Parkinsons disease - Clinical and Genetic

Question 1

What anatomical aspect of the brain is related to movement disorders?

Answer 1

Disorder of the basal ganglia.
However poor correlation between movement disorder and basal ganglial lesions

Question 2

What are the names of the basal ganglia?

Answer 2

Substantia Nigra
Putamen
Caudate nucleus (body and tail)
Globus Palidus (internal and external)
Subthalamic nucleus
Red Nucleus

Question 3

What basal ganglia is affected in Parkinsons’ disease?

Answer 3

Substantia Nigra

Question 4

What are motor disorders sub-categorized into?

Answer 4

Akinetic-rigid Disorders
- e.g. Parkinsons Diseases

Hyperkinetic Disorders
- e.g. Huntingtons disease

Question 5

Why should we be mindful of the organization of the basal ganglia?

Answer 5

Basal ganglia are interconnected with many other systems than just motor system (e.g Limbic)
So location of Stimulation of the ganglia in treatment of movement disorders can have side effects in other systems.

Question 6

Cardinal motor symptoms of Parkinsons disease?

Answer 6

Tremor (Shaking)
Rigidity (Stiffness)
Akinesia (Slowness of movement)
Postural gait instability (balance issues)

Question 7

What are the non motor symptoms associated with parkinsons?

Answer 7

Bladder/Bowel problems, psychiatric features, pain

Question 8

What is distinctive of a Parkinson’s diseases dementia syndrome?

Answer 8

Transient periods of inattentiveness
Difficulties with subjective recall
Seeing objects and people who are not there (complex visual hallucinations)

Question 9

What is Braak Staging and what does it do?

Answer 9

Braak staging is 2 methods used to classify the degree of pathology in Parkinsons and Alzheimers disease.

The stages progress with the location of Lewy Bodies in the brain, with Stage 1 having Lewy bodies confined to the brainstem and olfactory system and stage 6 having Lewy bodies spread through the neocortex.

Question 10

What does each stage in Braak staging signify in terms of pathology of the disease?

Answer 10

Stages 1&2 - Autonomic/olfactory disturbances
Stages 3&4 - Sleep/Motor disturbances
Stages 5&6 - Emotional/cognitive disturbances

Question 11

What is the difference between Parkinsons Disease and Parkinsonism?

Answer 11

Parkinsonism is a broad term referring to many disorders that affect movement.
Pathology (presence of Lewy Bodies) determines Parkinsons Disease

Question 12

What other pathologies can elicit Parkinsonism?

Answer 12

Multiple systems atrophy (MSA)
Mitochondrial diseases (e.g. POLG)
Neurodegeneration with brain iron accumulation
Wilsons disease (Accumulation of copper in brain)
Neuroferritinopathy

Question 13

What imaging technique would help with Ante-mortem diagnoses of Parkinsons Disease?

Answer 13

FP-CIT SPECT imaging of dopamine transporter. Would show a loss of dopaminergic input to striatum from substantia nigra.

Question 14

What is the protein that aggregates in Parkinsons Disease and how does it propagate?

Answer 14

Alpha-synuclein aggregates and propagates in a prion-like manner.

Question 15

What is RT-QuIC?

Answer 15

Real Time Quaking induced conversion - a diagnostic technique that enables detection of aSyn prions in bodily fluids.

Question 16

What is the most common gene affected in familial PD?

Answer 16

LRRK2
Others include SNCA and parkin

Question 17

What does SNCA encode and what mutations can occur?

Answer 17

Encodes Alpha-synuclein protein
Mutations include duplications and triplications

Question 18

What does parkin encode and what is a prominent feature of pathological parkin variant?

Answer 18

Encodes a protein associated with mitophagy.
Dystonia (muscle spasms) are a prominent feature

Question 19

What does LRRK2 encode and what is the pathway in which it causes disease?

Answer 19

Encodes a kinase, dardarin, which is involved in many processes
Mutations in Dardarin affect protein synthesis, autophagy, golgi sorting, synaptic vesicle endocytosis.
leads to dopamine neuron death and subsequent Parkinsons Disease

Question 20

How could autophagic impairment underlie PD?

Answer 20

Autophagic impairment could potentially reduce the clearance of Alpha-synuclein which underlies the aggregation seen in PD

Question 21

Which allele of APOE exacerbates aSyn pathology?

Answer 21

APOE E4

Question 22

What is the function of Apolipoprotein?

Answer 22

Involved in the catabolism of triglyceride lipoproteins and the cholesterol transport pathway from astrocytes to neurones.

Question 23

What is the biggest risk gene for sporadic PD?

Answer 23

GBA - encodes glucocerebrosidase (GCase)
Heterozygous variants associated with PD
Bi-allelic variants associated with Gaucher disease (build up of these cells in liver,spleen)

Question 24

How does GBA influence PD?

Answer 24

Loss of GCase activity and lysosomal dysfunction = impaired alpha-synuclein metabolism and subsequent increase in aggregation

Question 25

What is a tremor?

Answer 25

Involuntary, rhythmic, oscillatory movement of a body body

Question 26

What is Dystonia?

Answer 26

Sustained muscle contractions, which frequently cause twisting and repetitive movements or abnormal posture

Question 27

What is Chorea?

Answer 27

Irregular, unpredictable, brief jerky movements that flit from one body part to another in random sequence

Question 28

Two types of tremor

Answer 28

Rest and action. (Rest in fulling resting limb, “pill-rolling motion”)
Action can be further subcatagorized into
Postural
Kinetic
Task-specific
isometric

Question 29

What is an orthostatic tremor?

Answer 29

13-18Hz tremor which predominanly affects the weight bearing limbs whilst standing.
High coherence between antagonistic and contralateral muscle groups

Question 30

What are other Hyperkinetic phenomena?

Answer 30

Ballism - violent flinging
Tic - abrupt jerky movement involving discrete muscle groups
Myoclonus - Sudden brief shock like involuntary movement

Question 31

What are hypokinetic phenomena?

Answer 31

Bradykinesia - Slowness and poverty of movements
Rigidity - increase in muscle tone
Postural distrubances

Question 32

What posture is prominent in parkinsons?

Answer 32

Stooped posture due to rigidity of flexor muscles

Question 33

What is Pisa syndrome?

Answer 33

A reversible lateral bending of the trunk with a tendency to lean to one side