[1-11C]-Butanol Positron Emission Tomography reveals an impaired brain to nasal turbinates pathway in aging amyloid positive subjects.

BACKGROUND: Reduced clearance of cerebrospinal fluid (CSF) has been suggested as a pathological feature of Alzheimer's disease (AD). With extensive documentation in non-human mammals and contradictory human neuroimaging data it remains unknown whether the nasal mucosa is a CSF drainage site in humans. Here, we used dynamic PET with [1-11C]-Butanol, a highly permeable radiotracer with no appreciable brain binding, to test the hypothesis that tracer drainage from the nasal pathway reflects CSF drainage from brain. As a test of the hypothesis, we examined whether brain and nasal fluid drainage times were correlated and affected by brain amyloid. METHODS: 24 cognitively normal subjects (≥ 65 years) were dynamically PET imaged for 60 min. using [1-11C]-Butanol. Imaging with either [11C]-PiB or [18F]-FBB identified 8 amyloid PET positive (Aß+) and 16 Aß- subjects. MRI-determined regions of interest (ROI) included: the carotid artery, the lateral orbitofrontal (LOF) brain, the cribriform plate, and an All-turbinate region comprised of the superior, middle, and inferior turbinates. The bilateral temporalis muscle and jugular veins served as control regions. Regional time-activity were used to model tracer influx, egress, and AUC. RESULTS: LOF and All-turbinate 60 min AUC were positively associated, thus suggesting a connection between the brain and the nose. Further, the Aß+ subgroup demonstrated impaired tracer kinetics, marked by reduced tracer influx and slower egress. CONCLUSION: The data show that tracer kinetics for brain and nasal turbinates are related to each other and both reflect the amyloid status of the brain. As such, these data add to evidence that the nasal pathway is a potential CSF drainage site in humans. These data warrant further investigation of brain and nasal contributions to protein clearance in neurodegenerative disease.

Depth-encoding using optical photon TOF in a prism-PET detector with tapered crystals.

BACKGROUND: High-resolution brain positron emission tomography (PET) scanner is emerging as a significant and transformative non-invasive neuroimaging tool to advance neuroscience research as well as improve diagnosis and treatment in neurology and psychiatry. Time-of-flight (TOF) and depth-of-interaction (DOI) information provide markedly higher PET imaging performance by increasing image signal-to-noise ratio and mitigating spatial resolution degradation due to parallax error, respectively. PET detector modules that utilize light sharing can inherently carry DOI information from the multiple timestamps that are generated per gamma event. The difference between two timestamps that are triggered by scintillation photons traveling in opposite directions signifies the event's depth-dependent optical photon TOF (oTOF). However, light leak at the crystal-readout interface substantially degrades the resolution of this oTOF-based depth encoding. PURPOSE: We demonstrate the feasibility of oTOF-based depth encoding by mitigating light leak in single-ended-readout Prism-PET detector modules using tapered crystals. Minimizing light leak also improved both energy-based DOI and coincidence timing resolutions. METHODS: The tapered Prism-PET module consists of a 16  × $\times$  16 array of 1.5  × $\times$  1.5  × $\times$  20  mm 3 ${\rm {mm}}^3$ lutetium yttrium oxyorthosillicate (LYSO) crystals, which are tapered down to 1.2  × $\times$  1.2  mm 2 ${\rm {mm}}^2$ at the crystal-readout interface. The LYSO array couples 4-to-1 to an 8  × $\times$  8 array of 3  × $\times$  3  mm 2 ${\rm {mm}}^2$ silicon photomultiplier (SiPM) pixels on the tapered end and to a segmented prismatoid light guide array on the opposite end. Performance of tapered and non-tapered Prism-PET detectors was experimentally characterized and evaluated by measuring flood histogram, energy resolution, energy-, and oTOF-based DOI resolutions, and coincidence timing resolution. Sensitivities of scanners using different Prism-PET detector designs were simulated using Geant4 application for tomographic emission (GATE). RESULTS: For the tapered (non-tapered) Prism-PET module, the measured full width at half maximum (FWHM) energy, timing, energy-based DOI, and oTOF-based DOI resolutions were 8.88 (11.18)%, 243 (286) ps, 2.35 (3.18) mm, and 5.42 (13.87) mm, respectively. The scanner sensitivities using non-tapered and tapered crystals, and 10 rings of detector modules, were simulated to be 30.9 and 29.5 kcps/MBq, respectively. CONCLUSIONS: The tapered Prism-PET module with minimized light leak enabled the first experimental report of oTOF-based depth encoding at the detector module level. It also enabled the utilization of thinner (i.e., 0.1 mm) inter-crystal spacing with barium sulfate as the reflector while also improving energy-based DOI and timing resolutions.

A conformal TOF-DOI Prism-PET prototype scanner for high-resolution quantitative neuroimaging.

BACKGROUND: Positron emission tomography (PET) has had a transformative impact on oncological and neurological applications. However, still much of PET's potential remains untapped with limitations primarily driven by low spatial resolution, which severely hampers accurate quantitative PET imaging via the partial volume effect (PVE). PURPOSE: We present experimental results of a practical and cost-effective ultra-high resolution brain-dedicated PET scanner, using our depth-encoding Prism-PET detectors arranged along a compact and conformal gantry, showing substantial reduction in PVE and accurate radiotracer uptake quantification in small regions. METHODS: The decagon-shaped prototype scanner has a long diameter of 38.5 cm, a short diameter of 29.1 cm, and an axial field-of-view (FOV) of 25.5 mm with a single ring of 40 Prism-PET detector modules. Each module comprises a 16 × 16 array of 1.5 × 1.5 × 20-mm3 lutetium yttrium oxyorthosillicate (LYSO) scintillator crystals coupled 4-to-1 to an 8 × 8 array of silicon photomultiplier (SiPM) pixels on one end and to a prismatoid light guide array on the opposite end. The scanner's performance was evaluated by measuring depth-of-interaction (DOI) resolution, energy resolution, timing resolution, spatial resolution, sensitivity, and image quality of ultra-micro Derenzo and three-dimensional (3D) Hoffman brain phantoms. RESULTS: The full width at half maximum (FWHM) DOI, energy, and timing resolutions of the scanner are 2.85 mm, 12.6%, and 271 ps, respectively. Not considering artifacts due to mechanical misalignment of detector blocks, the intrinsic spatial resolution is 0.89-mm FWHM. Point source images reconstructed with 3D filtered back-projection (FBP) show an average spatial resolution of 1.53-mm FWHM across the entire FOV. The peak absolute sensitivity is 1.2% for an energy window of 400-650 keV. The ultra-micro Derenzo phantom study demonstrates the highest reported spatial resolution performance for a human brain PET scanner with perfect reconstruction of 1.00-mm diameter hot-rods. Reconstructed images of customized Hoffman brain phantoms prove that Prism-PET enables accurate radiotracer uptake quantification in small brain regions (2-3 mm). CONCLUSIONS: Prism-PET will substantially strengthen the utility of quantitative PET in neurology for early diagnosis of neurodegenerative diseases, and in neuro-oncology for improved management of both primary and metastatic brain tumors.