Partial volume correction in longitudinal tau PET studies: is it really needed?

BACKGROUND: [18F]flortaucipir (FTP) tau PET quantification is known to be affected by non-specific binding in off-target regions. Although partial volume correction (PVC) techniques partially account for this effect, their inclusion may also introduce noise and variability into the quantification process. While the impact of these effects has been studied in cross-sectional designs, the benefits and drawbacks of PVC on longitudinal FTP studies is still under scrutiny. The aim of this work was to study the performance of the most common PVC techniques for longitudinal FTP imaging. METHODS: A cohort of 247 individuals from the Alzheimer's Disease Neuroimaging Initiative with concurrent baseline FTP-PET, amyloid-beta (Aß) PET and structural MRI, as well as with follow-up FTP-PET and MRI were included in the study. FTP-PET scans were corrected for partial volume effects using Meltzer's, a simple and popular analytical PVC, and both the region-based voxel-wise (RBV) and the iterative Yang (iY) corrections. FTP SUVR values and their longitudinal rates of change were calculated for regions of interest (ROI) corresponding to Braak Areas I-VI, for a temporal meta-ROI and for regions typically displaying off-target FTP binding (caudate, putamen, pallidum, thalamus, choroid plexus, hemispheric white matter, cerebellar white matter, and cerebrospinal fluid). The longitudinal correlation between binding in off-target and target ROIs was analysed for the different PVCs. Additionally, group differences in longitudinal FTP SUVR rates of change between Aß-negative (A-) and Aß-positive (A+), and between cognitively unimpaired (CU) and cognitively impaired (CI) individuals, were studied. Finally, we compared the ability of different partial-volume-corrected baseline FTP SUVRs to predict longitudinal brain atrophy and cognitive decline. RESULTS: Among off-target ROIs, hemispheric white matter showed the highest correlation with longitudinal FTP SUVR rates from cortical target ROIs (R2=0.28-0.82), with CSF coming in second (R2=0.28-0.42). Application of voxel-wise PVC techniques minimized this correlation, with RBV performing best (R2=0.00-0.07 for hemispheric white matter). PVC also increased group differences between CU and CI individuals in FTP SUVR rates of change across all target regions, with RBV again performing best (No PVC: Cohen's d = 0.26-0.66; RBV: Cohen's d = 0.43-0.74). These improvements were not observed for differentiating A- from A+ groups. Additionally, voxel-wise PVC techniques strengthened the correlation between baseline FTP SUVR and longitudinal grey matter atrophy and cognitive decline. CONCLUSION: Quantification of longitudinal FTP SUVR rates of change is affected by signal from off-target regions, especially the hemispheric white matter and the CSF. Voxel-wise PVC techniques significantly reduce this effect. PVC provided a significant but modest benefit for tasks involving the measurement of group-level longitudinal differences. These findings are particularly relevant for the estimations of sample sizes and analysis methodologies of longitudinal group studies.

Increased Medial Temporal Tau Positron Emission Tomography Uptake in the Absence of Amyloid-ß Positivity.

Importance: An increased tau positron emission tomography (PET) signal in the medial temporal lobe (MTL) has been observed in older individuals in the absence of amyloid-ß (Aß) pathology. Little is known about the longitudinal course of this condition, and its association with Alzheimer disease (AD) remains unclear. Objective: To study the pathologic and clinical course of older individuals with PET-evidenced MTL tau deposition (TMTL+) in the absence of Aß pathology (A-), and the association of this condition with the AD continuum. Design, Setting, and Participants: A multicentric, observational, longitudinal cohort study was conducted using pooled data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain Study (HABS), and the AVID-A05 study, collected between July 2, 2015, and August 23, 2021. Participants in the ADNI, HABS, and AVID-A05 studies (N = 1093) with varying degrees of cognitive performance were deemed eligible if they had available tau PET, Aß PET, and magnetic resonance imaging scans at baseline. Of these, 128 participants did not meet inclusion criteria based on Aß PET and tau PET biomarker profiles (A+ TMTL-). Exposures: Tau and Aß PET, magnetic resonance imaging, cerebrospinal fluid biomarkers, and cognitive assessments. Main Outcomes and Measures: Cross-sectional and longitudinal measures for tau and Aß PET, cortical atrophy, cognitive scores, and core AD cerebrospinal fluid biomarkers (Aß42/40 and tau phosphorylated at threonine 181 p-tau181 available in a subset). Results: Among the 965 individuals included in the study, 503 were women (52.1%) and the mean (SD) age was 73.9 (8.1) years. A total of 51% of A- individuals and 78% of A+ participants had increased tau PET signal in the entorhinal cortex (TMTL+) compared with healthy younger (aged <39 years) controls. Compared with A- TMTL-, A- TMTL+ participants showed statistically significant, albeit moderate, longitudinal (mean [SD], 1.83 [0.84] years) tau PET increases that were largely limited to the temporal lobe, whereas those with A+ TMTL+ showed faster and more cortically widespread tau PET increases. In contrast to participants with A+ TMTL+, those with A- TMTL+ did not show any noticeable Aß accumulation over follow-up (mean [SD], 2.36 [0.76] years). Complementary cerebrospinal fluid analysis confirmed longitudinal p-tau181 increases in A- TMTL+ in the absence of increased Aß accumulation. Participants with A- TMTL+ had accelerated MTL atrophy, whereas those with A+ TMTL+ showed accelerated atrophy in widespread temporoparietal brain regions. Increased MTL tau PET uptake in A- individuals was associated with cognitive decline, but at a significantly slower rate compared with A+ TMTL+. Conclusions and Relevance: In this study, individuals with A- TMTL+ exhibited progressive tau accumulation and neurodegeneration, but these processes were comparably slow, remained largely restricted to the MTL, were associated with only subtle changes in global cognitive performance, and were not accompanied by detectable accumulation of Aß biomarkers. These data suggest that individuals with A- TMTL+ are not on a pathologic trajectory toward AD.

