Accepted Manuscript Title: Molecular Imaging of Dopamine Transporters Author: David J Brooks PII: DOI: Reference:
S1568-1637(15)30043-X http://dx.doi.org/doi:10.1016/j.arr.2015.12.009 ARR 630
To appear in:
Ageing Research Reviews
Received date: Revised date: Accepted date:
29-10-2015 26-12-2015 29-12-2015
Please cite this article as: Brooks, David J, Molecular Imaging of Dopamine Transporters.Ageing Research Reviews http://dx.doi.org/10.1016/j.arr.2015.12.009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Molecular Imaging of Dopamine Transporters
David J Brooks 1,2,3
1. Dept of Nuclear Medicine, Aarhus University, Denmark 2. Division of Neuroscience, Imperial College London, UK 3. Division of Neuroscience, Newcastle University, UK
Address for correspondence: David J Brooks MD DSc FRCP FMedSci Professor of Neurology Dept.of Nuclear Medicine and PET Centre Aarhus University Hospital Nørrebrogade 44 DK - 8000 Aarhus C
Abstract The dopamine transporter (DAT) is responsible for clearance of dopamine from the synaptic cleft after its release. Imaging DAT availability provides a measure of dopamine terminal function and a method for detecting the striatal dopamine terminal dysfunction present in idiopathic Parkinson’s disease (PD) and atypical neurodegenerative parkinsonian disorders such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). DAT imaging with positron emission tomography (PET) or single photon emission computed tomography (SPECT) can be used to support or refute a diagnosis of dopamine deficient parkinsonism in cases where this is unclear and rationalise a trial of dopamine replacement agents as therapy. It can also detect subclinical dopaminergic dysfunction when present in subjects at risk for PD such as relatives of patients, susceptibility gene mutation carriers, and subjects with late onset hyposmia or sleep disorders. The presence of normal DAT availability on imaging can help categorise "subjects without evidence of dopamine deficiency" (SWEDDs) who on occasion mimic PD (SWEDDs) and include dystonic tremors, drug-induced and psychogenic parkinsonism in their ranks. Reduced levels of baseline striatal DAT availability on PET or SPECT scanning, however, should be regarded as supportive rather than diagnostic of dopamine deficient parkinsonism.
Keywords: SPECT; PET; dopamine; transporter; parkinson; tremor.
Introduction The basal ganglia receive input from cortical areas and relay information back to the cortex via the thalamus in a series of parallel loops (Alexander and Crutcher, 1990). They modulate movement and cognition, filtering and focussing the cortical traffic. Diseases that affect the basal ganglia can result in hypo- or hyperactivity. In the case of movement disorders this manifests as bradykinesia or dyskinesia (Bhatia and Marsden, 1994) while cognitive dysfunction manifests as bradyphrenia or failure to control impulsive behaviour (Lawrence et al., 1996). The striatum (caudate and putamen) receives cortical input while the internal pallidum and substantia nigra pars reticulata relay basal ganglia output to the cortex and brainstem. The substantia nigra pars compacta, a midbrain nucleus with melanin pigmented dopaminergic neurons, sends dense projections to the striatal spiny neurons synapsing with the necks of their dendritic projections. The terminals of dopaminergic neurons in the nigrostriatal pathway express dopamine transporters (DAT) responsible for uptake of dopamine from the synaptic cleft after its release. Loss of nigrostriatal terminal function results in decreased striatal dopamine production and release into the synaptic cleft resulting in parkinsonism (rigidity and bradykinesia) when the deficiency becomes severe (Kish et al., 1988). There is an additional loss of DAT in remaining terminals as an adaptive mechanism in order to try and preserve synaptic dopamine levels (Lee et al., 2000). As a consequence, measures of DAT availability with PET or SPECT will tend to overestimate the true degree of terminal loss. Blockade of DAT with drugs such as methylphenidate causes synaptic dopamine levels to rise.
