L53 - Molecular basis of neurological disease II - Alzheimer's and Parkinson's

Question 1

Epidemiology of Parkinson’s? Prevalence ?

Answer 1

2nd most common neurodegenerative disorder

1.5 times more common in men than in women

Majority = sporadic; 10-20%: family history 
Minority = monogenic (rare)

Question 2

Inheritance pattern of Parkinson’s?

Answer 2

Inheritance depends on the mutant gene (PARK 1 -11 mutation all have different inheritance patterns)

• All autosomal inheritance, split between AR and AD

Question 3

List 6 cardinal features of Parkinson’s?

Answer 3

1. Tremor at rest (asymmetric)
2. Bradykinesia
3. Back Rigidity with forward tilt + abnormal gait
4. Loss of postural reflex
5. Flexed posture of neck, trunk and limbs
6. Freezing phenomenon

Question 4

Which brain region is most affected by Parkinson’s?

Answer 4

substantia nigra pars compacta (SNpc),

locus ceruleus (LC)

Question 5

Describe the pathological changes to brain areas affected in Parkinson’s?

Answer 5

At substantia nigra pars compacta (SNpc), locus ceruleus (LC):

1. Depigmentation due to dopamine depletion&raquo_space; loss of neuromelanin
2. Loss of monoamine neurons causing dopamine depletion
3. Presence of Lewy bodies ( intracytoplasmic eosinophilic
   inclusion bodies) + Increased glial cells

Question 6

Lewy- bodies is a pathological hallmark specific to Parkinson’s. T or F?

Answer 6

False

pathologic hallmark of PD, but not specific

(found in 10% brains with other neurodegenerative diseases)

Question 7

Composition of Lewy-bodies? Pathological function in PD?

Answer 7

α-synuclein*** + other proteins (e.g. ubiquitin)

Cause mitochondrial dysfunction and neurodegeneration

Question 8

Explain how neurological changes in Parkinsons cause motor deficit?

Answer 8

Loss of monoamine neurons at substantia nigra pars compacta + Locus ceruleus

> > dopamine depletion in substantia nigra and nigrostriatal pathway to caudate, putamen

> > Less direct pathway, More indirect pathway = increase inhibition of thalamus and more output to supplementary motor area

> > Bradykinesia, rigidity, other parkinsonian signs

Question 9

List the 2 most important genes in the pathogenesis of PD?

Answer 9

PARK1: a- synuclein mutation
PARK2: Parkin (ubiquitin ligase) mutation

Question 10

Compare the normal and pathological function of a-synuclein?

Answer 10

Normal:

• Dynamic aggregation to form α-helix-like structures
• Associated with membrane, in equilibrium with cytosol

Pathological:

• mutated α-synuclein aggregates via small oligomeric intermediates into larger fibrillar forms (β-sheet)
• bound by ubiquitin into Lewy bodies*****

Question 11

Compare the normal and pathological function of Parkin (ubiquitin ligase)?

Answer 11

Normal:
Involved in ubiquitin-proteasome pathway: E3 ubiquitin ligase/ Parkin
» Tag polyubiquitin chains to proteins for degradation

Pathological:
2 defective copies of Parkin = no Parkin
» Parkin substrates accumulate in neurons
» OXIDATIVE TOXICITY to dopaminergic (DA) nigral neurons *****

Question 12

Explain why Parkin mutation exerts more effect on neurons in substantia nigra?

Answer 12

Dopaminergic nigral neurons:

• intrinsic exposure to oxidative stress***
  » easier protein damage and misfolding
  » More vulnerable to Parkin mutation

Question 13

Classify Alzheimer’s by onset and family history

Answer 13

By the age of onset:
 Early onset <= 65

 Late onset >65

By family history:
 Familial case (~10%): genes with high penetrance, large effect

 Sporadic case: commoner risk alleles with small effect size

Question 14

List the 3 autosomal dominant genes responsible for almost all early-onset AD

Answer 14

APP
PSEN1
PSEN2

Question 15

2 pathological hallmarks of AD in brain?

Answer 15

1) Amyloid plaques:
Amyloid protein, other associated proteins, non-nerve cells

2) Neurofibrillary tangles:
abnormal form of the microtubule associated protein tau

Question 16

Twin concordance rate of AD?

