[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.

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.

18F-Florbetaben PET/CT for the Diagnosis and Subtyping of Cardiac Amyloidosis: A Case Series and Review of the Literature.

Objectives: Cardiac amyloidosis (CA) is a type of systemic amyloidosis. Amyloid-targeting positron emission tomography (PET) has shown potential as an imaging method for CA. However, the optimal imaging protocol and role of 18F-florbetaben (FBB) PET in the diagnosis and subtyping of CA have yet to be determined. Methods: Patients with suspected CA who had positive or equivocal results of technetium-99m pyrophosphate (PYP) scintigraphy were enrolled for dynamic and late FBB PET imaging. In addition to visual assessment, a kinetic modeling-based approach including target-to-background ratio (TBR) and myocardial retention fraction (RF) of serial images reconstructed from a 20-min dynamic acquisition, and a late image at 110 min post-injection were performed. We compared FBB PET measures of four typical patients with light chain amyloidosis (AL), wild-type transthyretin amyloidosis (ATTRwt), variant transthyretin amyloidosis (ATTRv), and heart failure, respectively. We also reviewed the literature on the clinical use of amyloid PET in CA. Results: Myocardial tracer retention was only found in the AL patient on the late images. TBR and RF were highest in the AL patient followed by the ATTRwt patient, and lowest in the ATTRv and non-CA patients. Conclusions: FBB PET has potential in the detection and non-invasive subtyping of CA, especially in subjects with equivocal PYP findings or monoclonal gammopathy.

Parametric imaging of dual-time window [18F]flutemetamol and [18F]florbetaben studies.

Optimal pharmacokinetic models for quantifying amyloid beta (Aß) burden using both [18F]flutemetamol and [18F]florbetaben scans have previously been identified at a region of interest (ROI) level. The purpose of this study was to determine optimal quantitative methods for parametric analyses of [18F]flutemetamol and [18F]florbetaben scans. Forty-six participants were scanned on a PET/MR scanner using a dual-time window protocol and either [18F]flutemetamol (N=24) or [18F]florbetaben (N=22). The following parametric approaches were used to derive DVR estimates: reference Logan (RLogan), receptor parametric mapping (RPM), two-step simplified reference tissue model (SRTM2) and multilinear reference tissue models (MRTM0, MRTM1, MRTM2), all with cerebellar grey matter as reference tissue. In addition, a standardized uptake value ratio (SUVR) was calculated for the 90-110 min post injection interval. All parametric images were assessed visually. Regional outcome measures were compared with those from a validated ROI method, i.e. DVR derived using RLogan. Visually, RPM, and SRTM2 performed best across tracers and, in addition to SUVR, provided highest AUC values for differentiating between Aß-positive vs Aß-negative scans ([18F]flutemetamol: range AUC=0.96-0.97 [18F]florbetaben: range AUC=0.83-0.85). Outcome parameters of most methods were highly correlated with the reference method (R2≥0.87), while lowest correlation were observed for MRTM2 (R2=0.71-0.80). Furthermore, bias was low (≤5%) and independent of underlying amyloid burden for MRTM0 and MRTM1. The optimal parametric method differed per evaluated aspect; however, the best compromise across aspects was found for MRTM0 followed by SRTM2, for both tracers. SRTM2 is the preferred method for parametric imaging because, in addition to its good performance, it has the advantage of providing a measure of relative perfusion (R1), which is useful for measuring disease progression.

Visual interpretation of [18F]Florbetaben PET supported by deep learning-based estimation of amyloid burden.

PURPOSE: Amyloid PET which has been widely used for noninvasive assessment of cortical amyloid burden is visually interpreted in the clinical setting. As a fast and easy-to-use visual interpretation support system, we analyze whether the deep learning-based end-to-end estimation of amyloid burden improves inter-reader agreement as well as the confidence of the visual reading. METHODS: A total of 121 clinical routines [18F]Florbetaben PET images were collected for the randomized blind-reader study. The amyloid PET images were visually interpreted by three experts independently blind to other information. The readers qualitatively interpreted images without quantification at the first reading session. After more than 2-week interval, the readers additionally interpreted images with the quantification results provided by the deep learning system. The qualitative assessment was based on a 3-point BAPL score (1: no amyloid load, 2: minor amyloid load, and 3: significant amyloid load). The confidence score for each session was evaluated by a 3-point score (0: ambiguous, 1: probably, and 2: definite to decide). RESULTS: Inter-reader agreements for the visual reading based on a 3-point scale (BAPL score) calculated by Fleiss kappa coefficients were 0.46 and 0.76 for the visual reading without and with the deep learning system, respectively. For the two reading sessions, the confidence score of visual reading was improved at the visual reading session with the output (1.27 ± 0.078 for visual reading-only session vs. 1.66 ± 0.63 for a visual reading session with the deep learning system). CONCLUSION: Our results highlight the impact of deep learning-based one-step amyloid burden estimation system on inter-reader agreement and confidence of reading when applied to clinical routine amyloid PET reading.