Basal Forebrain Atrophy, Cortical Thinning, and Amyloid-ß Status in Parkinson's disease-Related Cognitive Decline.

BACKGROUND: Degeneration of the cortically-projecting cholinergic basal forebrain (cBF) is a well-established pathologic correlate of cognitive decline in Parkinson's disease (PD). In Alzheimer's disease (AD) the effect of cBF degeneration on cognitive decline was found to be mediated by parallel atrophy of denervated cortical areas. OBJECTIVES: To examine whether the association between cBF degeneration and cognitive decline in PD is mediated by parallel atrophy of cortical areas and whether these associations depend on the presence of comorbid AD pathology. METHODS: We studied 162 de novo PD patients who underwent serial 3 T magnetic resonance imaging scanning (follow-up: 2.33 ± 1.46 years) within the Parkinson's Progression Markers Initiative. cBF volume and regional cortical thickness were automatically calculated using established procedures. Individual slopes of structural brain changes and cognitive decline were estimated using linear-mixed models. Associations between longitudinal cBF degeneration, regional cortical thinning, and cognitive decline were assessed using regression analyses and mediation effects were assessed using nonparametric bootstrap. Complementary analyses assessed the effect of amyloid-ß biomarker positivity on these associations. RESULTS: After controlling for global brain atrophy, longitudinal cBF degeneration was highly correlated with faster cortical thinning (PFDR < 0.05), and thinning in cBF-associated cortical areas mediated the association between cBF degeneration and cognitive decline (rcBF-MoCA = 0.30, P < 0.001). Interestingly, both longitudinal cBF degeneration and its association with cortical thinning were largely independent of amyloid-ß status. CONCLUSIONS: cBF degeneration in PD is linked to parallel thinning of cortical target areas, which mediate the effect on cognitive decline. These associations are independent of amyloid-ß status, indicating that they reflect proper features of PD pathophysiology. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Characteristics of amnestic patients with hypometabolism patterns suggestive of Lewy body pathology.

A clinical diagnosis of Alzheimer's disease dementia (ADD) encompasses considerable pathological and clinical heterogeneity. While Alzheimer's disease patients typically show a characteristic temporo-parietal pattern of glucose hypometabolism on 18F-fluorodeoxyglucose (FDG)-PET imaging, previous studies have identified a subset of patients showing a distinct posterior-occipital hypometabolism pattern associated with Lewy body pathology. Here, we aimed to improve the understanding of the clinical relevance of these posterior-occipital FDG-PET patterns in patients with Alzheimer's disease-like amnestic presentations. Our study included 1214 patients with clinical diagnoses of ADD (n = 305) or amnestic mild cognitive impairment (aMCI, n = 909) from the Alzheimer's Disease Neuroimaging Initiative, who had FDG-PET scans available. Individual FDG-PET scans were classified as being suggestive of Alzheimer's (AD-like) or Lewy body (LB-like) pathology by using a logistic regression classifier trained on a separate set of patients with autopsy-confirmed Alzheimer's disease or Lewy body pathology. AD- and LB-like subgroups were compared on amyloid-ß and tau-PET, domain-specific cognitive profiles (memory versus executive function performance), as well as the presence of hallucinations and their evolution over follow-up (≈6 years for aMCI, ≈3 years for ADD). Around 12% of the aMCI and ADD patients were classified as LB-like. For both aMCI and ADD patients, the LB-like group showed significantly lower regional tau-PET burden than the AD-like subgroup, but amyloid-ß load was only significantly lower in the aMCI LB-like subgroup. LB- and AD-like subgroups did not significantly differ in global cognition (aMCI: d = 0.15, P = 0.16; ADD: d = 0.02, P = 0.90), but LB-like patients exhibited a more dysexecutive cognitive profile relative to the memory deficit (aMCI: d = 0.35, P = 0.01; ADD: d = 0.85 P < 0.001), and had a significantly higher risk of developing hallucinations over follow-up [aMCI: hazard ratio = 1.8, 95% confidence interval = (1.29, 3.04), P = 0.02; ADD: hazard ratio = 2.2, 95% confidence interval = (1.53, 4.06) P = 0.01]. In summary, a sizeable group of clinically diagnosed ADD and aMCI patients exhibit posterior-occipital FDG-PET patterns typically associated with Lewy body pathology, and these also show less abnormal Alzheimer's disease biomarkers as well as specific clinical features typically associated with dementia with Lewy bodies.

