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Additional file 1: Supplementary Figure 1. Differentially expressed genes at follow-up compared to baseline in amyloid non-accumulators. Data points are based coloured on significance: grey = non-significant, blue = non-significant but with FDR p-value < 0.05, red = significant with FDR p-value < 0.05 and log2FoldChange ± 1. N = 53. Pval on y-axis represents the uncorrected p-value < 0.05 threshold for visualisation. Supplementary Figure 2. Detection of modules using baseline expression data. (A) Scale independence and (B) mean connectivity used to derive the soft power threshold. (C) Clustering of module eigengenes, where similar clusters were merged using a cutHeight =0.25 (red line). (D) Cluster dendrogram of co-expression modules shown, both with the 28 dynamic modules (top row) and final merged 17 modules (bottom row). Supplementary Figure 3. Top 20 general cell types derived from cell-specific enrichment of the highly interconnected genes from the baseline blue WGCNA module. The genes are displayed from left to right ranked by the most significant human tissue-cell-type. The red dotted line is the Bonferronicorrected significance (p = 3.69 × 10 × 10−5) by 1355 tissue-cell types. The grey line is the nominal significance (p = 1 × 10 × 10−3). The Y-axis indicates the tissue-cell-type specificity (–log10 (combined p value)) for each tissue-cell-type from the cell-specific enrichment. Supplementary Figure 4. Detection of modules using follow-up expression data. (A) Scale independence and (B) mean connectivity used to derive the soft power threshold. (C) Clustering of module eigengenes, where similar clusters were merged using a cutHeight =0.25 (red line). (D) Cluster dendrogram of co-expression modules shown, both with the 32 dynamic modules (top row) and final merged 35 modules (bottom row). Supplementary Figure 5. Top 20 general cell types derived from cell-specific enrichment of the highly interconnected genes from the follow-up blue WGCNA module. The genes are displayed from left to right ranked by the most significant human tissue-cell-type. The red dotted line is the Bonferronicorrected significance (p = 3.69 × 10 × 10−5) by 1355 tissue-cell types. The grey line is the nominal significance (p = 1 × 10 × 10−3). The Y-axis indicates the tissue-cell-type specificity (–log10 (combined p value)) for each tissue-cell-type from the cell-specific enrichment. Supplementary Figure 6. Top 20 general cell types derived from cell-specific enrichment of the highly interconnected genes from the follow-up turquoise WCGNA module. The genes are displayed from left to right ranked by the most significant human tissue-cell-type. The red dotted line is the Bonferroni-corrected significance (p = 3.69 × 10 × 10−5) by 1355 tissue-cell types. The grey line is the nominal significance (p = 1 × 10 × 10−3). The Y-axis indicates the tissue-cell-type specificity (–log10 (combined p-value)) for each tissue-cell-type from the cell-specific enrichment. Supplementary Figure 7. Detection of modules using follow-up expression data. (A) Scale independence and mean connectivity used to derive the soft power threshold. (B) Cluster dendrogram of consensus modules.

