CNS pathology - Neurodegenrative Diseases

Question 1

What is the definition of ND?

Answer 1

‘Types of disease in which neurons &/or glial cells of the central (or peripheral) nervous system cease functioning or die’

Question 2

What are the general features / symptoms of ND?

Answer 2

Associated symptoms usually first appear at older ages (e.g., after 65 years) & get progressively worse over time, with available treatments providing some (variable) relief but no ultimate cure

Question 3

Why is the differential diagnosis problematic?

Answer 3

: Symptoms can be quite similar in different diseases, with their definitive diagnosis once reliant on post-mortem examinations of the underlying cellular pathology. New genetic analyses or neuro-imaging methods can now be used to provide such diagnoses in some selected cases or particular disease processes

Question 4

What are the most common CNS diseases by classification ?

Answer 4

Cognitive Impairment/Dementia
Alzheimer’s Disease*
Lewy Body Disease*

Motor/Movement  Impairment
Parkinson’s Disease*
Huntington’s Chorea
Amyotrophic Lateral Sclerosis
Friedreich Ataxia

Question 5

What are the 3 diseases that increase in prevalence with age & are associated with ocular problems ?

Answer 5

Parkinson’s Disease*
Alzheimer’s Disease*
Lewy Body Disease*

Question 6

What are the causes of CNS ND?

Answer 6

Genetics (rarely primary)

Autosomal dominant, with full penetrance
Huntington’s Chorea; early-onset Alzheimer’s Disease
+ ‘Risk factor’ genes, with incomplete penetrance (susceptibility)

Environmental (more often primary)
But mostly unknown causes = sporadic or idiopathic
Except for Head injury/brain trauma
Dementia Pugilistica (boxers)
Chronic §Traumatic Encephalopathy (footballers)

Question 7

Alzeihmer disease case :

Answer 7

First described by German psychiatrist & neuroanatomist Alois Alzheimer in 1906.

Case study of early-onset (pre-senile) dementia in a 50-year old woman suffering confusion, spatial dis-orientation, memory loss, paranoid delusions & aggression.

Post-mortem revealed cortical atrophy & 2 characteristic degenerative neuron losses in her brain: amyloid-beta plaques and neurofibrillary tangles

Question 8

What is the gross neuropathology of AD?(Alzeihmers Disease)

Answer 8

by Brian atrophy
Neuron loss in Cerebral Cortex grey matter leading to reduced gyral thickness tissue& wide sulci + enlarged ventricles general brain atrophy

Question 9

What is Definitive Cellular Neuropathology of AD (Alzeihmers Disease)
based on ?

Answer 9

ceulluar neuropathology

Deposition of [1] amyloid- (Aβ) protein forming extracellular ‘plaques’ (5-200 m diameter) & [2] toxic clumps intracellular hyperphosphorylated tau protein as ‘neurofibrillary tangles’:
Causes: Neuron cell death by apoptosis

Question 10

What is the new combined neuroimaging methods for diagnosis of AD invivo?

Answer 10

Temporo-Parieto-Frontal atrophy (blue) in AD associated with selective fluorodeoxyglucose (FDG) hypo-metabolism (green) and amyloid & tau marker deposition in the same areas, with generalized reactive glial inflammatory translocator protein (TSPO) & synapse (SV2A) loss, revealed by protein binding of radiolabelled markers with Positron Emission Tomography (PET)

Question 11

What re the causes of AD?

Answer 11

Causes: Mainly sporadic/idiopathic, but…

Early-onset, ~10% cases hereditary, autosomal dominant (APP, Presenelin-1 or -2) or risk factor (APOE-e4) genes

Question 12

What is the prevalence of the AD?

Answer 12

Prevalence: 1 in 15 adults
~1,000,000 cases in UK (200,000 new cases/year)
20% pre-senile, 80% aged 65 years or older

Question 13

What is the progression of AD?

Answer 13

intellectual functions gradually deteriorate
New/old memory impairment, spatial disorientation
Visual agnosias, paranoid delusions>hallucinations, dysphasias
Immobility, incontinence, apathy, dysphagias

Question 14

What are the AD genes

Answer 14

Amyloid Precursor Protein (APP): chr 21, autosomal dom’t
APP is trans-membrane, role in neuron growth & repair
But accumulates & extruded as extra-cellular plaques; toxic to neurons

Presenilin (PS) -1 & -2: chr 14 & 1, autosomal dom’t
PS proteins part of gamma secretase enzyme complex, role in
APP clearance, but incomplete digestion; so accumulates and forms

APOE-e4: chr 19, risk factor, 50% AD cases mutation both genes
Apolipoprotein E, like PS, role in the APP clearance, but also in
Packaging cholesterol: Mediterranean diet reduces the risk!

