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Summary

  • Neurodegenerative diseases are a significant cause of death and disability
    • There is no cure, and no disease modifying treatments
      • Just symptomatic treatments – that can be successful depending on disease type and stage
    • Each disorder has specific pathological features, but the pathways of cell death can be similar

Definitions

  • A progressive disease leading to brain cell damage and death – the cause of which is often unknown

Alzheimer’s disease (AD)

  • A dementia disorder
    • Dementia – a syndrome resulting from a chronic brain disease
      • The most common cause is AD
      • Involves:
        • Impaired memory
        • + impairment of one of: abstract thinking, judgement, language, emotional expression
        • Impairment of function/ADLs
        • Impairment is not associated with another disorder
  • Clinical
    • 6.7% of 60 year olds, 25% of 80 year olds have some degree of Alzheimer’s
      • more common in females than males, has a duration of 2-10 years
    • Diagnosis – can only be possible or probably during life – based solely on clinical assessment
    • Causes: 10% are familial , 50% of these have gene defects
      • Ie: defects with the proteins: presenilin-1, presenilin-2 or amyloid precursor protein
        • P1 and P2 are involved in metabolism of amyloid precursor protein
  • Signs
    • Brain atrophy in specific cortical areas (frontal, cingulate, temporal)
      • somatosensory and motor strips aren't affected; as the disease progresses, volume of brain is drastically reduced
    • 30% of neurons will have some apoptotic evidence
  • Pathology
    • Amyloid plaques
      • Extracellular protein accumulation and aggregation forming plaques - coned/diffuse
      • Process of formation:
  • Amyloid precursor protein can be processed by 2 paths:
    • 90% - α-secretase then γ-secretase leading to functional protein
    • 10% - β-secretase then γ-secretase leading to β-amyloid formation
      • these are sticky and form aggregates
  • In Alzheimer’s – there is an increase in the β pathway due to various factors
    • Factors: age, ApoE4 etc
    • Neurofibrillary tangles
      • Intracellular aggregates of an insoluble form of the tau protein
  • Tau proteins become hyperphosphorylated making them insoluble
    • Tau proteins accumulate incide cells, producing aggregates of microtubule precursor proteins
  • Treatment
    • Acetylcholinesterase inhibitors
      • Symptomatic treatment, better for mild to moderate AD (no pharm to reverse disease process)
      • AD presents with apoptosis of cholinergic neurons, thus AChEIs restore ACh/DA balance (note that ACh neurons are targeted in AD)
    • NMDA antagonist
      • Loss of ACh, overactive glutamate system – blocked by this antagonist to reduce damage
  • AD or normal ageing?
    • Normal ageing, people normally have plaques, tangles and reduced brain volume
      • However, in normal ageing:
        • Neurons are preserved
        • Glial cells are lost, white matter loss of 2ml/year in the healthy brain --> benign forgetfulness of old age
    • Thus communication is slowed down
    • AD – loss of neurons via a disease process (no neuron loss in AD; also, note that NFT and plaques also occur in the healthy. Amount of plaques/NFT correspond to earlier death)

Parkinson’s disease (PD)

  • A progressive movement disorder normally with an unknown cause (can be genetic)
  • Clinical
    • 6% of people >50, increases with age (hence prevalence increasing)
      • average age is 62, duration of 20 years
    • symptoms: tremor at rest, lead-pipe rigidity, bradykinesia
      • need >1 for diagnosis
    • expressionless face, shuffling gate, stooped forward, tremor starts on one side then spreads
  • Pathology
    • Substantia nigra p.c. contains dopamine producing cells, also produces neuromelanin (black)
      • PD – cells progressively die (doesn't affect cortex; weight of PD brain is the same as normal)
      • Lack of dopamine affects the indirect and direct circuits (see Tancred's lecture)
    • Formation of Lewy bodies – aggregates of insoluble α-synuclein
      • Involved in the repackaging of dopamine, excess intracellular dopamine leads to cell death
  • Treatment
    • L-dopa – gold standard
      • The precursor of dopamine (converted to dopamine via DDC) in the few surviving dopaminergic neurons. A problem with this paradigm is the reliance on a few working remaining dopaminergic neurons. So when the disease progresses to having no more dopaminergic neurons, we use dopamine agonists.
        • can’t use dopamine as a treatment because it doesn’t cross the BBB
    • L-dopa on the other hand is transported by normal AA transporters
      • 95% of l-dopa is metabolised in the periphery and thus we need large amounts (ARx in periphery = nausea and vomiting)
  • adjunct therapy can be used to increase the amount of l-dopa that reaches the CNS
    • COMT, DDC, MAO inhibitors
      • Still only 15-20% gets to the brain
    • Dopamine agonists
      • Mimics endogenous dopamine
      • Clinically not as effective as l-dopa
        • Generally given early in the disease or late with l-dopa
      • Side effects – pergolide and cabegoline cause cardiac valve disorders and sudden onset sleep disorders
    • Other side-effects – dyskinesia, after a long period of taking treatments
  • Giving dopamine agonists (as you would give in end-stage PD), it is less effective than giving L-dopa. Also, if you give the agonist with L-dopa, then you don't need to use as much L-dopa (to reduce dyskinesia).

Dementia with Lewy bodies – a mix between PD and AD

  • Clinical
    • Causes 20-30% of dementia; looks clinically like AD
    • Progressive dementia with fluctuating dementia, visual hallucinations, delusions and parkinsonism
      • Fluctuating – worse at times, better at times
      • Parkinsonism – PD motor problems
  • Pathology
    • Cell loss in the SN and frontal cortex
    • Lewy bodies found in the cortex and SN, plaques in the neuropil
  • Very difficult to treat - using dopaminergic drugs for dementia, then it makes movement problems worse, and treating with AChEI makes movement problems worse.

Huntington’s disease

  • Clinical
    • Most common in the 4-5th decades, 5:100 000, 15 year duration
    • Symptoms – progressive disorder of cognition, movement and emotions/psychosis, chorea (dance-like movements)
  • Pathology
    • Atrophy of the cortex and basal ganglia (can lose 60-80% of caudate/putamen), and increased ventricular size
      • This may lag behind symptoms and some don’t have atrophy
    • Huntingtin – insoluble and aggregates, not well understood; builds up in vulnerable cells in the cortex and BG. Autophagy systems (protein removal systems) are not working, so the proteins build up, and you get cell loss
    • Genetic (Ch4, AD) – too many triplet repeats of CAG at 5’ end
      • Normal is <38 repeats, HD is 38-121 repeats
      • Age of onset is inversely proportional to number of repeats – more repeats, younger onset
  • Children of people with disease have increased repeats and earlier onset: as it's passed down the generations, people get it at a younger and younger age.
  • Onset can also be spontaneous and be without family history (which is why the disease hasn't died out)
  • Treatment
    • Symptomatic – try to treat chorea: ?antipsychotics?, side effects of depression/suicidal thoughts
      • See table: chorea, bradykinesia/rigor, gait disorder, dysphagia/dysarthria, impaired fine motor tasks, depression, aggression/psychosis, dementia/apathy

Summary

  • Neurodegenerative diseases are a significant cause of disability and death, especially in the aged population
  • None can be cured and there are no therapies targeting degenerative mechanisms in current clinical use
  • Symptomatic treatments are variably successful, depending on the disease type and stage
  • Selective neuronal vulnerability and variable histopathologies suggest multiple aetiologies, however mechanisms of cell death may share common pathways
  • Research to understand mechanisms of degeneration may provide avenues for slowing or preventing disease