L3

Question 1

What is the most important RF of strokes?

Answer 1

AGE~~

it can impact:

• • the type/nature of insult
• • the amount/extent of injury
• • mechanisms of recovery
• • occurrence of co-morbidities and complications
• • treatment choices

Question 2

What is the difference between strokes in young and old individuals?

Answer 2

• • mortality is lower in children than young and old adults
• • recurrence rate is slightly lower in children
• • overall worse functional outcome in children than adults (the consequences of strokes differ, and the effect of age differs – in children, increasing age is associated with better outcomes, while in adults increasing age is associated with worse outcomes; of course, location and type of deficit matters, where complex skills fare worse than simple ones)
• • greater costs per person associated with stroke in children

[overall] numerous underlying mechanisms account for age effects

• • susceptibility to injury
• • spontaneous recovery
• • response to treatment

Question 3

Explain why old age worsens brain injury.

Answer 3

1. generally, young individuals have less injury with a comparable insult (tolerate hypoxia and ischemia better than older individuals)
2. old age worsens damage such as after focal ischemia, global ischemia, ICH and TBI
3. co-morbidities (ie. impaired collateral circulation worsens ischemia, and hyperglycemia aggravates injury)
4. numerous deleterious and protective processes change with age (ie. greater excitotoxicity, additional mitochondrial dysfunction, altered inflammation; accelerated glial scarring following injury, limited free radical defense mechanisms, estrogen is neuroprotective and is lost in menopause, diminished growth factors, and so on)

– [from later notes]: impairs neuroplasticity and neuroprotectants aren’t as effective; rehabilitation is also less effective in older individuals

Question 4

Why are neuroprotectants less effective in older animals?

Answer 4

Due to alterations in stroke pathophysiology, and accounting for comorbidities, there is greater and more rapid damage in older animals.

As well, there is a diminished tolerance for aggressive treatments (age-related alterations in drug metabolism and cardiovascular complications with age)

Question 5

What is the effect of old age on neuroplasticity?

Answer 5

It impairs it!

This affects normal and stroke damaged brains

• • structural changes (neuronal atrophy, loss of synapses, less neurogenesis)
• • underlying biochemical changes (alterations in nt and their receptors, lesser induction of growth factors [BDNF and IGF], greater upregulation of negative factors after injury [ie. growth inhibitory receptors], impaired cortical map plasticity)
• • limited cognitive reserve (already being used for other things)

Question 6

How does rehabilitation effect older individuals?

Answer 6

It is less effective!

There is:

• • greater injury
• • impaired neuroplasticity
• • comorbidities and medical complications that interfere with participation in activities that promote recovery
• • weakened support
• • attitude that aged individuals don’t respond as ell thus refocusing resources on younger patients

Question 7

What does OAI stand for?

Answer 7

Onset-admission interval; how long it takes a patient to arrive to the place (in this case, a rehabilitation facility) after their stroke

Question 8

What is the Barthel Index?

Answer 8

A measure of activities of daily living (ADL); this is important to look at in adjunct to neurological functioning.

Question 9

What were the conclusions from the “Aging and Stroke Rehabilitation; a Case-Comparison Study” by Paolucci et al?

Answer 9

1. advanced age has a negative effect on recovery after stroke and rehabilitation
2. even the very old benefit somewhat from rehabilitation

Question 10

What are some hormones related to stroke research?

Answer 10

1. estrogens (estrone - E1, estradiol - E2, estriol - E3)
2. progesterone
3. testosterone

Question 11

What role might hormones play in strokes and stroke research?

Answer 11

• • hormones have a diverse effect on the body (neuroprotection via improved CBF, reduced free radicals, inhibited apoptosis, etc.)
• • clinical studies have largely examined hormone replacement (ie. for treating osteoporosis while looking at stroke incidence along with other risks)
• • animal stroke studies have largely looked at neuroprotections and relevant mechanisms

(estradiol is the most studied; estrogen in females provides a NP function)

Question 12

Why is estrogen thought to be neuroprotective?

Answer 12

• • in multiple stroke models (global and focal ischemia, hemorrhage)
• • protection observed in other injury models (ie. trauma)

[general findings] estrogen allows for greater tolerance for ischemia, less cell death (with equivalent insults), improved functional recovery from reduced injury*

*not 100% agreement; significant problems

Question 13

Give some examples of how estrogen acts as a neuoprotectant.

