Susanna Jakobson Mo

Functional brain activity and presynaptic dopamine uptake in patients with Parkinson's disease and mild cognitive impairment: a cross-sectional study

BACKGROUND Many patients with Parkinsons disease have mild cognitive impairment (MCI). Deficits in executive functions and working memory suggest dysfunctional frontostriatal brain circuitry. We aimed to assess brain responses during a working memory task in a cohort of newly diagnosed drug-naive patients with Parkinsons disease with and without MCI. METHODS Participants were recruited within a prospective cohort study of incident patients with idiopathic parkinsonism, including Parkinsons disease. Between Jan 1, 2004, and April 30, 2009, all physicians in the Umeå catchment area were requested to refer all individuals with suspected parkinsonism to the Department of Neurology at Umeå University. Included patients fulfilled the UK Parkinsons Disease Society Brain Bank clinical diagnostic criteria for Parkinsons disease. Control individuals were matched on the basis of age and sex with the first 50 patients included in the study. Participants who scored 1·5 SDs or more below the population mean on at least two cognitive measures were diagnosed with MCI. The primary outcome measures were functional MRI blood-oxygen-level-dependent signal and SPECT presynaptic uptake. Functional MRI was done during a verbal two-back working memory task. Presynaptic dopamine SPECT was done to assess presynaptic striatal dopaminergic system integrity. Event-related transient analyses of functional MRI data were done for the whole brain and for frontostriatal regions of interest, and semi-quantitative SPECT analyses were done for striatal regions of interest. FINDINGS Compared with controls (n=24), patients with Parkinsons disease (n=77) had under-recruitment in an extensive brain network including bilateral striatal and frontal regions (p<0·001). Within the Parkinsons disease group, patients with Parkinsons disease and MCI (n=30) had additional under-recruitment in the right dorsal caudate nucleus (p=0·005) and the bilateral anterior cingulate cortex (p<0·001) compared with patients with Parkinsons disease without MCI (n=26). In patients with Parkinsons disease and MCI, SPECT uptake in the right caudate was lower than in patients with Parkinsons disease without MCI (p=0·008) and correlated with striatal functional MRI blood-oxygen-level-dependent signal (r=0·32, p=0·031). INTERPRETATION These altered brain responses in patients with Parkinsons disease and MCI suggest that cognitive impairment is linked to frontostriatal dysfunction. FUNDING Swedish Medical Research Council, Swedish Parkinson Foundation, Swedish Parkinsons Disease Association, Umeå University, Kempe Foundation, Foundation for Clinical Neuroscience at Umeå University Hospital, Västerbotten County Council (ALF), King Gustaf Vs and Queen Victorias Freemason Foundation, Knut and Alice Wallenberg Foundation, and Swedish Brain Power.

Correction for scatter and septal penetration using convolution subtraction methods and model-based compensation in I-123 brain SPECT imaging – a Monte Carlo study

Scatter and septal penetration deteriorate contrast and quantitative accuracy in single photon emission computed tomography (SPECT). In this study four different correction techniques for scatter and septal penetration are evaluated for 123I brain SPECT. One of the methods is a form of model-based compensation which uses the effective source scatter estimation (ESSE) for modelling scatter, and collimator-detector response (CDR) including both geometric and penetration components. The other methods, which operate on the 2D projection images, are convolution scatter subtraction (CSS) and two versions of transmission dependent convolution subtraction (TDCS), one of them proposed by us. This method uses CSS for correction for septal penetration, with a separate kernel, and TDCS for scatter correction. The corrections are evaluated for a dopamine transporter (DAT) study and a study of the regional cerebral blood flow (rCBF), performed with 123I. The images are produced using a recently developed Monte Carlo collimator routine added to the program SIMIND which can include interactions in the collimator. The results show that the method included in the iterative reconstruction is preferable to the other methods and that the new TDCS version gives better results compared with the other 2D methods.

