Imaging of dopamine transporters and D2 receptors in vascular parkinsonism: a report of four cases

Summary. The role of nuclear medicine imaging in the diagnosis of vascular parkinsonism (VP) has been addressed by only few studies up to now. Most previous reports suggest no or only mild impairment of DAT and D2 receptors in VP. In contrast, in four patients with VP, reported here, the combined DAT and D2 receptor SPECT showed highly unusual changes in the pre- and/or postsynaptic dopaminergic system. The possible value of combined DAT/D2 receptor SPECT imaging should be investigated by future prospective studies. These two authors contributed equally     

Imaging of serotonin transporters and its blockade by citalopram in patients with major depression using a novel SPECT ligand [123I]-ADAM

Summary. We studied the midbrain SERT availability in patients with major depression and assessed the relation of SERT occupancy by citalopram to the treatment response. 21 non-medicated patients with major depression and 13 healthy controls were examined by [¹²³I]-ADAM SPECT. The midbrain SERT availability (SERT V₃″) was calculated using individual MRI scans. In 13/21 patients SPECT was repeated 7 days after oral medication with citalopram (10 mg/day). We found no significant difference in the mean midbrain SERT availability between the studied patients with major depression and healthy controls (0.86 ± 0.27 vs. 0.71 ± 0.44, p = 0.069). The mean SERT occupancy accounted to 61%. The degree of SERT blockade by citalopram did not correlate with the reduction in HAMD total score. Treatment with low-dosed citalopram caused individually variable occupancy of the midbrain-SERT and a rapid clinical improvement in 54% of the investigated patients.     

Nigro-striatal degeneration demonstrated in parkinsonian patients with iodine-123-beta-CIT SPECT: Methods of quantitation

Single photon emission computed tomography (SPECT) images were obtained in 3 healthy volunteers and 7 parkinsonian patients 22 h after injection of 120 MBq iodine-123-beta-CIT. There was a high radioactivity in the striatal region against a uniform background in the volunteers but pronouncedly reduced striatal activity in the patients. Total striatal activity in each hemisphere of each individual was calculated as the sum of all activity in excess of the background in all reconstructed images. There was a high correlation between reduction of striatal activity and motor scores in the unified rating scale for parkinsonism (URSP) for the patients. A method developed for calculation of the activity distribution along the length axis of the striatum indicated a more pronounced degeneration in the putamen compared with the caudate nucleus in the patients. Iodine-123-beta-CIT SPECT appears to be a good quantitative method for nigro-striatal degeneration in parkinsonian patients.     

DaTSCAN (123I-FP-CIT SPECT) imaging in early versus mid and late onset Parkinson's disease: Longitudinal data from the PPMI study

IntroductionIt has been reported that early onset Parkinson's Disease (PD) patients have a less profound dopaminergic degeneration. The aim of the current study was to determine whether there are longitudinal differences in dopaminergic denervation [signal reduction in 123I-FP-CIT SPECT] in early versus mid and late onset PD.MethodsDaTSCAN (123I-FP-CIT SPECT) imaging was acquired at Parkinson's Progression Markers Initiative (PPMI) imaging centers and sent to the imaging core for calculation of striatal binding ratios. Data from the PPMI database of 58 early de novo PD patients (age ≤ 50 years) were compared to those of 362 mid and late onset PD patients (age > 50 years).ResultsAlthough raw striatal binding ratios were higher in early onset versus mid/late onset PD, especially on the ipsilateral side, such differences were not observed, and were in fact reversed in the contralateral putamen, after age correction. The rate of signal decline was similar between the two groups. Interestingly, based on both raw and age-adjusted data, caudate nucleus and putamen asymmetry (contralateral/ipsilateral ratio) was more pronounced in early onset PD. Striatal asymmetry also significantly correlated with age at onset as a continuous variable.ConclusionEarly onset PD patients exhibited similar rates of decline of dopaminergic denervation compared to mid/late onset PD. These results are not supportive of a more benign disease in this subgroup. The more pronounced asymmetry in early onset PD may however signify a qualitatively different pattern of neurodegeneration compared to mid/late onset PD.     