BACKGROUND: The positron emission tomography (PET) radiotracer [18F]MK-6240 exhibits high specificity for neurofibrillary tangles (NFTs) of tau protein in Alzheimer's disease (AD), high sensitivity to medial temporal and neocortical NFTs, and low within-brain background. Objectives were to develop and validate a reproducible, clinically relevant visual read method supporting [18F]MK-6240 use to identify and stage AD subjects versus non-AD and controls. METHODS: Five expert readers used their own methods to assess 30 scans of mixed diagnosis (47% cognitively normal, 23% mild cognitive impairment, 20% AD, 10% traumatic brain injury) and provided input regarding regional and global positivity, features influencing assessment, confidence, practicality, and clinical relevance. Inter-reader agreement and concordance with quantitative values were evaluated to confirm that regions could be read reliably. Guided by input regarding clinical applicability and practicality, read classifications were defined. The readers read the scans using the new classifications, establishing by majority agreement a gold standard read for those scans. Two naïve readers were trained and read the 30-scan set, providing initial validation. Inter-rater agreement was further tested by two trained independent readers in 131 scans. One of these readers used the same method to read a full, diverse database of 1842 scans; relationships between read classification, clinical diagnosis, and amyloid status as available were assessed. RESULTS: Four visual read classifications were determined: no uptake, medial temporal lobe (MTL) only, MTL and neocortical uptake, and uptake outside MTL. Inter-rater kappas were 1.0 for the naïve readers gold standard scans read and 0.98 for the independent readers 131-scan read. All scans in the full database could be classified; classification frequencies were concordant with NFT histopathology literature. DISCUSSION: This four-class [18F]MK-6240 visual read method captures the presence of medial temporal signal, neocortical expansion associated with disease progression, and atypical distributions that may reflect different phenotypes. The method demonstrates excellent trainability, reproducibility, and clinical relevance supporting clinical use. HIGHLIGHTS: A visual read method has been developed for [18F]MK-6240 tau positron emission tomography.The method is readily trainable and reproducible, with inter-rater kappas of 0.98.The read method has been applied to a diverse set of 1842 [18F]MK-6240 scans.All scans from a spectrum of disease states and acquisitions could be classified.Read classifications are consistent with histopathological neurofibrillary tangle staging literature. ispartof: ALZHEIMERS & DEMENTIA-TRANSLATIONAL RESEARCH & CLINICAL INTERVENTIONS vol:9 issue:1 ispartof: location:United States status: published

Additional file 2: Supplementary Table 1. APOE4 follow-up versus baseline significant differentially expressed genes. Supplementary Table 2. APOE4 non-carriers follow-up versus baseline significant differentially expressed genes. Supplementary Table 3. Cell deconvolution contributions generated using CIBERSORT. Supplementary Table 4. Amyloid non-accumulators follow-up versus baseline significant differentially expressed genes. Supplementary Table 5. Follow-up versus baseline significant differentially expressed genes in amyloid negative-positive and amyloid positive-positive individuals. Supplementary Table 6. Follow-up versus baseline significant differentially expressed genes in amyloid negative individuals. Supplementary Table 7. Direct association scores of significant differentially expressed genes at follow-up versus baseline in APOE4 carriers. Supplementary Table 8. Direct association scores of significant differentially expressed genes at follow-up versus baseline in amyloid negativepositive and amyloid positive-positive individuals. Supplementary Table 9. APOE4 carriers gene set enrichment analysis gene ontology upregulated. Supplementary Table 10. APOE4 non-carriers gene set enrichment analysis gene ontology upregulated. Supplementary Table 11. APOE4 carriers gene set enrichment analysis gene ontology downregulated. Supplementary Table 12. APOE4 non-carriers gene set enrichment analysis gene ontology downregulated. Supplementary Table 13. Amyloid non-accumulators gene set enrichment analysis gene ontology upregulated. Supplementary Table 14. Amyloid non-accumulators gene set enrichment analysis gene ontology downregulated. Supplementary Table 15. Amyloid negative-positive/positive-positive gene set enrichment analysis gene ontology upregulated. Supplementary Table 16. Amyloid negative-negative gene set enrichment analysis gene ontology upregulated. Supplementary Table 17. Amyloid negative-positive/positive-positive gene set enrichment analysis gene ontology downregulated. Supplementary Table 18. Amyloid negative-negative gene set enrichment analysis gene ontology downregulated. Supplementary Table 19. Baseline Blue module enrichment. Supplementary Table 20. Follow-up Blue module enrichment. Supplementary Table 21. Follow-up Turquoise module enrichment.

