le DAT scan “The day may not be far off when molecular imaging

Conclusion slide: AMA-UCL May 12, 2007
“The day may not be far off when molecular imaging
methods are standard tools for clinical practice in
neurology.”
Nouveautés en Imagerie :
le DAT scan
Roger L Albin
Geriatrics Research, Education and Clinical Center, Ann Arbor. VAMC, Ann Arbor,
MI, USA; and Department of Neurology, University of Michigan, Ann Arbor, MI,
USA
Prof. Thierry Vander Borght
Service de Médecine Nucléaire
UCL Mont-Godinne
Lancet Neurol 2007; 6:288-9.
Global
Function
Anatomy
Specific
Function
DA Pathways
1) Tuberoinfundibular
2) Mesolimbic
Ctscan/MRI
fMRI, SPECT, PET
SPECT, PET
Atrophy
Distribution pattern
Cellular dysfunction
• reward/salience
• pleasure, euphoria
• motor function
• compulsion
• Perseveration
3) Nigrostriatal
Size
Earliness
Dopaminergic synapse
A Good Radiotracer
NigroNigro-striatal neuron
Glial cell
Tyrosine
MAOMAO-A
TyrosineTyrosine-hydroxylase
L-Dopa
DopaDopa-decarboxylase
D2
Dopamine
metabolites
²
Design
Parameters
MAOMAO-B
COMT
Test
Criteria
COMT
D2
D1
COMT
PostPost-synaptic neuron
D2
1.
2.
3.
4.
5.
Must have an appropriate target
High in vitro affinity and selectivity for target
Able to be radiolabeled routinely
Target accessibility
Low non-specific binding
6. Good signal to noise ratio in vivo
7. Appropriate in vivo pharmacokinetics
8. Appropriate in vivo distribution and pharmacology
9. Low amounts of labeled metabolites in the ROI
10. Sensitivity towards target
1
Assessment of the presynaptic DA system with PET & SPECT
Dopaminergic synapse
[11C]C]-deprenyl
[11C]C]-befloxatone
NigroNigro-striatal neuron
[11C]DTBZ PET
[11C]FE-CIT PET
AADC
VMAT2
DAT
Prof. Bartenstein
Univ. Mainz
Prof. Frey
Univ. of Michigan
Prof. Antonini
Milano
[123I]ß-CIT SPECT
[123I]FP-CIT SPECT
[99mTc]TRODAT-1 SPECT
DAT
DAT
DAT
18-24 h p.i.
3-6 h p.i.
3-4 h p.i.
Glial cell
Tyrosine
MAOMAO-A
[11C]C]-tetrabenazine
TyrosineTyrosine-hydroxylase
métabolites
²
L-Dopa
[18F]F]-FluoroDOPA
[18F]FDOPA PET
MAOMAO-B
COMT
D2
DopaDopa-decarboxylase
Dopamine
[11C]C]-SCH 23390
[123I]I]-FPFP-CIT (DaTSCAN
(DaTSCAN®)
[11C]C]-PE2I, [123I]I]-PE2I
123I][COMT
I]-b-CIT
[76Br]D2
Br]-FEFE-CBT
[11C]C]-CFT, [11C]C]-RTI32
[11C]C]-raclopride
D1
D2
COMT
PostPost-synaptic neuron
Metabolite Analogues: FDOPA
BRAIN
Presynaptic DA Terminal
FDA
DAT
vesicle
OMeFDOPA
FDOPA
FDA
FDOPAC
FHVA
BBB
OMeFDOPA
VMAT2
ATP
ADP
Vesicular Lumen
CaM
Kinase II
Extracellular
FDOPA
Pi
Pase
H2O
Exocytosis
Recycling
H2N
HOOC
Cytoplasm
COOH
CIRCULATION
NH2
Cytoplasm
Limitations
SERVICE HOSPITALIER
FREDERIC JOLIOT
1000 40 nm vesicles
Proton exchange
Monoamine
(-) reserpine, TBZ, ketanserin
• Expensive
• Metabolization
• Not specific for DA neurons
• Uptake = f(dopamine turnover)
1000 DAT
Cotransport of cation
Dopamine
(-) antidepressant, cocaine
Dopaminergic function and dopamine transporter binding in
Parkinson’s disease
[18F]-DOPA
1.6
%
Putamen
100
[18F]-DOPA
[76Br]-FE-CBT
80
~20%
60
[76Br]-FE-CBT
0
2.8
40
Poewe & Scherfler. Mov Disoder 2003;18:S16-21.