Peripheral Inflammation Is Associated with Dopaminergic Degeneration in Parkinson's Disease.

BACKGROUND: Peripheral inflammatory immune responses are suggested to play a major role in dopaminergic degeneration in Parkinson's disease (PD). The neutrophil-to-lymphocyte ratio (NLR) is a well-established biomarker of systemic inflammation in PD. Degeneration of the nigrostriatal dopaminergic system can be assessed in vivo using [123 I]FP-CIT single photon emission computed tomography imaging of striatal dopamine transporter (DAT) density. OBJECTIVES: To assess the relationship between the peripheral immune profile (NLR, lymphocytes, and neutrophils) and striatal DAT density in patients with PD. METHODS: We assessed clinical features, the peripheral immune profile, and striatal [123 I]FP-CIT DAT binding levels of 211 patients with PD (primary-cohort). Covariate-controlled associations between the immune response and striatal DAT levels were assessed using linear regression analyses. For replication purposes, we also studied a separate cohort of 344 de novo patients with PD enrolled in the Parkinson's Progression Markers Initiative (PPMI-cohort). RESULTS: A higher NLR was significantly associated with lower DAT levels in the caudate (primary-cohort: ß = -0.01, p < 0.001; PPMI-cohort: ß = -0.05, p = 0.05) and the putamen (primary-cohort: ß = -0.05, p = 0.02; PPMI-cohort: ß = -0.06, p = 0.02). Intriguingly, a lower lymphocyte count was significantly associated with lower DAT levels in both the caudate (primary-cohort: ß = +0.09, p < 0.05; PPMI-cohort: ß = +0.11, p = 0.02) and the putamen (primary-cohort: ß = +0.09, p < 0.05, PPMI-cohort: ß = +0.14, p = 0.01), but an association with the neutrophil count was not consistently observed (caudate; primary-cohort: ß = -0.05, p = 0.02; PPMI-cohort: ß = 0, p = 0.94; putamen; primary-cohort: ß = -0.04, p = 0.08; PPMI-cohort: ß = -0.01, p = 0.73). CONCLUSIONS: Our findings across two independent cohorts suggest a relationship between systemic inflammation and dopaminergic degeneration in patients with PD. This relationship was mainly driven by the lymphocyte count. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Differential diagnosis of amnestic dementia patients based on an FDG-PET signature of autopsy-confirmed LATE-NC.

INTRODUCTION: Limbic age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is common in advanced age and can underlie a clinical presentation mimicking Alzheimer's disease (AD). We studied whether an autopsy-derived fluorodeoxyglucose positron emission tomography (FDG-PET) signature of LATE-NC provides clinical utility for differential diagnosis of amnestic dementia patients. METHODS: Ante mortem FDG-PET patterns from autopsy-confirmed LATE-NC (N = 7) and AD (N = 23) patients were used to stratify an independent cohort of clinically diagnosed AD dementia patients (N = 242) based on individual FDG-PET profiles. RESULTS: Autopsy-confirmed LATE-NC and AD groups showed markedly distinct temporo-limbic and temporo-parietal FDG-PET patterns, respectively. Clinically diagnosed AD dementia patients showing a LATE-NC-like FDG-PET pattern (N = 25, 10%) were significantly older, showed less abnormal AD biomarker levels, lower APOE ε4, and higher TMEM106B risk allele load. Clinically, they exhibited a more memory-predominant profile and a generally slower disease course. DISCUSSION: An autopsy-derived temporo-limbic FDG-PET signature identifies older amnestic patients whose clinical, genetic, and molecular biomarker features are consistent with underlying LATE-NC.

Differential Effects of Tau Stage, Lewy Body Pathology, and Substantia Nigra Degeneration on 18F-FDG PET Patterns in Clinical Alzheimer Disease.

