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Indications for PET/SPECT in parkinsonism and tracer development

Dr Marie‐Odile Habert

Nuclear Medicine Department

Pitié‐Salpêtrière Hospital

ESNR 2019 in Paris PET/SPECT imaging in Parkinson : what purpose?

• Clinico‐pathological studies suggest that the clinicaldiagnosis of IPD is incorrect in about 25 % of cases

– Versus essential tremor, vascular parkinsonism, drug‐inducedparkinsonism and atypical parkinsonian syndromes

– About 30% of patients with MSA or PSP, and more with CBD  are not correctly diagnosed , even at late stage

• PET/SPECT imaging is used with 3 aims

1. To identify patients with progressive nigrostriataldegeneration

2. To identify brain dysfunction related to cognitive deterioration in patients with PD and cognitive impairment

3. To differentiate between atypical parkinsonian syndromes

Tolosa et al. Lancet neurol 2006

1) Imaging nigrostriatal degenerationin parkinsonism

DAT

Tyrosine

L-Dopa

Dopamine

Dopa-decarboxylaseor AADC

Tyrosine-hydroxylase

COMT

metabolites

COMT

MAO

MAO

COMT

D2D1D2

VMAT2

STRIATUM : DOPAMINERGIC SYNAPSE

Post-synaptic neuron

Nigro-striatal neuron

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Radioligands for dopaminergic neurotransmission

[99Tc]TRODAT, [123I]-β-CIT,

[123I]-FP-CIT

[123I]-IBZM

Molecular target PET SPECT

[18F]-6-L-DOPA

[11C]-PE2I, [11C]-CFT, [11C]-RTI-32

[11C]-DTBZ

[11C]-SCH 23390, [11C]-NNC 112

[11C]-Raclopride, [11C]-FLB 457

[18F]-fallypride

[11C]-deprenyl, [11C]-clorgyline

DOPA‐decarboxylase (AADC) 

Membrane transporter (DAT)

Vesicular transporter

D1 receptors

D2 receptors

Monoamine Oxydase

Radioligands for dopaminergic neurotransmission

[99Tc]TRODAT, [123I]‐β‐CIT, 

[123I]‐FP‐CIT

[123I]‐IBZM

Molecular target PET SPECT

[18F]‐6‐L‐DOPA

[11C]‐PE2I, [11C]‐CFT, [11C]‐RTI‐32

[18F]‐LBT‐99

[11C]‐DTBZ

[11C]‐SCH 23390, [11C]‐NNC 112

[11C]‐Raclopride, [11C]‐FLB 457

[18F]‐fallypride

[11C]‐deprenyl, [11C]‐clorgyline

DOPA‐decarboxylase (AADC) 

Membrane transporter (DAT)

Vesicular transporter (VMAT2)

D1 receptors

D2 receptors

Monoamine Oxydase

Presynaptic tracers for assessment of nigrostriatal integrity

DAT

Tyrosine

L-Dopa

Dopamine

Dopa-decarboxylaseor AADC

Tyrosine-hydroxylase

COMT

métabolites

COMT

MAO

MAO

COMT

D2D1D2

VMAT2

STRIATUM : DOPAMINERGIC SYNAPSE

Post-synaptic neuron

Nigro-striatal neuron

18F-DOPA

123I-FP-CIT DaTSCAN®

Post‐mortem correlations: 123I‐FP‐CIT reflects the number of dopaminergic neurons in Substantia Nigra

Kraemmer et al. Movement disorders 2014

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At symptoms onset (compared to VMAT2):

‐ 18F‐Fluorodopareflects dopamine synthesis and stockage + density of presynaptic dopaminergic neurons

upregulation

‐ 11C‐MP (DAT ligand) reflects density of presynaptic dopaminergicneurons

downregulation

At later stages, measures of neuronal integrityare similar breakdown of initial compensatory mechanisms

Presynaptic dopaminergic denervation in PD 

• Early significant decrease of striatal uptake in PD

– More prominent on the contralateral side to motor symptoms

– DaTSCAN: Specificity > 90 % (Benamer 2003: PD de novo vs. ET; Marshall 2009: 

uncertain PD vs diagnosis at 3 years follow‐up)

• Postero‐dorsal  rostro‐ventral progression gradient

– Begins at the posterodorsal part of the putamen

– More severe damage to putamen compared to caudate

– In agreement with post‐mortem data (Kish, 1988)

• Worsens when PD progresses

– F‐DOPA  ‐ 8‐10 % / year (N: ‐0.6 % / year)

– DAT :       ‐ 8 %  / year (N: ‐3.3 ‐10 % / 10 years)

• Well correlated with motor symptoms (except tremor)

– Motor score UPDRS, bradykinesia

• Does not allow to differentiate between IPD and APS

– Sub regional striatal uptakes show differences on group analyses but

accuracy is insufficient on an individual basis  

- 25%- 50%

H & Y = I

Hemi-parkinson de novo : asymmetricalbut bilateraldecrease in putamens

123I-FP-CIT: “when the diagnosis of Parkinson is uncertain”

Normal Abnormal type 1 Abnormal type 2 Abnormal type 3

• Essential tremor• Drug‐induced

parkinsonism• Dopa responsive 

dystonia• Psychogenic• AD, FTD• Vascular

parkinsonism (?)

