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analyses 123I-ioflupane Discriminating degenerative advanced parkinsonisms SPECT using among

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21.12.2018

Content:

  • analyses 123I-ioflupane Discriminating degenerative advanced parkinsonisms SPECT using among
  • Discriminating among degenerative parkinsonisms using advanced (123)I-ioflupane SPECT analyses.
  • MATERIALS AND METHODS
  • Discriminating among degenerative parkinsonisms using advanced ()I- ioflupane SPECT analyses. Badoud S(1), Van De Ville D(2). Discriminating among degenerative parkinsonisms using advanced I- ioflupane SPECT analyses. Article (PDF Available) in NeuroImage. Discriminating among degenerative parkinsonisms using advanced. I- ioflupane SPECT analyses. Simon Badouda,b,c, Dimitri Van De.

    analyses 123I-ioflupane Discriminating degenerative advanced parkinsonisms SPECT using among

    Potency of ioflupane was much greater than for cocaine IC High binding affinity of ioflupane in human striatum has been shown autoradiographically using a C labeled compound [ 71 ]. High specificity to the presynaptic DAT was demonstrated by competition studies with GBR 12,, the serotonin reuptake inhibitor citalopram and the norepinephrine reuptake inhibitor desipramine in post-mortem human brain slices exposed to radiolabeled ioflupane. Autoradiographically, binding was at high concentrations in the DAT-rich striatum; in other words, the caudate nucleus and the putamen and this binding to the striatum was abolished in the presence of high concentrations of GBR 12, In our own experience, no doses less than MBq 4 mCi should be applied, since lower amounts of activity may have an impact on scan quality and hence, diagnostic performance.

    Overall, imaging agents contain only a small quantity of active compound so that no pharmacologic effects are expected. In general, the DAT-binding tropanes are good markers for the integrity of the nigrostriatal systems. This indicated a high sensitivity of both radiotracers in PD.

    However, [ 18 F]FDOPA demonstrated a higher unspecific uptake that was probably due to extensive compensatory metabolism. Since the uptake of the latter was heavily reduced in degeneration stage two, a downregulation of DAT was hypothesized.

    Another lesion study in rats using [ I]b-CIT and [14C] L-DOPA provides similar results, indicating that the marker of the decarboxylase underestimated the decrease of dopaminergic neurons and that DAT levels more precisely reflected the decrease [ 73 ]. The pharmacokinetics of [ I]FP-CIT were studied by monitoring radioactivity following intravenous injection and whole-body scintigraphy. The striatum-to-background ratio is relatively constant between 3 and 6 h after the injection, meaning that clinical imaging is feasible with comparative results during this time window.

    The biodistribution, metabolism and dosimetry of ioflupane in nonhuman primates and in humans are further described in several papers [ 71 , 80 — 83 ]. Based on published data, it is likely that several drugs of abuse, including cocaine, amphetamines, modafinil, certain antidepressants e. Interestingly, one study showed a significant higher binding in patients with ADP without antiparkinsonian medication in comparison to subjects in drugs-on state [ 23 ].

    A prerequisite for fully utilizing the diagnostic potential of DaTSCAN imaging is, however, good quality control and standardization of the entire procedure, from patient preparation through to positioning, g camera specifications, acquisition, reconstruction parameters and quality control of the acquired data.

    In addition data should be analyzed and reported according to guidelines i. Technical issues with regard to data acquisition comprise correct field of view, rotational radius, energy window set at the photopeak, additional scatter windows if applicable , matrix size and zoom factor, among others. Strict standardizations of acquisition time after radiotracer injection and collection of sufficient numbers of total counts within the acquisition time also have to be considered.

    After reviewing the projection data i. Employing the correct filter is mandatory for either visual or quantitative readings. Attenuation correction is recommended, either with simultaneously or sequentially acquired transmission scans, or calculated, as with a correction matrix, according to Chang [ 86 ].

    For display, images are reformatted into slices in three planes axial, coronal and sagittal. Reorientation makes visual interpretation easier and is essential when semi-quantification is used not least to ensure the right placement of the reference region.

