Beyond Clinic: How Can Imaging Help in the Diagnosis of Parkinson´s Disease?
There is no simple way to diagnose the event-changing life of Parkinson´s disease (PD). Despite all the advancements in the biomarkers field, PD diagnosis still remains a clinical one based on the centrality of the motor features namely the presence of bradykinesia, rigidity, tremor and postural instability.
However, non-motor symptoms are now considered in the PD diagnostic process as “supportive criteria” such as the occurrence of hyposmia (partial or complete loss of sense of smell) and autonomic dysfunction (drops in BP on standing, bladder and sexual dysfunction) as exemplified by cardiac sympathetic denervation using MIBG scintigraphy (an imaging test used to detect whether the heart is receiving normal levels of innervation from the sympathetic nerves).
The MDS clinical diagnostic criteria have also the novelty of including “absolute exclusion criteria”, as the presence of a normal presynaptic dopaminergic terminal scan using brain imaging. Therefore, the PD diagnostic process is moving beyond the limits of the motor syndrome. Increasing recognition to non-motor manifestations is given and imaging biomarkers are considered.
The most accessible imaging method to diagnose PD is the use of a marker for the dopamine transporter (DAT) which resides in the dopamine nerve terminal – such that when the signal is lost so must the dopaminergic nerve terminal. SPECT with 123I-fluoropropyl CIT (ioflupane, DaTSCAN) was approved by FDA for routine clinical use in the differential diagnosis of PD and Essential Tremor. This study shows a sensitivity and specificity of 95% and 93% respectively. In practical terms, DAT scans allow for the differentiation of degenerative from non-degenerative parkinsonisms in daily practice, one of the main questions that clinicians need to answer when assessing a parkinsonian syndrome, especially if patients are also on medications that can cause parkinsonism as a side effect (as in these cases the DAT scan is also normal).
It is of importance to note that DaTSCANS are not useful for the differential diagnosis of PD and other neurodegenerative parkinsonisms such as Multiple System Atrophy (MSA) or Progressive Supranuclear Palsy (PSP), unless they are combined with a postsynaptic dopaminergic terminal scan. However, D2 receptor imaging compounds are not approved for clinical use by the FDA and most clinical centers do not perform the combination of presynaptic and postsynaptic dopaminergic terminal imaging as they typically require more sophisticated imaging cameras/set ups.
Another imaging method relevant in daily clinical practice is the glucose metabolism imaging with FDG PET, which enables the identification of “patterns of brain hypometabolism”. This is because brain cells use glucose as their energy source when active so when inactive (i.e. unhappy or dead) their metabolism goes down or is lost and this can be seen using FDG PET. They have the advantage of being “at hand” in the majority of clinical centers and a strong “imaging-clinical” correlation where the reciprocity with the clinical symptoms is more significant than with the underlying pathology. They can reliably differentiate PD from atypical parkinsonisms (APD) and they have demonstrated to be superior to D2/D3 SPECT in differentiating PD from APD. The most recent diagnostic criteria of MSA and PSP support the use of FDG PET for discriminating PD from APD.
In our clinic, we routinely use imaging methods for the diagnosis and differential diagnosis of PD and Parkinsonisms, albeit not in every patient that we see with a parkinsonian syndrome.
Conventional Magnetic Resonance Imaging (MRI) is used to exclude secondary causes of parkinsonism such as space-occupying, vascular or demyelinating lesions, toxic or traumatic injury or metal deposition in basal ganglia or brainstem. MRI cannot be used to diagnose PD as you only lose very few cells when you first develop PD so the scan is not sensitive enough to detect this. If atypical features are observed or if the patient does not respond positively to dopaminergic medications, then we undertake presynaptic dopaminergic terminal imaging to differentiate degenerative from non-degenerative parkinsonism and/or a FDG PET to evaluate patterns of brain hypometabolism that help in the differentiation of PD and APD.
Our research has focused on the development of 18 F-DOPA PET study for the differential diagnosis of PD from healthy controls (HC). We published results showing that this study reliably allowed the differentiation of PD from HC. Nowadays, we use 18 F-DOPA PET to study patients who present with an incomplete triad of motor problems of bradykinesia, rigidity and tremor and compare the diagnostic reliability of the triad of motor symptoms to the 18 F-DOPA PET study. Moreover, we also compare the visual and quantitative interpretation of the 18 F-DOPA uptake in the putamen and caudate (where dopamine terminals are to be found in the brain and first lost in PD).
Our results show that when people with Parkinson´s PDPs present with all 3 features of the triad, a putaminal low uptake is more frequently observed (67% of cases) than when PDPs present with only 2 of the features or less. When comparing the accuracy of detection of 18F-DOPA uptake, the visual and quantitative analysis show similar results.
Molecular imaging studies give the best opportunity to understand pathogenesis in Parkinsonisms and currently they also provide the possibility of imaging protein aggregation. Tau PET imaging is a challenging area in parkinsonisms. Studies usign 18F-FDDNP or THK5351 tracers in PD and PSP showed tracer retention in areas known to be involved in PSP pathology and a distinction between PD and controls was possible. However, its use is still in the early stages and one of the major limitations is a lack of validation in postmortem studies and the binding to other proteins in the brain.
Molecular imaging targeting alpha-synuclein is fascinating and holds great interest. New PET tracers are under investigation. The possibility to image alpha-synuclein deposition may be transformative given the clinical trials that are ongoing with therapies that specifically target alpha- synuclein.
Newer MR techniques are emerging, such as the high-field MR using qualitative techniques of Neuromelanin and Nigrosome imaging, which now allow the identification of the ongoing neurodegenerative process, the loss of dopaminergic cells and the decrease in neuromelanin signal. Their diagnostic capacity compared to DaTSCAN need yet to be determined.
There are still great challenges to overcome in the use of imaging methods for the diagnosis and differential diagnosis of PD and Parkinsonisms such as the standardization of imaging interpretation, the detection of early disease and the measurement of disease progression. The combination of different imaging modalities using PET and MRI and automated algorithms will substantially increase the accuracy of PD diagnosis and differential diagnosis.
Dr. Maria Cecilia Peralta, PhD is an associate professor of the Department of Neurology at CEMIC University Faculty of Medicine. She is a current member of the Program Committee for the 6th World Parkinson Congress in Barcelona, Spain
Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions of the World Parkinson Coalition®