Striatal Dopamine Transporter Imaging Correlates with Anxiety and Depression Symptoms in Parkinson’s Disease

Subjects

Patients with clinically diagnosed idiopathic PD (n = 76) underwent ^99mTc-TRODAT-1 SPECT as part of a study measuring DAT availability in PD. They were referred from 2 large movement-disorders clinics in the greater Philadelphia metropolitan area and a third research clinic at a nearby university medical center. As a result, all diagnoses of PD were confirmed by specialists in the field. In addition to having at least 2 of the 4 cardinal features of PD, all patients included in this study had a history of a favorable response to dopamine replacement therapy. Patients with an Axis I psychiatric disorder were excluded; the presence or absence of an Axis I disorder was based on a structured clinical interview that was conducted with all potential subjects and that focused on psychiatric symptoms and treatment (24).

Because studies with rats and baboons showed that antiparkinsonian drug regimens that act on postsynaptic receptors do not affect the uptake of TRODAT-1 (25), the design allowed patients to be studied while they were taking most of their usual medications. Specifically, all patients were on dopamine replacement therapy. Drugs that act or could act on presynaptic transporters (e.g., tricyclic antidepressants) were discontinued for 7 half-lives before the study. Prospective patients taking selective serotonin reuptake inhibitors were excluded, because the half-lives of these medications are too long.

Healthy volunteers (an age-matched subset of a larger comparison population; n = 46) were recruited by investigators at the Division of Nuclear Medicine, Department of Radiology, University of Pennsylvania, to participate in the establishment of a normative database for ^99mTc-TRODAT-1 SPECT studies. The comparison subjects were found to have no axis I diagnosis when interviewed with a structured clinical interview (24). All were free from psychotropic medications, and none had a history of central nervous system disease. PD patients were more likely than healthy volunteers to be male and white (Table 1).

All subjects were provided with a detailed description of the study purpose and procedures in accordance with the ethical standards set forth by the institutional review board of the University of Pennsylvania. All subjects provided written informed consent before enrolling in the study.

Imaging Acquisition, Processing, and Analysis

The TRODAT-1 imaging protocol was previously described in detail (26). All individuals in the study were injected with a single bolus dose of 740 MBq (20 mCi) of ^99mTc-TRODAT-1. Brain SPECT images were obtained from 3 to 4 h after injection at a framing rate of 5 min per scan with a triple-head camera equipped with fanbeam collimators (Picker 3000; Picker International). All image data were acquired in a 128 × 128 matrix through 40 projection angles over a 120° arc with a pixel width of 2.11 mm and a slice thickness of 3.56 mm. A simple, low-pass filter was applied with an order of 4 and a cutoff of 0.351 cm⁻¹. Photon attenuation correction was performed with Chang’s first-order correction method (27).

Standardized templates representing various structures of the striatum were superimposed on the acquired images. Six primary regions of interest (ROIs) were assessed: right and left caudate, right and left anterior putamen, and right and left posterior putamen. The putamen was selected because it shows the most severe TRODAT-1 abnormalities in early PD. Each ROI on a template was slightly smaller than the actual structure it represented and was placed only on the 2 slices with the highest activity to minimize problems with ill-defined edges and effects of volume averaging (Fig. 1).

• Download figure
• Open in new tab
• Download powerpoint

FIGURE 1.

TRODAT-1 SPECT image of healthy volunteer (control) demonstrating ROI analysis for caudate, anterior putamen, and posterior putamen (shown within a larger region outlining the striatum).

Supratentorial areas (at least 5 slices above the last slice containing the basal ganglia) other than the occipital cortex or cerebellum were used to model nonspecific activity because previous experience showed that the occipital cortex and cerebellum might have low counting rates that could destabilize kinetic analyses. The total number of counts in each ROI were divided by the total number of corresponding pixels for that region. Mean distribution volume ratios (DVRs) were calculated with the following equation from the ratios for the ROI and the reference region: (ROI − reference region)/reference region.

All analyses of imaging parameters were conducted without knowledge of nonmotor test results. Intrarater reliability for analyses of the manually defined ROIs was estimated with intraclass correlation coefficients. The procedures were implemented with a commercial statistical package (StatS; Think Point Software). This procedure resulted in a high correlation because the high-contrast images were particularly amenable to “punch biopsy” approaches to image analysis and the “large” ROIs were difficult to misplace. The reliability of the image analysis techniques was found to be high, with intraclass correlations consistently above 0.95.

TRODAT-1 DVRs were used as surrogate measures of PD severity because previous research showed that both 6-¹⁸F-fluorodopa PET and ¹²³I-β-CIT SPECT of the DAT correlate with symptom severity in PD (28–30). For the purposes of this study, subjects were placed into groups representing less and more severe cases of PD by use of the median TRODAT-1 DVR (0.48) for the left anterior putamen (i.e., less severe cases with higher TRODAT-1 DVRs and more severe cases with lower TRODAT-1 DVRs).

All procedures were approved by the institutional review boards of all of the participating clinics as well as by the U.S. Food and Drug Administration.

Psychiatric Assessments

The State–Trait Anxiety Scale (31) and the Profile of Mood States (POMS) (32) instruments were administered to all subjects at the time of SPECT. The State–Trait Anxiety Scale is a 40-item self-administered instrument that contains 20 items pertaining to the current level of anxiety symptoms and 20 items inquiring about enduring anxiety symptoms. The POMS is a 65-item self-administered instrument that is well validated and widely used for rating mood and other affective symptoms. The POMS has 6 subscales: tension (commonly equated with anxiety), depression, fatigue, anger, confusion, and vigor. Higher scores on the State–Trait Anxiety Scale and the POMS indicate increasing severity of psychiatric symptoms. For the purposes of this study, we chose to include only the tension (or anxiety), depression, and fatigue subscales, as each of these symptoms is commonly reported in PD.

For secondary analyses, a composite affect score was created by use of an anxiety score (Trait Anxiety Scale score) and a depression measure (POMS depression subscale); these 2 measures were highly correlated in our population (r = 0.55; P < 0.001). The raw score for each of these measures was transformed to a z score to provide equal weighting, and then an average z score for the 2 measures was calculated. This composite score (hereafter referred to as the total affect score) was used in subsequent analyses. Similar composite psychiatric scores are commonly used in the study of neuropsychiatric diseases (33). For the purposes of this study, an elevated total affect score was defined as ≥1 SD above the mean (i.e., a z score of ≥1).

Statistical Analyses

Group comparisons of demographic characteristics, neuropsychiatric measures, and DAT availability for each ROI were analyzed by use of the χ² statistic, multiple ANOVA, or the unpaired Student t test. The association between neuropsychiatric measures and DAT availability for each ROI was calculated by use of the Pearson correlation, controlling for age, sex, and duration of PD (when applicable). As the goal of this study was to probe for an association between DAT availability and neuropsychiatric symptoms in PD, corrections for multiple comparisons were not made. Statistical significance was defined as P ≤ 0.05.