Case 2 - Parkinson's

Question 1

epidemiolgy

Answer 1

• The prevalence of PD has doubled in the past 25 years. Global estimates in 2019 showed over 8.5 million individuals with PD.
• PD prevalence is increasing with age and PD affects 1% of the population above 60 years
• 1.4 odds ratio for male sex

Question 2

pathophysiology

Answer 2

• The main neuropathological finding is α-synuclein-containing Lewy bodies and loss of dopaminergic neurons in the substantia nigra, manifesting as reduced facilitation of voluntary movements.
• Both environmental and genetic factors converging on a common set of pathways including mitochondrial dysfunction, oxidative stress, protein aggregation, impaired autophagy and neuroinflammation

Question 3

lewy bodies

Answer 3

• Alpha synuclein aggregates form Lewy bodies (aggregate) and stay intracellular in dopaminergic neurons
• Lewy bodies spread throughout brain (Braak staging)
  1. Start in vagus nerve or olfactory bulb (not sure how that starts but it is thought to be an external cause –> virus)
  2. Then spread through brain
• oligomers are most toxic form
• oligomers and fibrils can cause alfasynuclein seeding

Question 4

toxicity alfa-synuclein oligomers

Answer 4

intracellular:
* Impaired cellular respiration (mitochondrial dysfunction)
* ER stress
* Impairment of protein degradation
* Pore formation  loss of ion homeostasis

extra:
* Alpha-syn leads to microglia activation  neuroinflammation
* Disruption of neuronal signalling
* Uptake by other neurons leads to alpha-syn seeding  spreading through brain

Question 5

mitochondrial dysfunction

Answer 5

• Deficiency of the mitochondrial complex-I, which is a vital component of the electron transport chain (not just in neurons also platelets and muscle cells)
• Genetics can cause this (PINK and PARKIN)
• Alfa-syn can cause this
• Leads to high ROS which leads to alfa-syn production and inflammation
• Toxins like MPTP can also cause this

Question 6

symptoms

Answer 6

1. Autonomic and olfactory symptoms
2. Sleep and motor disturbances (tremor, stiffness, etc.)
3. Emotional and cognitive disturbances

Question 7

risk factors

Answer 7

• Rural living (including years of rural residency and ground-water use)
• Pesticide use
• Male lifestyle (male gender, head trauma, male-dominated occupations)
• Genetics
• Depression
• Age

Question 8

genetics

Answer 8

• The genes that have been found to potentially cause PD are assigned a “PARK” name in the order they were identified.
• To date, 23 PARK genes have been linked to PD.
• Mutations in the PARK genes demonstrate either autosomal dominant (e.g., SCNA, LRRK2, and VPS32) or autosomal recessive inheritance (e.g., PRKN, PINK1, and DJ-1)
• AS normally causes early-onset PD

Question 9

AD PD

Answer 9

• 5 different types of point mutations and gene duplication of triplication in the α-synuclein gene (SNCA)  PARK1 and 4 proteins
• The most frequent autosomal dominant monogenic PD is caused by mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2)  PARK8 protein
• Six LRRK2 mutations have been confirmed as pathogenic
• In total 7 genes are found to be involved in AD PD

Question 10

AR PD

Answer 10

• Autosomal recessive forms of PD typically present with an earlier onset than classical PD.
• Three of the PARK-designated genes causing autosomal recessive PD have been linked to mitochondrial homeostasis
• PRKN
• PINK1
• DJ-1 (alters mitochondrial morphology)
• Specifically, the proteins PINK1 and parkin are both involved in the same mitochondrial quality control pathway, with PINK1 recruiting parkin to dysfunctional mitochondria and thereby initiating mitophagy
• Mutations in PRKN are the most common cause of autosomal recessive familial PD, occurring in up to 50% of all early-onset cases

Question 11

biomarkers

Answer 11

• clinical: RBD and tremor and stiffness
• imaging: F-dopa (loss of dopamine) and NM-MRI (loss of neurons)
• fluid: CSF alfa-synuclein is low

Question 12

treatment

Answer 12

• There are currently no disease-modifying treatments for PD, and management predominantly consists of dopaminergic drugs.
• Dopamine agonists, such as ropinirole or rotigotine, are also used.
• Monoamine oxidase B inhibitors, such as rasagiline and selegiline, and catechol-O-methyltransferase (COMT) inhibitors such as entacapone, can be used to reduce the metabolism of endogenous dopamine
• Dopamine precursor (levodopa)
• DBS