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Background: Dynamic PET imaging studies provide accurate estimates of specific binding, but also measure the relative tracer delivery (R 1 ), which is a proxy for relative cerebral blood flow (rCBF). Recently, studies suggested that R 1 obtained from different tracers could be used interchangeably and is irrespective of target tissue. However, the similarities or differences of R 1 obtained from different PET tracers still require validation. Therefore, the goal of the current study was to compare R 1 estimates, derived from dynamic [ 18 F]florbetapir (amyloid) and [ 18 F]flortaucipir (tau) PET, in the same subjects with subjective cognitive decline (SCD)., Results: Voxel-wise analysis presented a small cluster (1.6% of the whole brain) with higher R 1 values for [ 18 F]flortaucipir compared to [ 18 F]florbetapir in the Aβ-negative group. These voxels were part of the hippocampus and the left middle occipital gyrus. In part of the thalamus, midbrain and cerebellum, voxels (2.5% of the whole brain) with higher R 1 values for [ 18 F]florbetapir were observed. In the Aβ-positive group, a cluster (0.2% of the whole brain) of higher R 1 values was observed in part of the hippocampus, right parahippocampal gyrus and in the left sagittal stratum for [ 18 F]flortaucipir compared to [ 18 F]florbetapir. Furthermore, in part of the thalamus, left amygdala, midbrain and right parahippocampal gyrus voxels (0.4% of the whole brain) with higher R 1 values for [ 18 F]florbetapir were observed. Despite these differences, [ 18 F]florbetapir R 1 had high correspondence with [ 18 F]flortaucipir R 1 across all regions of interest (ROIs) and subjects (Aβ-:r 2  = 0.79, slope = 0.85, ICC = 0.76; Aβ+: r 2  = 0.87, slope = 0.93, ICC = 0.77)., Conclusion: [ 18 F]flortaucipir and [ 18 F]florbetapir showed similar R 1 estimates in cortical regions. This finding, put together with previous studies, indicates that R 1 could be considered a surrogate for relative cerebral blood flow (rCBF) in the cortex and may be used interchangeably, but with caution, regardless of the choice of these two tracers., (© 2023. The Author(s).)