Purpose: Measuring longitudinal changes in amyloid load in the asymptomatic stage of Alzheimer’s disease is of high relevance for clinical research and progress towards more efficacious, timely treatments. Apolipoprotein E ε4 (APOE4) has a well-established effect on the rate of amyloid accumulation. Here we investigated which region of interest and which reference region perform best at detecting the effect of APOE4 on longitudinal amyloid load in individuals participating in the Flemish Prevent Alzheimer’s Disease Cohort KU Leuven (F-PACK). Methods: Ninety cognitively intact F-PACK participants (baseline age: 68 (52–80) years, 46 males, 42 APOE4 carriers) received structural MRI and 18F-Flutemetamol PET scans at baseline and follow-up (6.2 (3.4–10.9) year interval). Standardised uptake value ratios (SUVRs) and Centiloids (CLs) were calculated in a composite cortical volume of interest (SUVRcomp/CL) and in the precuneus (SUVRprec), and amyloid rate of change derived: (follow-up amyloid load – baseline amyloid load) / time interval (years). Four reference regions were used to derive amyloid load: whole cerebellum, cerebellar grey matter, eroded subcortical white matter, and pons. Results: When using whole cerebellum or cerebellar grey matter as reference region, APOE4 carriers had a significantly higher SUVRcomp amyloid rate of change than non-carriers (pcorr=0.004, t=3.40 (CI 0.005–0.018); pcorr=0.036, t=2.66 (CI 0.003–0.018), respectively). Significance was not observed for eroded subcortical white matter or pons (pcorr=0.144, t=2.13 (CI 0.0003–0.008); pcorr=0.116, t=2.22 (CI 0.005–0.010), respectively). When using CLs as the amyloid measurement, and whole cerebellum, APOE4 carriers had a higher amyloid rate of change than non-carriers (pcorr=0.012, t=3.05 (CI 0.499–2.359)). Significance was not observed for the other reference regions. No significance was observed with any of the reference regions and amyloid rate of change in the precuneus (SUVRprec). Conclusion: In this cognitively intact cohort, a composite neocortical volume of interest together with whole cerebellum or cerebellar grey matter as reference region are the methods of choice for detecting APOE4-dependent differences in amyloid rate of change.

Importance: One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design.Objective: To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates.Design, Setting, and Participants: This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria.Exposures: Alzheimer disease biomarkers detected on PET or in CSF.Main Outcomes and Measures: Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations.Results: Among the 19 097 participants (mean [SD] age, 69.1 [9.8] years; 10 148 women [53.1%]) included, 10 139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P = .04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P = .004), subjective cognitive decline (9%; 95% CI, 3%-15%; P = .005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P = .004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P = .18).Conclusions and Relevance: This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.

Supplemental material, sj-pdf-1-jcb-10.1177_0271678X221076023 for Impact of meningeal uptake and partial volume correction techniques on [18F]MK-6240 binding in aMCI patients and healthy controls by Nathalie Mertens, Laura Michiels, Greet Vanderlinden, Mathieu Vandenbulcke, Robin Lemmens, Koen Van Laere and Michel Koole in Journal of Cerebral Blood Flow & Metabolism

Additional file 1. Supplementary Figures.

Supplemental material, sj-pdf-1-jcb-10.1177_0271678X221076023 for Impact of meningeal uptake and partial volume correction techniques on [18F]MK-6240 binding in aMCI patients and healthy controls by Nathalie Mertens, Laura Michiels, Greet Vanderlinden, Mathieu Vandenbulcke, Robin Lemmens, Koen Van Laere and Michel Koole in Journal of Cerebral Blood Flow & Metabolism

Purpose: To assess the brain metabolic correlates of the different regional extent of ALS, evaluated with the King’s staging system, using brain 18F-2-fluoro-2-deoxy-d-glucose-PET (18F-FDG-PET). Methods: Three hundred ninety ALS cases with King’s stages 1, 2, and 3 (n = 390), i.e., involvement of 1, 2, and 3 body regions respectively, underwent brain 18F-FDG-PET at diagnosis. King’s stage at PET was derived from ALSFRS-R and was regressed out against whole-brain metabolism in the whole sample. The full factorial design confirmed the hypothesis that differences among groups (King’s 1, King’s 2, King’s 3, and 40 healthy controls (HC)) existed overall. Comparisons among stages and between each group and HC were performed. We included age at PET and sex as covariates. Results: Brain metabolism was inversely correlated with stage in medial frontal gyrus bilaterally, and right precentral and postcentral gyri. The full factorial design resulted in a significant main effect of groups. There was no significant difference between stages 1 and 2. Comparing stage 3 to stage 1+2, a significant relative hypometabolism was highlighted in the former in the left precentral and medial frontal gyri, and in the right medial frontal, postcentral, precentral, and middle frontal gyri. The comparisons between each group and HC showed the extension of frontal metabolic changes from stage 1 to stage 3, with the larger metabolic gap between stages 2 and 3. Conclusions: Our findings support the hypothesis that in ALS, the propagation of neurodegeneration follows a corticofugal, regional ordered pattern, extending from the motor cortex to posterior and anterior regions.

