Positronium image of the human brain in vivo

Abstract

Positronium is abundantly produced within the molecular voids of a patient's body during positron emission tomography (PET). Its properties dynamically respond to the submolecular architecture of the tissue and the partial pressure of oxygen. Current PET systems record only two annihilation photons and cannot provide information about the positronium lifetime. This study presents the in vivo images of positronium lifetime in a human, for a patient with a glioblastoma brain tumor, by using the dedicated Jagiellonian PET system enabling simultaneous detection of annihilation photons and prompt gamma emitted by a radionuclide. The prompt gamma provides information on the time of positronium formation. The photons from positronium annihilation are used to reconstruct the place and time of its decay. In the presented case study, the determined positron and positronium lifetimes in glioblastoma cells are shorter than those in salivary glands and those in healthy brain tissues, indicating that positronium imaging could be used to diagnose disease in vivo.

Fig. 1.. Positronium imaging of a human brain.

(A) Photograph of the patient in the modular J-PET tomograph. The patient diagnosed with brain glioma was intravenously and intratumorally administered with pharmaceuticals labeled with the ⁶⁸Ga radionuclide, which emits positrons and prompt gamma rays (the course of imaging is illustrated in Fig. 2). The superimposed arrows represent photons from electron-positron annihilation (blue dashed arrow) and prompt gamma from the deexcitation of the ⁶⁸Zn* radionuclide (red solid arrow). The plastic strips of the tomograph in which the gamma rays interacted have been highlighted in yellow. (B) Pictorial illustration of the ⁶⁸Ga isotope decay chain (⁶⁸Ga → ⁶⁸Zn* + e⁺ + ν → ⁶⁸Zn + γ + e⁺ + ν) and possible ways of positron and positronium annihilation within molecules on the example of the PSMA molecule overexpressed at the membrane of the microvascular endothelial cell (38). Positron (black dashed arrow) emitted by ⁶⁸Ga may annihilate directly (e⁺e⁻ → photons) or via the formation of positronium (e⁺e⁻ → Ps → photons) (1). Positronium (Ps) is formed as pPs (yellow) or oPs (blue). Blue dashed arrows indicate annihilations into two photons used for imaging. Main annihilation mechanisms mentioned in order of decreasing probabilities include (2): (i) direct annihilation (yellow ellipse), (ii) annihilation of a positron from oPs by picking off the electron from the atom (red ellipse), (iii) self-annihilation of pPs, (iv) conversion of oPs to pPs on the O₂ molecule proceeded by self-annihilation of pPs (oPs + O₂ → pPs + O₂ → 2γ + O₂), and (v) self-decay of oPs into three photons (orange arrows) inside the free space between atoms.

Fig. 2.. Course of diagnosis and treatment of a patient with secondary recurrent glioblastoma.

(A) The solid black curve indicates the decrease in the activity of the ⁶⁸Ga radionuclide after intravenous injection of a 178-MBq activity of the [⁶⁸Ga]Ga-PSMA-11 radiopharmaceutical followed 131 min later by intratumoral administration of 8 MBq of [⁶⁸Ga]Ga-DOTA-SP (black dashed curve) together with 20 MBq of [²²⁵Ac]Ac-DOTAGA-SP (red curve). After the first and the second administration of pharmaceuticals, the patient was imaged with the Siemens PET/CT Biograph 64 TruePoint and then with a modular J-PET for the time indicated in the graph in yellow and turquoise, respectively. (B) The T2-weighed MRI coronal image of the head (Magnetom 3T, Siemens Healthcare) showing the tumor and the position of the cat-cath system (visible on the upper left part of the head) for the administration of a radiopharmaceutical for the local treatment of glioblastoma. (C to F) Photographs illustrating the course of patient imaging with the modular J-PET scanner. (C) Modular J-PET scanner placed behind the PET/CT Biograph 64. (D) View of the patient’s bed from the inside of the J-PET tomograph. (E) The patient was moved on the table so that the torso and legs were in the Biograph PET/CT and the head in the J-PET scanner. In this view, only the patient’s feet are visible on the edge of the Biograph PET/CT. (F) Photograph of the patient with the head inside of the J-PET scanner during imaging after intravenous administration of the [⁶⁸Ga]Ga-PSMA-11 radiopharmaceutical.

Fig. 3.. Positronium images of the head of a patient with recurrent secondary glioblastoma in the right frontoparietal lobe.