Both plasma tau phosphorylated at threonine-181 (pTau181) and tau PET show potential for detecting Alzheimer's disease (AD) pathology and predicting clinical progression. In this study, we performed a head-to-head comparison between plasma pTau181 and tau PET along the AD continuum. Methods: We included participants from the Amsterdam Dementia Cohort who underwent 18 F-flortaucipir (tau) PET and had a plasma sample biobanked within 12 mo from tau PET. Fifty subjective cognitive decline (SCD) participants (31 Aβ-negative and 19 Aβ-positive) and 60 Aβ-positive participants with mild cognitive impairment (MCI) or dementia due to AD were included. A subset had 2-y longitudinal plasma pTau181 and tau PET available ( n = 40). Longitudinal neuropsychological test data covering 3.2 ± 2.7 y from both before and after tau PET were available. Plasma pTau181 and tau PET were compared in their accuracies in discriminating between cognitive stage (MCI/AD vs. SCD) and preclinical Aβ status (SCD Aβ-positive vs. SCD Aβ-negative), their associations with cross-sectional and longitudinal neuropsychological test performance, and their longitudinal changes over time. Results: When discriminating between preclinical Aβ status, the area under the curve (AUC) for plasma pTau181 (0.83) and tau PET (entorhinal, 0.87; temporal, 0.85; neocortical, 0.67) were equally high (all DeLong P > 0.05), but tau PET outperformed plasma pTau181 in discriminating MCI/AD from SCD (AUC for plasma pTau181: 0.74; AUCs for tau PET: entorhinal, 0.89; temporal, 0.92; neocortical, 0.89) (all P < 0.01). Overall, tau PET showed stronger associations with cognitive decline and was associated with a wider variety of cognitive tests than plasma pTau181 (plasma pTau181, -0.02 > β < -0.12; tau PET, -0.01 > β < -0.22). Both plasma pTau181 and tau PET increased more steeply over time in MCI/AD than in SCD ( P < 0.05), but only tau PET annual changes were associated with cognitive decline. Conclusion: Our results suggest that plasma pTau181 and tau PET perform equally well in identifying Aβ pathology but that tau PET better monitors disease stage and clinical progression., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Semiquantitative PET measures such as SUV ratio (SUVr) have several advantages over quantitative measures, such as practical applicability and relative computational simplicity. However, SUVr may potentially be affected by changes in blood flow, whereas quantitative measures such as nondisplaceable binding potential (BP ND ) are not. For 18 F-flortaucipir PET, the sensitivity of SUVr for changes in blood flow is currently unknown. Therefore, we compared semiquantitative (SUVr) and quantitative (BP ND ) parameters of longitudinal 18 F-flortaucipir PET scans and assessed their vulnerability to changes in blood flow. Methods: Subjects with subjective cognitive decline ( n  = 38) and Alzheimer disease patients ( n  = 24) underwent baseline and 2-y follow-up dynamic 18 F-flortaucipir PET scans. BP ND and relative tracer delivery were estimated using receptor parametric mapping, and SUVr at 80-100 min was calculated. Regional SUVrs were compared with corresponding distribution volume ratio (BP ND + 1) using paired t tests. Additionally, simulations were performed to model effects of larger flow changes in different binding categories. Results: Results in subjective cognitive decline and Alzheimer disease showed only minor differences between SUVr and BP ND changes over time. Relative tracer delivery changes were small in all groups. Simulations illustrated a variable bias for SUVr depending on the amount of binding. Conclusion: SUVr provided an accurate estimate of changes in specific binding for 18 F-flortaucipir over a 2-y follow-up during which changes in flow were small. Notwithstanding, simulations showed that large(r) flow changes may affect 18 F-flortaucipir SUVr. Given that it is currently unknown to what order of magnitude pharmacotherapeutic interventions may induce changes in cerebral blood flow, caution may be warranted when changes in flow are potentially large(r), as in clinical trials., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Tau accumulation starts during the preclinical phase of Alzheimer's disease and is closely associated with cognitive decline. For preventive purposes, it is important to identify factors associated with tau accumulation and spread. Studying genetically identical twin-pairs may give insight into genetic and environmental contributions to tau pathology, as similarities in identical twin-pairs largely result from genetic factors, while differences in identical twin-pairs can largely be attributed to non-shared, environmental factors. This study aimed to examine similarities and dissimilarities in a cohort of genetically identical older twin-pairs in (i) tau load; and (ii) spatial distribution of tau, measured with 18F-flortaucipir PET. We selected 78 genetically identical twins (39 pairs; average age 73 ± 6 years), enriched for amyloid-β pathology and APOE ε4 carriership, who underwent dynamic 18F-flortaucipir PET. We extracted binding potentials (BPND) in entorhinal, temporal, widespread neocortical and global regions, and examined within-pair similarities in BPND using age and sex corrected intra-class correlations. Furthermore, we tested whether twin-pairs showed a more similar spatial 18F-flortaucipir distribution compared to non-twin pairs, and whether the participant's co-twin could be identified solely based on the spatial 18F-flortaucipir distribution. Last, we explored whether environmental (e.g. physical activity, obesity) factors could explain observed differences in twins of a pair in 18F-flortaucipir BPND. On visual inspection, Alzheimer's disease-like 18F-flortaucipir PET patterns were observed, and although we mainly identified similarities in twin-pairs, some pairs showed strong dissimilarities. 18F-flortaucipir BPND was correlated in twins in the entorhinal (r = 0.40; P = 0.01), neocortical (r = 0.59; P < 0.01) and global (r = 0.56; P < 0.01) regions, but not in the temporal region (r = 0.20; P = 0.10). The 18F-flortaucipir distribution pattern was significantly more similar between twins of the same pair [mean r = 0.27; standard deviation (SD) = 0.09] than between non-twin pairings of participants (mean r = 0.01; SD = 0.10) (P < 0.01), also after correcting for proxies of off-target binding. Based on the spatial 18F-flortaucipir distribution, we could identify with an accuracy of 86% which twins belonged to the same pair. Finally, within-pair differences in 18F-flortaucipir BPND were associated with within-pair differences in depressive symptoms (0.37 < β < 0.56), physical activity (-0.41 < β < -0.42) and social activity (-0.32 < β < -0.36) (all P < 0.05). Overall, identical twin-pairs were comparable in tau load and spatial distribution, highlighting the important role of genetic factors in the accumulation and spreading of tau pathology. Considering also the presence of dissimilarities in tau pathology in identical twin-pairs, our results additionally support a role for (potentially modifiable) environmental factors in the onset of Alzheimer's disease pathological processes, which may be of interest for future prevention strategies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Purpose: Early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD) differ in neuropathological burden and type of cognitive deficits. Assessing tau pathology and relative cerebral blood flow (rCBF) measured with [ 18 F]flortaucipir PET in relation to cognition may help explain these differences between EOAD and LOAD., Methods: Seventy-nine amyloid-positive individuals with a clinical diagnosis of AD (EOAD: n = 35, age-at-PET = 59 ± 5, MMSE = 23 ± 4; LOAD: n = 44, age-at-PET = 71 ± 5, MMSE = 23 ± 4) underwent a 130-min dynamic [ 18 F]flortaucipir PET scan and extensive neuropsychological assessment. We extracted binding potentials (BP ND ) and R 1 (proxy of rCBF) from parametric images using receptor parametric mapping, in medial and lateral temporal, parietal, occipital, and frontal regions-of-interest and used nine neuropsychological tests covering memory, attention, language, and executive functioning. We first examined differences between EOAD and LOAD in BP ND or R 1 using ANOVA (region-of-interest analysis) and voxel-wise contrasts. Next, we performed linear regression models to test for potential interaction effects between age-at-onset and BP ND /R 1 on cognition., Results: Both region-of-interest and voxel-wise contrasts showed higher [ 18 F]flortaucipir BP ND values across all neocortical regions in EOAD. By contrast, LOAD patients had lower R 1 values (indicative of more reduced rCBF) in medial temporal regions. For both tau and flow in lateral temporal, and occipitoparietal regions, associations with cognitive impairment were stronger in EOAD than in LOAD (EOAD BP ND  - 0.76 ≤ stβ ≤  - 0.48 vs LOAD - 0.18 ≤ stβ ≤  - 0.02; EOAD R 1 0.37 ≤ stβ ≤ 0.84 vs LOAD - 0.25 ≤ stβ ≤ 0.16)., Conclusions: Compared to LOAD, the degree of lateral temporal and occipitoparietal tau pathology and relative cerebral blood-flow is more strongly associated with cognition in EOAD., (© 2022. The Author(s).)

[ 11 C]UCB-J is a PET radioligand that binds to the presynaptic vesicle glycoprotein 2A. Therefore, [ 11 C]UCB-J PET may serve as an in vivo marker of synaptic integrity. The main objective of this study was to evaluate the quantitative accuracy and the 28-day test-retest repeatability (TRT) of various parametric quantitative methods for dynamic [ 11 C]UCB-J studies in Alzheimer's disease (AD) patients and healthy controls (HC). Eight HCs and seven AD patients underwent two 60-min dynamic [ 11 C]UCB-J PET scans with arterial sampling over a 28-day interval. Several plasma-input based and reference-region based parametric methods were used to generate parametric images using metabolite corrected plasma activity as input function or white matter semi-ovale as reference region. Different parametric outcomes were compared regionally with corresponding non-linear regression (NLR) estimates. Furthermore, the 28-day TRT was assessed for all parametric methods. Spectral analysis (SA) and Logan graphical analysis showed high correlations with NLR estimates. Receptor parametric mapping (RPM) and simplified reference tissue model 2 (SRTM2) BP ND , and reference Logan (RLogan) distribution volume ratio (DVR) regional estimates correlated well with plasma-input derived DVR and SRTM BP ND . Among the multilinear reference tissue model (MRTM) methods, MRTM1 had the best correspondence with DVR and SRTM BP ND . Among the parametric methods evaluated, spectral analysis (SA) and SRTM2 were the best plasma-input and reference tissue methods, respectively, to obtain quantitatively accurate and repeatable parametric images for dynamic [ 11 C]UCB-J PET., (© 2022. The Author(s).)