[<Superscript>123</Superscript>I] ADAM brainstem binding correlates with the loudness dependence of auditory evoked potentials

The in vivo assessment of brain serotonergic function might be of clinical relevance in neuropsychiatry. The loudness dependence of auditory evoked potentials (LD) has been proposed as an indirect indicator of cortical serotonergic activity, whereas single photon emission computed tomography (SPECT) and [¹²³I]ADAM allow the selective assessment of brain serotonin transporters (SERT). The aim of this study was to investigate LD and SERT availability as independent variables of the brain serotonergic system in healthy volunteers. Fifteen (six male, nine female) subjects received both neurophysiological and imaging investigations. Evoked potentials were recorded following the application of acoustic stimuli with increasing intensities; the LD was analyzed using dipole source analysis. SPECT was performed four hours after injection of 137 ± 11.4 MBq [¹²³I]ADAM. As a measure of SERT availability specific ADAM brainstem binding was used. LD correlated significantly with SERT availability (Pearson’s correlations: rho = −0.57, p < 0.05). The correlations remained significant after controlling for the effects of age or gender (partial correlations: rho = −0.60, p < 0.05) but were pronounced in the female group (rho = −0.83, p < 0.01). Associations between LD and SERT availability contribute to the understanding of the central serotonergic system and further validate the use of neurophysiological approaches as indirect measures of neurochemical brain activity.     

Single Photon Emission Computed Tomography (SPECT) Findings Using N-Isopropyl-p-[123I]iodoamphetamine (123I-IMP) in Schizophrenia and Atypical Psychosis

Abstract: As a basis for possible classification of schizophrenic psychoses into schizophrenia and atypical psychosis, we studied the brain functional differences among 16 schizophrenic patients, 16 atypical psychosis patients and 16 healthy volunteers by single photon emission computed tomography (SPECT) using N-isopropyl-p-[¹²³I]iodoamphetamine. As a result, schizophrenics showed hypofrontality. On the other hand, atypical psychotics had no such hypofrontality but showed a reduced uptake rate in the right thalamic region. No influence of sex, duration of illness and medication was confirmed by the findings. The results suggest that schizophrenics might have some lesions in the frontal regions, whereas atypical psychotics might have no such lesions, but dysfunction in the right thalamic region. Consequently, the SPECT findings at least indicate possibly different etiologies for schizophrenia and atypical psychosis.     

Progression of dopaminergic degeneration in Parkinson's disease and atypical parkinsonism: a longitudinal beta-CIT SPECT study.

Atypical parkinsonian syndromes (APS) such as multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration are characterized by poor response to antiparkinsonian medication and rapid clinical deterioration. We used SPECT and [123I]beta-CIT as a label of dopamine transporters to study the progression of presynaptic dopaminergic degeneration in Parkinson's disease (PD) and APS. Twenty-four PD patients with short disease duration (2.4 +/- 1.5 years), 12 PD patients with long disease duration (9.2 +/- 2.6 years), 10 patients with APS (disease duration 2.1 +/- 1.5 years), and nine patients with essential tremor (ET) underwent sequential [123I]beta-CIT SPECT imaging with an interval of 25.5 +/- 10.3 (13-63) months. The age-related decline of striatal beta-CIT binding was studied cross-sectionally in 30 healthy subjects. The ratio of striatum/cerebellum -1 at 20 hours after tracer injection, reflecting specific-to-nondisplaceable binding, was used as the primary SPECT outcome measure. At scan 1, striatal beta-CIT binding was reduced in PD patients with short disease duration (-42% compared with age-corrected normal values) and long disease duration (-51%), and APS (-36%), but normal in ET. During the observation period striatal beta-CIT binding significantly declined in patients with APS (14.9% per year) and short duration PD (7.1% per year), whereas PD patients with long disease duration and patients with ET showed no significant change of striatal beta-CIT binding between scans 1 and 2. The relative annual reduction from age-corrected normal values at the time of scan 1 was significantly higher in patients with APS than in PD patients with short disease duration (9.6 vs. 4.3%, P = 0.004). These results demonstrate a rapid decline of striatal beta-CIT binding in patients with atypical parkinsonian syndromes, exceeding the reduction in PD. The dopaminergic degeneration in PD appears to slow down during the course of the disease. SPECT with [123I]beta-CIT is a sensitive marker of disease progression in parkinsonian disorders.     

