Prediction and early biomarkers of cognitive decline in Parkinson disease and atypical parkinsonism: a population-based study.

The progression of cognitive decline is heterogeneous in the three most common idiopathic parkinsonian diseases: Parkinson disease, multiple system atrophy and progressive supranuclear palsy. The causes for this heterogeneity are not fully understood, and there are no validated biomarkers that can accurately identify patients who will develop dementia and when. In this population-based, prospective study, comprehensive neuropsychological testing was performed repeatedly in new-onset, idiopathic parkinsonism. Dementia was diagnosed until 10 years and participants (N = 210) were deeply phenotyped by multimodal clinical, biochemical, genetic and brain imaging measures. At baseline, before the start of dopaminergic treatment, mild cognitive impairment was prevalent in 43.4% of the patients with Parkinson disease, 23.1% of the patients with multiple system atrophy and 77.8% of the patients with progressive supranuclear palsy. Longitudinally, all three diseases had a higher incidence of cognitive decline compared with healthy controls, but the types and severity of cognitive dysfunctions differed. In Parkinson disease, psychomotor speed and attention showed signs of improvement after dopaminergic treatment, while no such improvement was seen in other diseases. The 10-year cumulative probability of dementia was 54% in Parkinson disease and 71% in progressive supranuclear palsy, while there were no cases of dementia in multiple system atrophy. An easy-to-use, multivariable model that predicts the risk of dementia in Parkinson disease within 10 years with high accuracy (area under the curve: 0.86, P < 0.001) was developed. The optimized model adds CSF biomarkers to four easily measurable clinical features at baseline (mild cognitive impairment, olfactory function, motor disease severity and age). The model demonstrates a highly variable but predictable risk of dementia in Parkinson disease, e.g. a 9% risk within 10 years in a patient with normal cognition and CSF amyloid-ß42 in the highest tertile, compared with an 85% risk in a patient with mild cognitive impairment and CSF amyloid-ß42 in the lowest tertile. Only small or no associations with cognitive decline were found for factors that could be easily modifiable (such as thyroid dysfunction). Risk factors for cognitive decline in multiple system atrophy and progressive supranuclear palsy included signs of systemic inflammation and eye movement abnormalities. The predictive model has high accuracy in Parkinson disease and might be used for the selection of patients into clinical trials or as an aid to improve the prevention of dementia.

Distant metastases and synchronous malignancies on FDG-PET/CT in patients with head and neck cancer: a retrospective study.

BACKGROUND: Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) has been proven to be a good method to detect distant spread of head and neck cancer (HNC). However, most prior studies are based on Asian populations and may not be directly transferable to western populations. PURPOSE: To investigate the frequency and distribution of distant metastases and synchronous malignancies detected by PET/CT in HNC in a northern Swedish population. MATERIAL AND METHODS: All primary whole-body FDG-PET/CT examinations performed on the suspicion of HNC (n = 524 patients) between 1 January 2013 and 31 December 2016 at Umeå University Hospital in Sweden were retrospectively reviewed . After the exclusion of 189 examinations without evidence of primary HNC, 335 examinations were analyzed. RESULTS: Distant metastases were detected in 10 (3%) patients, all with advanced primary tumors corresponding to TNM stage 3-4, most frequently in salivary gland adenocarcinoma, where 50% of patients had distant spread. Four patients had metastases below the diaphragm, representing 20% of the salivary gland malignancies. In the remaining six patients, metastases were supraphrenic, of which all but one were identified by CT alone. Synchronous malignancies were discovered in 14 (4.2%) patients, of which five were below the diaphragm. CONCLUSION: The overall frequency of distant spread and synchronous malignancy in primary HNC was generally low. However, the risk for distant metastases below the diaphragm was relatively higher in salivary gland adenocarcinoma, supporting whole-body FDG-PET/CT in the primary diagnostic work-up in these patients.

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

18F-(E)-N-(3-iodoprop-2-enyl)-2ß-carbofluoroethoxy-3ß-(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.

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

Dementia is a devastating manifestation of Parkinson's 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.

Fractional Anisotropy and Mean Diffusion as Measures of Dopaminergic Function in Parkinson's Disease: Challenging Results.

