DIS - Ocular Ageing and Histopathology - Week 1

Question 1

List four major eye diseases are common with age and an approximate percentage of incidence at age 75.

Answer 1

Cataract 50%
Glaucoma 4-8%
AMD - 4-10%
Diabetes - 8-12%

Question 2

At what age does ageing become a major risk factor for eye disease?

Answer 2

> 60

Question 3

Can biological functions be kept going indefinitely if maintained optimally?

Answer 3

No, all biological functions have a finite and natural lifespan, even if optimally maintained

Question 4

What leads to the onset of age-related disease?

Answer 4

Genetic and environmental factors through lifestyle and exposure result in tissue becoming taxed beyond their regenerative capacity

Question 5

Can epigenetic factors slow down or stop diseases?

Answer 5

Slow down yes, but cannot stop them

Question 6

How do cells lose their capacity to replicate? What is the exception?

Answer 6

Telomeres shorten with increasing number of mitoses
Except in stem cells

Question 7

What two external reactions contribute to protein dysfunction?

Answer 7

Increasing amounts of advanced glycation end-products (AGEs)
Increasing UV exposure promotes protein crosslinking (forming aggregates)

Question 8

In what way can tissue dysfunction occur due to exaggerated normal interactions?

Answer 8

Progressive lipid deposition of cholesterol/lipid on elastin, reducing BV elasticity

Question 9

What is a consequence of increased elastase expression and does it increase or decrease with age?

Answer 9

Increased elastase expression with age limits build up of inflexible elastin

Question 10

What is the mechanism behind mitochondrial ageing and what is a consequence of this (2)?

Answer 10

Due to changes in mDNA, resulting in reduced ATP production and increased free radical production

Question 11

What happens to cellular autophagy with age and what is a consequence of this?

Answer 11

Decreases, resulting in a reduced ability to eliminate abnormal byproducts

Question 12

List 7 major ageing changes of the eye (including diseases).

Answer 12

Presbyopia
Age related lens pathology (cataract)
AMD
Primary glaucoma
Ateriosclerotic retinopathy
Vitreous liquefaction
Retinal and corneal dystrophies

Question 13

What is the most common form of ocular pathology encountered by eyecare practitioners?

Answer 13

Age related cataract

Question 14

How many forms does age-related cataract have and when do they occur? List them and briefly describe their appearance.

Answer 14

Nuclear - milky-yellow
Anterior cortical - spokes/wedges
Posterior subcapsular
They often occur together

Question 15

List the mechanism of age-related cataract (for each form).

Answer 15

Nuclear - fibre cell compaction in the nucleus (gamma protein aggregation)
Anterior cortical - fibre cell degeneration, liquefaction, and fragmentation
Posterior subcapsular - cytokine-induced abnormal epithelial proliferation

Question 16

Describe the specific lens changes that occur in age related nuclear cataract including why it appears yellow, changes to the refractive index, and a consequence of this on visiond.

Answer 16

Fibres become more compact, increasing its density, causing the selective absorption of blue light, resulting in a yellowed lens - called bruescence
Denser tissue causes an increase to refractive index, causing a myopic shift

Question 17

What happens to the crystalline deposits with cataracts and what does this cause?

Answer 17

They are reflective, causing glare

Question 18

Describe how the lens cortex contributes to age-related nuclear compaction.

Answer 18

Compartment formation by the cortex results in higher tissue density in the nucleus

Question 19

Give three factors that contribute to nuclear cataract with age (aside from the lens cortex) and their mechanisms.

Answer 19

Tissue density border
-decreased O2 flow to the nucleus
-oxygen pools at the edge (oxidative stress)
-decreased antioxidant access (glutathione)

Light (UV) exposure to O2 generating free-radicals
-fewer antioxidants to control these

Lens proteins reacting with free-radicals
-causes crosslinking

Question 20

What happens to the lens capsule with age (2)? List a consequence of this.

Answer 20

Capsule becomes dense and thins with age, becoming less porous
-reduces inward flux of metabolites needed to support lens fibres

Question 21

What do fragmented lens cells eventually form? Describe how proteins eventually accumulate. What is a consequence of this?

Answer 21

They splinter with protein release and pieces break off (globules)
Liquefied cells form channels in the lens, resulting in the accumulation of proteins, forming a protein gradient, increasing water diffusion and pooling along the fibre channel

Question 22

Describe the structure of a lens fibre and how UV light disrupts it.

Answer 22

Composed of a bilayer with crystalline proteins (trans-membrane and surface)
UV breaks the membrane
Suphydryl bond crosslinking gives infolding and causes aggregation
Forms globules where fibres once were

Question 23

What region of the lens has the thinnest capsule and the highest concentration of TGF-β?

Answer 23

The equator has the thinnest capsule and also the highest concentration of TGF-β.

