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Although age differences in the dopamine system have been suggested to contribute to age-related cognitive decline based on cross-sectional data, recent large-scale cross-sectional studies reported only weak evidence for a correlation among aging, dopamine receptor availability, and cognition. Regardless, longitudinal data remain essential to make robust statements about dopamine losses as a basis for cognitive aging. We present correlations between changes in D2/3 dopamine receptor availability and changes in working memory measured over 5 yr in healthy, older adults (n = 128, ages 64 to 68 yr at baseline). Greater decline in D2/3 dopamine receptor availability in working memory-relevant regions (caudate, middle frontal cortex, hippocampus) was related to greater decline in working memory performance in individuals who exhibited working memory reductions across time (n = 43; caudate: rs = 0.494; middle frontal cortex: rs = 0.506; hippocampus; rs = 0.423), but not in individuals who maintained performance (n = 41; caudate: rs = 0.052; middle frontal cortex: rs = 0.198; hippocampus; rs = 0.076). The dopamine–working memory link in decliners was not observed in the orbitofrontal cortex, which does not belong to the core working memory network. Our longitudinal analyses support the notion that aging-related changes in the dopamine system contribute to working memory decline in aging.

Background: Glioblastoma is the most aggressive and malignant brain tumor, characterized by a high degree of heterogeneity, invasiveness, and resistance to treatment. Patients with glioblastoma have a very poor prognosis despite multimodal interventions. In this study, we investigated how 18F-fluorothymidine (18F-FLT) PET combined with contrast-enhanced MRI and blood metabolomics can contribute to evaluate prognosis and treatment response for patients with glioblastoma.

Methods: Patients, scheduled for surgery due to suspected high-grade glioma were included in this clinical study and underwent four 18F-FLT-PET/MRI examinations prior to surgery and during standard treatment. Blood samples were collected and analyzed by metabolomics. Patients were grouped according to survival as long-time survivors (>3 years) and short-time survivors (<500 days).

Results: Both 2 and 6 weeks into treatment, short-time survivors displayed a significantly larger tumor volume than long-time survivors. When comparing MRI findings during treatment, long-time survivors displayed a substantial tumor decrease, whereas the short-time survivors showed minor or no effect. Regarding 18F-FLT-PET the results were not as unambiguous. Furthermore, there was a clear and significant separation in the metabolomic pattern in blood between the survival groups and across treatment time points.

Conclusions: MRI measures of tumor volume and growth during treatment appear to be prognostic clinical factors that affect outcome. Metabolomic patterns in blood differ significantly between the defined survival groups and may serve as support for an early forecast of prognosis. We also observe a clear separation in metabolite levels between different time points during treatment, which likely reflects treatment effects.

Purpose: To evaluate current MRI-based criteria for malignancy in mesorectal nodal structures in rectal cancer.

Method: Mesorectal nodal structures identified on baseline MRI as lymph nodes were anatomically compared to their corresponding structures histopathologically, reported as lymph nodes, tumour deposits or extramural venous invasion. All anatomically matched nodal structures from patients with primary surgery and all malignant nodal structures from patients with neoadjuvant treatment were included. Mixed-effects logistic regression models were used to evaluate the morphological criteria irregular margin, round shape, heterogeneous signal and nodal size, as well as the combined 2016 European Society of Gastrointestinal and Abdominal Radiology (ESGAR) consensus criteria, with histopathological nodal status as the gold standard.

Results: In total, 458 matched nodal structures were included from 46 patients (mean age, 67.7 years ± 1.5 [SD], 27 men), of which 19 received neoadjuvant treatment. The strongest associations in the univariable model were found for short-axis diameter ≥ 5 mm (OR 21.43; 95% CI: 4.13–111.29, p < 0.001) and heterogeneous signal (OR 9.02; 95% CI: 1.33–61.08, p = 0.024). Only size remained significant in multivariable analysis (OR 12.32; 95% CI: 2.03–74.57, p = 0.006). When applying the ESGAR consensus criteria to create a binary classification of nodal status, the OR of malignant outcome for nodes with positive ESGAR was 8.23 (95% CI: 2.15–31.50, p = 0.002), with corresponding sensitivity and specificity of 54% and 85%, respectively.

Conclusion: The results confirm the role of morphological and size criteria in predicting lymph node metastases. However, the current criteria might not be accurate enough for nodal staging.

BACKGROUND: The delineation of intraprostatic lesions is vital for correct delivery of focal radiotherapy boost in patients with prostate cancer (PC). Errors in the delineation could translate into reduced tumour control and potentially increase the side effects. The purpose of this study is to compare PET-based delineation methods with histopathology.

