Lecture 7 Neuroimaging in Disease Flashcards
what is dementia?
an umbrella term used to describe a collection of symptoms e.g. memory loss, caused by brain diseases such as AD
not a normal part of ageing
overview AD
- 15% genetic causes, 85% sporadic
- current beliefs are amyloid beta plaques extracellularly and tau tangles intracellularly leading to neuroinflammation and cell death
- the amyloid cascade hypothesis has dominated since 1980s, however, the removal of amyloid plaques doesn’t treat AD in all models
discuss structural MRI in dementia/AD research
structural MRI focusses on changes in brain size over time. In AD usually a loss of the mass of an orange over disease progression.
MRI is good at tracking changes in volume over time, however, it’s expensive and doesn’t have the resolution to image plaques
discuss PET imaging in AD research
the only method to image tau and amyloid-beta plaques in living brains. Uses FDG to look at glucose uptake (metabolism) and PiB to look at amyloid-beta (seeing how plaques alter metabolism)
discuss functional connectivity in research
it has transformed fMRI, and led to the discovery of functional/structural networks such as DMN (Raichle)
through looking at a seed voxel and another voxel (area) of interest and seeing how correlated their activity is in different states to understand how functionally they connect
model free methods, such as independent component analysis (ICA) are used to search for underlying sources that explain resting sate processes
the goal is to combine structural and functional connectivity and observe whether changes are biomarkers for disease
what are the 2 key large co-ort studies into AD?
Alzheimer’s Disease Neuroimaging Initiative (US) (ADNI)
Biobank (UK)
overview ADNI
a large study taking multimodal data from elderly controls and AD patients to look at detailed history of health/education, neuropsychological testing, gene testing, scans etc. to try and give a timeline of disease to find early biomarkers/early interventions
Itturia-Medina 2016
looked at data from large cohort of LOAD patients and a number of biomarkers and found the first system to start dysfunctioning in AD is the cerebrovascular system
overview Biobank
500,000 people ages 40-69 recruited 2006-2010 and taking many measures such as blood and saliva and scans over years to understand AD development
what is the issue with using fMRI and connectivity as biomarkers for AD?
it relies on the assumption that spontaneous neural activity will drive spontaneous BOLD signals (through NV coupling), which is a fairly fairly assumption in healthy subject, however, what if NV coupling changes as a result of disease- it can no longer be accurate
discuss the neurovascular degeneration hypothesis
the original cause of AD by Alois Alzheimer was believed to be vascular, however, with the discovery of amyloid plaques in 1980s the interest swung to this. However, vascular theories are returning
Zlokovic’s lab focusses on neurovascular aspect, suggesting that vascular damage is what leads to build up of proteins/ plaques which cause neurodegeneration
he developed a ‘2 hit’ hypothesis whereby the 1st hit is breakdown of pericytes hence BBB function and 2nd hit is that this leads to amyloid beta plaque and tau buildup and dementia/cell death
his lab crossed APP (amyloid beta plaque) mice mutants with pericyte deficient mice. Previous research found that APP mice showed some symptoms of AD (plaques and memory loss), however not all (no tau pathology/neuronal loss), however, this cross showed all these characteristics- tau pathology in hippocampus, loss of neurons, BBB leakage etc.
suggests role of pericytes
they later suggested that pericyte degeneration leads to uncoupling and limits O2 supply, which is deep in the cortex which over time causes AD
Atwell’s group 2019 used human and rat brain tissue and found alpha-beta plaques to cause constriction of blood flow by pericytes
discuss glymphatic system in AD
Glymphatic system is similar to lymphatic in periphery.
Pressure in the interstitial outside veins and arteries pushes CSF through brain ‘washing it’, particularly in sleep to remove harmful proteins. This has been shown in sleeping mice imaging and looking at CSF of healthy young people after 1 lost night of sleep, showing double Amyloid beta proteins compared to normal controls