Comorbid Lewy body (LB) pathology is common in Alzheimer disease (AD). The effect of LB copathology on 18F-FDG PET patterns in AD is yet to be studied. We analyzed associations of neuropathologically assessed tau pathology, LB pathology, and substantia nigra neuronal loss (SNnl) with antemortem 18F-FDG PET hypometabolism in patients with a clinical AD presentation. Methods: Twenty-one patients with autopsy-confirmed AD without LB neuropathologic changes (LBNC) (pure-AD), 24 with AD and LBNC copathology (AD-LB), and 7 with LBNC without fulfilling neuropathologic criteria for AD (pure-LB) were studied. Pathologic groups were compared regarding regional and voxelwise 18F-FDG PET patterns, the cingulate island sign ratio (CISr), and neuropathologic ratings of SNnl. Additional analyses assessed continuous associations of Braak tangle stage and SNnl with 18F-FDG PET patterns. Results: Pure-AD and AD-LB showed highly similar patterns of AD-typical temporoparietal hypometabolism and did not differ in CISr, regional 18F-FDG SUVR, or SNnl. By contrast, pure-LB showed the expected pattern of pronounced posterior-occipital hypometabolism typical for dementia with LB (DLB), and both CISr and SNnl were significantly higher compared with the AD groups. In continuous analyses, Braak tangle stage correlated significantly with more AD-like, and SNnl with more DLB-like, 18F-FDG PET patterns. Conclusion: In autopsy-confirmed AD dementia patients, comorbid LB pathology did not have a notable effect on the regional 18F-FDG PET pattern. A more DLB-like 18F-FDG PET pattern was observed in relation to SNnl, but advanced SNnl was mostly limited to relatively pure LB cases. AD pathology may have a dominant effect over LB pathology in determining the regional neurodegeneration phenotype.

PET study of intravitreal adalimumab pharmacokinetics in a uveitis rat model.

Adalimumab is an anti-TNFα drug approved for uveitis treatment by subcutaneous injection. This administration route exposes patients to systemic adverse effects and makes difficult to obtain therapeutic drug concentrations in the site of action due to the anatomical and physiological barriers of the eye. These inconveniences could be avoided by intravitreal injection. The aim of this study is to evaluate the pharmacokinetic profile and the biodistribution of the intravitreal administration of 89Zr-adalimumab in a uveitis rat model using PET imaging. Adalimumab was radiolabelled to 89Zr with a maximum specific activity of 10 MBq/mg. Four µL containing ≃1.74 MBq of 89Zr-labelled adalimumab were injected into the vitreous. A microPET acquisition was carried out immediately after the injection and at different time points through a 10-day study and blood samples were obtained through the tail vein. Radiolabelling was successfully performed with a radiochemical purity after ultrafiltration of 99.69 %. The antibody ocular pharmacokinetics followed a one-compartment model, showing an intraocular elimination half-life of 15.57 h for healthy rats and  33.64 h for rats with uveitis, implying that 89Zr-adalimumab remains around two times longer in rats with the disease compared to healthy ones. However, blood concentration half-life had similar values in both groups. In conclusion, this study shows for the first time the ocular and blood pharmacokinetic analysis of adalimumab in a uveitis model in rats.

Impact of spill-in counts from off-target regions on [18F]Flortaucipir PET quantification.

BACKGROUND: [18F]Flortaucipir (FTP) PET quantification is usually hindered by spill-in counts from off-target binding (OFF) regions. The present work aims to provide an in-depth analysis of the impact of OFF in FTP PET quantification, as well as to identify optimal partial volume correction (PVC) strategies to minimize this problem. METHODS: 309 amyloid-beta (Aß) negative cognitively normal subjects were included in the study. Additionally, 510 realistic FTP images with different levels of OFF were generated using Monte Carlo simulation (MC). Images were corrected for PVC using both a simple two-compartment and a multi-region method including OFF regions. FTP standardized uptake value ratio (SUVR) was quantified in Braak Areas (BA), the hippocampus (which was not included in Braak I/II) and different OFF regions (caudate, putamen, pallidum, thalamus, choroid plexus (ChPlex), cerebellar white matter (cerebWM), hemispheric white matter (hemisWM) and cerebrospinal fluid (CSF)) using the lower portion of the cerebellum as a reference region. The correlations between OFF and cortical SUVRs were studied both in real and in simulated PET images, with and without PVC. RESULTS: In-vivo, we found correlations between all OFF and target regions, especially strong for the hemisWM (slope>0.63, R2>0.4). All the correlations were attenuated but remained significant after applying PVC, except for the ChPlex. In MC simulations, the hemisWM and CSF were the main contributors to PVE in all BA (slopes 0.15-0.26 and 0.13-0.21 respectively). The hemisWM (slope=0.2), as well as the ChPlex (slope=0.02), influenced SUVRs in the hippocampus. The CerebWM was negatively correlated with all target regions (slope<-0.02, R2>0.8). While no other correlations between OFF and target regions were found, hemisWM was correlated with all OFF regions but the cerebWM (slopes 0.06-0.33). HemisWM correlations attenuated (slopes<0.06) when applying two-compartment PVC, but the hippocampus-ChPlex and the cerebWM correlations required more complex PVC with dedicated compartments for these regions. In-vivo, PVC removed a notably higher fraction of the correlation between OFF regions found to be affected by PVE in the simulation studies and BA (≈50%) than for OFF regions not affected by PVE (16%). CONCLUSION: HemisWM is the main driver of spill-in effects in FTP PET, affecting both target regions and the rest of OFF regions. PVC successfully reduces PVE, even when using a simple two-compartment method. Despite PVC, non-zero correlations were still observed between target and OFF regions in vivo, which suggests the existence of biological or tracer-related contributions to these correlations.

