3. PET-Principle
• Image and quantify a physiological function or molecular target of
interest (e.g., blood flow, metabolism, receptor binding) in vivo by
noninvasively assessing the spatial and temporal distribution of the
radiation emitted by an intravenously injected target-specific probe
(radiotracer)
• Molecular imaging techniques
4. Positron Emission Tomography(PET)
• Positron-emitting radiotracer is injected
• The emitted positron travels a short distance in tissue (effective range
< 1 mm for common PET nuclides) before it encounters an electron,
yielding a pair of two photons emitted in opposite directions
• Photon pair leaving the body is detected quasi-simultaneously (within
a few nanoseconds) by scintillation detectors of the PET detector
rings that surround the patient’s head
5.
6. PET
• Spatial resolution is about 3 to 5mm
• Rapid temporal sampling (image frames of seconds to minutes)
• Radionuclides in neurological PET studies are
1) Oxygen-15 (15O, half-life = 2.03 minutes)
2) Carbon-11 (11C, half-life = 20.4 minutes)
3) Fluorine-18 (18F, half-life = 1097 minutes)
8. PET in Parkinsonism
• Parkinson’s disease (PD) is the second most common
neurodegenerative disorder after Alzheimer’s disease
• Histopathological lesions in PD precede the development of
symptoms by several years, leading to motor disturbances after
approximately 50–70% of dopaminergic neurons are lost
• Nigrostriatal loss in patients with PD is estimated to be at least 5% per
year, which is substantially higher than the age-associated physiologic
loss of nigrostriatal neurons, estimated to be 8% per decade
14. Imaging of the dopaminergic system
1) Dopamine synthesis
2) Dopamine storage in synaptic vesicles
3) Dopamine transporters
4) Dopamine receptors
15. Dopamine synthesis
• The PET tracer 3,4-dihy-droxy-6-[18F]fluoro-l-phenylalanine
([18F]DOPA) has been used in PD studies to evaluate the first step in
dopaminergic transmission, namely dopamine synthesis, which takes
place in the presynaptic dopaminergic neurons.
• [18F]DOPA is taken up into neurons by an active transport system and
is converted to [18F]dopamine by aromatic amino-acid decarboxylase
(AADC), which represents the rate-limiting step in dopamine synthesis
in dopaminergic neurons
• As such, [18F]DOPA uptake reflects the synthetic ability of
dopaminergic neurons to produce dopamine through AADC.
16. Dopamine synthesis
• Significant reduction of [18F]DOPA striatal uptake in PD patients
compared to control subjects
• The reduction is more severe in the putamen than in the caudate
nucleus, and most prominent in the caudal parts of the putamen
• [18F]DOPA uptake correlates with clinical disease severity and with
disease progression, with 8–9% annual decline in uptake rate
constant in the putamen and 4–6% decline in caudate nucleus of
clinical PD patients
17. Dopamine synthesis
• However, at disease onset, false negative cases have been reported
due to the compensatory upregulation of AADC in preserved
dopaminergic terminals, which implies that at this stage of the
disease, [18F]-Dopa underestimates the degenerative process
• This is not in the using dopamine transporter because dopamine
transporters activity is not regulated like dopadecarboxylase
• DAT imaging is more sensitive than [18F]-Dopa to detect
dopaminergic degeneration especially in early-stage PD
18. Dopamine storage in synaptic vesicles
• The dopamine produced at the synaptic level is stored in synaptic
vesicles by the type-2 vesicular monoamine transporter (VMAT2),
which is responsible for translocating monoamine neurotransmitters
from the cytoplasm into vesicles
• PET radiotracer [11C]dihydrotetrabenazine ([11C]DTBZ) is a specific
ligand of VMAT2 and is used as an in vivo marker of nigrostriatal
dopaminergic system integrity
19. Dopamine storage in synaptic vesicles
• Studies with [11C]DTBZ PET showed the expected pattern of
decreased uptake in the corpus striatum in PD patients compared to
control subjects, involving preferentially the putamen
• [11C]DTBZ uptake is not affected by synaptic dopamine levels or
dopaminergic agents, which makes the tracer one of the best
available radioligands to examine dopaminergic system integrity
20. Dopamine transporters
• Dopamine transporters (DAT) are located in the presynaptic
dopaminergic nerve terminal
• Dopamine reuptake through the DAT is the primary mechanism of
dopamine removal from the region of the synaptic cleft
• Among many DAT-specific tracers used mainly to assess decreased
DAT density, which may precede clinical symptoms in PD
21. Dopamine transporters
• PET studies evaluating DAT availability, particularly with N-(3-
[18F]fluoropropyl)-2α carbomethoxy- 3α -(4-iodophenyl)nortropane
([18F]FP-CIT) and 2α-carbomethoxy-3α-(4- [18F]fluorophenyl)tropane
([18F]CFT) showed a reduction of striatal tracer uptake in PD patients
compared to control subjects, affecting primarily the putamen and to
a lesser extent the caudate nucleus
• The reduction is typically more severe in the striatum contralateral to
the earliest and most affected body side
• Striatal DAT levels, particularly in the putamen, correlate with disease
severity and decrease with PD progression
22. Dopamine receptors
• PET studies with [11C]raclopride showed that striatal dopamine D2 binding
to the postsynaptic dopaminergic receptors was either normal or increased
in PD patients
• This increase has been interpreted as a compensatory reaction to the
reduction of striatal dopaminergic terminals
• D2 receptor upregulation is most evident at early stages and contralateral
to the clinically most affected side and is usually the site of onset in PD.
