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Abstract Background A brain glucose metabolism pattern related to phenoconversion in patients with idiopathic/isolated REM sleep behaviour disorder (iRBDconvRP) was recently identified. However, the validation of the iRBDconvRP in an external, independent group of iRBD patients is needed to verify the reproducibility of such pattern, so to increase its importance in clinical and research settings. The aim of this work was to validate the iRBDconvRP in an independent group of iRBD patients. Methods Forty iRBD patients (70 ± 5.59 years, 19 females) underwent brain [18F]FDG-PET in Seoul National University. Thirteen patients phenoconverted at follow-up (7 Parkinson disease, 5 Dementia with Lewy bodies, 1 Multiple system atrophy; follow-up time 35 ± 20.56 months) and 27 patients were still free from parkinsonism/dementia after 62 ± 29.49 months from baseline. We applied the previously identified iRBDconvRP to validate its phenoconversion prediction power. Results The iRBDconvRP significantly discriminated converters from non-converters iRBD patients (p = 0.016; Area under the Curve 0.74, Sensitivity 0.69, Specificity 0.78), and it significantly predicted phenoconversion (Hazard ratio 4.26, C.I.95%: 1.18–15.39). Conclusions The iRBDconvRP confirmed its robustness in predicting phenoconversion in an independent group of iRBD patients, suggesting its potential role as a stratification biomarker for disease-modifying trials.

Background Isolated rapid eye movement sleep behavior disorder is known to be prodromal for alpha-synucleinopathies, such as Parkinson's disease (PD) and dementia with Lewy bodies. The [18 F]fluorodeoxyglucose-positron emission tomography (PET)-based PD-related brain pattern can be used to monitor disease progression. Objective We longitudinally investigated PD-related brain pattern expression changes in 20 subjects with isolated rapid eye movement sleep behavior disorder to investigate whether this may be a suitable technique to study prodromal PD progression in these patients and to identify potential phenoconverters. Methods Subjects underwent two [18 F]fluorodeoxyglucose-PET brain scans ~3.7 years apart, along with baseline and repeated motor, cognitive, and olfactory testing within roughly the same time frame. Results At baseline, 8 of 20 (40%) subjects significantly expressed the PD-related brain pattern (with z scores above the receiver operating characteristic-determined threshold). At follow-up, six additional subjects exhibited significant PD-related brain pattern expression (70% in total). PD-related brain pattern expression increased in all subjects (P = 0.00008). Four subjects (20%), all with significant baseline PD-related brain pattern expression, phenoconverted to clinical PD. Conclusions Suprathreshold PD-related brain pattern expression and greater score rate of change may signify greater shorter-term risk for phenoconversion. Our results support the use of serial PD-related brain pattern expression measurements as a prodromal PD progression biomarker in patients with isolated rapid eye movement sleep behavior disorder. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society.

Parkinson’s disease (PD) commences several years before the onset of motor features. Pathophysiological understanding of the pre-clinical or early prodromal stages of PD are essential for the development of new therapeutic strategies. Two categories of patients are ideal to study the early disease stages. Idiopathic rapid eye movement sleep behavior disorder (iRBD) represents a well-known prodromal stage of PD in which pathology is presumed to have reached the lower brainstem. The majority of patients with iRBD will develop manifest PD within years to decades. Another category encompasses non-manifest mutation carriers, i.e. subjects without symptoms, but with a known mutation or genetic variant which gives an increased risk of developing PD. The speed of progression from preclinical or prodromal to full clinical stages varies among patients and cannot be reliably predicted on the individual level. Clinical trials will require inclusion of patients with a predictable conversion within a limited time window. Biomarkers are necessary that can confirm pre-motor PD status and can provide information regarding lead time and speed of progression. Neuroimaging changes occur early in the disease process and may provide such a biomarker. Studies have focused on radiotracer imaging of the dopaminergic nigrostriatal system, which can be assessed with dopamine transporter (DAT) single photon emission computed tomography (SPECT). Loss of DAT binding represents an effect of irreversible structural damage to the nigrostriatal system. This marker can be used to monitor disease progression and identify individuals at specific risk for phenoconversion. However, it is known that changes in neuronal activity precede structural changes. Functional neuro-imaging techniques, such as 18F-2-fluoro-2-deoxy-D-glucose Positron Emission Tomography (18F-FDG PET) and functional magnetic resonance imaging (fMRI), can be used to model the effects of disease on brain networks when combined with advanced analytical methods. Because these changes occur early in the disease process, functional imaging studies are of particular interest in prodromal PD diagnosis. In addition, fMRI and 18F-FDG PET may be able to predict a specific future phenotype in prodromal cohorts, which is not possible with DAT SPECT. The goal of the current review is to discuss the network-level brain changes in pre-motor PD.

Rationale In Parkinson’s disease (PD), spatial covariance analysis of 18F-FDG PET data has consistently revealed a characteristic PD-related brain pattern (PDRP). By quantifying PDRP expression on a scan-by-scan basis, this technique allows objective assessment of disease activity in individual subjects. We provide a further validation of the PDRP by applying spatial covariance analysis to PD cohorts from the Netherlands (NL), Italy (IT), and Spain (SP). Methods The PDRPNL was previously identified (17 controls, 19 PD) and its expression was determined in 19 healthy controls and 20 PD patients from the Netherlands. The PDRPIT was identified in 20 controls and 20 “de-novo” PD patients from an Italian cohort. A further 24 controls and 18 “de-novo” Italian patients were used for validation. The PDRPSP was identified in 19 controls and 19 PD patients from a Spanish cohort with late-stage PD. Thirty Spanish PD patients were used for validation. Patterns of the three centers were visually compared and then cross-validated. Furthermore, PDRP expression was determined in 8 patients with multiple system atrophy. Results A PDRP could be identified in each cohort. Each PDRP was characterized by relative hypermetabolism in the thalamus, putamen/pallidum, pons, cerebellum, and motor cortex. These changes co-varied with variable degrees of hypometabolism in posterior parietal, occipital, and frontal cortices. Frontal hypometabolism was less pronounced in “de-novo” PD subjects (Italian cohort). Occipital hypometabolism was more pronounced in late-stage PD subjects (Spanish cohort). PDRPIT, PDRPNL, and PDRPSP were significantly expressed in PD patients compared with controls in validation cohorts from the same center (P < 0.0001), and maintained significance on cross-validation (P < 0.005). PDRP expression was absent in MSA. Conclusion The PDRP is a reproducible disease characteristic across PD populations and scanning platforms globally. Further study is needed to identify the topography of specific PD subtypes, and to identify and correct for center-specific effects.