The dopamine transporter While dopamine transporter protein is most densely expressed in the terminals of nigrostriatal dopamine neurons, it is also present in the anterior cingulate, amydala, and midbrain but sparse in cortical areas (Piccini, 2003). DAT transports dopamine released by neurons into the synaptic cleft back inside the terminals where it may be re-packaged by the vesicular monoamine transporter (VMAT2) into vesicles for re-release. DAT, therefore, plays an integral role in buffering synaptic dopamine levels, both during normal brain function and when exogenous levodopa is given as dopamine replacement treatment to PD patients. DAT expression is regulated by internalisation, mRNA expression, and levels of phosphorylation. Acute and chronic exposure to cocaine and methylphenidate acts to decrease DAT availability and expression (Booij and Kemp, 2008).
Imaging DAT function The availability of pre-synaptic dopamine transporters (DAT) can be measured in vivo with SPECT and PET using radiotracer ligands, many of which are tropane based. SPECT tropane tracers include: altropane and
123
I-beta-CIT (DopaScan™),
99m
123
I-FP-CIT (DatScan™),
Tc-TRODAT. PET tropane derivatives include
11
C-RTI 32,
11
123
I-
C-CFT,
and 18F-FP-CIT (Brooks, 2008) while 11C-methylphenidate and 11C-nomifensine are nontropane radioligands (Brooks et al., 2003).
The PET and SPECT radiotracers currently available for measuring striatal dopamine transporter (DAT) binding are relatively non-selective also binding to noradrenaline, and serotonin transporters with a similar or lower nanomolar affinity (Benamer et al., 2000 Jul;
Fischman et al., 1998; Marek et al., 2001 Dec 11; Mozley et al., 2000). As the cerebellum is devoid of DAT it is common to use it as a reference tissue for non-specific tracer uptake. In practice
123
I-beta-CIT gives the highest striatal:cerebellar uptake ratios but this reflects
a low cerebellar non-specific signal rather than high striatal specific binding. 123I-beta-CIT binds with similar affinity to dopamine, noradrenaline, and serotonin transporters and has the disadvantage that it takes 24 hours to equilibrate throughout the brain following intravenous injection so scanning has to be delayed. For this reason, SPECT tracers such as
123
I-FP-CIT and
123
I-altropane were developed so that a diagnostic scan could be
performed within 3 hours or 60 minutes of tracer injection. However, these tracers yield lower striatal:cerebellar uptake ratios due to their higher non-specific background signals. The technetium based tropane tracer,
99m
Tc-TRODAT-1, has the advantage that
99m
Tc is
readily available from a generator but this agent gives a lower specific striatal signal than 123
I based SPECT tracers and is less well extracted by the brain. As a consequence it can
be harder to visually discriminate subtle DAT loss in cases of early Parkinson's disease (PD) with TRODAT SPECT.