    The anterior commissure-posterior commissure line represents a good anatomical standard here as it is used for brain MRI. A simultaneously acquired CT scan or, alternatively, coregistration with individual MRI by commercial available software e. Visual assessment is robust in detecting presynaptic DAT binding.

    However, in visually uncertain cases and for intergroup, as well as for interinstitutional comparisons, semiquantitative approaches using regions of interest ROIs might help and have been recommended by nuclear medicine associations to be incorporated in the routine work-up of DAT-SPECT.

    With semi-quantification, striatal binding ratios specific striatal binding are calculated by comparing the activity in the target region with the activity in a reference region with a very low DAT-density according to listed formula Box 1. Other parameters are described in Box 1. ROIs are manually drawn on to one or more slices usually three or four adjacent slides with the highest striatal activity.

    This method is simple and provides a quantitative measure to allow comparisons of healthy reference data where an age-dependent decline in healthy volunteers always has to be considered but interobserver variability is considerable due to variability in ROI placement.

    Therefore, it is important to standardize realignment using predefined ROIs. Here, coregistration with individual MRI for delineation of striatal and reference volumes of interest offers the most accurate manual results [ 87 ].

    Besides these observer-dependent approaches, fully-automated image analysis techniques are under validation in the clinical setting and have the potential as tools to improve the diagnostic accuracy and confidence in DAT-SPECT in patients who have parkinsonian features. No adverse event has been directly correlated with the tracer itself. However, several symptoms e. Cost—effectiveness may also derive from the incorrect screening of suitable candidates for drug trials or complex surgical procedures e.

    Some suggestions may derive from asymmetry and diffusion of dopaminergic deficit or from targeting the brainstem. No additional value to the clinical experience is added instead in discriminating between ADPs. Stepwise forward analysis was used to identify possible multiple variables for optimal discrimination, with a decision scheme based on the smallest F ratio maximum significance of F to enter 0. The a priori classification probability was set as being equal to ascertain a conservative estimate.

    Classification performance was initially tested using the training error—that is, by post hoc classification statistics. To estimate a more unbiased and generalized performance measure for new patient cases, the a priori discriminant value or discriminant cross-validity was tested using a classical leave-one-out procedure In this cross-validation CV , each case is classified by the functions derived from all cases other than that case.

    Data presented include CV and are presented as —CV Subject demographic data are given in Table 1 for all patient groups. Disease duration was highest for the essential tremor ET group 7. Disease duration was not significantly different for the neurodegenerative entities. ET patients were characterized by a higher perfusion in the posterior striatum bilaterally, most pronounced on the left side compared with IPD, as well as in the upper parietal cortex bilaterally.

    MSA patients showed a decrease in perfusion bilaterally in the cerebellar cortex and vermis, as well as in the left and right posterior putamen. The inverse contrast did not show cortical or subcortical differences at the aforementioned thresholds.

    PSP patients showed multiple areas of significant hypoperfusion most pronounced in the left prefrontal and supplementary motor area SMA cortex, left periinsular cortex, left caudate, and bilateral rostral anterior cingulate and medial thalamic and mesencephalon. The inverse contrast showed higher relative perfusion in the occipital and right primary motor cortex than IPD. Finally, patients with LBD showed pronounced cortical hypoperfusion in the posterior temporoparietal area bilaterally, most prominent on the right ipsilateral side.

    IPD patients showed a bilateral decrease in CIT binding index over both striatal volumes, most pronounced on the right side and least present in the left caudate head. Note that a lower t-value here does not correspond to lower binding index but is influenced by the larger number of cases in the IPD group.

    Combined CIT and perfusion data resulted in a higher discrimination value of After Tukey's post hoc correction, this value was significantly different between PSP 0. Perfusion imaging as a stand-alone technique allowed separation of However, the combination of both imaging techniques augmented overall classification accuracy to Ellipses show minimal extent of contours that cover all plotted group data. The regions with the largest coefficients in the canonical discriminant functions were cerebellum and posterior putamen for MSA, dorsolateral and prefrontal cortex BA 9, 10, 44, 47 and left caudate for PSP; occipital BA 18, 19 , premotor BA 6 and right , temporoparietal BA 21, 22, 39, 40 areas for LBD.