Answer 13

1. In global ischmia, CA1 injury is attenuated by estrogen pre-injury treatment (in OVX females and in males; OVX worsens injury to make the damage more like that occurring in males)

• • this effect is not seen in aged animals (12 - 14 month old gerbils, who no longer produce estrogen, don’t show noticeable effects in CA1 protection)
• • this is because TIMING MATTERS; if given too late after ovarian hormone deprivation (from age or from OVX) the E2 treatment is limited/abolishes neuroprotection

2. in collagenase models estrogen helps to clot the blood (stops the bleed or makes it smaller); this is for pretreatment

– may therefore explain gender differences, but unhelpful for treatment

3. in autologous whole blood injections (ICH model) there is less edema (24 hrs) in female rats and males given E2; since this is an injection, and there is therefore no active bleeding, there is clearly some type of effect independent of estrogen’s clotting effect

Question 14

How can genetic screening help with strokes?

Answer 14

1. it can predict and manage RF’s
2. help with prognosis
   - - an individual’s outcome
   - - screening tool for entry into clinical studies
3. can help with treatment
   - - neuroprotection
   - - rehabilitation
   - - possibly replacing or augmenting the function of a particular protein

Question 15

What types of stroke studies are there for genetics?

Answer 15

1. patients
   - - identifying polymorphisms and relationships to measures such as learning in naive persons, incidence and type of stroke, severity of injury, and course of recovery
2. animal studies:
   - - selective breeding
   - - gene KO’s
   - - gene knock-ins
   - - transgenic
   - - local transfection (via. virus)
   - - targeting specific genes for a short period (ie. antisense oligonucleotides against BDNF)

Question 16

What is a polymorphism?

Answer 16

[definition] several alleles of a gene within a population leading to different phenotypes (ie. the gene encoding BDNF)

Question 17

What are some potential issues with genetic studies?

Answer 17

1. confounding effects; loss of function vs. gain of function
2. possibility of multiple interactions among genes, genes and non-genetic factors, and epigenetics
3. the ethical issues such as basing medical treatment on genetic screening

Question 18

Give an example of polymorphism and its role in brain plasticity?

Answer 18

BDNF val66met (66 codine, val-val vs val-met vs met-met); is associated with modified experience-dependent plasticity in human motor cortex.
-- suggests that BDNF is involved in mediating experience-dependent plasticity of human motor cortex

[testing] can be tested by:

• • subject recruitment (DNA analysis for BDNF genes)
• • fine motor tasks
• • TMS/MRI/EMG
• • thirty minutes of muscle activity training
• • TMS (assessed soon after training)
• • those with val/val see the greatest improvement
• • not that there are new connections, just that the brain is encouraged to use more existing ones
• • causes better functional gains
• • on the flip side, other studies show that having the met allele results in poorer outcome of SAH
• • means that augmentation of BDNF signalling may be beneficial to recovery!

Question 19

What is the problem with the idea that lesion size and location predicts functional outloook?

Answer 19

While this is something that is generally supported by a lot of studies, there is considerable variability:

• • among models for a given stroke type
• • among stroke types
• • among behavioural tests

Additionally there are a lot of other factors to consider; dendritic responses, plasticity responses, rehab treatments. Look at what impact do differences have on our ability to compare among studies and to translate findings to patients.

This is all particular true in animal models (especially translational issues)

Question 20

What is a good predictor between lesion size and behaviour?

Answer 20

Batteries of tests; individually there is a range from weak to good correlations, but with multiple tests you cover your bases.

• • these tests vary in their ability to detect differences in lesion sizes, and these vary over time
• • this was noted for ICH but has also been observed in ischemic strokes

Problem arises however with time and money, as well as the potential rehabilitation effects of multiple behavioural tests/time passing

Question 21

What are the general clinical findings of lesions size/location relating to stroke research?

Answer 21

1. that they roughly predict mortality and extent and rate of recovery

BUT

2. relationships are far from perfect, and or sometimes poor or non-existent; the factors that predict mortality do not necessarily predict morbidity equally well, and vice versa

Question 22

So, WHY are lesion size and location often weak predictors of outcome?

Answer 22

1. mathematics (non-linear multivariate relationships since size and location interact; noise or chance)
2. individual (baseline) differences (structural and functional differences among brains, education, motivation, comorbitidies, prestroke disability, etc.)
   - - BL is often estimated
3. structural and physiological responses to injury vary
   - - shock factors (edema, diaschesis)
   - - neuroplasticity (spontaneous and rehab-facilitated)
   - - complications (seizures, infections)
   - - motivation, depression, etc.
4. different treatments applied (heterogeneous rehab treatments)
5. imprecision in measuring injury
   - - lesion boundaries
   - - categorizing locations
   - - defining grey vs. white matter damage
   - - distal injury
   - - covert damage (ie. sick neurons)
   - - laterality not always considered
6. choice of behaviour measure
   - - body function vs. structural impairments (ie. balance vs. muscle weakness)
   - - activity limitations
   - - participation (ie. going to the mall, aerobic classes)
7. timing of assessment (lesion and behaviour)