Statistical modeling of positron emission tomography images in wavelet space.

A new method is introduced for the analysis of multiple studies measured with emission tomography. Traditional models of statistical analysis (ANOVA, ANCOVA and other linear models) are applied not directly on images but on their correspondent wavelet transforms. Maps of model effects estimated from these models are filtered using a thresholding procedure based on a simple Bonferroni correction and then reconstructed. This procedure inherently represents a complete modeling approach and therefore obtains estimates of the effects of interest (condition effect, difference between conditions, covariate of interest, and so on) under the specified statistical risk. By performing the statistical modeling step in wavelet space. the procedure allows the direct estimation of the error for each wavelet coefficient; hence, the local noise characteristics are accounted for in the subsequent filtering. The method was validated by use of a null dataset and then applied to typical examples of neuroimaging studies to highlight conceptual and practical differences from existing statistical parametric mapping approaches.     

Modeling dynamic PET-SPECT studies in the wavelet domain.

This work develops a theoretical framework and corresponding algorithms for the modeling of dynamic PET-SPECT studies both in time and space. The problem of estimating the spatial dimension is solved by applying the wavelet transform to each scan of the dynamic sequence and then performing the kinetic modeling and statistical analysis in the wavelet domain. On reconstruction through the inverse wavelet transform, one obtains parametric images that are consistent estimates of the spatial patterns of the kinetic parameter of interest. The theoretical setup allows the use of linear techniques currently used in PET-SPECT for kinetic analysis. The method is applied to artificial and real data sets. The application to dynamic PET-SPECT studies was performed both for validation purposes, when the spatial patterns are known, and for illustration of the advantages offered by the technique in case of tracers with an unknown pattern of distribution.     

Positron emission tomography studies in parkinsonism.

PET imaging is a rapidly expanding technique with growing clinical utility. In this review, we have discussed the contribution of functional neuroimaging with PET in elucidating the pathophysiology of parkinsonism. In addition, we emphasize the growing role of this technique in the clinical setting. FDG/PET has become increasingly available at major medical centers and is especially suitable as an aid in the clinical assessment of patients with akinetic-rigid or other movement disorders. Although this technique is essentially quantitative and ideally suited for broad population studies, qualitative and semiquantitative approaches may suffice in the evaluation of individual patients. To the extent that several of the functional imaging models are linear with raw count rates, blood sampling may not be needed in each instance. Moreover recent advances in SPECT perfusion imaging may permit the extension of PET diagnostic criteria to other imaging modalities that are less costly and more accessible in the community setting. New statistical methods for the detection of regional metabolic covariation patterns hold special promise for the development of disease-specific imaging markers, which may permit rapid differential diagnosis, improved drug trials, and possible preclinical detection. F-dopa/PET has provided many important in vivo insights into the nigrostriatal dopamine system and its role in the development of parkinsonism. In contrast to FDG/PET, this technique demands specialized radiochemistry, plasma analysis, and modeling approaches that currently restrict its applicability to a few research PET centers. Several promising developments in radiochemical synthesis, data acquisition, and kinetic modeling may simplify the technique sufficiently to be used in the clinical domain. F-dopa/PET holds particular promise in preclinical screening of individuals at risk for Parkinson's disease on genetic or environmental grounds. This has great significance in view of the concurrent availability of potentially neuroprotective pharmaceuticals. Similarly this technique has great potential in objectively measuring rates of disease progression in normal and treated populations. We believe that with greater availability, these PET techniques and others currently under development will have significant impact on the diagnosis and management of patients with Parkinson's disease and related disorders.     

Positron emission tomography receptor studies in epilepsy.

Investigations with specific PET ligands that bind to specific neuro-receptors give information on abnormalities of neurotransmission involved in the pathophysiology of the epilepsies. Data need to be interpreted in the light of optimal structural imaging. Objective voxel-based and region-based analyses, with correction of partial volume effect, are complementary. Central benzodiazepine (cBZR) and opioid receptors have been studied most. Reduced cBZR binding is commonly seen at an epileptic focus, in a more restricted distribution than an area of hypometabolism, and sometimes also in projection areas. In contrast to acquired lesions causing partial seizures, focal increases in cBZR binding have been demonstrated in malformations of cortical development and also in areas of brain that appear normal on MRI, indicating the widespread nature of the abnormalities. Focal abnormalities of cBZR are also commonly found in patients with partial seizures and normal MRI. It is not yet clear how useful these data will prove to be in presurgical evaluation. Mu- and delta-opioid receptors have been found to be increased in temporal neocortex overlying mesial temporal epileptic foci, but with different patterns of increase. Dynamic studies of the binding of 11C-diprenorphine to opioid receptors are possible using PET, and have implied the release of cerebral endogenous opioids at the time of serial absences and reflex seizures induced by reading. Other tracers, that have been applied less widely, label the enzyme monoamine oxidase type B and peripheral benzodiazepine and histamine H1 receptors.     

