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Dementia and neurodegeneration

  • Definitions:
    • Dementia
      • The chronic, progressive and irreversible loss of memory, perception or thinking
      • The chronic or progressive loss of cortical or subcortical functions resulting in a complex cognitive decline
    • Neurodegeneration
      • The progressive and irreversible loss of neurons from specific regions of the brain
    • Neurodegeneration can cause dementia
  • Epidemiology
    • Dementia
      • 1.5% of 65 year olds, 30% of 80 year olds
    • Types of dementia
      • Alzheimer’s – 50-75%, Frontotemporal dementia (FTD) – 10-20%
      • Vascular dementia – 10-15%, Dementia with Lewy bodies – 10-15%
    • Annual cost in Australia is about 1% of GDP: $6.5 billion, expected to increase to 3% by 2040

Neurodegeneration

  • Progressive irreversible loss of neurons
  • Aetiology
    • Vascular – stroke (acute cerebral ischaemia)
    • Infectious – AIDs related
  • Neurodgenerative Demenetias are often associated with protein misfolding
    • Parkinson’s disease (PD)
      • α-synuclein, Lewy bodies
    • Alzheimer’s disease (AD)
      • β-amyloid (Aβ), amyloid plaques
    • Huntington’s disease (HD)
      • Huntingtin, genetic disease, no gross lesions
    • Amyotrophic lateral sclerosis (ALS)
      • Superoxide dismutase, loss of motor neurons (motor neuron disease)
    • Creutzfeldt-Jakob disease (CJD)
      • Prion protein, insoluble prion protein aggregates

Parkinson’s disease

  • Pathophysiology
    • Loss of dopaminergic neurons in the substantia nigra 􏰀 Causes:
  • Environmental factors
    • Viral (encephalitis lethargica), MPP+ (MPTP), herbicide (rotenone)
  • Genetic (0.5%) – autosomal dominant/recessive
    • Vast majority are unknown
  • Damage is by protein misfolding and aggregation
    • α-synuclein is not broken down properly and prevents proper repackaging of dopamine
    • thus excess dopamine in the cytosol results in increased excitotoxicity, oxidative stress and eventually apoptosis
  • Dopamine pathways project from the VTA and SN into the frontal cortex and striatum
    • Those in the SN are affected
  • Dopaminergic and cholinergic receptors are in a balance, if there is a decrease in dopamine, there is too much cholinergic effects leading to cognitive effects etc of Parkinson’s

 • Drug targets • Treatment o No disease modifying therapies available o Current therapies are mostly symptomatic 􏰀 Methods: • Increased dopamine synthesis • Decreased catabolism • Dopamine receptor agonists • Anti-muscarinic – counters cholinergic and therefore restores the balance 􏰀 Replace dopamine – doesn’t halt the neurodegeneration, but can improve symptoms (L- DOP A) • Given orally, >90% is metabolised in the periphery, thus need to give large doses o Can be given with COMT, DDC, MAO inhibitors to improve amount of dopamine the synapse (Catechol-O-methyl transferase, dopamine decarboxylase, monamine oxidase) • Works for 10-12 years, then end-dose deterioration (duration of benefit gets shorter and shorter) 

Alzheimer’s disease

  • Epidemiology
    • Usually begins in the 7th – 9th decades
    • Costs $4 billion/year, death within 6-12 years
      • Treatment that delays onset reduces cost by 50%
  • Pathophysiology
    • Neuronal loss in basal forebrain, hypothalamus, cortex 􏰀 Largely cholinergic
    • Causes:
      • Genetic – autosomal dominant, 3-5%
      • Ischaemia/?hyperthermia?
      • Often unknown cause
    • Starts subcortical, often in the pathways to the hippocampus • Neuropathology
    • Diagnosis is often clinical
    • Diagnosis can be made post-mortem by the presence of:
      • β-amyloid plaques
        • extracellular
        • generates H2O2 which then produces ROS
      • ROS cause cell death (however, amyloid plaques don’t always correlate withn cell death geography)
        • β-amyloid proteins sequester away Fe, Cu, Zn
      • React with H2O2 producing OH.have many microglial cells
      • Neurofibrillary tangles
        • Intracellular – ionside neurons
        • Due to hyperphosphorylation of tau protein
      • Amyloid plaque causes increased phosphorylation leading to significant structural changes and then cell death
      • Amyloid plaques are formed by abnormal cutting of the protein

􏰀 Normally APP (amyloid beta precursor protein) is cut by alpha secretase, if cut by beta or gamma, the resultant protein aggregates more easily to form plaques 􏰀 Aggregation can be further enhanced by ApoE4 mutations  • Drug targets

Therapies

• Symptomatic o Try to increase cholinergic activity to compensate for loss of cholinergic neurons in the basal forebrain o Approved drugs: cholinesterase inhibitors 􏰀 Eg: Tacrine – short acting, reversible 􏰀 Eg: Donepezil – short acting, reversible, AChE selective 􏰀 Eg: Rivastigmine – slowly reversible 􏰀 Eg: Galantamine – reversible, non-selective, also enhances nicotinic cholinergic receptors • Disease modifying o NMDA receptor antagonists (Memantine) – reduce calcium influx and thus apoptosis o Anti-inflammatory (NSAIDS) – bind to γ-secretase and reduce the production of Aβ42 􏰀 Not shown to be effective clinically o Cholesterol lowering drugs (statins) o Antioxidants (vitamin E) o Chelation therapies – binding to Fe2+ and Cu, lowering potential for ROS 

ALS – amyotrophic lateral sclerosis

• Motor neuron or Lou Gehrig’ s disease o A fatal disorder caused by progressive motor neuron degeneration (upper and lower) • Epidemiology o Most common in the 6th and 7th decades 􏰀 Majority die in 5 years • Causes o Sporadic >90% o Familial <10% 􏰀 Often autosomal dominant, recessive and x-linked are possible o Degeneration is caused by glutamate toxicity and oxidative stress • Therapies o Symptomatic 􏰀 Sialorrhea (salivation) (Benztropine) 􏰀 Pathological crying or laughing (Amytryptaline (TCA), Fluvoxamine (SSRI)) 􏰀 Spasticity – Baclofen, Tizanidine, benzodiazepines 􏰀 Cramps – Baclofen, Tizanidine 􏰀 Depression 􏰀 Air hunger – supplementary oxygen o Disease modifying 􏰀 Glutamate release inhibitor and glutamate antagonist (Riluzole) • May improve early survival and enable individuals to remain the early stages longer • Side effects: diarrhoea, fatigue, nausea, headache, decreased lung function 􏰀 Future therapies • Anti-inflammatory agents, inhibitors of oxidative stress, • Overall: there are currently no significantly effective disease modifying therapies for major neurodegenerative diseases