The clinical feasibility of deep learning-based classification of amyloid PET images in visually equivocal cases.

PURPOSE: Although most deep learning (DL) studies have reported excellent classification accuracy, these studies usually target typical Alzheimer's disease (AD) and normal cognition (NC) for which conventional visual assessment performs well. A clinically relevant issue is the selection of high-risk subjects who need active surveillance among equivocal cases. We validated the clinical feasibility of DL compared with visual rating or quantitative measurement for assessing the diagnosis and prognosis of subjects with equivocal amyloid scans. METHODS: 18F-florbetaben scans of 430 cases (85 NC, 233 mild cognitive impairment, and 112 AD) were assessed through visual rating-based, quantification-based, and DL-based methods. DL was trained using 280 two-dimensional PET images (80%) and tested by randomly assigning the remaining (70 cases, 20%) cases and a clinical validation set of 54 equivocal cases. In the equivocal cases, we assessed the agreement among the visual rating, quantification, and DL and compared the clinical outcome according to each modality-based amyloid status. RESULTS: The visual reading was positive in 175 cases, equivocal in 54 cases, and negative in 201 cases. The composite SUVR cutoff value was 1.32 (AUC 0.99). The subject-level performance of DL using the test set was 100%. Among the 54 equivocal cases, 37 cases were classified as positive (Eq(deep+)) by DL, 40 cases were classified by a second-round visual assessment, and 40 cases were classified by quantification. The DL- and quantification-based classifications showed good agreement (83%, κ = 0.59). The composite SUVRs differed between Eq(deep+) (1.47 [0.13]) and Eq(deep-) (1.29 [0.10]; P < 0.001). DL, but not the visual rating, showed a significant difference in the Mini-Mental Status Examination score change during the follow-up between Eq(deep+) (- 4.21 [0.57]) and Eq(deep-) (- 1.74 [0.76]; P = 0.023) (mean duration, 1.76 years). CONCLUSIONS: In visually equivocal scans, DL was more related to quantification than to visual assessment, and the negative cases selected by DL showed no decline in cognitive outcome. DL is useful for clinical diagnosis and prognosis assessment in subjects with visually equivocal amyloid scans.

Therapeutic effect of mesenchymal stem cells in an animal model of Alzheimer's disease evaluated by ß-amyloid positron emission tomography imaging.

OBJECTIVE: We evaluated the effects of bone marrow-derived mesenchymal stem cells in a model of Alzheimer's disease using serial [18F]Florbetaben positron emission tomography. METHODS: 3xTg Alzheimer's disease mice were treated with intravenously injected bone marrow-derived mesenchymal stem cells, and animals without stem cell therapy were used as controls. Serial [18F]Florbetaben positron emission tomography was performed after therapy. The standardized uptake value ratio was measured as the cortex standardized uptake value divided by the cerebellum standardized uptake value. Memory function and histological changes were observed using the Barnes maze test and ß-amyloid-reactive cells. RESULTS: Standardized uptake value ratio decreased significantly from day 14 after stem cell administration in the bone marrow-derived mesenchymal stem cells-treated group (n = 28). In contrast, there was no change in the ratio in control mice (n = 25) at any time point. In addition, mice that received bone marrow-derived mesenchymal stem cell therapy also exhibited significantly better memory function and less ß-amyloid-immunopositive plaques compared to controls. CONCLUSION: The therapeutic effect of intravenously injected bone marrow-derived mesenchymal stem cells in a mouse model of Alzheimer's disease was confirmed by ß-amyloid positron emission tomography imaging, memory functional studies and histopathological evaluation.

Assessment of brain beta-amyloid deposition in transgenic mouse models of Alzheimer's disease with PET imaging agents 18F-flutemetamol and 18F-florbetaben.

