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•We developed a reading algorithm to enhance objectivity in [18F]PI-2620 PET scans.•Focus on a 20–40-minute window and basal ganglia for diagnosing 4R-Tauopathies.•Parametric images from dynamic scans improve diagnostic accuracy. Standardized evaluation of [18F]PI-2620 tau-PET scans in 4R-tauopathies represents an unmet need in clinical practice. This study aims to investigate the effectiveness of visual evaluation of [18F]PI-2620 images for diagnosing 4R-tauopathies and to develop a straight-forward reading algorithm to improve objectivity and data reproducibility. A total of 83 individuals with [18F]PI-2620 PET scans were included. Participants were classified as probable 4R-tauopathies (n = 29), Alzheimer's disease (AD) (n = 20), α-synucleinopathies (n = 15), and healthy controls (n = 19) based on clinical criteria. Visual assessment of tau-PET scans (choice: 4R-tauopathy, AD-tauopathy, no-tauopathy) was conducted using either 20–40-minute or 40–60-minute intervals, with raw (common) and cerebellar grey matter scaled standardized reading settings (intensity-scaled). Two readers evaluated scans independently and blinded, with a third reader providing consensus in case of discrepant primary evaluation. A regional analysis was performed using the cortex, basal ganglia, midbrain, and dentate nucleus. Sensitivity, specificity, and interrater agreement were calculated for all settings and compared against the visual reads of parametric images (0–60-minutes, distribution volume ratios, DVR). Patients with 4R-tauopathies in contrast to non-4R-tauopathies were detected at higher sensitivity in the 20–40-minute frame (common: 79%, scaled: 76%) compared to the 40–60-minute frame (common: 55%, scaled: 62%), albeit with reduced specificity in the common setting (20–40-min: 78%, 40–60-min: 95%), which was ameliorated in the intensity-scaled setting (20–40-min: 91%, 40–60-min: 96%). Combined assessment of multiple brain regions did not significantly improve diagnostic sensitivity, compared to assessing the basal ganglia alone (76% each). Evaluation of intensity-scaled parametric images resulted in higher sensitivity compared to intensity-scaled static scans (86% vs. 76%) at similar specificity (89% vs. 91%). Visual reading of [18F]PI-2620 tau-PET scans demonstrated reliable detection of 4R-tauopathies, particularly when standardized processing methods and early imaging windows were employed. Parametric images should be preferred for visual assessment of 4R-tauopathies.

Objectives Reactive gliosis is a common pathological hallmark of CNS pathology resulting from neurodegeneration and neuroinflammation. In this study we investigate the capability of a novel monoamine oxidase B (MAO-B) PET ligand to monitor reactive astrogliosis in a transgenic mouse model of Alzheimer`s disease (AD). Furthermore, we performed a pilot study in patients with a range of neurodegenerative and neuroinflammatory conditions. Methods A cross-sectional cohort of 24 transgenic (PS2APP) and 25 wild-type mice (age range: 4.3–21.0 months) underwent 60 min dynamic [ 18 F]fluorodeprenyl-D2 ([ 18 F]F-DED), static 18 kDa translocator protein (TSPO, [ 18 F]GE-180) and β-amyloid ([ 18 F]florbetaben) PET imaging. Quantification was performed via image derived input function (IDIF, cardiac input), simplified non-invasive reference tissue modelling (SRTM2, DVR) and late-phase standardized uptake