Neuroinflammatory glial response may contribute to degenerative processes in Parkinson's disease (PD). To investigate changes in microglial activity associated with changes in the presynaptic dopamine transporter density in the PD brain in vivo, we studied 10 early-stage drug-naive PD patients twice using positron emission tomography with a radiotracer for activated microglia [(11)C](R)-PK11195 and a dopamine transporter marker [(11)C]CFT. Quantitative levels of binding potentials (BPs) of [(11)C](R)-PK11195 and [(11)C]CFT in the nigrostriatal pathway were estimated by compartment analyses. The levels of [(11)C](R)-PK11195 BP in the midbrain contralateral to the clinically affected side were significantly higher in PD than that in 10 age-matched healthy subjects. The midbrain [(11)C](R)-PK11195 BP levels significantly correlated inversely with [(11)C]CFT BP in the putamen and correlated positively with the motor severity assessed by the Unified Parkinson's Disease Rating Scale in PD. In healthy subjects, the [(11)C](R)-PK11195 BP in the thalamus and midbrain showed an age-dependent increase. In vivo demonstration of parallel changes in microglial activation and corresponding dopaminergic terminal loss in the affected nigrostriatal pathway in early PD supports that neuroinflammatory responses by intrinsic microglia contribute significantly to the progressive degeneration process of the disease and suggests the importance of early therapeutic intervention with neuroprotective drugs.

Microglial activation and dopamine terminal loss in early Parkinson's disease.

PET is widely considered the most sensitive technique available for noninvasively studying physiology, metabolism, and molecular pathways in the living human being. However, the utility of PET, being a photon-deficient modality, remains constrained by factors including low signal-to-noise ratio, long imaging times, and concerns about radiation dose. Two developments offer the potential to dramatically increase the effective sensitivity of PET. First by increasing the geometric coverage to encompass the entire body, sensitivity can be increased by a factor of about 40 for total-body imaging or a factor of about 4-5 for imaging a single organ such as the brain or heart. The world's first total-body PET/CT scanner is currently under construction to demonstrate how this step change in sensitivity affects the way PET is used both in clinical research and in patient care. Second, there is the future prospect of significant improvements in timing resolution that could lead to further effective sensitivity gains. When combined with total-body PET, this could produce overall sensitivity gains of more than 2 orders of magnitude compared with existing state-of-the-art systems. In this article, we discuss the benefits of increasing body coverage, describe our efforts to develop a first-generation total-body PET/CT scanner, discuss selected application areas for total-body PET, and project the impact of further improvements in time-of-flight PET.

https://jnm.snmjournals.org/content/jnumed/early/2017/09/21/jnumed.116.184028.full.pdf

Total-Body PET: Maximizing Sensitivity to Create New Opportunities for Clinical Research and Patient Care.

Reliable attenuation correction represents an essential component of the long chain of modules required for the reconstruction of artifact-free, quantitative brainpositron emission tomography(PET)images. In this work we demonstrate the proof of principle of segmented magnetic resonance imaging (MRI)-guided attenuation and scatter corrections in three-dimensional (3D) brainPET. We have developed a method for attenuation correction based on registered T1-weighted MRI, eliminating the need of an additional transmission (TX) scan. The MRimages were realigned to preliminary reconstructions of PET data using an automatic algorithm and then segmented by means of a fuzzy clustering technique which identifies tissues of significantly different density and composition. The voxels belonging to different regions were classified into air, skull, brain tissue and nasal sinuses. These voxels were then assigned theoretical tissue-dependent attenuation coefficients as reported in the ICRU 44 report followed by Gaussian smoothing and addition of a good statistics bed image. The MRI-derived attenuation map was then forward projected to generate attenuation correction factors (ACFs) to be used for correcting the emission (EM) data. The method was evaluated and validated on 10 patient data where TX and MRIbrainimages were available. Qualitative and quantitative assessment of differences between TX-guided and segmented MRI-guided 3D reconstructions were performed by visual assessment and by estimating parameters of clinical interest. The results indicated a small but noticeable improvement in image quality as a consequence of the reduction of noise propagation from TX into EM data. Considering the difficulties associated with preinjection TX-based attenuation correction and the limitations of current calculated attenuation correction, MRI-based attenuation correction in 3D brainPET would likely be the method of choice for the foreseeable future as a second best approach in a busy nuclear medicine center and could be applied to other functional brainimaging modalities such as SPECT.

