Parkinson’s Plus Disorders:MSA and Related Conditions

Question 1

List some cases of parkinsonism

Answer 1

Multiple system atrophy
Progressive supranuclear palsy
Corticobasal degeneration

Idiopathic PD
Drug-induced PD
Vascular pseudo-parkinsonism

Question 2

What is Multiple system atrophy (MSA)?

Answer 2

a-synucleinopathy

Covers 3 disorders:

• olivopontocerebella atrophy (OPCA)
• Shy-Drager syndrome
• Striatonigral degeneration

Question 3

How to categorise MSA?

Answer 3

MSA-P: predominant parkinsonism

MSA-C: cerebellar features

Question 4

Macroscopic pathology of MSA?

Answer 4

• cortical atrophy
• cerebellar atrophy
• shrinkage of middle cerebella peduncle, pons and inferior olive
• pallor of locus coeruleus and substantia nigra

Question 5

Microscopic pathology of MSA?

Answer 5

• oligo inclusions of a-syn {Papp-Lantos bodies)
• mixed neuronal & glial pathology
• a-synuclein immunoreactive glial cytoplasmic inclusions (GCI)
• neuronal cytoplasmic inclusions, neuronal nuclear inclusions, glial nuclear inclusions and neuropil threads

Question 6

Clinical features of corticobasal degeneration (CBD)?

Answer 6

Rigidity, clumsiness, stiffness, arm jerking, “alien limb”

Question 7

Affected sites in CBD?

Answer 7

Cerebral cortex (fronto-parietal atrophy)
Deep cerebellar nuclei
Substantia nigra

Question 8

Histological features of CBD

Answer 8

Neuronal and glial inclusions

Neuropil threads

Balloon neurons and astrocytic plaques

Question 9

Clinical features of Progressive Supranuclear Palsy (PSP)?

Answer 9

Supranuclear gaze palsy & postural instability

Question 10

Affected sites in PSP?

Answer 10

Atrophy of:

• basal ganglia
• subthalamus
• brainstem

Question 11

Histological features of PSP?

Answer 11

Neuronal loss and gliosis

Neuronal and glial tau-positive inclusions

Tufted astrocytes and coiled bodies (in oligodendrocytes)

Question 12

Chromosomal location of tau and number of exons?

Answer 12

Single gene on 17q21

16 exons

Question 13

Isoforms of tau?

Answer 13

6 isoforms

3R or 4R -tau (microtubule-binding domains)

2 further inserts w/ unknown function
(0N,1N,2N)

[shortest form 3R/0N foetal]

Question 14

Function of tau?

Answer 14

Binds and stabilises microtubules

Promotes microtubule polymerisation

4R-tau more efficient

[other MAPS (microtubule associated proteins) have similar functions]

Question 15

Role of phosphorylation in tau?

Answer 15

Tau function is phosphorylation dependent (79 potential serine/threonine sites)

Clustered around MT binding sites

Increased phosphorylation reduces MT binding

Balance between kinases (GSK 3beta and CDK 5) and phosphatases

Question 16

Specific proteinopathy in MSA, CBD and PSP

Answer 16

MSA: a-synucleinopathy
CBD: tauopathy
PSP: tauopathy

Question 17

How to distinguish Parkinson’s plus disorders whilst the pt is still alive?

Answer 17

Biomarkers (although a single protein in CSF cannot define a disease) -> need algorithm to assess many different proteins

MSA has increased a-syn in CSF in PM (distinguishing it from other a-synopathies)

CSF neurofilament levels can indicate signs of CNS damage

Question 18

Using imagine to distinguish Parkinson’s plus disorders?

Answer 18

PET can distinguish PSP from CBD, MSA-P and PD

Question 19

Effects of tau knockout?

Answer 19

No phenotype (other MAPs compensate)

Question 20

Western blot: Pathological correlations of tau?

Answer 20

Normal: 6 soluble bands

Alzheimer's: all 6 isoforms involved w/ pathology
Pick's disease: 3R tauopathy
CBD/PSP: 4R tauopathy
FTLD-17 (N296N mutation): 3R tauopathy
FTLD-17 (P301L mutation): 4R tauopathy