20
0
early
drug-naive PD
advanced
PD
0
less more
affected
Early PD
less more
affected
Advanced PD
Ribeiro et al. Arch Neurol 2002
2
Practical aspects for clinical use:
Medication-interactions for DAT imaging
DAT Radioligands
Radioligand
STR/CBL
Time Max DA/5HT
Brain
metabolites
(min)
[123I]β-CIT
>12
> 1200
1.7
+
[123I]FP-CIT
4
90-120
2.8
-
[123I]Altropane
6
30
28
-
[99mTc]Trodat
2
120-140
“5/1”
-
CNS Stimulants
cocaine, crack cocaine
amfetamine + analogs
methylphenidate (Ritaline)
dextroamphetamine
phenylpropanolamine
phentermine, mazindol
norephedrine
phenylpropanolamine
amoxapine, buspirone
R/ for ADHD, epilepsy, nacrolepsy
Most anti-anorectic and anti-obesities drugs
Sympathomimetics (nasal decongestant)
Some antidepressants (esp. tricyclic)
NO effect:
levodopa, amantadine, benzhexol (trihexifenidyl), budipine,
selegeline (Deprenyl), metoprolol, propranolol en primidon
NO interference expected from dopamine receptor-agonists
123I-Ioflupane
Nigrostriatal Pathway
SPECT Procedure
Striatum
Single i.v. injection of
123I-Ioflupane (3-5 mCi)
Thyroid
blockade
Effect of Normal Aging on Specific
[11C]DTBZ DVtot in the Putamen
SPECT
2.5
•
•
•
•
Gamma cameras : Two-headed or three-headed
Collimators: high resolution or fan beam
Photopeak 159KeV; Energy Window ±10%
Minimum of 750k counts/slice
SPECIFIC DVtot
3-6 h.
Substantia
Nigra
- tremor
- rigidity
- bradykinesia
-
postural abnormalities
gait
cognitive decline
autonomous signs
speech disturbance
1.0
0.5
20
2
3
30
4
40
5
50
6
60
7
70
Frey et al. Ann Neurol
1996; 40:873.
AGE (yr)
Parkinsonian Signs in the Elderly
Idiopathic Parkinson’s
Disease
>> 90%
1.5
0.0
Clinical level
Parkinsonism
DVtot = 1.432 - 0.011[age]
r = 0.53, p = 0.04.
2.0
Multiple System Atrophy
• 467 residents > 64 years
• > 2 specified parkinsonism features
PSP
Essential tremor
Vascular
Toxic
Corticobasal degeneration
Wilson’s disease
Age
65-74 y
75-84 y
85 y +
BK
11%
21%
37%
Gait
13%
28%
52%
Rigid
19%
30%
44%
Tremor Parkinsonism
19%
15%
24%
30%
30%
52%
…
Bennett et al. NEJM 1996;334:71-6.
3
THE BRAIN BANK : 100 CASES
Parkinson’s Disease
Hughes et al, JNNP 1992
• Second most prevalent neurodegenerative disorder
• Prevalence 1-2 % (> 65 y)
• Etiology : ?
– Genetic factors
N
PM
•
•
•
Parkin
Alpha-synuclein
Ubiquitin C hydrolase L1
76 histological IPD
46 IPD
and...
24 not IPD
6 PSP
5 MSA
30 IPD only
3 Alzheimer
– Environmental
•
Same numbers : Rajput et al,
J Can Neurol Sci 1991
3 lacunar
26 vascular disease
Oxidative stress
1 post-encephalitis
10 Alzheimer-type
– Protein
aggregation
in SNc common to all forms
1 ET
BUT : Hughes, Lees et al (Brain 2002):
Accuracy in specialist movement disorder service > 85 % for
IPD, MSA and PSP
Tatsch, EANM 2000
Diagnostic Accuracy: Specialist and Generalist
Features Improving Accuracy in PD
Initial Diagnosis PD n=131
Specialist
n=97
Hughes et al Neurol 1992; 42: 1142-6
Brain Bank Criteria
+ Asymmetric onset
+ No atypical features
+ No possible cause for other PS
Confirmed
n=86 (89%)
Refuted
n=11 (11%)
Non-specialist
n=34
Confirmed
n=25 (74%)
Refuted
n=9 (26%)
Initial Diagnosis not PD n=69
Specialist
n=26
Non-specialist
n=43
Diagnostic accuracy 93%
But
32% of pathologically proven PD not identified
Confirmed
n=20 (77%)
Refuted
n=6 (23%)
Confirmed
n=34 (79%)
Refuted
n=9 (21%)
Schrag et al; JNNP 2002;73:529-534.