/pdf/magnetic-resonance-imaging-guided-attenuation-and-scatter-jciqrrgg3t.pdf

Magnetic resonance imaging-guided attenuation and scatter corrections in three-dimensional brain positron emission tomography.

Context In animals, methamphetamine is known to have a neurotoxic effect on serotonin neurons, which have been implicated in the regulation of mood, anxiety, and aggression. It remains unknown whether methamphetamine damages serotonin neurons in humans. Objective To investigate the status of brain serotonin neurons and their possible relationship with clinical characteristics in currently abstinent methamphetamine abusers. Design Case-control analysis. Setting A hospital research center. Participants Twelve currently abstinent former methamphetamine abusers (5 women and 7 men) and 12 age-, sex-, and education-matched control subjects recruited from the community. Interventions The brain regional density of the serotonin transporter, a structural component of serotonin neurons, was estimated using positron emission tomography and trans -1,2,3,5,6,10-beta-hexahydro-6-[4-(methylthio)phenyl]pyrrolo-[2,1-a]isoquinoline ([ 11 C](+)McN-5652). Estimates were derived from region-of-interest and statistical parametric mapping methods, followed by within-case analysis using the measures of clinical variables. Main Outcome Measures The duration of methamphetamine use, the magnitude of aggression and depressive symptoms, and changes in serotonin transporter density represented by the [ 11 C](+)McN-5652 distribution volume. Results Methamphetamine abusers showed increased levels of aggression compared with controls. Region-of-interest and statistical parametric mapping analyses revealed that the serotonin transporter density in global brain regions (eg, the midbrain, thalamus, caudate, putamen, cerebral cortex, and cerebellum) was significantly lower in methamphetamine abusers than in control subjects, and this reduction was significantly inversely correlated with the duration of methamphetamine use. Furthermore, statistical parametric mapping analyses indicated that the density in the orbitofrontal, temporal, and anterior cingulate areas was closely associated with the magnitude of aggression in methamphetamine abusers. Conclusions Protracted abuse of methamphetamine may reduce the density of the serotonin transporter in the brain, leading to elevated aggression, even in currently abstinent abusers.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/209191/yoa40481.pdf

Brain Serotonin Transporter Density and Aggression in Abstinent Methamphetamine Abusers

There have been major advances in PET technology that cumulatively have helped improve image quality, increased the range of applications for PET, and contributed to the more widespread use of PET. Examples of these technologic advances include whole-body imaging, 3-dimensional imaging, new scintillator materials, iterative reconstruction algorithms, combined PET/CT, and preclinical PET. New advances on the immediate horizon include the reintroduction of time-of-flight PET, which takes advantage of the favorable timing properties of newer scintillators; the integration of PET and MRI scanners into a dual-modality imaging system; and the possibility of further significant improvements in spatial resolution in preclinical PET systems. Sensitivity remains a limiting factor in many PET studies. Although, conceptually, huge gains in sensitivity are still possible, realizing these gains is thwarted largely by economic rather than scientific concerns. Predicting the future is fraught with difficulty; nonetheless, it is apparent that ample opportunities remain for new development and innovation in PET technology that will be driven by the demands of molecular medicine, notably sensitive and specific molecular diagnostic tools and the ability to quantitatively monitor therapeutic entities that include small molecules, peptides, antibodies, nanoparticles, DNA/RNA, and cells.

https://jnm.snmjournals.org/content/jnumed/47/11/1735.full.pdf

The 2006 Henry N. Wagner Lecture: Of Mice and Men (and Positrons)—Advances in PET Imaging Technology

A high-resolution positron emission tomography (PET) scanner dedicated to brain studies has been developed and its physical performance was evaluated. The block detector consists of a new compact position-sensitive photomultiplier tube (PS-PMT, Hamamatsu R7600-C12) and an 8/spl times/4 bismuth germanate (BGO) array. The size of each crystal is 2.8 mm/spl times/6.55 mm/spl times/30 mm. The system has a total of 11 520 crystals arranged in 24 detector rings 508 mm in diameter (480 per ring). The field of view (FOV) is 330 mm in diameter/spl times/163 mm, which is sufficient to measure the entire human brain. The diameter of the scanner's opening is equal to the transaxial FOV (330 mm). The system can be operated in three-dimensional (3-D) data acquisition mode, when the slice septa are retracted. The mechanical motions of the gantry and bed are specially designed to measure the patient in various postures; lying, sitting, and even standing postures. The spatial resolution of 2.9 mm in both the transaxial and axial directions is obtained at the center of the FOV. The total system sensitivity is 6.4 kc/s/kBq/ml in two-dimensional (2-D) mode, with a 20-cm-diameter cylindrical phantom. The imaging capabilities of the scanner were studied with the Hoffman brain phantom and with a normal volunteer.