• Parkinson’s disease• Lewy body disease• Progressive Supranuclear palsy• Multisystem Atrophy• Corticobasal degeneration

No presynapticdopaminergic loss

Presynaptic dopaminergic loss

Presynaptic dopaminergic denervation in LBD

Lancet neurol 2007

Sens Spec Acc PPV NPV

77,7% 90,4% 85,7% 82,4% 87,5%

To detect clinicalprobable LBD

A normal DAT SPECT does not eliminateLBD

Only useful in cases of LBD withoutclinical parkinsonian syndrome (about 25 %)

Colloby et al. Brain 2012

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Semi‐quantitative assessment: calculation of binding potential

• helpful in visually inconclusive

scans(10%?)

Abi‐Dargham et al., 1996; Laruelle et al., 1994

BP = (As / Ans) ‐ 1 As: striatumAns: occipital cx or cerebellum

But there may be issues with :‐ the quality of the registering between ROIs and datscan‐ morphologic abnormalities in the reference region‐ with the charateristics of the normal database: must be matched

for gender and age, caméra, reconstruction (Tossici‐Bolt 2017)…

Development of new DAT PET ligands for clinical use

Jacobson Mo et al. EJNMMI 2018 Chalon et al. Frontiers in medicine 2019

18F‐PE2I versus 123I‐FP‐CIT

18F‐LBT‐999

• Better sensitivity (at early stage) than Fluorodopa

• No need to stop antiparkinsonian drugs

• Better resolution of PET compared to SPECT

• Reduced injection delay and acquisition time  

PET ligands for alpha‐synucleinopathies?

Adapted from Mathias et al. Seminars in Nuclear Medicine 2018

2) Identify brain dysfunction related to cognitive deterioration in patients with PD and 

cognitive impairment

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FDG‐PET in Lewy body disease

• Hypometabolism more prominent in visual cortex (compared to AD)

– Small sample with autopsy(Minoshima 2001)

– Spec 99% Sens 71% (Mosconi2008)

– Well correlated with the severityand frequency of visualhallucinations (Firbank 2015) 

» Cingulate island sign »

– Spec 80% Sens 77% (Lim 2009)

– Independant of amyloid co‐pathology (Graff‐Radford 2014)

Glucose hypometabolism in primary visual cortex is commonlyassociated with clinical features of dementia with Lewy bodies

regardless of cognitive conditions.  Fujishiro et al. 2012 Int J Geriat Psychiatry

• 145 MCI, including 25 with hypometabolism in primary visual cortex

38 HC > 20 PD‐NC 38 HC > 41 PD‐MCI

Also: Tard et al. J Park Disease 2015;      Baba et al. J Neurol Sci

3) Differential diagnosis of atypicalparkinsonian syndromes

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J Nucl Med 2017 Si‐Shun Gu et al. 2019 Ahead of print

Overall diagnostic accuracy of 18F-FDG in differentiating PD from APS:

- pooled sensitivity of 0.88 [95% confidence interval (95% CI), 0.85–0.91]

- pooled specificity of 0.92 (95% CI, 0.89–0.94), with sensitivity analyses

indicating statistically consistent results.

Additional analyses : overall sensitivity and specificity

- 0.87 (95% CI, 0.76–0.94) and 0.93 (95% CI, 0.89–0.96) for MSA

- 0.91 (95% CI, 0.78–0.95) and 0.96 (95% CI, 0.92–0.98) for PSP

Kim et al.EJNMMI 2016

Metabolic pattern in PSP

Juh et al. J Neurosci 2005Zalewski et al. J neurol 2014

Amtage et al. Parkinsonism and Related Disorders 2014 

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14 CBS‐CBD10 CBS‐AD5 CBS‐PSP

Pardini et al. Neurol 2019

A HC minus CBS‐CBD B HC minus CBS‐AD

C HC minus CBS‐PSP

Cardiac 123I‐MIBG scintigraphy

Orimo 2016 review

• analog of guanethidine, an adrenergic blocking agent, and its mechanism of uptake and storage is similar to that of noradrenaline 

• Reveals the presence of post‐ganglionic presynaptic sympathetic denervation in PD

Heart/mediastinum

ratio 

• Meta‐analyses have shown a sensitivity of 82–88% and a specificity of 77–89%.

• Quantification issues (threshold?) and many drug interactions

Cho H et al, Mov Disord 2017;32:134‐140

HC : 15PD : 15PSP : 14

Matthias Brendel et al. J Nucl Med 2019;60:54Copyright © Society of Nuclear Medicine and Molecular Imaging

Novel second generation tau‐PET ligand 18F‐PI2620 in PSP

17 PSP, 10 HC

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Smith et al. Neurology 2017

Increased retention of AV‐1451 in the motorcortex, the cortico‐spinal tract and the basal ganglia

Thank you for your attention

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