Download Targets for dopaminergic ligands

Synaptic Function
1: Dopamine
Targets for dopaminergic ligands
Tyrosine
Dopamine
synthesis
L-DOPA
DA
Glial cell
Vesicles
Pre-synaptic terminal
Dopamine
Transporters
MAO-B
COMT
D2 Receptors
Post-synaptic cell
Targets for dopaminergic ligands
Tyrosine
L-DOPA
F18-Dopa
DA
Glial cell
Vesicles
Pre-synaptic terminal
MAO-B
COMT
I123 IBZM
or epidepride
I123 FPCIT
or ß-CIT
Post-synaptic cell
***
Dopamine transporter imaging
Normal Dopamine Transporter (DATSCAN) images
Head of Caudate
MRI
Putamen
DATSCAN
SPECT
Body of Caudate
A PD image with DaTSCAN
Medial part of SN projects to caudate
Lateral part of SN projects to putamen
In PD the lateral part of SN always degenerates first
preferential loss in putamen
relative to caudate
Diagnosis and staging of Parkinson’s Disease
Clinical diagnosis
Imaging
diagnosis
Accuracy of Diagnosis in Presumed PD
Meara J et al Age and Ageing 1999;28:99-102
.
•26% of patients receiving inappropriate treatment
Post-mortem data suggests figure may even be higher
Even on first presentation SPECT
shows loss of 50% of neurones
Objective measurement of progression in assessment of therapy
Normal
PD: H&Y1
PD: H&Y2
PD: H&Y3
Can we show progression in an individual patient?
51 year old lady,
first Presentation
Caudate
Putamen
18 months
36 months
–––––––––––––––––––––––––––––––––––––––––––––––––
R
L
R
L
R
L
4.29
3.84
4.14 3.14
3.31 2.40
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------2.05 1.32
1.56 1.17
1.17 1.07
–––––––––––––––––––––––––––––––––––––––––––––––––
Specific/Non-specific ratios
2: Serotonin
Serotonin Transporter [SERT] imaging
Clinical depression
Major Depression
•
•
prevalence as high as 10%
key symptoms
low mood
diminished interest in pleasure
hopelessness, guilt, suicidality
cognitive impairment
changes in sleep, appetite, libido
•
World Bank report - global burden second only to IHD by 2020
Treatment of depression
The Monoamine Hypothesis
•
1950s - drugs used to treat TB and schizophrenia were found to elevate
mood and stimulate activity
•
First tricyclic antidepressant - found to increase the activity of the
monoamine neurotransmitters by inhibiting their reuptake
•
Thus, antidepressants appeared to work by normalising a deficit in
monoamines, especially serotonin
•
Drugs highly selective for the serotonin system were developed
Action of SSRI antidepressants
Pre-synaptic terminal
Serotonin transporters
(SERT)
Synapse
Serotonin
Serotonin reuptake
inhibitor (SSRI)
123I-beta-CIT
Post-synaptic cell
Image available
binding sites
Analysis of 123I-beta-CIT scans for SERT availability
SPECT scans at 3 hours reflect SERT binding in midbrain regions
These are sagittal views through the midline in 2 patients
High drug effect
on transporters
Lower drug effect
on transporters
Availability is a measure of the number of transporters
available to transport neurotransmitter [serotonin] from the
synapse back into the pre-synaptic terminal.
SERT availability = (MB - OCC)/ OCC
where MB and O CC are tracer count rates in the mid-brain
and in the occipital reference region.
Analysis of 123I-beta-CIT scans for DAT availability
SPECT scans at 24 hours reflect DAT binding in the striatum
This is an axial view through the basal ganglia.
DAT availability = (ST - OCC)/ OCC
where ST and O CC are tracer count rates in the
striatum and in the occipital reference region.
SERT availability for patients on SSRIs or venlafaxine
1.00
0.80
The normal
availability
index is
around 2.7
0.60
SERT
Availability
0.40
0.20
0.00
Non-responders
Responders
•9 out of 11 patients in the SSRI or SNRI groups with binding indices
between 0.2 and 0.6 were responders and all 7 outside this range
were non-responders
•This suggests that response could be improved by better regulation
of the degree of transporter downregulation - See also( Meyer et al, Amer J Psych
2004)
DAT binding indices for patients on antidepressants as
a function of age
12.00
10.00
8.00
DAT
6.00
Availability
4.00
2.00
0.00
0
10
20
30
40
50
60
70
Age
•This is consistent with the literature and indicates a decline
of 7.3% per decade.
Dementia: the diagnostic dilemma
•
Alzheimer's disease
•
Dementia with Lewy bodies
•
Frontal lobe dementia, including Pick's disease
•
Alcohol related dementia
•
Vascular dementia
[email protected]
Therapy for AD
Cholinergic projections
The acetylcholine
neurotransmitter
system is selectively
affected in AD
Therapies aim to
improve cholinergic
neurotransmission
Septum
Basal
nucleus
MR in psychiatry
• Alzheimer’s disease - progression
Normal ageing
Early onset AD
difference at 12m
difference at 12m
Alzheimer’s disease - progression
A typical SPECT perfusion scan
The AD perfusion pattern
• The probability that patients with
memory loss and normal
perfusion had Alzheimer's
disease was 19 %.
• The probability of Alzheimer's
disease with bilateral temporoparietal defects was 82%
Alzheimer's disease progression
•
57 year old man presenting with gradually deteriorating memory
Initial
99mTcHMPAO
SPECT
Follow-up
at 4.5
years
Frontal lobe dementia
• Frontal hypo-perfusion sometimes including temporal lobes
Alzheimer’s disease
Bi-lateral temporo-parietal
deficits
Frontal lobe dementia
Bi-lateral frontal lobe
deficits
Vascular dementia
• Multiple regions of focally reduced perfusion
Early diagnosis?
Ann Neurol 2004;55:306-319