Scientific aspects of a ff erent visual dysfunction in neuro-degenerative disease Geo ff rey K Aguirre, MD, PhD K G A A G G G K K A K K LAB K K G A K G G A G A G K A A A
GKA is an inventor on U.S. Patent Application No. 14/852,001, “ROBUST TARGETING OF PHOTOSENSITIVE MOLECULES” Melanopsin foreshadowing
What I won’t talk about: • animal models • diseases other than Alzheimer’s
Q1. What is the primary Optical Coherence Tomography (OCT) change associated with Alzheimer’s disease? A. Thinning of the RPE (retinal pigmented epithelium) B. RPE deformation suggestive of drusen C. Thinning of the RNFL (retinal nerve fiber layer) D. Thinning of macular outer plexiform layer
Q2. Age-related changes in the eye may alter circadian function. Which change is not seen in normal aging? A. “Yellowing" of the lens, decreasing retinal irradiance for short-wave light B. Loss of intrinsically photosensitive retinal ganglion cells C. Senile miosis D. A-beta deposits with the neural retina
AD patients don’t see as well as age-matched controls AD patients don’t sleep as well as age-matched controls
AD patients don’t see as well as age-matched controls Javaid, Fatimah Zara, et al. "Visual and ocular manifestations of Alzheimer’s disease and their use as biomarkers for diagnosis and progression." Frontiers in neurology 7 (2016). AD patients don’t sleep as well as age-matched controls Mattis, Joanna, and Amita Sehgal. "Circadian rhythms, sleep, and disorders of aging." Trends in Endocrinology & Metabolism 27.4 (2016): 192-203.
AD patients don’t see as well as age-matched controls elementary • Reductions in contrast sensitivity and low-luminance acuity • Perimetric deficits, particularly in the inferior field • Impaired motion perception, depth perception, and stereopsis higher cortical [ disputed: color vision deficits ] Reviewed in Javaid et al., 2016 Frontiers in Neurology
Why? • Less light entering eye (pupil and lens) • Retinal degeneration linked • Cortical degeneration The e ff ects of AD are mixed with age-related e ff ects
Reductions in pupil size with age pupil diameter [mm] 44 cd/m 2 8 6 4 2 20 30 40 50 60 70 80 90 age [years] A smaller pupil improves acuity, at the expense of low-light sensitivity Watson and Yellot, 2012 JoV; replotted data from Winn et al., 1994 IOVS
Is pupil function altered in Alzheimer’s disease? • There have been numerous studies of pupil size, dynamics, and pharmacologic response in Alzheimer’s disease • Any systematic e ff ects that do exist have been too small to harness clinically
Is pupil function altered in Alzheimer’s disease? • There have been numerous studies of pupil size, dynamics, and pharmacologic response in Alzheimer’s disease • Any systematic e ff ects that do exist have been too small to harness clinically • No study yet of pupil response by retinal ganglion cell class… Melanopsin foreshadowing
Reductions in lens transmittance with age The crystalline lens darkens and yellows with age, reducing retinal irradiance and spectral content Lerman, Sidney. Radiant energy and the eye. Vol. 1. Macmillan, 1980.
Reductions in lens transmittance with age Melanopsin foreshadowing The crystalline lens darkens and yellows with age, reducing retinal irradiance and spectral content Lerman, Sidney. Radiant energy and the eye. Vol. 1. Macmillan, 1980.
Alzheimer’s pathology amyloid plaques: - composed of A β 42 - non-specific; seen in normal aging - neuritic plaque burden correlates with dementia neurofibrillary tangles: - composed of tau - not seen in normal aging
A specific cataract in Alzheimer’s? A β is present in the lens in Alzheimer’s disease, and has been associated with supra-nuclear cataracts. Goldstein, Lee E., et al. The Lancet 361.9365 (2003): 1258-1265. However…this has not proven to be a useful pre-clinical marker (see work by Greg van Stavern and colleagues) Bei, Ling, et al. Experimental eye research 140 (2015): 117-123.
Why vision deficits in Alzheimer’s disease? • Less light entering eye (pupil and lens) • Retinal degeneration • Cortical degeneration
Retinal nerve fiber layer thinning in AD Multiple OCT studies show excessive thinning of the RNFL in Alzheimer’s, presumably from loss of retinal ganglion cells (although see Lad et al., PLOS One 2018) Coppola, Gianluca, et al. PLoS One 10.8 (2015): e0134750.
Thinning due to Alzheimer’s pathology in the retina? Not clear… • A β collects in the sub-retinal space in normal aging, at the interface of the RPE and photoreceptors • In post-mortem retinae of AD patients, A β deposits within the neural retina can also be found (Koronyo-Hamaoui et al.., NeuroImage 2011; Morgia et al., Annals Neurology 2016) • There is an interest in novel OCT techniques to assess A β burden in patients • OCT–angiography is being studied as well (see talk by Bliss O’Bryhim; Tuesday 8:45 AM) Masuzzo, Ambra, et al. Frontiers in Neurology 7 (2016).
