Evaluating the effect of rapamycin treatment in Alzheimer's disease and aging using in vivo imaging: the ERAP phase IIa clinical study protocol.

BACKGROUND: Rapamycin is an inhibitor of the mechanistic target of rapamycin (mTOR) protein kinase, and preclinical data demonstrate that it is a promising candidate for a general gero- and neuroprotective treatment in humans. Results from mouse models of Alzheimer's disease have shown beneficial effects of rapamycin, including preventing or reversing cognitive deficits, reducing amyloid oligomers and tauopathies and normalizing synaptic plasticity and cerebral glucose uptake. The "Evaluating Rapamycin Treatment in Alzheimer's Disease using Positron Emission Tomography" (ERAP) trial aims to test if these results translate to humans through evaluating the change in cerebral glucose uptake following six months of rapamycin treatment in participants with early-stage Alzheimer's disease. METHODS: ERAP is a six-month-long, single-arm, open-label, phase IIa biomarker-driven study evaluating if the drug rapamycin can be repurposed to treat Alzheimer's disease. Fifteen patients will be included and treated with a weekly dose of 7 mg rapamycin for six months. The primary endpoint will be change in cerebral glucose uptake, measured using [18F]FDG positron emission tomography. Secondary endpoints include changes in cognitive measures, markers in cerebrospinal fluid as well as cerebral blood flow measured using magnetic resonance imaging. As exploratory outcomes, the study will assess change in multiple age-related pathological processes, such as periodontal inflammation, retinal degeneration, bone mineral density loss, atherosclerosis and decreased cardiac function. DISCUSSION: The ERAP study is a clinical trial using in vivo imaging biomarkers to assess the repurposing of rapamycin for the treatment of Alzheimer's disease. If successful, the study would provide a strong rationale for large-scale evaluation of mTOR-inhibitors as a potential disease-modifying treatment in Alzheimer's disease. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT06022068, date of registration 2023-08-30.

Spatial resolution, noise properties, and detectability index of a deep learning reconstruction algorithm for dual-energy CT of the abdomen.

BACKGROUND: Iterative reconstruction (IR) has increasingly replaced traditional reconstruction methods in computed tomography (CT). The next paradigm shift in image reconstruction is likely to come from artificial intelligence, with deep learning reconstruction (DLR) solutions already entering the clinic. An enduring disadvantage to IR has been a change in noise texture, which can affect diagnostic confidence. DLR has demonstrated the potential to overcome this issue and has recently become available for dual-energy CT. PURPOSE: To evaluate the spatial resolution, noise properties, and detectability index of a commercially available DLR algorithm for dual-energy CT of the abdomen and compare it to single-energy (SE) CT. METHODS: An oval 25 cm x 35 cm custom-made phantom was scanned on a GE Revolution CT scanner (GE Healthcare, Waukesha, WI) at two dose levels (13 and 5 mGy) and two iodine concentrations (8 and 2 mg/mL), using three typical abdominal scan protocols: dual-energy (DE), SE 80 kV (SE-80 kV) and SE 120 kV (SE-120 kV). Reconstructions were performed with three strengths of IR (ASiR-V: AR0%, AR50%, AR100%) and three strengths of DLR (TrueFidelity: low, medium, high). The DE acquisitions were reconstructed as mono-energetic images between 40 and 80 keV. The noise power spectrum (NPS), task transfer function (TTF), and detectability index (d') were determined for the reconstructions following the recommendations of AAPM Task Group 233. RESULTS: Noise magnitude reductions (relative to AR0%) for the SE protocols were on average (-29%, -21%) for (AR50%, TF-M), while for DE-70 keV were (-28%, -43%). There was less reduction in mean frequency (fav ) for DLR than for IR, with similar results for SE and DE imaging. There was, however, a substantial change in the NPS shape when using DE with DLR, quantifiable by a marked reduction in the peak frequency (fpeak ) that was absent in SE mode. All protocols and reconstructions (including AR0%) exhibited slight to moderate shifts towards lower spatial frequencies at the lower dose (<12% in fav ). Spatial resolution was consistently superior for DLR compared to IR for SE but not for DE. All protocols and reconstructions (including AR0%) showed decreased resolution with reduced dose and iodine concentration, with less decrease for DLR compared to IR. DLR displayed a higher d' than IR. The effect of energy was large: d' increased with lower keV, and SE-80 kV had higher d' than SE-120 kV. Using DE with DLR could provide higher d' than SE-80 kV at the higher dose but not at lower dose. CONCLUSIONS: DE imaging with DLR maintained spatial resolution and reduced noise magnitude while displaying less change in noise texture than IR. The d' was also higher with DLR than IR, suggesting superiority in detectability of iodinated contrast. Despite these trends being consistent with those previously established for SE imaging, there were some noteworthy differences. For DE imaging there was no improvement in resolution compared to IR and a change in noise texture. DE imaging with low keV and DLR had superior detectability to SE DLR at the high dose but was not better than SE-80 kV at low dose.