Answer 16

Twins concordance rate: monozygotic (40-50%) vs. dizygotic (10-20%)

Question 17

Criteria for dx of AD? (3)

Answer 17

• Deficits in 2 or more areas of cognition
• MMSE score < 24
• neuropsychological test evaluation shows progressive worsening of cognitive function

Question 18

What is the most common cause of dementia in elderlies?

Answer 18

AD

Question 19

List some risk factors for AD?

Answer 19

• Age **
• Down’s syndrome
• Family history dementia especially early onset **
• Severe head injury
• Vascular risk factors?
• Genetic factors **
• Lifestyles **

Question 20

Describe the defects in memory caused by AD?

Answer 20

 Impaired anterograde episodic memory: cannot remember recent events but can remember long-term

 Delayed recall of stories

 Difficulty in Paired associates (visual memory and new learning)

 Working memory is spared

Question 21

Describe the attentional and executive deficits caused by AD?

Answer 21

 Poor concentration, selective attention

 Problem with complex tasks, e.g. Wisconsin Card Sorting Test

Question 22

Describe the language and knowledge deficits caused by AD?

Answer 22

 Impaired semantics, category fluency, word definitions, word finding

 Later phonological, syntactic deficits

Question 23

Describe the visuospatial, perceptual deficits caused by AD?

Answer 23

 Impaired drawing (especially 3D)

 Apraxia (mainly conceptual, e.g. cannot plan specific movement)

Question 24

List some neuropsychiatric features of AD?

Answer 24

Common:

• Apathy
• Anxiety
• Depression

Late symptoms:

• Agitation, disruptive behavior
• Delusion
• Paranoia (theft of items)
• Phantom lodger

Question 25

Typical age of onset of AD?

Answer 25

 Age 65-74: 3%
 Age 75-84: 19%
 Age >85: 47%

Question 26

Methods for Dx of AD?

Answer 26

Structural and functional imagining by PET, SPECT

Biological markers: i.e. CSF amyloid, tau…etc

Question 27

List the severely atrophic brain areas in AD?

Answer 27

Superior frontal association cortex

Temporal lobe

Hippocampus, Entorhinal cortex

Question 28

What is the pattern of inheritance of AD in patients with early onset AD?

Answer 28

Autosomal dominant

Question 29

What is the pattern of inheritance of AD in patients with late onset cases and lots of affected family members?

Answer 29

Familial aggregation + late onset = Autosomal dominant, age- dependent, high penetrance

Question 30

Pathogenesis of amyloid plaques in AD?

Answer 30

APP mutation (precursor of amyloid protein) or defective γ-secretase (PSEN1 mutation):

APP cannot be processed normally:

• Cannot be cleaved by α-secretase
• Cannot be processed by β-secretase and γ-secretase

> > Failure to degrade Amyloid- β subunit of APP **

> > accumulation form amyloid plaque

Question 31

Pathogenesis of tau in AD?

Answer 31

Normal:
Tau/ MAPT facilitates microtubule stabilization within cells

Pathology:

1. Tau hyperphosphorylation
2. Sequestration of hyperphosphorylated tau into abundant neurofibrillary tangles (NFTs), neuropil threads around plaque

> > decrease tau binding to microtubules
microtubule dissociation
Defective axonal transport**

Question 32

Describe how ApoE functions as a risk factor in the development of AD?

Answer 32

ApoE transports plasma lipids within tissues

3 alleles:
ε2 = 2 Cys = protective against AD, but higher CVS disease risk
ε3 = 1 Cys, 1 Arg = normal allele
ε4 (apoE4) = 2 Arg = RISK ALLELE**

apoE4 = increase risk of developing AD (3x) + Decrease age of onset of AD

Question 33

Pathogical function of apoE4 in AD?

Answer 33

Normal apoE involved in amyloid-β clearance at blood-brain barrier, neuronal repair

apoE4 cause more Aβ deposition

Form more amyloid plaques

Question 34

List all the genetic defects seen in AD?

Answer 34

ApoE4
Tau
APP
PSEN1, PSEN 2