Lecture 22 - Introduction to Movement Disorders

Question 1

What are movement disorders?

Answer 1

Clinical disorders associated with basal ganglia disease.

Question 2

What can movement disorders be sub-divided into?

Answer 2

Too little movement (hypo kinetic disorders)
Too much movement (hyperkinetic disorders)

Question 3

What is Parkinson’s disease?

Answer 3

A degeneration disease characterised by a group of cardinal features that include rigidity, resting tremor, slowness in movement (bradykinesia) and balance problems.

Question 4

Why is Parkinson’s and Lewy body dementia linked?

Answer 4

The main proteins involved in both are alpha-synuclein deposits in the brain.
LBD patients eventually get PD and PD patients sometimes get LBD.

Question 5

Why do PD patients lose their smell and taste?

Answer 5

Basal monoamines in the brainstem are affected.

Question 6

What does the basal ganglia contain?

Answer 6

Putamen
External globus pallidus (GPe)
Internal globus pallidus (GPi)
Substantia nigra
Subthalamic nucleus (STN)
Thalamus
Caudate nucleus

Question 7

Where is the basal ganglia located in the brain?

Answer 7

Cerebrum

Question 8

Describe the loops in the basal ganglia.

Answer 8

Four largely segregated cortical loops that have some cross talk.
Links the basal ganglia to the limbic system so movement selection can be informed by emotional and motivational state.
Links to the frontal lobe so that it is receiving proprioceptive feedback of ongoing motor activity.

Question 9

Describe the direct pathway in the basal ganglia.

Answer 9

Striatum to GPi directly.
Activation = GPi inhibition > thalamic disinhibition > cortical activation.

Question 10

Describe the indirect pathway in the basal ganglia.

Answer 10

Striatum to GPi indirectly via GPI and STN. GPi activation > thalamic inhibition > cortical inhibition.

Question 11

What does the direct pathway in the basal ganglia facilitate?

Answer 11

The activation of desired movement pathways.

Question 12

What does the indirect pathway in the basal ganglia facilitate?

Answer 12

The activation of inappropriate/conflicting movement pathways.

Question 13

What is overactivity of the GPi predicted to cause?

Answer 13

A reduced activation of desired movements - bradykinesia.

Question 14

What is under activity of the GPi predicted to cause?

Answer 14

Excessive activation of undesired movements - chorea.

Question 15

What are the causes of Parkinson’s symptoms?

Answer 15

Parkinson’s disease
Drugs such as anti-dopaminergics
Cerebrovascular disease
Structural lesion in the basal ganglia.

Question 16

What are the 4 main clinical signs of PD?

Answer 16

Tremor
Bradykinesia
Problems with initiating movements
Postural instability

Question 17

What are the 2 separate groups of tremors?

Answer 17

Rest
Postural

Question 18

Describe the pathophysiology of bradykinesia.

Answer 18

Normally dopaminergic fibres stimulate the direct pathway via D1 receptors and inhibit the indirect pathway via D2 receptors.
In bradykinesia the direct (activating) pathway becomes underactive and the indirect pathway (inhibitory) pathway becomes overactive leading to an overactive GPi.
The overactive GPi inhibits the motor thalamus and cortex leading to reduced cortical activity > bradykinesia.

Question 19

Describe the relationship between bradykinesia and abnormal oscillatory basal ganglia activity.

Answer 19

Excessive beta band oscillations seen in LFPs of PD patients.
The strong, extensive synchronisation in beta bands prevents neurons coding information in time and space.
The pathological oscillations cause distributed cortical activation that degrades movements.

Question 20

Describe levodopa as a treatment for Parkinson’s.

Answer 20

Dopamine is the key drug as it is the main chemical that is dropped in PD, but high doses of dopamine can’t be given as it is involved in too many other things.
So, the dopamine precursor levodopa (LDOPA) is given as it can cross the BBB and be taken up into nigral neurons, decarboxylates into dopamine, released into the synaptic cleft to activate post stratal dopamine receptors.

Question 21

Describe deep brain stimulation (DBS) as a treatment for PD.

Answer 21

DBS can block the output of the STN or GPi and reduces the level of inhibition and improves bradykinesia.
Stimulation frequency and amplitude titrated against clinical impairment.
The stimulating electrode blocks the firing of neurons in its vicinity.
DBS of the striatum and GPi is effective in treating advanced pD.

Question 22

Describe hyperkinetic disorders.

Answer 22

A heterogenous group of diseases that are characterised by the presence of excessive involuntary movements with a range of different clinical manifestations.
Characteristic of a tic is that it can be suppressed to a certain extent.

Question 23

What is Huntington’s disease?

Answer 23

Autosomal dominant genetic condition with excess Huntington gene (Chr4p) causing there to be excess Huntington protein which causes excessive movement.

Question 24

What are the clinical features of Huntington’s disease?

Answer 24

Chorea
Dementia
Anxiety
Depression

Question 25

Describe the Huntington gene.

Answer 25

Chromosome 4p.
CAG repeat at N terminus, <36 repeats = unaffected, 36-40 repeats = reduced penetrance, >40 repeats = full penetrance.
CAG repeat explains 60% of onset variability, the more repeats, the younger the onset.

Question 26

Describe inclusions in Huntington’s disease.

Answer 26

Mutantform of Huntingtin (Htt) with repeated glutamine residues.
These aggregate to form inclusion bodies.

Question 27

Describe pathology of Huntington’s.

Answer 27

Atrophy of the striatum (caudate and putamen)
Particularly affects spiny neurons projecting from the putamen to GPe.

Question 28

What is the mechanism of chorea?

Answer 28

Degeneration of indirect pathway leads to disinhibition of motor thalamus and over-activation of inappropriate motor commands.

Question 29

What is dystonia?

Answer 29

Loss of precise movement.
Involuntary, sustained muscle contractions leading to abnormal postures and repetitive movements.
Non-degenrative disorder, just happens and manifests with precise movements.

Question 30

What are the 3 types of classification for dystonia?

Answer 30

Primary (genetic) dystonia
Secondary dystonia - due to structural lesions, metabolic disease and hereditary degenerative disorders.

Question 31

Describe primary torsion dystonia.

Answer 31

Initially mapped to DYTI locus on chromosome 8.
Gene codes for Torsin A (heat shock protein)
30% penetrance
Presents in childhood with lower limb dystonia and then subsequent generalisation.

Question 32

Where are almost all the lesions that cause dystonia located?

Answer 32

Basal ganglia

Question 33

What did animal models with a basal ganglia lesion show?

Answer 33

Reduced functional activity and grey matter volume on MRI.
Neuronal activity in GPi correlated with dystonic EMG activity