value ratios (SUVr). Immunohistochemical (IHC) analyses of glial fibrillary acidic protein (GFAP) and MAO-B were performed to validate PET imaging by gold standard assessments. Patients belonging to the Alzheimer’s disease continuum (AD, n  = 2), Parkinson’s disease (PD, n  = 2), multiple system atrophy (MSA, n  = 2), autoimmune encephalitis ( n  = 1), oligodendroglioma ( n  = 1) and one healthy control underwent 60 min dynamic [ 18 F]F-DED PET and the data were analyzed using equivalent quantification strategies. Results We selected the cerebellum as a pseudo-reference region based on the immunohistochemical comparison of age-matched PS2APP and WT mice. Subsequent PET imaging revealed that PS2APP mice showed elevated hippocampal and thalamic [ 18 F]F-DED DVR when compared to age-matched WT mice at 5 months (thalamus: + 4.3%; p  = 0.048), 13 months (hippocampus: + 7.6%, p  = 0.022) and 19 months (hippocampus: + 12.3%, p  < 0.0001; thalamus: + 15.2%, p  < 0.0001). Specific [ 18 F]F-DED DVR increases of PS2APP mice occurred earlier when compared to signal alterations in TSPO and β-amyloid PET and [ 18 F]F-DED DVR correlated with quantitative immunohistochemistry (hippocampus: R  = 0.720, p  < 0.001; thalamus: R  = 0.727, p  = 0.002). Preliminary experience in patients showed [ 18 F]F-DED V T and SUVr patterns, matching the expected topology of reactive astrogliosis in neurodegenerative (MSA) and neuroinflammatory conditions, whereas the patient with oligodendroglioma and the healthy control indicated [ 18 F]F-DED binding following the known physiological MAO-B expression in brain. Conclusions [ 18 F]F-DED PET imaging is a promising approach to assess reactive astrogliosis in AD mouse models and patients with neurological diseases.

PurposeDynamic 60-min positron emission tomography (PET) imaging with the novel tau radiotracer [18F]PI-2620 facilitated accurate discrimination between patients with progressive supranuclear palsy (PSP) and healthy controls (HCs). This study investigated if truncated acquisition and static time windows can be used for [18F]PI-2620 tau-PET imaging of PSP.MethodsThirty-seven patients with PSP Richardson syndrome (PSP-RS) were evaluated together with ten HCs. [18F]PI-2620 PET was performed by a dynamic 60-min scan. Distribution volume ratios (DVRs) were calculated using full and truncated scan durations (0–60, 0–50, 0–40, 0–30, and 0–20 min p.i.). Standardized uptake value ratios (SUVrs) were obtained 20–40, 30–50, and 40–60 min p.i.. All DVR and SUVr data were compared with regard to their potential to discriminate patients with PSP-RS from HCs in predefined subcortical and cortical target regions (effect size, area under the curve (AUC), multi-region classifier).Results0–50 and 0–40 DVR showed equivalent effect sizes as 0–60 DVR (averaged Cohen’s d: 1.22 and 1.16 vs. 1.26), whereas the performance dropped for 0–30 or 0–20 DVR. The 20–40 SUVr indicated the best performance of all static acquisition windows (averaged Cohen’s d: 0.99). The globus pallidus internus discriminated patients with PSP-RS and HCs at a similarly high level for 0–60 DVR (AUC: 0.96), 0–40 DVR (AUC: 0.96), and 20–40 SUVr (AUC: 0.94). The multi-region classifier sensitivity of these time windows was consistently 86%.ConclusionTruncated and static imaging windows can be used for [18F]PI-2620 PET imaging of PSP. 0–40 min dynamic scanning offers the best balance between accuracy and economic scanning.