Purpose Subthalamotomy using magnetic resonance-guided focused ultrasound (MRgFUS) has become a potential treatment option for the cardinal features of Parkinson's disease (PD). The purpose of this study was to evaluate the effects of MRgFUS-subthalamotomy on brain metabolism using different scale levels. Methods We studied resting-state glucose metabolism in eight PD patients before and after unilateral MRgFUS-subthalamotomy using hybrid [F-18]FDG-PET/MR imaging. We used statistical nonparametric mapping (SnPM) to study regional metabolic changes following this treatment and also quantified whole-brain treatment-related changes in the expression of a spatial covariance-based Parkinson's disease-related metabolic brain pattern (PDRP). Modulation of regional and network activity was correlated with clinical improvement as measured by changes in Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor scores. Results After subthalamotomy, there was a significant reduction in FDG uptake in the subthalamic region, globus pallidus internus, motor and premotor cortical regions, and cingulate gyrus in the treated hemisphere, and the contralateral cerebellum (p

BASICS: Nuclear Medicine Imaging Tracers for Neurology.- 18F-Fluorodeoxyglucose Positron Emission Tomography Procedures.- Tracer-Kinetic Modeling.- Quantification in Brain SPECT.- MRI/PET Brain Imaging.- An Investigation of Statistical Power of [15O]-H2O PET Perfusion Imaging.- Molecular Imaging Using Magnetic Resonance Spectroscopy in Neurology.- The Default Network of the Brain.- DEMENTIA: Dementia Due to Neurodegenerative Disease - Molecular Imaging Findings.- Abeta Imaging in Aging, Alzheimer's Disease and Other Neurodegenerative Conditions.- PET Imaging of the Alpha4Beta2*-Nicotinic Acetylcholine Receptors in Alzheimer's.- Neuroimaging Findings in Mild Cognitive Impairment.- Impact of the IWG/Dubois Criteria for Alzheimer's Disease in Imaging Studies.- Perfusion SPECT.- Nuclear Imaging in Frontotemporal.- Parkinson Dementia: PET Findings.- SPECT/PET Findings in Lewy Body Dementia.- Vascular.- Value of MIBG in the Differential Diagnosis of Neurodegenerative Disorders.- Linking Molecular Biology to Therapeutic Approaches for Alzheimer Disease with PET.- CEREBROVASCULAR DISORDERS: PET and SPECT Studies of Ageing and Cardiovascular Risk Factors for Alzheimer's Disease.- Carotid Plaque Imaging with SPECT-CT and PET-CT.- ET in Brain Arteriovenous Malformations and Cerebral Proliferative Angiopathy.- Transient Ischemic Attack.- PET Reveals Pathophysiology in Ischemic Stroke.- MOVEMENT DISORDERS: Parkinson Disease.- SPECT Imaging for Idiopathic M.Parkinson and Parkinsonian Syndromes.- PET and SPECT Imaging in Parkinsonian Syndromes.- Amyotrophic Lateral Sclerosis.- PET in Huntington's Disease.- PET and SPECT Imaging in Dystonia.- PET and SPECT Imaging in Hyperkinetic Movement Disorders.- Clinical Applications of [123I]FP-CIT SPECT Imaging.- INFLAMMATORY DISORDERS: PET Imaging of Microglia Activation in Neuropsychiatric Disorders with Potential Infectious Origin.- PET Imaging in Multiple Sclerosis.- PET and SPECT Imaging of Neurotoxicity.- PET and SPECT in Hepatic and Uremic Encephalopathy.- EPILEPSY: PET in Epilepsy.- Subtraction ictal SPECT coregistered to MRI (SISCOM).- Nuclear Medicine Neuroimaging and Electromagnetic Source Localization in Nonlesional Drug-Resistant Focal.- TUMORS OF THE NERVOUS SYSTEM: PET Imaging of Gliomas.- Single-Photon Emission Computed Tomography [Neuro-SPECT] Imaging of Brain Tumors.- The Value of 11C-Methionine PET in the Differential Diagnosis between Brain Tumor Recurrence and Radionecrosis.- Imaging Brain Metastases of Neuroendocrine Tumors.- OTHER SUBJECTS: Traumatic Brain Injury.- Whiplash: real or not real? A review and new concept.- Positron Emission Tomography Imaging in Altered States of Consciousness.- Anaesthesia and PET of the Brain.- Modulation of Brain Functioning by Deep Brain Stimulation.- Radionuclide Imaging Studies in Pediatric Neurology.

Imaging of brain glucose metabolism with 18F-2-fluoro-2-deoxy-d-glucose positron emission tomography (18F-FDG PET) can give important information regarding disease-related changes in underlying neuronal systems, when combined with appropriate analytical methods. One such method is the scaled subprofile model combined with principal component analysis (SSM PCA). This model takes into account the relationships (covariance) between voxels to identify disease-related patterns. By quantifying disease-related pattern expression on a scan-by-scan basis, this technique allows objective assessment of disease activity in individual subjects. This chapter provides an overview of steps involved in pattern identification in 18F-FDG PET data and is divided into three sections. Section 1 introduces basic concepts in nuclear imaging and explores the cellular underpinnings of signals measured with 18F-FDG PET. Section 2 describes relevant basic concepts in 18F-FDG PET image analysis including anatomical registration, normalization, and analysis of variance and covariance. Section 3 is dedicated to SSM PCA specifically. The goal of this chapter is to make the technique more accessible to readers without a mathematics or neuroimaging background. Although many excellent texts on this topic exist, the current chapter aims to provide a more conceptual overview, including some discussion points that are not always formally described in literature.