Difficult Clinical Cases
Patients with a tremor dominant disorder
Diagnostic Revision in PD
•
n
“error rate”
•
•
Long-standing tremor-dominant disorder, considered essential tremor but with
features raising uncertainty
Tremor treatment: poorly tolerated
Antiparkinson treatment: little effect
Study
Type
CALM-PD 2002
β-CIT SPECT
82
4%
Benamer et al 2003
FP-CIT SPECT
38
13%
•
•
•
Real-PET 2003
18F-Dopa
PET
186
11%
Patients with “multiple pathology”
Ell-dopa 2003
β-CIT SPECT
>100
14%
Drug-induced or unmasked PD
•
Patients with current or recent drug R/ known to cause drug-induced parkinsonism
Persistence of features after stopping or amending treatment
Or clinical features more suggestive of idiopathic PD
Patients with co-existent medical conditions which affect interpretation of the
movement disorder
- small vessel cerebrovascular disease
- depression / anxiety
- chronic obstructive pulmonary disease
- osteoarthritis and osteoporosis
4
Visual Assessment of SPECT image
Summary: Clinical Diagnosis of PD
Abnormal
•
A majority of cases can be diagnosed clinically
•
Therapy response and monitoring over time improves diagnostic
accuracy
Normal
Type 1
Type 2
Type 3
Clinical Aspects of Early Diagnosis
•
PD has a long pre-symptomatic phase
•
Early clinical features are mild / subtle
•
Clinical monitoring / therapy trial over 6 months to 2 years
•
Average time to ‘confirmed and accepted’ diagnosis is 18 months
123I-Ioflupane
Yielding
(Uncertain diagnosis)
SPECT
n= 33
True Positive
True Negative
False Negative
Rate
100%
92%
8%
(Booij et al. Eur J Nucl Med 2001, 28: 266-272)
Visual
assessment
n=158 PD, 27 ET, 35 HV
Institutional
read
Consensus
Blinded read
Sensitivity for PD
97%
95%
Specificity for ET
100%
93%
(Benamer et al. Movement Disorders 2000, 15: 303-510)
Pirker. Mov Disoder 2003;18:S43-51.
STUDY POPULATION
Patients with Clinically Uncertain Parkinsonian Syndrome
Patients recruited
(written informed consent)
125
DaTSCAN
not performed
5
Patients included
120
Prohibited
medications
2
Evaluable Patients
118
Marshall & Grosset. Mov Disoder 2003;18:22-7.
Demographics & Clinical Symptoms
Number of patients
118
Sex
Male/female
59/59
Race
Caucasian/others
116/2
Age (years ± SD)
65.5 ± 11.2
Unilateral symptoms
Bradykinesia
Tremor
Rigidity
Postural instability
62%
69%
74%
63%
36%
Exclusion criteria:
• Diagnosed PS but clinical uncertainty between PD, PSP and MSA
• Medications suspecting to interact with 123I-Ioflupane uptake
• History of drug abuse
• Others
5
Results of DaTSCAN image versus
initial suspected clinical diagnosis
?
Normal
?