Possible impact of dopamine SPECT on decision-making for drug treatment in Parkinsonian syndrome

Summary. Single-photon emission computed tomography (SPECT) markers allow measuring the integrity of the brain dopaminergic system in vivo. We used dopamine transporter (DAT) SPECT with [¹²³I]FP-CIT and dopamine D₂/D₃ receptor SPECT with [¹²³I]IBZM to evaluate whether there is a reduction of DAT and/or D₂/D₃ receptor SPECT in treated and untreated patients with Parkinsonian syndrome (PS). We found that almost a quarter of our patients treated with anti-Parkinsonian medication prior to SPECT imaging did not show evidence of a presynaptic dopaminergic deficit while 37% of untreated patients were diagnosed as having Parkinson’s disease. 17% of treated patients had additional loss of D₂/D₃ receptor binding capacity in concordance with the clinical follow-up diagnoses of multiple system atrophy, progressive nuclear palsy, and vascular Parkinsonism. Apart from 38% clinically uncertain cases, SPECT was in concordance with 75% of initial clinical diagnoses. 25% were reclassified as indicated by SPECT findings and confirmed by a 1.5-year clinical follow-up. We conclude that dopamine SPECT may support establishing or refuting the clinical diagnosis and, therefore, help to make the decision for or against dopaminomimetic treatment in cases with PS.     

Neuropsychological tests and [99mTc]-HM PAO SPECT in the diagnosis of Alzheimer's dementia

Twenty-three patients with Alzheimer's dementia (AD) in relatively early stages and 40 patients with other cognitive disorders of vascular or degenerative aetiology underwent neuropsychological examination and [^99mTc]-HM PAO single photon emission computed tomography (SPECT). In contrast to the commonly accepted notion of a posterior temporoparietal reduction of tracer uptake as the typical SPECT pattern of AD, the most consistent feature found in the SPECT images of our AD patients was a hippocampal uptake deficit, associated with a variable degree of temporal, parietal and frontal deficit (extending from the posterior to the anterior regions), according to the severity of the disease. These results support the theory of AD as a hippocampal dementia, at least in the early stages. Neuropsychological tests were found to be somewhat more specific and more accurate than SPECT in distinguishing AD from non-AD cases.     

High reproducibility of regional abnormalities on interictal123I-IMP SPECT brain scans in adults with partial epilepsy

Summary The reproducibility of twoN-isopropyl-(iodine 123)p-iodoamphetamine (¹²³I-IMP single photon emission computed tomography (SPECT) scans both taken during interictal periods was studied in 13 adult patients with partial epilepsy who had normal CT scans. The frequency of the seizures and the nature of the ictal symptoms were virtually unchanged during the interval between the two SPECT scans performed in each case. In 8 (72.7%) of 11 patients who had abnormal images consisting of focal hypofixation images of¹²³I-IMP, i.e. zones of decreased regional cerebral blood flow on the first scans, complete or partial regional reproduction of the SPECT abnormalities was observed. This high reproducbility supports the usefulness of SPECT scans in the regional diagnosis of epileptic foci.     

Evaluation of the GABAergic nervous system in autistic brain: (123)I-iomazenil SPECT study

Purpose

To evaluate the GABA_A receptor in the autistic brain, we performed ¹²³I-IMZ SPECT in patients with ASD. We compared ¹²³I-IMZ SPECT abnormalities in patients who showed intellectual disturbance or focal epileptic discharge on EEG to those in patients without such findings.

Subjects and methods

The subjects consisted of 24 patients with ASD (mean age, 7.3 ± 3.5 years), including 9 with autistic disorder (mean age, 7.0 ± 3.7 years) and 15 with Asperger’s disorder (mean age, 7.5 ± 3.2 years). We used 10 non-symptomatic partial epilepsy patients (mean age, 7.8 ± 3.6 years) without intellectual delay as a control group.For an objective evaluation of the ¹²³I-IMZ SPECT results, we performed an SEE (Stereotactic Extraction Estimation) analysis to describe the decrease in accumulation in each brain lobule numerically.

Results

In the comparison of the ASD group and the control group, there was a dramatic decrease in the accumulation of ¹²³I-IMZ in the superior and medial frontal cortex. In the group with intellectual impairment and focal epileptic discharge on EEG, the decrease in accumulation in the superior and medial frontal cortex was greater than that in the group without these findings.

Conclusion

The present results suggest that disturbance of the GABAergic nervous system may contribute to the pathophysiology and aggravation of ASD, since the accumulation of ¹²³I-IMZ was decreased in the superior and medial frontal cortex, which is considered to be associated with inference of the thoughts, feelings, and intentions of others (Theory of Mind).     

Measuring the rate of progression of Parkinson's disease over a 5-year period with beta-CIT SPECT.