Background Isolated rapid eye movement sleep behavior disorder is known to be prodromal for alpha‐synucleinopathies, such as Parkinson's disease (PD) and dementia with Lewy bodies. The [18F]fluorodeoxyglucose‐positron emission tomography (PET)–based PD‐related brain pattern can be used to monitor disease progression. Objective We longitudinally investigated PD‐related brain pattern expression changes in 20 subjects with isolated rapid eye movement sleep behavior disorder to investigate whether this may be a suitable technique to study prodromal PD progression in these patients and to identify potential phenoconverters. Methods Subjects underwent two [18F]fluorodeoxyglucose‐PET brain scans ~3.7 years apart, along with baseline and repeated motor, cognitive, and olfactory testing within roughly the same time frame. Results At baseline, 8 of 20 (40%) subjects significantly expressed the PD‐related brain pattern (with z scores above the receiver operating characteristic–determined threshold). At follow‐up, six additional subjects exhibited significant PD‐related brain pattern expression (70% in total). PD‐related brain pattern expression increased in all subjects (P = 0.00008). Four subjects (20%), all with significant baseline PD‐related brain pattern expression, phenoconverted to clinical PD. Conclusions Suprathreshold PD‐related brain pattern expression and greater score rate of change may signify greater shorter‐term risk for phenoconversion. Our results support the use of serial PD‐related brain pattern expression measurements as a prodromal PD progression biomarker in patients with isolated rapid eye movement sleep behavior disorder. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Summary Background Most patients with Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies do not carry mutations in known disease-causing genes. The aim of this study was to identify a novel gene implicated in the development of these disorders. Methods Our study was done in three stages. First, we did genome-wide linkage analysis of an Italian family with dominantly inherited Parkinson's disease to identify the disease locus. Second, we sequenced the candidate gene in an international multicentre series of unrelated probands who were diagnosed either clinically or pathologically with Parkinson's disease, Parkinson's disease dementia, or dementia with Lewy bodies. As a control, we used gene sequencing data from individuals with abdominal aortic aneurysms (who were not examined neurologically). Third, we enrolled an independent series of patients diagnosed clinically with Parkinson's disease and controls with no signs or family history of Parkinson's disease, Parkinson's disease dementia, or dementia with Lewy bodies from centres in Portugal, Sardinia, and Taiwan, and screened them for specific variants. We also did mRNA and brain pathology studies in three patients from the international multicentre series carrying disease-associated variants, and we did functional protein studies in in-vitro models, including neurons from induced pluripotent stem-like cells. Findings Molecular studies were done between Jan 1, 2008, and Dec 31, 2017. In the initial kindred of ten affected Italian individuals (mean age of disease onset 59·8 years [SD 8·7]), we detected significant linkage of Parkinson's disease to chromosome 14 and nominated LRP10 as the disease-causing gene. Among the international series of 660 probands, we identified eight individuals (four with Parkinson's disease, two with Parkinson's disease dementia, and two with dementia with Lewy bodies) who carried different, rare, potentially pathogenic LRP10 variants; one carrier was found among 645 controls with abdominal aortic aneurysms. In the independent series, two of these eight variants were detected in three additional Parkinson's disease probands (two from Sardinia and one from Taiwan) but in none of the controls. Of the 11 probands from the international and independent cohorts with LRP10 variants, ten had a positive family history of disease and DNA was available from ten affected relatives (in seven of these families). The LRP10 variants were present in nine of these ten relatives, providing independent—albeit limited—evidence of co-segregation with disease. Post-mortem studies in three patients carrying distinct LRP10 variants showed severe Lewy body pathology. Of nine variants identified in total (one in the initial family and eight in stage 2), three severely affected LRP10 expression and mRNA stability (1424+5delG, 1424+5G→A, and Ala212Serfs*17, shown by cDNA analysis), four affected protein stability (Tyr307Asn, Gly603Arg, Arg235Cys, and Pro699Ser, shown by cycloheximide-chase experiments), and two affected protein localisation (Asn517del and Arg533Leu; shown by immunocytochemistry), pointing to loss of LRP10 function as a common pathogenic mechanism. Interpretation Our findings implicate LRP10 gene defects in the development of inherited forms of α-synucleinopathies. Future elucidation of the function of the LRP10 protein and pathways could offer novel insights into mechanisms, biomarkers, and therapeutic targets. Funding Stichting ParkinsonFonds, Dorpmans-Wigmans Stichting, Erasmus Medical Center, ZonMw—Memorabel programme, EU Joint Programme Neurodegenerative Disease Research (JPND), Parkinson's UK, Avtal om Lakarutbildning och Forskning (ALF) and Parkinsonfonden (Sweden), Lijf and Leven foundation, and cross-border grant of Alzheimer Netherlands–Ligue Europeene Contre la Maladie d'Alzheimer (LECMA).

Background Idiopathic REM sleep behavior disorder is a prodromal stage of Parkinson's disease and dementia with Lewy bodies. Hyposmia, reduced dopamine transporter binding, and expression of the brain metabolic PD-related pattern were each associated with increased risk of conversion to PD. The objective of this study was to study the relationship between the PD-related pattern, dopamine transporter binding, and olfaction in idiopathic REM sleep behavior disorder. Methods In this cross-sectional study, 21 idiopathic REM sleep behavior disorder subjects underwent 18F-fluorodeoxyglucose PET, dopamine transporter imaging, and olfactory testing. For reference, we included 18F-fluorodeoxyglucose PET data of 19 controls, 20 PD patients, and 22 patients with dementia with Lewy bodies. PD-related pattern expression z-scores were computed from all PET scans. Results PD-related pattern expression was higher in idiopathic REM sleep behavior disorder subjects compared with controls (P = 0.048), but lower compared with PD (P = 0.001) and dementia with Lewy bodies (P

The Patlak graphical analysis (PGAREF) for quantification of irreversible tracer binding with a reference tissue model was approximated by a dual time point imaging approach (DTPREF). The DTPREF was applied to 18 [18F]-FDOPA brain scans using the occipital cortex as reference region (DTPOCC) and compared to both PGAOCC and striatal-to-occipital ratios (SOR). Pearson correlation analysis and Bland–Altman plots showed an excellent correlation and good agreement between DTPOCC and PGAOCC, while correlations between SOR and PGAOCC were consistently lower. Linear discriminant analysis (LDA) demonstrated a similar performance for all methods in differentiating patients with Parkinson’s disease (PD) from healthy controls (HC). Specifically for [18F]-FDOPA brain imaging, these findings validate DTPOCC as an approximation for PGAOCC, providing the same quantitative information while reducing the acquisition time to two short static scans. For PD patients, this approach can greatly improve patient comfort while reducing motion artifacts and increasing image quality. In general, DTPREF can improve the clinical applicability of tracers with irreversible binding characteristics when a reference tissue is available.

