Parkinsonism and Related Disorders 20S1 (2014) S180–S183
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Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Developments in neuroimaging: positron emission tomography A. Jon Stoessl * Pacific Parkinson’s Research Centre, University of British Columbia & Vancouver Coastal Health. Vancouver, Canada
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Keywords: Positron emission tomography Dopamine Vesicular monoamine transporter type 2 (VMAT2) Dopamine transporter (DAT) 6-[18 F]fluoro-L-dopa (F-dopa) 5-hydroxytryptamine (5HT, serotonin) Acetylcholine Beta-amyloid Alpha-synuclein Microglia
Positron emission tomography (PET) is a powerful technique to quantitatively assess brain function in vivo. In Parkinson’s disease (PD), PET can assist in the identification of dopamine deficiency, the characterization of dopamine and other neurotransmitter receptors and transporters, serve as a biomarker and provide insights into motor and non-motor complications of PD. PET can also shed light on mechanisms that underlie disease, such as aberrant protein deposition and neuroinflammation. Emerging developments in multimodal imaging offer the opportunity to study multiple questions concurrently and offer great promise for the future.
1. Introduction Positron emission tomography (PET) has a well-established history in the assessment and investigation of Parkinson’s disease (PD), primarily as a means to assess dopaminergic function. The assessment of presynaptic dopaminergic integrity remains an important application of this technique. PET studies of glucose metabolism or cerebral blood flow have been used to study regional activation in response to a variety of stimuli, as well as patterns of regional connectivity. Regional activation and connectivity can also be well addressed by functional MRI. PET can also be used to assess the function of neurotransmitters other than dopamine (DA) and shows increasing promise as a means to investigate mechanisms that contribute to disease. The increasing number of functional imaging techniques now available should be seen as complementary rather than competitive, as many questions are best addressed by a combination of approaches. 2. Clinical and research applications 2.1. Diagnosis PD is typically associated with loss of presynaptic DA markers (dopamine transporter – DAT, vesicular monoamine transporter type 2 – VMAT2, or 6-[18 F]fluoro-L-dopa – F-dopa) which is asymmetric, and with a rostral–caudal gradient, in which the posterior striatum is maximally affected. The same pattern is seen * Correspondence: 2221 Wesbrook Mall, Vancouver, BC Canada V6T 2B5. Tel.: +1 604 822 7967; fax: +1 604 822 7866. E-mail address: [email protected] (J.A. Stoessl). 1353-8020/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.
© 2013 Elsevier Ltd. All rights reserved.
using SPECT with a variety of markers for the DAT. However, while this reliably identifies DA deficiency (and may therefore distinguish between PD and essential or dystonic tremor), the pattern is not specific for PD and may be seen in other akinetic–rigid syndromes, in particular multiple system atrophy (MSA). The additional use of a marker for DA receptors, which are typically lost in MSA or progressive supranuclear palsy (PSP) but preserved in PD, may help, but this approach has not found widespread use. In contrast, PD is associated with a typical pattern of glucose metabolism or cerebral blood flow, while MSA, PSP and corticobasal syndrome all have distinct patterns that can be visually identified and quantified using a form of principal components analysis [1]. 2.2. Preclinical detection and disease biomarker All markers of presynaptic DA integrity decline according to an exponential function that is estimated to start deviating from normal age-related changes several years prior to onset of clinical disease. Based on extrapolation of our exponential model, we have found that VMAT2 binding declines first (approximately 17 years prior to disease onset), followed by decline in DAT binding (13 years prior) and then by F-dopa uptake (6 years prior) [2]. The latency between decline in DA function and clinical disease onset varies as a function of age. Patients with younger age of onset have a greater degree of DA dysfunction at disease onset (and longer duration of preclinical DA dysfunction). It should also be noted that in the posterior putamen, most of the damage has been done by the time of clinical disease onset, and even in the anterior putamen there is relatively little further decline beyond 10 years disease duration. By the time disease becomes
A.J. Stoessl / Parkinsonism and Related Disorders 20S1 (2014) S180–S183
Fig. 1. VMAT2 binding assessed with [11 C]dihydrotetrabenazine PET in a healthy control subject (left), an asymptomatic LRRK2 mutation carrier (middle) and a patient with PD due to LRRK2 mutation (right).