BACKGROUND: Although amyloid beta (Aß) imaging is widely used for diagnosing and monitoring Alzheimer's disease in clinical fields, paralleling comparison between 18F-flutemetamol and 18F-florbetaben was rarely attempted in AD mouse model. We performed a comparison of Aß PET images between 18F-flutemetamol and 18F-florbetaben in a recently developed APPswe mouse model, C57BL/6-Tg (NSE-hAPPsw) Korl. RESULTS: After an injection (0.23 mCi) of 18F-flutemetamol and 18F-florbetaben at a time interval of 2-3 days, we compared group difference of SUVR and kinetic parameters between the AD (n = 7) and control (n = 7) mice, as well as between 18F-flutemetamol and 18F-florbetaben image. In addition, bio-distribution and histopathology were conducted. With visual image and VOI-based SUVR analysis, the AD group presented more prominent uptake than did the control group in both the 18F-florbetaben and 18F-flutemetamol images. With kinetic analysis, the 18F-florbetaben images showed differences in K1 and k4 between the AD and control groups, although 18F-flutemetamol images did not show significant difference. 18F-florbetaben images showed more prominent cortical uptake and matched well to the thioflavin S staining images than did the 18F-flutemetamol image. In contrast, 18F-flutemetamol images presented higher K1, k4, K1/k2 values than those of 18F-florbetaben images. Also, 18F-flutemetamol images presented prominent uptake in the bowel and bladder, consistent with higher bio-distribution in kidney, lung, blood and heart. CONCLUSIONS: Compared with 18F-flutemetamol images, 18F-florbetaben images showed prominent visual uptake intensity, SUVR, and higher correlations with the pathology. In contrast, 18F-flutemetamol was more actively metabolized than was 18F-florbetaben (Son et al. in J Nucl Med 58(Suppl 1):S278, 2017].

Additive value of amyloid-PET in routine cases of clinical dementia work-up after FDG-PET.

PURPOSE: In recent years, several [18F]-labeled amyloid-PET tracers have been developed and have obtained clinical approval. Despite their widespread scientific use, studies in routine clinical settings are limited. We therefore investigated the impact of [18F]-florbetaben (FBB)-PET on the diagnostic management of patients with suspected dementia that was still unclarified after [18F]-fluordeoxyglucose (FDG)-PET. METHODS: All subjects were referred in-house with a suspected dementia syndrome due to neurodegenerative disease. After undergoing an FDG-PET exam, the cases were discussed by the interdisciplinary dementia board, where the most likely diagnosis as well as potential differential diagnoses were documented. Because of persistent diagnostic uncertainty, the patients received an additional FBB-PET exam. Results were interpreted visually and classified as amyloid-positive or amyloid-negative, and we then compared the individual clinical diagnoses before and after additional FBB-PET. RESULTS: A total of 107 patients (mean age 69.4 ± 9.7y) were included in the study. The FBB-PET was rated as amyloid-positive in 65/107. In 83% of the formerly unclear cases, a final diagnosis was reached through FBB-PET, and the most likely prior diagnosis was changed in 28% of cases. The highest impact was observed for distinguishing Alzheimer's dementia (AD) from fronto-temporal dementia (FTLD), where FBB-PET altered the most likely diagnosis in 41% of cases. CONCLUSIONS: FBB-PET has a high additive value in establishing a final diagnosis in suspected dementia cases when prior investigations such as FDG-PET are inconclusive. The differentiation between AD and FTLD was particularly facilitated by amyloid-PET, predicting a considerable impact on patient management, especially in the light of upcoming disease-modifying therapies.

PET-CT evaluation of amyloid systemic involvement with [18F]-florbetaben in patient with proved cardiac amyloidosis: a case report.

BACKGROUND: One of the most frequent disorders which lead to cardiac amyloidosis is transthyretin-related amyloidosis (ATTR). Some PET radio-pharmaceuticals for the detection of beta-amyloid deposits within the brain have shown to be able to detect also cardiac amyloid deposits. We present a case of a man with ATTR studied with [18F]-florbetaben PET-CT. RESULTS: Total-body scan showed a moderate uptake in the bone marrow, especially in correspondence of the vertebral column, while no significant myocardial uptake was present. Cardiac-focused scans showed low mean cardiac SUV values confirming the absence of significant myocardial uptake. Brain scan showed a significant cortical brain uptake of the radio-pharmaceutical more evident in correspondence of frontal and temporal lobes. CONCLUSIONS: Distinct subtypes of amyloidosis show different uptake of the radiotracer. Brain amyloid deposition in the presence of a systemic disease could not be caused by the same amyloid precursor.

