3.21
MD: -4.74PSD: 5.64
MD: -30.8PSD: 3.37
Case: A 61yo Male with POAG
25
OD OS
288µmOptic DiscThickness
: 190µmOptic DiscThickness
:
#Meds :BCVA :
IOP :CDR :
Peripapillary RNFL :Macular FPF :
Optic Disc FPF :
2
20/40 15 mmHg 0.55 107 µm 550±7.69 569±21.1
#Meds :BCVA :
IOP :CDR :
Peripapillary RNFL :Macular FPF :
Optic Disc FPF :
2
20/100 13 mmHg 0.99 38.8 µm 695±15.1 828±3.21
MD: -4.74PSD: 5.64
MD: -30.8PSD: 3.37
Case: A 61yo Male with POAG
26
Optic Disc FPF:569±21.1
Optic Disc FPF:828±3.21
OD OS
#Meds :BCVA :
IOP :CDR :
Peripapillary RNFL :Macular FPF :
Optic Disc FPF :
2
20/40 15 mmHg 0.55 107 µm 550±7.69 569±21.1
#Meds :BCVA :
IOP :CDR :
Peripapillary RNFL :Macular FPF :
Optic Disc FPF :
2
20/100 13 mmHg 0.99 38.8 µm 695±15.1 828±3.21
MD: -4.74PSD: 5.64
MD: -30.8PSD: 3.37
Conclusions
27
▶ FPF measured by the RMA appears sensitive to the increased mitochondrial dysfunction in POAG.
▶ Search continues for indices of disease that FPF may correlate with– Although lack of correlation should not discount FPF
as useful
Future Studies
28
▶ Expanding current POAG FPF database
▶ Creating an age-matched normative FPF database at the optic disc
▶ Exploring the use of RMA for earlier POAG diagnosis
▶ Longitudinal studies using RMA for assessing adequacy of therapy in POAG, including substances that enhance mitochondrial function
Thank You From The Team!
29Richard B Rosen MDJoseph Panarelli MD
Moataz Razeen MD
Matthew Field
Theodora Danias Nadim Choudhury
Nikhil Menon
John Choi
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