Objective: To assess the [ 18 F]flortaucipir binding distribution across MAPT mutations in presymptomatic and symptomatic carriers., Methods: We compared regional [ 18 F]flortaucipir binding potential (BP ND ) derived from a 130-minute dynamic [ 18 F]flortaucipir PET scan in 9 (pre)symptomatic MAPT mutation carriers (4 with P301L [1 symptomatic], 2 with R406W [1 symptomatic], 1 presymptomatic L315R, 1 presymptomatic S320F, and 1 symptomatic G272V carrier) with 30 cognitively normal controls and 52 patients with Alzheimer disease., Results: [ 18 F]Flortaucipir BP ND images showed overall highest binding in the symptomatic carriers. This was most pronounced in the symptomatic R406W carrier in whom tau binding exceeded the normal control range in the anterior cingulate cortex, insula, amygdala, temporal, parietal, and frontal lobe. Elevated medial temporal lobe BP ND was observed in a presymptomatic R406W carrier. The single symptomatic carrier and 1 of the 3 presymptomatic P301L carriers showed elevated [ 18 F]flortaucipir BP ND in the insula, parietal, and frontal lobe compared to controls. The symptomatic G272V carrier exhibited a widespread elevated cortical BP ND , with at neuropathologic examination a combination of 3R pathology and encephalitis. The L315R presymptomatic mutation carrier showed higher frontal BP ND compared to controls. The BP ND values of the S320F presymptomatic mutation carrier fell within the range of controls., Conclusion: Presymptomatic MAPT mutation carriers already showed subtle elevated tau binding, whereas symptomatic MAPT mutation carriers showed a more marked increase in [ 18 F]flortaucipir BP ND . Tau deposition was most pronounced in R406W MAPT (pre)symptomatic mutation carriers, which is associated with both 3R and 4R tau accumulation. Thus, [ 18 F]flortaucipir may serve as an early biomarker for MAPT mutation carriers in mutations that cause 3R/4R tauopathies., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Purpose: Dynamic positron emission tomography (PET) protocols allow for accurate quantification of [ 18 F]flortaucipir-specific binding. However, dynamic acquisitions can be challenging given the long required scan duration of 130 min. The current study assessed the effect of shorter scan protocols for [ 18 F]flortaucipir on its quantitative accuracy., Procedures: Two study cohorts with Alzheimer's disease (AD) patients and healthy controls (HC) were included. All subjects underwent a 130-min dynamic [ 18 F]flortaucipir PET scan consisting of two parts (0-60/80-130 min) post-injection. Arterial sampling was acquired during scanning of the first cohort only. For the second cohort, a second PET scan was acquired within 1-4 weeks of the first PET scan to assess test-retest repeatability (TRT). Three alternative time intervals were explored for the second part of the scan: 80-120, 80-110 and 80-100 min. Furthermore, the first part of the scan was also varied: 0-50, 0-40 and 0-30 min time intervals were assessed. The gap in the reference TACs was interpolated using four different interpolation methods: population-based input function 2T4k&#95;V B (POP-IP&#95;2T4k&#95;V B ), cubic, linear and exponential. Regional binding potential (BP ND ) and relative tracer delivery (R 1 ) values estimated using simplified reference tissue model (SRTM) and/or receptor parametric mapping (RPM). The different scan protocols were compared to the respective values estimated using the original scan acquisition. In addition, TRT of the RPM BP ND and R 1 values estimated using the optimal shortest scan duration was also assessed., Results: RPM BP ND and R 1 obtained using 0-30/80-100 min scan and POP-IP&#95;2T4k&#95;V B reference region interpolation had an excellent correlation with the respective parametric values estimated using the original scan duration (r 2  > 0.95). The TRT of RPM BP ND and R 1 using the shortest scan duration was - 1 ± 5 % and - 1 ± 6 % respectively., Conclusions: This study demonstrated that [ 18 F]flortaucipir PET scan can be acquired with sufficient quantitative accuracy using only 50 min of dual-time-window scanning time., (© 2021. The Author(s).)

Purpose: The simplified reference tissue model (SRTM) is commonly applied for the quantification of brain positron emission tomography (PET) studies, particularly because it avoids arterial cannulation. SRTM requires a validated reference region which is obtained by baseline-blocking or displacement studies. Once a reference region is validated, the use should be verified for each new subject. This verification normally requires volume of distribution (V T ) of a reference region. However, performing dynamic scanning and arterial sampling is not always possible, specifically in elderly subjects and in advanced disease stages. The aim of this study was to investigate the use of non-invasive standardised uptake value (SUV) approaches, in comparison to V T , as a verification of the previously validated grey matter cerebellum reference region for [ 18 F]flortaucipir and [ 18 F]florbetapir PET imaging in Alzheimer's disease (AD) patients and controls., Procedures: Dynamic 130-min [ 18 F]flortaucipir PET scans obtained from nineteen subjects (10 AD patients) and 90-min [ 18 F]florbetapir dynamic scans obtained from fourteen subjects (8 AD patients) were included. Regional V T 's were estimated for both tracers and were considered the standard verification of the previously validated reference region. Non-invasive SUVs corrected for body weight (SUV BW ), lean body mass (SUL), and body surface area (SUV BSA ) were obtained by using later time intervals of the dynamic scans. Simulations were also performed to assess the effect of flow and specific binding (BP ND ) on the SUVs., Results: A low SUV corresponded well with a low V T for both [ 18 F]flortaucipir and [ 18 F]florbetapir. Simulation confirmed that SUVs were only slightly affected by flow changes and that increases in SUV were predominantly determined by the presence of specific binding., Conclusions: In situations where dynamic scanning and arterial sampling is not possible, a low SUV (80-100 min) for [ 18 F]flortaucipir and a low SUV (50-70 min) for [ 18 F]florbetapir may be used as indication for absence of specific binding in the grey matter cerebellum reference region., (© 2021. The Author(s).)

