Scientific aspects of a ff erent visual dysfunction in - - PowerPoint PPT Presentation

Scientific aspects of afferent visual dysfunction in neuro-degenerative disease

Geoffrey K Aguirre, MD, PhD

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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 AD patients don’t sleep 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). 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

• Reductions in contrast sensitivity and low-luminance acuity
• Perimetric deficits, particularly in the inferior field
• Impaired motion perception, depth perception, and stereopsis

Reviewed in Javaid et al., 2016 Frontiers in Neurology

[ disputed: color vision deficits ] elementary higher cortical

Why?

• Less light entering eye (pupil and lens)
• Retinal degeneration
• Cortical degeneration

linked The effects of AD are mixed with age-related effects

Reductions in pupil size with age

A smaller pupil improves acuity, at the expense of low-light sensitivity age [years] pupil diameter [mm]

Watson and Yellot, 2012 JoV; replotted data from Winn et al., 1994 IOVS

20 30 40 50 60 70 80 90 8 6 4 2

44 cd/m2

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 effects that do exist have been too

small to harness clinically

• There have been numerous studies of pupil size,

dynamics, and pharmacologic response in Alzheimer’s disease

• Any systematic effects that do exist have been too

small to harness clinically

• No study yet of pupil response by retinal ganglion cell

class…

Melanopsin foreshadowing

Is pupil function altered in Alzheimer’s disease?

Reductions in lens transmittance with age

Lerman, Sidney. Radiant energy and the eye. Vol. 1. Macmillan, 1980.

The crystalline lens darkens and yellows with age, reducing retinal irradiance and spectral content

Reductions in lens transmittance with age

Lerman, Sidney. Radiant energy and the eye. Vol. 1. Macmillan, 1980.

The crystalline lens darkens and yellows with age, reducing retinal irradiance and spectral content

Melanopsin foreshadowing

Alzheimer’s pathology amyloid plaques:

• composed of Aβ42
• non-specific; seen in normal aging
• neuritic plaque burden correlates with dementia
• composed of tau
• not seen in normal aging

neurofibrillary tangles:

A specific cataract in Alzheimer’s?

Goldstein, Lee E., et al. The Lancet 361.9365 (2003): 1258-1265.

Aβ is present in the lens in Alzheimer’s disease, and has been associated with supra-nuclear cataracts. 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

Coppola, Gianluca, et al. PLoS One 10.8 (2015): e0134750.

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)

Masuzzo, Ambra, et al. Frontiers in Neurology 7 (2016).

Thinning due to Alzheimer’s pathology in the retina? Not clear…

• Aβ collects in the sub-retinal space in normal aging, at

the interface of the RPE and photoreceptors

• In post-mortem retinae of AD patients, Aβ 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

Aβ burden in patients

• OCT–angiography is being studied as well (see talk by

Bliss O’Bryhim; Tuesday 8:45 AM)

Rosenbloom, M. H., et al. Neurology 76.21 (2011): 1789-1796.

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)

Why vision deficits in Alzheimer’s disease?

• Less light entering eye (pupil and lens)
• Retinal degeneration
• Cortical degeneration

linked

It is well established that V1 cortical lesions cause trans-synaptic degeneration of retinal ganglion cells (see recent work by Vivek Patel)

At the initial visit 24 months RE LE

a c b

RE LE

Goto, Katsutoshi, et al. Graefe's Archive for Clinical and Experimental Ophthalmology 254.4 (2016): 745-756. Cowey, Alan, et al., Brain 134.7 (2011): 2149-2157.

Ong, Yi-Ting, et al. Neuroscience letters 584 (2015): 12-16.

Multivariable-adjusted estimated mean change in GC-IPL and RNFL thicknesses (95%CI) per standard deviation change in MRI markers. GC-IPL thickness (95%CI) (m)* RNFL thickness (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)

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

Sleep becomes fragmented early in AD, with disruption of normal circadian photoentrainment

La Morgia, Chiara, et al. Frontiers in Neurology 8 (2017): 162.

Actigraphy disrupted normal

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 has peak sensitivity for short-wavelength (480 nm) light

S M Melanopsin L 500 400 600 700 800

Wavelength [nm] Sensitivity

The lens “yellows” with age and blocks short wavelength light from reaching the retina

S M Melanopsin L 500 400 600 700 800

Wavelength [nm] Transmittane Sensitivity Lens young

• ld

The number of ipRGCs declines with age

Esquiva, Gema, et al. Frontiers in Aging Neuroscience 9 (2017).

Retinal cell loss

La Morgia, Chiara, et al. Annals of neurology 79.1 (2016): 90-109.

People with AD have a further reduction in ipRGCs compared to age-matched controls

Retinal cell loss

La Morgia, Chiara, et al. Annals of neurology 79.1 (2016): 90-109.

A subtlety is that this loss appears to have occurred and then stabilized before the age of 50.

Retinal degeneration Retinal cell loss

La Morgia, Chiara, et al. Annals of neurology 79.1 (2016): 90-109.

Aβ deposits (red) are found within and around the ipRGCs (stained green) in Alzheimer’s retinae

C

Retinal cell loss

There are methods to measure the melanopsin contribution to the pupil response.

Post-illumination pupil response (PIPR) indirect measure Silent-substitution isolation of melanopsin direct measure

–30 % pupil Δ 13 seconds

Spitschan, Manuel, et al. PNAS 114.46 (2017): 12291-12296

A functional correlate of ipRGC loss? Don’t know yet…

Gamlin PDR, et. al. Vision Res. 2007;47(7):946-954

The short-wavelength pupil response is not proportionately decreased in normal aging, despite lens changes. Measurements have not yet been reported for Alzheimer’s…

AV Rukmini, et al. Scientific Reports. 7 (2017): 43832.

A functional correlate of ipRGC loss? Don’t know yet…

| 7:43832 | DOI: 10.1038/srep43832

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