Elevated cerebral blood flow proxy with increased beta-amyloid burden in Alzheimer's disease preclinical phase evaluated by dual-phase 18F-florbetaben positron emission tomography.

This study investigated the earliest change of cerebral blood flow (CBF) and its relationship with ß-amyloid (Aß) burden in preclinical Alzheimer's disease (AD) employing dual-phase 18F-florbetaben (FBB) PET. Seventy-one cognitively normal (NC) individuals were classified as Aß negative (Aß-NC) or positive (Aß+NC) based on two different cutoff values: an SUVR of > 1.08 and a Centiloid scale of > 20. The PET scans were acquired in two phases: an early phase (0-10 min, eFBB) and a delayed phase (90-110 min, dFBB), which were averaged to generate single-frame images for each phase. Furthermore, an R1 parametric map was generated from the early phase data using a simplified reference tissue model. We conducted regional and voxel-based analyses to compare the eFBB, dFBB, and R1 images between the Aß positive and negative groups. In addition, the correlations between the CBF proxy R1 and the dFBB SUVR were analyzed. The Aß+NC group showed significantly higher dFBB SUVR in both the global cerebral cortex and target regions compared to the Aß-NC group, while no significant differences were observed in eFBB SUVR between the two groups. Furthermore, the Aß+NC group exhibited significantly higher R1 values, a proxy for cerebral perfusion, in both the global cerebral cortex and target regions compared to the Aß-NC group. Significant positive correlations were observed between R1 and dFBB SUVR in both the global cerebral cortex and target regions, which remained significant after controlling for demographics and cognitive profiles, except for the medial temporal and occipital cortices. The findings reveal increased CBF in preclinical AD and a positive correlation between CBF and amyloid pathology. The positive correlation between R1 and amyloid burden may indicate a compensatory mechanism in the preclinical stage of Alzheimer's disease, but to elucidate this hypothesis, further longitudinal observational studies are necessary.

[18F]-florbetaben PET/CT is sensitive for cardiac AL amyloidosis.

Often differential diagnosis between AL and ATTR amyloidosis is difficult. Concerning ATTR, sensitive diagnostic tool, as diphosphonate scintigraphy, was validated, instead of no imaging approach is as accurate in AL. Cardiac ultrasound and circulating biomarkers may raise the clinical suspicion but biopsy remains the only option for diagnosis. We aimed to explore the sensitivity of 18F-Florbetaben PET respect to blood tests or periumbilical fat (POF), cardiac, bone marrow (BM) or other tissues biopsies in a cohort of 33 patients.

Sensitivity of unconstrained quantitative magnetization transfer MRI to Amyloid burden in preclinical Alzheimer's disease.

Magnetization transfer MRI is sensitive to semi-solid macromolecules, including amyloid beta, and has previously been used to discriminate Alzheimer's disease (AD) patients from controls. Here, we fit an unconstrained 2-pool quantitative MT (qMT) model, i.e., without constraints on the longitudinal relaxation rate R 1 s of semi-solids, and investigate the sensitivity of the estimated parameters to amyloid accumulation in preclinical subjects. We scanned 15 cognitively normal volunteers, of which 9 were amyloid positive by [18F]Florbetaben PET. A 12 min hybrid-state qMT scan with an effective resolution of 1.24 mm isotropic and whole-brain coverage was acquired to estimate the unconstrained 2-pool qMT parameters. Group comparisons and correlations with Florbetaben PET standardized uptake value ratios were analyzed at the lobar level. We find that the exchange rate and semi-solid pool's R 1 s were sensitive to the amyloid concentration, while morphometric measures of cortical thickness derived from structural MRI were not. Changes in the exchange rate are consistent with previous reports in clinical AD, while changes in R 1 s have not been reported previously as its value is typically constrained in the literature. Our results demonstrate that qMT MRI may be a promising surrogate marker of amyloid beta without the need for contrast agents or radiotracers.

Non-invasive quantification of 18F-florbetaben with total-body EXPLORER PET.