    Figure 4 shows a box plot comparison for the most discriminating regions to illustrate the quantitative differences between these regional parameters in the disease entities. As in many clinical cases, additional information e. Objective biomarkers have the possibility of allowing an unbiased evaluation of new patients.

    Although there is ongoing debate whether radiotracer-based imaging allows the final diagnosis of IPD or parkinsonian syndromes 28 , individualized molecular imaging has become a crucial contribution in clinical characterization of movement disorder patients, which is of importance in therapy selection and prognosis In this work, we have characterized dual-tracer DAT and perfusion patterns that exist in a patient population referred to a tertiary movement disorder clinic, for the majority of patients relatively early in the disease course.

    The patterns observed for DAT imaging are qualitatively in correspondence with individual studies comparing neurodegenerative parkinsonism and ET. This was also not the case when considering only those patients with a predominant parkinsonian form of MSA MSA-p based on the clinical evaluation and perfusion pattern. In this and other studies using perfusion SPECT ligands, however, there tends to be a pattern of relative striatal hypoperfusion in both early and later disease stages 16 , a finding that is at odds with early hypermetabolism found in FDG PET studies.

    The perfusion pattern observed in PSP with both striatal and widespread frontal hypoperfusion is in correspondence with earlier findings of diminished glucose use in the frontal cortex Also, in LBD, the pattern of hypometabolism in posterior parietal and associated temporal areas 34 was the most discriminating finding for this analysis, but it must be pointed out that this may not be specific for cognitive deficit, as such regional hypometabolism has also been observed in some studies in nondemented IPD patients In our study, no patients in the IPD group presented with overt cognitive impairment.

    An overall problem with imaging biomarkers in the central nervous system is the lack of a gold standard The standard used in this work was based on years of clinical follow-up of the patients by well-described clinical guidelines. However, in the absence of anatomopathologic confirmation, the canonical discriminant functions derived from this work are expected to lead to a diagnostic accuracy that is comparable to a high standard of the specialist long-term evaluation and provide an objective, operator-independent classification in early stage of the disease.

    A second important design item and limitation of the study is that some bias may have been introduced in our findings. Although no quantitative information was available to the referring neurologist, he was not strictly unaware of the qualitative results of SPECT.

    In our opinion, this may have had an impact in a minority of patients in the setting of the differentiation between ET and neurodegenerative causes, where visual interpretation of I-FP-CIT has been shown to give a high discriminatory yield. As for perfusion, however, in the patient work-up these data were not considered in the final clinical diagnosis.

    In the interpretation of functional neuroimaging data, multiple factors such as compensatory mechanisms or effects of the medication themselves, which can modify the results, need to be considered 6. We have not included variables such as disease duration and levels of various medication use at present. However, as the primary aim was to investigate the functional imaging data in a clinical setting, where generally medication is discontinued only for a small number of drugs specifically known to interfere with DAT imaging, such a situation may be less informative from a pathophysiologic viewpoint, but more generally relevant for evaluating new patients.

    From the methodologic viewpoint, the estimates from this study have been made conservatively. First, apart from incorporation of the side of the main clinical symptoms, the pretest likelihood was not based on the clinical picture and all groups were set as equally probable in the discriminant analysis.

    When taking this information into account or adjusting the a priori likelihood of, for example, a distribution more related to clinical prevalence, the overall accuracy of this technique may further improve. The sensitivity of the currently applied technique of VOI-based discriminant analysis may also be augmented by using advanced voxel-based techniques such as logistic discriminant mapping, which was already used in the setting of parkinsonism with 99m Tc-TRODAT imaging 36 , or network analysis techniques such as principal component analysis to evaluate Parkinson's disease-related expression patterns 37 and which may be used for differential diagnostic classification.

    Multitracer imaging has been explored previously with smaller numbers of patients and in specific entities 13 , 18 , Because of the small number, however, the precise contribution to clinical diagnostic accuracy was difficult to assess. In contrast to most previous studies, care was taken here to provide also cross-validated results as a more unbiased predictor for future novel cases, because it is well known that discriminant analysis without CV can yield overly optimistic discrimination values Recently, Eckert et al.

