Swen Hesse

Serotonin and dopamine transporter imaging in patients with obsessive-compulsive disorder.

In obsessive-compulsive disorder (OCD), the success of pharmacological treatment with serotonin re-uptake inhibitors and atypical antipsychotic drugs suggests that both the central serotonergic and dopaminergic systems are involved in the pathophysiology of the disorder. We applied [123I]-2beta-carbomethoxy-3beta-(4-idiophenyl)tropane (beta-CIT) and a brain-dedicated high-resolution single photon emission computed tomography (SPECT) system to quantify dopamine transporter (DAT) and serotonin transporter (SERT) availability. By comparing 15 drug-naïve patients with OCD and 10 controls, we found a significantly reduced availability (corrected for age) of striatal DAT and of thalamic/hypothalamic, midbrain and brainstem SERT in OCD patients. Severity of OCD symptoms showed a significant negative correlation with thalamic/hypothalamic SERT availability, corrected for age and duration of symptoms. Our data provide evidence for imbalanced monoaminergic neurotransmitter modulation in OCD. Further studies with more selective DAT and SERT radiotracers are needed.

99mTechnetium-Ethyl-Cysteinate-Dimer Single-Photon Emission CT Can Predict Fatal Ischemic Brain Edema

BACKGROUND AND PURPOSE We sought to study the prognostic value of early 99mtechnetium-ethyl-cysteinate-dimer single-photon emission CT (99mTc-ECD SPECT) for fatal ischemic brain edema in patients with middle cerebral artery (MCA) stroke compared with the prognostic value of CT and of clinical findings. METHODS We prospectively studied 108 patients clinically, with 99mTc-ECD SPECT, and with CT within 6 hours of symptom onset (Scandinavian Stroke Scale <40 points) appropriate to MCA ischemia. The follow-up consisted of Scandinavian Stroke Scale and CT on days 1 and 7, Barthel Index, and Modified Rankin Scale after 3 months. An activity deficit of the complete MCA territory on the SPECT scans and a parenchymal hypoattenuation of the complete MCA territory on CT scans were considered as predictors for a fatal MCA infarction due to mass effect and midbrain herniation. RESULTS In 11 of 108 patients (10%), the MCA infarction was the cause of death. The sensitivity of SPECT for fatal outcome was 82% in both visual and semiquantitative analyses, while specificity was 98% and 99%, respectively. The sensitivity and specificity of baseline CT were 36% and 100%, respectively; the sensitivity and specificity of clinical findings (Scandinavian Stroke Scale, depressed level of consciousness, gaze deviation) varied from 36% to 73% and from 45% to 88%, respectively. In a multivariate logistic regression model, only SPECT findings were found to be independent predictors of malignant MCA infarction/death. CONCLUSIONS We were able to identify patients with fatal MCA infarction with high accuracy by using 99mTc-ECD SPECT within 6 hours of stroke onset. This technique offers great potential to select stroke patients for specific therapies, eg, decompressive hemicraniectomy, soon after onset of symptoms.

Reduced α4β2*–Nicotinic Acetylcholine Receptor Binding and Its Relationship to Mild Cognitive and Depressive Symptoms in Parkinson Disease

CONTEXT Cognitive or depressive disorders are frequently noted in patients with Parkinson disease (PD) and may be related to altered signaling through alpha4beta2*-nicotinic acetylcholine receptors (alpha4beta2*-nAChRs). OBJECTIVE To assess the availability of alpha4beta2*-nAChRs and their relationship to mild cognitive and mild depressive symptoms in vivo in patients with PD. DESIGN Crossover comparison between patients with PD and healthy volunteers (control group) using the alpha4beta2*-nAChR-specific radioligand 2-[(18)F]fluoro-3-(2[S]-2-azetidinylmethoxy)-pyridine (2-[(18)F]FA-85380) and positron emission tomography. SETTING Departments of Neurology and Nuclear Medicine, University of Leipzig, Leipzig, Germany. PARTICIPANTS Twenty-two nonsmoking patients with PD and 9 nonsmoking healthy volunteers. MAIN OUTCOME MEASURES Level of 2-[(18)F]FA-85380 binding potential (2-FA BP), a measure of alpha4beta2*-nAChR availability. The relationship between severity of cognitive symptoms as rated using the Mini-Mental State Examination and DemTect scale and the level of depressive symptoms as indicated using the Beck Depression Inventory, and 2-FA BP were assessed. RESULTS In patients with PD compared with healthy volunteers, there was widespread reduced 2-FA BP, especially in the midbrain, pons, anterior cingulate cortex, frontoparietal cortex, and cerebellum. In subgroups of patients with PD with possible depression, reduced 2-FA BP was most pronounced in the cingulate cortex and frontoparieto-occipital cortex, whereas in patients with PD with mild cognitive impairment, 2-FA BP was reduced in the midbrain, pons, and cerebellum. In patients with PD, the strongest associations between depressive symptoms and reduced 2-FA BP were noted in the anterior cingulate cortex, putamen, midbrain, and occipital cortex. In contrast, cognitive symptoms correlated only weakly with reduced 2-FA BP in the thalamus, midbrain, temporal cortex, hippocampus, and cerebellum. CONCLUSIONS There is a broad reduction of alpha4beta2*-nAChR availability in patients with PD without clinically manifest dementia or depression compared with healthy volunteers. Reduced alpha4beta2*-nAChR binding in patients with PD within the subcortical and cortical regions is associated with the severity of mild cognitive or depressive symptoms. These results provide novel in vivo evidence for a role of the cholinergic neurotransmission in psychiatric comorbidity of PD.

