Positron emission tomography
Positron emission tomography (PET) is a versatile imaging modality that utilizes radioactive ligands to gauge the integrity of the dopamine system, cerebral glucose metabolism, pathological Aβ and tau protein accumulation and neuroinflammation [46]. 6‐18F‐fluoro‐L‐dopa (18F-dopa) is a presynaptic PET tracer that is converted to18F-dopamine by aromatic L-amino acid decarboxylase (AADC). Thus, 18F-dopa measures the activity of AADC and provides an indirect estimation of the nigrostriatal dopamine storage pools.
In line with DAT-SPECT findings, striatal PET imaging of presynaptic DAT, using for example 18F-FP-CIT or11C-methylphenidate tracers, has found reduced uptake in the putamen and SN in PD and atypical parkinsonism [46]. As compared with DAT-PET, DAT-SPECT or AADC-PET, PET imaging of VMAT-2 using 11C-dihydrotetrabenazine (11C-DTBZ) seems to be less prone to compensatory changes. Thus, decreased striatal VMAT-2 binding more reliably reflects the nigrostriatal degeneration in PD. This has been confirmed in experimental settings, too [52].
Animal models indicate that lesion of locus coeruleus, the main noradrenergic nucleus in the brain, may be important for the pathogenesis of non-motor symptoms of PD [53]. PET ligand (S,S)-11C-2-(α-(2-methoxyphenoxy)benzyl)morpholine (11C-MeNER) labels noradrenaline transporter, and several studies in PD patients show reduced noradrenergic innervation in the brain supporting the view that 11C-MeNER can be used as one imaging biomarker for non-motor symptoms of PD.
PD causes functional changes in multiple neuronal networks. These changes are reflected by a specific pattern of abnormal glucose metabolism in resting-state 18F-fluorodeoxyglucose (18F-FDG) PET referred to as PD-related pattern (PDRP), or a distinct PD-related cognitive pattern (PDCP) [54]. PDRP can be used to discriminate between idiopathic PD, atypical parkinsonian syndrome and healthy controls. PDRP and PDCP also show promise as biomarkers to follow the progression of the disease.
PET ligands can be used to assess the degree of neuroinflammation in the brain [55]. 11C-(R )-PK11195 binds to mitochondrial translocator protein (formally a peripheral benzodiazepine receptor), the upregulation of which is indicative of augmented microglial activation. 11C-(R )-PK11195 uptake correlates with various aspects of PD pathology in the brain and can be used in combination with other markers to support the diagnosis.
A major limitation in the development of valid imaging biomarkers for PD is the incapacity for direct a-syn imaging in vivo . Considerable efforts are underway to develop a-syn-specific radiotracers for PET imaging [56]. Such tracer would allow for tracking the degree and location of a-syn pathology over time and monitoring efficacy of a-syn targeting therapies.
In addition to CNS imaging also peripheral imaging modalities warrant attention as the initial pathological a-syn inclusions appear in the peripheral autonomic and enteric nervous systems even decades prior to the diagnosis of PD [57]. For example, loss of sympathetic and parasympathetic nerve terminals can be visualized using 18F-dopamine and 11C-donepezil PET imaging, and radiological techniques can reveal dysmotility and prolonged transit time through the gastrointestinal tract in PD patients.
Collectively, brain imaging modalities seem to comprise the most promising biomarker candidates in PD because they provide a direct approach to measure specific neurofunctional properties and the same methodology can be applied both to experimental animals and humans [57]. Even though imaging modalities assure relatively accurate conclusions, they are expensive, may entail harmful radiation and are available only in specific centers limiting their usefulness in standard diagnostics [58]. Thus, they may not be feasible to be used in screening purposes in large populations. Imaging, however, may prove to be the most useful approach in confirming the diagnosis triggered by more accessible screening methods.