Week 5 - Neurodegenerative Diseases

Basal ganglia anatomical regions

Basal ganglia proper = caudate and putamen (striatum) + globus pallidus

Strong connections to substantia nigra (+ thalamus and cortex)

Basal ganglia circuitry and feedback loops

BG forms closed feedback loops with the cortex and thalamus
^cortex is ‘talking to itself’ via the basal ganglia and thalamus^

1. Direct path: cortex → D1 striatal neurons —• GPi/SNr —• thalamus → cortex

   • Thalamus disinhibited = inc. thalamocortical feedback

   • Positive feedback loop (cortex boosts own activity)

   • Amplification effect (converging inputs but diverging outputs)
     
     

2. Indirect path: cortex → D2 striatal neurons —• GPe —• STN → GPi/SNr —• thalamus → cortex

   • Thalamus inhibited = dec. thalamocortical feedback

   • Negative feedback loop

   • Net decrease in excitation
     
     

3. Hyperdirect path: cortex → STN → GPi/SNr —• thalamus → cortex

   • Thalamus inhibited = dec. thalamocortical feedback

   • Negative feedback loop

   • Rapid cancellation, global action halting

Movement selection and correction in the basal ganglia

DIRECT LOOPS ⇒ initiating movement

• Among competing neuronal populations, boosts specific motor programs in the cortex
  
  

INDIRECT LOOPS ⇒ terminating movement

• Dampens unwanted motor programs / neural populations

• Reduces noise, inhibits or cancels competing motor programs

• Increases signal : noise ratio

How does dopamine input affect basal ganglia feedback loops?

Dopamine input comes from SNc

• Direct loop ⇒ D1 (E) receptors in striatum

  • Inhibits GPi / SNr

  • Disinhibits thalamus

  • Net increase in activity
    
    

• Indirect loop ⇒ D2 (I) receptors in striatum

  • Disinhibits GPe

  • Inhibits thalamus

  • Net decrease in activity
    
    

This means drugs like DA agonists are psychomotor stimulants (increase CNS activity, alertness, physical energy)

Huntington’s Disease

• Genetic disease (fatal autosomal dominant gene) but effect is delayed until 30s-40s

• Movement disorder + dementia

• Twitches in face and hands → progresses to whole body tremors (resembles voluntary movements)

Basal ganglia in Parkinson’s Disease

Degeneration of dopaminergic neurons in the SNc that project to striatum = increased thalamocortical feedback

Direct pathway is underactive (striatum no longer excited by D1 Rs)

• Harder to initiate movements

• Cannot selectively boost motor programs to send them to the body

Indirect pathway is overactive (striatum no longer inhibited by D2 Rs)

• Excessive inhibition of the thalamus

• Motor cortex cannot execute voluntary movements

Theories of basal ganglia function

1. Helping the brain select which candidate movement to make

   • Action termination vs boosting motor programs
     
     

2. Motivational control over response selection

   • DA input allows for reward signals and motivation to contribute to movement selection
     
     

3. Error correction

   • Uses a closed feedback loop, rapid feedback on a specific action’s output

   • Internal ‘predictive’ feedback for faster correction than just with slow, peripheral feedback

   • Can correct motor signal projections ahead of time (errors in strength etc.)
     → rather than waiting for the movement to be executed

^VS open loop uses external sensory feedback, slow and unstable^

4. Brain can ‘offline control’ its own function

   • Includes functions such as attention, decision-making

   • Multiple parallel loops exist relaying through the BG and returning to their origin in the cortex

Basal ganglia in Huntington’s Disease

Caused by progressive loss of GABA neurons in the striatum (caudate)

• Neuronal degeneration is not selective for either pathway

• Results in decreased output from GPi to thalamus
  
  

Cortex
↓
Striatum (death of MSNs = hypoactive)
| lack of inhibition
GPe (hyperactive)
| over inhibition
STN (hypoactive)
↓ lack of excitation
GPi / SNr (hypoactive)
| no inhibition
Thalamus (hyperactive)
↓ over excitation
Cortex