Parkinson's disease is characterized not only by bradykinesia, rigidity, and tremor, but also by impairments of expressive and receptive linguistic prosody. The facilitating effect of music with a salient beat on patients' gait suggests that it might have a similar effect on vocal behavior, however it is currently unknown whether singing is affected by the disease. In the present study, fifteen Parkinson patients were compared with fifteen healthy controls during the singing of familiar melodies and improvised melodic continuations. While patients' speech could reliably be distinguished from that of healthy controls matched for age and gender, purely on the basis of aural perception, no significant differences in singing were observed, either in pitch, pitch range, pitch variability, and tempo, or in scale tone distribution, interval size or interval variability. The apparent dissociation of speech and singing in Parkinson's disease suggests that music could be used to facilitate expressive linguistic prosody. (C) 2016 The Authors. Published by Elsevier Inc.

Introduction The implementation of spatial-covariance [18F]fluorodeoxyglucose positron emission tomography–based disease-related metabolic brain patterns as biomarkers has been hampered by intercenter imaging differences. Within the scope of the JPND-PETMETPAT working group, we illustrate the impact of these differences on Parkinson's disease–related pattern (PDRP) expression scores. Methods Five healthy controls, 5 patients with idiopathic rapid eye movement sleep behavior disorder, and 5 patients with Parkinson's disease were scanned on one positron emission tomography/computed tomography system with multiple image reconstructions. In addition, one Hoffman 3D Brain Phantom was scanned on several positron emission tomography/computed tomography systems using various reconstructions. Effects of image contrast on PDRP scores were also examined. Results Human and phantom raw PDRP scores were systematically influenced by scanner and reconstruction effects. PDRP scores correlated inversely to image contrast. A Gaussian spatial filter reduced contrast while decreasing intercenter score differences. Discussion Image contrast should be considered in harmonization efforts. A Gaussian filter may reduce noise and intercenter effects without sacrificing sensitivity. Phantom measurements will be important for correcting PDRP score offsets.

Introduction: Distinguishing between different tremor disorders can be challenging. Some tremor disorders are thought to have typical tremor characteristics: the current study aims to provide sensitivity and specificity for five 'typical' tremor phenomena.Methods: Retrospectively, we examined 210 tremor patients referred for electrophysiological recordings between January 2008 and January 2014. The final clinical diagnosis was used as the gold standard. The first step was to determine whether patients met neurophysiological criteria for their type of tremor. Once established, we focused on 'typical' characteristics: tremor frequency decrease upon loading (enhanced physiological tremor (EPT)), amplitude increase upon loading, distractibility and entrainment (functional tremor (Fr)), and intention tremor (essential tremor (ET)). The prevalence of these phenomena in the 'typical' group was compared to the whole group.Results: Most patients (87%) concurred with all core clinical neurophysiological criteria for their tremor type. We found a frequency decrease upon loading to be a specific (95%), but not a sensitive (42%) test for EPT. Distractibility and entrainment both scored high on sensitivity (92%, 91%) and specificity (94%, 91%) in FL whereas a tremor amplitude increase was specific (92%), but not sensitive (22%). Intention tremor was a specific finding in ET (85%), but not a sensitive test (45%). Combination of characteristics improved sensitivity.Conclusion: In this study, we retrospectively determined sensitivity and specificity for five 'typical' tremor characteristics. Characteristics proved specific, but few were sensitive. These data on tremor phenomenology will help practicing neurologists to improve distinction between different tremor disorders. (C) 2016 Elsevier Ltd. All rights reserved.

Objective DNAJC6 mutations were recently described in two families with autosomal recessive juvenile parkinsonism (onset age

Neuroimaging in Parkinson's disease (PD) and other primary Parkinsonian disorders has been increasingly used in the routine clinical work in the last years. The paradigm has changed from an "exclusionary" use, i.e., to rule out causes of secondary Parkinsonism, to an "inclusionary" one, i.e., finding image and network characteristics allowing to identify a specific disease. This is allowed by analyses spanning from the commonly used visual analysis to the most sophisticated postprocessing leading to the identification of covariance patterns both in morphological and functional neuroimaging. However, paralleling the advancement in covariance and connectivity analyses, the issues of standardization and harmonization of data acquisition, and image reconstruction and postprocessing among centers are emerging in the scientific community. Also, the building of scientific evidence still suffers from the lack of large, formal studies and relies on relatively small cohort studies from one or few centers. Joint actions to face these issues are now ongoing in Europe, supported by specific programs, such as the Joint Programming on Neurodegenerative Diseases (JPND). In the present review, some of the most recent and relevant achievements in the field of diffusion tensor magnetic resonance imaging (MRI), functional MRI, fludeoxyglucose-positron-emission tomography, dopamine transporter single-photon emission computed tomography and non-dopaminergic imaging in PD and primary Parkinsonisms are reported.

Background Idiopathic REM sleep behavior disorder is a prodromal stage of Parkinson's disease and dementia with Lewy bodies. Hyposmia, reduced dopamine transporter binding, and expression of the brain metabolic PD‐related pattern were each associated with increased risk of conversion to PD. The objective of this study was to study the relationship between the PD‐related pattern, dopamine transporter binding, and olfaction in idiopathic REM sleep behavior disorder. Methods In this cross‐sectional study, 21 idiopathic REM sleep behavior disorder subjects underwent 18F‐fluorodeoxyglucose PET, dopamine transporter imaging, and olfactory testing. For reference, we included 18F‐fluorodeoxyglucose PET data of 19 controls, 20 PD patients, and 22 patients with dementia with Lewy bodies. PD‐related pattern expression z‐scores were computed from all PET scans. Results PD‐related pattern expression was higher in idiopathic REM sleep behavior disorder subjects compared with controls (P = 0.048), but lower compared with PD (P = 0.001) and dementia with Lewy bodies (P

Over the last years convolutional neural networks (CNNs) have shown remarkable results in different image classification tasks, including medical imaging. One area that has been less explored with CNNs is Positron Emission Tomography (PET). Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) is a PET technique employed to obtain a representation of brain metabolic function. In this study we employed 3D CNNs in FDG-PET brain images with the purpose of discriminating patients diagnosed with Parkinson’s disease (PD) from controls. We employed Scaled Subprofile Modeling using Principal Component Analysis as a preprocessing step to focus on specific brain regions and limit the number of voxels that are used as input for the CNNs, thereby increasing the signal-to-noise ratio in our data. We performed hyperparameter optimization on three CNN architectures to estimate the classification accuracy of the networks on new data. The best performance that we obtained was [Formula: see text] and area under the receiver operating characteristic curve [Formula: see text] on the test set. We believe that, with larger datasets, PD patients could be reliably distinguished from controls by FDG-PET scans alone and that this technique could be applied to more clinically challenging tasks, like the differential diagnosis of neurological disorders with similar symptoms, such as PD, Progressive Supranuclear Palsy (PSP) and Multiple System Atrophy (MSA).

