L6 PE & Offspring Neurodevelopment

Question 1

PE risk factors

Answer 1

obesity, advanced maternal age, diabetes, chronic hypertension, history of PE in a previous pregnancy

Question 2

PE symptoms

Answer 2

• onset of chronic hypertension on or after week 20 of gestation
• proteinuria
• placental insufficiency
• endothelial dysfunction
• systemic inflammation

Question 3

PE treatment

Answer 3

No effective treatment except for the immediate delivery of the baby & placenta

Question 4

Untreated PE can lead to…

Answer 4

• liver, kidney or brain damage
• eclampsia
• death

Question 5

Children born to a mother with PE have an increased risk of…

Answer 5

CVD, obesity, asthma, stroke

Question 6

The risk for which brain disorders is increased by about 30-35% in children born to a mother with PE?

Answer 6

ASD, ADHD, ID

Question 7

Neuroimaging studies in offspring of women who had PE

Answer 7

• altered regional grey matter volumes
• altered structural and functional connectivity
• reduced white matter maturation

Question 8

Findings from animal studies of PE

Answer 8

• behavioural deficits
• altered regional brain volumes
• reduced neurogenesis and oligodendrogliogenesis
• altered brain transcriptome

Question 9

Known risk genes for PE are mostly involved in…

Answer 9

endothelial cell function (VEGF) or cytokine signalling (TNFα & ERAP1)

Question 10

Most common risk genes for ASD

Answer 10

synapse proteins (Shank & Neuroligin genes)
transcription factors that regulate neurodevelopment (FoxP1 & MeCP2)

Question 11

A study that controlled for genetic factors by comparing PE-exposed children to their unexposed siblings found that PE, independent of sibling matching, increased the risk of…

Answer 11

ASD and ADHD

Question 12

Potential mechanisms (interconnected) that could link PE with neurodevelopmental disorders

Answer 12

• altered placental nutrient transfer
• impaired angiogenesis
• perturbed placental signalling systems
• inflammation
• oxidative stress
• epigenetics
• microbiota

Question 13

2 of the earliest and most well-characterised events in PE

Answer 13

• shallow trophoblast invasion
• failure to remodel the spiral arteries of the myometrium
  (lead to placental insufficiency)

Question 14

Nutrient levels in PE newborns

Answer 14

• altered placental expression of nutrient transporters
• higher total amino acids
• lower DHA levels
• higher homocysteine levels
• lower nervonic acid levels (esp males)

Question 15

The effect of PE on angiogenic factors

Answer 15

Decrease in pro-angiogenic factors (PlGF & VEGF), and a large increase in anti-angiogenic factors (sFlt-1 & sENG) in both maternal & fetal circulation

Question 16

What does impaired development of the cerebrovasculature affect?

Answer 16

• oxygen & nutrient supply to developing brain
• BBB development & permeability

Question 17

Women with PE exhibit __ levels of stress

Answer 17

increased

Question 18

Excessive cortisol affects genes involved in neurodevelopment, such as…

Answer 18

BDNF and Shh

Question 19

Expression of what placental enzyme is reduced in PE?

Answer 19

HSD11β2

Question 20

Dysregulation of which neurotransmitter is involved in PE pathophysiology

Answer 20

Serotonin

Question 21

What drives the increase in 5-HT in PE?

Answer 21

Altered placental tryptophan metabolism i.e. decreased catabolism & increased availability of tryptophan precursor

Question 22

How are neurotrophins affected in PE?

Answer 22

Decreased BDNF and increased NGF in the placenta and fetal circulation

Question 23

How does exaggerated oxidative stress in PE affect the placenta?

Answer 23

It causes the placenta to secrete unknown molecules into fetal circulation, which can adversely affect neuronal development

Question 24

Examples of neurodevelopmental processes that ROS regulate

Answer 24

NPC proliferation and differentiation, axonal guidance

Question 25

What is observed in animal models of oxidative stress?

Answer 25

sub-optimal neurodevelopment

Question 26

What are epigenetic modifications?

Answer 26

Heritable changes to gene expression which do not affect the actual DNA sequence e.g. DNA methylation

Question 27

Example of where epigenetic changes have been observed in a neurodevelopmental disorder

Answer 27

Some ASD risk genes are for chromatin-remodelling enzymes (e.g. ACTL6B)

Question 28

Epigenetic modifications in PE

Answer 28

Babies born to a PE pregnancy have altered DNA methylation in their circulation (no study has yet examined histone modifications)

Question 29

Microbiota changes in PE

Answer 29

It has been reported that women with PE have an altered gut and vaginal microbiota composition. Women with PE are also much more likely to delivery via C-section, thereby colonising the baby with distinctly different microbes

Question 30

How is breast milk composition altered in PE?

Answer 30

increased DHA and nervonic acid, decreased BDNF, altered metabolites (influenced by maternal microbiome)

Question 31

Conclusion of paper by Scott et al. (2018)

Answer 31

Pre-eclamptic placentae release factors that affect neuronal development - largely mediated through astrocytes and glutamate signalling

Question 32

In the paper by Scott et al. (2018), how did pre-eclamptic placenta medium affect neurite length and astrocyte numbers?

Answer 32

• decreased neurite length
• altered neurotransmitter receptor expression
• increased astrocyte numbers

Question 33

In the paper by Scott et al. (2018), what’s the role of MK801?

Answer 33

MK801 is a glutamate NMDA receptor antagonist that prevents PE-induced neurite growth deficits

Question 34

What are responsible for the effects of PE placenta media on neurons (Scott et al., 2018)?

Answer 34

Astrocytes, via glutamate NMDA signalling