BACKGROUND: Kinetic modeling of 18F-florbetaben provides important quantification of brain amyloid deposition in research and clinical settings but its use is limited by the requirement of arterial blood data for quantitative PET. The total-body EXPLORER PET scanner supports the dynamic acquisition of a full human body simultaneously and permits noninvasive image-derived input functions (IDIFs) as an alternative to arterial blood sampling. This study quantified brain amyloid burden with kinetic modeling, leveraging dynamic 18F-florbetaben PET in aorta IDIFs and the brain in an elderly cohort. METHODS: 18F-florbetaben dynamic PET imaging was performed on the EXPLORER system with tracer injection (300 MBq) in 3 individuals with Alzheimer's disease (AD), 3 with mild cognitive impairment, and 9 healthy controls. Image-derived input functions were extracted from the descending aorta with manual regions of interest based on the first 30 s after injection. Dynamic time-activity curves (TACs) for 110 min were fitted to the two-tissue compartment model (2TCM) using population-based metabolite corrected IDIFs to calculate total and specific distribution volumes (VT, Vs) in key brain regions with early amyloid accumulation. Non-displaceable binding potential ([Formula: see text] was also calculated from the multi-reference tissue model (MRTM). RESULTS: Amyloid-positive (AD) patients showed the highest VT and VS in anterior cingulate, posterior cingulate, and precuneus, consistent with [Formula: see text] analysis. [Formula: see text]and VT from kinetic models were correlated (r² = 0.46, P < 2[Formula: see text] with a stronger positive correlation observed in amyloid-positive participants, indicating reliable model fits with the IDIFs. VT from 2TCM was highly correlated ([Formula: see text]= 0.65, P < 2[Formula: see text]) with Logan graphical VT estimation. CONCLUSION: Non-invasive quantification of amyloid binding from total-body 18F-florbetaben PET data is feasible using aorta IDIFs with high agreement between kinetic distribution volume parameters compared to [Formula: see text]in amyloid-positive and amyloid-negative older individuals.

Individuals with Alzheimer's disease and low tau burden: Characteristics and implications.

INTRODUCTION: Abnormal amyloid-beta (Aß) and tau deposition define Alzheimer's Disease (AD), but non-elevated tau is relatively frequent in patients on the AD pathway. METHODS: We examined characteristics and regional patterns of 397 Aß+ unimpaired and impaired individuals with low tau (A+T-) in relation to their higher tau counterparts (A+T+). RESULTS: Seventy-one percent of Aß+ unimpaired and 42% of impaired Aß+ individuals were categorized as A+T- based on global tau. In impaired individuals only, A+T- status was associated with older age, male sex, and greater cardiovascular risk. α-synuclein was linked to poorer cognition, particularly when tau was low. Tau burden was most frequently elevated in a common set of temporal regions regardless of T+/T- status. DISCUSSION: Low tau is relatively common in patients on the AD pathway and is linked to comorbidities that contribute to impairment. These findings have implications for the selection of individuals for Aß- and tau-modifying therapies.

Early-Frame [18F]Florbetaben PET/MRI for Cerebral Blood Flow Quantification in Patients with Cognitive Impairment: Comparison to an [15O]Water Gold Standard.

Cerebral blood flow (CBF) may be estimated from early-frame PET imaging of lipophilic tracers, such as amyloid agents, enabling measurement of this important biomarker in participants with dementia and memory decline. Although previous methods could map relative CBF, quantitative measurement in absolute units (mL/100 g/min) remained challenging and has not been evaluated against the gold standard method of [15O]water PET. The purpose of this study was to develop and validate a minimally invasive quantitative CBF imaging method combining early [18F]florbetaben (eFBB) with phase-contrast MRI using simultaneous PET/MRI. Methods: Twenty participants (11 men and 9 women; 8 cognitively normal, 9 with mild cognitive impairment, and 3 with dementia; 10 ß-amyloid negative and 10 ß-amyloid positive; 69 ± 9 y old) underwent [15O]water PET, phase-contract MRI, and eFBB imaging in a single session on a 3-T PET/MRI scanner. Quantitative CBF images were created from the first 2 min of brain activity after [18F]florbetaben injection combined with phase-contrast MRI measurement of total brain blood flow. These maps were compared with [15O]water CBF using concordance correlation (CC) and Bland-Altman statistics for gray matter, white matter, and individual regions derived from the automated anatomic labeling (AAL) atlas. Results: The 2 methods showed similar results in gray matter ([15O]water, 55.2 ± 14.7 mL/100 g/min; eFBB, 55.9 ± 14.2 mL/100 g/min; difference, 0.7 ± 2.4 mL/100 g/min; P = 0.2) and white matter ([15O]water, 21.4 ± 5.6 mL/100 g/min; eFBB, 21.2 ± 5.3 mL/100 g/min; difference, -0.2 ± 1.0 mL/100 g/min; P = 0.4). The intrasubject CC for AAL-derived regions was high (0.91 ± 0.04). Intersubject CC in different AAL-derived regions was similarly high, ranging from 0.86 for midfrontal regions to 0.98 for temporal regions. There were no significant differences in performance between the methods in the amyloid-positive and amyloid-negative groups as well as participants with different cognitive statuses. Conclusion: We conclude that eFBB PET/MRI can provide robust CBF measurements, highlighting the capability of simultaneous PET/MRI to provide measurements of both CBF and amyloid burden in a single imaging session in participants with memory disorders.