63%
60%
94%
normal(44)
54%
36%
abnormal(73)
80%
46%
40%
100%
100%
68%
32%
Abnormal
%of patients
80%
Final diagnosis vs. results of DaTSCAN
59%
60%
41%
40%
20%
20%
0%
PS (n=66*)
Non-PS (n=26)
* in one patient the image was not interpretable
Inconclusive
(n=25)
6%
0%
0%
PS (n=62)*
Initial diagnosis
non-PS (n=33)
Inconclusive (n=22)
Final diagnosis
* in one patient the image was not interpretable
Analytical Model (simple version)
Clinical Impact of 123I-Ioflupane (DaTSCANTM) SPECT
Impact on diagnosis in 109/118 patients (92.4%):
• Change initial diagnosis: 53 (45%)
• More confident with initial diagnosis: 56 (47%)
Choice
Test
Diagnostic
outcome
+ve: ?PS
Use of
DatSCAN
Change to PS
20%
PS supported
31%
Confidence in PS:
63.9±19.7 to 90.5±13.3%, p<0.0001
Treatment
selection
PS therapy
-ve: ?ET
ET therapy
Target
Cohort:?P
S
PS therapy
Change to
other than PS
25%
No impact
on diagnosis
8%
No use of
DatSCAN
Other than PS
supported
16%
ET therapy
Confidence in PS:
41.1± 24.2 to 8.7±13.6%, p<0.0001
PS = Parkinson syndrome
TP/TN = True Positive/True Negative
Costs of Diagnosis, Treatment and Adverse Events (€)
Current diagnosis and treatment
• Current diagnosis and treatment
• 123I-FP-CIT SPECT
• 1 year PD drug treatment first line
• 1 year PD drug treatment second line
• 1 year PD specialist visits
• Follow-up diagnosis 6 months
• follow-up diagnosis over 2–5 years
• No treatment 6 months
• ET drug treatment 6 months
Costs of treating adverse events
• Dyskinesia
• Psychosis
• Orthostatic hypotension
216
900
1,625
1,819
170
86
162
131
230
1,584
2,172
1,115
Final Results
True result plus
Consequences
TP: PS
Benefit, AEs
FP
No benefit, AEs
FN: PS
No benefit
TN
Benefit
PS
Benefit, AEs
Other
No benefit, AEs
PS
No benefit
Other
Benefit
ET = Essential tremor
FP/FN = False positive/ False Negative
CURRENT
DatSCAN
DIFF
Total cost
6464
6569
105
Adequately treated yrs
1.998
3.397
1.398
Cost per adequately treated year
3235
1934
74.8
Prevalence of
PS
Total cost
current
ATY
current
Total cost
DaTSCAN
ATY
DaTSCAN
Diff. cost
Diff.
ATY
Cost per
ATY
39%
€ 6,253
1.753
5727
3.369
-526
1.616
-325
46%
€ 6,359
1.876
6150
3.383
-209
1.507
-139
53%
€ 6,465
2.000
6573
3.397
108
1.397
77
59%
€ 6,556
2.105
6936
3.408
380
1.303
291
66%
€ 6,663
2.228
7360
3.422
697
1.194
584
Van Laere et al. Eur J Nucl Med Mol Imaging 2008;35:1367-76.
6
SPECT, Diagnosis and Management Results from the Registry Study
Detection of Preclinical PD
•
Hemiparkinsonism: striatal DAT binding : ↓ 39% contralateral, ↓ 28%
ipsilateral (Staffen W et al. Nucl Med Commun 2000;21:417)
•
MPTP: (Calne DB et al. Nature 1985;246)
•
Twins:
•
Susceptibility in familial PD: 34% asymptomatic relatives FDOPA < 2.5 SD
•
Essential tremor: 20-33% → PD (Brooks DJ et al. Neurology 1992;29:673)
asymptomatic co-twins of affected PD patients, ↓ FDOPA 53%
MZ; 13% DZ (Burn DJ et al. Neurology 1992;41:1894)
(Piccini P et al. Ann Neurol 1997;41:222)
Van Laere et al. Eur J Nucl Med Mol Imaging 2008;35:1367-76.
Annual Percentage Changes in Striatal β-CIT Uptake in PD
Change (%)
Pirker et al., 2002
mean disease duration 9.2 ± 2.6 yrs
mean disease duration 2.4 ± 1.5 yrs
Marek et al., 2001
Pat. (N)
2.4 ± 9.6
7.1 ± 7.1
11.2 ± 8.3
12
24
32
Chouker et al., 2001
6.6
8
Staffen et al., 2000
5.6
15
Seppi et al., 2001
Contralat. to affected limb
Ipsilateral to affected limb
9
5.7 ± 3.8
6.4 ± 3.5
% Residual DA neurons in the SN
References
Models of Disease Progression
100 %
90 %
80 %
70 %
60 %
50 %
40 %
30 %
Threshold for
clinical symptoms
20 %
10 %
Symptomatic (H&Y stage)
st I
st II st III st IV st V
0%
Lifetime
Poewe & Scherfler. Mov Disoder 2003;18:S16-21.