Stopping-power ratio estimation for proton radiotherapy using dual-energy computed tomography and prior-image constrained denoising.

BACKGROUND: Dual-energy computed tomography (DECT) is a promising technique for estimating stopping-power ratio (SPR) for proton therapy planning. It is known, however, that deriving electron density (ED) and effective atomic number (EAN) from DECT data can cause noise amplification in the resulting SPR images. This can negate the benefits of DECT. PURPOSE: This work introduces a new algorithm for estimating SPR from DECT with noise suppression, using a pair of CT scans with spectral separation. The method is demonstrated using phantom measurements. MATERIALS AND METHODS: An iterative algorithm is presented, reconstructing ED and EAN with noise suppression, based on Prior Image Constrained Denoising (PIC-D). The algorithm is tested using a Siemens Definition AS+ CT scanner (Siemens Healthcare, Forchheim, Germany). Three phantoms are investigated: a calibration phantom (CIRS 062M), a QA phantom (CATPHAN 700), and an anthropomorphic head phantom (CIRS 731-HN). A task-transfer function (TTF) and the noise power spectrum are derived from SPR images of the QA phantom for the evaluation of image quality. Comparisons of accuracy and noise for ED, EAN, and SPR are made for various versions of the algorithm in comparison to a solution based on Siemens syngo.via Rho/Z software and the current clinical standard of a single-energy CT stoichiometric calibration. A gamma analysis is also applied to the SPR images of the head phantom and water-equivalent distance (WED) is evaluated in a treatment planning system for a proton treatment field. RESULTS: The algorithm is effective at suppressing noise in both ED and EAN and hence also SPR. The noise is tunable to a level equivalent to or lower than that of the syngo.via Rho/Z software. The spatial resolution (10% and 50% frequencies in the TTF) does not degrade even for the highest noise suppression investigated, although the average spatial frequency of noise does decrease. The PIC-D algorithm showed better accuracy than syngo.via Rho/Z for low density materials. In the calibration phantom, it was superior even when excluding lung substitutes, with root-mean-square deviations for ED and EAN less than 0.3% and 2%, respectively, compared to 0.5% and 3%. In the head phantom, however, the SPR accuracy of the PIC-D algorithm was comparable (excluding sinus tissue) to that derived from syngo.via Rho/Z: less than 1% error for soft tissue, brain, and trabecular bone substitutes and 5-7% for cortical bone, with the larger error for the latter likely related to the phantom geometry. Gamma evaluation showed that PIC-D can suppress noise in a patient-like geometry without introducing substantial errors in SPR. The absolute pass rates were almost identical for PIC-D and syngo.via Rho/Z. In the WED evaluations no general differences were shown. CONCLUSIONS: The PIC-D DECT algorithm provides scanner-specific calibration and tunable noise suppression. It is vendor agnostic and applicable to any pair of CT scans with spectral separation. Improved accuracy to current methods was not clearly demonstrated for the complex geometry of a head phantom, but the suppression of noise without spatial resolution degradation and the possibility of incorporating constraints on image properties, suggests the usefulness of the approach.

Hepatic enhancement at computed tomography: is there a dependence on body weight past institutional contrast dosing limits?

