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Eric Dolinar, Thomas MacPherson, Alex Laliberté, Jolien Van Gaalen, Cindy M L Hutnik, Kathleen Hill; Non-metric Multidimensional Scaling of Electroretinogram Oscillatory Potential Data achieves Early Diagnosis of Retinal Degeneration in a Mouse Model of Mitochondrial Dysfunction. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6188.
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© ARVO (1962-2015); The Authors (2016-present)
Early mechanisms of retinal degeneration (RD) in humans are poorly understood. As a proxy, we study the harlequin (hq) mouse which carries an X-linked Apoptosis-inducing factor mutation leading to mitochondrial dysfunction and subsequent RD. The hqY genotype exhibits severe disease with early onset whereas female carriers (hqX) exhibit delayed onset and moderate disease. We reported parainflammation in hqY retinas with functional deficits at two months and structural deficits by four months of age. We seek a non-invasive, in vivo diagnostic for assessing retinal integrity at high resolution. Components of an electroretinogram (ERG) for four flash intensities (0.63, 4, 10, 25 cd*s/m2) are used to assess retinal layer function. Oscillatory potentials (OPs) are associated with inner plexiform (IPL) and ganglion cell layer (GCL) function. We used OPs to track retinal integrity with hq disease onset and progression.
Two mutant genotypes (hqY and hqX) were compared to gender-matched WT mice at multiple ages relevant to disease progression. A 5th order Butterworth filter (65-300Hz) was applied to smooth OPs and filter out the a and b-wave contribution. Latencies and amplitudes of OPs1-4 (OP parameters) were measured as they model neural activity and response. A Fast Fourier Transform (FFT) converted OP waveforms from time-domain to frequency-domain. The major frequency and total power were recorded. Total energy of the neural-retinal response was calculated by integration of the frequency-domain OP waveform. Due to the longitudinal attritive nature of the study, a non-metric multidimensional scaling analysis (NMDS) was applied.
In NMDS, early hqY disease (2 months) cluster due to energy, power and frequency changes. By three months, the OP parameters influencing distinct hqY NMDS clustering are reduced amplitude and increased latency. With age, hqX retinas show specific NMDS clustering reflective of reduced FFT power and energy. hqX NMDS clustering for OP parameters reflects reduced amplitude and increased latency with disease progression.
We established a sensitive and comprehensive experimental framework using 44 parameters associated with ERG OPs, that with NMDS detects IPL and GCL deficits arising early in hq mitochondrial dysfunction that lead to later photoreceptor losses.
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