Neuroimaging in disease

Question 1

What is dementia?

Answer 1

An umbrella term used to describe a collection of symptoms caused by brain diseases - it is not a normal part of ageing

Main symptoms involve loss of memory and thinking abilities that interfere with every day activities

Question 2

Why do people get dementia?

Answer 2

Biggest factor = age
Genes = familial dementia (used in research)
Environment

Question 3

What causes dementia?

Answer 3

15% of cases are genetic - mutated gene
85% of cases is sporadic - we still do not know why although many factors contribute

Question 4

What was the main hypothesis of Alzheimer’s for a long time?

Answer 4

Amyloid cascade hypothesis

Question 5

What has structural MRI found about dementia?

Answer 5

A reduction in brain size
MRI does not have the resolution to image beta amyloid plaques

Question 6

What is useful about PET imaging?

Answer 6

Only method where tau and beta amyloid can be measured in the brain

Question 7

What does most present research focus on?

Answer 7

FDG for metabolism and PiB for beta amyloid

Question 8

What are FDG and PiB measures?

Answer 8

FDG = fluorodeoxyglucose - measurement of glucose uptake
PiB = Pittsburgh compound B (radioactive analog of thioflavin T which can be used in PET to image beta amyloid plaques in neuronal tissue)

Question 9

What else can MRI give in the fight against disease?

Answer 9

Functional connectivity of the human brain - not only for disease

Question 10

What has fMRI told us about functional connectivity?

Answer 10

Functional connectivity has transformed fMRI research

Most dominant measure in fMRI field and has identified many networks

Primary visual
Primary motor
Extra-striate visual
Insular-temporal/ACC
Parietal-frontal (left and right)
Default mode network
Frontal

Question 11

What is the significance of functional connectivity in disease?

Answer 11

Appears to be changing in many diseases
ALS (amyotrophic lateral sclerosis)
Multiple sclerosis
Depression
Parkinson’s disease
Alzheimer’s

Question 12

How are the functional connectivity regions identified?

Answer 12

Most basic way is using seed based correlation
Based on the time series of a seed voxel (ROI), connectivity is calculated as the correlation of time series for all other voxels in the brain

Example:
In a resting state experiment, pp placed in MRI scanner and asked to think of nothing in particular
BOLD fMRI signal is measured
Conventional task-dependent fMRI can be used to select a seed region of interest
To examine the level of functional connectivity between the selected seed voxel and a second brain region e.g., motor cortex, the resting state time series of the seed voxel is correlated with the resting state time series of the motor cortex
A high correlation between the time series of both voxels is reflecting a high level of functional activity between these regions

Question 13

What is ICA?

Answer 13

Independent component analysis
= Attempts to extract underlying signals that, when combined, produce the resulting brain signal

ICA methods are designed to search for a mixture of underlying sources that can explain the resting state patterns, looking for the existence of spatial sources of resting-state signals that are maximally independent from each other

Question 14

What is linked to ICA?

Answer 14

Graph analysis - a way of seeing how all the networks interact with each other

Model the brain as a complex network represented graphically as a collection of nodes (anatomical elements e.g., brain regions) and edges (functional connectivity

Question 15

What is the major goal of brain imaging?

Answer 15

Combining structural and functional connectivity
Structural DTI imaging - high resolution fibre tracts
Using graph theory to define functional networks working across the brain
Understanding the entire brain connectome - the brain initiative

Question 16

What is ADNI?

Answer 16

Alzheimer’s disease neuroimaging initiative
Large cohort studies in disease
Detailed history of each patient and assessment of health and education
Neuropsychological tests
Genetic testing for risk factors
MRI both structural and functional scans
PET for glucose consumption tau beta amyloid
Post mortem histology

Question 17

What is the UK version of the ADNI?

Answer 17

Biobank UK - large cohort funded imaging/patient data scheme
Aim to scan 100,000 participants (brain, heart, abdomen, bones & carotid artery)
Most likely a lot of these people will go on to get disease - therefore, researchers can investigate their data to assess what caused the disease and compare to similar people who did not get the disease

Question 18

Are there any issues of using fMRI and connectivity as a biomarker?

Answer 18

Functional connectivity relies on the fact that spontaneous neuronal activity will drive spontaneous BOLD signals - this is expected because of NVC - this is a valid assumption in healthy subjects
BUT
What if NVC was changing as a result of disease progression
There is a risk that the gold standard biomarker may fail
This has been largely ignored

Question 19

What is the neurovascular degeneration hypothesis?

Answer 19

Zlokovic
Vascular damage causes reduced brain-blood perfusion and hypoxia and blood-brain dysfunction
Causes neuronal injury
Causes neurodegeneration

Question 20

What is the 2-hit hypothesis?

Answer 20

Zlokovic - developed further from neurovascular degeneration hypothesis
Hit 1 = vascular factors (hypertension, diabetes, cardiac disease etc)
Leads to BBB dysfunction and oligaemia (decreased blood flow)
This causes hit 2
Hit 2 = increase in beta-amyloid and tau (BBB dysfunction disrupts amyloid clearance and oligaemia causes an increase in amyloid production)
This leads to neuronal dysfunction and injury leading to neurodegeneration/cognitive decline causing dementia

Question 21

What mouse model is used in research and what characteristics do they displace?

Answer 21

Swedish human APP mutant - produce beta amyloid plaques and have memory problems but do not develop tau pathology and neuronal loss

Question 22

What did Zlokovic find when he crossed APP mice with pericyte deficient transgenic mice?

Answer 22

Resultant mice had all characteristics of AD
Increased beta amyloid plaques especially around vessels
Showed marked phosphorylated tau pathology
Significant neuronal loss
Significant BBB leakage

Question 23

What was the pathway Zlokovic suggested after crossing APP mice with pericyte deficient transgenic mice?

Answer 23

Pericyte loss causes disrupted beta amyloid clearance and vascular damage (BBB dysfunction, microvascular reductions)
This creates all the characteristic symptoms of AD in the mice: tau pathology, neuronal degeneration and neuronal loss which are not observed in either the beta amyloid pathway or vascular pathway alone.

Question 24

What did Kisler et al. (2017) find?

Answer 24

Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to the brain
Blood flow response to a hind paw stimulus is delayed in pericyte deficient mice
Really low levels of tissue oxygen in deep cortex

Question 25

What is the glymphatic system?

Answer 25

Another potential brain pathway thought to be involved in disease
May be a major pathway to remove beta amyloid
Waste clearance system that utilises a unique system of perivascular channels formed by astroglial cells to promote efficient elimination of soluble proteins and metabolites
Sleep is important for this system to function and drives the metabolite clearance from the brain