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Dopamine transporter imaging with [123I]FP-CIT (DaTSCAN) in Parkinson's disease with depressive symptoms: a biological marker for causal relationships?
  1. Igor D Grachev
  1. Correspondence to Dr Igor Grachev, Medical Affairs, New Product Development, GE Healthcare—Life Sciences, 101 Carnegie Center, Princeton, NJ 08540, USA; igor.grachev{at}ge.comor grachevi{at}hotmail.com

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Comorbidity of depression, or depressive symptoms and Parkinson's disease (PD), is a common condition with a high prevalence,1 which may start developing before the formal clinical diagnosis of PD during the so-called premotor (non-motor or preclinical or prodromal) stage of the disease. Such association may be further strengthened during the progression of continuous neuronal loss and disease. The underlying pathophysiological mechanisms of the association between depression and PD are not clearly understood, and it is hypothesised that changes in brain pathology, neurotransmitter signalling pathways and, particularly, abnormalities of dopaminergic, noradrenergic and serotoninergic projections may substantially contribute to its development.1 Psychological factors, life stresses and internal perception of PD as a devastating neurodegenerative condition with no effective cure may also contribute to the development of depression in patients with PD. Commonly observed key PD symptoms, such as rigidity, bradykinesia and hypomimia, may add complexity in clinical differentiation between depression or depressive symptoms and PD.

Vriend et al2 use dopamine transporter (DaT) imaging with Iodine-123-fluoropropyl (FP)-carbomethoxy-3 β-(4-iodophenyltropane) (CIT) [123I]FP-CIT (DaTSCAN or DaTscan) in patients with PD with associated depressive symptoms and demonstrate that motor impairment (as assessed by the Unified Parkinson's Disease Rating Scale part III [UPDRS-III]) correlated negatively with DaT uptake in all four basal ganglia subregions (right and left putamen, right and left caudate). They also observed that severity of depressive symptoms as assessed by the Beck Depression Inventory (BDI) correlated negatively with DaT uptake in the right caudate, but not in any of the other three subregions. Multiple regression analysis showed that the BDI score explained a significant amount of the variance of the DaT uptake in the right caudate above and beyond the variance explained by age. Conversely, the UPDRS-III score explained a significant amount of variance of DaT uptake in the right putamen, but not in the right caudate. Additionally, the authors conducted a voxel-based analysis using statistical parametric mapping and showed a similar segregation between depressive and motor symptoms within the striatum.

However, performing correlation and multiple regression analyses to demonstrate relationships between DaT semiquantitative parameters, and UPDRS-III and/or BDI score ratings does not overcome all potential limitations and pitfalls in this study. As the authors acknowledged, correlational study analysis design limits the ability to draw cause and effect conclusions suggesting that dopaminergic loss in the caudate nucleus may be a contributing factor in the development of depressive symptoms in PD. Also, the results cannot explain why depressive symptoms are observed during the early premotor stage of the disease with the frequently observed phenomenon of reduced DaT uptake around the tail of putamen (where DaT uptake loss typically first observed (abnormal scan subtype 1)) and not the caudate, which is typically involved in more advanced stages of PD and associated with visually abnormal scan subtypes 2 and 33 in the presence of existing depressive symptoms.

Other factors may have influenced the data, such as use of a retrospective study design, basing assessment of depressive symptoms on a patient self-reporting questionnaire (BDI) and not on a structured clinical psychiatric interview for DSM disorders, were acknowledged by the authors. A recent study using the objective Hamilton depression rating scale found an inverse correlation between severity of depression symptoms in PD and DaT availability in the left caudate.4 The question about laterality of DaT involvement in the pathophysiology of depressive symptoms in PD should be clarified in future studies.

Use of a formal visual read-based classification of images as normal or abnormal (including abnormal image subtypes) by a nuclear medicine physician assessment and a semiquantitative, purely research (software-based) approach could add value to this type of clinical research. A formal visual read assessment approach in PD subjects with associated depressive symptoms would contribute to a better understanding of relationships between the level of caudate DaT semiquantitative uptake and detection of abnormal images, and may support decision making in complex clinical cases that require thoughtfully planned therapeutic intervention and clinical management. Depressive symptoms in untreated PD may be alleviated after initiation of dopaminergic therapy.5 ,6

On the positive side, the study is strengthened by the exclusion of patients on medications that can influence the binding of the [123I]FP-CIT by the known potential confounding effects of selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors commonly used for treatment of depression. It would be important to compare treatment-naïve and medicated patients to better understand the underpinning neurobiology and drug interaction with [123I]FP-CIT images, particularly if a more sensitive semiquantitative approach were used.

The main question of whether or not [123I]FP-CIT imaging can be used as a marker to characterise a causal relationship between Parkinson's disease and depression remains to be answered. Can we visually distinguish [123I]FP-CIT images in patients with PD with associated depressive symptoms from those in patients with PD without associated depressive symptoms? New studies will be important in understanding the diagnostic potential of [123I]FP-CIT for depression or depressive symptoms in PD, as conflicting results in the literature suggest higher DaT density in PD patients with depression.7 The study conclusion indicating that depressive symptoms in PD are related to reduced [123I]FP-CIT binding in the right caudate nucleus is not yet substantiated in medical diagnostic practice and routine clinical management which would be important next steps.

References

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Footnotes

  • Competing interests IDG is employee of GE Healthcare, the manufacturer of [123I]FP-CIT.

  • Provenance and peer review Commissioned; internally peer reviewed.

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