18F-florbetapir PET as a marker of myelin integrity across the Alzheimer's disease spectrum.

PURPOSE: Recent evidence suggests that PET imaging with amyloid-ß (Aß) tracers can be used to assess myelin integrity in cerebral white matter (WM). Alzheimer's disease (AD) is characterized by myelin changes that are believed to occur early in the disease course. Nevertheless, the extent to which demyelination, as measured with Aß PET, contributes to AD progression remains unexplored. METHODS: Participants with concurrent 18F-florbetapir (FBP) PET, MRI, and cerebrospinal fluid (CSF) examinations were included (241 cognitively normal, 347 Aß-positive cognitively impaired, and 207 Aß-negative cognitively impaired subjects). A subset of these participants had also available diffusion tensor imaging (DTI) images (n = 195). We investigated cross-sectional associations of FBP retention in the white matter (WM) with MRI-based markers of WM degeneration, AD clinical progression, and fluid biomarkers. In longitudinal analyses, we used linear mixed models to assess whether FBP retention in normal-appearing WM (NAWM) predicted progression of WM hyperintensity (WMH) burden and clinical decline. RESULTS: In AD-continuum individuals, FBP retention in NAWM was (1) higher compared with WMH regions, (2) associated with DTI-based measures of WM integrity, and (3) associated with longitudinal progression of WMH burden. FBP uptake in WM decreased across the AD continuum and with increasingly abnormal CSF biomarkers of AD. Furthermore, FBP retention in the WM was associated with large-calibre axon degeneration as reflected by abnormal plasma neurofilament light chain levels. Low FBP uptake in NAWM predicted clinical decline in preclinical and prodromal AD, independent of demographics, global cortical Aß, and WMH burden. Most of these associations were also observed in Aß-negative cognitively impaired individuals. CONCLUSION: These results support the hypothesis that FBP retention in the WM is myelin-related. Demyelination levels progressed across the AD continuum and were associated with clinical progression at early stages, suggesting that this pathologic process might be a relevant degenerative feature in the disease course.

SimPET-An open online platform for the Monte Carlo simulation of realistic brain PET data. Validation for 18 F-FDG scans.

PURPOSE: SimPET (www.sim-pet.org) is a free cloud-based platform for the generation of realistic brain positron emission tomography (PET) data. In this work, we introduce the key features of the platform. In addition, we validate the platform by performing a comparison between simulated healthy brain FDG-PET images and real healthy subject data for three commercial scanners (GE Advance NXi, GE Discovery ST, and Siemens Biograph mCT). METHODS: The platform provides a graphical user interface to a set of automatic scripts taking care of the code execution for the phantom generation, simulation (SimSET), and tomographic image reconstruction (STIR). We characterize the performance using activity and attenuation maps derived from PET/CT and MRI data of 25 healthy subjects acquired with a GE Discovery ST. We then use the created maps to generate synthetic data for the GE Discovery ST, the GE Advance NXi, and the Siemens Biograph mCT. The validation was carried out by evaluating Bland-Altman differences between real and simulated images for each scanner. In addition, SPM voxel-wise comparison was performed to highlight regional differences. Examples for amyloid PET and for the generation of ground-truth pathological patients are included. RESULTS: The platform can be efficiently used for generating realistic simulated FDG-PET images in a reasonable amount of time. The validation showed small differences between SimPET and acquired FDG-PET images, with errors below 10% for 98.09% (GE Discovery ST), 95.09% (GE Advance NXi), and 91.35% (Siemens Biograph mCT) of the voxels. Nevertheless, our SPM analysis showed significant regional differences between the simulated images and real healthy patients, and thus, the use of the platform for converting control subject databases between different scanners requires further investigation. CONCLUSIONS: The presented platform can potentially allow scientists in clinical and research settings to perform MC simulation experiments without the need for high-end hardware or advanced computing knowledge and in a reasonable amount of time.