The adenosine A(2A) receptor (A(2A)R) is highly concentrated in the striatum, and a therapeutic target for Parkinson's disorder (PD) and Huntington's disease. High affinity and selective radiolabeled A(2A)R antagonists can be important research and diagnostic tools for PD. Positron Emission Tomography (PET) can play an important role by measuring radiolabeled A(2A) antagonists non-invasively in the brain. However, till date no complete review on A(2A)R PET ligands is available. The present article has been therefore focused on available PET tracers for A(2A)R and their detailed biological evaluation in rodents, nonhuman primates and humans. Drug design and development by molecular modeling including new lead structures that are potential candidates for radiolabeling and mapping of cerebral A(2A)Rs is discussed in the present article. A brief overview of functions of adenosine in health and disease, including the relevance of A(2A)R for PD has also been presented.

Background: The objective of this study was to validate disease-related metabolic brain patterns for Parkinson’s disease, multiple system atrophy, and progressive supranuclear palsy. Methods: The study included 20 patients with Parkinson’s disease, 21 with multiple system atrophy, and 17 with progressive supranuclear palsy, all of whom had undergone a clinically motivated [18F]-fluoro-deoxyglucose positron emission tomography scan at an early stage of their disease. At a follow-up time after the scan of 2–4 years, a clinical diagnosis was made according to established clinical research criteria. Patient groups were compared with 18 healthy controls using a multivariate covariance image analysis technique called scaled subprofile model/principal component analysis. Results: Disease-related metabolic brain patterns for these parkinsonian disorders were identified. Validation showed that these patterns were highly discriminative of the 3 disorders. Conclusions: Early diagnosis of parkinsonian disorders is feasible when the expression of disease-related metabolic brain patterns is quantified at a single-subject level.

The delay associated with cerebral processing time implies a lack of real-time representation of changes in the observed environment. To bridge this gap for motor actions in a dynamical environment, the brain uses predictions of the most plausible future reality based on previously provided information. To optimise these predictions, adjustments to actual experiences are necessary. This requires a perceptual memory buffer. In our study we gained more insight how the brain treats (real-time) information by comparing cerebral activations related to judging past-, present- and future locations of a moving ball, respectively. Eighteen healthy subjects made these estimations while fMRI data was obtained. All three conditions evoked bilateral dorsal-parietal and premotor activations, while judgment of the location of the ball at the moment of judgment showed increased bilateral posterior hippocampus activation relative to making both future and past judgments at the one-second time-sale. Since the condition of such 'real-time' judgments implied undistracted observation of the ball's actual movements, the associated hippocampal activation is consistent with the concept that the hippocampus participates in a top-down exerted sensory gating mechanism. In this way, it may play a role in novelty (saliency) detection.

The differential diagnosis of neurodegenerative brain diseases on clinical grounds is difficult, especially at an early disease stage. Several studies have found specific regional differences of brain metabolism applying [(18)F]-fluoro-deoxyglucose positron emission tomography (FDG-PET), suggesting that this method can assist in early differential diagnosis of neurodegenerative brain diseases.We have studied patients who had an FDG-PET scan on clinical grounds at an early disease stage and included those with a retrospectively confirmed diagnosis according to strictly defined clinical research criteria. Ninety-six patients could be included of which 20 patients with Parkinson's disease (PD), 21 multiple system atrophy (MSA), 17 progressive supranuclear palsy (PSP), 10 corticobasal degeneration (CBD), 6 dementia with Lewy bodies (DLB), 15 Alzheimer's disease (AD), and 7 frontotemporal dementia (FTD). FDG PET images of each patient group were analyzed and compared to18 healthy controls using Statistical Parametric Mapping (SPM5).Disease-specific patterns of relatively decreased metabolic activity were found in PD (contralateral parietooccipital and frontal regions), MSA (bilateral putamen and cerebellar hemispheres), PSP (prefrontal cortex and caudate nucleus, thalamus, and mesencephalon), CBD (contralateral cortical regions), DLB (occipital and parietotemporal regions), AD (parietotemporal regions), and FTD (frontotemporal regions).The integrated method addressing a spectrum of various neurodegenerative brain diseases provided means to discriminate patient groups also at early disease stages. Clinical follow-up enabled appropriate patient inclusion. This implies that an early diagnosis in individual patients can be made by comparing each subject's metabolic findings with a complete database of specific disease related patterns.

Carriers of the Huntington disease (HD) mutation develop a progressive neurodegenerative disorder after a pre-clinical phase. We examined the value of (11)C-raclopride PET (RAC) as a biomarker for pre-clinical HD pathophysiology.In a prospective cohort study with clinical and neuropsychological assessment we collected complete RAC data in 18 pre-clinical mutation carriers (HD-PMC) and 11 controls. Follow-up was 2 years. We calculated striatal RAC binding potential (BP) to measure dopamine D2 receptor availability.No HD-PMC had overt neuropsychological dysfunction. RAC-BP in putamen was abnormal in up to 44% of HD-PMC. The rate of RAC-BP decline (2.6% per year) was not significantly higher than in controls. Follow-up putaminal BP correlated weakly with predicted distance to onset of clinical HD (P = 0.034), but the rate of decline did not. Three HD-PMC developed motor abnormalities suspect for HD but did not show an increased rate of decline of putaminal BP.Many HD-PMC have striatal abnormalities but we found no clearly increased rate of D2 receptor changes around the onset of clinical HD. A longer follow-up of the present study cohort is needed to establish the value of RAC-BP in assessing the risk of clinical conversion from striatal D2 binding data.