Aim We aimed to investigate the impact of microglial activity and microglial FDG uptake on metabolic connectivity, since microglial activation states determine FDG–PET alterations. Metabolic connectivity refers to a concept of interacting metabolic brain regions and receives growing interest in approaching complex cerebral metabolic networks in neurodegenerative diseases. However, underlying sources of metabolic connectivity remain to be elucidated. Materials and methods We analyzed metabolic networks measured by interregional correlation coefficients (ICCs) of FDG–PET scans in WT mice and in mice with mutations in progranulin ( Grn ) or triggering receptor expressed on myeloid cells 2 ( Trem2 ) knockouts ( −/− ) as well as in double mutant Grn −/− / Trem2 −/− mice. We selected those rodent models as they represent opposite microglial signatures with disease associated microglia in Grn −/− mice and microglia locked in a homeostatic state in Trem2 −/− mice ; however, both resulting in lower glucose uptake of the brain . The direct influence of microglia on metabolic networks was further determined by microglia depletion using a CSF1R inhibitor in WT mice at two different ages. Within maps of global mean scaled regional FDG uptake, 24 pre-established volumes of interest were applied and assigned to either cortical or subcortical networks. ICCs of all region pairs were calculated and z-transformed prior to group comparisons. FDG uptake of neurons, microglia, and astrocytes was determined in Grn −/− and WT mice via assessment of single cell tracer uptake (scRadiotracing). Results Microglia depletion by CSF1R inhibition resulted in a strong decrease of metabolic connectivity defined by decrease of mean cortical ICCs in WT mice at both ages studied (6–7 m; p  = 0.0148, 9–10 m; p  = 0.0191), when compared to vehicle-treated age-matched WT mice.  Grn −/− , Trem2 −/− and Grn −/− /Trem2 −/− mice all displayed reduced FDG–PET signals when compared to WT mice. However, when analyzing metabolic networks, a distinct increase of ICCs was observed in Grn −/− mice when compared to WT mice in cortical ( p  < 0.0001) and hippocampal ( p  < 0.0001) networks. In contrast, Trem2 −/− mice did not show significant alterations in metabolic connectivity when compared to WT. Furthermore, the increased metabolic connectivity in Grn −/− mice was completely suppressed in Grn −/− /Trem2 −/− mice. Grn −/− mice exhibited a severe loss of neuronal FDG uptake (− 61%, p  < 0.0001) which shifted allocation of cellular brain FDG uptake to microglia (42% in Grn −/− vs. 22% in WT). Conclusions Presence, absence, and activation of microglia have a strong impact on metabolic connectivity of the mouse brain. Enhanced metabolic connectivity is associated with increased microglial FDG allocation. Highlights Microglial activation influences metabolic connectivity. Microglial depletion results in distinct decreases of metabolic connectivity. Metabolic connectivity increases in progranulin deficient mice. Cellular FDG allocation in progranulin deficient mice is shifted to microglia.

•Three distinct small animal PET scanners show high agreement in Aβ-PET quantification, crucial for multicentric AD research.•Variability in scanner sensitivity affects individual-level interpretation despite stable group differences.•Spatial analysis confirms consistency, while PET imaging correlates well with histological staining, validating its reliability. β-amyloid (Aβ) small animal PET facilitates quantification of fibrillar amyloidosis in Alzheimer's disease (AD) mouse models. Thus, the methodology is receiving growing interest as a monitoring tool in preclinical drug trials. In this regard, harmonization of data from different scanners at multiple sites would allow the establishment large collaborative cohorts and may facilitate efficacy comparison of different treatments. Therefore, we objected to determine the level of agreement of Aβ-PET quantification by a head-to-head comparison of three different state-of-the-art small animal PET scanners, which could help pave the way for future multicenter studies. Within a timeframe of 5 ± 2 weeks, transgenic APPPS1 (n = 9) and wild-type (WT) (n = 8) mice (age range: 