123I-FP-Cit and 123I-IBZM SPECT uptake in a prospective normal material analysed with two different semi-quantitative image evaluation tools

ObjectiveThe need for age-adjusted and/or sex-adjusted reference values in dopamine transporter (DAT) and dopamine D2 receptor (D2R) imaging with single-photon emission computed tomography (SPECT) in a longitudinal study of parkinsonian diseases was investigated. We used two different image evaluation tools with a cross-sectional and longitudinal statistical approach. Materials and methodsBaseline DAT and/or D2R SPECT were performed in 51 healthy controls (HC), age-matched to patients in an ongoing prospective study on idiopathic parkinsonism. Twenty-four HC were re-examined after 3 years and 21 HC were examined again after 5 years. SPECT was performed with 123I-FP-Cit and 123I-IBZM on a two-headed hybrid gamma camera. Regions of interest and volumes of interest (VOIs) were used for image evaluation. A cross-sectional and longitudinal statistical analysis was carried out. ResultsFewer sex-based differences and less age dependency were seen in DAT SPECT uptake ratios compared with D2R SPECT uptake ratios and when comparing uptake ratios obtained with regions of interest against those with VOIs. In the cross-sectional analysis, a significant age-dependent decline was seen in women in both DAT and D2R uptakes with the VOI method but not in men with either evaluation method. In the longitudinal dataset, both a slight decline and increase over time were seen in DAT uptake; however, a general pattern of decrease was seen in both men and women in D2R uptake. ConclusionThe choice of the image evaluation method can influence the pattern of sex-based and age-related differences. The results speak for the use of age-stratified reference values for women, in particular when using a VOI method.

Rotation Radius Dependence of 123I-FP-CIT and 123I-IBZM SPECT Uptake Ratios: A Monte Carlo Study

In dopamine brain SPECT, semiquantitative techniques are in use, mostly for research purposes, to calculate activity uptake in the striatum relative to the background. The measured uptake ratios depend on both acquisition and reconstruction, and one important parameter is the rotation radius of the γ-camera detectors, which affects spatial resolution. In brain SPECT research studies, the rotation radius is typically set to a constant value to maintain a constant resolution, but because of variations in patient anatomy and compliance, this is not always possible. Methods: In this study, correction factors as a function of rotation radius are developed to correct the uptake ratios where the rotation radius has deviated from the reference value, 15 cm. Monte Carlo simulations of a digital brain phantom were used to produce images with a high and a low uptake ratio, and for both studies the rotation radius was varied between 14 and 23 cm. Two different methods, one based on 2-dimensional (2D) regions of interest of constant shape and size, and one based on predefined 3-dimensional (3D) volumes of interest, were used to calculate the semiquantitative uptake ratios. Results: For the 2D method, the change in uptake ratio was 1.2%/cm for the high uptake ratio and 0.9%/cm for the low uptake ratio. The corresponding results for the 3D method were 2.1% and 1.7%, respectively. Conclusion: The 3D method was found to be more dependent on rotation radius than the 2D method, which was expected because of the 3D nature of the partial-volume effect. The correction factors were, however, less dependent on which of the 2 uptake ratios was simulated, which is positive for the application of the correction equations on patient data.

Dopamine D2 receptor SPECT with I-123-IBZM: evaluation of collimator and post-filtering when using model-based compensation-a Monte Carlo study

In (123)I-IBZM brain SPECT, the main interest is the activity uptake in the striatum relative to the background, and semi-quantitative techniques using regions of interest are typically used for this purpose. Uncertainties in the measured uptakes can however be a problem due to low contrasts and high noise levels. Like SPECT in general, IBZM SPECT should benefit from reconstruction methods that include model-based compensation, but it is important that image acquisition is optimized for this technique. An important factor is the choice of collimator. In this study we compare four different parallel-hole collimators for IBZM SPECT regarding overall quantitative accuracy and measured uptake ratio as a function of image noise and uncertainty. The collimators are low-energy high-resolution (LEHR), low-energy general-purpose (LEGP), extended LEGP (ELEGP) and medium-energy general-purpose (MEGP). The effect of three Butterworth post-filters with cut-off frequencies of 0.3, 0.45 and 0.6 cm(-1) (power factor 8) is also studied. All raw-data projections are produced using Monte Carlo simulations. Of the investigated collimators, the one that is most sensitive to the primary photons, ELEGP, proved to be the most optimal for realistic noise levels. Butterworth post-filtering is advantageous, and the cut-off frequency 0.45 cm(-1) was the best compromise in this study.