manifest, DAT binding is reduced relative to VMAT2 binding, while F-dopa uptake is relatively increased. A recent post-mortem study found that tyrosine hydroxylase (TH) and DAT immunocytochemical staining is virtually absent in the dorsal putamen by 4 years disease duration [3]. Taken together, these findings highlight the importance of compensatory mechanisms in maintaining motor function in the face of severe loss of striatal DA innervation. F-dopa uptake is decreased in subjects who are at risk of developing PD, including monozygotic twins of PD patients and subjects exposed to the nigral toxin MPTP. DAT and VMAT2 binding are decreased in asymptomatic carriers of LRRK2 mutations, although symptoms do not become apparent until F-dopa uptake is also reduced (Fig. 1). In LRRK2 mutation carriers, one of the earliest imaging abnormalities appears to be an increase in DA turnover [4], measured with F-dopa and long scan times (4 hours, as opposed to the routine 90-minute scan time, which predominantly reflects tracer uptake). This suggests that the mutation itself may result in abnormal vesicular dynamics, even prior to DA neuronal degeneration. Our findings to date suggest that the progression of DA degeneration in asymptomatic LRRK2 mutation carriers is in keeping with the preclinical trajectory predicted from extrapolation of the exponential function derived in patients with sporadic PD. Not surprisingly, there is a broad correlation between markers of presynaptic DA function and clinical severity. However, most studies have failed to show a correlation between the change in PET markers and change in clinical function (Unified Parkinson Disease Rating Scale [UPDRS] or equivalent). There are several potential reasons for this disappointing lack of correlation between imaging and clinical measures of deterioration, including subjectivity of clinical scores, effects of medication and other symptomatic therapies, compensatory changes affecting the expression of DA markers as well as engagement of non-DA mechanisms, and the related but different problem that clinical progression may reflect degeneration of non-DA systems. This problem should not be seen as a fatal flaw in the use of functional imaging measures, but rather as a requirement for caution in interpreting the results. 2.3. Motor complications of PD The DA D2/3 receptor ligand [11 C]raclopride (RAC) has a relatively weak affinity for DA receptors and its binding is accordingly subject to competition from endogenous DA. The practical significance is that by examining a change in RAC binding before and after an intervention, one can estimate the degree of DA release. Using this approach, we have found that DA release increases with increased duration of PD, and is of greater magnitude but shorter duration in patients with dyskinesias [5]. Furthermore, a similar aberrant pattern of DA release is seen in stable patients who later go on to develop motor fluctuations, compared to those patients who maintain a stable clinical response to treatment for 3 years after the scans [6]. This is in keeping with impaired storage of levodopaderived DA in synaptic vesicles, as is also suggested by increased DA turnover as PD progresses [7]. This will presumably result in pulsatile stimulation of DA receptors, but suggests that some patients (those with greater DA turnover and a pattern of high
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magnitude but short duration DA release) are more prone to develop fluctuations and dyskinesias. One factor that may contribute to this is DA production by striatal serotonin (5HT) nerve terminals. While 5HT neurons are able to synthesize DA from levodopa, they do not store DA in vesicles nor is its release regulated in a physiological fashion [8]. It is therefore of great interest that PD patients who develop severe dyskinesias following fetal nigral transplantation demonstrate increased striatal binding of [11 C]DASB, a selective ligand for the 5HT transporter [9]. PET has shown very few changes in DA receptors related to the emergence of long-term motor complications. However, pulsatile stimulation can result in changes downstream to these receptors. It is therefore of interest that PD patients with dyskinesias have reduced opioid receptor binding, presumably reflecting occupancy secondary to increased release of endogenous opioids [10]. Cannabinoid receptor expression is decreased in the substantia nigra but increased in DA projection sites of patients with PD, but its expression is not related to the presence or absence of levodopainduced dyskinesias [11]. In contrast, striatal adenosine A2A receptor expression is no different between control and PD subjects without dyskinesias, but greatly increased in those with dyskinesia [12]. The mGluR5 receptor has attracted a great deal of interest with respect to its potential role in levodopa-induced dyskinesias. A number of radiolabelled mGluR5 ligands have been developed for PET, but there are to date no published studies on their application to the study of PD in humans. 