13–16 months) were examined three times by Aβ-PET ([18F]florbetaben) using a Siemens Inveon DPET, a MedisonanoScan PET/MR, and a MedisonanoScan PET/CT with harmonized reconstruction protocols. Cortex-to-white-matter 30–60 min p.i. standardized uptake value ratios (SUVRCTX/WM) were calculated to compare binding differences, effect sizes (Cohen's d) and z-score values of APPPS1 relative to WT mice. Correlation coefficients (Pearson's r) were calculated for the agreement of individual SUVR between different scanners. Voxel-wise analysis was used to determine the agreement of spatial pathology patterns. For validation of PET imaging against the histological gold standard, individual SUVR values were subject to a correlation analysis with area occupancy of methoxy‑X04 staining. All three small animal PET scanners yielded comparable group differences between APPPS1 and WT mice (∆PET=20.4 % ± 2.9 %, ∆PET/MR=18.4 % ± 4.5 %, ∆PET/CT=18.1 % ± 3.3 %). Voxel-wise analysis confirmed a high degree of congruency of the spatial pattern (Dice coefficient (DC)PETvs.PET/MR=83.0 %, DCPETvs.PET/CT=69.3 %, DCPET/MRvs.PET/CT=81.9 %). Differences in the group level variance of the three scanners resulted in divergent z-scores (zPET=11.5 ± 1.6; zPET/MR=5.3 ± 1.3; zPET/CT=3.4 ± 0.6) and effect sizes (dPET=8.5, dPET/MR=4.5, dPET/CT=4.1). However, correlations at the individual mouse level were still strong between scanners (rPETvs.PET/MR=0.96, rPETvs.PET/CT=0.91, rPET/MRvs.PET/CT=0.87; all p ≤ 0.0001). Methoxy-X04 staining exhibited a significant correlation across all three PET machines combined (r = 0.76, p < 0.0001) but also at individual level (PET: r = 0.81, p = 0.026; PET/MR: r = 0.89, p = 0.0074; PET/CT: r = 0.93, p = 0.0028). Our comparison of standardized small animal Aβ-PET acquired by three different scanners substantiates the possibility of moving towards a multicentric approach in preclinical AD research. The alignment of image acquisition and analysis methods achieved good overall comparability between data sets. Nevertheless, differences in variance of sensitivity and specificity of different scanners may limit data interpretation at the individual mouse level and deserves methodological optimization.

Heterozygous pathogenic variants in the STIP1 homologous and U-box containing protein 1 ( STUB1 ) gene have been identified as causes of autosomal dominant inherited spinocerebellar ataxia type 48 (SCA48). SCA48 is characterized by an ataxic movement disorder that is often, but not always, accompanied by a cognitive affective syndrome. We report a severe early onset dementia syndrome that mimics frontotemporal dementia and is caused by the intronic splice donor variant c.524+1G>A in STUB1 . Impaired splicing was demonstrated by RNA analysis and in minigene assays of mutated and wild-type constructs of STUB1 . The most striking consequence of this splicing impairment was retention of intron 3 in STUB1 , which led to an in-frame insertion of 63 amino acids (aa) (p.Arg175_Glu176ins63) into the highly conserved coiled-coil domain of its encoded protein, C-terminus of HSP70-interacting protein (CHIP). To a lesser extent, activation of two cryptic splice sites in intron 3 was observed. The almost exclusively used one, c.524+86, was not predicted by in silico programs. Variant c.524+86 caused a frameshift (p.Arg175fs*93) that resulted in a truncated protein and presumably impairs the C-terminal U-box of CHIP, which normally functions as an E3 ubiquitin ligase. The cryptic splice site c.524+99 was rarely used and led to an in-frame insertion of 33 aa (p.Arg175_Glu176ins33) that resulted in disruption of the coiled-coil domain, as has been previously postulated for complete intron 3 retention. We additionally detected repeat expansions in the range of reduced penetrance in the TATA box-binding protein ( TBP ) gene by excluding other genes associated with dementia syndromes. The repeat expansion was heterozygous in one patient but compound heterozygous in the more severely affected patient. Therefore, we concluded that the observed severe dementia syndrome has a digenic background, making STUB1 and TBP important candidate genes responsible for early onset dementia syndromes.