DAT binding is highest in the putamen, caudate, and ventral striatum and in normal subjects it slowly declines with age. Sequential SPECT scans in normal healthy subjects have reported a decline in [123I] β-CIT striatal uptake of 0.8%/year from the baseline value (Marek et al., 2001 Dec 11). Idiopathic Parkinson's disease is characteristically asymmetric in clinical onset. Early hemi-parkinsonian patients show bilaterally reduced putamen DAT binding, the signal being most depressed in the posterior putamen contralateral to clinically affected limbs (Benamer et al., 2000 May; Marek et al., 1996). Head of caudate and ventral
striatal DAT binding is relatively preserved in early PD. Clinical parkinsonism occurs when PD patients have lost 40-50% of normal mean levels of putamen dopamine terminal function (Benamer et al., 2000 Jul; Marek et al., 2001 Dec 11). Given this, there is a potential window for detecting loss of putamen DAT binding in at-risk subjects for PD who have subclinical dysfunction. A longitudinal study reported an 11.2%/year decline in [123I] β-CIT striatal uptake from the PD baseline value, significantly faster (p
S1568-1637(15)30043-X http://dx.doi.org/doi:10.1016/j.arr.2015.12.009 ARR 630
To appear in:
Ageing Research Reviews
Received date: Revised date: Accepted date:
29-10-2015 26-12-2015 29-12-2015
Please cite this article as: Brooks, David J, Molecular Imaging of Dopamine Transporters.Ageing Research Reviews http://dx.doi.org/10.1016/j.arr.2015.12.009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Molecular Imaging of Dopamine Transporters
David J Brooks 1,2,3
1. Dept of Nuclear Medicine, Aarhus University, Denmark 2. Division of Neuroscience, Imperial College London, UK 3. Division of Neuroscience, Newcastle University, UK
Address for correspondence: David J Brooks MD DSc FRCP FMedSci Professor of Neurology Dept.of Nuclear Medicine and PET Centre Aarhus University Hospital Nørrebrogade 44 DK - 8000 Aarhus C
Abstract The dopamine transporter (DAT) is responsible for clearance of dopamine from the synaptic cleft after its release. Imaging DAT availability provides a measure of dopamine terminal function and a method for detecting the striatal dopamine terminal dysfunction present in idiopathic Parkinson’s disease (PD) and atypical neurodegenerative parkinsonian disorders such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). DAT imaging with positron emission tomography (PET) or single photon emission computed tomography (SPECT) can be used to support or refute a diagnosis of dopamine deficient parkinsonism in cases where this is unclear and rationalise a trial of dopamine replacement agents as therapy. It can also detect subclinical dopaminergic dysfunction when present in subjects at risk for PD such as relatives of patients, susceptibility gene mutation carriers, and subjects with late onset hyposmia or sleep disorders. The presence of normal DAT availability on imaging can help categorise "subjects without evidence of dopamine deficiency" (SWEDDs) who on occasion mimic PD (SWEDDs) and include dystonic tremors, drug-induced and psychogenic parkinsonism in their ranks. Reduced levels of baseline striatal DAT availability on PET or SPECT scanning, however, should be regarded as supportive rather than diagnostic of dopamine deficient parkinsonism.
Keywords: SPECT; PET; dopamine; transporter; parkinson; tremor.
Introduction The basal ganglia receive input from cortical areas and relay information back to the cortex via the thalamus in a series of parallel loops (Alexander and Crutcher, 1990). They modulate movement and cognition, filtering and focussing the cortical traffic. Diseases that affect the basal ganglia can result in hypo- or hyperactivity. In the case of movement disorders this manifests as bradykinesia or dyskinesia (Bhatia and Marsden, 1994) while cognitive dysfunction manifests as bradyphrenia or failure to control impulsive behaviour (Lawrence et al., 1996). The striatum (caudate and putamen) receives cortical input while the internal pallidum and substantia nigra pars reticulata relay basal ganglia output to the cortex and brainstem. The substantia nigra pars compacta, a midbrain nucleus with melanin pigmented dopaminergic neurons, sends dense projections to the striatal spiny neurons synapsing with the necks of their dendritic projections. The terminals of dopaminergic neurons in the nigrostriatal pathway express dopamine transporters (DAT) responsible for uptake of dopamine from the synaptic cleft after its release. Loss of nigrostriatal terminal function results in decreased striatal dopamine production and release into the synaptic cleft resulting in parkinsonism (rigidity and bradykinesia) when the deficiency becomes severe (Kish et al., 1988). There is an additional loss of DAT in remaining terminals as an adaptive mechanism in order to try and preserve synaptic dopamine levels (Lee et al., 2000). As a consequence, measures of DAT availability with PET or SPECT will tend to overestimate the true degree of terminal loss. Blockade of DAT with drugs such as methylphenidate causes synaptic dopamine levels to rise.