BACKGROUND: Although described in product monographs, the maximum contrast media (CM) dose at computed tomography (CT) varies among institutions. PURPOSE: To investigate whether an upper limit of 40 g of iodine in women and 50 g in men is sufficient or if there is a body weight (BW) dependence of mean hepatic enhancement (MHE) beyond those thresholds. MATERIAL AND METHODS: At our institution, CM injection duration is fixed to 30 s and dosed 600 mg iodine/kg up to 40 g in women and 50 g in men. Pre- and post-contrast hepatic attenuation values (HU) were retrospectively obtained in 200 women and 200 men with glomerular filtration rate >45 mL/min undergoing 18-flurodeoxyglucose PET-CT (18F-FDG PET-CT) of which half weighed below and half above those dose thresholds using iodixanol 320 mg iodine/mL or iomeprol 400 mg iodine/mL. The correlation between BW and MHE was assessed by simple linear regression. RESULTS: Weight range was 41-120 kg in women and 47-137 kg in men. There was no significant relationship between MHE and BW in women receiving <40 g (r = -0.05, P = 0.63) or in men receiving <50 g (r = 0.18, P = 0.07). Above those thresholds there was an inverse relationship (r = -0.64, P<0.001 in women and r = -0.30, P<0.002 in men). There was no apparent upper limit where the dependence of hepatic MHE on BW decreased. Hepatosteatosis limited MHE. CONCLUSION: Adjusting CM to BW diminishes the dependence of MHE on BW. There was no apparent upper limit for the relationship between BW and MHE in heavier patients at CM-enhanced CT.

Simplified dosimetry for kidneys and tumors in 177Lu-labeled peptide receptor radionuclide therapy.

PURPOSE: To evaluate if satisfactory post-therapeutic image-based dosimetry can be achieved for Lu-177-DOTATATE treatments using a reduced number of image acquisitions to improve patient comfort and reduce economical costs. METHODS: 39 patients who underwent 147 treatment cycles of Lu-177-DOTATATE for neuroendocrine tumors were included in the study. A total of 291 and 284 absorbed doses were calculated to kidneys and tumors, respectively. Single-point dosimetry was performed using one SPECT/CT image acquired at 1 d or 7 d post-treatment using a fixed effective half-life (Teff) or using a patient-specific Teff determined for the initial cycle. Also, dose-per-activity values, (D/A)1, were determined from the first cycle and used to calculate doses for subsequent cycles. All absorbed doses were evaluated against "true" doses calculated using both the 1 d and 7 d images. The relation between tumor grade and absorbed doses was also investigated. All dosimetry was performed on SPECT images. RESULTS: Absorbed doses to kidneys were most accurate when single-point dosimetry was performed using 1 d images with median ratios in relation to "true" doses in total dose of 1.00 (IQR: 0.97-1.03) when using fixed Teff and 1.01 (IQR: 0.98-1.04) when using Teff from the initial cycle. Calculations based on the 7 d image were most accurate for tumors with corresponding ratios in total absorbed dose of 0.98 (IQR: 0.96-1.00) and 1.00 (IQR: 0.99-1.01) when using a fixed Teff or Teff from the first cycle, respectively. The (D/A)1 approach performed worse, as 2 of 77 total absorbed doses to the kidneys deviated with > 30%, and tumor-absorbed doses were increasingly overestimated with every cycle. Absorbed doses, Teff and 1 d uptake were higher for G1 tumors than G2 tumors. CONCLUSION: Dosimetry can be performed with satisfactory accuracy when using single SPECT/CT images acquired at 1 d for kidneys or at 7 d for tumors.

Radioiodine treatment outcome by dosimetric parameters and renal function in hyperthyroidism.

BACKGROUND: Hyperthyroidism has been treated with radioiodine therapy for eight decades, with known benefits and side-effects. No consensus exists on which activity dosage and pre-therapeutic measurements are required for optimal treatment, balancing risk of incomplete response, therapy-induced hypothyroidism and radiation exposure. A retrospective analysis was performed to assess these questions. METHODS: Data was collected on radioiodine treatment outcomes for 904 patients treated for Graves' disease or toxic nodular goitres at our institution during 2016-2020. The prescribed absorbed doses were 120 Gy (Graves' disease), 200 Gy (toxic multinodular goitre) and 300 Gy (solitary toxic adenoma). Univariate analysis and multivariate regression modelling were used to find factors linked to treatment outcome. RESULTS: The cure rate of hyperthyroidism after one administration of radioiodine was 79% for Graves' disease, 94% for toxic multinodular goitre and 98% for solitary toxic adenoma. Thyroid mass, uptake and effective half-life were all significantly associated with cure in Graves' disease, but not in toxic multinodular goitre. The rates of therapy-induced hypothyroidism were 20% and 29% for toxic multinodular goitre and solitary toxic adenoma. Neither the cure rate nor the hypothyroidism rate was found to be superior among patients with individualised effective half-life measurements in toxic nodular goitres. Poor renal function was associated with dubious iodine uptake measurements but was not found to correlate with worse outcome. CONCLUSIONS: Multiple measurements of individual iodine uptake for kinetics estimation may be unnecessary, and a population-based value can be used instead. Patients with renal impairment had similar outcome as other patients, but with a higher risk of dubious uptake measurements.