Positron emission tomography in juvenile Alexander disease.

A 13-year-old boy with cervical kyphosis was diagnosed as having juvenile Alexander disease because of the typical MRI findings, abnormally elevated alphaB-crystallin and heat shock protein 27 in the cerebrospinal fluid. Positron emission tomography with 18F-fluorodeoxyglucose demonstrated hypometabolism in the frontal white matter corresponding to the areas with leukodystrophy. However, the overlying gray matter preserved normal glucose metabolism.     

Single-photon emission computed tomography of the dopamine transporter in parkinsonism.

The known dopaminergic abnormalities in Parkinson's disease have facilitated the development of radiolabeled biomarkers for diagnostic and research applications in humans. Presynaptic, intrasynaptic, and postsynaptic imaging now is possible using single-photon emission computed tomography. In particular, the development of new radiotracers that target the dopamine transporter located on degenerating dopamine neurons in Parkinson's disease and related disorders is directly relevant to improved clinical diagnosis, disease monitoring, and assessment of putative neuroprotective strategies in patients. In addition, the ability to characterize in vivo neuronal degeneration in these disorders provides a powerful research tool to better understand the natural course of these disorders and could provide clues to etiology.     

Thalamocortical diaschisis: positron emission tomography in humans.

To investigate further the relations between cortical energy metabolism and neuropsychological impairment after unilateral thalamic lesion, 55 patients underwent positron emission tomography studies of either cortical oxygen consumption or glucose utilisation, including eight repeat studies, at times ranging from 4 days to 98 months after the onset of the lesion [stroke (n = 44) or stereotaxic VL-Vim thalamotomy performed for movement disorders (n = 11)]. Patients with thalamotomy were also studied preoperatively and the surgery induced a significant fall in cortical metabolism on both sides (more so ipsilaterally); post-operatively the magnitude of the ipsilateral cortex hypometabolism was positively correlated to the severity of global neuropsychological impairment; similar but less significant findings were obtained for the ipsilateral/contralateral cortical metabolic asymmetry. With respect to the whole patient sample, the cortical metabolic asymmetry was initially pronounced, with subsequent monoexponential recovery, in the cognitively impaired study group, but it was only mild and showed no meaningful trend for recovery in the cognitively unaffected study group; yet even soon (< 3 months) after thalamic lesion there was a noticeable overlap of individual asymmetry values among the two study groups. These results lend further support to the view that the neuropsychological impairment that frequently follows unilateral thalamic lesions is reflected in a depression of synaptic activity in both the overlying and the contralateral cerebral cortices. For individual patients, this study also illustrates the potentially misleading nature of the measured cortical metabolic asymmetry with respect to neuropsychological status, especially at late times after lesion, in part because side to side metabolic ratios do not reflect bilateral changes.     

Single-photon emission computed tomography in distal field hypoperfusion.

To assess the ability of technetium-99m hexamethylpropyleneamineoxime single-photon emission computed tomography (SPECT) imaging to differentiate distal field hypoperfusion from other stroke mechanisms, 24 patients with acute cerebral ischemia were studied. SPECT scans were read by two physicians according to a preestablished set of criteria for distal field hypoperfusion. SPECT patterns read as "probable" or "definite" for distal field hypoperfusion were found in 42% (10/24); of these, 80% (8/10) had ipsilateral carotid occlusion or high-grade stenosis. Severe carotid stenosis was found in 43% (6/14) with SPECT scans negative for distal field hypoperfusion (Fisher exact test [1-tailed] p = 0.0796). The results suggest that a distal field hypoperfusion pattern on SPECT may identify patients with hemodynamically significant large vessel disease.     

Positron emission tomography of the brain

Positron emission tomography (PTE) is a technique that allows imaging of the temporal and spatial distribution of positron-emitting radionuclides. The purpose of this article is to outline the current clinical use for PET imaging in the brain and other radiopharmaceutical used for assessing various physiologic parameters pertaining to tumor metabolism.     

