Pharmacology of Neurodegenerative Diseases (DONE) Flashcards
Huntington’s Disease overview
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
Motor deficits
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
Cognitive decline
Some areas affected are:
Executive function- planning, cognitive flexibility, abstract thinking, rule acquisition
Perceptual and spatial skills of self and surrounding environment
Memory
Learning
Psychiatric dysfunction
These vary more than cognitive and physical symptoms. Possible conditions may be: blunting, egocentrism, anxiety, depression, aggression, compulsions, hypersexuality
Pathology
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
Huntingtin
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
The mutation
CAG repeats: 7-34 = normal 35-39 = ?? >40 = HD >70 = Juvenile HD
The effects of a mutant protein- aggregation
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
Effects of the mutant protein
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
Treatment of HD
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
Motor Neuron Disease overview
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
Types of neuron
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
ALS pathology
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
ALS symptoms
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
Risk factors
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