Neurodegenerative Diseases

Question 1

What is Neurodegeneration?

Answer 1

• Collective term for diseases characterised by the death of neurons
• Can be selective for particular classes of cells or more generalised

Examples include:
* Alzheimer’s
* Parkinson’s
* Huntington’s
* Amyotrophic lateral sclerosis (MND, lou Gherigs)
* MS

Question 2

What do neurons lost correlate to?

Answer 2

• Symptoms reflect neurons lost.

Question 3

What is ALS?

Answer 3

• Selective loss of motor neurons in cortex, brainstem and spinal cord
• Several clinical subsets of ALS can be distinguished by anatomical location first affected
• Progressive loss of muscle control till loss of respiratory function

Question 4

What is Alzheimer’s?

Answer 4

• Loss of cholinergic and adrenergic nuclei in brainstem
• Widespread, progressive loss starting in hippocampus and entorhinal cortex
• Memory and learning impairments, leading to severe dementia

Question 5

What is Parkinson’s?

Answer 5

• Loss of dopaminergic neurons in substantia nigra
• Defects in motor control and coordination

Question 6

What are the mechanisms of neurodegeneration?

Answer 6

• Complex and multifactorial
• Many hypotheses, little actual drug development

Some common hallmarks:
* Aggregation of misfolded proteins
* Neuroinf
* Reactive gliosis
* Vulnerability to oxidative or metabolic stress
* Sporadic and hereditary froms

Question 7

What is protein misfolding and aggregation?

Answer 7

• Several neuronal proteins can become misfolded, expressed in abnormal forms, or incorrectly processed
  1. Tau, b-amyloid, a-synuclein, Huntingtin
• These misfolded proteins can form aggregates
• Reactive gliosis and neuroinf often reuslt
• Calssic example is Alzheimer’s senile plaque

Question 8

What is seeding and the spread of misfolded proteins?

Answer 8

• Protein monomers can aggregate randomly, or form oligomers and fibrils that can spread between cells and brain regions
• Analogous to prions

Question 9

What is the Huntington’s disease mechanism?

Answer 9

• Clear genetic component–Dominant autosomal allele
• Polyglutamine repeat addedto huntintin protein
• Degeneration of neurons in basal ganglia (especiallu caudate nucleus and putamen)

Question 10

What are the symptoms of Huntington’s?

Answer 10

• Memory lapses
• Difficulty conc
• Involuntary movts
• Mood swings, depression
• Loss of motor control
• Personality changes
• Onset around 30-50 years old and symptoms get progressively worse

Question 11

What are the treatments for Huntington’s?

Answer 11

• No available treatments to alter course of disease
• Focus on alleviation of symptoms
• Antidepressants
• Lifestyle changes etc

Question 12

What is the mechanism for Alzheimer’s?

Answer 12

• Senile plques (b-amyloid)
• Neurofibrillary tangles (tau)
• Reduced acetylcholine transmission
• Glutamate-induced excitotoxicity

Question 13

What are treatments for Alzheimer’s?

Answer 13

• AChE inhibitors:
  1. Prolong acetylcholine synaptic transient
  2. Inc tonic ACh
• Memantine (NMDA rec antagonist)
  1. Block NMDAR Ca-permeable pore
  2. Reduces excitotoxicity
• Antidepressants and antipsychotics
  1. Manage symptoms of worsening dementia

Question 14

What are plaque busting drugs?

Answer 14

• New monoclonal antibody treatments that clear b-amyloid aggregates
• Several ongoing trials
• Red rate of clinical decline
• Modes results (Best so far ~32% red in decline)

Question 15

What is the mechanism for Parkinson’s?

Answer 15

• Lewy bodies
• Loss of nigrostratal neurons
• Vulnerability to excitotoxicity
• Compromised dopamine transmission in stiatum

Question 16

What is the Extrapyrimidal motor system?

Answer 16

• Control of involuntary movt, reflexes and posture
• Multiple centres (striatum, cerebellum, thalamus etc)
• Dopamine projections from substantia nigra to caudate nucleus and putamen key regulatory mechanism

Question 17

What are the symptoms of Parkinson’s?

Answer 17

Motor coordination deficits:
* Tremor
* Slow movement
* Rigidity

Other symptims:
* Genitourinary problems
* Constipation
* Dizziness
* Depression, anxiety
* Dementia

Question 18

What is the treatment for Parkinson’s?

Answer 18

• Enhance dopamine transmission to compensate for loss of striatal dopamine
• L-DOOA
• Improves symptoms in short term but long term problems
• LID (levodopa induced dyskinesia)

Question 19

What are the Levodopa pharmacokinetics?

Answer 19

• Co-admin with benserazide or carbidopa
• Prev bdown of levodopa by peripheral L-DOPA decarboxylase enzymes
• Do not cross BBB
• Improves pharmacokinetics of levodopa

Question 20

What is treatment for parkinson’s?

(Dopamine receptor agonists)

Answer 20

Dopamine receptor agonists:
* Direct activation of (Primarily) D2 receptors in basal ganglia
* Compensates for loss of nigrostriatal input
* Apomorphine (D1 & D2), bromocriptine, ropinirole, pramipexole

Question 21

What are side effects of Dopamine receptor agonists?

Answer 21

• Hallucinations and delusions
• Compulsive an impulsive behaviour
• Activation of mesolimbic and mesocortical targets

Question 22

What are other methods of treating parkinson’s?

(Monoamine oxidase B inhibitors)

Answer 22

• Block breakdown of dopamine
• Less effective than other treatments
• Usually used in conjunction with DR agonist and/or L-DOPA

Question 23

Why are neurodegenarative disease a problem?

Answer 23

• Ageing pop=growing incidence
• Inc prevalence of dementia
• Disease burden growing
• Clinical trials disappointing