MATERIALS AND METHODS: The study population consisted of 15 patients with confirmed high-risk PC intended for prostatectomy. [68Ga]-PSMA-PET/MR was performed prior to surgery. Prostate lesions identified in histopathology were transferred to the in vivo [68Ga]-PSMA-PET/MR coordinate system. Four radiation oncologists manually delineated intraprostatic lesions based on PET data. Various semi-automatic segmentation methods were employed, including absolute and relative thresholds, adaptive threshold, and multi-level Otsu threshold.

RESULTS: The gross tumour volumes (GTVs) delineated by the oncologists showed a moderate level of interobserver agreement with Dice similarity coefficient (DSC) of 0.68. In comparison with histopathology, manual delineations exhibited the highest median DSC and the lowest false discovery rate (FDR) among all approaches. Among semi-automatic approaches, GTVs generated using standardized uptake value (SUV) thresholds above 4 (SUV > 4) demonstrated the highest median DSC (0.41), with 0.51 median lesion coverage ratio, FDR of 0.66 and the 95th percentile of the Hausdorff distance (HD95%) of 8.22 mm.

INTERPRETATION: Manual delineations showed a moderate level of interobserver agreement. Compared to histopathology, manual delineations and SUV > 4 exhibited the highest DSC and the lowest HD95% values. The methods that resulted in a high lesion coverage were associated with a large overestimation of the size of the lesions.

Whole-brain mapping of drug effects are needed to understand the neural underpinnings of drug-related behaviors. Amphetamine administration is associated with robust increases in striatal dopamine (DA) release. Dopaminergic terminals are, however, present across several associative brain regions, which may contribute to behavioral effects of amphetamine. Yet the assessment of DA release has been restricted to a few brain regions of interest. The present work employed positron emission tomography (PET) with [¹¹C]raclopride to investigate regional and temporal characteristics of amphetamine-induced DA release across twenty sessions in adult female Sprague Dawley rats. Amphetamine was injected intravenously (2 mg/kg) to cause displacement of [¹¹C]raclopride binding from DA D2-like receptors, assessed using temporally sensitive pharmacokinetic PET model (lp-ntPET). We show amphetamine-induced [¹¹C]raclopride displacement in the basal ganglia, and no changes following saline injections. Peak occupancy was highest in nucleus accumbens, followed by caudate-putamen and globus pallidus. Importantly, significant amphetamine-induced displacement was also observed in several extrastriatal regions, and specifically in thalamus, insula, orbitofrontal cortex, and secondary somatosensory area. For these, peak occupancy occurred later and was lower as compared to the striatum. Collectively, these findings demonstrate distinct amphetamine-induced DA responses across the brain, and that [¹¹C]raclopride-PET can be employed to detect such spatiotemporal differences.

The dopaminergic system is firmly implicated in reversal learning but human measurements of dopamine release as a correlate of reversal learning success are lacking. Dopamine release and hemodynamic brain activity in response to unexpected changes in action-outcome probabilities are here explored using simultaneous dynamic [11C]Raclopride PET-fMRI and computational modelling of behavior. When participants encounter reversed reward probabilities during a card guessing game, dopamine release is observed in associative striatum. Individual differences in absolute reward prediction error and sensitivity to errors are associated with peak dopamine receptor occupancy. The fMRI response to perseverance errors at the onset of a reversal spatially overlap with the site of dopamine release. Trial-by-trial fMRI correlates of absolute prediction errors show a response in striatum and association cortices, closely overlapping with the location of dopamine release, and separable from a valence signal in ventral striatum. The results converge to implicate striatal dopamine release in associative striatum as a central component of reversal learning, possibly signifying the need for increased cognitive control when new stimuli-responses should be learned.

Background: Central nervous system symptoms, such as cognitive dysfunction, have been reported in Hereditary Transthyretin Amyloidosis (ATTRv). However, there is a lack of neuroimaging studies investigating structural alterations in the brain related to cognition in ATTRv amyloidosis. This study aimed to investigate cognition and cortical morphology in a cohort of ATTRv patients.

Methods: 29 ATTRv patients and 26 healthy controls completed neuropsychological assessment. 21 of these patients underwent 3T brain MRI, and 23 healthy subjects constituted the control group for MRI. Cortical measures of volume, thickness, fractional anisotropy (FA), and mean diffusivity (MD) were obtained for both groups. Correlation analyses between brain and cognitive measurements were performed.

Results: Patients displayed worse performance than controls in executive functions, verbal and visual memory, visuospatial domains, and language tests. Our study indicated cortical thinning in ATTRv patients in the temporal, occipital, frontal, and parietal areas. The inferior temporal gyrus correlated with verbal memory. Insula and, pars opercularis correlated with both verbal memory and executive function.