Correlation Between Amyloid PET Imaging and Discordant Cerebrospinal Fluid Biomarkers Results in Patients with Suspected Alzheimer's Disease.

BACKGROUND: Although the concordance between cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers and amyloid-PET findings is well known, there are no data regarding the concordance of amyloid-PET with inconclusive CSF values of amyloid-ß (Aß)1 - 42 and p-tau for the diagnosis of AD. OBJECTIVE: To investigate the relationship between the amyloid-PET results with discordant AD biomarkers values in CSF (Aß1 - 42+/p-tau-or Aß1 - 42-/p-tau+). METHODS: An observational retrospective study, including 62 patients with mild cognitive impairment (32/62) or dementia (30/62), suspicious of AD who had undergone a lumbar puncture to determine CSF AD biomarkers, and presented discordant values in CSF between Aß1 - 42 and p-tau (Aß1 - 42+/p-tau-or Aß1 - 42-/p-tau+). All of them, underwent an amyloid-PET with 18F-Florbetaben. An extensive neuropsychological testing as part of their diagnostic process (MMSE and TMA-93), was performed, and it was also obtained the Global Deterioration Scale. RESULTS: Comparing the discordant CSF results of each patient with the cerebral amyloid-PET results, we found that in the group with Aß1 - 42+ and p-tau-CSF values, the amyloid-PET was positive in 51.2% and negative in 48.8% of patients, while in the group with Aß1 - 42-and p-Tau+ CSF values, the amyloid-PET was positive in 52.6% of patients and negative in 47.4% of them. No significant association was found (p = 0.951) between the results of amyloid-PET and the two divergent groups in CSF. CONCLUSIONS: No significant relationship was observed between the results of discordant AD biomarkers in CSF and the result of amyloid-PET. No trend in amyloid-PET results was observed in relation to CSF biomarker values.

Distinct amyloid-dependent patterns of nigra dopamine depletion in Lewy body diseases.

Introduction: Concomitant amyloid pathology is not uncommon and contributes to the clinical characteristics of Lewy body disease (LBD). We investigated the effect of amyloid on striatal18F-FP-CIT uptake patterns in LBD, including Parkinson's disease (PD) and dementia with Lewy bodies. Methods: We enrolled 125 patients with LBD who underwent18F-florbetaben positron emission tomography (PET) and18F-FP-CIT PET. Patients were divided into amyloid-positive and amyloid-negative groups. We investigated the effect of amyloid on striatal dopamine transporter (DAT) availability, depending on the type of LBD, using general linear models with interaction analysis after controlling for age, sex, education, deep white matter hyperintensity (WMH), periventricular WMH, and cognitive status. Results: There was a significant interaction effect between the disease group and the presence of amyloid on DAT availability in the anterior putamen, posterior putamen, caudate, and ventral striatum. In the presence of amyloid, only the PD group exhibited decreased DAT availability in the anterior and posterior putamen. In both groups, the presence of amyloid was not associated with DAT availability in the caudate and ventral striatum. The presence of amyloid was not directly related to the worse parkinsonian motor symptoms in both groups. However, there was a significant indirect effect of amyloid on parkinsonian motor symptoms, which was mediated by anterior and posterior putaminal DAT availability in the PD group alone. Discussion: This study demonstrates different amyloid-dependent or amyloid-independent18F-FP-CIT PET patterns in patients with LBD, suggesting distinctive interactions between α-synuclein and amyloid pathology based on the type of LBD.