Purpose: In 2017, the Geneva Alzheimer's disease (AD) Biomarker Roadmap initiative adapted the framework of the systematic validation of oncological diagnostic biomarkers to AD biomarkers, with the aim to accelerate their development and implementation in clinical practice. With this work, we assess the maturity of [ 18 F]flortaucipir PET and define its research priorities., Methods: The level of maturity of [ 18 F]flortaucipir was assessed based on the AD Biomarker Roadmap. The framework assesses analytical validity (phases 1-2), clinical validity (phases 3-4), and clinical utility (phase 5)., Results: The main aims of phases 1 (rationale for use) and 2 (discriminative ability) have been achieved. [ 18 F]Flortaucipir binds with high affinity to paired helical filaments of tau and has favorable kinetic properties and excellent discriminative accuracy for AD. The majority of secondary aims of phase 2 were fully achieved. Multiple studies showed high correlations between ante-mortem [ 18 F]flortaucipir PET and post-mortem tau (as assessed by histopathology), and also the effects of covariates on tracer binding are well studied. The aims of phase 3 (early detection ability) were only partially or preliminarily achieved, and the aims of phases 4 and 5 were not achieved., Conclusion: Current literature provides partial evidence for clinical utility of [ 18 F]flortaucipir PET. The aims for phases 1 and 2 were mostly achieved. Phase 3 studies are currently ongoing. Future studies including representative MCI populations and a focus on healthcare outcomes are required to establish full maturity of phases 4 and 5.

Background: The 2017 Alzheimer's disease (AD) Strategic Biomarker Roadmap (SBR) structured the validation of AD diagnostic biomarkers into 5 phases, systematically assessing analytical validity (Phases 1-2), clinical validity (Phases 3-4), and clinical utility (Phase 5) through primary and secondary Aims. This framework allows to map knowledge gaps and research priorities, accelerating the route towards clinical implementation. Within an initiative aimed to assess the development of biomarkers of tau pathology, we revised this methodology consistently with progress in AD research., Methods: We critically appraised the adequacy of the 2017 Biomarker Roadmap within current diagnostic frameworks, discussed updates at a workshop convening the Alzheimer's Association and 8 leading AD biomarker research groups, and detailed the methods to allow consistent assessment of aims achievement for tau and other AD diagnostic biomarkers., Results: The 2020 update applies to all AD diagnostic biomarkers. In Phases 2-3, we admitted a greater variety of study designs (e.g., cross-sectional in addition to longitudinal) and reference standards (e.g., biomarker confirmation in addition to clinical progression) based on construct (in addition to criterion) validity. We structured a systematic data extraction to enable transparent and formal evidence assessment procedures. Finally, we have clarified issues that need to be addressed to generate data eligible to evidence-to-decision procedures., Discussion: This revision allows for more versatile and precise assessment of existing evidence, keeps up with theoretical developments, and helps clinical researchers in producing evidence suitable for evidence-to-decision procedures. Compliance with this methodology is essential to implement AD biomarkers efficiently in clinical research and diagnostics.

[ 11 C]UCB-J is a novel radioligand that binds to synaptic vesicle glycoprotein 2A (SV2A). The main objective of this study was to determine the 28-day test-retest repeatability (TRT) of quantitative [ 11 C]UCB-J brain positron emission tomography (PET) imaging in Alzheimer's disease (AD) patients and healthy controls (HCs). Nine HCs and eight AD patients underwent two 60 min dynamic [ 11 C]UCB-J PET scans with arterial sampling with an interval of 28 days. The optimal tracer kinetic model was assessed using the Akaike criteria (AIC). Micro-/macro-parameters such as tracer delivery (K 1 ) and volume of distribution (V T ) were estimated using the optimal model. Data were also analysed for simplified reference tissue model (SRTM) with centrum semi-ovale (white matter) as reference region. Based on AIC, both 1T2k&#95;V B and 2T4k&#95;V B described the [ 11 C]UCB-J kinetics equally well. Analysis showed that whole-brain grey matter TRT for V T , DVR and SRTM BP ND were -2.2% ± 8.5, 0.4% ± 12.0 and -8.0% ± 10.2, averaged over all subjects. [ 11 C]UCB-J kinetics can be well described by a 1T2k&#95;V B model, and a 60 min scan duration was sufficient to obtain reliable estimates for both plasma input and reference tissue models. TRT for V T , DVR and BP ND was <15% (1SD) averaged over all subjects and indicates adequate quantitative repeatability of [ 11 C]UCB-J PET.