Recent imaging studies suggest a rapid degeneration of the dopaminergic system in early Parkinson's disease (PD), followed by a slowing of the degenerative process in advanced disease. In the present study, a group of early-stage PD patients underwent three sequential [123I]beta-CIT SPECT studies to assess the decline of striatal dopamine transporter binding over a 5-year period. Twenty-one of a cohort of 24 early PD patients who participated in an earlier longitudinal beta-CIT SPECT imaging study [Mov Disord 2002;17:45-53] were included. Scan intervals were 26 +/- 11 months (scan 1-2) and 38 +/- 15 months (scan 2-3), respectively. The relative annual rate of decline of striatal beta-CIT binding from age-expected normal values at the time of Scan 1 was used as primary outcome variable. The relative annual decline of striatal binding from Scan 1 to Scan 2 (4.5 +/- 4.6%) and from Scan 2 to Scan 3 (3.0 +/- 3.0%) was not significantly different. The non-significant difference in progression rate was due mainly to the rapid early decline of striatal binding in 1 patient who subsequently developed a severe dysexecutive dementia syndrome. These data are not suggestive of substantial change in the course of dopaminergic degeneration in PD within the first 5 to 7 years after symptom onset.     

Striatal dopamine release after prefrontal repetitive transcranial magnetic stimulation in major depression: preliminary results of a dynamic [123I] IBZM SPECT study

Though there is considerable evidence that prefrontal repetitive transcranial magnetic stimulation (rTMS) exerts antidepressant effects, the neurobiological action of rTMS in patients with depression is poorly understood. Preclinical studies in animals and humans have demonstrated that prefrontal rTMS can induce dopamine release in mesostriatal and mesolimbic regions. We therefore investigated whether rTMS also modulates striatal dopaminergic neurotransmission in depressed patients using a dynamic [123I] iodobenzamide (IBZM) single photon emission computed tomography (SPECT) approach. Five patients with a major depressive episode (DSM-IV) underwent an acute 10 Hz rTMS challenge with 3000 stimuli over the left dorsolateral prefrontal cortex during an [123I] IBZM-SPECT bolus and constant infusion protocol. In four subjects the protocol was repeated after a three week rTMS standard treatment. Striatal IBZM binding to dopamine D2 receptors was assessed with a region-of-interest (ROI) technique. The change in striatal IBZM binding after the rTMS challenge was regarded as measure of change in endogenous striatal dopamine. Data of nine SPECT investigations showed a significant reduction by 9.6+/-6.2% in IBZM binding to striatal dopamine D2 receptors after rTMS challenge compared to baseline (p=0.01, Wilcoxon test). In this preliminary study, the reduction of IBZM binding observed after rTMS challenge is suggestive of a release in endogenous dopamine induced by prefrontal rTMS. In future, this approach can be used to differentiate specific and non-specific reward-related effects of rTMS on dopaminergic neurotransmission.     

SPECT imaging of dopamine receptors with [123I]epidepride: characterization of uptake in the human brain

Summary [¹²³I]Epidepride is a new ligand for single photon emission computerized tomography (SPECT) that specifically labels D₂-like dopamine receptors with very high affinity. Here, we report on the regional kinetic uptake of [¹²³I]epidepride in the brain of 4 normal volunteers and 3 patients with choreatic movement disorders. In healthy subjects striatal activity peaked at 2.5 hours after injection of the tracer and decreased slowly thereafter. There were no significant differences between left and right brain hemispheres. Activity above background was also measurable in areas corresponding to the thalamus, temporal cortex and frontal cortex. The striatal to cerebellar ratio was about 14 after 2.5 hours and this ratio steadily increased with time. The striatal to cerebellar ratio was clearly reduced in all 3 patients with choreatic movement disorders (from about 14 in control subjects after 2.5 hours to about 7 in choreatic patients). [¹²³I]Epidepride may be a useful SPECT ligand for studying D₂ receptors in the living human brain because of its high target to background ratio, its high affinity and the possibility to investigate extrastriatal D₂ receptors.     

Left superior temporal blood flow increases in schizophrenic and schizophreniform patients with auditory hallucination: A longitudinal case study using123I-IMP SPECT

Summary Serial assessments of regional cerebral blood flow were performed using¹²³I-IMP SPECT in two schizophrenic and three schizophreniform patients with persistent auditory hallucination. The initial SPECT study in the period with prominent auditory hallucination revealed an increased accumulation of¹²³I-IMP in the left superior temporal area which corresponded to the auditory association cortex. In the follow-up SPECT study performed after clinical improvement, the distribution of¹²³I-IMP had normalized. One of the case with schizophrenia showed a similar increased uptake of¹²³I-IMP in the left superior temporal area in the third SPECT scan performed when a psychotic relapse with auditory hallucination occurred. MRI scans in two of the five patients demonstrated reduced volume of the temporal lobes. These findings suggest that the auditory hallucinations in schizophrenia may be involved in functional hyperactivity in the left superior temporal cortex which might be based partly on structural abnormalities in the temporal lobes.     

