Neurological Diseases 2

Question 1

What are 6 characteristic features of neurodegenerative disorders?

Answer 1

1. Progressive loss of neurons
2. Protein accumulation
3. Age is the major risk factor
4. They’re chronic diseases
5. Sporadic or familial
6. Can target specific regions of the brain

Question 2

Problems with different proteins are associated with different neurodegenerative disorders. Which proteinopathies are associated with: Alzheimer’s disease, Parkinson’s disease, Motor Neuron Disease/Frontotemporal Dementia?

Answer 2

AD: TAUopathies
PD: SYNUCLEINopathies
MNR/FTD: TDP-43opathies

Question 3

What are 5 brain characteristics of an ageing brain?

Answer 3

1. Less efficient energy production
2. Blood vessels changes - hypertension, atherosclerosis
3. Atrophy
4. Pigments + protein inclusions
5. Cognitive decline

Question 4

As the brain ages does the amount of grey or white matter or both change?

Answer 4

No change in grey matter. White matter decreases at a rate of 2mL/year.

Question 5

When is AD most likely to occur? Is it easy to diagnose?

Answer 5

In the 8th decade. No, there aren’t any definitive tests except for looking at the brain during autopsy.

Question 6

What is 1 MACRO and 4 MICRO features of AD?

Answer 6

Macro: 
1. Atrophy
Micro:
1. Beta amyloid plaques
2. Tau neurofibrillary tangles
3. Gliosis
4. Loss of neurons

Question 7

Atrophy of brain with AD:

Early on: End stage:
_______ atrophy –> ___ + ___ atrophy –> ____ atrophy

Answer 7

Hippocampal

Hippocampal and temporal

Global

Question 8

What are 3 features of beta-amyloid plaques?

Answer 8

1. Variable in terms of size and shape
2. Found throughout neocortex
3. Mainly comprise beta-amyloid

Question 9

What are 5 features of neurofibrillary tangles?

Answer 9

1. Bundles of neurofilaments in the cytoplasm of neurons
2. Found mainly near: hippocampus, temporal lobe
3. Made up of paired helical filaments (PHF)
4. Made up mostly of hyperphosphorylated tau
5. The spread of the tangles is correlated with the severity and progression of the disease

Question 10

The tangles and plaques don’t really overlap but when they do they are known as _______.

Answer 10

‘Neuritic’ plaques

Question 11

In non-amyloidogenic proteolysis, Amyloid Precursor Protein (APP) is cleaved by ________?
In amyloidogenic proteolysis, Amyloid Precursor Protein (APP) is cleaved by ________?

Answer 11

Alpha and gamma-secratase

Beta and gamma secratase

Question 12

What are the 4 stages on NFT progression?

Answer 12

1. Pre-tangle
2. Early
3. Mature
4. Ghost

Question 13

What % of all AD cases are familial?

Familial AD is the result of (known) mutation in 1 of 3 proteins. What are they?

Answer 13

<2%

1. Amyloid Precursor Protein (APP) (rarest)
2. Presenilin 1 (commonest)
3. Presenilin 2

*** Mutations in tau have not been found in familial AD

Question 14

What are the 6 steps in the Amyloid Cascade Hypothesis proposed for development of sporadic AD?

Answer 14

1. Dysregulation of APP metabolism
2. Production of soluble oligomeric forms of beta amyloid
3. Altered neuronal ionic homeostasis
4. Altered kinase/phosphatase activities
5. NFT formation
6. Neuronal dysfunction + death

Question 15

What are the 5 known risk factors for development of sporadic AD?

Answer 15

1. AGE!!!
2. Female
3. Dementia in first degree relative
4. Inheriting the e4 allele of the Apolipoprotein E (ApoE) gene
5. Multiple small effects of other gene variants

Question 16

______ > protective = sAD

Answer 16

risk factors

Question 17

There are 3 variations of the ApoE gene - e2, e3 and e4. Why is inheritance e4 not good compared to inheriting the other two.
Inheriting 1 x e4 allele increases the risk of AD by ___.
Inheriting 2 x e4 allele increases the risk of AD by ___.

Answer 17

ApoE thought to have a role in breaking down beta amyloid plaques. 2 + 3 are good at this but 4 is shit, meaning plaques build up.
Doubles it –> 2x
12x !!!!

Question 18

Can we use beta amyloid modifying therapies to prevent cognitive decline.

Answer 18

No - people who are against the Amyloid Cascade Hypothesis show that it doesn’t halt cognitive decline. It would need to be introduced v early on. These people also think beta amyloid is not primarily respponsible as well for AD. Instead maybe: tau? oxidative stress? inflammation?

Question 19

What does DIAN stand for and what is it? Who is recruited?

Answer 19

Dominantly Inherited Alzheimer Network.
A study that aims to find biomarkers for Alzheimer’s disease that are detectable long before the initial clinical symptoms.
People with siblings or parents who have AD.

Question 20

Area of research for a potential AD cure?

Answer 20

Stem cells - however it is expensive, ethics, invasive.