(A to C) Standard PET/CT images obtained with Biograph 64 TruePoint. An accumulation of [⁶⁸Ga]Ga-DOTA-SP in the capsule and cavity of the tumor in transverse (A), coronal (B), and sagittal (C) planes is presented. (D to F) Images of the density distribution of positron annihilation accompanied by the emission of the prompt gamma are shown in transverse (D), coronal (E), and sagittal (F) planes. These images were acquired with the J-PET tomograph. The white thin dashed lines in each (A) to (F) image indicate a cross section with the other two planes presented. (G to I) Positronium images shown in transverse (G), coronal (H), and sagittal (I) planes. (J to L) Distributions of positron annihilation lifetime (ΔT) determined in the glioblastoma tumor (J), salivary glands (K), and healthy brain tissues (L). Black histograms denote experimental data. The superimposed curves indicate the result of the fit of the function describing contributions from oPs (C_oPs), from pPs and direct annihilations (C_short), and from the background due to accidental coincidences (BG). The red curve denotes the sum of all contributions (Fit). (M and N) Mean oPs lifetime [τ_oPs; (M)] and mean value of the positron lifetime in the range between 0 and 5 ns [Mean; (N)] determined for the glioblastoma tumor (G; black squares), salivary glands (SG; red circles), and healthy brain tissues (B; blue triangles). The blue dotted line and orange dashed line indicate the mean oPs lifetime in cardiac myxoma tumor (1.92 ns) and adipose tissue (2.72 ns) (6).

Fig. 4.. Comparison of positronium and standard PET imaging sensitivities.

(A) Positronium imaging sensitivity profiles for registration of γγ+γ_p events (blue) are compared to sensitivity profiles for standard PET metabolic imaging based on registration of γγ events (red). Sensitivity profiles of modular J-PET applied in this study are shown together with the sensitivity profiles for the design of the total-body J-PET with 250-cm AFOV (50, 84). (B) Decay scheme of the ⁶⁸Ga radionuclide. EC denotes the electron capture, while “e⁺” denotes the emission of a positron. The mean lifetime of the excited nucleus ⁶⁸Zn* and the energy of the deexcitation (prompt) gamma are indicated. In this research, the ⁶⁸Ga → ⁶⁸Zn* + e⁺ + ν → ⁶⁸Zn + γ_p + e⁺ + ν decay chain was used, occurring only in about 1.3% of all e⁺ emissions. (C) Decay scheme of the ⁴⁴Sc radionuclide, the most suited isotope for positronium imaging (50, 51, 85). In ⁴⁴Sc decay, the emission of positron is accompanied by the prompt gamma in 100% cases. (D) Estimated gain of positronium imaging sensitivity by increasing the AFOV with respect to the modular J-PET used in this research. The gain is calculated for the sensitivity at the center (solid lines) and for the whole-body positronium imaging (dashed lines). Results for standard crystal-based PET systems (based on the uEXPLORER) are shown in red, and the result for the J-PET based on plastic scintillators is shown in blue. The sensitivity at the center for positronium imaging would increase by a factor of 28 for the total-body J-PET and by a factor of 87 for uEXPLORER with AFOV = 194 cm (25).

Fig. 5.. Modular J-PET tomograph.

(A) Photograph of the modular J-PET system with a human placed inside the scanner. The superimposed blue dashed arrows indicate photons from the electron-positron annihilation (e⁺e⁻ →γγ), while the red solid arrow indicates prompt gamma (γ_p) from the decay of the ⁶⁸Ga radionuclide. The modular J-PET scanner enables registration and identification of both γγ and γγ+γ_p events, which are used in this study for the standard PET imaging (γγ) and positronium imaging (γγ+γ_p). (B) Cross section of the modular J-PET showing the 24-module structure of the scanner, where each module is composed of 13 scintillator strips. Scintillators that register the photons are marked in yellow in (A) and (B). (C) Block diagram of the data processing (43). Light signals generated by gamma photons in the tomograph are collected by a triggerless DAQ system (20) and stored on discs in the form of the continuous sequence of timestamps. Timestamps are used for signal reconstruction including the place and time of gamma photon interaction. Signals are then used for event reconstruction. Next, the true γγ and γγ+γ_p events are selected by event selection algorithms. Last, the selected events, in the list mode format, are used for the standard 2γ PET image reconstruction and positronium image reconstruction.

Fig. 6.. Pictorial representation of events and signals used for positronium imaging.

