Imaging Depression in Parkinson's Disease: Role of the Limbic System

Abstract & Commentary

By Claire Henchcliffe, MD Dr. Henchcliff is Assistant Professor, Department of Neurology, Weill Medical College, Cornell University. Dr. Henchcliffe is on the speaker's bureau for GlaxoSmithKline, Teva/Eisai, and Boehringer Ingelheim.

Synopsis: Depression and anxiety in Parkinson's disease might be associated with a specific loss of dopamine and noradrenaline innervation in the limbic system.

Source: Remy P, et al. Depression in Parkinson's Disease: Loss of Dopamine and Noradrenalin Innervation in the Limbic System. Brain. 2005;128:1314-1322.

This study examined positron emission tomography (PET) images using [11C]RTI-32 as tracer to study catecholaminergic neurotransmission in depression in Parkinson's disease (PD). [11C]RTI-32 binds with similar nanomolar affinities to the dopamine (DAT) and noradrenalin (NAT) membrane transporters. Patients fulfilling the diagnostic UK PDS Brain Bank criteria for idiopathic PD were divided into 2 groups according to the presence (n = 8) or absence (n = 12) of major depression episodes, defined by DSM-IV. Subjects had a mean age of 58.5 ± 7.9 years, disease duration of 0.5 to 9 years, and no major depression prior to PD onset. All had a Mini-Mental Status score > 23, and were antidepressant-free for at least 3 months. The 2 groups were well matched for age, disease duration, severity, and antiparkinsonian medications. Neuropsychiatric evaluation included the Beck Depression Inventory (BDI), the Apathy Evaluation Scale (AES), and the State Trait Anxiety Inventory (STAI) for quantification of depression, apathy, and anxiety. PET and MRI images were acquired with subjects off PD medication. Images were analyzed by regions of interest (ROI) and voxel-based statistical parametric mapping (SPM99). Depressed PD patients had higher mean scores than the non-depressed patients on BDI (19.1 ± 7.0 vs 5.5 ± 2.5 points), AES (18.8 ± 7.3 vs 5.2 ± 2.7) and STAI (50.3 ± 16.6 vs 32.3 ± 8.7) scales. Tracer uptake, analyzed by ROI, was higher in non-depressed compared to depressed PD patients, in the thalamus, locus coeruleus, amygdala, and anterior cingulate cortex. SPM99 analysis revealed higher tracer binding for non-depressed over depressed PD patients in the locus coeruleus bilaterally, the mediodorsal and inferior thalamus bilaterally, the left ventral striatum, and the right amygdala. Moreover, there was an inverse correlation of BDI score with tracer binding in the left ventral striatum, of AES score with tracer binding to ventral striatum bilaterally, and of STAI score with left ventral striatum, left caudate, left locus coeruleus, left inferior thalamic region, and bilateral amygdala and medial thalamus tracer binding.

Commentary

Depression prevalence rates reported vary widely between 20 to 45% in PD,1 and its diagnosis in PD patients is confounded by non-motor phenomena, such as psychomotor slowing, apathy, and abulia, overlapping with depressive symptoms. The present study exploits functional neuroimaging to obtain insight into the pathophysiology of this often difficult to treat, co-morbid condition of PD. It demonstrates reduced binding of [11C]RTI-32 to crucial regions of the limbic system in depressed, compared to non-depressed PD subjects. Since [11C]RTI-32 binds both DAT and NAT, interpretation of binding changes depends on knowledge of the distribution of these transporters. Remy and colleagues suggest that changes in the locus coeruleus and thalamus, as well as amygdala and ventral striatum (to which the locus coeruleus sends noradrenergic projections), are due at least in part to changes in noradrenergic neurotransmission. Despite limitations, clinical implications for PD depression are interesting. Many depressed PD patients are treated with serotonin re-uptake inhibitors (SSRI), which have little direct effect upon the noradrenergic system, and strong evidence supporting their efficacy is lacking. Nortriptyline, affecting both noradrenergic and serotonergic systems, has been shown in a small trial to be effective in treating depressed PD patients. Unfortunately, its use is hampered by anticholinergic and sedating side effects. Based on results of this article, serotonin-noradrenalin re-uptake inhibitors (SNRI), such as venlafaxine, may prove to be more effective than SSRIs for relief of PD depression, and this is under examination by the NIH-sponsored phase III Study of Anti-depressants for Parkinson's Disease (SAD-PD) comparing paroxetine versus venlafaxine.2

References

1. Rickards H. Depression in Neurological Disorders: Parkinson's Disease, Multiple Sclerosis, and Stroke. J Neurol Neurosurg Psychiatry. 2005;76:i48-i52.

2. National Institute of Neurological Disorders and Stroke (NINDS). Study of Anti-depressants for Parkinson's Disease (SAD-PD). Accessed July 2005 at www.clinicaltrials.gov