Single Photon Emission Computed Tomography/Positron Emission Tomography Molecular Imaging for Parkinsonism: A Fast‐Developing Field

Presynaptic Dopaminergic Imaging

The European Association of Nuclear Medicine and the Society of Nuclear Medicine and Molecular Imaging recently published guidelines for dopaminergic imaging of parkinsonism. ⁷ These guidelines predominantly focus on two commonly used nuclear medicine examinations of presynaptic dopaminergic function, namely, single photon emission computed tomography (SPECT) using ¹²³I‐labeled dopamine transporter ligands and positron emission tomography (PET) using ¹⁸F‐fluorodopa (Fig 2A). These differentiate neurodegenerative parkinsonism from other dementias (particularly DLB from Alzheimer disease [AD]), from other forms of parkinsonism (drug‐induced, psychogenic, and vascular parkinsonism, whose diagnosis requires images to be fused with magnetic resonance imaging [MRI]) and from essential tremor. These scans can also detect early degenerative parkinsonism. ⁷ SPECT, with specific ¹²³I‐labeled dopamine transporter ligands and ¹⁸F‐fluorodopa PET, detects different molecular dopaminergic targets. ¹²³I‐labeled dopamine transporter ligands identify presynaptic dopamine active transporters (DATs). ¹⁸F‐fluorodopa PET visualizes L‐dopa, which is subsequently decarboxylated to dopamine by the aromatic L‐amino‐acid decarboxylase. Both types of dopaminergic imaging need to take into account radiotracer–drug interactions prior to performing acquisitions. Current guidelines recommend discontinuing antiparkinsonian drugs before ¹⁸F‐fluorodopa PET imaging. ⁷ DAT and L‐dopa targets decrease in parallel but not necessarily synchronously with progression of neurodegenerative parkinsonism. ⁸ This may be due to the presence of compensatory mechanisms in the presymptomatic and early symptomatic phases: a reduction in the number of presynaptic DATs, which increases the intrasynaptic availability of dopamine, and an upregulation of the fluorodopa to dopamine conversion by aromatic L‐amino acid decarboxylase in nerve terminals. ⁸ , ⁹ Clinical ¹⁸F‐fluorodopa PET studies focusing on the presymptomatic stage have confirmed the high sensitivity of the method. ¹⁰ Albeit performed on a relatively small number of patients, comparative study confirmed that SPECT and PET diagnose presynaptic dopaminergic deficiencies in early stage PD. ¹¹ Fluorodeoxyglucose (¹⁸F‐FDG) PET and ¹²³I‐metaiodobenzylguanidine (¹²³I‐MIBG) scintigraphy are also routinely used to evaluate parkinsonism (see Fig 1). ¹²

¹⁸F‐FDG PET

Brain ¹⁸F‐FDG PET images glycolytic metabolism in the brain. It may identify significant levels of brain dysfunction more consistently than any potential brain atrophies detected by MRI. ^{13 18}F‐FDG PET differentially diagnoses PD and parkinsonian “plus” syndromes at sensitivities and specificities greater than 75 and 90%. ¹⁴ This is particularly significant, because differential diagnoses based on dopaminergic imaging are somewhat limited for these entities. ^{15 18}F‐FDG PET provides a number of disease‐specific metabolic patterns. DLB is characterized by the preservation of posterior cingulate metabolism (as opposed to posterior associative cortical hypometabolism in the occipital cortex). PSP is distinguished by prefrontal mesial, putamen, and pons hypometabolism. CBD displays asymmetrical frontoparietal hypometabolism. MSA exhibits a somewhat lesser extent of basal ganglia or cerebellum hypometabolism (see Fig 2B). ¹⁶