A new high resolution PET scanner dedicated to brain research

A new positron emission tomography (PET) scanner for whole-body studies has been developed. The scanner has 720 block detectors, each of which consists of a flat panel position-sensitive photomultiplier and a 16/spl times/8 BGO crystal array. The detector system is composed of 12 layers of block detector rings stacked axially, and each ring consists of a circular array of 60 block detectors. Since each block detector ring contains eight crystal rings, the total number of detector rings is 96 and the axial field of view (FOV) is 685 mm, which is sufficient to measure a whole-body with two steps of scan. The detector ring diameter is 1 020 mm and the transaxial FOV is 600 mm in diameter. Coarse slice septa are placed between the block detector rings, which are effective to reduce scattered coincidence events while keeping a high detection sensitivity. Parallel 16 personal computers are used for the data acquisition and processing to deal with a large amount of event data. The acquired data in 3-D manner are converted to 2-D data set with Fourier rebinning algorithm and reconstructed with a fast iterative algorithm "DRAMA". The reconstructed images for the whole body are obtained within 5 min after the scan. By using the coarse septa, the scatter fraction measured with NEMA NU2-2001 standard was 31.4% whose value was significantly lower than that of 3-D PET without septa. The system sensitivity was 9.72 cps/kBq, and the peak counts of the noise equivalent count rate used with direct random-subtraction was 113.6 kcps at 10.5 kBq/ml.

A high-throughput whole-body PET scanner using flat panel PS-PMTs

A small animal PET scanner using 256-channel PS-PMTs has been designed, constructed, and evaluated. The scanner has twelve detector modules, each of which consists of a double-layer array of LYSO crystals and three PS-PMTs (Hama- matsu R8400-00-M256). In the LYSO crystal block, 32 times 53 crystal elements are optically coupled to 32 times 54 crystal elements with a shift of half the element pitch in the axial direction. The dimension of each crystal element is 1.275 times 2.675 mm2 in cross section and 7 mm in depth. The twelve detector modules are positioned on a 182 mm diameter ring to form 107 detector rings with 1.4 mm pitch. The transaxial FOV is 100 mm in diameter and the axial FOV is 151 mm, which is sufficient to cover the whole body of a mouse. In order to compensate for non-uniform outputs from the multi-anodes of the PS-PMTs, ASICs having 64-channel variable gain amplifiers and summing amplifiers are used in the front-end circuits. The preliminary experimental results are the transaxial resolution of 2.0 mm FWHM in the CFOV, and the axial resolution of 2.8 mm FWHM on the axis of the ring. The absolute coincidence sensitivity is 8.1% for a point source at the CFOV with setting an energy window of 350-750 keV and a timing window of 10 ns. The applicable imaging capability of the scanner was demonstrated by animal studies with a rat.

Development of a Small Animal PET Scanner Using DOI Detectors

A new PET scanner having coarse septa provides high sensitivity with suppressing single and scattered events. Data correction and normalization methods for the PET scanner have been developed, which include a new scatter correction method utilizing measured scatter event data, component-based normalization for the detector sensitivity and segmentation attenuation correction using X-ray CT scanner data. Some coincidence lines among the detectors are intercepted by the coarse septa. The data intercepted by the septa, shady data, mostly consist of scatter events, while those not intercepted by the septa, sunny data, include both true and scatter events. Thus the scatter components can be corrected by the subtraction of the shady data from the sunny data. Preliminary studies of new scatter correction were performed with phantoms.

M. Takahashi

Papers

A new high resolution PET scanner dedicated to brain research

A high-throughput whole-body PET scanner using flat panel PS-PMTs

Development of a Small Animal PET Scanner Using DOI Detectors

Data correction and normalization for a new PET scanner having coarse septa