BACKGROUND: Diffusion tensor imaging (DTI) has been purported as an imaging technique to assess dopaminergic degeneration in Parkinson's disease. OBJECTIVE: To test if fractional anisotropy (FA) and mean diffusion (MD) in the basal ganglia as measured by DTI correlates with dopaminergic function as measured by dopamine transporter (DAT) and dopamine D2-receptor (D2R) SPECT. METHODS: One-hundred and eleven patients with Parkinson's disease (71±10 years) and thirty-one controls (68±7 years) performed DTI, DAT and D2R SPECT at baseline and four follow-ups (1-year: 89 patients/zero controls; 3-year: 72/11; 5-year: 48/17; and 8-year: 13/13). Four equipment combinations of MRI scanners/SPECT gamma cameras were used during the study. Data from each combination were analyzed separately. Regions-of-interest were outlined in the substantia nigra (three subareas, DTI only) and in the striatum (putamen and caudate). Side differences and bilateral averages were correlated using linear regression. The significance threshold was set at P < 0.001 and 0.001 < P< 0.05 was defined as a trend towards significance. RESULTS: For side differences, no significant correlations were observed, but in patients, there was a trend towards a negative correlation between MD in the middle nigra and putaminal DAT uptake in two combinations (P = 0.04 and P = 0.03). For averages, in patients, striatal MD correlated negatively with striatal DAT uptake in one combination (P = 0.0005) and trended towards negative correlations with striatal D2R uptake (one combination, P = 0.03) and with the sum of striatal DAT and D2R uptake (two combinations P = 0.002 and P = 0.03). FA showed no correlations in patients, and no correlations were found in controls. CONCLUSIONS: The poor correlations between MD and dopamine activity -and absent correlations for FA - imply that additional diffusion measures must be developed to reliably assess the dopaminergic degeneration in Parkinson's disease.

Long-term dopamine transporter imaging in Parkinson's disease treated with zona incerta stimulation.

OBJECTIVE: The caudal zona incerta (cZI) is a promising, clinically beneficial target for deep brain stimulation (DBS) in Parkinson's disease (PD). To assess whether DBS of the cZI affects the rate of dopamine terminal dysfunction, PD patients with and without DBS were followed prospectively with I FP-Cit single photon emission tomography from the first diagnosis and up to 8 years. METHODS: Six patients underwent DBS of the cZI during the survey period. Twenty-two PD patients only on pharmacotherapy served as controls. I FP-Cit and clinical assessment were performed at baseline and after 1, 3 and 5 years in all patients. Ten patients also underwent a I FP-Cit after 8 years. Image data were evaluated semiquantitatively. Mixed-model analysis was used to assess the relative change in I FP-Cit uptake and comparison between surgically and conservatively treated PD patients. RESULTS: The relative decrease in I FP-Cit uptake was more pronounced in DBS-treated patients than in controls in the more affected caudate (P=0.037) and putamen (P=0.013). The annual decrease rates were higher in the less affected than the more affected putamen, and were slightly greater in DBS-treated patients (4.8%, 95%confidence interval: 8.5-2.2%) than in controls (4.0%, 95% confidence interval: 5.1-3.1%). CONCLUSION: This long-term prospective study confirms that the underlying dopaminergic dysfunction continues despite clinical improvement in PD patients with DBS of the cZI. A slightly faster rate of decrease in I FP-Cit uptake in these patients compared with conservatively treated PD patients may reflect a more aggressive form of PD.

Cross-camera comparison of ROI-based semi-quantitative ¹²³I-IBZM SPECT data in healthy volunteers using an anthropomorphic phantom for calibration.