Objective: The clinical phenotype of the rare behavioural variant of Alzheimer's disease (bvAD) is insufficiently understood. Given the strong clinico-anatomical correlations of tau pathology in AD, we investigated the distribution of tau deposits in bvAD, in-vivo and ex-vivo, using positron emission tomography (PET) and postmortem examination., Methods: For the tau PET study, seven amyloid-β positive bvAD patients underwent [ 18 F]flortaucipir or [ 18 F]RO948 PET. We converted tau PET uptake values into standardised (W-)scores, adjusting for age, sex and mini mental state examination in a 'typical' memory-predominant AD (n=205) group. W-scores were computed within entorhinal, temporoparietal, medial and lateral prefrontal, insular and whole-brain regions-of-interest, frontal-to-entorhinal and frontal-to-parietal ratios and within intrinsic functional connectivity network templates. For the postmortem study, the percentage of AT8 (tau)-positive area in hippocampus CA1, temporal, parietal, frontal and insular cortices were compared between autopsy-confirmed patients with bvAD (n=8) and typical AD (tAD;n=7)., Results: Individual regional W-scores ≥1.96 (corresponding to p<0.05) were observed in three cases, that is, case #5: medial prefrontal cortex (W=2.13) and anterior default mode network (W=3.79), case #2: lateral prefrontal cortex (W=2.79) and salience network (W=2.77), and case #7: frontal-to-entorhinal ratio (W=2.04). The remaining four cases fell within the normal distributions of the tAD group. Postmortem AT8 staining indicated no group-level regional differences in phosphorylated tau levels between bvAD and tAD (all p>0.05)., Conclusions: Both in-vivo and ex-vivo, patients with bvAD showed heterogeneous distributions of tau pathology. Since key regions involved in behavioural regulation were not consistently disproportionally affected by tau pathology, other factors are more likely driving the clinical phenotype in bvAD., Competing Interests: Competing interests: OH has acquired research support (for the institution) from Roche, Pfizer, GE Healthcare, Biogen, Eli Lilly and AVID Radiopharmaceuticals. In the past 2 years, he has received consultancy/speaker fees (paid to the institution) from Biogen and Roche. GDR reports research support from Avid Radiopharmaceuticals, GE Healthcare, Eli Lilly, Life Molecular Imaging; Scientific advisory boards for Axon Neurosciences, Eiasi, Merck, Roche; Associate Editor for JAMA Neurology. PS serves/has served on the advisory boards of: Genentech, Novartis, Pfizer, Roche, Danone, Nutricia, Jansen AI, Baxter and Lundbeck. He has been a speaker at symposia organised by Lundbeck, Lilly, Merz, Pfizer, Jansen AI, Danone, Novartis, Roche and Genentech. He serves on the editorial board of Alzheimer’s Research & Therapy and Alzheimer. Disease and Associated Disorders and is a member of the scientific advisory board of the EU Joint Programming Initiative and the French National Plan Alzheimer. The Alzheimer Center receives unrestricted funding from various sources through the VUmc Fonds. He receives no personal compensation for the activities mentioned above., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: The mechanism of synaptic loss in Alzheimer's disease is poorly understood and may be associated with tau pathology. In this combined positron emission tomography (PET) and magnetoencephalography (MEG) study, we aimed to investigate spatial associations between regional tau pathology ([ 18 F]flortaucipir PET), synaptic density (synaptic vesicle 2A [ 11 C]UCB-J PET) and synaptic function (MEG) in Alzheimer's disease., Methods: Seven amyloid-positive Alzheimer's disease subjects from the Amsterdam Dementia Cohort underwent dynamic 130-min [ 18 F]flortaucipir PET, dynamic 60-min [ 11 C]UCB-J PET with arterial sampling and 2 × 5-min resting-state MEG measurement. [ 18 F]flortaucipir- and [ 11 C]UCB-J-specific binding (binding potential, BP ND ) and MEG spectral measures (relative delta, theta and alpha power; broadband power; and peak frequency) were assessed in cortical brain regions of interest. Associations between regional [ 18 F]flortaucipir BP ND , [ 11 C]UCB-J BP ND and MEG spectral measures were assessed using Spearman correlations and generalized estimating equation models., Results: Across subjects, higher regional [ 18 F]flortaucipir uptake was associated with lower [ 11 C]UCB-J uptake. Within subjects, the association between [ 11 C]UCB-J and [ 18 F]flortaucipir depended on within-subject neocortical tau load; negative associations were observed when neocortical tau load was high, gradually changing into opposite patterns with decreasing neocortical tau burden. Both higher [ 18 F]flortaucipir and lower [ 11 C]UCB-J uptake were associated with altered synaptic function, indicative of slowing of oscillatory activity, most pronounced in the occipital lobe., Conclusions: These results indicate that in Alzheimer's disease, tau pathology is closely associated with reduced synaptic density and synaptic dysfunction.

The aim of this study was to investigate the test-retest (TRT) repeatability of various parametric quantification methods for [ 18 F]Flortaucipir positron emission tomography (PET). We included eight subjects with dementia or mild cognitive impairment due to Alzheimer's disease and six cognitively normal subjects. All underwent two 130-min dynamic [ 18 F]Flortaucipir PET scans within 3 ± 1 weeks. Data were analyzed using reference region models receptor parametric mapping (RPM), simplified reference tissue method 2 (SRTM2) and reference logan (RLogan), as well as standardized uptake value ratios (SUVr, time intervals 40-60, 80-100 and 110-130 min post-injection) with cerebellar gray matter as reference region. We obtained distribution volume ratio or SUVr, first for all brain regions and then in three tau-specific regions-of-interest (ROIs). TRT repeatability (%) was defined as |retest-test|/(average (test + retest)) × 100. For all methods and across ROIs, TRT repeatability ranged from (median (IQR)) 0.84% (0.68-2.15) to 6.84% (2.99-11.50). TRT repeatability was good for all reference methods used, although semi-quantitative models (i.e. SUVr) performed marginally worse than quantitative models, for instance TRT repeatability of RPM: 1.98% (0.78-3.58) vs. SUVr 80-100 : 3.05% (1.28-5.52), p  < 0.001. Furthermore, for SUVr 80-100 and SUVr 110-130 , with higher average SUVr, more variation was observed. In conclusion, while TRT repeatability was good for all models used, quantitative methods performed slightly better than semi-quantitative methods.

Purpose: We aimed to investigate associations between tau pathology and relative cerebral blood flow (rCBF), and their relationship with cognition in Alzheimer's disease (AD), by using a single dynamic [ 18 F]flortaucipir positron emission tomography (PET) scan., Methods: Seventy-one subjects with AD (66 ± 8 years, mini-mental state examination (MMSE) 23 ± 4) underwent a dynamic 130-min [ 18 F]flortaucipir PET scan. Cognitive assessment consisted of composite scores of four cognitive domains. For tau pathology and rCBF, receptor parametric mapping (cerebellar gray matter reference region) was used to create uncorrected and partial volume-corrected parametric images of non-displaceable binding potential (BP ND ) and R 1 , respectively. (Voxel-wise) linear regressions were used to investigate associations between BP ND and/or R 1 and cognition . RESULTS: Higher [ 18 F]flortaucipir BP ND was associated with lower R 1 in the lateral temporal, parietal and occipital regions. Higher medial temporal BP ND was associated with worse memory, and higher lateral temporal BP ND with worse executive functioning and language. Higher parietal BP ND was associated with worse executive functioning, language and attention, and higher occipital BP ND with lower cognitive scores across all domains. Higher frontal BP ND was associated with worse executive function and attention. For [ 18 F]flortaucipir R 1 , lower values in the lateral temporal and parietal ROIs were associated with worse executive functioning, language and attention, and lower occipital R 1 with lower language and attention scores. When [ 18 F]flortaucipir BP ND and R 1 were modelled simultaneously, associations between lower R 1 in the lateral temporal ROI  and worse attention remained, as well as for lower parietal R 1 and worse executive functioning and attention., Conclusion: Tau pathology was associated with locally reduced rCBF. Tau pathology and low rCBF were both independently associated with worse cognitive performance. For tau pathology, these associations spanned widespread neocortex, while for rCBF, independent associations were restricted to lateral temporal and parietal regions and the executive functioning and attention domains. These findings indicate that each biomarker may independently contribute to cognitive impairment in AD.