Additional file 1. Description of positive findings (localization and number) in the [18F]PSMA-1007-PET/CT scans. Logistic regression analysis of the parameters predicting the presence and number of soft tissue, bone and (pelvic and extrapelvic) lymph node lesions on [18F]PSMA-1007-PET/CT scan and the presence of oligo-recurrence and local recurrence on [18F]PSMA-1007-PET/CT scan.

Supplemental material, sj-pdf-1-jcb-10.1177_0271678X211047759 for Changes in synaptic density in the subacute phase after ischemic stroke: A 11C-UCB-J PET/MR study by Laura Michiels, Nathalie Mertens, Liselot Thijs, Ahmed Radwan, Stefan Sunaert, Mathieu Vandenbulcke, Geert Verheyden, Michel Koole, Koen Van Laere and Robin Lemmens in Journal of Cerebral Blood Flow & Metabolism

Supplemental material, sj-pdf-1-jcb-10.1177_0271678X211047759 for Changes in synaptic density in the subacute phase after ischemic stroke: A 11C-UCB-J PET/MR study by Laura Michiels, Nathalie Mertens, Liselot Thijs, Ahmed Radwan, Stefan Sunaert, Mathieu Vandenbulcke, Geert Verheyden, Michel Koole, Koen Van Laere and Robin Lemmens in Journal of Cerebral Blood Flow & Metabolism

Accurate MR-based attenuation correction (MRAC) is essential for quantitative PET/MR imaging of the brain. In this study, we analyze the regional bias caused by MRAC based on Zero-Echo-Time MR images (ZTEAC) compared to CT-based AC (CTAC) in static and dynamic PET imaging. In addition the results are compared to the performance of the current default Atlas-based AC (AtlasAC) implemented in the GE SIGNA PET/MR. Methods: Thirty static [18F]FDG and 11 dynamic [18}F]PE2I acquisitions from a GE SIGNA PET/MR were reconstructed using ZTEAC (using a research tool, GE Healthcare), single-subject AtlasAC (the current default AC in GE's SIGNA PET/MR) and CTAC (from a PET/CT acquisition of the same day). In the 30 static [18F]FDG reconstructions, the bias caused by ZTEAC and AtlasAC in the mean uptake of 85 anatomical volumes of interest (VOIs) of the Hammers' atlas was analyzed in PMOD. For the 11 dynamic [18}F]PE2I reconstructions, the bias caused by ZTEAC and AtlasAC in the non displaceable binding potential BPnd in the striatum was calculated with cerebellum as the reference region and a simplified reference tissue model. Results: The regional bias caused by ZTEAC in the static [18F]FDG reconstructions ranged from -8.0% to +7.7% (mean 0.1%, SD 2.0%). For AtlasAC this bias ranged from -31.6% to +16.6% (mean -0.4%, SD 4.3%). The bias caused by AtlasAC showed a clear gradient in the cranio-caudal direction (-4.2% in the cerebellum, +6.6% in the left superior frontal gyrus). The bias in the striatal BPnd for the [18F]PE2I reconstructions ranged from -0.8% to +4.8% (mean 1.5%, SD 1.4%) using ZTEAC and from -0.6% to +9.4% using AtlasAC (mean 4.2%, SD 2.6%). Conclusion: ZTEAC provides excellent quantitative accuracy for static and dynamic brain PET/MR, comparable to CTAC, and is clearly superior to the default AtlasAC currently implemented in the GE SIGNA PET/MR., Comment: 23 pages in total, 7 figures, 1 table, 3 supplementary figures, 5 supplementary tables