Background/Objectives: 123Iodo-metaiodobenzylguanidine single photon emission computed tomography/computed tomography (123I-MIBG SPECT/CT) is used to evaluate the cardiac sympathetic nervous system in cardiac diseases such as arrhythmogenic right ventricular cardiomyopathy (ARVC) and α-synucleinopathies such as Parkinson’s diseases. A common feature of these diseases is denervation. We aimed to compare quantitative and semi-quantitative cardiac sympathetic innervation using 123I-MIBG imaging of ARVC and α-synucleinopathies. Methods: Cardiac innervation was assessed using 123I-MIBG SPECT/CT in 20 patients diagnosed with definite ARVC and 8 patients with clinically diagnosed α-synucleinopathies. Heart-to-mediastinum-ratio (H/M-ratio), as semi-quantitative, was evaluated. Additionally, standardized uptake value (SUV), as quantitative, was measured as SUVmedian, SUVmax, and SUVpeak in the left ventricle (LV), the right ventricle (RV), and in the global heart, based on a CT scan following quantitative image reconstruction. Results: The quantification of 123I-MIBG uptake in the LV, the RV, and the global heart was feasible in patients suffering from α-synucleinopathies. SUVmedian, and SUVpeak demonstrated a significant difference between ARVC and α-synucleinopathies across all regions, with the α-synucleinopathy group showing a lower uptake. In addition, the H/M ratio showed significantly lower uptake in patients with α-synucleinopathies than in patients with ARVC. Conclusions: Patients with α-synucleinopathies demonstrate significantly lower cardiac innervation in semi-quantitative and quantitative examinations than ARVC patients. The comparison of semi-quantitative and quantitative examinations suggests that quantitative examination offers an advantage. Quantitative analysis can be performed separately for the LV, RV, and global heart. However, analyzing the LV or RV does not provide additional benefit over analyzing the global heart in distinguishing between α-synucleinopathies and ARVC. Considering the different clinical manifestations of these two diseases, the absolute SUV values should not be generalized across different pathologies, and disease-specific ranges should be used instead.

Abstract PurposeEarly after [18F]PI-2620 PET tracer administration, perfusion imaging has potential for regional assessment of neuronal injury in neurodegenerative diseases. This is while standard late-phase [18F]PI-2620 tau-PET is able to discriminate the 4-repeat tauopathies progressive supranuclear palsy and corticobasal syndrome (4RTs) from disease controls and healthy controls. Here, we investigated whether early-phase [18F]PI-2620 PET has an additive value for biomarker based evaluation of 4RTs.MethodsSeventy-eight patients with 4RTs (71 ± 7 years, 39 female), 79 patients with other neurodegenerative diseases (67 ± 12 years, 35 female) and twelve age-matched controls (69 ± 8 years, 8 female) underwent dynamic (0–60 min) [18F]PI-2620 PET imaging. Regional perfusion (0.5–2.5 min p.i.) and tau load (20–40 min p.i.) were measured in 246 predefined brain regions [standardized-uptake-value ratios (SUVr), cerebellar reference]. Regional SUVr were compared between 4RTs and controls by an ANOVA including false-discovery-rate (FDR, p < 0.01) correction. Hypoperfusion in resulting 4RT target regions was evaluated at the patient level in all patients (mean value − 2SD threshold). Additionally, perfusion and tau pattern expression levels were explored regarding their potential discriminatory value of 4RTs against other neurodegenerative disorders, including validation in an independent external dataset (n = 37), and correlated with clinical severity in 4RTs (PSP rating scale, MoCA, activities of daily living).ResultsPatients with 4RTs had significant hypoperfusion in 21/246 brain regions, most dominant in thalamus, caudate nucleus, and anterior cingulate cortex, fitting to the topology of the 4RT disease spectrum. However, single region hypoperfusion was not specific regarding the discrimination of patients with 4RTs against patients with other neurodegenerative diseases. In contrast, perfusion pattern expression showed promise for discrimination of patients with 4RTs from other neurodegenerative diseases (AUC: 0.850). Discrimination by the combined perfusion-tau pattern expression (AUC: 0.903) exceeded that of the sole tau pattern expression (AUC: 0.864) and the discriminatory power of the combined perfusion-tau pattern expression was replicated in the external dataset (AUC: 0.917). Perfusion but not tau pattern expression was associated with PSP rating scale (R = 0.402; p = 0.0012) and activities of daily living (R =  − 0.431; p = 0.0005).Conclusion[18F]PI-2620 perfusion imaging mirrors known topology of regional hypoperfusion in 4RTs. Single region hypoperfusion is not specific for 4RTs, but perfusion pattern expression may provide an additive value for the discrimination of 4RTs from other neurodegenerative diseases and correlates closer with clinical severity than tau pattern expression.