Purpose: In vivo Alzheimer's disease (AD) biomarkers for tau pathology are cerebrospinal fluid (CSF) phosphorylated tau (p-tau) and [ 18 F]flortaucipir positron emission tomography (PET). Our aim was to assess associations between CSF p-tau with [ 18 F]flortaucipir PET and the associations of both tau biomarkers with cognition and atrophy., Methods: We included 78 amyloid positive cognitively impaired patients (clinical diagnoses mild cognitive impairment (MCI, n = 8) and AD dementia (n = 45) and 25 cognitively normal subjects with subjective cognitive decline (SCD) (40% amyloid-positive)). Dynamic 130 min [ 18 F]flortaucipir PET scans were acquired to generate binding potential (BP ND ) images using receptor parametric mapping and standardized uptake values ratios of 80-100 min (SUVr 80-100min ) post injection. We obtained regional BP ND and SUVr from entorhinal, limbic, and neocortical regions-of-interest (ROIs), closely aligning to the neuropathological tau staging schemes. Cognition was assessed using MMSE and composite scores of four cognitive domains, and atrophy was measured using gray matter volume covering the major brain lobes. First, we used linear regressions to investigate associations between CSF p-tau (independent variable) and tau PET (dependent variable). Second, we used linear regressions to investigate associations between CSF p-tau, tau PET (separate independent variables, model 1), and cognition (dependent variable). We then assessed the independent effects of CSF p-tau and tau PET on cognition by simultaneously adding the other tau biomarker as a predictor (model 2). Finally, we performed the same procedure for model 1 and 2, but replaced cognition with atrophy. Models were adjusted for age, sex, time lag between assessments, education (cognition only), and total intracranial volume (atrophy only)., Results: Higher [ 18 F]flortaucipir BP ND was associated with higher CSF p-tau (range of standardized betas (sβ) across ROIs, 0.43-0.46; all p < 0.01). [ 18 F]flortaucipir BP ND was more strongly associated with cognition and atrophy than CSF p-tau. When [ 18 F]flortaucipir BP ND and CSF p-tau were entered simultaneously, [ 18 F]flortaucipir BP ND (range sβ = - 0.20 to - 0.57, all p < 0.05) was strongly associated with multiple cognitive domains and atrophy regions. SUVr showed comparable results to BP ND ., Conclusion: Regional [ 18 F]flortaucipir BP ND correlated stronger with cognition and neurodegeneration than CSF p-tau, suggesting that tau PET more accurately reflects disease severity in AD.

[ 18 F]Flortaucipir is a PET tau tracer used to visualize tau binding in Alzheimer's disease (AD) in vivo. The present study evaluated the performance of several methods to obtain parametric images of [ 18 F]flortaucipir. One hundred and thirty minutes dynamic PET scans were performed in 10 AD patients and 10 controls. Parametric images were generated using different linearization and basis function approaches. Regional binding potential (BP ND ) and volume of distribution (V T ) values obtained from the parametric images were compared with corresponding values derived using the reversible two-tissue compartment model (2T4k&#95;V B ). Performance of SUVr parametric images was assessed by comparing values with distribution volume ratio (DVR) and SRTM-derived BP ND estimates obtained using non-linear regression (NLR). Spectral analysis (SA) ( r 2  = 0.92; slope = 0.99) derived V T correlated well with NLR-derived V T . RPM ( r 2  = 0.95; slope = 0.98) derived BP ND correlated well with NLR-derived DVR. Although SUVr 80-100 min correlated well with NLR-derived DVR ( r 2  = 0.91; slope = 1.09), bias in SUVr appeared to depend on uptake time and underlying level of specific binding. In conclusion, RPM and SA provide parametric images comparable to the NLR estimates. Individual SUVr values are biased compared with DVR and this bias requires further study in a larger dataset in order to understand its consequences.