BACKGROUND: In (123)I-Iolopride (IBZM) SPECT reference values may diverge between camera systems. If multicenter pooling of normal material databases is needed, differences in measured semi-quantitative data due to equipment performance and reconstruction parameters have to be investigated in each instance to determine the comparability. PURPOSE: To explore the differences in (123)I-IBZM measured uptake ratios between two different gamma cameras in healthy controls, the intra-rater reproducibility of the image evaluation method and the possibility to equalize uptake ratios by calibration through an anthropomorphic phantom. MATERIAL AND METHODS: Differences in ROI-based semi-quantitative data from two different gamma camera systems, the three-headed brain dedicated Neurocam and the two-headed multipurpose hybrid system Infinia Hawkeye, were studied using image data from a group of healthy volunteers and an anthropomorphic brain-phantom scanned with both cameras. Several reconstruction methods and corrections were applied. To test the reliability of the ROI method, the intra-observer reproducibility was determined for the ROI method in this study. RESULTS: The ROI method had a high reliability. Differences in mean measured uptake (123)I-IBZM ratios in healthy controls varied between 2.9% and 6.5% depending on reconstruction and correction for attenuation and scatter. After calibration, the differences decreased. There were no statistically significant differences between corrected ratios from the two camera systems in the study when images were reconstructed with attenuation correction. CONCLUSION: The conformity of uptake ratios in attenuation corrected (123)I-IBZM images derived from the two different cameras was improved by using an anthropomorphic phantom for calibration.

Rotation radius dependence of 123I-FP-CIT and 123I-IBZM SPECT uptake ratios: a Monte Carlo study.

UNLABELLED: 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.

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 Parkinson's 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 Parkinson's disease with and without MCI. METHODS: Participants were recruited within a prospective cohort study of incident patients with idiopathic parkinsonism, including Parkinson's 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 Parkinson's Disease Society Brain Bank clinical diagnostic criteria for Parkinson's 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 Parkinson's disease (n=77) had under-recruitment in an extensive brain network including bilateral striatal and frontal regions (p<0·001). Within the Parkinson's disease group, patients with Parkinson's 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 Parkinson's disease without MCI (n=26). In patients with Parkinson's disease and MCI, SPECT uptake in the right caudate was lower than in patients with Parkinson's 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 Parkinson's disease and MCI suggest that cognitive impairment is linked to frontostriatal dysfunction. FUNDING: Swedish Medical Research Council, Swedish Parkinson Foundation, Swedish Parkinson's Disease Association, Umeå University, Kempe Foundation, Foundation for Clinical Neuroscience at Umeå University Hospital, Västerbotten County Council (ALF), King Gustaf V's and Queen Victoria's Freemason Foundation, Knut and Alice Wallenberg Foundation, and Swedish Brain Power.

Pre- and postsynaptic dopamine SPECT in the early phase of idiopathic parkinsonism: a population-based study.

PURPOSE: The aim of this study was to assess the diagnostic contribution of pre- and postsynaptic dopamine SPECT in drug-naïve patients with early idiopathic parkinsonism and to investigate possible differences between idiopathic Parkinson's disease (PD) and atypical parkinsonian syndromes (APS) and possible differences in motor subtypes of parkinsonism. METHODS: A group of 128 newly diagnosed idiopathic parkinsonian patients and 48 healthy controls was studied. Presynaptic baseline SPECT with (123)I-FP-CIT was performed in all patients and in 120 patients also a baseline postsynaptic SPECT with (123)I-IBZM. Clinical diagnoses were reassessed after 12 months. RESULTS: Presynaptic uptake in the putamen and caudate was significantly reduced in patients compared to controls. Presynaptic uptake ratios were not different between PD patients and patients with APS, and postsynaptic uptake in APS was not significantly reduced compared to PD or controls. In half of the APS patients both pre- and postsynaptic uptake ratios were reduced on the same side in the striatum. Impaired motor performance was associated with decreased presynaptic uptake in the putamen in PD. The postural instability and gait difficulty (PIGD) subtype of PD had lower presynaptic uptake ratios than patients with tremor-dominated (TD) symptoms. CONCLUSION: Not only presynaptic putamen uptake ratios, but also caudate ratios were reduced in a majority of the patients in our study. At baseline scan, i.e. in an early stage of the disease, the accuracy of excluding APS in the whole study population was 85% using a combination of pre- and postsynaptic SPECT. Already at baseline, lower presynaptic SPECT ratios were seen in PD with PIGD at onset compared to those with TD subtype.

Dopamine D2 receptor SPECT with (123)I-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.

Correction for scatter and septal penetration using convolution subtraction methods and model-based compensation in 123I 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.