Lecture 31; Premature brain injury 2

Question 1

What are the two patterns seen in preterm brain injury?

Answer 1

Focal/Diffuse WMI (preOLS)

Delayed impairment of cortical growth

Question 2

When does the focal diffuse WMI (PVL) occur predominantly?

Answer 2

24-32 weeks

Question 3

What is the equivalent stage of rat development to the 24-32 week human?

Answer 3

P2-P4

preOLS are the same.

Question 4

In the rat what is seen when in response to P2 hypoxia ischemia?

Answer 4

Continued cell loss from P4 to P7

Question 5

What was seen when measuring caspase activation in P2 cells during hypoxia ischemia?

Answer 5

Very little caspase activation at P2 and high levels at P7

Thus different types of cell death, Necrotic early and apoptosis later.

Thus loss of preOLS = loss of potential mature oligiodendrocytes.

= Myelination failure

Question 6

What is seen regarding preOL numbers in the mouse after hypoxia ischemia?

Answer 6

There is actually a huge increase in factor O4 markers right through to P14 compared to the control!!

WTF?

= Huge proliferation at the same time as early necrosis and late apoptosis following injury

Question 7

Why do preOLs increase?

Answer 7

arrested preOL maturation contributes to myelination failure in premature infants

Question 8

In what instances do we see Impaired OL Maturation as Mechanism of Myelination?

Answer 8

• WM lesions in neonatal rats following hypoxia-ischemia or infection
• WM of fetal sheep following hypoxia-ischemia
• WM lesions in preterm born infants
• Demyelinated lysolecithin lesions in adult mice
• Demyelinated lesions in human MS

Question 9

What are there high levels of in preterm babies and why is it mysterious?

Answer 9

• Preterm infants exhibit high rates of cognitive and learning deficits at childhood age and later life.–Causes unknown?
• Cognition and learning primarily related to grey matter structures, not white matter–E.g., cerebral cortex, hippocampus, thalamus
• No acute damage to grey matter structures!

Question 10

What is found in babies with WMI?

Answer 10

There is a reduction in the total grey matter volume.

Question 11

What did studies about cortical growth and predictive cognition show?

Answer 11

Babies with high rates of cortical growth had higher cognition

Question 12

When are babies susceptible to grey matter deficits?

Answer 12

24-32 weeks

Question 13

What are the two main factors in cortical growth that may be affected?

Answer 13

–Neuronal migration into the cortex

–Neuronal arborization (growth of dendrites)

Question 14

What did human pathological studies indicate the loss of GM to be?

Answer 14

•Human pathology studies suggest role of loss of cortical neurons
–Controversial as severe insults/injury
–Infants also exhibit patterns of cystic white matter that not common in modern cohorts

Question 15

Do preterm babies loose neurons?

Answer 15

In diffuse WMI no. Role of neural aborization then?- probably

Cystic injury = loss of pyramidal layer five neurons remember.

Question 16

What did justin think the loss of grey matter volume was due to;

Answer 16

Deficits in cortical growth in preterm infants relates to impaired maturation of dendritic processes of cortical neurons, but not neuronal loss

Question 17

What model did justin use to test his hypothesis?

Answer 17

•Cerebral ischemia (30min)
•Preterm equivalent age (95d gestation)
•Model of diffuse white matter injury
•Recovery for 1, 2, and 4 weeks
•Postmortem DTI scans (12T) – calculation of FA
•Histology
–Neuronal counts
–Dendritic growth of cortical pyramidal neurons
–Spine counts

Question 18

What did justin find?

Answer 18

With increasing age, cortical volume increases

But preterm, HI babies, there is a reduced volume

No difference in the number of neurons though

Question 19

What did hypoxia ischemia do to the dendrites?

Answer 19

• Reduced number of branches
• Reduced length
• Reduced number of nodes

~20% for all of them

And less dendritic spines (connectivity)

Question 20

How could they measure reduced dendrite aborisation?

Answer 20

Fractional Anistropy.

In term babies there is a high density of dendritic branches. Therefore reduce FA

In HI there is far less decrease in FA (meaning less complexity of dendrites)

Question 21

What is happening in the DWI?

Answer 21

Diffuse WMI=

• preOL death
• preOL regeneration
• failure of preOL maturation
  = Disturbance in WM myelination
  = Cerebral palsy

Question 22

What is happening in reduced grey matter volume / delayed impairment of cortical growth?

Answer 22

• Altered neuronal development
• Impaired cortical connectivity
• Cognitive deficits