= inappropriate motor programmed are not filtered out
(intrude on behaviour, causes rapid, dance-like movements)

Parkinson’s disease

• Mostly affects individuals over 60

• Some genetic component

• Symptoms

  • Hypokinesia (reduced movement amplitude, become smaller and lose force, loss of voluntary movement)

  • Akinesia (complete absence or inability to initiate movement)

  • Bradykinesia (slow movement)

  • Abnormal gait (shuffling)

  • Resting tremor (NOT essential tremor)

  • Rigidity

Prion disease

Misfolded proteins (denatured, destroyed)

• Lack genetic material like DNA, RNA (don’t target nucleic acids)

• Not living pathogens and doesn’t reproduce

  • Converts proteins from normal to misfolded

  • However normal PrP must be present to infect cells

• Can trigger normal proteins in the brain to fold abnormally

• Prion proteins (PrPs) exist in everyone, encoded by a specific gene (same amino acid sequence, different folding structure)
  
  

  1. Normal form (PrP^C) ⇒ degraded by enzymes

  2. Aberrant form (PrP^Sc) ⇒ resistant to enzymes

     • Cannot be degraded as it’s misfolded, causes disease

     • Accumulates in cells, becomes toxic = neuronal death

How do prions cause Creutzfeldt-Jakob Disease?

Role of proteins in the pathogenesis of Huntington’s Disease

Caused by mutation in HTT gene (Chr 4)

• HTT codes for Huntingtin protein (in all cells, higher in neurons)

• Normal HTT gene has 10-35 repeats of a CAG sequence

• HD disease contains >40 repeats

  • Longer DNA sequence = abnormally long Huntingtin protein

  • Breakdown of this protein produces fragments that misfold and aggregate

• Disease has a delayed onset

  • Neurons don’t undergo death / replacement but DNA repair

  • Long sequence increases chance of error in repair process

  • Number of repeats may increase over lifespan

Role of proteins in the pathogenesis of Parkinson’s Disease

Loss of SNc dopaminergic neurons AND
accumulation of Lewy bodies in surviving neurons

• Aggregation of α-synuclein protein, forms inclusions leading to neuronal death

• Cannot be denatured by normal enzymes

• Due to loss of function of ‘Parkin’ protein

  • Parkin sticks onto misfolded α-synuclein, identifying them for enzyme destruction

Beta-amyloid and tau in the pathology of Alzheimer’s Disease

• Global loss of cortical tissue targeting ‘association cortices’ (anterior temporal, PPC, PFC)

• Severe degeneration of hippocampus, entorhinal cortex, MTL

• Also specific subcortical nuclei

  • Nucleus basalis (cholinergic)

  • Locus coeruleus (noradrenergic)

  • Raphe nuclei (serotonergic)

1. Amyloid (‘senile’) plaques: collection of neural debris including β-amyloid (found in cell wals)

   • Comes from β-amyloid precursor protein (APP)

   • APP is chopped into 3 pieces (middle is Aβ)

   • Can be short (40 AAs) or long (42 AAs)
     → normally <10% long form, AD up to 40%

   • Distributed in DMN (TPJ, PFC, anterior tem0poral))

2. Neurofibrillary tangles (NFTs): clumps of tau protein that are displaced from cytoskeleton structure

Cognitive tools and neuropsychological tests for assessing cognitive impairments in AD

Dementia is a decline in cognitive abilities including:

• Memory

  • Episodic, semantic

  • Anterograde, retrograde

  • Working memory

• Language (aphasia)

  • Naming

  • Word and sentence comprehension

  • Language production (i.e., describing pictures)

• Visuospatial function (agnosia, apraxia)

  • Construction (i.e., copying pictures in MMSE)

  • Orientation (i.e., judging the direction of lines)

• Executive function & attention

  • Planning (i.e., copying figures)

  • Regulating goal-directed behaviour (i.e., stroop task)

Pharmacological and surgical treatments for Parkinson’s Disease

• L-DOPA, DA agonists

• Pallidotomy or other surgical ablation (GPi/e, STN, thalamus)

• Deep brain stimulation