Aim/introduction Quantitative 177 Lu-SPECT allows for patient specific dosimetry, but due to the limited spatial resolution absorbed doses (AD) can be underestimated. Implementation of the Lucy-Richardson deconvolution (LRD) algorithm for spill-over correction in PET has been investigated. Therefore, the aim of this study was to extend the potential application of LRD to 177 Lu-SPECT based tumor dosimetry. Materials/methods The NEMA IEC Body Phantom (foreground-to-background ratio 8:1, 237:30 kBq/mL) was measured according to the local imaging and reconstruction protocol. The two main parameters of LRD, sigma and number of iterations, were determined in two steps. First, a matched filter resolution analysis was conducted on the ground truth activity distribution as segmented from the NEMA IEC Body Phantom data to define the sigma of a 3D Gaussian point-spread-function, which describes the system’s spatial resolution. Secondly, using this sigma, a suitable number of LRD iterations was determined by comparing sphere recovery coefficients (RC) and signal-to-noise ratios. The selected parameters were then applied to the reconstructed SPECT series (24, 48, and 72 h post-injection) of 20 patients who received either [ 177 Lu]Lu-DOTA-TATE ( n  = 10) or [ 177 Lu]Lu-PSMA-I&T (y = 10) treatment, in order to evaluate its impact on AD estimates. Lesion AD from the original reconstruction (OR) and OR + LRD were estimated using MIM SurePlan™ MRT. The AD from OR, OR + LRD, and OR + RC (phantom-based recovery correction based on volume) were compared. Results A sigma of 6.0 mm and four iterations resulted in an average improvement of 18.9 ± 4.7% and 17.4 ± 7.6% in the sphere recovery coefficients and the signal to noise ratio, respectively. In total, 98 lesions were evaluated ([ 177 Lu]Lu-DOTA-TATE: n  = 42) ([ 177 Lu]Lu-PSMA-I&T: y = 56). For OR + LRD and OR + RC an average increase of 22 ± 12% and 57 ± 36% of tumor AD was found. Conclusion OR + LRD increased AD compared to OR, independent of administered radiopharmaceutical and lesion location. This study suggests that implementing LRD may be a promising option for image-based spill-over correction in 177 Lu-SPECT based dosimetry. Further studies are necessary to investigate the effect of different PVC methods, such as LRD or phantom-based correction factors, on overall uncertainty of lesion ADs. Graphical Abstract

Background Accurate tumor delineation in somatostatin receptor (SSTR) PET/CT is imperative for quantifying tumor burden, therapy monitoring, and response assessment in gastroenteropancreatic neuroendocrine tumors (GEPNETs). This study aimed to evaluate different SSTR PET-based tumor delineation approaches, based on a lymph node metastasis as reference standard, and determine the most robust method for volume assessment. Singular, non-bulky lymph node metastases with a short axis diameter ≥ 1.0 cm from [¹⁸F]SiTATE PET/CT scans were included. Different tumor delineation methods were applied: fixed SUV thresholds, isocontours relative to SUV max , and individual backwards thresholding. The correlation between PET-derived volumes and CT-derived volumes (reference standard) were investigated. Results An isocontour approach using 45% of SUV max demonstrated the strongest correlation with CT-derived volumes ( r  = 0.874; r² = 0.764; p  < 0.001), outperforming fixed SUV thresholds, e.g. SUV 4.0 ( r  = 0.727; r 2  = 0.529; p  < 0.001). The application of a backwards threshold approach resulted in the identification of significant variability (CoV: 59.6% for fixed SUV, 31.3% for isocontour). Conclusion The 45% isocontour-thresholding relative to lesional SUV max approach constitutes a robust and clinically applicable method for SSTR PET-based tumor delineation in GEPNET patients, irrespective of changes of SSTR avidity of reference tissues (e.g. liver). Further validation is required to establish its role in total tumor volume assessment and therapy monitoring.