Gaussian prefiltering of 123I DAT SPECT images when using depth-independent resolution recovery

Previously we have investigated a depth-independent compensation for collimator detector response (CDR) included in the OSEM reconstruction, intended for SPECT images that have been corrected for scatter and septal penetration using convolution-based methods. In this work, the aim was to study how different filtering strategies affect contrast as a function of noise when using Gaussian smoothing filters in combination with the above-described CDR compensation. The evaluation was performed for (123)I dopamine transporter (DAT) SPECT images. Prefiltering with 2D Gaussian filter kernels, where the deterioration in resolution is included in the depth-independent CDR compensation, was compared to conventional postfiltering with 3D Gaussian filter kernels. Images reconstructed without filtering are also included in the comparison. It was found that there is little benefit in noise reduction when using CDR compensation. However, this variant of prefiltering gives consistently higher contrasts as a function of noise compared with the postfiltering alternative, and that could be of interest when using other types of filters with contrast improving properties.

Pre- and Postsynaptic Dopamine SPECT in Idiopathic Parkinsonian Diseases: A Follow-Up Study

We prospectively evaluated the diagnostic contribution of 123I-FP-Cit (DAT) and 123I-IBZM (IBZM) SPECT in 29 patients with Parkinsons disease (PD) (74.4 ± 4.2 years) and 28 patients with atypical parkinsonian diseases (APD) (74.3 ± 9.2 years). Twelve had multiple system atrophy (MSA) and 16 progressive supranuclear palsy (PSP). Sixteen age-matched healthy controls (HC) were included. DAT and IBZM SPECTs were made at baseline and after 1 year in all PD patients and in 20 (DAT) and 18 (IBZM) of the APD patients, and after 3 years in 22 (DAT) and 17 (IBZM) of the PD patients and in 10 (DAT) and 10 (IBZM) of the APD patients. The relative DAT uptake decrease was faster in PD and PSP than in HC and MSA. In PSP the DAT uptake was lower than in MSA after 1 year but not after 3 years. Baseline IBZM uptake was not significantly different between patients and HC or between PD and APD. One year after initiated dopaminergic treatment the mean IBZM uptake in the MSA patients remained high compared to PSP and after 3 years compared to PD, PSP, and HC. Thus, the pattern of uptake of these ligands over time may be of value in discriminating between these diagnoses.

PITX3 genotype and risk of dementia in Parkinson's disease : A population-based study

Dementia is a devastating manifestation of Parkinsons disease (PD). This study investigates whether a common polymorphism in the PITX3 gene (rs2281983), which is of importance for the function of dopaminergic neurons, affects the risk of developing dementia in PD and whether it affects dopamine transporter (DAT) uptake. We PITX3 genotyped 133 patients with new-onset, idiopathic PD, participating in a population-based study in Sweden. Patients were followed prospectively during 6-11years with extensive investigations, including neuropsychology and DAT-imaging with 123I FP-CIT. The primary outcome was the incidence of PD dementia (PDD), diagnosed according to published criteria, studied by the Kaplan-Meier method and Cox proportional hazards. Performance in individual cognitive domains, the incidence of visual hallucinations, disease progression and striatal DAT uptake on imaging was also investigated. PD patients carrying the PITX3 C allele had an increased risk of developing PDD (hazard ratio: 2.87, 95% CI: 1.42-5.81, p=0.003), compared to the PD patients homozygous for the T-allele. Furthermore, the PITX3 C allele carriers with PD had a poorer cognitive performance in the visuospatial domain (p<0.001) and a higher incidence of visual hallucinations. A trend towards a lower striatal DAT uptake in the PITX3 C allele carriers was suggested, but could not be confirmed. Our results show that a common polymorphism in the PITX3 gene affects the risk of developing PDD and visuospatial dysfunction in idiopathic PD. If validated, these findings can provide new insights into the neurobiology and genetics of non-motor symptoms in PD.