Impact of dopamine transporter SPECT using 123I-Ioflupane on diagnosis and management of patients with clinically uncertain Parkinsonian syndromes.

Imaging with (123)I-Ioflupane single-photon emission computed tomography (SPECT) is a marker of nigrostriatal neuronal integrity, allowing differentiation of parkinsonism with loss of dopaminergic terminals (presynaptic Parkinson syndrome [PS]) from parkinsonism without nigrostriatal degeneration. This study assessed SPECT imaging in 118 patients with clinically uncertain parkinsonian syndromes (CUPS). In 36% of patients with presynaptic PS and 54% with nonpresynaptic PS, imaging results were not consistent with the initial diagnosis. After imaging, diagnosis was changed in 52% of patients. All patients with a final diagnosis of presynaptic PS had an abnormal image, whereas 94% of patients with nonpresynaptic PS had a normal scan. Imaging increased confidence in diagnosis, leading to changes in clinical management in 72% of patients. Consequently, visual assessment of (123)I-Ioflupane SPECT may have a significant impact on the clinical management of CUPS patients.     

Measuring the progression of idiopathic Parkinson's disease with [123I] β-CIT SPECT

Summary. Idiopathic Parkinson's disease (PD) is the most common neurodegenerative disorder. An important step in diagnosing the dis-ease has been achieved with the development of the cocaine derivative [¹²³I] β-CIT for single photon emission computed tomography (SPECT). The aim of this study was to demonstrate the disease progression by repeated measuring presynaptic dopamine transporter density and relating it to clinical data. Methods: The presynaptic dopamine transporter densitiy of 15 PD patients was measured two times with a mean interval of 15 months. All patients were clinically assessed at the time of the experiments according to the classification scheme of Hoehn and Yahr. 11 healthy volunteers were used as a control group. [¹²³I] β-CIT was injected intravenously and measured with a triple-headed camera twenty hours later. The pictures were evaluated semiquantitatively by using the ratio of specific to non-displaceable binding. Results: Presynaptic dopamine transporter density differed significantly between controls and PD patients. A significant correlation between imaging data and clinical stages (H/Y I −27%, H/Y II −40%, H/Y III −58%) was observed for the patient group in the initial experiment. The subsequent decrease of dopamine transporter binding depended on the initial clinical stage (H/Y I −6.81%; H/Y II −6.05%; H/Y III −1.25%) of the patients, and regression analysis revealed that. 91.4% of the variance of the second measurement were predicted by the initial measurement. No correlations were found for age, gender and disease progression. All patients were treated with L-DOPA and those given a higher dose showed a more rapid decrease of dopamine transporter density. This result could be interpreted as an indication for in vivo neurotoxicity of high concentrations of L-DOPA. Conclusion: We conclude that combining [¹²³I] β-CIT with SPECT imaging is not only a powerful tool for diagnosing PD patients, but may also be used to demonstrate neurodegeneration in vivo. Received June 9, 1999; accepted October 6, 1999     

Steele-Richardson-Olszewski-syndrome: reduction of dopamine D2 receptor binding relates to the severity of midbrain atrophy in vivo: (123)IBZM SPECT and MRI study.

Patients with the clinical diagnosis of progressive supranuclear palsy (PSP) show heterogeneous neuropathological findings. In neuropathologically proven cases with numerous neurofibrillary tangles of neuropil threads, the brainstem and striatum are always affected. We compared (123)I-iodobenzamide single photon emission computed tomography (IBZM-SPECT) for imaging of striatal dopamine D(2) receptors in vivo with high-resolution magnetic resonance imaging (MRI) in 13 patients with possible or probable PSP. Clinically, all patients exhibited similar signs including supranuclear vertical-down-gaze palsy, axial rigidity especially involving the neck, bradykinesia, instability of balance with easy falls, and a poor response to dopaminergic drugs.Specific striatal dopamine D(2) receptor binding in IBZM-SPECT was reduced in 10 patients but was normal in three patients. Mean midbrain diameter was 23.7 mm. The reduction of IBZM-binding was statistically significantly correlated to midbrain atrophy (P = 0.010) either in all 13 patients or in those without striatal or white matter lesions (P = 0.015). We suggest that technical investigations, mainly MRI, are able to corroborate the in vivo diagnosis, if PSP is clinically suspected.