Feasibility evaluation of middle-phase 18F-florbetaben positron emission tomography imaging using centiloid quantification and visual assessment.

Background: 18F-florbetaben (FBB) positron emission tomography (PET) scan has been widely used in research and routine clinical practice. Most studies used late-phase (scanning from 90 to 110 min after injection) FBB scans to generate beta-amyloid accumulation data. The feasibility of middle-phase scan is seldom discussed. Using the middle-phase data can shorten the patients' waiting between the injection and scan, and hospital can acquire more flexible schedule of routine scan. Methods: Paired middle-phase (60-80 min) FBB scans and standard (90-110 min) FBB scans were obtained from 27 subjects (12 neurodegenerative dementia, 8 mild cognitive impairment, 3 normal control, and 4 patients not suffering from neurodegenerative dementia). Standardized uptake value ratios (SUVRs) were calculated and converted to centiloid (CL) scale to investigate the impact on image quantification. CL pipeline validation were performed to build an equation converting the middle-phase data into equivalent standard scans. Cohen's kappa of binary interpretation and brain amyloid plaque load (BAPL) score were also used to evaluate the intrareader agreement of the FBB image from the two protocols. Results: The middle-phase FBB SUVR showed an excellent correlation, which provided a linear regression equation of SUVRFBB60-80 = 0.88 × SUVRFBB90-110 + 0.07, with R2=0.98. The slope of the equation indicated that there was bias between the middle and standard acquisition. This can be converted into the CL scale using CL = 174.68 × SUVR - 166.39. Cohen's kappa of binary interpretation and BAPL score were 1.0 (P<0.0001). Conclusions: Our findings indicate that the middle-phase FBB protocol is feasible in clinical applications for scans that are at either end of beta-amyloid spectrum, which provides comparable semiquantitative results to standard scan. Patient's waiting time between the injection and scan can be shortened.

Generation of Conventional 18F-FDG PET Images from 18F-Florbetaben PET Images Using Generative Adversarial Network: A Preliminary Study Using ADNI Dataset.

Background and Objectives: 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) (PETFDG) image can visualize neuronal injury of the brain in Alzheimer's disease. Early-phase amyloid PET image is reported to be similar to PETFDG image. This study aimed to generate PETFDG images from 18F-florbetaben PET (PETFBB) images using a generative adversarial network (GAN) and compare the generated PETFDG (PETGE-FDG) with real PETFDG (PETRE-FDG) images using the structural similarity index measure (SSIM) and the peak signal-to-noise ratio (PSNR). Materials and Methods: Using the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, 110 participants with both PETFDG and PETFBB images at baseline were included. The paired PETFDG and PETFBB images included six and four subset images, respectively. Each subset image had a 5 min acquisition time. These subsets were randomly sampled and divided into 249 paired PETFDG and PETFBB subset images for the training datasets and 95 paired subset images for the validation datasets during the deep-learning process. The deep learning model used in this study is composed of a GAN with a U-Net. The differences in the SSIM and PSNR values between the PETGE-FDG and PETRE-FDG images in the cycleGAN and pix2pix models were evaluated using the independent Student's t-test. Statistical significance was set at p ≤ 0.05. Results: The participant demographics (age, sex, or diagnosis) showed no statistically significant differences between the training (82 participants) and validation (28 participants) groups. The mean SSIM between the PETGE-FDG and PETRE-FDG images was 0.768 ± 0.135 for the cycleGAN model and 0.745 ± 0.143 for the pix2pix model. The mean PSNR was 32.4 ± 9.5 and 30.7 ± 8.0. The PETGE-FDG images of the cycleGAN model showed statistically higher mean SSIM than those of the pix2pix model (p < 0.001). The mean PSNR was also higher in the PETGE-FDG images of the cycleGAN model than those of pix2pix model (p < 0.001). Conclusions: We generated PETFDG images from PETFBB images using deep learning. The cycleGAN model generated PETGE-FDG images with a higher SSIM and PSNR values than the pix2pix model. Image-to-image translation using deep learning may be useful for generating PETFDG images. These may provide additional information for the management of Alzheimer's disease without extra image acquisition and the consequent increase in radiation exposure, inconvenience, or expenses.