Dual source abdominal computed tomography: the effect of reduced X-ray tube voltage and intravenous contrast media dosage in patients with reduced renal function.

BACKGROUND: X-ray tube voltage (kVp) reduction increases intravenous contrast medium (CM) attenuation at computed tomography (CT), but tube output limits its use in large patients. PURPOSE: To evaluate the feasibility and image quality of reducing CM dose by low kVp and using dual X-ray source at liver CT. MATERIAL AND METHODS: Patients with estimated glomerular filtration rate (eGFR) < 45 mL/min (n = 43) aged 60-91 years (75 ± 7.7), weighing 42-114 kg (75 ± 15) were prospectively scanned using a reduced CM dose of 0.25 or 0.3 g iodine (I)/kg with 70 or 80 kVp respectively, using either single-source or dual-source CT depending on patient size. Liver contrast-to-noise ratio (CNR), liver noise, and muscle noise were quantitatively compared with those of 43 consecutive patients aged > 65 years with eGFR > 45 mL/min scanned using a standard abdominal protocol at 120 kVp after receiving 0.5 gI/kg. RESULTS: There was no statistically significant difference in CNR, liver noise, or muscle noise at reduced CM protocols compared to the standard protocol: CNR was 4.6 (95% CI = 4.2-5.0) vs. 5.0 (95% CI = 4.5-5.5), liver noise was 11.1 (95% CI = 10.7-11.6) vs. 11.0 (95% CI = 10.5-11.6), muscle noise was 11.7 (95% CI = 11.2-12.1) vs. 10.8 (95% CI = 10.1-11.4). The mean SSDE was 70% higher with the reduced CM protocol. CONCLUSION: CM dosage can be reduced by 40-50% with maintained measured noise and CNR in patients with BMIs of 15-36 kg/m2 by lowering the tube voltage and dual-source CT scanning of the liver.

Low tube voltage dual source computed tomography to reduce contrast media doses in adult abdomen examinations: A phantom study.

PURPOSE: To evaluate the potential of low tube voltage dual source (DS) single energy (SE) and dual energy (DE) computed tomography (CT) to reduce contrast media (CM) dose in adult abdominal examinations of various sizes while maintaining soft tissue and iodine contrast-to-noise ratio (CNR). METHODS: Four abdominal phantoms simulating a body mass index of 16 to 35 kg/m(2) with four inserted syringes of 0, 2, 4, and 8 mgI/ml CM were scanned using a 64-slice DS-CT scanner. Six imaging protocols were used; one single source (SS) reference protocol (120 kV, 180 reference mAs), four low kV SE protocols (70 and 80 kV using both SS and DS), and one DE protocol at 80/140 kV. Potential CM reduction with unchanged CNRs relative to the 120 kV protocol was calculated along with the corresponding increase in radiation dose. RESULTS: The potential contrast media reductions were determined to be approximately 53% for DS 70 kV, 51% for SS 70 kV, 44% for DS 80 kV, 40% for SS 80 kV, and 20% for DE (all differences were significant, P < 0.05). Constant CNR could be achieved by using DS 70 kV for small to medium phantom sizes (16-26 kg/m(2)) and for all sizes (16-35 kg/m(2)) when using DS 80 kV and DE. Corresponding radiation doses increased by 60%-107%, 23%-83%, and 6%-12%, respectively. CONCLUSIONS: DS single energy CT can be used to reduce CM dose by 44%-53% with maintained CNR in adult abdominal examinations at the cost of an increased radiation dose. DS dual-energy CT allows reduction of CM dose by 20% at similar radiation dose as compared to a standard 120 kV single source.