Decreased cerebral α4β2* nicotinic acetylcholine receptor availability in patients with mild cognitive impairment and Alzheimer's disease assessed with positron emission tomography.

PurposePostmortem studies indicate a loss of nicotinic acetylcholine receptor (nAChRs) in Alzheimer’s disease (AD). In order to establish whether these changes in the cholinergic system occur at an early stage of AD, we carried out positron emission tomography (PET) with a specific radioligand for the α4β2* nicotinic acetylcholine receptor (α4β2* nAChR) in patients with mild to moderate AD and in patients with amnestic mild cognitive impairment (MCI), who have a high risk to progress to AD.MethodsNine patients with moderate AD, eight patients with MCI and seven age-matched healthy controls underwent 2-[18F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[18F]FA-85380) PET. After coregistration with individual magnetic resonance imaging the binding potential (BPND) of 2-[18F]FA-85380 was calculated using either the corpus callosum or the cerebellum as reference regions. PET data were analysed by region of interest analysis and by voxel-based analysis.ResultsBoth patients with AD and MCI showed a significant reduction in 2-[18F]FA-85380 BPND in typical AD-affected brain regions. Thereby, the corpus callosum was identified as the most suitable reference region. The 2-[18F]FA-85380 BPND correlated with the severity of cognitive impairment. Only MCI patients that converted to AD in the later course (n = 5) had a reduction in 2-[18F]FA-85380 BPND.Conclusion2-[18F]FA-85380 PET appears to be a sensitive and feasible tool for the detection of a reduction in α4β2* nAChRs which seems to be an early event in AD. In addition, 2-[18F]FA-85380 PET might give prognostic information about a conversion from MCI to AD.

Reduced serotonin transporter–availability in obsessive–compulsive disorder (OCD)

Abstract.We investigated the availability of brain serotonin transporters in 10 drug–free patients with obsessive–compulsive disorder (OCD) and age–matched healthy controls in vivo using single–photon emission computed tomography (SPECT) and the radioligand [123I]–2β–carbomethoxy–3β–(4–idiophenyl)-tropane ([123I]β–CIT). For quantification of regional serotonin transporter a ratio of specific to non–specific [123I]β–CIT–binding was used. The availability of serotonin transporter was calculated using regions of interests (ROI) for thalamus/hypothalamus, midbrain, brainstem (highest density of serotonin transporter) and cerebellum as a reference. The mean specific to non–specific [123I]β–CIT binding ratios in the thalamic/hypothalamic ROI were 4.95 ± 0.57 (OCD patients), and 5.48 ± 0.87 (control group). The mean ratios in the midbrain ROI were 3.51 ± 0.45 (OCD patients) and 4.89 ± 1.23 (controls) and in the brainstem ROI the ratios were 2.38 ± 0.76 (OCD patients) and 3.53 ± 1.01 (controls). This in vivo finding of significant reduced serotonin transporter availability in midbrain/brainstem using [123I] β–CIT SPECT further supports the serotonin deficit hypothesis of OCD.

Advances in in vivo imaging of serotonergic neurons in neuropsychiatric disorders

Alterations of central serotonergic neurotransmission, particularly changes in the presynaptically located serotonin transporter (SERT) availability, are thought to be one of the major pathomechanisms of neuropsychiatric symptoms. Modern neuroimaging techniques such as single-photon emission computed tomography and positron emission tomography employ radiolabeled tracers, which bind to SERT, and thus, allow detection of cerebral SERT availability in vivo. We review SERT imaging studies in patients with depression, anxiety disorders, eating disorders and patients with neurological diseases. We furthermore elucidate the potential of SERT imaging techniques in estimating the effect of selective serotonin reuptake-inhibitors.

Monoamine transporter availability in Parkinson's disease patients with or without depression

