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week 9 part 2 Flashcards

1
Q

What does neuroimaging provide?

A

Immediate structural and functional information on the brain

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2
Q

What is Neuroimaging helpful in?

A

Predicting and monitoring disease progression

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3
Q

In relation to AD, what can neuroimaging detect?

A

specific protein and aggregates (e.g. amyloid plaques and tau tangles)

provide insight into brain structure and physiology

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4
Q

What are examples of Neuroimaging biomarkers for PET?

A
  1. Amyloid PET
  2. Tau PET
  3. [18F]-fluorodeoxyglucose (FDG) PET
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5
Q

What are examples of neuroimaging biomarkers for MRI?

A
  1. Structural MRI

2. Functional MRI

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6
Q

What was the first PET ligand to selectively visualise amyloid?

A
  1. [11C]-labelled Pittsburgh compound B (PiB)
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7
Q

What is the half-life of [11C]-PiB?

A

20 minutes

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8
Q

What does the half-life of [11C]-PiB limits its use to?

A

Imaging centres with onsite capability to synthesise this radiotracer

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9
Q

What does Amyloid PET ligand highlight the need for?

A
  1. [18F]-ligands to make amyloid PET imaging broadly available
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10
Q

What is a problem with PiB?

A

Radiotracer can only be synthesised/performed where the 11C-labelled Pittsburgh compound B is synthesised

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11
Q

What is Florbetapir F 18?

A

(PET) imaging ligand for the detection of amyloid aggregation associated with Alzheimer’s disease

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12
Q

What does Quantitative and visual assessment of amyloid PET reveal?

A

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

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13
Q

Where is the Amyloid PET deposition pattern found?

A

medial temporal lobe before spreading to other regions of the cortex

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14
Q

What does amyloid PET scan show?

A

ab is consistently deposited in posterior cingulate cortex

one of the earliest region of brain is the posterior cingulate cortex

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15
Q

What does posterior cingulate cortex have?

A

number of connections with other regions- has reciprocal connections with hippocampus which is associated with learning and memory

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16
Q

What does first-generation tau PET traces include?

A
  1. [11C]-pyridinyl-butadienyl-benzotiazole 3 [PBB3]
  2. [18f]- fLORTAUCIPIR
  3. [18F] -THK5351
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17
Q

What does tracers have?

A

A range of off target actions

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18
Q

Where does a number of Tau tracers bind?

A

Regions of:

  1. Basal Ganglia
  2. Thalamus
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19
Q

What do a number of PET tracers bind to?

A
  1. Monoamine oxidase B in Basal Ganglia
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20
Q

What can staining hinder?

A

Interpretation of the final image

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21
Q

What leads to second generation of tau pet tracers?

A

Off-target binding events

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22
Q

What have Pharmaceutical companies been trying to impove?

A

Binding selectivity and pharmacokinetic profile of tau PET tracers

e.g. [18F]-MK-6240

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23
Q

Where was off-target binding of [18F]-MK-6240 not observed?

A
  1. Basal Ganglia

2. Choroid plexus

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24
Q

What was observed in substantia nigra and meninges?

A

mild tracer retention

25
What has [18F]-FDG PET been used to measure?
measure cerebral metabolic rates of glucose (CMRglc), which is a proxy for neuronal activity
26
What is [18F]-FDG PET helpful in?
distinguishing control patients from Alzheimer’s disease patients.
27
What is metabolic activity linked to?
1. neuronal activity | 2. which is linked to neuronal cell death
28
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.
29
Where is a lack of metabolic activity seen in?
1. posterior cingulate cortex 2. Lateral temporal lobe 3. Frontal lobes
30
What has MRI been widely used for?
Early detection and diagnosis of AD
31
Where does atrophy typically start in?
1. Medial temporal and limbic areas 2. spread to parietal association areas 3. Frontal and primary cortices
32
What does structural imaging provide?
anatomical information of the brain
33
What does functional imaging provide?
Physiological processes that underscore neural activity
34
What are advantages of Neuroimaging?
1. Non-invasive 2. Provides immediate structural and functional details of the brain 3. Can reveal disease progression
35
What are disadvantages to Neuroimaging?
1. Expensive 2. Requires experienced personnel 3. Sensitivity and specifity to Alzheimer's disease is not satisfactory
36
What is the first to change in AD?
1. CSF amyloid beta 42
37
What are GWAS?
hypothesis free methods to identify associations between genetic regions (loci) and traits.
38
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.
39
Variants associated with the disease
found at a higher frequency in cases than controls.
40
What is statistical analysis carried out to indicate?
how likely a variant is to be associated with a trait
41
What are number of genes associated with AD?
1. CLU 2. PICAM 3. CR1
42
What is the strongest risk factor gene for late onset of AD?
APOE
43
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
44
What does CLU gene encode for?
Clusterin
45
What is clusterin?
highly conserved glycoprotein that functions primarily as an extracellular chaperone
46
What has Clusterin level shown to be?
elevated in Alzheimer’s disease, but how the protein affects pathogenesis is still being explored
47
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.
48
What does PICALM gene encode for?
Accessory protein in the endocytic pathway
49
What is the function of PICALM?
regulates the formation of the clathrin lattice during endocytosis
50
What has been associated with AD
• Multiple SNPs within and around the PICALM gene
51
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
52
What are the two ways of looking at role of PICALM?
1. Directly interacting with APP | 2. Interacting with other molecules involved in normal neuronal function
53
Define Metabolome
complete set of metabolites found in a biological cell, tissue, organ or organism, representing the end products of cellular processes.
54
Define Metabolomics
the systematic identification and quantification of small-molecule metabolite profiles of a biological system at a specific point in time
55
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.
56
What was LC-MS used to determine?
global metabolic changes in plasma and cerebrospinal fluid (CSF) from individuals with different Alzheimer’s disease severity.
57
What is metabolome providing us with?
opportunities to see differences between ad patients and controls
58
What can be affected in AD?
Cholesterol metabolism

markers xxx (11 decks)

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