Impact of partial volume effect correction on cerebral ß-amyloid imaging in APP-Swe mice using [(18)F]-florbetaben PET.

We previously investigated the progression of ß-amyloid deposition in brain of mice over-expressing amyloid-precursor protein (APP-Swe), a model of Alzheimer's disease (AD), in a longitudinal PET study with the novel ß-amyloid tracer [(18)F]-florbetaben. There were certain discrepancies between PET and autoradiographic findings, which seemed to arise from partial volume effects (PVE). Since this phenomenon can lead to bias, most especially in the quantitation of brain microPET studies of mice, we aimed in the present study to investigate the magnitude of PVE on [(18)F]-florbetaben quantitation in murine brain, and to establish and validate a useful correction method (PVEC). Phantom studies with solutions of known radioactivity concentration were performed to measure the full-width-at-half-maximum (FWHM) resolution of the Siemens Inveon DPET and to validate a volume-of-interest (VOI)-based PVEC algorithm. Several VOI-brain-masks were applied to perform in vivo PVEC on [(18)F]-florbetaben data from C57BL/6(N=6) mice, while uncorrected and PVE-corrected data were cross-validated with gamma counting and autoradiography. Next, PVEC was performed on longitudinal PET data set consisting of 43 PET scans in APP-Swe (13-20months) and age-matched wild-type (WT) mice using the previously defined masks. VOI-based cortex-to-cerebellum ratios (SUVR) were compared for uncorrected and PVE-corrected results. Brains from a subset of transgenic mice were ultimately examined by autoradiography ex vivo and histochemistry in vitro as gold standard assessments, and compared to VOI-based PET results. The phantom study indicated a FWHM of 1.72mm. Applying a VOI-brain-mask including extracerebral regions gave robust PVEC, with increased precision of the SUVR results. Cortical SUVR increased with age in APP-Swe mice compared to baseline measurements (16months: +5.5%, p<0.005; 20months: +15.5%, p<0.05) with uncorrected data, and to a substantially greater extent with PVEC (16months: +12.2% p<0.005; 20months: +36.4% p<0.05). WT animals showed no binding changes, irrespective of PVEC. Relative to autoradiographic results, the error [%] for uncorrected cortical SUVR was 18.9% for native PET data, and declined to 4.8% upon PVEC, in high correlation with histochemistry results. We calculate that PVEC increases by 10% statistical power for detecting altered [(18)F]-florbetaben uptake in aging APP-Swe mice in planned studies of disease modifying treatments on amyloidogenesis.

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.

Automated Neural Architecture Search for Cardiac Amyloidosis Classification from [18F]-Florbetaben PET Images.

Medical image classification using convolutional neural networks (CNNs) is promising but often requires extensive manual tuning for optimal model definition. Neural architecture search (NAS) automates this process, reducing human intervention significantly. This study applies NAS to [18F]-Florbetaben PET cardiac images for classifying cardiac amyloidosis (CA) sub-types (amyloid light chain (AL) and transthyretin amyloid (ATTR)) and controls. Following data preprocessing and augmentation, an evolutionary cell-based NAS approach with a fixed network macro-structure is employed, automatically deriving cells' micro-structure. The algorithm is executed five times, evaluating 100 mutating architectures per run on an augmented dataset of 4048 images (originally 597), totaling 5000 architectures evaluated. The best network (NAS-Net) achieves 76.95% overall accuracy. K-fold analysis yields mean ± SD percentages of sensitivity, specificity, and accuracy on the test dataset: AL subjects (98.7 ± 2.9, 99.3 ± 1.1, 99.7 ± 0.7), ATTR-CA subjects (93.3 ± 7.8, 78.0 ± 2.9, 70.9 ± 3.7), and controls (35.8 ± 14.6, 77.1 ± 2.0, 96.7 ± 4.4). NAS-derived network performance rivals manually determined networks in the literature while using fewer parameters, validating its automatic approach's efficacy.

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.

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.

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.

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).