The dopamine transporter While dopamine transporter protein is most densely expressed in the terminals of nigrostriatal dopamine neurons, it is also present in the anterior cingulate, amydala, and midbrain but sparse in cortical areas (Piccini, 2003). DAT transports dopamine released by neurons into the synaptic cleft back inside the terminals where it may be re-packaged by the vesicular monoamine transporter (VMAT2) into vesicles for re-release. DAT, therefore, plays an integral role in buffering synaptic dopamine levels, both during normal brain function and when exogenous levodopa is given as dopamine replacement treatment to PD patients. DAT expression is regulated by internalisation, mRNA expression, and levels of phosphorylation. Acute and chronic exposure to cocaine and methylphenidate acts to decrease DAT availability and expression (Booij and Kemp, 2008).
Imaging DAT function The availability of pre-synaptic dopamine transporters (DAT) can be measured in vivo with SPECT and PET using radiotracer ligands, many of which are tropane based. SPECT tropane tracers include: altropane and
123
I-beta-CIT (DopaScan™),
99m
123
I-FP-CIT (DatScan™),
Tc-TRODAT. PET tropane derivatives include
11
C-RTI 32,
11
123
I-
C-CFT,
and 18F-FP-CIT (Brooks, 2008) while 11C-methylphenidate and 11C-nomifensine are nontropane radioligands (Brooks et al., 2003).
The PET and SPECT radiotracers currently available for measuring striatal dopamine transporter (DAT) binding are relatively non-selective also binding to noradrenaline, and serotonin transporters with a similar or lower nanomolar affinity (Benamer et al., 2000 Jul;
Fischman et al., 1998; Marek et al., 2001 Dec 11; Mozley et al., 2000). As the cerebellum is devoid of DAT it is common to use it as a reference tissue for non-specific tracer uptake. In practice
123
I-beta-CIT gives the highest striatal:cerebellar uptake ratios but this reflects
a low cerebellar non-specific signal rather than high striatal specific binding. 123I-beta-CIT binds with similar affinity to dopamine, noradrenaline, and serotonin transporters and has the disadvantage that it takes 24 hours to equilibrate throughout the brain following intravenous injection so scanning has to be delayed. For this reason, SPECT tracers such as
123
I-FP-CIT and
123
I-altropane were developed so that a diagnostic scan could be
performed within 3 hours or 60 minutes of tracer injection. However, these tracers yield lower striatal:cerebellar uptake ratios due to their higher non-specific background signals. The technetium based tropane tracer,
99m
Tc-TRODAT-1, has the advantage that
99m
Tc is
readily available from a generator but this agent gives a lower specific striatal signal than 123
I based SPECT tracers and is less well extracted by the brain. As a consequence it can
be harder to visually discriminate subtle DAT loss in cases of early Parkinson's disease (PD) with TRODAT SPECT.
DAT binding is highest in the putamen, caudate, and ventral striatum and in normal subjects it slowly declines with age. Sequential SPECT scans in normal healthy subjects have reported a decline in [123I] β-CIT striatal uptake of 0.8%/year from the baseline value (Marek et al., 2001 Dec 11). Idiopathic Parkinson's disease is characteristically asymmetric in clinical onset. Early hemi-parkinsonian patients show bilaterally reduced putamen DAT binding, the signal being most depressed in the posterior putamen contralateral to clinically affected limbs (Benamer et al., 2000 May; Marek et al., 1996). Head of caudate and ventral
striatal DAT binding is relatively preserved in early PD. Clinical parkinsonism occurs when PD patients have lost 40-50% of normal mean levels of putamen dopamine terminal function (Benamer et al., 2000 Jul; Marek et al., 2001 Dec 11). Given this, there is a potential window for detecting loss of putamen DAT binding in at-risk subjects for PD who have subclinical dysfunction. A longitudinal study reported an 11.2%/year decline in [123I] β-CIT striatal uptake from the PD baseline value, significantly faster (p