(A) Schematic cross section of the modular J-PET scanner with the superimposed illustration of an exemplary event used for positronium imaging. A deexcitation photon and two annihilation photons are shown as red solid lines and blue dashed lines, respectively. Scintillators that registered photons are marked in yellow. The reconstructed position and time of photons’ interaction (hit position and hit time) are indicated as ${\overrightarrow{r}}_i$ and t_i (i = 1, …, 3), respectively. For the purpose of the event selection, the relative angles between photons (θ₁₂ and θ₁₃) are calculated with respect to the center as angles in the plane transverse to the scanner axis (XY plane), as illustrated in the figure. (B) Example of an event with more than three hits, which are also used for positronium imaging. The position and time of interaction of the scattered photon are indicated as ($t_4,{\overrightarrow{r}}_4$). (C) Pictorial definition of the TOT for a single SiPM signal. For each SiPM, the timestamps at the leading and trailing edge of the signals are measured at two predefined voltage levels (thresholds): thr₁ and thr₂. This enables us to determine the signal widths at two levels (TOT₁ and TOT₂) and to estimate the area of the signal as ${\text{TOT}}_{\text{SiPM}}=\text{th}{{\mathrm{r}}_1}^{*}\text{TO}{\mathrm{T}}_1+\left(\text{th}{\mathrm{r}}_2-\text{th}{\mathrm{r}}_1\right)*\text{TO}{\mathrm{T}}_2$. The average of TOT_SiPM from eight SiPMs attached to each scintillator is used as a measure of the deposited energy (81).

Fig. 7.. Event selection criteria for positronium imaging.

(A) Distribution of TOT (TOT_Hit), used for photon identification. The ranges of TOT_Hit values for selecting annihilation and deexcitation photons are marked in red and blue, respectively. (B) Distribution of a number of hits in the event (hit multiplicity μ). The gray shadowed histogram shows the hit multiplicity for events including one identified deexcitation photon, two identified annihilation photons, and other possible hits identified as scattered photons. (C) Distribution of the relative angle (θ) between hit position vectors ${\overrightarrow{r}}_1$, ${\overrightarrow{r}}_2$, ... (defined in Fig. 6A). The figure includes all relative angles in the measured event (θ₁₂, θ₂₃, ...). In the analysis, the relative angle between deexcitation and annihilation photons is restricted to the range marked in blue (θ > 30°), and the red range (θ > 90°) shows the restriction used for the relative angle between annihilation photons. (D) Distribution of the ST value used to suppress misidentification of scattered photons as annihilation photons (indicated in Fig. 8A). For hits assigned to annihilation photons [($t_2,{\overrightarrow{r}}_2$) and ($t_3,{\overrightarrow{r}}_3$)], the ST is defined as a difference between the measured times (Δt = ∣ t₃ − t₂∣) and the time the photon would need to pass from ${\overrightarrow{r}}_3$ to ${\overrightarrow{r}}_2$ (ST = $\mathrm{\Delta }t-\mid {\overrightarrow{r}}_3-{\overrightarrow{r}}_2\mid /c$). ST is equal to zero for the scattered photons, while for the annihilation photons, ST is negative. The region used to select events with annihilation photons (ST < − 0.5 ns) is marked in red. Such selection also reduces a large fraction of events due to the accidental coincidences (as indicated in Fig. 8D) that are spread over the whole range of ST.

Fig. 8.. Topology of background events in positronium imaging with modular J-PET tomograph.

Examples of background events superimposed upon the cross section of the modular J-PET scanner. The prompt gamma is represented by a red solid arrow. Primary and scattered annihilation photons are indicated by blue dashed and blue dotted arrows, respectively. Scintillators where photons interacted are highlighted in yellow. (A) Example of a background event where one annihilation photon remained undetected while the prompt gamma interacted twice within the detector, leading to the misidentification of the registered scattered photon as the annihilation photon. (B) Example of a background event where one annihilation photon remains undetected, while the other annihilation photon interacts twice within the detector, leading to the misidentification of the registered scattered photon as an annihilation photon. Such events can be suppressed using the ST (Fig. 7D). (C) Example of the background arising from the accidental coincidence of a prompt gamma from one event and annihilation photons from the other event. A portion of these events can be eliminated using the ST (Fig. 7D). (D) Example of the background arising from the accidental coincidence of registering a prompt gamma and one annihilation photon from one event and the other annihilation photon from the other event. A portion of these events can be eliminated by restricting the range of angle θ (Fig. 7C) and by using the ST (Fig. 7D).