2.4. Non-motor complications Non-motor complications represent the greatest source of disability in PD. Cognitive impairment affects a large proportion of patients and some authors argue that the majority of patients with PD will ultimately develop dementia. Dementia in PD is associated with a pattern of glucose hypometabolism in which occipital cortex is disproportionately affected, in contrast to Alzheimer’s disease (AD). Cholinergic activity is reduced throughout the cortex in PD, more so in those with cognitive impairment, in whom the abnormality is of greater magnitude than that seen in AD. There is growing interest in brainstem–thalamic cholinergic projections, which are affected to a more variable degree in PD, in association with REM behaviour disorder, olfactory dysfunction and postural instability [13–15]. Depression is another major problem in PD. Although it has long been assumed that this reflects loss of 5HT neurons, as is known to occur in PD, two imaging studies have independently demonstrated increased [11 C]DASB binding in depressed PD patients [16,17]. Another recent paper has suggested a correlation between depression in unmedicated PD patients and reduced striatal F-dopa uptake [18]. The interpretation of such studies can be confounded by the possibility that transporter binding could potentially be increased if there is reduced occupancy by endogenous ligands (i.e. DA or 5HT), although there is limited evidence to support this explanation as a basis for the imaging findings reported to date. DA, in addition to its important role in motor function, is thought to signal the delivery of unanticipated reward, the anticipation of expected reward, and through this, incentive salience and learning. DA release can be demonstrated in response to natural rewards such as food and music, monetary rewards and placebo (expectation of therapeutic benefit). However, aberrant reward signaling may lead to addiction, and impulse control disorders (ICD) including pathological gambling, compulsive shopping, hobbyism, hypersexuality and compulsive eating affect affect some 17% or more of patients taking DA agonists [19,20]. The basis for this may represent a combination of hyperactivity in DA reward projections from ventral tegmental area (VTA) to ventral striatum (VS) and loss of normal behavioural inhibitory mechanisms. Thus, PD patients
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A.J. Stoessl / Parkinsonism and Related Disorders 20S1 (2014) S180–S183
with pathological gambling demonstrated increased DA release in the VS while performing a monetarily rewarded card task compared to PD patients without gambling tendency [21], and increased levodopa-induced DA release in the VS of patients with ICD compared to those without can be demonstrated using RAC PET in response to visual stimuli [22]. As is the case for other addictions, the degree of DA release as measured by change in RAC binding correlates to the degree of drug wanting rather than the degree of drug liking. In addition to the problem of excessive reward-related DA release in the VTA–VS projection, PD patients with ICDs fail to inhibit behavioural patterns despite knowledge of the likely negative longterm consequences. In this regard, it is of interest that using fMRI, van Eimeren and colleagues found reduced deactivation of orbitofrontal cortex in response to a negative reward prediction error in PD patients given pramipexole as opposed to levodopa [23]. In a related PET study of cerebral blood flow PET, the same authors found differential responses to the short-acting dopamine agonist apomorphine in an inhibitory network (lateral orbitofrontal cortex, rostral cingulate, amygdala and external pallidum). Structures within this network were activated in response to apomorphine in PD patients without gambling but deactivated in PD patients with gambling [24].
severity. [11 C]PK 11195 is a difficult ligand to work with, in view of limited signal-to-noise ratio and lack of a robust kinetic model. Indeed, the results of [11 C]PK 11195 PET have been shown to vary widely, depending upon the model used to analyze the data, and there is no convincing reduction of [11 C]PK 11195 binding in response to COX-2 inhibitors [29]. A number of newer agents have been developed to label the TSPO, with much better signal-to-noise properties compared to [11 C]PK 11195. However, the affinity of these agents to bind to the TSPO is dictated by polymorphic variation in a single codon of the TSPO gene, thus the agents are only useful in individuals with medium- or high-affinity variants [30]. 4. Concluding comments While MRI provides exquisite anatomical information and is increasingly the preferred technique for studying both structural and functional connectivity, PET remains the best method to study neurotransmitter and neuroreceptor function in vivo. Increasingly, PET may play a role in understanding factors that contribute to disease pathogenesis. PET remains a valuable tool as a biomarker and for understanding complications of disease and its treatment. By combining PET and MRI in a single scanner, it will be possible to concurrently assess changes in cerebral blood flow, regional connectivity and neurotransmitter function.