Purpose: Alpha-synuclein often co-occurs with Alzheimer's disease (AD) pathology in Dementia with Lewy Bodies (DLB). From a dynamic [ 18 F]flortaucipir PET scan we derived measures of both tau binding and relative cerebral blood flow (rCBF). We tested whether regional tau binding or rCBF differed between DLB patients and AD patients and controls and examined their association with clinical characteristics of DLB., Methods: Eighteen patients with probable DLB, 65 AD patients and 50 controls underwent a dynamic 130-minute [ 18 F]flortaucipir PET scan. DLB patients with positive biomarkers for AD based on cerebrospinal fluid or amyloid PET were considered as DLB with AD pathology (DLB-AD+). Receptor parametric mapping (cerebellar gray matter reference region) was used to extract regional binding potential (BP ND ) and R 1 , reflecting (AD-specific) tau pathology and rCBF, respectively. First, we performed regional comparisons of [ 18 F]flortaucipir BP ND and R 1 between diagnostic groups. In DLB patients only, we performed regression analyses between regional [ 18 F]flortaucipir BP ND , R 1 and performance on ten neuropsychological tests., Results: Regional [ 18 F]flortaucipir BP ND in DLB was comparable with tau binding in controls (p > 0.05). Subtle higher tau binding was observed in DLB-AD+ compared to DLB-AD- in the medial temporal and parietal lobe (both p < 0.05). Occipital and lateral parietal R 1 was lower in DLB compared to AD and controls (all p < 0.01). Lower frontal R 1 was associated with impaired performance on digit span forward (standardized beta, stβ = 0.72) and category fluency (stβ = 0.69) tests. Lower parietal R 1 was related to lower delayed (stβ = 0.50) and immediate (stβ = 0.48) recall, VOSP number location (stβ = 0.70) and fragmented letters (stβ = 0.59) scores. Lower occipital R 1 was associated to worse performance on VOSP fragmented letters (stβ = 0.61), all p < 0.05., Conclusion: The amount of tau binding in DLB was minimal and did not differ from controls. However, there were DLB-specific occipital and lateral parietal relative cerebral blood flow reductions compared to both controls and AD patients. Regional rCBF, but not tau binding, was related to cognitive impairment. This indicates that assessment of rCBF may give more insight into disease mechanisms in DLB than tau PET., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Off-target [ 18 F]flortaucipir (tau) PET binding in the choroid plexus causes spill-in into the nearby hippocampus, which may influence the correlation between [ 18 F]flortaucipir binding and measures of cognition. Previously, we showed that partial volume correction (combination of Van Cittert iterative deconvolution and HYPR denoising; PVC HDH) and manually eroding the hippocampus resulted in a significant decrease of the choroid plexus spill-in. In this study, we compared three different approaches for the quantification of hippocampal [ 18 F]flortaucipir signal using a semi-automated technique, and assessed correlations with cognitive performance across methods., Methods: Dynamic 130 min [ 18 F]flortaucipir PET scans were performed in 109 subjects (45 cognitively normal subjects (CN) and 64 mild cognitive impairment/Alzheimer's disease (AD) dementia patients. We extracted hippocampal binding potential (BP ND ) using receptor parametric mapping with cerebellar grey matter as reference region. PVC HDH was performed. Based on our previous study in which we manually eroded 40% ± 10% of voxels of the hippocampus, three hippocampal volumes-of-interest (VOIs) were generated: a non-optimized 100% hippocampal VOI [100%], and combining HDH with eroding a percentage of the highest hippocampus BP ND voxels (i.e. lowering spill-in) resulting in optimized 50%[50%HDH] and 40%[40%HDH] hippocampal VOIs. Cognitive performance was assessed with the Mini-Mental State Examination (MMSE) and Rey auditory verbal learning delayed recall. We performed receiver operating characteristic analyses to investigate which method could best discriminate MCI/AD from controls. Subsequently, we performed linear regressions to investigate associations between the hippocampal [ 18 F]flortaucipir BP ND VOIs and MMSE/delayed recall adjusted for age, sex and education., Results: We found higher hippocampal [ 18 F]flortaucipir BP ND in MCI/AD patients (BP ND100% =0.27±0.15) compared to CN (BP ND100% = 0.07±0.13) and all methods showed comparable discriminative effects (AUC 100% =0.85[CI=0.78-0.93]; AUC 50%HDH =0.84[CI=0.74-0.92]; AUC 40%HDH =0.83[CI=0.74-0.92]). Across groups, higher [ 18 F]flortaucipir BP ND was related to lower scores on MMSE (standardized β 100% =-0.38[CI=-0.57-0.20]; β 50%HDH = -0.37[CI=-0.54-0.19]; β 40%HDH =-0.35[CI=-0.53-0.17], all p<0.001) and delayed recall (standardized β 100% =-0.64[CI=-0.79-0.49]; β 50%HDH = -0.61[CI=-0.76-0.46]; β 40%HDH =-0.59[CI=-0.75-0.44]; all p<0.001), with comparable effect sizes for all hippocampal VOIs., Conclusions: Hippocampal tau load measured with [ 18 F]flortaucipir PET is strongly associated with cognitive function. Both discrimination between diagnostic groups and associations between hippocampal [ 18 F]flortaucipir BP ND and memory were comparable for all methods. The non-optimized 100% hippocampal VOI may be sufficient for clinical interpretation. However, proper correction for choroid plexus spillover and may be required in case of smaller effect sizes between subject groups or for longitudinal studies., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Neuropathological studies have linked tau aggregates to neuronal loss. To describe the spatial distribution of neurofibrillary tangle pathology in post-mortem tissue, Braak staging has been used. The aim of this study was to examine in vivo associations between tau pathology, quantified with [ 18 F]flortaucipir PET in regions corresponding to Braak stages, and atrophy across the Alzheimer's disease (AD) spectrum., Methods: We included 100 subjects, including 58 amyloid-β positive patients with mild cognitive impairment (MCI, n = 6) or AD dementia (n = 52) and 42 controls with subjective cognitive decline (36% amyloid-β positive). All subjects underwent a dynamic [ 18 F]flortaucipir PET to generate non-displaceable binding potential (BP ND ) maps. We extracted average [ 18 F]flortaucipir BP ND entorhinal, Braak III-IV (limbic) and Braak V-VI (neocortical) regions of interest (ROIs). T1-weighted MRI was used to assess gray matter (GM) volumes. We performed linear regression analyses using [ 18 F]flortaucipir BP ND ROIs as independent and GM density (ROI or voxelwise) as dependent variable., Results: In MCI/AD subjects (age [mean ± SD] 65 ± 8 years, MMSE 23 ± 4), [ 18 F]flortaucipir BP ND was higher than in controls (age 65 ± 8, MMSE 29 ± 1) across all ROIs (entorhinal 0.06 ± 0.21 vs 0.46 ± 0.25 p < 0.001, Braak III-IV 0.11 ± 0.10 vs 0.46 ± 0.26, p < 0.001, Braak V-VI 0.07 ± 0.07 vs 0.38 ± 0.29, p < 0.001). In MCI/AD, greater [ 18 F]flortaucipir BP ND in entorhinal cortex was associated with lower GM density in medial temporal lobe (β - 0.40, p < 0.001). Greater [ 18 F]flortaucipir BP ND in ROI Braak III-IV and Braak V-VI was associated with smaller GM density in lateral and inferior temporal, parietal, occipital, and frontal lobes (range standardized βs - 0.30 to - 0.55, p < 0.01), but not in medial temporal lobe (β - 0.22, p 0.07). [ 18 F]Flortaucipir BP ND in ROI Braak I-II was not associated with GM density loss anywhere. When quantifying [ 18 F]flortaucipir BP ND across brain lobes, we observed both local and distant associations with GM atrophy. In controls, there were no significant associations between [ 18 F]flortaucipir BP ND and GM density (standardized βs ranging from - 0.24 to 0.02, all p > 0.05)., Conclusions: In MCI/AD patients, [ 18 F]flortaucipir binding in entorhinal, limbic, and neocortical regions was associated with cortical atrophy.