Question 24

What effect does high concentrations of TGF-β have on lens epithelial cells?

Answer 24

Results in excess cell migration and overgrowth

Question 25

When cells abnormally migrate to the posterior subcapsular area, what do they form?

Answer 25

Bladder cells

Question 26

Is vitreous liquefaction normal?

Answer 26

Yes as part of ageing

Question 27

Is vitreous liquefaction often harmful or innocuous?

Answer 27

Often innocuous

Question 28

List one consequence of vitreous liquefaction that can occur.

Answer 28

Posterior vitreous detachment

Question 29

What is the degree of vitreous liquefaction related to and what disease exacerbates it?

Answer 29

Degree of liquefaction age-related and exacerbated by high myopia

Question 30

What is the vitreous composed of (2)?

Answer 30

Hydrophilic hyaluronan fibres kept apart by water molecules

Question 31

What can high sugar levels lead to?

Answer 31

AGE formation

Question 32

What two things can damage hyaluronan and what does this lead to?

Answer 32

UV and high sugar levels (AGE) damage hyaluronan, leading to water loss and fibril collapse
This results in a loss of gell structure with water pooling

Question 33

What is the association between cataract and vitreous liquefaction? Explain why this occurs in terms of oxygen tension.

Answer 33

Cataract development is lower in eyes with an intact vitreous
Oxygen tension at the lens is greater after vitreous liquefaction

Question 34

Describe what the partial oxygen pressure is like in a gel vs water vitreous and explain how this relates to cataract.

Answer 34

It is low in vitreous as a gel and high as a fluid as its more soluble in fluid vitreous
-it diffuses to the lens, easier if liquefied
-this increases oxidative stress on the lens
-promotes protein crosslinking, leading to cataract formation

Question 35

What are the two forms of AMD and what is the hallmark for each?

Answer 35

Dry - non-exudative
-hallmark is a change in pigmentation
Wet - exudative
-hallmark is ingrowth of blood vessels

Question 36

Describe what pigmentation can be like in dry AMD and what this is called.

Answer 36

Hyper or hypopigmentation
Called geographic atrophy

Question 37

Describe why there is prolific fluid formation in wet AMD, and three things it can lead to. Note which are end-stage.

Answer 37

The ingrowth of blood vessels are a choroidal neovascular membrane, which is leaky, leading to fluid formation
Can lead to:
RPE detachment
Subretinal haemorrhage
Disciform scar formation (end stage)

Question 38

What segment of photoreceptors shed and what happens to them eventually? What happens if they are light damaged? What can form in this case and what can it lead to?

Answer 38

They shed the outer segment discs, which RPE enzymes degrade and recycle
Light damaged components cannot be degraded and recycled
Results in the formation of lipofuscin vesicles, which coalesce to give BLamD

Question 39

Where do BLamD accumulate? What is a consequence of this and what can happen to it eventually (2)? What two componds does it eventually form (note the composition for each)?

Answer 39

Under the basement membrane of the RPE, reducing its capacity to function
They are shed by the RPE to give rise to BlinD (fat) and sub-retinal drusen (protein)

Question 40

What happens to drusen with age? What does this result in (3)?

Answer 40

Cholesterol coats drusen and deposits into the basement mebrane over time, restricting clearance and exchange from the RPE (atherosclerosis)
Choroidal vessels fail to get VEGF support, causing shrinking and atrophy and relative hypoxia

Question 41

What can the formation of drusen promote and how does factor H affect the type of AMD caused?

Answer 41

It promotes an immune response
If genotype is negative for factor H, it is higher, resulting in wet AMD
If the genotype is positive for factor H, there is a low-grade immune response and a hostile environment for the RPE, causing apoptosis, resulting in dry AMD

Question 42

Define BlamD and BlinD and where they form.

Answer 42

BlamD - basal lamina deposit, between the RPE and RPE basal lamina
BlinD - basal linear deposit, between the RPE basal lamina and bruchs membrane

Question 43

What cells appear to have a role in removing BlamD and BlinD deposits? What happens with age?

Answer 43

Glia naturally remove these, but with age, volume of the deposits exceeds clearance capacity

Question 44

What is the current theory on why cholesterol coats drusen deposits?

Answer 44

Deposits in bruchs membrane from choroidal blood - like a generalised atheroma

Question 45

What do studies imply of the reaction of complement proteins to drusen deposits in AMD? Which is unlikely and why?

Answer 45

They bind to drusen, indicating humoral components of the innate system have targetted these ‘abnormal’ cholesterol coated elements
It implies that either:
Drusen causes an inflammatory response
Abnormal inflammation causes drusen
-the second is unlikely as it doesnt fit with the RPE changes

Question 46

Do soft and hard drusen have similar or very different composition?

Answer 46

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