PurposeDepression is a common symptom in patients suffering from Parkinson’s disease (PD) and markedly reduces their quality of life. As post-mortem studies have shown, its presence may reflect extensive cell loss in the midbrain and brainstem with imbalances in monoaminergic neurotransmitters. However, in vivo evidence of specific monoaminergic deficits in depressed PD patients is still sparse. Therefore, we studied PD patients with depression (PD+D) and without depression (PD−D) using high-resolution single-photon emission computed tomography (SPECT) and the monoamine transporter marker [123I]FP-CIT.MethodsA magnetic resonance imaging-based region-of-interest analysis was applied to quantify the specific-to-nondisplaceable [123I]FP-CIT binding coefficient V3″ in the striatum, thalamus and midbrain/brainstem regions.ResultsPD+D patients had significantly lower V3″ compared with PD−D patients in the striatum (p<0.001), thalamus (p=0.002), and midbrain/brainstem (p=0.025). Only PD+D patients without selective serotonin reuptake inhibitor (SSRI) treatment showed lower thalamic and midbrain V3″ than controls (p<0.001, p=0.029). In a small sub-group of SSRI-treated PD+D patients neither thalamic V3″ nor midbrain/brainstem V3″ differed from those in PD−D patients (p=0.168, p=0.201) or controls (p=0.384, p=0.318).ConclusionOur data indicate that depression in PD is associated with a more pronounced loss of striatal dopamine transporter availability that is most likely secondary to increased dopaminergic degeneration. In addition, depressed PD patients have a lower availability of midbrain/brainstem monoamine transporters than nondepressed PD patients. These findings provide in vivo evidence in support of the known post-mortem data demonstrating more extensive nerve cell loss in PD with depression and indicate that SPECT imaging can help to identify pathophysiological changes underlying nonmotor symptoms in this common movement disorder.

The degree of depression in Hamilton rating scale is correlated with the density of presynaptic serotonin transporters in 23 patients with Wilson's disease.

Abstract.Objective: One of the most frequent psychiatric symptoms in patients with Wilsons disease (WD) is depression. It has been suggested that depression is associated with deficits in serotonergic neurotransmission, but, hitherto, no measurements have been performed in WD. Methods: We prospectively examined 23 adult patients (12 women, 11 men, mean age 40 years) with WD for symptoms of depression using the Hamilton rating scale for depression (HAMD). We correlated the data with the presynaptic serotonin transporter density (SERT density) in the thalamus–hypothalamus and the midbrain–pons regions measured with high resolution single-photon emission computed tomography (SPECT) 24 hours after the application of 180 MBq 2β-carbomethoxy-3β-(4 [123I]iodophenyl)tropane ( [123I]b-CIT). The regions of interest were determined by coregistration with a standard MRI dataset. Results: A significant negative correlation was found between HAMD and SERT density in the thalamus–hypothalamus region (r = −0.49, p = 0.02), but not in the midbrain–pons (r = −0.31, p = 0.15). Conclusions: We conclude that depression in patients with Wilsons disease is correlated with alterations of serotonergic neurotransmission in the thalamus–hypothalamus region.

Differentiation between Transient Ischemic Attack and Ischemic Stroke within the First Six Hours after Onset of Symptoms by Using 99mTc-ECD-SPECT

The aim of this study was to define the accuracy of 99mTc-ethyl cysteinate dimer-single photon emission computed tomography (99mTc-ECD-SPECT) in distinguishing transient ischemic attack from completed ischemic stroke at early stages after the onset of symptoms. In a prospective study we examined 82 patients within 6 hours after the onset of symptoms (neurologic deficit caused by middle cerebral artery ischemia) using both 99mTc-ECD-SPECT and computed tomography (CT). The follow-up was based on Scandinavian Stroke Scale (SSS) 24 hours and 5–7 days, as well as on CT 7 days, after the event. SPECT evaluation was performed both visually and using semiquantitative region-of-interest (ROI) analysis. According to visual SPECT analysis, on admission 59 of 82 patients had activity deficits in the symptomatic hemisphere. After 7 days, all these patients had neurologic symptoms (SSS 28 ± 12 points), caused by a cerebral infarction as evidenced with CT. Twenty-three of 82 patients displayed no early activity deficit despite clinical symptoms. None of these patients had neurologic symptoms after 7 days (indicating transient ischemic attack or prolonged reversible ischemic neurologic deficit). In the semiquantitative SPECT analysis, all patients had abnormal count densities in the respective ROI (activity <90% compared with the contralateral side). All patients with transient ischemia (n = 23) had count rate densities more than 70% of the respective contralateral ROI, whereas all patients with subsequent infarction (n = 59) had values < 70%. Use of 99mTc-ECD-SPECT allows transient ischemia to be distinguished from ischemic infarction using relative regional activity thresholds within the first 6 hours after onset of symptoms.

Is correction for age necessary in neuroimaging studies of the central serotonin transporter

The central neurotransmitter serotonin plays a major role in a number of neuropsychiatric disorders. However, results from post-mortem and in vivo neuroimaging studies of the influence of age on the number of presynaptic serotonin transporters (SERT) are controversial. To provide further evidence of relevance for this ongoing discussion, SERT were imaged in 22 persons without neuropsychiatric impairment using [123I]2β-carbomethoxy-3β-(iodophenyl)tropane ([123I]β-CIT) and high-resolution single-photon emission tomography (SPET). The SPET analysis method was based on magnetic resonance image co-registration in order to quantify SERT with acceptable inter- and intra-observer variability. Using this technique, we found a significant age-related decline in the thalamic/hypothalamic and midbrain/upper brainstem SERT density, which was more pronounced than that previously reported in the literature. From these results we conclude that age-related changes in SERT density need to be considered in future clinical studies.