Question 15

How is AD affect the eye?

Answer 15

cause Cataract: Aβ-protein deposited in lens
Early marker? Prior to dementia, but correlates with brain plaques

affect Retina: extension of the CNS, Aβ-plaques
All cell body layers (ONL, INL, GCL)
RGC degeneration & thinning of NFL, correlating with
Pattern ERG P50 wave: reduced amplitude, increased latency
Inflammatory responses, with microglia reactivity

cause Vascular damage: amyloid angiopathy, Aβ-protein deposited
In retinal blood vessels, reduced circulation

Question 16

How does the AD affect the retina ?

Answer 16

Aβ-plaques (brown) in all 3 cell layers and deposit in capillary (bv) wall - check slide
Superior & inferior peripheral retinal quadrants most affected (why? unknown) with associated VF deficits (confused with glaucoma)

Question 17

How does AD affect Visual Dysfunctions?

Answer 17

Also different Neuron susceptibilities to degeneration:

[1] SW/blue cones: tritan colour deficits

[2] Parasol/Magno RGCs: reduced contrast & motion sensitivity

[3] Melanopsin RGCs: circadian disturbances & reduced/slower pupillary light responses

Primary (V1) Visual Cortex rarely atrophic, but
[4] InferoTemporal Cortex: object & face agnosias

[5] Posterior Parietal Cortex: Delayed, slow & inaccurate saccadic and smooth pursuit eye movements + visuo-spatial disorientation

Question 18

What is Posterior Cortical Atrophy (PCA) ?

Answer 18

PCA may be a relatively rare (prevalence unknown) variant of AD with Aβ plaques & tangles selectively affecting the Occipital Cortex

Whereas……atrophy of the Frontal, Temporal & Parietal lobes is most common in AD, with less Occipital involvement

Question 19

How does PCA affect AD?

Answer 19

Onset of PCA is typically early (ages 50-65 years). Because neurodegeneration extends into the Occipito-Temporal (LOC, Fusiform Face Area) & Occipito-Posterior Parietal Cortex (PEF, SPL), Px’s typically have more marked visual disturbances – in acuity, visual fields & agnosias with hallucinations, in reading, hand & eye movements - than in AD

Question 20

What is Lewy Body Dementia (LBD)?

Answer 20

First described in 1912 by Frederich Lewy, a German neurologist working with Alzheimer

Post-mortem brains of patients with dementia, some with amyloid plaques & tau tangles, but also abnormal intracellular inclusions in degenerating neurons = the definitive characteristic of the disease

Question 21

What are the LBD: Cause, Symptoms & Risks?

Answer 21

10-15% of dementia cases in people aged >65 years
3rd most common after AD & vascular dementia
Widespread brain neuron death by apoptosis
Cognitive impairment, depression, insomnia
Attentional deficits, autonomic dysfunctions
Visual Hallucinations (less than PCA, more than AD)

Lewy bodies = accumulated alpha-synuclein protein
Normally regulates vesicle trafficking & transmitter release
Bodies = toxic clumped misfolded α-synuclein ‘protofibrils’
Cause is unknown/sporadic: male > female prevalence

Question 22

What is Parkinsons? (Parkinsons disease : PD)

Answer 22

First described in 1817 by James Parkinson, an English surgeon & anthropologist, as the ‘Shaking Palsy’ or paralysis agitans

Question 23

What are the symptoms of movement disorder ?

Answer 23

Limbs: 
4-8 Hz tremor (worse when anxious)
rigidity of muscle tone
difficulty initiating movement (akinesia)
movements slow (bradykinesia) with a shuffling gait
Hand: 
‘pill-rolling’ action at rest
Face:
Immobile, expressionless

Question 24

What is Definitive Neuropathology of PD associated with ?

Answer 24

Apoptotic death of dopamine (& melanin) producing neurons in the substantia nigra (SN) of the basal ganglia (BG) base of midbrain, which normally make excitatory connections with other BG neurons in the caudate & putamen nuclei via nigro-striatal pathways

Question 25

What are the Causes, Prevalence, Progression of PD?