¹²³I‐MIBG Scintigraphy

¹²³I‐MIBG scintigraphy/SPECT imaging targets the peripheral sympathetic noradrenergic stores. It can help differentiate PD/DLB (decreased cardiac binding) from MSA and PSP (normal binding) based on their sympathetic myocardial innervations (see Fig 2C). ¹²³I‐MIBG scintigraphy differentiates PD/DLB from cognitive decline and/or parkinsonism (AD, MSA, PSP, frontotemporal lobe and vascular dementia) with a specificity of 91% and sensitivity of 94%. ¹⁷ Advances in ¹⁸F‐fluorodopa PET heart scans ¹⁸ and PET MIBG radiotracer analogues ¹⁹ may further enhance these performances. Current parkinsonism SPECT/PET diagnoses rely on a combination of dopaminergic imaging, ¹⁸F‐FDG PET, and ¹²³I‐MIBG scintigraphy. Imaging biomarker research has the potential to improve disease recognition and allow earlier diagnosis and treatment. ²⁰ The development of in vivo biomarkers may be envisaged to follow the progress of personalized drug treatments. In vivo biomarkers may also become integrated in the earliest stages of parkinsonism rehabilitation. This review summarizes recent advances in radiopharmaceuticals and imaging technologies/analyses that improve the diagnosis of parkinsonism.

New PET Radiotracers for Dopaminergic Imaging

New dopaminergic PET tracers target presynaptic DATs. ⁹ , ²¹ , ²² In addition to overcoming the technical performance limitations of SPECT, PET imaging of DATs with ¹⁸F‐FE‐PE2I (N‐[3‐iodoprop‐2E‐enyl]‐2β‐carbo‐¹⁸F‐fluoroethoxy‐3β‐[4‐methylphenyl]‐nortropane) allows routine performance of 10‐minute static acquisitions only 30 minutes after administration of radiotracer. This represents a definite advantage over DAT SPECT imaging. ²³ Another dopaminergic PET radiotracer that targets DATs, the [18F] (2S,3S)‐methyl‐8‐([E]‐4‐fluorobut‐2‐en‐1‐yl)‐3‐(p‐tolyl)‐8‐azabicyclo(3.2.1)octane‐2‐carboxylate, namely, ¹⁸F‐LBT‐999, is being developed (Fig 3A). ²⁴

Additional molecular dopaminergic pathway targets are also being developed. ¹⁸F‐FP‐DTBZ ([+]‐α‐9‐O‐[3‐¹⁸F‐fluoropropyl]‐dihydrotetrabenazine) is a PET radiotracer that specifically binds to VMAT2 (vesicular monoamine transporter type 2), an integral membrane protein that transports dopamine from the cytoplasm into synaptic vesicles. ²⁵ This PET radiotracer is expected to suffer from the same limitations as ¹⁸F‐fluorodopa PET due to potential compensation phenomena at the early stages of PD. The iodobenzamide, ¹²³I‐IBZM, is used for postsynaptic dopaminergic SPECT imaging and ¹¹C‐raclopride, ¹⁸F‐fallypride, and ¹⁸F‐desmethoxyfallypride for PET imaging. ²⁶ Postsynaptic dopaminergic imaging predominantly aims to differentiate PD from atypical parkinsonism. ²⁶ Although radiotracers for this application are still in the research phase, one report already suggests that ¹⁸F‐FDG PET outperforms these postsynaptic dopaminergic radiotracers in terms of the differential diagnosis of PD/DLB and atypical parkinsonism. ¹⁵