• On the other hand, the increase in postsynaptic D2 receptor binding could
also be due to loss of endogenous dopamine, thereby unloading the post-
synaptic receptors and ultimately increasing uptake of [11C]raclopride or
similar PET tracers in these receptors.
23. Dopamine receptors
• D2 receptor imaging is widely used for the differential diagnosis of
parkinsonism, since uptake is typically normal or increased in patients
with PD, whereas patients with other forms of parkinsonism, such as
multiple system atrophy and progressive supranuclear palsy show
reduced tracer uptake
• Chronic pharmacologic treatment may reduce D2 receptor availability,
probably due to downregulation
25. DAT-PET
• Specificity-100%
• Sensitivity : 38% to 100%
• 15% of patients diagnosed as having PD had normal DaT-PET study-
classified as “scans without evidence of dopaminergic deficit”
(SWEDD)
• SWEDD-Dystonic tremor
26. DAT-PET
• Because most dopaminergic
transmission occurs in the striatum,
this area will show the maximum
uptake of DaT radiotracers, with
minimal background activity in the
remainder of the brain.
• In scans with normal findings, the
striata appear as symmetric “comma”
shapes
• Any asymmetry or distortion of this
shape, in the absence of patient
motion, implies an abnormal scan
finding.
27. PET in Parkinsonism
• In PD, antero-posterior gradient noted that posterior putamen more
affected ( then anterior putamen>caudate) while in PSP uniformity
• F-DOPA uptake may be normal in early PSP which reflects, PSP is more
a postsynaptic receptor problem
33. FDG-PET
• PET studies using the glucose analog, 2-deoxy-2-(18F)fluoro-d-glucose
([18F]FDG), to assess cerebral glucose metabolism
• After uptake in cerebral tissue it is phosphorylated by hexokinase into
[18F]FDG-6-P
• Since [18F]FDG-6-P is neither a substrate for transport back out of the
cell nor can it be metabolized further, it is virtually irreversible
trapped in cells
• Therefore, the distribution of [18F]FDG in tissue imaged by PET
(started 30-60 minutes after injection to allow for sufficient uptake; 5-
20 minute scan duration) closely reflects the regional distribution of
cerebral glucose metabolism
34. FDG-PET
• Sensitivity of the clinical diagnosis was to be 92.8% for PD, while the
sensitivity was only 70.1% for MSA, 73.1% for PSP, and 26.3% for CBD.
Specificity was 85.8% for PD and more than 95% for MSA, PSP, and
CBD
• With FDG-PET, sensitivity is, 97.7% in early PD, 91.6% in late PD,
96.0% in MSA, 85.0% in PSP, 90.1% in CBD while specificity exceeded
90% in all the groups
35. FDG-PET in PD
• Relatively increased activity is
usually observed in putamen,
globus pallidus, thalamus, pons,
cerebellum, and primary motor
cortex, whereas decreased
activity is detected in bilateral
parietal, occipital, and frontal
cortices (dorsolateral prefrontal,
premotor, and supplementary
motor areas)
36. FDG-PET in PD
• Increased striatal FDG uptake in PD patients is explained by loss of
inhibitory nigrostriatal dopaminergic input, leading to functional
overactivation of the putamen
37. FDG-PET in MSA
• Patients with MSA-C have
predominant cerebellar
hypometabolism while
predominant striatal
hypometabolism is in MSA-P
• There is a reduction of cerebral
glucose metabolism in the
frontal cortices, which appears
to spread to temporal and
parietal cortices during the
disease course, with subsequent
cognitive decline
38. FDG-PET in PSP
• In PSP, glucose metabolism was
consistently reported to be
reduced in caudate nucleus and
putamen, thalamus, pons/
midbrain, and the mesial and
dorsal frontal cortex (most
notably in anterior cingulate
cortex, precentral, dorso- and
ventrolateral premotor and
prefrontal areas)
39. FDG-PET in CBD
• Highly asymmetrical cerebral
hypometabolism in the
thalamus, striatum, and
predominantly parietal cortex
but also frontal cortex (including
cingulate cortex, precentral,
premotor, and prefrontal areas)
of the hemisphere contralateral
to the side most clinically
affected
40. FDG-PET
1) PD- hypermetabolism in putamen;
2) MSA- hypometabolism in putamen and cerebellum;
3) PSP- hypometabolism in brainstem and midline frontal cortex;
4) CBD- hypometabolism in parietal cortex and basal ganglia