3. Mechanisms underlying disease The pathological hallmark of PD is the deposition of aberrantly folded a-synuclein in the form of Lewy bodies and Lewy neurites. A non-invasive means of visualizing and quantifying abnormal synuclein deposition in the brain would be of considerable utility for diagnosis and preclinical detection, as well as monitoring disease progression and the effects of disease-modifying therapies. This is particularly true given the current development of immunotherapies targeting synuclein deposition. While this approach has been fairly successful in the Alzheimer field, it has proven more difficult in the case of PD. Benzoxazole compounds have been labeled with 11 C [25] and 18 F [26], but these compounds bind to amyloid-b as well as a-synuclein, as is also the case for the recently described [123 I]SIL23 [27], a phenothiazine that also binds to tau. In addition to problems with selectivity, a-synuclein is intracellular, as opposed to amyloid-b, which is extracellular and therefore more accessible to radioligands. Numerous studies have used PET to examine amyloid-b deposition in cognitive impairment associated with PD. Although the findings do differ somewhat from one study to another, the prevailing view is that most cases of PD-dementia do not demonstrate amyloid-b deposition, but levels are generally higher in dementia with Lewy bodies (DLB), and amyloid deposition may predict the future development of dementia in PD [28]. In the last few months, a number of PET ligands for tau deposition have been reported. These are likely to be of greater interest for the investigation of AD, or frontotemporal dementias, and atypical parkinsonism such as PSP than for PD. PD, like other neurodegenerative disorders, is associated with evidence of neuroinflammation. Post-mortem studies do not allow the determination of whether inflammation occurs early and plays a role in disease pathogenesis, or whether it occurs later, secondary to neuronal death. The peripheral benzodiazepine receptor (PBR; now more commonly referred to as the translocator protein – TSPO) is expressed on the outer mitochondrial membrane and is a relatively good indicator of microglial activation. Studies with the TSPO ligand [11 C]PK 11195 have suggested microglial activation in PD, but there has been disparity as to whether this is restricted to the midbrain and correlates with disease severity, or whether the response is much more widespread and fails to correlate with
Acknowledgements This work was supported by the Canadian Institutes of Health Research, the Michael J. Fox Foundation, the Pacific Alzheimer Research Foundation and the Canada Research Chairs program. Conflict of interests The author has no conflict of interest to report. References [1] Tang CC, Poston KL, Eckert T, Feigin A, Frucht S, Gudesblatt M, et al. Differential diagnosis of parkinsonism: a metabolic imaging study using pattern analysis. Lancet Neurol 2010;9:149–58. [2] de la Fuente-Fernandez R, Schulzer M, Kuramoto L, Cragg J, Ramachandiran N, Au WL, et al. Age-specific progression of nigrostriatal dysfunction in Parkinson’s disease. Ann Neurol 2011;69:803–10. [3] Kordower JH, Olanow CW, Dodiya HB, Chu Y, Beach TG, Adler CH, et al. Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease. Brain 2013;136:2419–31. [4] Sossi V, Fuente-Fernandez R, Nandhagopal R, Schulzer M, McKenzie J, Ruth TJ, et al. Dopamine turnover increases in asymptomatic LRRK2 mutations carriers. Mov Disord 2010;25:2717–23. [5] de la Fuente-Fernandez R, Sossi V, Huang Z, Furtado S, Lu JQ, Calne DB, et al. Levodopa-induced changes in synaptic dopamine levels increase with progression of Parkinson’s disease: implications for dyskinesias. Brain 2004;127:2747–54. [6] de la Fuente-Fernandez R, Lu JQ, Sossi V, Jivan S, Schulzer M, Holden JE, et al. Biochemical variations in the synaptic level of dopamine precede motor fluctuations in Parkinson’s disease: PET evidence of increased dopamine turnover. Ann Neurol 2001;49:298–303. [7] Sossi V, Fuente-Fernandez R, Holden JE, Schulzer M, Ruth TJ, Stoessl J. Changes of dopamine turnover in the progression of Parkinson’s disease as measured by positron emission tomography: their relation to disease-compensatory mechanisms. J Cereb Blood Flow Metab 2004;24:869–76. [8] Carta M, Carlsson T, Kirik D, Bjorklund A. Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats. Brain 2007;130:1819–33. [9] Politis M, Wu K, Loane C, Quinn NP, Brooks DJ, Rehncrona S, et al. Serotonergic neurons mediate dyskinesia side effects in Parkinson’s patients with neural transplants. Sci Transl Med 2010;2:38ra46. [10] Piccini P, Weeks RA, Brooks DJ. Alterations in opioid receptor binding in Parkinson’s disease patients with levodopa-induced dyskinesias. Ann Neurol 1997;42:720–6. [11] Van Laere K, Casteels C, Lunskens S, Goffin K, Grachev ID, Bormans G, et al. Regional changes in type 1 cannabinoid receptor availability in Parkinson’s disease in vivo. Neurobiol Aging 2012;33:620–8.