Imaging Outcome Measures to Evaluate Efficacy of Putative
Neuroprotective Agents
Pre
sympto
matic
Imaging of the presynaptic DA system: Indications
1. Parkinson Disease
-
PD: establishment of early and preclinical diagnosis
-
PD: assessment of the severity of disease
-
PD: measuring disease progression
-
PD: monitoring neuroprotection/neurorescue
2. Differential diagnosis of parkinsonian syndromes
Pavese & Brooks. Biochim Biophys Acta 2008; in press.
3. Assessment of LBD
7
Confirmation / exclusion
of parkinsonian syndromes
DAT SPECT
No presynapt.
dopamin. deficit
Essential
Tremor
ΔΔ Parkinsonism with Presynaptic DA ligands
Presence of a presynaptic dopaminergic deficit
PD
PSP
MSA
1.5 / 100.000
4.0 / 100.000
• Clinical status and presynaptic DA integrity
[123I]β-CIT Binding and Clinical Status
(n)
All
Control
Stage I
Stage II
Stage III
6.0 ± 1.6 (11)
IPD
3.4 ± 0.8 (58)* 3.9 ± 0.5 (9)
3.6 ± 0.6 (25)
3.0 ± 0.8 (24)
SPD
5.5 ± 1.4 (29)*
6.2 ± 1.1 (14)*
4.7 ± 1.3 (14)*
4.8 (1)
Staffen et al. Nucl Med Commun 2000;21:417.
+
+
+
+
vertical gaze palsy
postural instability
dysphagia
subcortical dementia
+ cerebellar signs
+ autonomic dysfunction
• Topography of the striatal DA deficit
DA Imaging in sOPCA
Striatal Projections & Parkinsonism
Striatal FDA Uptake, Concurrent and Subsequent Vital Status
V3’’ (ROI 1 - ROI 4)
6
Patient FDOPA (91) Parkinsonism(91) Parkinsonismlater
4
2
0
Normals
PD
PSP
#1
#2
#3
#4
#5
#6
#7
#8
#9
#10
¯
¯
N
¯
¯
¯
N
¯
¯
by 1SD
¯
Unknown
Yes
No
Yes
Yes
Yes
No
Yes
Yes
Yes
Shrag et al. Ann Neurol 1998;44:151.
Mesa C et al. Eur J Nucl Med 1998;25:1270.
Corticobasal Degeneration
Presynaptic site
Nigrostriatal
Pathway
Unilateral parkinsonism and:
•
•
•
•
•
No
No
No
No
No
No
No
Yes
Yes
Yes
dyspraxia
cortical sensor. deficits
alien limb syndrome
myoclonus
dementia
Striatum
no levodopa response
rapid progression
Substantia
Nigra
Unilateral atrophy of the
central region in > 50%
Postsynaptic site
8
Discriminative Power IPD / MSA (/ PSP)
MRI Signal Changes and Parkinsonism
Presynaptic binding
- 18F-dopa and 123 I-beta/FP-CIT
Signal Changes within the Putamen in 90 Patients
with Parkinsonism of Various Origins
- discrimination in 50-60% of patients (Pirker et al., Mov Disord 2000) *
MRI
(Putamen)
Perfusion and metabolism
- 18FDG PET and 99mTc-ECD SPECT
- posterior lentiform nucleus hypometabolism/perfusion in 70-80% of
patients (Brooks, Brain Mapping 2000; Bosman et al. EJNM 2002)
Postsynaptic binding
11C-raclopride : highest discriminating capacity
: up to 100%
(Antonini et al., Brain1997, Ghaemi et al JNNP 2002) *
123 I-IBZM : sensitivity and specificity 70-80% (Larisch & Klimke,
Nuclearmedizin 1998) * – higher if combined with presynaptic studies ?
Normal
Only
Hypointense
Hypointense &
Hyperintense
Total
MSA
1
5
9
15
PSP
PD
6
59
4
6
0
0
10
65
Kraft E et al. Arch Neurol 1999; 56:225.