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

Purpose: 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 seconds after injection. Dynamic time-activity curves (TACs) for 110 minutes 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 (BPND) 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 BPND analysis. BPND and VT from kinetic models were correlated (r2 = 0.46, P<2e-16) with a stronger positive correlation observed in amyloid-positive participants, indicating reliable model fits with the IDIFs. VT from 2TCM was highly correlated (r2 = 0.65, P< 2e-16) 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 BPND in amyloid-positive and negative older individuals.

Beta amyloid deposition and cognitive decline in Parkinson's disease: a study of the PPMI cohort.

The accumulation of beta amyloid in the brain has a complex and poorly understood impact on the progression of Parkinson's disease pathology and much controversy remains regarding its role, specifically in cognitive decline symptoms. Some studies have found increased beta amyloid burden is associated with worsening cognitive impairment in Parkinson's disease, especially in cases where dementia occurs, while other studies failed to replicate this finding. To better understand this relationship, we examined a cohort of 25 idiopathic Parkinson's disease patients and 30 healthy controls from the Parkinson's Progression Marker Initiative database. These participants underwent [18F]Florbetaben positron emission tomography scans to quantify beta amyloid deposition in 20 cortical regions. We then analyzed this beta amyloid data alongside the longitudinal Montreal Cognitive Assessment scores across 3 years to see how participant's baseline beta amyloid levels affected their cognitive scores prospectively. The first analysis we performed with these data was a hierarchical cluster analysis to help identify brain regions that shared similarity. We found that beta amyloid clusters differently in Parkinson's disease patients compared to healthy controls. In the Parkinson's disease group, increased beta amyloid burden in cluster 2 was associated with worse cognitive ability, compared to deposition in clusters 1 or 3. We also performed a stepwise linear regression where we found an adjusted R2 of 0.495 (49.5%) in a model explaining the Parkinson's disease group's Montreal Cognitive Assessment score 1-year post-scan, encompassing the left gyrus rectus, the left anterior cingulate cortex, and the right parietal cortex. Taken together, these results suggest regional beta amyloid deposition alone has a moderate effect on predicting future cognitive decline in Parkinson's disease patients. The patchwork effect of beta amyloid deposition on cognitive ability may be part of what separates cognitive impairment from cognitive sparing in Parkinson's disease. Thus, we suggest it would be more useful to measure beta amyloid burden in specific brain regions rather than using a whole-brain global beta amyloid composite score and use this information as a tool for determining which Parkinson's disease patients are most at risk for future cognitive decline.

Differential Diagnosis Between Alzheimer's Disease-Related Depression and Pseudo-Dementia in Depression: A New Indication for Amyloid-ß Imaging?

BACKGROUND: Alzheimer's disease and depression can start with combined cognitive and depressive symptoms [1, 2]. Accurate differential diagnosis is desired to initiate specific treatment. OBJECTIVE: We investigated whether amyloid-ß PET imaging can discriminate both entities. METHODS: This retrospective observational study included 39 patients (20 female, age = 70±11years) with both cognitive and depressive symptoms who underwent amyloid-ß PET imaging and in whom clinical follow-up data was available. Amyloid-ß PET was carried out applying [18F]Florbetaben or [11C]PiB. The PET images were analyzed by standardized visual and relative-quantitative evaluation. Based on clinical follow-up (median of 2.4 years [range 0.3 to 7.0 years, IQR = 3.7 years] after amyloid PET imaging which was not considered in obtaining a definite diagnosis), discrimination ability between AD-related depression and pseudo-dementia in depression/depression with other comorbidities was determined. RESULTS: Visually, all 10 patients with pseudo-dementia in depression and all 15 patients with other depression were rated as amyloid-ß-negative; 2 of 14 patients with AD-related depression were rated amyloid-ß-negative. ROC curve analysis of the unified composite standardized uptake value ratios (cSUVRs) was able to discriminate pseudo-dementia in depression from AD-related depression with high accuracy (AUC = 0.92). Optimal [18F]Florbetaben discrimination cSUVR threshold was 1.34. In congruence with the visual PET analysis, the resulting sensitivity of the relative-quantitative analysis was 86% with a specificity of 100%. CONCLUSION: Amyloid-ß PET can differentiate AD-related depression and pseudo-dementia in depression. Prospective clinical studies are warranted to confirm this result and to potentially broaden the spectrum of clinical applications for amyloid-ß PET imaging.