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[12] Ramlackhansingh AF, Bose SK, Ahmed I, Turkheimer FE, Pavese N, Brooks DJ. Adenosine 2A receptor availability in dyskinetic and nondyskinetic patients with Parkinson disease. Neurology 2011;76:1811–6. [13] Bohnen NI, Muller ML, Koeppe RA, Studenski SA, Kilbourn MA, Frey KA, et al. History of falls in Parkinson disease is associated with reduced cholinergic activity. Neurology 2009;73:1670–6. [14] Bohnen NI, Muller ML, Kotagal V, Koeppe RA, Kilbourn MA, Albin RL, et al. Olfactory dysfunction, central cholinergic integrity and cognitive impairment in Parkinson’s disease. Brain 2010;133:1747–54. [15] Kotagal V, Albin RL, Muller ML, Koeppe RA, Chervin RD, Frey KA, et al. Symptoms of rapid eye movement sleep behavior disorder are associated with cholinergic denervation in Parkinson disease. Ann Neurol 2012;71:560–8. [16] Boileau I, Warsh JJ, Guttman M, Saint-Cyr JA, McCluskey T, Rusjan P, et al. Elevated serotonin transporter binding in depressed patients with Parkinson’s disease: a preliminary PET study with [11 C]DASB. Mov Disord 2008;23:1776–80. [17] Politis M, Wu K, Loane C, Turkheimer FE, Molloy S, Brooks DJ, et al. Depressive symptoms in PD correlate with higher 5-HTT binding in raphe and limbic structures. Neurology 2010;75:1920–7. [18] Joutsa J, Rinne JO, Eskola O, Kaasinen V. Reduced striatal dopamine synthesis capacity is associated with symptoms of depression in patients with de novo unmedicated Parkinson’s disease. J Parkinsons Dis 2013;3:325–9. [19] Weintraub D, Koester J, Potenza MN, Siderowf AD, Stacy M, Voon V, et al. Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients. Arch Neurol 2010;67:589–95. [20] Hassan A, Bower JH, Kumar N, Matsumoto JY, Fealey RD, Josephs KA, et al. Dopamine agonist-triggered pathological behaviors: surveillance in the PD clinic reveals high frequencies. Parkinsonism Relat Disord 2011;17:260–4. [21] Steeves TD, Miyasaki J, Zurowski M, Lang AE, Pellecchia G, van Eimeren T, et al. Increased striatal dopamine release in Parkinsonian patients with pathological gambling: a [11 C] raclopride PET study. Brain 2009;132:1376–85.
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[22] O’Sullivan SS, Wu K, Politis M, Lawrence AD, Evans AH, Bose SK, et al. Cueinduced striatal dopamine release in Parkinson’s disease-associated impulsive– compulsive behaviours. Brain 2011;134:969–78. [23] van Eimeren T, Ballanger B, Pellecchia G, Miyasaki JM, Lang AE, Strafella AP. Dopamine agonists diminish value sensitivity of the orbitofrontal cortex: a trigger for pathological gambling in Parkinson’s disease? Neuropsychopharmacology 2009;34:2758–66. [24] van Eimeren T, Pellecchia G, Cilia R, Ballanger B, Steeves TD, Houle S, et al. Druginduced deactivation of inhibitory networks predicts pathological gambling in PD. Neurology 2010;75:1711–6. [25] Kikuchi A, Takeda A, Okamura N, Tashiro M, Hasegawa T, Furumoto S, et al. In vivo visualization of alpha-synuclein deposition by carbon-11-labelled 2-[2(2-dimethylaminothiazol-5-yl)ethenyl]-6-[2-(fluoro)ethoxy]benzoxazole positron emission tomography in multiple system atrophy. Brain 2010;133:1772–8. [26] Fodero-Tavoletti MT, Mulligan RS, Okamura N, Furumoto S, Rowe CC, Kudo Y, et al. In vitro characterisation of BF227 binding to alpha-synuclein/Lewy bodies. Eur J Pharmacol 2009;617:54–8. [27] Bagchi DP, Yu L, Perlmutter JS, Xu J, Mach RH, Tu Z, et al. Binding of the radioligand SIL23 to alpha-synuclein fibrils in Parkinson disease brain tissue establishes feasibility and screening approaches for developing a Parkinson disease imaging agent. PLoS One 2013;8:e55031. [28] Donaghy P, Thomas AJ, O’Brien JT. Amyloid PET imaging in Lewy body disorders. Am J Geriatr Psychiatry 2013 Jul 3 [Epub ahead of print]. [29] Bartels AL, Willemsen AT, Doorduin J, de Vries EF, Dierckx RA, Leenders KL. [11 C]-PK11195 PET: quantification of neuroinflammation and a monitor of antiinflammatory treatment in Parkinson’s disease? Parkinsonism Relat Disord 2010;16:57–9. [30] Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, et al. An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab 2012;32:1–5.
Contents lists available at SciVerse ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Developments in neuroimaging: positron emission tomography A. Jon Stoessl * Pacific Parkinson’s Research Centre, University of British Columbia & Vancouver Coastal Health. Vancouver, Canada
article info
summary
Keywords: Positron emission tomography Dopamine Vesicular monoamine transporter type 2 (VMAT2) Dopamine transporter (DAT) 6-[18 F]fluoro-L-dopa (F-dopa) 5-hydroxytryptamine (5HT, serotonin) Acetylcholine Beta-amyloid Alpha-synuclein Microglia
Positron emission tomography (PET) is a powerful technique to quantitatively assess brain function in vivo. In Parkinson’s disease (PD), PET can assist in the identification of dopamine deficiency, the characterization of dopamine and other neurotransmitter receptors and transporters, serve as a biomarker and provide insights into motor and non-motor complications of PD. PET can also shed light on mechanisms that underlie disease, such as aberrant protein deposition and neuroinflammation. Emerging developments in multimodal imaging offer the opportunity to study multiple questions concurrently and offer great promise for the future.