The multidrug resistance protein 1 (MDR1 or ABCB1) gene encodes a P-glycoprotein that protects the brain against neurotoxicants. Certain MDR1 genetic variants are known to compromise the function of this transporter and may thus be associated with Parkinson disease (PD). We therefore conducted a large case-control study investigating the potential relationship between MDR1 variants and PD. We determined the frequency of three MDR1 variants in 599 European PD patients and controls and further stratified the population by ethnicity, age at onset, and exposure to pesticides. We detected no relevant association in either the entire sample, or when separately investigating by ethnic origin or age at onset. However, the distribution of c.3435C/T differed significantly between PD patients exposed to pesticides compared to those non-exposed (odds ratio = 4.74; confidence interval = [1.009; 22.306]); p = 0.047), suggesting that common MDR1 variants might influence the risk to develop PD in conjunction with exposure to pesticides.

Background: Motor symptoms form the hallmark of Parkinson's Disease (PD), although features like depression are often present. Depression rating scales [e.g. Montgomery-Asberg Depression Rating Scale (MADRS)] used in PD measure affective, cognitive and somatic symptoms. An important clinical question is which items of the MADRS are likely to be influenced by PD symptoms. Methods: Depression was assessed in 43 PD patients who scored below the cut-off of the MADRS and who differed widely in motor severity. Results: Parkinson's Disease patients scored relatively highest on Concentration difficulties, Reduced sleep and Inner tension. Reduced sleep, Lassitude and Suicidal thoughts were associated with motor severity and specifically with Bradykinesia, Rigidity and Axial impairment, however not with Tremor.To avoid a possible influence on our results of coincidentally included PD patients with a depression, all associations between somatic MADRS items and motor severity were corrected for the influence of affective symptoms of depression. All associations remained significant. Discussion: In conclusion, the items Reduced sleep and Lassitude of the MADRS are likely to be influenced by motor symptoms. The high score on Concentration difficulties is suggested to be a reflection of cognitive dysfunction in PD. Thus, when assessing depression in PD, using a depression rating scale like the MADRS, adjusted cut-off scores are required.

Objectives: The relief of cervical dystonia by sensory tricks points at complex sensorimotor interaction. The relation between such stimulus-induced normalization of posture and parietal activation further supports the idea of disturbed higher-order motor control and suggests that the organization of movement is affected beyond the level of a local output channel. Dysbalance beyond a restricted output channel is also supported by the spread of focal dystonia to adjacent body parts. In this fMRI study, we aimed to determine whether cervical dystonia patients have indeed different patterns of cerebral activation during clinically normal hand performance [Naumann M, Magyar-Lehmann S, Reiners K, Erbguth F, Leenders KL. Sensory tricks in cervical dystonia: perceptual dysbalance of parietal cortex modulates frontal motor programming. Ann Neurol 2000;47:322-8].Patients and methods: By means of statistical parametric mapping (SPM) of 3T fMRI results, task-related cerebral activations measured in eight cervical dystonia patients were compared to data of nine healthy volunteers.Results: Compared to controls, the patient group showed a relative reduction of activations in bilateral parietal, left premotor and cingulate cortex regions during imagining of movement, while activation of right (ipsilateral) putamen, insula and cingulate cortex was impaired during movement execution.Conclusion: Cervical dystonia appears to concern a general disorganization of cerebral motor control, which indicates a pre-dystonic state of clinically normal hand movements. The latter may imply an increased vulnerability for deteriorating triggers such as minor accidents. (C) 2007 Elsevier B.V. All rights reserved.

Sequential ordering of purposeful movements includes distinct transitions between muscle contraction and relaxation. To explore cerebral activation patterns underlying such movement initiation and inhibition, we applied functional magnetic resonance imaging to test the effects of (1) ballistic movement (dominated by initiation), (2) movement with stepwise interruption (dominated by inhibition) and (3) smooth movements. Right-hand movements were performed by 21 healthy participants. In the basal ganglia, ballistic movements evoked putamen activation, indicating its specific contribution to initiation. Stepwise interrupted movement induced increased activation of the caudate nucleus, globus pallidus and subthalamic nucleus whereas, at the cortical level, supplementary motor area activation increased. This indicates a specific basal ganglia-thalamocortical circuit involved in motor inhibition.

Motor symptoms form the hallmark of Parkinson's disease (PD), although other features such as depression are often present. Currently-used depression rating scales measure affective and somatic symptoms. These somatic symptoms of depression can also be core PD symptoms, suggesting an overlap of symptoms between depression and PD. Using in vivo radiotracer methods, striatal dopaminergic dysfunction is found in both PD and depression. This study investigates to what extent the overlapping symptoms of depression and PD are associated with the striatal dopaminergic dysfunction typical of PD. Symptoms of depression were assessed in 23 PD patients who did not have major depression according to the Montgomery-angstrom sberg depression rating scale (MADRS; cut-off

We assessed the efficacy of chronic stimulation of the subthalamic nucleus (STN-DBS) in 20 patients with Parkinson's disease (PD) by means of clinical assessments and patient diaries 12 months after surgery. STN-DBS reduced the UPDRS part III off-medication score by 33%, and successively improved complete daily on-time without dyskinesia at 12 months significantly. In conclusion, our study demonstrates the efficacy of chronic STN-DBS on motor features in a selected population of advanced PD patients. In addition to clinical assessments, patients' diaries serve as an essential tool to evaluate the functional motor status after STN-DBS. (c) 2006 Elsevier Ltd. All rights reserved.

Dopamine agonists are used as initial treatment in patients with Parkinson's disease (PD) to reduce incidence and severity of motor complications. This paradigm is based on long-term studies, allowing "rescue" therapy with levodopa. The present strict monotherapy study (PELMOPET, the acronym for the pergolide-versus-L-dopa-monotherapy-and-positron-emission-tomography trial) evaluated the efficacy and safety of pergolide versus levodopa without levodopa "rescue" medication. This multicenter, double-blind, randomized, 3-year trial compared pergolide monotherapy (n=148) with levodopa monotherapy (n=146) in dopamine-naive patients with early PD (Hoehn and Yahr stage 1-2.5). Primary efficacy measures were clinical efficacy, severity and time to onset of motor complications, and disease progression. During the 3 years, severity of motor complications was significantly lower and time to onset of dyskinesia was significantly delayed in the group receiving pergolide (3.23 mg/day) compared with those receiving levodopa (504 mg/day). However, time to onset of motor complications was not longer in patients receiving pergolide after 3 years. Symptomatic relief (assessed by Unified Parkinson's Disease Rating Scale [UPDRS], UPDRS II, and III, Clinical Global Impressions [CGI] severity, and CGI and Patient Global Impressions [PGI] improvement) was significantly greater in patients receiving levodopa. Adverse events led to discontinuation of therapy in 17.6% of pergolide patients and 9.6% of levodopa patients. This is the first study comparing strict monotherapy with a dopamine agonist versus levodopa in previously untreated early PD. In principle, both levodopa and a dopamine agonist such as pergolide seem to be suitable options as initial PD therapy. The choice remains with the treating physician based on the different efficacy and adverse event profiles.

