Neuroimaging In Disease Flashcards
Why do people get dementia?
Genes and environment.
Have the best treatment for dementia we’ve had but cases are dropping?? Seem to be nicely correlated with statins used to treat high blood pressure
How will we defeat dementia?
By understanding the causes.
Get diagnosed when it’s too late.
Need to find new biomarkers to identify dementia earlier to have better chance at treating.
Current treatment is occurring when it’s too late.
Why do we need new treatments?
None that can slow or stop the diseases which cause dementia.
To develop these we must:
Gain a better understanding of the diseases.
Find suitable targets first treatments.
Test them in the right people at the right time.
These can cause disease:
Tau tangles and amyloid plaques
15% of dementia cases are genetic from mutated genes and the rest is sporadic (but dk why)
Research to understand dementia has been dominated by
Amyloid pathology
Cascade of amyloids found in AD patients
MRI for dementia has focussed on measuring brain size reduction
BUT it doesn’t have the resolution to image beta amyloid plaques
It does indicate the functional connectivity of the brain not only for disease but to try and understand how all the brain networks interact with each other
PET imaging is the only method tau and beta amyloid can be measured in the brain
Prevailing theory is the interaction between them drives disease forward
PET = quite invasive (radioactive tracer injected into blood stream)
Most research is focussing on fluorodeoxyglucose (FDG; measurement of glucose uptake) for metabolism and Pittsburgh compound B for measuring beta amyloid
Combining PET and fMRI can get a more in-depth detailed measure
Functional connectivity has transformed fMRI research - Biswal et al (1995)
Patient sat in the fMRI thinking about whatever (no task) and found if they put a seed in one brain area and looked for any pixels of BOLD signal which correlated with that seed, areas they theorised were functionally connected lit up - allowed for very detailed mapping of how the brains communicating with the cell
Suggested brain areas were talking and actually connected
Default mode of brain function
An abstract brain network was always active when subjects were in a scanner and told to think of nothing - default firing in different areas of the brain
Functional connectivity
Loads of different brain networks have been identified from subjects sitting in a scanner not doing tasks, talking to each other
These have also been identified to change in disease
Independent component analysis (ICA)
Most popular
Independently looks at all the pixels of BOLD signals in the brain and find areas that are mathematically in rhythm with each other - sees basic activity.
Then uses a graph analysis to see how all the networks interact with each other.
Bigger increase in size = bigger node = more strongly connected
Large cohort studies in disease
Study them throughout their lives, some will get AD and PD
Idea is cos have all their medical info, can hopefully find biomarkers across the diseased ones - get a complete timeline of disease progression and potential to detect early biomarkers and critical time points for intervention to point to a possible treatment
Findings from cohort studies?
Cerebrovascular system is the first to go - blood flow to the brain
Are there any issues of using fMRI and connectivity as a biomarker?
Functional connectivity relies on the fact that spontaneous neural activity will drive spontaneous BOLD signals - expected cos of NVC and a valid assumption in healthy subjects but not diseased ones
What if NVC was changing as a result of disease progression?
Neurovascular degeneration hypothesis
Suggests vascular damage first which either reduces brain perfusion or a breakdown in BBB which could result in breakdown of pathways and cascades causing neurodegeneration
Either a decrease in amyloid clearance or an increase in amyloid production which drives disease forwards - 2 hit hypothesis
Pericytes may be the main driver of neurodegeneration
Use transgenic mice bred to have AD - doesn’t perfectly replicate humans tho as it doesn’t happen naturally in mice
Swedish human APP mice - produce beta amyloid plaques and have memory problems but don’t develop tau pathology or have neuronal loss
Breed APP mice and pericytes deficient mouse the resultant offspring develops the characteristics of AD
So looks like perfect mouse model but not been replicated
What did APP-pericyte deficient mice show?
They had more beta amyloid especially around blood vessels and marked phosphorylated tau pathology - tau builds up in cells when there’s no pericytes
This mouse showed significant neuronal loss in brain volume, mimicking human AD
And had a significant BBB leakage - put dye into blood vessels and saw when deficient in pericytes there was increased BBB breakdown - could also be inflammation causing a leak in BBB cos neural inflammation has been suggested a predictor for AD?
SO pericytes could be v important for dementia
Pericytes deficient mice also showed …
Smaller blood flow response of capillaries to hindpaw stimulation
And v low oxygen levels in the deep cortex - these areas of anoxia a risk factor for dementia?
Suggest pericytes could be important for maintaining healthy oxygen levels in capillary beds and if they are deficient this could over time cause dementia
Glymphatic system
Major pathway to remove beta amyloid - plaques get in the way and can block the system, causing AD?
Importance of sleep
Found amount of amyloid in CSF of subject forced to stay awake was double the amount in controls = importance of sleep
Sleep as a biomarker? Poor sleep over years may increase dementia risk? Active research