1. Introduction Positron emission tomography (PET) has a well-established history in the assessment and investigation of Parkinson’s disease (PD), primarily as a means to assess dopaminergic function. The assessment of presynaptic dopaminergic integrity remains an important application of this technique. PET studies of glucose metabolism or cerebral blood flow have been used to study regional activation in response to a variety of stimuli, as well as patterns of regional connectivity. Regional activation and connectivity can also be well addressed by functional MRI. PET can also be used to assess the function of neurotransmitters other than dopamine (DA) and shows increasing promise as a means to investigate mechanisms that contribute to disease. The increasing number of functional imaging techniques now available should be seen as complementary rather than competitive, as many questions are best addressed by a combination of approaches. 2. Clinical and research applications 2.1. Diagnosis PD is typically associated with loss of presynaptic DA markers (dopamine transporter – DAT, vesicular monoamine transporter type 2 – VMAT2, or 6-[18 F]fluoro-L-dopa – F-dopa) which is asymmetric, and with a rostral–caudal gradient, in which the posterior striatum is maximally affected. The same pattern is seen * Correspondence: 2221 Wesbrook Mall, Vancouver, BC Canada V6T 2B5. Tel.: +1 604 822 7967; fax: +1 604 822 7866. E-mail address: [email protected] (J.A. Stoessl). 1353-8020/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.
© 2013 Elsevier Ltd. All rights reserved.
using SPECT with a variety of markers for the DAT. However, while this reliably identifies DA deficiency (and may therefore distinguish between PD and essential or dystonic tremor), the pattern is not specific for PD and may be seen in other akinetic–rigid syndromes, in particular multiple system atrophy (MSA). The additional use of a marker for DA receptors, which are typically lost in MSA or progressive supranuclear palsy (PSP) but preserved in PD, may help, but this approach has not found widespread use. In contrast, PD is associated with a typical pattern of glucose metabolism or cerebral blood flow, while MSA, PSP and corticobasal syndrome all have distinct patterns that can be visually identified and quantified using a form of principal components analysis [1]. 2.2. Preclinical detection and disease biomarker All markers of presynaptic DA integrity decline according to an exponential function that is estimated to start deviating from normal age-related changes several years prior to onset of clinical disease. Based on extrapolation of our exponential model, we have found that VMAT2 binding declines first (approximately 17 years prior to disease onset), followed by decline in DAT binding (13 years prior) and then by F-dopa uptake (6 years prior) [2]. The latency between decline in DA function and clinical disease onset varies as a function of age. Patients with younger age of onset have a greater degree of DA dysfunction at disease onset (and longer duration of preclinical DA dysfunction). It should also be noted that in the posterior putamen, most of the damage has been done by the time of clinical disease onset, and even in the anterior putamen there is relatively little further decline beyond 10 years disease duration. By the time disease becomes
A.J. Stoessl / Parkinsonism and Related Disorders 20S1 (2014) S180–S183
Fig. 1. VMAT2 binding assessed with [11 C]dihydrotetrabenazine PET in a healthy control subject (left), an asymptomatic LRRK2 mutation carrier (middle) and a patient with PD due to LRRK2 mutation (right).
