Parkinson's Disease: Neuropathology

Question 1

Define Parkinson’s disease

Answer 1

Progressive neurological disorder defined by bradykinesia, tremor, rigidity and postural instability (at least two)

[commonly associated features: autonomic disfunction, cognitive disturbance, depression, dysphagia]

Question 2

Define parkinsonism

Answer 2

Clinical syndrome with some/all of the following features:

• bradykinesia
• tremor
• rigidity
• postural instability
• autonomic dysfunction/cognitive disturbance/depression/dysphagia

Question 3

Define parkinsonian disorders

Answer 3

Disorders in which Parkinsonism is a prominent feature: akinetic-rigid disorders

Question 4

What must occur before clinical symptoms of Parkinson’s appear?

Answer 4

Loss of 80-85% of dopaminergic neurons and deplete dopamine levels by 70%

Question 5

Describe how Parkinson’s can be modelled in animals?

Answer 5

MPTP: a prodrug to the neurotoxin MPP+

Can be accidentally produced during manufacturing of the opioid drug desmethylprodine (MPPP)

Intoxication causes parkinsonism associated w/ degeneration of dopaminergic neurons

Question 6

PD:

Site of LBs and clinical correlate?

Answer 6

LBs in substantia nigra

Akinetic-rigid syndrome

Question 7

Parkinson’s w/ dementia (PDD):

Site of LBs and clinical correlate?

Answer 7

LBs in substantia nigra and cerebral cortex

Dementia ≥1 y after dx
of PD

Question 8

Dementia w/ Lewy Bodies:

Site of LBs and clinical correlate?

Answer 8

LBs in substantia nigra and cerebral cortex

Dementia <1 y after
akinetic-rigid syndrome

Question 9

How can we classify Parkinson’s?

Answer 9

Degenerative:

• a-synuclein (PD, MSA)
• tau (prog supra palsy, CTE)
• TDP-43 (fronto-temporal lobar degen)
• nonspecific (genetic)

Non-degenerative:

• vascular
• toxic (MPTP, manganese poisoning)
• drug induced (antipsychotics
• infectious (flu)

Question 10

Pathological features of Parkinson’s disease

Answer 10

Neurodegeneration accompanied w/ neuronal inclusions composed of alpha-synuclein (Lewy Bodies)

Question 11

Pathological correlate of the symptoms of Parkinson’s

Answer 11

Neuronal loss in the substantia nigra (ventrolateral) and dopaminergic denervation of the striatum

Question 12

Describe physiological phenotype of DA neurons in the substantia nigra (SN)

Answer 12

Pacemaker-like properties lead to frequent intracellular calcium transients

Pacemaking maintains basal DA tone in target structures- without it there is no movement

Question 13

Describe physiological phenotype of DA neurons in the ventral tegmental area (VTA)`

Answer 13

Slow pacemakers

No calcium transients

Less Ca2+ channel density

High levels of calbindin (Ca2+ buffer)

Question 14

What is alpha-synuclein?

Answer 14

Abundant in brain

Unknown physiological function (maybe regulates synaptic plasticity and NT release?)

Question 15

Diagnostic Gold Standard for PD?

Answer 15

alpha-synuclein immunostaining

Question 16

Describe the oligomers of alpha-synuclein

Answer 16

A: normal
B: implants into membrane, forming pore -> cellular dysfunction

Question 17

Neuritic dystrophy hypothesis of neurodegradation

Answer 17

a-synuclein is transported from axon->synapse

Misfolding of a-helix to b-sheet -> aggregation -> axonal transport disrupted -> a-syn accumulates

Question 18

Braak PD staging

Answer 18

1. dorsal motor nucleus of vagus nerve
2. locus coeruleus
3. substantia nigra
4. basal forebrain
5. cortex

Question 19

Braak’s perception of PD progression

Answer 19

Begins in dorsal motor nucleus of vagus nerve and anterior olfactory nucleus

Proceeds rostrally towards neocortex

Question 20

Role of gut in PD?

Answer 20

PD hypothesised to start in gut peripheral ganglia- Gut biopsies to test for PD, constipation may be presenting symptom

Question 21

Role of olfactory bulb in PD?

Answer 21

exposure to organophosphpates?

agricultural workers have higher PD incidence

Anosmia found 10-20 yrs prior to motor symptoms PD

Question 22

Dual hit hypothesis for PD?

Answer 22

Genetic susceptibility w/ environmental trigger -> PD

Question 23

MSA pathology?

Answer 23

glial inclusions of alpha-synuclein

Question 24

PDD/DLB vs AD clinical features?

Answer 24

PD: frontal-executive + visuospatial + memory retrieval

AD: memory presentation (encoding)

Question 25

Prion hypothesis of alpha-synuclein?

Answer 25

Prion like spread of pathology may underlie all proteinopathies- alpha-synuclein may spread in a prion-like fashion

Question 26

ALL PATHOLOGICAL EXAMPLES

Answer 26

CHECK OLDER YEARS NOTES FOR THESE AS STUDIES HAVE BEEN OMITTED FROM ALL MY FLASHCARDS LOL