Patients with Parkinson's disease (PD) and levodopa-induced motor complications experience a short-duration response (SDR) to levodopa which can be considered the basis of motor fluctuations. The SDR is characterized by reduced response duration, increased magnitude of the response and reduced latency to the peak effect. A short latency and a high magnitude are the most salient pharmacological features of the SDR. Its pathophysiology is not totally understood. The pharmacological characteristics of the motor response to apomorphine and their relationship with 6-[(18)F]fluoro-L-dopa (FDOPA) and [(11)C]raclopride (RACLO) uptake were studied in 9 patients with PD. Latency to peak effect was positively correlated with putaminal FDOPA uptake (p0.05) and negatively correlated with RACLO uptake (P0.05). A trend towards significance (p:0.06) between magnitude of the response and FDOPA uptake was found which were negatively correlated. Levodopa-induced dyskinesias were negatively correlated with FDOPA uptake (p0.05) and a trend towards significance (positive correlation) with RACLO uptake was observed (p:0.07). These results suggest that both pre and postsynaptic mechanisms are involved in the origin of the SDR.

In the 'normal' ageing brain a decrease in the cerebral metabolic rate has been determined across many brain regions. This study determines whether age differences would affect metabolic rates in regions and different hemispheres of the brain. The regional metabolic rate of glucose (rCMRGlu) was examined in a group of 72 subjects, ages 22 to 82 years, with 36 regions of interest chosen from both hemispheres of the cortex, midbrain and cerebellum. To determine metabolic rates the in-vivo technique of positron emission tomography (PET) was employed. Three age groups were chosen to compare hemispherical differences. In both young and intermediate age groups the left hemisphere had higher rCMRGlu values than those of the right for the majority of regions with, although less pronounced in the intermediate group. Importantly, the older age group displayed little difference between hemispheres.

This study investigated the processing of increasing monetary reward in nonsmoking and smoking subjects. The choice of the subject populations has been motivated by the observation of differences between nonsmokers and smokers in response to rewarding stimuli in a previous study. Subjects performed a pattern recognition task with delayed response, while rCBF was measured with [(H2O)-O-15] PET. Correct responses to the task were reinforced with three different amounts of monetary reward. The subjects received the sum of the rewards at the end of the experiment. The results show that a cortico-subcortical loop, including the dorsolateral prefrontal cortex, the orbitofrontal cortex, the cingulate gyrus and the thalamus is involved in processing increasing monetary reward. Furthermore, the striatal response differentiates nonsmokers from smokers. Thus, we found significant correlations between rCBF increases in striatum and increasing monetary reward and between striatal rCBF increases and mood in nonsmokers, but not in smokers. Moreover, no significant mood changes among the different monetary rewards could be observed in smokers. We infer that the response of the striatum to reward is related to changes in subjective feelings. The differences between smokers and nonsmokers confirm our previous conclusions that the association between blood flow, performance, mood and amount of reward is more direct in nonsmokers.

A simple pharmacokinetic model to explain the time course of [O-15] water in human whole blood after bolus injection is described. The model has been derived from measurements in twelve healthy volunteers who were measured repeatedly, resulting in 67 datasets, made in the context of PET blood flow studies. In contrast to traditional volume of distribution estimates of total body water (TBW) which rely on measurements after many hours, the model and data provide insights into the fast uptake components in the distribution of water in the body. Data fitting shows that the volume of distribution of fast exchanging tissues is 21 l. TBW was calculated to be 37 l. Monte Carlo simulation showed that the expected inaccuracy of determination of parameters due to unsystematic sources in the measurement data was around 5% for most parameters. Our data show that water extraction to tissue is somewhat higher than would be predicted from the tabulated values, probably because skeletal blood flow is sensitive to physiological status and environmental conditions. The study provides valuable reference data on the distribution and kinetics of water in man. Using the parameters and model from this study, reference input time-activity curves can be calculated, e.g. for the Monte Carlo study of error propagation in PET studies.

Parkinson’s disease and parkinsonian disorders can present with a variety of symptoms, and there is often significant overlap between the different disorders. Diagnosis typically relies on clinical examination, especially at follow-up visits, which has limitations. Neuroimaging has played a major role in the elucidation of anatomical and functional abnormalities in different parkinsonian disorders. Various imaging techniques have been investigated for their potential to aid in diagnosis during routine clinical practice. In this chapter, we describe the use of functional imaging with PET and SPECT in the research of parkinsonian syndromes, including multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). We focus on the utility of these imaging techniques to facilitate differential diagnosis and assess disease progression in patients, especially in the early stages of disease.

According to the limited amount of literature available, there is no real difference in diagnostic accuracy between a DaT-SPECT scan and an 18F-FDOPA PET scan nor between an123I-IBZM SPECT and a 11C-raclopride PET. However, while DaT-SPECT and FDOPA PET have gained a role in the clinical evaluation of the parkinsonian patient, especially in the differential diagnosis with other pathologies such as essential tremor, less evidence has been presented for the use of IBZM SPECT in the differential diagnosis of Morbus Parkinson and parkinsonian syndromes. A promising role could be played by 18F-FDG PET or perfusion SPECT in this regard.

Many studies indicate a role of the cerebral dopaminergic reward system in addiction. Motivated by these findings, we examined in opiate addicts whether brain regions involved in the reward circuitry also react to human prototypical rewards. We measured regional cerebral blood flow (rCBF) with (H2O)-O-15 positron emission tomography (PET) during a visuo-spatial recognition task with delayed response in control subjects and in opiate addicts participating in a methadone program. Three conditions were defined by the types of feedback: nonsense feedback; nonmonetary reinforcement; or monetary reward, received by the subjects for a correct response. We found in the control subjects rCBF increases in regions associated with the meso-striatal and meso-corticolimbic circuits in response to both monetary reward and nonmonetary reinforcement. In opiate addicts, these regions were activated only in response to monetary reward. Furthermore, nonmonetary reinforcement elicited rCBF increases in limbic regions of the opiate addicts that were not activated in the control subjects. Because psychoactive drugs serve as rewards and directly affect regions of the dopaminergic system like the striatum, we conclude that the differences in rCBF increases between controls and addicts can be attributed to an adaptive consequence of the addiction process.