We examined the relationships between amyloid-β PET and concurrent and longitudinal cognitive performance in 107 cognitively normal individuals with subjective cognitive decline (age: 64 ± 8 years, 44% female, Mini-Mental State Examination score 29 ± 1). All underwent 90-minute dynamic [ 18 F]florbetapir PET scanning and longitudinal neuropsychological tests with a mean follow-up of 3.4 ± 3.0 years. Receptor parametric mapping was used to calculate [ 18 F]florbetapir binding potential (BP ND ), and we performed linear mixed models to assess the relationships between global [ 18 F]florbetapir BP ND and neuropsychological performance. Higher [ 18 F]florbetapir BP ND was related to lower concurrent Mini-Mental State Examination (β ± SE: -1.69 ± 0.63 p < 0.01) and to steeper rate of decline on tasks capturing memory (Rey Auditory Verbal Learning Task immediate [β ± SE -1.81 ± 0.81, p < 0.05] and delayed recall [β ± SE -1.19 ± 0.34, p < 0.01]), attention/executive functions (Stroop II [color] [β ± SE -0.02 ± 0.01, p < 0.05], Stroop III [word-color] [β ± SE -0.03 ± 0.02, p < 0.05]), and language (category fluency [β ± SE -0.04 ± 0.01, p < 0.01]). These findings suggest that higher amyloid-β load in cognitively normal individuals with subjective cognitive decline from a memory clinic is associated with lower concurrent global cognition and with faster rate of decline in a variety of cognitive domains., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Off-target binding in the choroid plexus (CP) may cause spill-in of the tau PET tracer [ 18 F] flortaucipir into the adjacent hippocampus region. The impact of this spill-in on hippocampal uptake was assessed using a novel partial volume correction method (PVC)., Methods: PVC was performed on 20 [ 18 F] flortaucipir dynamic PET scans (10 probable AD and 10 controls). Volumes of interest (VOIs) were defined for both hippocampus and CP. The correlation between hippocampal and CP distribution volume (V T ), with and without PVC, was determined. Both anatomically defined and eroded VOIs were used., Results: For controls, the correlation between hippocampal and CP V T was significantly reduced after using PVC along with an eroded VOI (r 2  = 0.59, slope = 0.80 versus r 2  = 0.15, slope = 0.15; difference: p < 0.05). The same was true for AD patients (p < 0.05)., Conclusion: PVC together with an optimized hippocampal VOI resulted in effective reduction of CP spill-in and improved accuracy of hippocampal V T .

Objective: Screening for Fabry disease in patients with small fiber neuropathy has been suggested, especially since Fabry disease is potentially treatable. However, the diagnostic yield of testing for Fabry disease in isolated small fiber neuropathy patients has never been systematically investigated. Our aim is to determine the presence of Fabry disease in patients with small fiber neuropathy., Methods: Patients referred to our institute, who met the criteria for isolated small fiber neuropathy were tested for Fabry disease by measurement of alpha-Galactosidase A activity in blood, lysosomal globotriaosylsphingosine in urine and analysis on possible GLA gene mutations., Results: 725 patients diagnosed with small fiber neuropathy were screened for Fabry disease. No skin abnormalities were seen except for redness of the hands or feet in 30.9% of the patients. Alfa-Galactosidase A activity was tested in all 725 patients and showed diminished activity in eight patients. Lysosomal globotriaosylsphingosine was examined in 509 patients and was normal in all tested individuals. Screening of GLA for mutations was performed for 440 patients, including those with diminished α-Galactosidase A activity. Thirteen patients showed a GLA gene variant. One likely pathogenic variant was found in a female patient. The diagnosis Fabry disease could not be confirmed over time in this patient. Eventually none of the patients were diagnosed with Fabry disease., Conclusions: In patients with isolated small fiber neuropathy, and no other signs compatible with Fabry disease, the diagnostic yield of testing for Fabry disease is extremely low. Testing for Fabry disease should be considered only in cases with additional characteristics, such as childhood onset, cardiovascular disease, renal failure, or typical skin lesions.

Background: Childhood cancer survival in low-income countries is low., Objective: Our study investigated health-care providers' perspectives on childhood cancer treatment in Indonesia. Their health beliefs and attitudes toward parental financial difficulties, protocol adherence, parental education, and communication were explored., Methods: A self-administered questionnaire was filled in by 222 health-care providers (156 doctors, 51 nurses, 6 social workers, 9 administrators), Results: Health of children with cancer is beyond doctor's control and determined by luck, fate or God according to 35% of health-care providers, 30% were uncertain about this statement, and 35% disagreed. Combination of chemotherapy and alternative treatment is best to achieve cure according to 15% of health-care providers, 50% were uncertain, and 35% disagreed. Prosperous parents adhere better with treatment (67%). Doctors adhere better with cancer treatment for prosperous patients (55%). When dealing with poor families, less elaborate explanation is given (62%), more difficult vocabulary is used (49%), and less cooperation is offered (46%). Reasons for non-adherence with treatment protocol were as follows: financial difficulties parents (82%), side-effects (77%), lack of motivation parents (75%), and inadequate drugs supply at pharmacy (70%). Information about cancer and treatment makes parents more afraid or depressed about future, and parents prefer not to know according to 27% of health-care providers, 20% were uncertain, and 53% disagreed. Communication with parents is hindered by differences in status and social hierarchical structures (83%)., Conclusions: Health-care providers' beliefs about childhood cancer treatment are characterized by much uncertainty and contradiction. This likely affects adherence of health-care providers, parents, and childhood cancer treatment outcome., (Copyright © 2013 John Wiley & Sons, Ltd.)