A universal neocortical mask for Centiloid quantification.

INTRODUCTION: The Centiloid (CL) project was developed to harmonize the quantification of amyloid beta (Aß) positron emission tomography (PET) scans to a unified scale. The CL neocortical mask was defined using 11C Pittsburgh compound B (PiB), overlooking potential differences in regional distribution among Aß tracers. We created a universal mask using an independent dataset of five Aß tracers, and investigated its impact on inter-tracer agreement, tracer variability, and group separation. METHODS: Using data from the Alzheimer's Dementia Onset and Progression in International Cohorts (ADOPIC) study (Australian Imaging Biomarkers and Lifestyle + Alzheimer's Disease Neuroimaging Initiative + Open Access Series of Imaging Studies), age-matched pairs of mild Alzheimer's disease (AD) and healthy controls (HC) were selected: 18F-florbetapir (N = 147 pairs), 18F-florbetaben (N = 22), 18F-flutemetamol (N = 10), 18F-NAV (N = 42), 11C-PiB (N = 63). The images were spatially and standardized uptake value ratio normalized. For each tracer, the mean AD-HC difference image was thresholded to maximize the overlap with the standard neocortical mask. The universal mask was defined as the intersection of all five masks. It was evaluated on the Global Alzheimer's Association Interactive Network (GAAIN) head-to-head datasets in terms of inter-tracer agreement and variance in the young controls (YC) and on the ADOPIC dataset comparing separation between HC/AD and HC/mild cognitive impairment (MCI). RESULTS: In the GAAIN dataset, the universal mask led to a small reduction in the variance of the YC, and a small increase in the inter-tracer agreement. In the ADOPIC dataset, it led to a better separation between HC/AD and HC/MCI at baseline. DISCUSSION: The universal CL mask led to an increase in inter-tracer agreement and group separation. Those increases were, however, very small, and do not provide sufficient benefits to support departing from the existing standard CL mask, which is suitable for the quantification of all Aß tracers. HIGHLIGHTS: This study built an amyloid universal mask using a matched cohort for the five most commonly used amyloid positron emission tomography tracers.There was a high overlap between each tracer-specific mask.Differences in quantification and group separation between the standard and universal mask were small.The existing standard Centiloid mask is suitable for the quantification of all amyloid beta tracers.

Validation of quantitative assessment of florbetaben PET scans as an adjunct to the visual assessment across 15 software methods.

PURPOSE: Amyloid positron emission tomography (PET) with [18F]florbetaben (FBB) is an established tool for detecting Aß deposition in the brain in vivo based on visual assessment of PET scans. Quantitative measures are commonly used in the research context and allow continuous measurement of amyloid burden. The aim of this study was to demonstrate the robustness of FBB PET quantification. METHODS: This is a retrospective analysis of FBB PET images from 589 subjects. PET scans were quantified with 15 analytical methods using nine software packages (MIMneuro, Hermes BRASS, Neurocloud, Neurology Toolkit, statistical parametric mapping (SPM8), PMOD Neuro, CapAIBL, non-negative matrix factorization (NMF), AmyloidIQ) that used several metrics to estimate Aß load (SUVR, centiloid, amyloid load, and amyloid index). Six analytical methods reported centiloid (MIMneuro, standard centiloid, Neurology Toolkit, SPM8 (PET only), CapAIBL, NMF). All results were quality controlled. RESULTS: The mean sensitivity, specificity, and accuracy were 96.1 ± 1.6%, 96.9 ± 1.0%, and 96.4 ± 1.1%, respectively, for all quantitative methods tested when compared to histopathology, where available. The mean percentage of agreement between binary quantitative assessment across all 15 methods and visual majority assessment was 92.4 ± 1.5%. Assessments of reliability, correlation analyses, and comparisons across software packages showed excellent performance and consistent results between analytical methods. CONCLUSION: This study demonstrated that quantitative methods using both CE marked software and other widely available processing tools provided comparable results to visual assessments of FBB PET scans. Software quantification methods, such as centiloid analysis, can complement visual assessment of FBB PET images and could be used in the future for identification of early amyloid deposition, monitoring disease progression and treatment effectiveness.

