Parkinson's disease (PD) and PET
Parkinson's disease is a progressive neurodegenerative movement disorder, characterized by motor symptoms, but causing also various non-motor symptoms. Motor symptoms include bradykinesia (slowness of movement), tremor, and rigidity (parkinsonism syndrome). Non-motor symptoms, related to the pathophysiology of PD, include depression, pain, anxiety, dementia, and fatigue. The pathological process in PD starts long before the clinical diagnosis is made.
Dopaminergic degeneration is an age-related process, but in PD the loss of dopaminergic neurons in the substantia nigra is much faster than in normal ageing. Parkinsonism is usually caused by idiopathic PD, but can be seen in patients without dopaminergic deficit, and is prevalent in disorders such as progressive supranuclear palsy, multiple system atrophy, and microvascular disease. Lesion network mapping suggests that claustrum has a central role in parkinsonism (Joutsa et al., 2018).
Pharmacotherapy for PD usually consists of the administration of a precursor of dopamine, L-DOPA, or a dopamine D2R agonist, which relieves the motor symptoms. Dual or multiple action pharmaceuticals that target also other neurotransmitter pathways and brain metabolism are considered a novel class of anti-Parkinsonian drugs (Ntetsika et al., 2021).
Presynaptic dopaminergic neurons can be studied with dopamine transporter (DAT) binding PET radiopharmaceuticals, including [11C]PE2I, [18F]FE-PE2I, [11C]CFT, and [18F]FP-CIT; the activity of aromatic amino acid decarboxylase (AADC) using 6-[18F]-L-DOPA (FDOPA); or vesicular monoamine transporter type 2 (VMAT2). Imaging studies of presynaptic striatal dopaminergic function show clear differences patient groups with Parkinson's disease or atypical parkinsonisms (Kaasinen et al., 2019). Postsynaptic (dopamine receptors can be targeted by many PET tracers. This allows the detection of possible upregulation in the early phase of PD, and also to assess changes in synaptic dopamine concentration.
Overall density of synapses in the brain can be assessed using PET radioligands binding to synaptic vesicle glycoprotein 2A (SV2A), such as [11C]UCB-J. In mild bilateral PD and in drug-naive PD patients, [11C]UCB-J PET has revealed markedly reduced synaptic density (Matuskey et al., 2020; Wilson et al., 2020). In early PD, [11C]UCB-J uptake is reduced in substantia nigra, while [18F]FE-PE2I binding is reduced more in the putamen (Delva et al., 2020). In two-year follow-up, [11C]UCB-J uptake did not change, while [18F]FE-PE2I binding declined further (Delva et al., 2022).
Serotonergic system is impaired in PD, and several serotonin system targeting PET radiopharmaceuticals have been used in studies of motor and non-motor symptoms of PD.
Cholinergic neurotransmission is decreased in PD. AChE, mAChR, nAChR, and VAChT radioligands have been used in PET studies of PD.
Neuroinflammatory processes are involved in development of PD, and TSPO radioligands are used to study microglial activation in PD. Mitochondrial dysfunction and oxidative stress induced apoptotic processes are central to neurodegenerative diseases, including PD and Alzheimer's disease. Mitochondria are main producers of reactive oxygen species (ROS), but also auto-oxidation of dopamine leads to ROS formation. In drug-naive early PD, a trend for lower levels of mitochondrial MC-1 activity and σ1R, with longitudinal increases, have been observed using [18F]BCPP-EF and [11C]SA-4503 (Wilson et al., 2020).
The endocannabinoid system is altered in PD brain (Van Laere et al., 2012; Ceccarini et al., 2019). CB1R inverse agonist [18F]FMPEP-d2 has shown reduced CB1R availability in PD, which is increased toward normal levels by PD medication (Ajalin et al., 2022).
Histamine H3 receptor modulates the release of neurotransmitters that are involved in the pathobiology of PD. H3R antagonists could be used to treat cognitive impairment, and studied using specific PET radioligands (Ghazanfari et al., 2022).
PD is neuropathologically characterized by intracellular misfolded α-synuclein-rich inclusions (Lewy bodies). In addition, extracellular deposits of amyloid-β and intraneuronal deposits of tau protein as neurofibrillary tangles are found in PD patients.
Leucine-rich repeat kinase 2 (LRRK2, dardarin) protein is expressed in most brain regions, including substantia nigra and putamen. Mutation of LRRK2 gene is the most common cause of dominantly inherited PD and mutations are implicated as risk factor for idiopathic PD (Tolosa et al., 2020). Selective LRRK2 inhibitors have been developed for treatment of PD, and labelled for in vivo PET imaging, including [18F]PF-06455943 (Malik et al., 2021; Chen et al., 2023; Yoo et al., 2023).
PD can be discriminated from atypical parkinsonism based on serum neurofilament light chain (Marquez et al., 2019).
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Updated at: 2023-02-02
Created at: 2017-11-16
Written by: Vesa Oikonen