L5

Question 1

Neurodegenerative Diseases
Characters

Answer 1

1-progressive loss of groups neurons with functional interconnections.
2-associated with the accumulation of abnormal proteins
3-Protein aggregates due to mutations or imbalance between protein synthesis and clearance ( فتتجمع تدريجي )
4-protein aggregates are resistant to degradation > inflammatory > toxic to neurons.

Question 2

• The clinical manifestations of degenerative diseases
are dictated by the ….

Answer 2

pattern of neuronal dysfunction.

Question 3

A- diseases that involve the hippocampus and associated cortices present with ………………
B. diseases in basal ganglia present with…………..
C. diseases in cerebellum present with……………….
D. diseases in motor neurons result in…………………….

Answer 3

cognitive changes & dementia

movement disorders.

ataxia

weakness and difficulty with swallowing

Question 4

Two features are common to many degenerative disease

Answer 4

1. The protein aggregates from affected neurons appear to be capable of spreading to healthy neuron (disease process may spread).
2. Activation of innate immune system

Question 5

most common cause of dementia

Answer 5

Alzheimer Disease

Question 6

is an important risk factor for Alzheimer Disease

Answer 6

Age

Question 7

Most cases of Alzheimer Disease are

Answer 7

sporadic

Question 8

……….manifests with the insidious onset of impaired higher intellectual function disorientation, memory loss, severe cortical dysfunction disabled, mute, and immobile. What The most common cause of death???

Answer 8

Alzheimer Disease
infections ( pneumonia).

Question 9

Pathogenesis of Alzheimer Disease ( AD)

Answer 9

fundamental abnormality*
-accumulation of two proteins
A -(Aβ peptides ——> Plaques in the neuropil ) extracellular
B -(tau——> tangles aggregates of the microtubule intracellularly)

1. Role of Aβ
2. Role of tau.
3. Other genetic risk factors
4. Role of inflammation

Question 10

1. Role of Aβ in AD

Answer 10

Aβ
is created when the transmembrane protein amyloid precursor protein (APP) is cleaved by the enzymes:
1-β-amyloid converting enzyme (BACE)
2-γ- secretase

Mutations in APP or in components of γ-secretase lead to familial type of AD

APP gene is located on chromosome 21
risk of AD is higher in those Down syndrome has extra copy of the APP ( 21)

Question 11

2. Role of tau in AD

Answer 11

• Neurofibrillary tangle contain the tau protein.
• Tau is a microtubule-associated protein present in axons in association with the microtubular network.
• With the development of tangles in AD, tau shifts to a somatic-dendritic distribution, becomes hyperphosphorylated and loses the ability to bind to microtubules.

-Two possible pathways have been suggested for the mechanism :
A. aggregates of tau protein elicit a stress response which leads to cell death.
B. microtubule stabilizing function of tau protein is lost leading to neuronal toxicity and death

Question 12

genetic risk factors for AD

Answer 12

ε4 (ApoE4).
-promotes Aβ aggregation and deposition.
-lower the age of onset

ممكن يخليه يجي بعمر ابكر وكل اليل يزيد ٤ اضعاف يعني ٢ اليل ٨ اضعاف الرسك

Question 13

Role of inflammation in AD

Answer 13

deposits of Aβ elicit an inflammatory response from microglia and astrocytes

Which assists in the clearance of the aggregated peptide, but may also stimulate the secretion of mediators that cause neuronal injury .

Question 14

large burden of plaques and tangles is highly associated with severe ………………….

number of …………………… correlates better with the degree of dementia

Biochemical markers that have been correlated with the degree of dementia include………………

Answer 14

cognitive dysfunction

neurofibrillary tangles

amyloid burden.

Question 15

Morphology of AD

Answer 15

1- cortical atrophy
2- widening of the cerebral sulci mostly frontal, temporal, and parietal lobes.
3-(hydrocephalus ex vacuo) significant atrophy, there is compensatory ventricular enlargement
4- presence of plaques (an extracellular lesion)
5- presence of neurofibrillary tangles (an intracellular lesion)

Question 16

Frontotemporal Lobar Degeneration ( FTLD)
distinguished from AD by

Answer 16

It’s focal degeneration of frontal and/or temporal lobes.
اللي يفرقه عن الزهايمر:
1-alterations in personality, behavior and language (aphasias) precede memory loss.
2- The onset of symptoms occurs at younger ages
than for (AD)

Question 17

Parkinson Disease

Answer 17

1-tremor, rigidity, bradykinesia and instability.
2-damage dopaminergic neurons which project from the substantia nigra to the striatum.
3-can be induced by drugs such as dopamine antagonists or toxins that selectively injure dopaminergic neurons.

Question 18

Pathogenesis of PD

Answer 18

1-protein accumulation and aggregation
2-mitochondrial abnormalities
3-neuronal loss in the substantia nigra
4-defect in autophagy and lysosomal degradation
5- neuronal inclusions Lewy body containing (α-synuclein)

Question 19

Parkinson Disease in most cases is ………….

Answer 19

( sporadic )

***and both autosomal dominant and recessive forms of the disease also exist.

Question 20

Type of mutation of the gene encoding α-synuclein in PD is

Answer 20

Point mutations and duplications of the gene

*( Which is a protein involved in synaptic transmission, and this mutation cause autosomal dominant Parkinson Disease )

Question 21

diagnostic feature of the Parkinson Disease is

Answer 21

Lewy body which is an
inclusion containing α-synuclein.

Question 22

Clinical Features Of PD

Answer 22

1- movement disorder in the absence of a toxic exposure
2- progresses over 10 to 15 years
3-Death result of intercurrent infection or trauma from frequent falls caused by postural instability.
4- Movement symptoms initially respond to (L-DOPA)

Question 23

Huntington Disease (HD)

Answer 23

1-an autosomal dominant disease

2-characterized by progressive movement disorders (involuntary jerky movements of all parts of the body - chorea)

3-dementia, caused by degeneration of striatal neurons (caudate and putamen).

Question 24

Huntington is caused by:

Answer 24

1-CAG trinucleotide repeat expansion in a gene (HTT) located on chromosome 4p16.3. encodes huntingtin protein

2-toxic gain- of-function related to huntingtin > proteolysis led to intranuclear aggregates.

Question 25

1-brain is small
2- shows striking atrophy of the caudate nucleus and the putamen and globus pallidus
3- lateral and third ventricles are dilated.

Answer 25

Huntington disease

*(globus pallidus secondarily atrophied )