A Systematic Review of PET Textural Analysis and Radiomics in Cancer.

BACKGROUND: Although many works have supported the utility of PET radiomics, several authors have raised concerns over the robustness and replicability of the results. This study aimed to perform a systematic review on the topic of PET radiomics and the used methodologies. METHODS: PubMed was searched up to 15 October 2020. Original research articles based on human data specifying at least one tumor type and PET image were included, excluding those that apply only first-order statistics and those including fewer than 20 patients. Each publication, cancer type, objective and several methodological parameters (number of patients and features, validation approach, among other things) were extracted. RESULTS: A total of 290 studies were included. Lung (28%) and head and neck (24%) were the most studied cancers. The most common objective was prognosis/treatment response (46%), followed by diagnosis/staging (21%), tumor characterization (18%) and technical evaluations (15%). The average number of patients included was 114 (median = 71; range 20-1419), and the average number of high-order features calculated per study was 31 (median = 26, range 1-286). CONCLUSIONS: PET radiomics is a promising field, but the number of patients in most publications is insufficient, and very few papers perform in-depth validations. The role of standardization initiatives will be crucial in the upcoming years.

Is FDG-PET texture analysis related to intratumor biological heterogeneity in lung cancer?

OBJECTIVES: We aimed at investigating the origin of the correlations between tumor volume and 18F-FDG-PET texture indices in lung cancer. METHODS: Eighty-five consecutive patients with newly diagnosed non-small cell lung cancer (NSCLC) underwent a 18F-FDG-PET/CT scan before treatment. Seven phantom spheres uniformly filled with 18F-FDG, and covering a range of activities and volumes similar to that found in lung tumors, were also scanned. Established texture indices were computed for lung tumors and homogeneous spheres. The dependence between textural indices and volume in homogeneous spheres was modeled and then used to predict texture indices in lung tumors. Correlation analyses were carried out between predicted and texture features measured in lung tumors. Cox proportional hazards regression was used to investigate the associations between overall survival and volume-adjusted textural features. RESULTS: All textural features showed strong, non-linear correlations with volume, both in tumors and homogeneous spheres. Correlations between predicted versus measured texture features were very high for contrast (r2 = 0.91), dissimilarity (r2 = 0.90), ZP (r2 = 0.90), GLNN (r2 = 0.86), and homogeneity (r2 = 0.82); high for entropy (r2 = 0.50) and HILAE (r2 = 0.53); and low for energy (r2 = 0.30). Cox regressions showed that among volume-adjusted features, only HILAE was associated with overall survival (b = - 0.35, p = 0.008). CONCLUSION: We have shown that texture indices previously found to be correlated with a number of clinically relevant outcomes might not provide independent information apart from that driven by their correlation with tumor volume, suggesting that these metrics might not be suitable as intratumor heterogeneity markers. KEY POINTS: • Associations between texture FDG-PET indices and overall survival have been widely reported in lung cancer, with tumor volume also being associated with overall survival, and therefore, it is still unclear whether the predictive power of textural indices is simply driven by this correlation. • Our results demonstrated strong non-linear correlations between textural indices and volume, showing an analogous behavior for lung tumors from patients and homogeneous spheres inserted in phantoms. • Our findings showed that texture FDG-PET indices might not provide independent information apart from that driven by their correlation with tumor volume.

Feasibility of Longitudinal Brain PET with Real-Time Arterial Input Function in Rats.

PURPOSE: Preclinical dynamic brain PET studies remain hampered by the limitations related to the measurement of the arterial input function (AIF). In this regard, the use of an arterial-venous shunt is a promising method for the generation of real-time AIFs, but its application in longitudinal studies is still impeded by the cumbersome surgeries and high failure rates. We studied the feasibility and reproducibility of double arterial-venous shunt strategies for conducting longitudinal PET studies with real-time AIFs in rats. PROCEDURES: We studied the feasibility of double arterial-venous shunts in rats in the right/left inguinal region and evaluated inter-animal and intra-animal AIF reproducibilities. Image-derived input function (IDIF) was also obtained for comparison. Dynamic brain FDG PET studies were conducted to estimate kinetic constants and Cerebral Metabolic Rate of Glucose (CMRglc) obtained from standard 2-tissue compartment (2TCM) and Patlak analysis. RESULTS: We showed that longitudinal AIFs from double arterial-venous shunts can be obtained with very high success rate of the surgeries (88 %). Our results provided highly reproducible AIF measurements with low inter-animal variabilities (11 %) and intra-animal variabilities (5-10 %) that were included into the kinetic models, such that longitudinal rate constants and CMRglc can be efficiently estimated without bias associated to the double shunt. Our results indicated that longitudinal IDIF can be also generated without bias along time but showing higher intra-animal uncertainties. CONCLUSIONS: We have demonstrated the feasibility and high reproducibility of conducting longitudinal AIF measurements and consequently accurate kinetic modeling using arterial shunt method.