UNLABELLED: Posterior cortical atrophy (PCA) is a rare focal neurodegenerative syndrome characterized by progressive visuoperceptual and visuospatial deficits, most often due to atypical Alzheimer's disease (AD). We applied insights from basic visual neuroscience to analyze 3D shape perception in humans affected by PCA. Thirteen PCA patients and 30 matched healthy controls participated, together with two patient control groups with diffuse Lewy body dementia (DLBD) and an amnestic-dominant phenotype of AD, respectively. The hierarchical study design consisted of 3D shape processing for 4 cues (shading, motion, texture, and binocular disparity) with corresponding 2D and elementary feature extraction control conditions. PCA and DLBD exhibited severe 3D shape-processing deficits and AD to a lesser degree. In PCA, deficient 3D shape-from-shading was associated with volume loss in the right posterior inferior temporal cortex. This region coincided with a region of functional activation during 3D shape-from-shadingin healthy controls. In PCA patients who performed the same fMRI paradigm, response amplitude during 3D shape-from-shading was reduced in this region. Gray matter volume in this region also correlated with 3D shape-from-shading in AD. 3D shape-from-disparity in PCA was associated with volume loss slightly more anteriorly in posterior inferior temporal cortex as well as in ventral premotor cortex. The findings in right posterior inferior temporal cortex and right premotor cortex are consistent with neurophysiologically based models of the functional anatomy of 3D shape processing. However, in DLBD, 3D shape deficits rely on mechanisms distinct from inferior temporal structural integrity. SIGNIFICANCE STATEMENT: Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by progressive visuoperceptual dysfunction and most often an atypical presentation of Alzheimer's disease (AD) affecting the ventral and dorsal visual streams rather than the medial temporal system. We applied insights fromfundamental visual neuroscience to analyze 3D shape perception in PCA. 3D shape-processing deficits were affected beyond what could be accounted for by lower-order processing deficits. For shading and disparity, this was related to volume loss in regions previously implicated in 3D shape processing in the intact human and nonhuman primate brain. Typical amnestic-dominant AD patients also exhibited 3D shape deficits. Advanced visual neuroscience provides insight into the pathogenesis of PCA that also bears relevance for vision in typical AD.

ImportanceAmyloid-β positron emission tomography (PET) imaging allows in vivo detection of fibrillar plaques, a core neuropathological feature of Alzheimer disease (AD). Its diagnostic utility is still unclear because amyloid plaques also occur in patients with non-AD dementia.ObjectiveTo use individual participant data meta-analysis to estimate the prevalence of amyloid positivity on PET in a wide variety of dementia syndromes.Data sourcesThe MEDLINE and Web of Science databases were searched from January 2004 to April 2015 for amyloid PET studies.Study selectionCase reports and studies on neurological or psychiatric diseases other than dementia were excluded. Corresponding authors of eligible cohorts were invited to provide individual participant data.Data extraction and synthesisData were provided for 1359 participants with clinically diagnosed AD and 538 participants with non-AD dementia. The reference groups were 1849 healthy control participants (based on amyloid PET) and an independent sample of 1369 AD participants (based on autopsy).Main outcomes and measuresEstimated prevalence of positive amyloid PET scans according to diagnosis, age, and apolipoprotein E (APOE) ε4 status, using the generalized estimating equations method.ResultsThe likelihood of amyloid positivity was associated with age and APOE ε4 status. In AD dementia, the prevalence of amyloid positivity decreased from age 50 to 90 years in APOE ε4 noncarriers (86% [95% CI, 73%-94%] at 50 years to 68% [95% CI, 57%-77%] at 90 years; n = 377) and to a lesser degree in APOE ε4 carriers (97% [95% CI, 92%-99%] at 50 years to 90% [95% CI, 83%-94%] at 90 years; n = 593; P

ImportanceCerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies.ObjectiveTo use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI).Data sourcesRelevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators.Study selectionStudies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity.Data extraction and synthesisIndividual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies.Main outcomes and measuresPrevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations.ResultsThe prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality.Conclusions and relevanceAmong persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.

