Pharmacology of Neurodegenerative Diseases (DONE) Flashcards

1
Q

Huntington’s Disease overview

A

Typical onset 30-50 years old
15-20 years from diagnosis to death
Incidence of 3-7:100,000
Motor deficits, cognitive decline and psychiatric dysfunction
Autosomal dominant gene mutation, 50% chance of passing it on
Gene affected encodes the protein huntingtin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Motor deficits

A

First motor signs: abnormal eye movements, inappropriate hand and toe movements, general restlessness
Midcourse- inset of involuntary movements, hypertonic rigidity and dystonia
Late stage- impaired voluntary movements, rigidity, bradykinesia, dystonia, convulsions, weight loss
Leading to death from: pneumonia, choking, chronic skin ulcers or nutritional deficits

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Cognitive decline

A

Some areas affected are:
Executive function- planning, cognitive flexibility, abstract thinking, rule acquisition
Perceptual and spatial skills of self and surrounding environment
Memory
Learning

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Psychiatric dysfunction

A

These vary more than cognitive and physical symptoms. Possible conditions may be: blunting, egocentrism, anxiety, depression, aggression, compulsions, hypersexuality

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Pathology

A

10-20% reduction in brain weight
Decreased striatal volume and cell death
Decreased cortical volume and cell death
Increased ventricle size
Proteinous inclusions throughout brain (huntingtin protein)
Loss of GABAergic medium spiny neurones esp in caudate and putamen

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Huntingtin

A

HD gene identified in 1993, codes for huntingtin
Widely expressed in the brain and periphery- does not explain cell death patterns
Essential for embryonic development
Mainly in the cytoplasm but also nuclear
Involved in transcription, intracellular transport, intracellular signalling, metabolism

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

The mutation

A
CAG repeats:
7-34 = normal
35-39 = ??
>40 = HD
>70 = Juvenile HD
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

The effects of a mutant protein- aggregation

A

The lengthened CAG repeat increases capacity of the protein to aggregate in vivo, producing insoluble polymers
Polymers may be pathogenic trigger
Aggregates may be protective

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Effects of the mutant protein

A

Alters endocytic and secretory pathways
Proteosomal function
Calcium handling and mitochondrial function
Reduced transport of growth factors
Triggers apoptotic cascades, free radical production (causes oxidative stress), glutamate toxicity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Treatment of HD

A

Mood disturbances: anti-psychotic
Depression: anti-depressants
Impulsiveness and aggressiveness: anti-epileptics e.g. valproate
Dystonia, myoclonus: anti-spasticity or anti-Parkinson’s drugs
Chorea: dopamine blocking agents

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Motor Neuron Disease overview

A

Progressive neurodegenerative disorder
Results in loss of cells in the motor cortex, brain stem and spinal cord
Lethal
Adult onset disease > 50 years
More common in men than women
Incidence is 2 per 100,000
Average course of the disease is 2-5 years

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Types of neuron

A

Upper motor neurons- brain to spine
Lower motor neurons- spine to muscles of the body
Most common variant of the disease is amyotrophic lateral sclerosis (ALS)- both types are affected
Other forms may only affect upper (primary lateral sclerosis) or lower (primary muscular atrophy) neuron groups

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

ALS pathology

A

Shrinkage and loss of anterior horn cells in spinal cord
Aggregations- spheroids, bunina bodies, hirano bodies
Loss of myelinated fibres in corticospinal tracts
Loss of large pyramidal cells in the motor cortex
Muscle atrophy

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

ALS symptoms

A

Progressive muscle weakness (arms, legs, hands)
Hyperreflexia
Muscle fasciculations (twitches) and cramps
Slurred speech and dysphagia
Weakening and paralysis spreads to trunk of body
Most people remain mentally unimpaired despite physical deterioration

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Risk factors

A

Genetic: age, EAAT2 (glut transporter), GluR2 AMPA receptor subunit, SMN1/2 (survival motor neuron protein), CNTF, VEGF, SOD1
Environmental: age, family history, heavy metal exposure, viral infection/prion infection, variable phenotypes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Causes of ALS: genetics

A

1993: a mutation superoxide dismutase SOD1 on chromosome 21 was associated
~100 mutations now identified
Most autosomal dominant
High variation in onset and progression

17
Q

Super-oxide Dismutase 1

A

Metalloenzyme
Free radical scavenger
Converts superoxide free radicals into H2O2
Abundant in the brain and other regions
No clear reason for motor neuron vulnerability
Post mortem: accumulation of mutant SOD1 enzyme, would alter the ability to handle reactive oxygen species

18
Q

Cellular basis of degradation in ALS

A

Oxidative stress- SOD1 catalyses cellular superoxide to oxygen and hydrogen peroxide, removing damaging ROS
Deficient Ca homeostasis
Alteration in the glutamate system: excitotoxicity as a result of compromised glutamate uptake and unusually high Ca permeability of AMPA channel

19
Q

Treatment of ALS

A

Riluzole- glutamate antagonist, only licensed drug for ALS, prolongs life by 2-3 months
Treat the symptoms: cramps- quinine sulphate, carbamazepine, spasticity- baclofen, reduce saliva- amitriptyline, pain relief, tranquilizers