A Case Report of Early-Onset Alzheimer's Disease Using 18F-FDG PET and 18F-FBB PET.

We describe a 40-year-old female patient who presented with sleep disturbance, intermittent headache, and gradual subjective cognitive decline. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) showed mild FDG hypometabolism in bilateral parietal and temporal lobes. However, 18F-florbetaben (FBB) amyloid PET revealed diffuse amyloid retention in the lateral temporal cortex, frontal cortex, posterior cingulate cortex/precuneus, parietal cortex, and cerebellum. This finding supports the clinical significance of amyloid imaging in diagnostic work-up of early-onset Alzheimer's disease (EOAD).

Clinical outcomes of increased focal amyloid uptake in individuals with subthreshold global amyloid levels.

Background: Although the standardized uptake value ratio (SUVR) method is objective and simple, cut-off optimization using global SUVR values may not reflect focal increased uptake in the cerebrum. The present study investigated clinical and neuroimaging characteristics according to focally increased ß-amyloid (Aß) uptake and global Aß status. Methods: We recruited 968 participants with cognitive continuum. All participants underwent neuropsychological tests and 498 18F-florbetaben (FBB) amyloid positron emission tomography (PET) and 470 18F-flutemetamol (FMM) PET. Each PET scan was assessed in 10 regions (left and right frontal, lateral temporal, parietal, cingulate, and striatum) with focal-quantitative SUVR-based cutoff values for each region by using an iterative outlier approach. Results: A total of 62 (6.4%) subjects showed increased focal Aß uptake with subthreshold global Aß status [global (-) and focal (+) Aß group, G(-)F(+) group]. The G(-)F(+) group showed worse performance in memory impairment (p < 0.001), global cognition (p = 0.009), greater hippocampal atrophy (p = 0.045), compared to those in the G(-)F(-). Participants with widespread Aß involvement in the whole region [G(+)] showed worse neuropsychological (p < 0.001) and neuroimaging features (p < 0.001) than those with focal Aß involvement G(-)F(+). Conclusion: Our findings suggest that individuals show distinctive clinical outcomes according to focally increased Aß uptake and global Aß status. Thus, researchers and clinicians should pay more attention to focal increased Aß uptake in addition to global Aß status.

Semiquantitative Approach to Amyloid Positron Emission Tomography Interpretation in Clinical Practice.

Objective Amyloid positron emission tomography (PET) plays a vital role in the in vivo detection of ß-amyloid accumulation in Alzheimer's disease. Increasingly, trainees and infrequent readers are relying on semiquantitative analyses to support clinical diagnostic efforts. Our objective was to determine if the visual assessment of amyloid PET may be facilitated by relying on semiquantitative analysis. Methods We conducted a retrospective review of [ 18 F]-florbetaben PET/computed tomographies (CTs) from 2016 to 2018. Visual interpretation to determine Aß+ status was conducted by two readers blinded to each other's interpretation. Scans were then post-processed utilizing the MIMneuro software, which generated regional-based semiquantitative Z-scores indicating cortical Aß-burden. Results Of 167 [ 18 F]-florbetaben PET/CTs, 92/167 (reader-1) and 101/167 (reader-2) were positive for amyloid deposition (agreement = 92.2%, κ = 0.84). Additional nine scans were identified as possible Aß-positive based solely on semiquantitative analyses. Largest semiquantitative differences were identified in the left frontal lobe (Z = 7.74 in Aß + ; 0.50 in Aß - ). All unilateral regions showed large statistically significant differences in Aß-burden ( P ≤ 2.08E-28). Semiquantitative scores were highly sensitive to Aß+ status and accurate in their ability to identify amyloid positivity, defined as a positive scan by both readers (AUC ≥ 0.90 [0.79-1.00]). Spread analyses suggested that amyloid deposition was most severe in the left posterior cingulate gyrus. The largest differences between Aß +/Aß- were in the left frontal lobe. Analyses using region-specific cutoffs indicated that the presence of amyloid in the temporal and anterior cingulate cortex, while exhibiting relatively low Z-scores, was most common. Conclusion Visual assessment and semiquantitative analysis provide highly congruent results, thereby enhancing reader confidence and improving scan interpretation. This is particularly relevant, given recent advances in amyloid-targeting disease-modifying therapeutics.