Tau PET Imaging

The cognitive proteinopathy field ²⁷ has predominantly focused on imaging targets involved in the neurodegenerative process. Tau PET imaging is undoubtedly the best choice for the differential diagnosis of PD/DLB and other forms of atypical parkinsonism (see Fig 3B). The atypical parkinsonism PSP and CBD are tauopathies. PSP patients exhibit increased ¹⁸F‐AV‐1451 signals in the pallidum, midbrain, dentate nucleus of the cerebellum, thalamus, caudate nucleus, and frontal regions compared to controls. ²⁸ CBD patients have increased ¹⁸F‐THK5351 retention contralateral to the side with the greater cortical dysfunction. ²⁹ These non‐AD tauopathy deposits consist mainly of 4R tau, located in subcortical nuclei. Because AD is associated with 3R and 4R deposits, there is substantial clinical and neuropathological overlap between these tauopathies. Given that many regions of interest in corticobasal syndrome (CBS) and PSP largely coincide with off‐target binding (eg, with monoamine oxidase B in the basal ganglia), there is substantial overlap of tracer binding load across the different diagnostic groups. This is particularly true for ¹⁸F‐AV‐1451, which has been tested in the largest number of patients. ³⁰ In CBS and PSP, tau burden determined by neuropathological assessment and in vivo ¹⁸F‐AV‐1451 imaging yield inconsistent results. ¹⁸F‐AV‐1451 PET, for instance, identifies in vivo areas with high postmortem tau in some brain areas but not others. This presumably reflects a reduced sensitivity of the tracer to non‐AD tau. ³¹ , ³² In vitro staining and/or autoradiography studies have, however, highlighted that tracers of the THK family do bind to CBS and PSP tau deposits to some extent, which is consistent with in vivo findings. ³³ A new generation of more specific 4R tau tracers with less off‐target binding is needed to improve the in vivo diagnosis of non‐AD tauopathies.

α‐Synuclein PET Imaging

Specific PET tracers targeting α‐synuclein aggregates have great potential for diagnosing movement disorders but are currently exclusively in the research phase. ³⁴ The identification of any additional transporter targets that facilitate movement across the blood–brain barrier is also required. The recently identified small, high α‐synuclein affinity molecules are nevertheless not ideal lead compounds for PET radiotracer development. Although other different chemical entities that bind to α‐synuclein, such as anle138b (¹¹C‐MODAG‐001), have been described, their selectivity for β‐amyloid and tau fibrils still needs to be resolved. ³⁵

Neuroinflammation PET Imaging

There are a number of PET radiotracers that target neuroinflammation in parkinsonian disorders. ³⁶ , ^{37 18}F‐DPA‐714 and ¹⁸F‐GE‐180 are translocator protein (TSPO) ligands. TSPO is an outer mitochondrial membrane protein expressed in activated microglial cells and macrophages in the brain. It is a marker of nervous system inflammation. Increased ¹⁸F‐DPA‐714 and ¹⁸F‐GE‐180 radiotracer uptake has been reported in the pons, basal ganglia, frontal and temporal cortex, and midbrain of PD patients compared to normal controls. ³⁶ Although PET neuroinflammation imaging assesses one aspect of neurodegenerative parkinsonian disorder neuropathology (ie, TSPO expression), it is unable to diagnose specific parkinsonian disorders. There is no consensus about the optimal method for analyzing PET data or for selecting an anatomically defined reference region. This is because TSPO is expressed constitutively in the brain and because neurodegenerative pathologies are perhaps more widespread than previously assumed. The recent identification of populations of high‐ and low‐affinity TSPO ligand binders has further complicated the issue. ³⁷ The significance and potential clinical relevance of PET radiotracers targeting neuroinflammation requires further research.

Other innovative treatments that were initially identified in preclinical studies are currently being evaluated in a number of clinical trials. These include antibody‐based treatments (anti–α‐synuclein, antitau), iron chelators, and α‐synuclein and tau aggregation inhibitors. ³⁸ These treatments could potentially influence the course of disease and improve patients' and caregivers' quality of life. It also highlights the importance of developing early PET brain neurodegeneration biomarkers that closely reflect the pathophysiology of these diseases, to rapidly identify patient profiles that would benefit from being included in these therapeutic trials. This would maximize the chances of offering patients a treatment that may potentially improve disease outcome. Figure 4 summarizes the pathophysiological mechanisms of SPECT/PET radiotracers used to assess neurodegenerative parkinsonism.