manifest, DAT binding is reduced relative to VMAT2 binding, while F-dopa uptake is relatively increased. A recent post-mortem study found that tyrosine hydroxylase (TH) and DAT immunocytochemical staining is virtually absent in the dorsal putamen by 4 years disease duration [3]. Taken together, these findings highlight the importance of compensatory mechanisms in maintaining motor function in the face of severe loss of striatal DA innervation. F-dopa uptake is decreased in subjects who are at risk of developing PD, including monozygotic twins of PD patients and subjects exposed to the nigral toxin MPTP. DAT and VMAT2 binding are decreased in asymptomatic carriers of LRRK2 mutations, although symptoms do not become apparent until F-dopa uptake is also reduced (Fig. 1). In LRRK2 mutation carriers, one of the earliest imaging abnormalities appears to be an increase in DA turnover [4], measured with F-dopa and long scan times (4 hours, as opposed to the routine 90-minute scan time, which predominantly reflects tracer uptake). This suggests that the mutation itself may result in abnormal vesicular dynamics, even prior to DA neuronal degeneration. Our findings to date suggest that the progression of DA degeneration in asymptomatic LRRK2 mutation carriers is in keeping with the preclinical trajectory predicted from extrapolation of the exponential function derived in patients with sporadic PD. Not surprisingly, there is a broad correlation between markers of presynaptic DA function and clinical severity. However, most studies have failed to show a correlation between the change in PET markers and change in clinical function (Unified Parkinson Disease Rating Scale [UPDRS] or equivalent). There are several potential reasons for this disappointing lack of correlation between imaging and clinical measures of deterioration, including subjectivity of clinical scores, effects of medication and other symptomatic therapies, compensatory changes affecting the expression of DA markers as well as engagement of non-DA mechanisms, and the related but different problem that clinical progression may reflect degeneration of non-DA systems. This problem should not be seen as a fatal flaw in the use of functional imaging measures, but rather as a requirement for caution in interpreting the results. 2.3. Motor complications of PD The DA D2/3 receptor ligand [11 C]raclopride (RAC) has a relatively weak affinity for DA receptors and its binding is accordingly subject to competition from endogenous DA. The practical significance is that by examining a change in RAC binding before and after an intervention, one can estimate the degree of DA release. Using this approach, we have found that DA release increases with increased duration of PD, and is of greater magnitude but shorter duration in patients with dyskinesias [5]. Furthermore, a similar aberrant pattern of DA release is seen in stable patients who later go on to develop motor fluctuations, compared to those patients who maintain a stable clinical response to treatment for 3 years after the scans [6]. This is in keeping with impaired storage of levodopaderived DA in synaptic vesicles, as is also suggested by increased DA turnover as PD progresses [7]. This will presumably result in pulsatile stimulation of DA receptors, but suggests that some patients (those with greater DA turnover and a pattern of high
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magnitude but short duration DA release) are more prone to develop fluctuations and dyskinesias. One factor that may contribute to this is DA production by striatal serotonin (5HT) nerve terminals. While 5HT neurons are able to synthesize DA from levodopa, they do not store DA in vesicles nor is its release regulated in a physiological fashion [8]. It is therefore of great interest that PD patients who develop severe dyskinesias following fetal nigral transplantation demonstrate increased striatal binding of [11 C]DASB, a selective ligand for the 5HT transporter [9]. PET has shown very few changes in DA receptors related to the emergence of long-term motor complications. However, pulsatile stimulation can result in changes downstream to these receptors. It is therefore of interest that PD patients with dyskinesias have reduced opioid receptor binding, presumably reflecting occupancy secondary to increased release of endogenous opioids [10]. Cannabinoid receptor expression is decreased in the substantia nigra but increased in DA projection sites of patients with PD, but its expression is not related to the presence or absence of levodopainduced dyskinesias [11]. In contrast, striatal adenosine A2A receptor expression is no different between control and PD subjects without dyskinesias, but greatly increased in those with dyskinesia [12]. The mGluR5 receptor has attracted a great deal of interest with respect to its potential role in levodopa-induced dyskinesias. A number of radiolabelled mGluR5 ligands have been developed for PET, but there are to date no published studies on their application to the study of PD in humans. 2.4. Non-motor complications Non-motor complications represent the greatest source of disability in PD. Cognitive impairment affects a large proportion of patients and some authors argue that the majority of patients with PD will ultimately develop dementia. Dementia in PD is associated with a pattern of glucose hypometabolism in which occipital cortex is disproportionately affected, in contrast to Alzheimer’s disease (AD). Cholinergic activity is reduced throughout the cortex in PD, more so in those with cognitive impairment, in whom the abnormality is of greater magnitude than that seen in AD. There is growing interest in brainstem–thalamic cholinergic projections, which are affected to a more variable degree in PD, in association with REM behaviour disorder, olfactory dysfunction and postural instability [13–15]. Depression is another major problem in PD. Although it has long been assumed that this reflects loss of 5HT neurons, as is known to occur in PD, two imaging studies have independently demonstrated increased [11 C]DASB binding in depressed PD patients [16,17]. Another recent paper has suggested a correlation between depression in unmedicated PD patients and reduced striatal F-dopa uptake [18]. The interpretation of such studies can be confounded by the possibility that transporter binding could