Comparison Between 18F-Florapronol and 18F-Florbetaben Imaging in Patients With Cognitive Impairment.

BACKGROUND AND PURPOSE: To determine the imaging characteristics and cutoff value of 18F-florapronol (FC119S) quantitative analysis for detecting ß-amyloid positivity and Alzheimer's disease (AD), we compared the findings of FC119S and 18F-florbetaben (FBB) positron-emission tomography (PET) in patients with cognitive impairment. METHODS: We prospectively enrolled 35 patients with cognitive impairment who underwent FBB-PET, FC119S-PET, and brain magnetic resonance imaging. We measured global and vertex-wise standardized uptake value ratios (SUVRs) using a surface-based method with the cerebellar gray matter as reference. Optimal global FC119S SUVR cutoffs were determined using receiver operating characteristic curves for ß-amyloid positivity based on the global FBB SUVR of 1.478 and presence of AD, respectively. We evaluated the global and vertex-wise SUVR correlations between the two tracers. In addition, we performed correlation analysis for global or vertex-wise SUVR of each tracer with the vertex-wise cortical thicknesses. RESULTS: The optimal global FC119S SUVR cutoff value was 1.385 both for detecting ß-amyloid positivity and for detecting AD. Based on the global SUVR cutoff value of each tracer, 32 (91.4%) patients had concordant ß-amyloid positivity. The SUVRs of FC119S and FBB had strong global (r=0.72) and vertex-wise (r>0.7) correlations in the overall cortices, except for the parietal and temporal cortices (0.4

Quantitative comparative analysis of amyloid PET images using three radiopharmaceuticals.

OBJECTIVE: Amyloid positron emission tomography (PET) with F-18 florbetaben (FBB), F-18 flutemetamol (FMM), and F-18 florapronol (FPN) is being used clinically for the evaluation of dementia. These radiopharmaceuticals are commonly used to evaluate the accumulation of beta-amyloid plaques in the brain, but there are structural differences between them. We investigated whether there are any differences in the imaging characteristics. METHODS: A total of 605 subjects were enrolled retrospectively in this study, including healthy subjects (HS) and patients with mild cognitive impairment or Alzheimer's disease. Participants underwent amyloid PET imaging using one of the three radiopharmaceuticals. The PET images were analyzed visually and semi-quantitatively using a standardized uptake value ratio (SUVR). In addition, we calculated and compared the cut-off SUVR of the representative regions for each radiopharmaceutical that can distinguish between positive and negative scans. RESULTS: In the negative images of the HS group, the contrast between the white matter and the gray matter was high in the FMM PET images, while striatal uptake was relatively higher in the FPN PET images. The SUVR showed significant differences across the radiopharmaceuticals in all areas except the temporal lobe, but the range of differences was relatively small. Accuracy levels for the global cut-off SUVR to discriminate between positive and negative images were highest in FMM PET, with a value of 0.989. FBB PET also showed a high value of 0.978, while FPN PET showed a relatively low value of 0.901. CONCLUSIONS: Negative amyloid PET images using the three radiopharmaceuticals showed visually and quantitatively similar imaging characteristics except in the striatum. Binary classification using the cut-off of the global cortex showed high accuracy overall, although there were some differences between the three PET images.

Blood-brain barrier opening of the default mode network in Alzheimer's disease with magnetic resonance-guided focused ultrasound.