Intensity normalization methods in brain FDG-PET quantification.

BACKGROUND: The lack of standardization of intensity normalization methods and its unknown effect on the quantification output is recognized as a major drawback for the harmonization of brain FDG-PET quantification protocols. The aim of this work is the ground truth-based evaluation of different intensity normalization methods on brain FDG-PET quantification output. METHODS: Realistic FDG-PET images were generated using Monte Carlo simulation from activity and attenuation maps directly derived from 25 healthy subjects (adding theoretical relative hypometabolisms on 6 regions of interest and for 5 hypometabolism levels). Single-subject statistical parametric mapping (SPM) was applied to compare each simulated FDG-PET image with a healthy database after intensity normalization based on reference regions methods such as the brain stem (RRBS), cerebellum (RRC) and the temporal lobe contralateral to the lesion (RRTL), and data-driven methods, such as proportional scaling (PS), histogram-based method (HN) and iterative versions of both methods (iPS and iHN). The performance of these methods was evaluated in terms of the recovery of the introduced theoretical hypometabolic pattern and the appearance of unspecific hypometabolic and hypermetabolic findings. RESULTS: Detected hypometabolic patterns had significantly lower volumes than the introduced hypometabolisms for all intensity normalization methods particularly for slighter reductions in metabolism . Among the intensity normalization methods, RRC and HN provided the largest recovered hypometabolic volumes, while the RRBS showed the smallest recovery. In general, data-driven methods overcame reference regions and among them, the iterative methods overcame the non-iterative ones. Unspecific hypermetabolic volumes were similar for all methods, with the exception of PS, where it became a major limitation (up to 250 cm3) for extended and intense hypometabolism. On the other hand, unspecific hypometabolism was similar far all methods, and usually solved with appropriate clustering. CONCLUSIONS: Our findings showed that the inappropriate use of intensity normalization methods can provide remarkable bias in the detected hypometabolism and it represents a serious concern in terms of false positives. Based on our findings, we recommend the use of histogram-based intensity normalization methods. Reference region methods performance was equivalent to data-driven methods only when the selected reference region is large and stable.

White matter hyperintensities are associated with subthreshold amyloid accumulation.

The association between white matter hyperintensities (WMH) and amyloid accumulation over time in cognitively normal, amyloid-negative elderly people remains largely unexplored. In order to study whether baseline WMH were associated with longitudinal subthreshold amyloid accumulation, 159 cognitively normal participants from the Alzheimer's Disease Neuroimaging Initiative who were amyloid-negative at baseline were examined. All the participants underwent a T1 and a Fluid-Attenuated Inversion Recovery MRI scan at baseline. Amyloid PET imaging was performed at baseline and follow-up visits in 2-year intervals for up to 8 years. Partial volume correction was applied for quantifying cortical Standardised Uptake Value Ratios (SUVR). The associations between global and regional WMH burden and amyloid accumulation were assessed using linear mixed models adjusted by demographic characteristics and baseline SUVR. Partial volume correction increased the measured annual rate of change (+2.4%) compared to that obtained from non-corrected data (+0.5%). There were no significant correlations between baseline WMHs and baseline subthreshold cortical amyloid uptake. In a longitudinal analysis, increased baseline cortical SUVR and increased baseline burden of global (p â€‹= â€‹0.006), frontal (p â€‹= â€‹0.006), and parietal WMH (p â€‹= â€‹0.003) were associated with faster amyloid accumulation. WMH-related amyloid accumulation occurred in parietal, frontal, and, to a lesser extent, cingulate cortices. These results remained unchanged after a sensitivity analysis excluding participants with the highest cortical SUVRs. This is the first study to identify a specific spatial distribution of WMH which is associated with future amyloid accumulation in cognitively normal elderly subjects without PET-detectable amyloid pathology. These findings may have important implications in prevention trials for the early identification of amyloid accumulation.

Spill-in counts in the quantification of 18F-florbetapir on Aß-negative subjects: the effect of including white matter in the reference region.