Positron emission tomography in neuropsychology

By positron emission tomography (PET) of 18F-2-fluoro-2-deoxy-D-glucose (FDG) local cerebral metabolic rate for glucose (LCMRGl) can be measured in man. Normal values in cerebral cortex and basal ganglia range from 35 to 50 mumol/100 g/min, the values in gray matter structures of the posterior fossa were 25-30 mumol/100 g/min, the lowest LCMRGl was found in the white matter (15-20 mumol/100 g/min). During sensory stimulation by various modalities functional activation increases LCMRGl in the respective special areas, while sleep decreases metabolic rate in all cortical and basal gray matter structures. In many neurological disorders CMRGl is altered in a disease-specific pattern. In dementia of the Alzheimer type CMRGl is impaired even in early stages with accentuation in the parieto-temporal cortex, while in multi-infarct dementia glucose uptake is mainly reduced in the multifocal small infarcts. In Huntington's chorea the most conspicuous changes are found in the caudate nucleus and putamen. In cases of focal lesions (e.g. ischemic infarcts) metabolic disturbances extend far beyond the site of the primary lesion and inactivation of metabolism is found in intact brain structures far away from the anatomical lesion. Additional applications of PET include determination of the metabolism of various substrates, of protein synthesis, of function and distribution of receptors, of tumor growth and of the distribution of drugs as well as the measurement of oxygen consumption, blood flow and blood volume.     

(15)O water positron emission tomography in language localization: a study comparing positron emission tomography visual and computerized region of interest analysis with the Wada test.

We compared (15)O water positron emission tomography (PET) auditory and visual confrontational naming activation with an intracarotid amobarbital (Amytal) injection procedure (IAP) for language lateralization in 12 patients with intractable epilepsy. PET scans were evaluated by three raters experienced in functional imaging as well as by a region of interest (ROI) approach. Compared with IAP, raters' positive predictive value for language lateralization ranged from 88 to 91%. ROI analysis had a positive predictive value of 80%. Six patients had surgery; 1 with right-sided IAP language dominance but left-sided PET activation had dysphasia for 6 months after left temporal lobectomy.     

Instrumentation in positron emission tomography

The past 40 years have seen PET scanning evolve from a tool that was used predominantly for research to a valued clinical, imaging modality. Current PET scanners must perform high quality, whole-body, as well as brain, PET. There are several levels of PET devices that range from the dedicated, high-end scanners down to the hybrid PET-SPECT systems that offer varying levels of performance. The incorporation of PET into single, hybrid, multi-modality units that can provide functional and anatomic information is becoming extremely popular. Several manufacturers now provide hybrid PET-CT scanners. There is also a growing interest in dedicated devices for specific applications, such as high-resolution scanners for imaging small animals.     

Positron emission tomography of the cerebellum in autism

On the basis of neurological evidence that autistic patients have fewer Purkinje and granule cells in the cerebellum as well as vermal cerebellar hypoplasia, the authors tested the hypothesis that autistic patients have cerebellar hypofunctioning. They used positron emission tomography of the cerebellum with 18F-labeled 2-deoxyglucose to study seven autistic patients and eight age-matched control subjects. The results showed no significant difference in mean cerebellar glucose metabolism between the two groups, but all mean glucose rates of the autistic patients were either equal to or greater than those of the control subjects. The implications of these findings are discussed.     

Positron emission tomography and single-photon emission computed tomography in central nervous system drug development

In this review, the value of functional imaging [positron emission tomography (PET)/single-photon emission computed tomography (SPECT)] in drug development is considered. Radionuclide imaging can help establish the diagnosis of neurodegenerative disorders where this is in doubt and provides a potential biomarker for following drug effects on disease progression. PET and SPECT can help understand mechanisms of disease and determine the functional effects of therapeutic approaches on neurotransmission and metabolism. Synthesizing radiotracer analogs of novel drugs can provide proof of principle that these agents reach their enzyme or receptor targets and delineate their regional brain distribution. If such radiotracers do not prove to have ideal properties for imaging, the concept of microdosing potentially allows multiple other drug analogs to be tested with less stringent regulatory requirements than for novel medicinals. Finally, PET tracers can provide receptor and enzyme active site dose occupancy profiles, thereby guiding dosage selection for phase 1 and phase 2 trials. The eventual hope is that radiotracer imaging will provide a surrogate marker for drug efficacy, although this has yet to be realized, and progress the concept of personalized medicine where receptor/enzyme binding profiles help predict therapeutic outcome.