The blood-brain barrier (BBB) protects the brain but is also an important obstacle for the effective delivery of therapeutics in Alzheimer's disease and other neurodegenerative disorders. Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) has been shown to reversibly disrupt the BBB. However, treatment of diffuse regions across the brain along with the effect on Alzheimer's disease relevant pathology need to be better characterized. This study is an open-labelled single-arm trial (NCT04118764) to investigate the feasibility of modulating BBB permeability in the default mode network and the impact on cognition, amyloid and tau pathology as well as BBB integrity. Nine participants [mean age 70.2 ± 7.2 years, mean Mini-Mental State Examination (MMSE) 21.9] underwent three biweekly procedures with follow-up visits up to 6 months. The BBB permeability of the bilateral hippocampi, anterior cingulate cortex and precuneus was transiently increased without grade 3 or higher adverse events. Participants did not experience worsening trajectory of cognitive decline (ADAS-cog11, MMSE). Whole brain vertex-based analysis of the 18F-florbetaben PET imaging demonstrated clusters of modest SUVR reduction in the right parahippocampal and inferior temporal lobe. However, CSF and blood biomarkers did not demonstrate any amelioration of Alzheimer's disease pathology (P-tau181, amyloid-ß42/40 ratio), nor did it show persistent BBB dysfunction (plasma PDGFRbeta and CSF-to-plasma albumin ratio). This study provides neuroimaging and fluid biomarker data to characterize the safety profile of MRgFUS BBB modulation in neurodegeneration as a potential strategy for enhanced therapeutic delivery.

Effect of Amyloid on Cognitive Performance in Parkinson's Disease and Dementia with Lewy Bodies.

BACKGROUND: Concomitant amyloid pathology contributes to the clinical heterogeneity of Lewy body diseases (LBDs). OBJECTIVE: The objective of this study was to investigate the pattern and effect of amyloid accumulation on cognitive dysfunction in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). METHODS: We retrospectively assessed 205 patients with LBD (91 with DLB and 114 with PD) who underwent 18 F-florbetaben positron emission tomography and divided them into amyloid-positive and amyloid-negative groups depending on global standardized uptake value ratios (SUVRs). We investigated the effect of group on the regional and global SUVRs using general linear models (GLMs) after controlling for age, sex, cognitive status, and score on the Korean version of the Mini-Mental State Examination. Moreover, the effect of amyloid on cognitive function, depending on the type of LBD, was evaluated using GLMs with interaction analysis. RESULTS: In all evaluated regions including the striatum, the DLB group showed a higher SUVR than the PD group. Among amyloid-positive patients, the DLB group had a higher regional SUVR than the PD group in the frontal and parietal cortices. There was a significant interaction effect between amyloid and disease groups in language and memory function. In patients with PD, global amyloid load was negatively associated with language (B = -2.03; P = 0.010) and memory functions (B = -1.96; P < 0.001). However, amyloid load was not significantly associated with cognitive performance in the DLB group. CONCLUSIONS: Although the burden of amyloid was higher in the DLB group, amyloid accumulation was negatively associated with the memory and language functions in the PD group only. © 2022 International Parkinson and Movement Disorder Society.

Quantification of amyloid beta and tau PET without a structural MRI.

INTRODUCTION: Relying on magnetic resonance imaging (MRI) for quantification of positron emission tomography (PET) images may limit generalizability of the results. We evaluated several MRI-free approaches for amyloid beta (Aß) and tau PET quantification relative to MRI-dependent quantification cross-sectionally and longitudinally. METHODS: We compared baseline MRI-free and MRI-dependent measurements of Aß PET ([18F]florbetapir [FBP], N = 1290, [18F]florbetaben [FBB], N = 290) and tau PET ([18F]flortaucipir [FTP], N = 768) images with respect to continuous and dichotomous agreement, effect sizes of Aß+ impaired versus Aß- unimpaired groups, and longitudinal standardized uptake value ratio (SUVR) slopes in a subset of individuals. RESULTS: The best-performing MRI-free approaches had high continuous and dichotomous agreement with MRI-dependent SUVRs for Aß PET and temporal flortaucipir (R2 ≥0.95; ± agreement ≥92%) and for Alzheimer's disease-related effect sizes; agreement was slightly lower for entorhinal flortaucipir and longitudinal slopes. DISCUSSION: There is no consistent loss of baseline or longitudinal AD-related signal with MRI-free Aß and tau PET image quantification.