5-bromodeoxyuridine (BUdR) provides in vitro measures of tumor cell proliferation. We used positron emission tomography to study tissue and plasma kinetics of [76Br]BUdR in tumor-bearing animals. In order to account for the slow washout of the major plasma metabolite, [76Br]bromide, a mathematical correction for the distribution volume of [76Br]bromide was applied. However, following correction specific tumor tracer retention was low or even zero and did not correlate with independent measures of proliferation. The kinetic characteristics of [76Br]BUdR make this tracer unsuitable for proliferation imaging.

Brain tissue samples, obtained from the Alzheimer Disease Brain Bank,Institute of Psychiatry, London, were taken from both left and right hemispheresof three regions of the cerebrum, namely the frontal, parietal and occipitallobes for both Alzheimer and 'normal' subjects. Trace elementconcentrations in the frontal lobe were determined for twenty six Alzheimer(15 male, 11 female) and twenty six 'normal' (8 male, 18 female)brain tissue samples. In the parietal lobe ten Alzheimer (2 male, 8 female)and ten 'normal' (8 male, 2 female) samples were taken along withten Alzheimer (4 male, 6 female) and ten 'normal' (6 male, 4 female)from the occipital lobe. For the frontal lobe trace element concentrationswere determined using proton induced X-ray emission (PIXE) analysis whilein parietal and occipital regions instrumental neutron activation analysis(INAA) was used. Additionally eighteen Alzheimer (9 male, 9 female) and eighteenage matched 'normal' (8 male, 10 female) living subjects wereexamined using positron emission tomography (PET) in order to determine regionalcerebral metabolic rates of glucose (rCMRGlu). The rCMRGlu of 36 regions ofthe brain was investigated including frontal, occipital and parietal lobesas in the trace element study. Hierarchical cluster analysis was applied tothe trace element and glucose metabolism data to discover which variablesin the resulting dendrograms displayed the most significant separation betweenAlzheimer and 'normal' subjects.

We used positron emission tomography and [C-11]flumazenil to analyze the benzodiazepine receptor binding in symptomatic and asymptomatic carriers of the Huntington's disease gene. We found an inverse relationship between [C-11] flumazenil and [C-11]raclopride binding in the putamen of symptomatic patients, and interpret this result as GABA receptor upregulation.

Cervical dystonia is a disabling basal ganglia disorder characterized by an involuntary head deviation to one side. A typical but also mysterious feature is the impressive improvement of muscle spasms and involuntary head posture by application of a sensory facial stimulus (sensory trick). Here, we report the effect of a sensory trick on cortical activation patterns in 7 patients with cervical dystonia by using H2(15)O positron emission tomography. The application of the sensory trick stimulus, resulting in a near-neutral head position, led to an increased activation mainly of the superior and inferior parietal lobule (ipsilateral to the original head turn) and bilateral occipital cortex and to a decreased activity of the supplementary motor area and the primary sensorimotor cortex (contralateral to the head turn). We propose that a perceptual dysbalance induced by a sensory trick maneuver leads to a relative displacement of the egocentric midvertical reference to the opposite side and a decrease in motor cortex activity. This modulation of motor programming gives novel insights into the mechanisms involved in sensorimotor integration in movement disorders.

Alzheimer's disease (AD) is a debilitating form of dementia which leads to impaired memory, thinking and behavior. This work examines elemental concentrations between "normal" and AD subjects as well as the hemispherical differences within the brain. Tissue samples from both hemispheres of the frontal lobe in both AD and normal subjects were examined for their trace element concentrations using PIXE and RBS analyses. Elemental concentrations were seen to differ between AD and normal brain tissue samples. While in the normal group concentrations were found to be significantly higher in the right hemisphere than in the left the converse was true in AD. A change in elemental concentrations may indicate possible alterations in the function of the blood brain barrier. This was examined by determining regional cerebral metabolic rates of glucose (rCMRGlu) using the in vivo technique of positron emission tomography (PET). Again variations between both hemispheres and between AD and normal were found.

The onset of Alzheimer's disease has been shown to affect trace element concentrations in the brain when compared to "normal" subjects in ex vivo samples. The techniques used to determine trace element concentrations were proton-induced X-ray emission and instrumental neutron activation analysis. With these methods, significant differences are seen between lobes within a hemisphere and between the same lobes of opposing hemispheres for "normal" brains. The change observed in trace element concentrations may indicate a possible alteration in the function of the blood-brain barrier, the effect of which can be investigated in vivo using the imaging technique of positron emission tomography (PET). A PET study was performed on nine female and nine male subjects to determine whether the regional metabolic rate of glucose (rCMRGlu) varied between hemispheres and sex in the Alzheimer diseased brain as was seen in the trace element study. Glucose metabolism was measured using [F-18]-fluorodeoxyglucose (F-18-FDG). Hemispherical differences were observed for the frontal, occipital, parietal lobes, and the temporolateral region in both males and females for rCMRGlu. Variation was also seen between sexes, where the frontal lobe had a lower rCMRGlu in females compared to that of males.

Recent work has shown that it is possible to apply linear kinetic models to dynamic projection data in PET in order to calculate parameter projections. These can subsequently be back-projected to form parametric images - maps of parameters of physiological interest. Critical to the application of these maps, to test for significant changes between normal and pathophysiology, is an assessment of the statistical uncertainty. In this context, parametric images also include simple integral images from, e.g., [O-15]-water used to calculate statistical parametric maps (SPMs). This paper revisits the concept of parameter projections and presents a more general formulation of the parameter projection derivation as well as a method to estimate parameter variance in projection space, showing which analysis methods (models) can be used. Using simulated pharmacokinetic image data we show that a method based on an analysis in projection space inherently calculates the mathematically rigorous pixel variance. This results in an estimation which is as accurate as either estimating variance in image space during model fitting, or estimation by comparison across sets of parametric images - as might be done between individuals in a group pharmacokinetic PET study. The method based on projections has, however, a higher computational efficiency, and is also shown to be more precise, as reflected in smooth variance distribution images when compared to the other methods.