Answer 25

Causes: mainly sporadic/idiopathic
But ~15% family history, several genes including αSNC

Prevalence: 1 in 350 adults
~150,000 cases in UK (10,000 new cases/year)
Increases with age, ~85% cases aged 65 years or older

Progression: mobility gradually deteriorates
With 50-75% developing ‘Parkinson’s Dementia’ after 10 years
Dementia similar to LBD: with visual hallucinations>paranoid delusions
Pathology: more generalized reduced excitatory dopaminergic activity, with Lewy Bodies, in Cerebral Cortex & other brain regions
Debate: is PD a special expression of LBD?

Question 26

What are the treatments of PD?

Answer 26

Pharmacological: mainstay routine re:motor symptoms
L-DOPA: a dopamine precursor which crosses the blood-brain barrier & increases its synthesis by SN neurons
But Px refractory as disease & SN neuron death progresses

High-frequency Deep Brain Stimulation:
Electrodes implanted in BG (mimics L-Dopa effects)

Experimental: clinical trials showing promise
Glial-cell Derived Neurotrophic Factor (GDNF) injections into SN to slow/prevent further neuron death
Alpha-synuclein (SNCA) gene and other gene therapies targeting the SN neuron death

Question 27

How does Pharmacological treatment of PD aims to increase dopamine levels ?

Answer 27

Mainstay is [Step 5]: administer the L-DOPA precursor for dopamine synthesis

There are alternative available drugs that work in these other ways [Steps 1, 3] that can be used when L-DOPA losses its effectiveness

For example, anticholinergic drugs can block dopamine re-uptake [Step 4] to increase its availability

Question 28

What are some ocular side effects of some drugs used to treat PD?- look at table in the POWEPOINT SLIDE 25

Answer 28

Anti-cholinergics affect the parasympathetic innervation of sphincter & ciliary muscles + lacrimal gland: but how does L-DOPA affect vision?

Question 29

How does L dopa affect vision ? Dopaminergic Amacrine Cells

Answer 29

Dopaminergic Amacrine Cells
Dopamine (DA) is a neurotansmitter & a neuromodulator in ~1% of retinal amacrine cells of the INL. They have widespread synapses from which DA also diffuses through large volumes of retinal tissue to influence all retinal cell types in complex ways
Green cell above is a DA amacrine, with widespread processes. Surrounded by other amacrine cell types (red)

Question 30

How does PD affect the Retina?

Answer 30

Midget & Parasol Retinal Ganglion Cells:
DA amacrine cells receive synaptic input from OFF cone bipolars
Normal: Increase ‘OFF’ & decrease ‘ON’ RGC activity
Normal: influence Midget centres & Parasol surround RFs
PD: Reduced contrast sensitivity, middle (peak) spatial frequencies
PD: Pattern ERG P50 wave: reduced amplitude, increased latency

Melanopsin- & Intrinsically Photosensitive (IP)- RGCs:
DA tissue volume release (neuromodulation), higher during the day
PD: Circadian dysregulation, with sleep disturbances (like AD)
PD: Changes in pupil light reflex reactivity (like AD)

Question 31

How does PD affect Visual Dysfunctions?

Answer 31

Many similar to AD, except [5 & 6]*:
[1] Parasol/Magno RGCs: reduced contrast & motion sensitivity

[2] Melanopsin RGCs: circadian disturbances & reduced/slower pupillary light responses

[3] OccipitoTemporal Cortex: dementia object & face agnosias

[4] Posterior Parietal Cortex: dementia abnormal saccadic and smooth pursuit eye movements + visuo-spatial disorientation

[5] Reduced excitation, slower visual processing times: longer latency, reduced amplitude VEP P100 & N135 waves*

[6] Reduced visual acuity, leading to visual hallucinations?*

Question 32

Relevance of Dementias to Optometry

Answer 32

[1] Patients may require routine eye care:
Home or Care-Home visits: watch TV, play games etc
But ‘uncooperative’: history taking, testing problematic

[2] Mis-diagnosis of Eye diseases: e.g.,
Peripheral Superior/inferior retinal degeneration in AD confused for glaucoma

[3] Brain pathologies mistaken for Eye diseases
Visual Cortex atrophies causing loss of visual acuity & leading to hallucinations: but both are problems with macular degeneration, late-stage glaucoma, cataract (re: Charles Bonnet Syndrome in >25% of Px with these ocular conditions)