    Advantages of this approach are the higher spatial resolution and single-scan approach; however, a potential disadvantage is that an operator-dependent factor of pattern recognition is still necessary, in contrast to discriminant analysis, which automatically provides classification probabilities for the disease entities.

    However, as can be seen from the above analysis, this increases the discriminating power because of the pathophysiologic alterations in the posterior putamen that are especially pronounced in MSA-p and the gradients that exist in the selective nigrostriatal affliction in IPD and PSP.

    Although our study is useful for pathophysiologic interpretation, a limitation is that we have not included a healthy volunteer control group, because of the absence of a validated control population for I-FP-CIT. Finally, in contrast to DAT imaging procedures using voxel-based analysis with anatomic standardization, we have used an indirect approach of anatomic standardization of DAT images, which may have offered some advantages.

    In the current study this potential problem was circumvented by initially applying a rigid transformation to the DAT data to fit the perfusion data, after which an accurate nonlinear transformation could be made.

    In this study we have validated an automated technique of using clinically available combined perfusion and DAT SPECT and studied its contribution in the differential diagnosis of parkinsonism under clinical circumstances. This technique may supplement confidence of existing clinical measures at an earlier stage for such differential diagnosis and, thus, also for prognosis assessment and selection for therapeutic trials.

    Even though CV was applied in this study and values found should be robust for novel cases, prospective confirmation of these data is currently being studied. Also, for widespread clinical use it should be demonstrated whether the technique and transfer of the canonical discriminant functions derived from this patient set to other nuclear medicine centers is feasible and retains the same discrimination accuracy.

    The authors thank Dr. Jimmy Vandeneynden for his contribution in data collection and preprocessing. Leuven, Leuven, Belgium For correspondence or reprints contact: Previous Section Next Section. Subjects In total, patients were studied in this cross-sectional, single-center study: Subject Demographics Subject demographic data are given in Table 1 for all patient groups.

    In this window In a new window. ET Versus Degenerative Disorders. Separation of Atypical Parkinsonism: CrossRef Medline Google Scholar.

    Accuracy of clinical diagnosis of idiopathic Parkinson's disease: J Neurol Neurosurg Psychiatry. Improved accuracy of clinical diagnosis of Lewy body Parkinson's disease.

    Piccini P, Whone A. Functional brain imaging in the differential diagnosis of Parkinson's disease. Frontal, midbrain and striatal dopaminergic function in early and advanced Parkinson's disease: PET studies on the function of dopamine in health and Parkinson's disease. Ann N Y Acad Sci.

    Discriminating among degenerative parkinsonisms using advanced (123)I-ioflupane SPECT analyses.

    Discriminating among degenerative parkinsonisms using advanced I- ioflupane SPECT analyses. @inproceedings{BadoudDiscriminatingAD. Discriminating among degenerative parkinsonisms using advanced I- ioflupane SPECT analyses. Overview of attention for article published in NeuroImage. I-Ioflupane/SPECT binding to striatal dopamine transporter (DAT) uptake in patients with Parkinson's disease, multiple system atrophy Discriminating among degenerative parkinsonisms using advanced ()Iioflupane SPECT analyses.

    MATERIALS AND METHODS



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    xzaxtorx

    Discriminating among degenerative parkinsonisms using advanced I- ioflupane SPECT analyses. @inproceedings{BadoudDiscriminatingAD.

    Pebhoctb23

    Discriminating among degenerative parkinsonisms using advanced I- ioflupane SPECT analyses. Overview of attention for article published in NeuroImage.

    quiny

    I-Ioflupane/SPECT binding to striatal dopamine transporter (DAT) uptake in patients with Parkinson's disease, multiple system atrophy Discriminating among degenerative parkinsonisms using advanced ()Iioflupane SPECT analyses.

    rastafarsh18

    P.R., Haller, S.: Discriminating among degenerative parkinsonisms using advanced I-ioflupane SPECT analyses. NeuroImage: Clin. 12, – ( ) 2.

    doomcrayer

    Discriminating among degenerative parkinsonisms using advanced I- ioflupane SPECT analyses. Simon Badoud; Dimitri Van De Ville; Nicolas Nicastro ;.

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