Cortical atrophy and vision changes in AD Cortical dysfunction and atrophy involves the parietal lobes in AD, and the occipital lobes in posterior-variant Alzheimer’s, and can explain many aspects of visual impairment (see work by Victoria Pelak) Rosenbloom, M. H., et al. Neurology 76.21 (2011): 1789-1796.
Why vision deficits in Alzheimer’s disease? • Less light entering eye (pupil and lens) • Retinal degeneration linked • Cortical degeneration
a b LE RE c RE LE At the initial visit 24 months Goto, Katsutoshi, et al. Graefe's Archive for Clinical and Cowey, Alan, et al., Brain 134.7 (2011): 2149-2157. Experimental Ophthalmology 254.4 (2016): 745-756. It is well established that V1 cortical lesions cause trans-synaptic degeneration of retinal ganglion cells (see recent work by Vivek Patel)
Multivariable-adjusted estimated mean change in GC-IPL and RNFL thicknesses (95%CI) per standard deviation change in MRI markers. GC-IPL thickness RNFL thickness (95%CI) ( � m) * (95%CI) ( � m) *, † Per SD decrease in occipital lobe Grey + white matter volume − 1.77 ( − 6.55, 0.01) − 1.87 ( − 4.44. 0.69) Grey matter volume − 1.78 ( − 3.20, − 0.36) − 1.72 ( − 3.79, 0.34) White matter volume 0.07 ( − 1.68, 1.81) − 0.27 ( − 2.79, 2.25) Per SD decrease in temporal lobe Grey + white matter volume − 3.45 ( − 5.40, − 1.49) − 2.70 ( − 2.61, 0.21) Grey matter volume − 2.94 ( − 4.46, − 1.41) − 2.56 ( − 4.85, − 0.27) White matter volume − 0.55 ( − 2.57, 1.46) 0.14 ( − 2.76, 3.05) Per SD decrease in frontal lobe Grey + white matter volume 0.05 ( − 2.67, 2.76) 1.16 ( − 2.72, 5.03) Grey matter volume − 0.34 ( − 3.20, 1.53) 0.59 ( − 2.09, 3.26) White matter volume 0.81 ( − 1.51, 3.14) 0.56 ( − 2.69, 3.82) Retinal thinning in aging is proportional to the degree of cortical gray matter thinning specifically in the occipital and temporal lobes (see work by Michael Ward) Ong, Yi-Ting, et al. Neuroscience letters 584 (2015): 12-16.
AD patients don’t see as well as age-matched controls AD patients don’t sleep as well as age-matched controls
AD patients don’t sleep as well as age-matched controls normal Actigraphy disrupted Sleep becomes fragmented early in AD, with disruption of normal circadian photoentrainment La Morgia, Chiara, et al. Frontiers in Neurology 8 (2017): 162. La Morgia, Chiara, et al. Annals of neurology 79.1 (2016): 90-109.
Why? • Less light entering eye (particularly short wavelength) • Retinal degeneration Melanopsin time
A small portion of retinal ganglion cells contain melanopsin cones bipolars RGCs ~1-3% of RGCs express the photopigment melanopsin, rendering them intrinsically photosensitive (ipRGCs) The ipRGCs project to the supra-chiasmatic nucleus and mediate photoentrainment of the circadian rhythm (among many other functions)
Melanopsin S M L Sensitivity 400 500 600 700 800 Wavelength [nm] Melanopsin has peak sensitivity for short-wavelength (480 nm) light
young Transmittane Lens old Melanopsin S M L Sensitivity 400 500 600 700 800 Wavelength [nm] The lens “yellows” with age and blocks short wavelength light from reaching the retina
Retinal cell loss The number of ipRGCs declines with age Esquiva, Gema, et al. Frontiers in Aging Neuroscience 9 (2017).
Retinal cell loss People with AD have a further reduction in ipRGCs compared to age-matched controls La Morgia, Chiara, et al. Annals of neurology 79.1 (2016): 90-109.
Retinal cell loss Retinal degeneration A subtlety is that this loss appears to have occurred and then stabilized before the age of 50. La Morgia, Chiara, et al. Annals of neurology 79.1 (2016): 90-109.
La Morgia, Chiara, et al. Annals of neurology 79.1 (2016): 90-109. C A β deposits (red) are found within and around the ipRGCs (stained green) in Alzheimer’s retinae Retinal cell loss
A functional correlate of ipRGC loss? Don’t know yet… Silent-substitution isolation of melanopsin Post-illumination pupil response (PIPR) 0 % pupil Δ 13 seconds –30 indirect measure direct measure There are methods to measure the melanopsin contribution to the pupil response. Gamlin PDR, et. al. Vision Res. 2007;47(7):946-954 Spitschan, Manuel, et al. PNAS 114.46 (2017): 12291-12296
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