BACKGROUND: We aim to provide a systematic study of the impact of white matter (WM) spill-in on the calculation of standardized uptake value ratios (SUVRs) on Aß-negative subjects, and we study the effect of including WM in the reference region as a compensation. In addition, different partial volume correction (PVC) methods are applied and evaluated. METHODS: We evaluated magnetic resonance imaging and 18F-AV-45 positron emission tomography data from 122 cognitively normal (CN) patients recruited at the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cortex SUVRs were obtained by using the cerebellar grey matter (CGM) (SUVRCGM) and the whole cerebellum (SUVRWC) as reference regions. The correlations between the different SUVRs and the WM uptake (WM-SUVRCGM) were studied in patients, and in a well-controlled framework based on Monte Carlo (MC) simulation. Activity maps for the MC simulation were derived from ADNI patients by using a voxel-wise iterative process (BrainViset). Ten WM uptakes covering the spectrum of WM values obtained from patient data were simulated for different patients. Three different PVC methods were tested (a) the regional voxel-based (RBV), (b) the iterative Yang (iY), and (c) a simplified analytical correction derived from our MC simulation. RESULTS: WM-SUVRCGM followed a normal distribution with an average of 1.79 and a standard deviation of 0.243 (13.6%). SUVRCGM was linearly correlated to WM-SUVRCGM (r = 0.82, linear fit slope = 0.28). SUVRWC was linearly correlated to WM-SUVRCGM (r = 0.64, linear fit slope = 0.13). Our MC results showed that these correlations are compatible with those produced by isolated spill-in effect (slopes of 0.23 and 0.11). The impact of the spill-in was mitigated by using PVC for SUVRCGM (slopes of 0.06 and 0.07 for iY and RBV), while SUVRWC showed a negative correlation with SUVRCGM after PVC. The proposed analytical correction also reduced the observed correlations when applied to patient data (r = 0.27 for SUVRCGM, r = 0.18 for SUVRWC). CONCLUSIONS: There is a high correlation between WM uptake and the measured SUVR due to spill-in effect, and that this effect is reduced when including WM in the reference region. We also evaluated the performance of PVC, and we proposed an analytical correction that can be applied to preprocessed data.

Staging the cognitive continuum in prodromal Alzheimer's disease with episodic memory.

It is unclear whether episodic memory is an appropriate descriptor of the cognitive continuum in mild cognitive impairment (MCI). Here, we investigated the ability of episodic memory to track cognitive changes in patients with MCI with biomarker evidence of Alzheimer's disease (AD). We examined 387 MCI amyloid-positive subjects, cognitively staged as "early" or "late" on the basis of episodic memory impairment. Cross-sectional and longitudinal comparisons between these 2 groups were performed for each amyloid, tau, and neurodegeneration (AT(N)) profile. Cross-sectional analyses indicate that "early" MCI represents a transitional phase between normal cognition and "late" MCI in the AD biomarker pathway. After adjusting by confounders and levels of A, T, and (N), "late" MCI progressed significantly faster than "early" MCI only in profiles with both abnormal amyloid and tau markers (A+T+(N)- p < 0.05, A+T+(N)+ p < 0.001). Episodic memory staging is useful for describing symptoms in prodromal AD and complements the AT(N) profiles. Our findings might have implications for the Numeric Clinical staging scheme of the National Institute on Aging and Alzheimer's Association research framework.

Prediction of Alzheimer's disease dementia with MRI beyond the short-term: Implications for the design of predictive models.

Magnetic resonance imaging (MRI) volumetric measures have become a standard tool for the detection of incipient Alzheimer's Disease (AD) dementia in mild cognitive impairment (MCI). Focused on providing an earlier and more accurate diagnosis, sophisticated MRI machine learning algorithms have been developed over the recent years, most of them learning their non-disease patterns from MCI that remained stable over 2-3 years. In this work, we analyzed whether these stable MCI over short-term periods are actually appropriate training examples of non-disease patterns. To this aim, we compared the diagnosis of MCI patients at 2 and 5 years of follow-up and investigated its impact on the predictive performance of baseline volumetric MRI measures primarily involved in AD, i.e., hippocampal and entorhinal cortex volumes. Predictive power was evaluated in terms of the area under the ROC curve (AUC), sensitivity, and specificity in a trial sample of 248 MCI patients followed-up over 5 years. We further compared the sensitivity in those MCI that converted before 2 years and those that converted after 2 years. Our results indicate that 23% of the stable MCI at 2 years progressed in the next three years and that MRI volumetric measures are good predictors of conversion to AD dementia even at the mid-term, showing a better specificity and AUC as follow-up time increases. The combination of hippocampus and entorhinal cortex yielded an AUC that was significantly higher for the 5-year follow-up (AUC = 73% at 2 years vs. AUC = 84% at 5 years), as well as for specificity (56% vs. 71%). Sensitivity showed a non-significant slight decrease (81% vs. 78%). Remarkably, the performance of this model was comparable to machine learning models at the same follow-up times. MRI correctly identified most of the patients that converted after 2 years (with sensitivity >60%), and these patients showed a similar degree of abnormalities to those that converted before 2 years. This implies that most of the MCI patients that remained stable over short periods and subsequently progressed to AD dementia had evident atrophies at baseline. Therefore, machine learning models that use these patients to learn non-disease patterns are including an important fraction of patients with evident pathological changes related to the disease, something that might result in reduced performance and lack of biological interpretability.