Purpose To assess the brain metabolic correlates of the different regional extent of ALS, evaluated with the King’s staging system, using brain 18F-2-fluoro-2-deoxy-d-glucose-PET (18F-FDG-PET). Methods Three hundred ninety ALS cases with King’s stages 1, 2, and 3 (n = 390), i.e., involvement of 1, 2, and 3 body regions respectively, underwent brain 18F-FDG-PET at diagnosis. King’s stage at PET was derived from ALSFRS-R and was regressed out against whole-brain metabolism in the whole sample. The full factorial design confirmed the hypothesis that differences among groups (King’s 1, King’s 2, King’s 3, and 40 healthy controls (HC)) existed overall. Comparisons among stages and between each group and HC were performed. We included age at PET and sex as covariates. Results Brain metabolism was inversely correlated with stage in medial frontal gyrus bilaterally, and right precentral and postcentral gyri. The full factorial design resulted in a significant main effect of groups. There was no significant difference between stages 1 and 2. Comparing stage 3 to stage 1+2, a significant relative hypometabolism was highlighted in the former in the left precentral and medial frontal gyri, and in the right medial frontal, postcentral, precentral, and middle frontal gyri. The comparisons between each group and HC showed the extension of frontal metabolic changes from stage 1 to stage 3, with the larger metabolic gap between stages 2 and 3. Conclusions Our findings support the hypothesis that in ALS, the propagation of neurodegeneration follows a corticofugal, regional ordered pattern, extending from the motor cortex to posterior and anterior regions.

Purpose Amyloid PET tracers have been developed for in vivo detection of brain fibrillar amyloid deposition in Alzheimer’s disease (AD). To serve as an early biomarker in AD the amyloid PET tracers need to be analysed in multicentre clinical studies. Methods In this study 238 [11C]Pittsburgh compound-B (PIB) datasets from five different European centres were pooled. Of these 238 datasets, 18 were excluded, leaving [11C]PIB datasets from 97 patients with clinically diagnosed AD (mean age 69 ± 8 years), 72 patients with mild cognitive impairment (MCI; mean age 67.5 ± 8 years) and 51 healthy controls (mean age 67.4 ± 6 years) available for analysis. Of the MCI patients, 64 were longitudinally followed for 28 ± 15 months. Most participants (175 out of 220) were also tested for apolipoprotein E (ApoE) genotype. Results [11C]PIB retention in the neocortical and subcortical brain regions was significantly higher in AD patients than in age-matched controls. Intermediate [11C]PIB retention was observed in MCI patients, with a bimodal distribution (64 % MCI PIB-positive and 36 % MCI PIB-negative), which was significantly different the pattern in both the AD patients and controls. Higher [11C]PIB retention was observed in MCI ApoE ε4 carriers compared to non-ApoE ε4 carriers (p

PURPOSE: The use of stably integrated reporter gene imaging provides a manner to monitor the in vivo fate of engrafted cells over time in a non-invasive manner. Here, we optimized multimodal imaging (small-animal PET, Cerenkov luminescence imaging (CLI) and bioluminescence imaging (BLI)) of mesenchymal stem cells (MSCs), by means of the human sodium iodide symporter (hNIS) and firefly luciferase (Fluc) as reporters. METHODS: First, two multicistronic lentiviral vectors (LV) were generated for multimodal imaging: BLI, 124I PET/SPECT and CLI. Expression of the imaging reporter genes was validated in vitro using 99mTcO4- radioligand uptake experiments and BLI. Uptake kinetics, specificity and tracer elution were determined as well as the effect of the transduction process on the cell's differentiation capacity. MSCs expressing the LV were injected intravenously or subcutaneously and imaged using small-animal PET, CLI and BLI. RESULTS: The expression of both imaging reporter genes was functional and specific. An elution of 99mTcO4- from the cells was observed, with 31% retention after 3 h. After labeling cells with 124I in vitro, a significantly higher CLI signal was noted in hNIS expressing murine MSCs. Furthermore, it was possible to visualize cells injected intravenously using BLI or subcutaneously in mice, using 124I small-animal PET, CLI and BLI. CONCLUSIONS: This study identifies hNIS as a suitable reporter gene for molecular imaging with PET and CLI, as confirmed with BLI through the expression of Fluc. It supports the potential for a wider application of hNIS reporter gene imaging and future clinical applications. ispartof: PLOS ONE vol:9 issue:4 ispartof: location:United States status: published