Hypointense putaminal changes - poor response to DA treatment
- clearly related to normal aging
- due to iron? gliosis? calcification?
Hypo- & hyperintense putaminal signal : specific for MSA, but tardive
* Most of these studies use post-hoc values and were not cross-validated !
Secondary Parkinsonism
Clinical Pointers for Structural Imaging in Parkinsonism
CO Intoxication
Putaminal hemorrhage
• Vascular risk factors / markers
• Predominantly lower body parkinsonism, usually
symmetrical
• Features suggesting normal pressure hydrocephalus
• Abnormally prolonged asymmetry
Adachi M et al. AJNR 1999;20:1500.
Pseudo PS
Normal pressure hydrocephalus (NPH)
difficulties with balance
upper limbs intact
„lower body parkinsonism“
important ΔΔ, treatable!!
DOPA Response Dystonia
GTP
Presynaptic site
Subcortical arteriosclerotic encephalopathy (SAE)
GCH-I
neopterin
Dihydroneopterin triphosphate
6-PPH synthase
6-Pyruvoyltetrahydropterin
Sepiapterin reductase
Tyr
Tetrahydrobiopterin
NAD
+
DHPR
TH
Dopa
Quinonoid Dihyhydrobiopterin
NADH + H
+
Juvenile PD
Jeon BS et al. Ann Neurol 1998.
9
Drug-Induced Parkinsonism
Psychogenic Parkinsonim
• Common, often underdiagnosis (25-35% PS)
• More in females and elderly
• Clinical aspect:
- Bucco-linguo-masticatory syndrome, focal dystonia, stereotypies, akathisia
- Tremor in 29%, asymmetry in 2/3
- Within few days of several years, not always reversible
• Drugs:
• 1.9-6.4% PS
• More in young females
• Unusual movement disorder:
–
–
–
- neuroleptiques
- few calcium-channel blockers (flunarizine, cinnarizine)
- DA-depleting agents (reserpine, tetrabenazin)
–
–
Sudden onset, may be trigger by minor injury
Complex tremor
rigidity=resistance
Fluctuation
Most, very effective dopaminergic treatment
Tolosa et al. Mov Disoder 2003;18:S28-33.
Differential Diagnosis of Dementia
Dementia with Lewy bodies
Parkinson’s disease
Diffuse Lewy body disease
Lewy body variant of AD
Vascular dementias
and AD
AD
5% 10%
Diffuse Lewy Body Disease
Other dementias
Frontal lobe dementia
Creutzfeld-Jakob disease
Corticobasal degeneration
Progressive supranuclear palsy
others
Vascular dementias
Multi-infarct dementia
Binswanger’s disease
● Lewy bodies in subcortical, allocortical, and neocortical structures
● Pure form or associated in conjunction with AD
● 13-26% dementia
● Clinical features:
(Ss 75%; Sp 79%)
fluctuating cognitive impairment
visual hallucinations
parkinsonism
• Adverse effects of typical antipsychotics;
2 “atypicals” recommended: Quetiapine (Seroquel®),
Clozapine (Clozapine®, Leponex®)
AD and dementia with
Lewy bodies
65%
Tolosa et al. Mov Disoder 2003;18:S28-33.
5% 7% 8%
• Cognition may differentially benefit from AChE inhibition
• Subtle bradykinesia/rigidity may benefit from antiparkinsonian
Small et al. JAMA 1997;278:1363-71
American Psychiatric Association. Am J Psychiatry 1997;154:1-39
Morris JC. Clin Geriatr Med 1994;10:275-6.
therapy; avoid DA agonists
Dementia Subtypes in FDG PET
Walker et al. Lancet 1999;354:646-7.
Minoshima et al., 2002.
10
DAT Imaging
With presynaptic deficit
Without presynaptic deficit
Neurodegenerative PS
Parkinsonian syndromes
• Parkinson’s disease
• Psychogenic PS
• Multiple system atrophy
• Drug induced PS
• Progressive supranuclear palsy
• Cortico basal degeneration
DLBD
Tremor syndromes
• essential tremor
• Psychogenic
• Drug induced
• cerebro-vascular
Walker et al. J Neurol Neurosurg Psychiatry 2007;78:1176-81.
Thank you for your attention...
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