Accuracy of Visual Assessment of Dopamine Transporter Imaging in Early Parkinsonism

Dopamine transporter (DaT) imaging may be supportive in the initial clinical diagnostic workup in patients with suspected parkinsonian diseases, given that the method has the potential to detect dopaminergic degeneration. We investigated the diagnostic accuracy of visual assessment of the initial DaT single‐photon emission CT (DaT‐SPECT) with 123I‐FP‐CIT in a large group of early‐stage parkinsonian patients. After inclusion in a long‐term multidisciplinary population‐based prospective study, a baseline DaT‐SPECT was done in 171 incidental, L‐dopa‐naïve, parkinsonian patients (102 men and 69 women) and 37 healthy controls (19 men and 18 women). The results of the DaT‐SPECTs were linked to criteria‐based clinical diagnoses, which were set after a mean follow‐up of 4.6 (±1.7) years. The outcome of the visual assessment was also compared with that of a semiquantitative evaluation method using regions of interest to measure uptake ratios in the caudate and putamen. We found that visual assessment of DaT‐SPECT in clinically diagnosed incidental Parkinsons disease patients had a sensitivity of 94% and a specificity of 92%, rendering a positive likelihood ratio of 11.75 and a negative likelihood ratio of 0.07. The proportion of false positives was 1.4% and false negatives 4.8% at baseline. These figures were comparable to those of the semiquantitative method. This study demonstrates that visual interpretation of presynaptic dopamine imaging with 123I‐FP‐CIT offers reliable support in the diagnostic procedure of early parkinsonian diseases.

Whole-Body Biodistribution and Dosimetry of the Dopamine Transporter Radioligand 18F-FE-PE2I in Human Subjects

18F-(E)-N-(3-iodoprop-2-enyl)-2β-carbofluoroethoxy-3β-(4′-methyl-phenyl) nortropane (18F-FE-PE2I) was recently developed and has shown adequate affinity and high selectivity for the dopamine transporter (DAT). Previous studies have shown promising results for 18F-FE-PE2I as a suitable radioligand for DAT imaging. In this study, we investigated the whole-body biodistribution and dosimetry of 18F-FE-PE2I in healthy volunteers to support its utility as a suitable PET imaging agent for the DAT. Methods: Five healthy volunteers were given a mean activity of 2.5 MBq/kg, and 3 PET scans, head to thigh, were performed immediately after injection followed by 4 whole-body PET/CT scans between 0.5 and 6 h after injection. Blood samples were drawn in connection with the whole-body scans, and all urine was collected until 6 h after injection. Volumes of interest were delineated around 17 organs on all images, and the areas under the time–activity curves were calculated to obtain the total number of decays in the organs. The absorbed doses to organs and the effective dose were calculated using the software IDAC. Results: The highest activity concentration was observed in the liver (0.9%–1.2% injected activity/100 g) up to 30 min after injection. At later time points, the highest concentration was seen in the gallbladder (1.1%–0.1% injected activity/100 g). The activity excreted with urine ranged between 23% and 34%, with a mean of 28%. The urinary bladder received the highest absorbed dose (119 μGy/MBq), followed by the liver (46 μGy/MBq). The effective dose was 23 μSv/MBq (range, 19–28 μSv/MBq), resulting in an effective dose of 4.6 mSv for an administered activity of 200 MBq. Conclusion: The effective dose is within the same order of magnitude as other commonly used PET imaging agents as well as DAT agents. The reasonable effective dose, together with the previously reported favorable characteristics for DAT imaging and quantification, indicates that 18F-FE-PE2I is a suitable radioligand for DAT imaging.