week 9 part 2 Flashcards
What does neuroimaging provide?
Immediate structural and functional information on the brain
What is Neuroimaging helpful in?
Predicting and monitoring disease progression
In relation to AD, what can neuroimaging detect?
specific protein and aggregates (e.g. amyloid plaques and tau tangles)
provide insight into brain structure and physiology
What are examples of Neuroimaging biomarkers for PET?
- Amyloid PET
- Tau PET
- [18F]-fluorodeoxyglucose (FDG) PET
What are examples of neuroimaging biomarkers for MRI?
- Structural MRI
2. Functional MRI
What was the first PET ligand to selectively visualise amyloid?
- [11C]-labelled Pittsburgh compound B (PiB)
What is the half-life of [11C]-PiB?
20 minutes
What does the half-life of [11C]-PiB limits its use to?
Imaging centres with onsite capability to synthesise this radiotracer
What does Amyloid PET ligand highlight the need for?
- [18F]-ligands to make amyloid PET imaging broadly available
What is a problem with PiB?
Radiotracer can only be synthesised/performed where the 11C-labelled Pittsburgh compound B is synthesised
What is Florbetapir F 18?
(PET) imaging ligand for the detection of amyloid aggregation associated with Alzheimer’s disease
What does Quantitative and visual assessment of amyloid PET reveal?
Consistent pattern of ligand retention that replicates sequence of AB deposition found in post-mortem studies of patients with Alzheimer’s disease e.g. posterior cingulate cortex
Where is the Amyloid PET deposition pattern found?
medial temporal lobe before spreading to other regions of the cortex
What does amyloid PET scan show?
ab is consistently deposited in posterior cingulate cortex
one of the earliest region of brain is the posterior cingulate cortex
What does posterior cingulate cortex have?
number of connections with other regions- has reciprocal connections with hippocampus which is associated with learning and memory
What does first-generation tau PET traces include?
- [11C]-pyridinyl-butadienyl-benzotiazole 3 [PBB3]
- [18f]- fLORTAUCIPIR
- [18F] -THK5351
What does tracers have?
A range of off target actions
Where does a number of Tau tracers bind?
Regions of:
- Basal Ganglia
- Thalamus
What do a number of PET tracers bind to?
- Monoamine oxidase B in Basal Ganglia
What can staining hinder?
Interpretation of the final image
What leads to second generation of tau pet tracers?
Off-target binding events
What have Pharmaceutical companies been trying to impove?
Binding selectivity and pharmacokinetic profile of tau PET tracers
e.g. [18F]-MK-6240
Where was off-target binding of [18F]-MK-6240 not observed?
- Basal Ganglia
2. Choroid plexus
What was observed in substantia nigra and meninges?
mild tracer retention
What has [18F]-FDG PET been used to measure?
measure cerebral metabolic rates of glucose (CMRglc), which is a proxy for neuronal activity
What is [18F]-FDG PET helpful in?
distinguishing control patients from Alzheimer’s disease patients.
What is metabolic activity linked to?
- neuronal activity
2. which is linked to neuronal cell death
What does cerebral metabolic rates of glucose reduction on FDG-PET precede?
the onset of symptoms in predisposed individuals, in both genetic early-onset and late-onset Alzheimer’s disease.
Where is a lack of metabolic activity seen in?
- posterior cingulate cortex
- Lateral temporal lobe
- Frontal lobes
What has MRI been widely used for?
Early detection and diagnosis of AD
Where does atrophy typically start in?
- Medial temporal and limbic areas
- spread to parietal association areas
- Frontal and primary cortices
What does structural imaging provide?
anatomical information of the brain
What does functional imaging provide?
Physiological processes that underscore neural activity
What are advantages of Neuroimaging?
- Non-invasive
- Provides immediate structural and functional details of the brain
- Can reveal disease progression
What are disadvantages to Neuroimaging?
- Expensive
- Requires experienced personnel
- Sensitivity and specifity to Alzheimer’s disease is not satisfactory
What is the first to change in AD?
- CSF amyloid beta 42
What are GWAS?
hypothesis free methods to identify associations between genetic regions (loci) and traits.
What does a typical GWAS study collect?
data to find out the common variants in a number of individuals with and without a common trait across the genome using genome wide SNP arrays.
Variants associated with the disease
found at a higher frequency in cases than controls.
What is statistical analysis carried out to indicate?
how likely a variant is to be associated with a trait
What are number of genes associated with AD?
- CLU
- PICAM
- CR1
What is the strongest risk factor gene for late onset of AD?
APOE
Gene-based biomarkers for AD?
♣ They were also able to see an association between two genes this was CLU and PICALM
♣ They were also able to see an association between two genes this was CLU and PICALM
What does CLU gene encode for?
Clusterin
What is clusterin?
highly conserved glycoprotein that functions primarily as an extracellular chaperone
What has Clusterin level shown to be?
elevated in Alzheimer’s disease, but how the protein affects pathogenesis is still being explored
What is prominent hypothesis of clusterin?
clusterin’s ability to bind Aβ peptides and thereby influence their aggregation, deposition and clearance, but the underlying mechanism(s) remain to be delineated.
What does PICALM gene encode for?
Accessory protein in the endocytic pathway
What is the function of PICALM?
regulates the formation of the clathrin lattice during endocytosis
What has been associated with AD
• Multiple SNPs within and around the PICALM gene
what does prominent hypothesis suggest about PICALM?
PICALM affects internalisation of APP (thus the production of Aβ) and endocytosis and trafficking of other molecules important for neuronal function
What are the two ways of looking at role of PICALM?
- Directly interacting with APP
2. Interacting with other molecules involved in normal neuronal function
Define Metabolome
complete set of metabolites found in a biological cell, tissue, organ or organism, representing the end products of cellular processes.
Define Metabolomics
the systematic identification and quantification of small-molecule metabolite profiles of a biological system at a specific point in time
What does metabolic profiling involve?
quantification of a specific group of metabolites for discrimination from different biological origins or status – with the goal of capturing the complexity of metabolic networks.
What was LC-MS used to determine?
global metabolic changes in plasma and cerebrospinal fluid (CSF) from individuals with different Alzheimer’s disease severity.
What is metabolome providing us with?
opportunities to see differences between ad patients and controls
What can be affected in AD?
Cholesterol metabolism