potentially be increased if there is reduced occupancy by endogenous ligands (i.e. DA or 5HT), although there is limited evidence to support this explanation as a basis for the imaging findings reported to date. DA, in addition to its important role in motor function, is thought to signal the delivery of unanticipated reward, the anticipation of expected reward, and through this, incentive salience and learning. DA release can be demonstrated in response to natural rewards such as food and music, monetary rewards and placebo (expectation of therapeutic benefit). However, aberrant reward signaling may lead to addiction, and impulse control disorders (ICD) including pathological gambling, compulsive shopping, hobbyism, hypersexuality and compulsive eating affect affect some 17% or more of patients taking DA agonists [19,20]. The basis for this may represent a combination of hyperactivity in DA reward projections from ventral tegmental area (VTA) to ventral striatum (VS) and loss of normal behavioural inhibitory mechanisms. Thus, PD patients
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with pathological gambling demonstrated increased DA release in the VS while performing a monetarily rewarded card task compared to PD patients without gambling tendency [21], and increased levodopa-induced DA release in the VS of patients with ICD compared to those without can be demonstrated using RAC PET in response to visual stimuli [22]. As is the case for other addictions, the degree of DA release as measured by change in RAC binding correlates to the degree of drug wanting rather than the degree of drug liking. In addition to the problem of excessive reward-related DA release in the VTA–VS projection, PD patients with ICDs fail to inhibit behavioural patterns despite knowledge of the likely negative longterm consequences. In this regard, it is of interest that using fMRI, van Eimeren and colleagues found reduced deactivation of orbitofrontal cortex in response to a negative reward prediction error in PD patients given pramipexole as opposed to levodopa [23]. In a related PET study of cerebral blood flow PET, the same authors found differential responses to the short-acting dopamine agonist apomorphine in an inhibitory network (lateral orbitofrontal cortex, rostral cingulate, amygdala and external pallidum). Structures within this network were activated in response to apomorphine in PD patients without gambling but deactivated in PD patients with gambling [24].
severity. [11 C]PK 11195 is a difficult ligand to work with, in view of limited signal-to-noise ratio and lack of a robust kinetic model. Indeed, the results of [11 C]PK 11195 PET have been shown to vary widely, depending upon the model used to analyze the data, and there is no convincing reduction of [11 C]PK 11195 binding in response to COX-2 inhibitors [29]. A number of newer agents have been developed to label the TSPO, with much better signal-to-noise properties compared to [11 C]PK 11195. However, the affinity of these agents to bind to the TSPO is dictated by polymorphic variation in a single codon of the TSPO gene, thus the agents are only useful in individuals with medium- or high-affinity variants [30]. 4. Concluding comments While MRI provides exquisite anatomical information and is increasingly the preferred technique for studying both structural and functional connectivity, PET remains the best method to study neurotransmitter and neuroreceptor function in vivo. Increasingly, PET may play a role in understanding factors that contribute to disease pathogenesis. PET remains a valuable tool as a biomarker and for understanding complications of disease and its treatment. By combining PET and MRI in a single scanner, it will be possible to concurrently assess changes in cerebral blood flow, regional connectivity and neurotransmitter function.
3. Mechanisms underlying disease The pathological hallmark of PD is the deposition of aberrantly folded a-synuclein in the form of Lewy bodies and Lewy neurites. A non-invasive means of visualizing and quantifying abnormal synuclein deposition in the brain would be of considerable utility for diagnosis and preclinical detection, as well as monitoring disease progression and the effects of disease-modifying therapies. This is particularly true given the current development of immunotherapies targeting synuclein deposition. While this approach has been fairly successful in the Alzheimer field, it has proven more difficult in the case of PD. Benzoxazole compounds have been labeled with 11 C [25] and 18 F [26], but these compounds bind to amyloid-b as well as a-synuclein, as is also the case for the recently described [123 I]SIL23 [27], a phenothiazine that also binds to tau. In addition to problems with selectivity, a-synuclein is intracellular, as opposed to amyloid-b, which is extracellular and therefore more accessible to radioligands. Numerous studies have used PET to examine amyloid-b deposition in cognitive impairment associated with PD. Although the findings do differ somewhat from one study to another, the prevailing view is that most cases of PD-dementia do not demonstrate amyloid-b deposition, but levels are generally higher in dementia with Lewy bodies (DLB), and amyloid deposition may predict the future development of dementia in PD [28]. In the last few months, a number of PET ligands for tau deposition have been reported. These are likely to be of greater interest for the investigation of AD, or frontotemporal dementias, and atypical parkinsonism such as PSP than for PD. PD, like other neurodegenerative disorders, is associated with evidence of neuroinflammation. Post-mortem studies do not allow the determination of whether inflammation occurs early and plays a role in disease pathogenesis, or whether it occurs later, secondary to neuronal death. The peripheral benzodiazepine receptor (PBR; now more commonly referred to as the translocator protein – TSPO) is expressed on the outer mitochondrial membrane and is a relatively good indicator of microglial activation. Studies with the TSPO ligand [11 C]PK 11195 have suggested microglial activation in PD, but there has been disparity as to whether this is restricted to the midbrain and correlates with disease severity, or whether the response is much more widespread and fails to correlate with
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