Conclusions: Cortical thickness in the inferior temporal gyrus, pars opercularis, and insula were linked to memory and executive function. We observed no correlations between cortical volume measures and cognition. Further investigations are imperative to confirm these findings across different populations.

Background and purpose: Dose escalation in external radiotherapy of prostate cancer shows promising results in terms of biochemical disease-free survival. Boost volume delineation guidelines are sparse which may cause high interobserver variability. The aim of this research was to characterize gross tumor volume (GTV) delineations based on multiparametric magnetic resonance imaging (mpMRI) and prostate specific membrane antigen-positron emission tomography (PSMA-PET) in relation to histopathology-validated Gleason grade 4 and 5 regions.

Material and methods: The study participants were examined with [68Ga]PSMA-PET/mpMRI prior to radical prostatectomy. Four radiation oncologists delineated GTVs in 15 study participants, on four different image types; T2-weighted (T2w), diffusion weighted imaging (DWI), dynamic contrast enhanced (DCE) and PSMA-PET scans separately. The simultaneous truth and performance level estimation (STAPLE) algorithm was used to generate combined GTVs. GTVs were subsequently compared to histopathology. We analysed how Dice similarity coefficient (DSC) and lesion coverage are affected by using single versus multiple image types as well as by adding a clinical target volume (CTV) margin.

Results: Median DSC (STAPLE) for different GTVs varied between 0.33 and 0.52. GTVPSMA-PET/mpMRI generated the highest median lesion coverage at 0.66. Combining different image types achieved similar lesion coverage as adding a CTV margin to contours from a single image type, while reducing non-malignant tissue inclusion within the target volume.

Conclusion: The combined use of mpMRI or PSMA-PET/mpMRI shows promise, achieving higher DSC and lesion coverage while minimizing non-malignant tissue inclusion, in comparison to the use of a single image type with an added CTV margin.

Purpose: To investigate the impact of reduced injected doses on the quantitative and qualitative assessment of the amyloid PET tracers [18F]flutemetamol and [18F]florbetaben.

Methods: Cognitively impaired and unimpaired individuals (N = 250, 36% Aβ-positive) were included and injected with [18F]flutemetamol (N = 175) or [18F]florbetaben (N = 75). PET scans were acquired in list-mode (90–110 min post-injection) and reduced-dose images were simulated to generate images of 75, 50, 25, 12.5 and 5% of the original injected dose. Images were reconstructed using vendor-provided reconstruction tools and visually assessed for Aβ-pathology. SUVRs were calculated for a global cortical and three smaller regions using a cerebellar cortex reference tissue, and Centiloid was computed. Absolute and percentage differences in SUVR and CL were calculated between dose levels, and the ability to discriminate between Aβ- and Aβ + scans was evaluated using ROC analyses. Finally, intra-reader agreement between the reduced dose and 100% images was evaluated.

Results: At 5% injected dose, change in SUVR was 3.72% and 3.12%, with absolute change in Centiloid 3.35CL and 4.62CL, for [18F]flutemetamol and [18F]florbetaben, respectively. At 12.5% injected dose, percentage change in SUVR and absolute change in Centiloid were < 1.5%. AUCs for discriminating Aβ- from Aβ + scans were high (AUC ≥ 0.94) across dose levels, and visual assessment showed intra-reader agreement of > 80% for both tracers.

Conclusion: This proof-of-concept study showed that for both [18F]flutemetamol and [18F]florbetaben, adequate quantitative and qualitative assessments can be obtained at 12.5% of the original injected dose. However, decisions to reduce the injected dose should be made considering the specific clinical or research circumstances.

Dopamine decline is suggested to underlie aging-related cognitive decline, but longitudinal examinations of this link are currently missing. We analyzed 5-year longitudinal data for a sample of healthy, older adults (baseline: n = 181, age: 64–68 years; 5-year follow-up: n = 129) who underwent positron emission tomography with 11C-raclopride to assess dopamine D2-like receptor (DRD2) availability, magnetic resonance imaging to evaluate structural brain measures, and cognitive tests. Health, lifestyle, and genetic data were also collected. A data-driven approach (k-means cluster analysis) identified groups that differed maximally in DRD2 decline rates in age-sensitive brain regions. One group (n = 47) had DRD2 decline exclusively in the caudate and no cognitive decline. A second group (n = 72) had more wide-ranged DRD2 decline in putamen and nucleus accumbens and also in extrastriatal regions. The latter group showed significant 5-year working memory decline that correlated with putamen DRD2 decline, along with higher dementia and cardiovascular risk and a faster biological pace of aging. Taken together, for individuals with more extensive DRD2 decline, dopamine decline is associated with memory decline in aging.