Diagnostic performance of a machine learning approach applied to delayed [18F]florbetaben positron emission tomography in patients with suspected light-chain cardiac amyloidosis

Background: Amyloid positron emission tomography (PET) has been proposed as a tool to monitor myelination in multiple sclerosis (MS). We present baseline results from an ongoing prospective study, which is the first to include both early and standard phases of amyloid PET in patients with newly diagnosed MS. Methods: The prospective study includes patients with newly diagnosed MS (January 2023-February 2024). Clinical evaluation includes neurological disability (EDSS) and neuropsychological assessment. Brain MRI, early [18F]florbetaben (FBB) PET (eFBB; 0-5, 0-10 min post-injection), and standard FBB PET (sFBB; 90 min post-injection) were acquired. Normal-appearing white matter (NAWM) and damaged white matter (DWM) in MRI were segmented and co-registered with PET images. Results are presented as standardized uptake values (SUV), with the ratio using cerebellum as the reference region (SUVR) and the percentage of change between the DWM and NAWM. Results: Twenty patients were included (35.05 ± 10.72 years; 75% women). Both eFBB and sFBB acquisitions showed significantly lower SUVRmax and SUVRmean, and higher SUVRmin in the DWM compared to NAWM (p < 0.001) in all patients. SUV parameters in both DWM and NAWM from eFBB and sFBB PET correlated with the number of relapses and EDSS (r = -0.454 and r = -0.446, respectively; p < 0.05). Additionally, SUVR values in the DWM during eFBB correlated with cognitive impairment (SDMT; r = -0.516, p < 0.01), fatigue (MFIS-5; r = -0.450, p < 0.05), and quality of life (EQ-5D; r = -0.490, p < 0.05). Conclusions: Quantitative analysis of dual-phase FBB PET demonstrates differential uptake between DWM and NAWM, which is probably associated with demyelination and neurodegeneration. These preliminary findings suggest that amyloid PET may have predictive value for disease activity and progression, supporting its potential as a biomarker in MS. Follow-up data from this study are needed to support the baseline results.

Although quantification of amyloid positron emission tomography (PET) is important for evaluating patients with cognitive impairment, its routine clinical use is hampered by complicated preprocessing steps and required MRI. Here, we suggested a one-step quantification based on deep learning using native-space amyloid PET images of different radiotracers acquired from multiple centers. Amyloid PET data of the Alzheimer Disease Neuroimaging Initiative (ADNI) were used for this study. A training/validation consists of 850 florbetapir PET images. Three hundred sixty-six florbetapir and 89 florbetaben PET images were used as test sets to evaluate the model. Native-space amyloid PET images were used as inputs, and the outputs were standardized uptake value ratios (SUVRs) calculated by the conventional MR-based method. The mean absolute errors (MAEs) of the composite SUVR were 0.040, 0.060, and 0.050 of training/validation and test sets for florbetapir PET and a test set for florbetaben PET, respectively. The agreement of amyloid positivity measured by Cohen's kappa for test sets of florbetapir and florbetaben PET were 0.87 and 0.89, respectively. We suggest a one-step quantification method for amyloid PET via a deep learning model. The model is highly reliable to quantify the amyloid PET regardless of multicenter images and various radiotracers.

The growing understanding of the use of biomarkers in Alzheimer's disease (AD) may enable physicians to make more accurate and timely diagnoses. Florbetaben, a beta-amyloid tracer used with positron emission tomography (PET), is one of these diagnostic biomarkers. This analysis was undertaken to explore the potential value of florbetaben PET in the diagnosis of AD among patients with suspected dementia and to identify key data that are needed to further substantiate its value. A discrete event simulation was developed to conduct exploratory analyses from both US payer and societal perspectives. The model simulates the lifetime course of disease progression for individuals, evaluating the impact of their patient management from initial diagnostic work-up to final diagnosis. Model inputs were obtained from specific analyses of a large longitudinal dataset from the New England Veterans Healthcare System and supplemented with data from public data sources and assumptions. The analyses indicate that florbetaben PET has the potential to improve patient outcomes and reduce costs under certain scenarios. Key data on the use of florbetaben PET, such as its influence on time to confirmation of final diagnosis, treatment uptake, and treatment persistency, are unavailable and would be required to confirm its value.

BackgroundWe aimed to investigate demographics, neuropsychological performance, and amyloid pathology in spouses of people with cognitive impairment.MethodA total of 30 patients and 30 spouse controls were enrolled in a prospective cohort for Alzheimer’s disease between June 2018 and December 2020. All subjects had a comprehensive interview, laboratory findings, formal neuropsychological test battery, brain computed tomography or magnetic resonance imaging, and 18F‐ Florbetaben positron emission tomography (FBB PET).ResultThere were no differences in age, sex, education level, family history of dementia, and vascular risk factors between the patient group and spouse group. APOE e4 carriers were more common in the patient group (40.0%) than in the spouse group (10.0%). Although none of the spouses complained of impaired cognition, 40.0% of them were shown to have mild cognitive impairment. Visual analysis of FBB PET showed that 24.1 % of spouses showed amyloid deposition.ConclusionForty percent of spouses of people with cognitive impairment showed mild cognitive impairment and about 24% of them had amyloid pathology. This finding implicates high risk of cognitive impairment in spouses of people with cognitive impairment, which may be associated with shared environmental factors and psychosocial burden as a caregiver. Early diagnosis and intervention for spouses of people with cognitive impairment may be necessary for both patients and spouses. In the future, further investigations in a larger cohort is warranted to confirm findings from this study.

18F]-Florbetaben PET/CT for Differential Diagnosis Among Cardiac Immunoglobulin Light Chain, Transthyretin Amyloidosis, and Mimicking Conditions

EXPLORING APOE GENOTYPE EFFECTS ON AD RISK AND BETA-AMYLOID BURDEN IN INDIVIDUALS WITH SUBJECTIVE COGNITIVE DECLINE: THE FACEHBI STUDY RESULTS

Alzheimer’s disease (AD) is characterized by formation of amyloid plaques and neurofibrillary tangles in the brain, which can be mimicked by transgenic mouse models. Here, we report on the characterization of amyloid load in the brains of two transgenic amyloidosis models using positron emission tomography (PET) with florbetaben (FBB), an 18F-labeled amyloid PET tracer routinely used in AD patients. Young, middle-aged, and old homozygous APP/PS1 mice (ARTE10), old hemizygous APPswe/PS1ΔE9, and old wild-type control mice were subjected to FBB PET using a small animal PET/computed tomography scanner. After PET, brains were excised, and ex vivo autoradiography was performed. Plaque pathology was verified on brain sections with histological methods. Amyloid plaque load increased progressively with age in the cortex and hippocampus of ARTE10 mice, which could be detected with both in vivo FBB PET and ex vivo autoradiography. FBB retention showed significant differences to wild-type controls already at 9 months of age by both in vivo and ex vivo analyses. An excellent correlation between data derived from PET and autoradiography could be obtained (rPearson = 0.947, p < 0.0001). Although amyloid load detected by FBB in the brains of old APPswe/PS1ΔE9 mice was as low as values obtained with young ARTE10 mice, statistically significant discrimination to wild-type animals was reached (p < 0.01). In comparison to amyloid burden quantified by histological analysis, FBB retention correlated best with total plaque load and number of congophilic plaques in the brains of both mouse models. In conclusion, the homozygous ARTE10 mouse model showed superior properties over APPswe/PS1ΔE9 mice for FBB small animal amyloid PET imaging. The absolute amount of congophilic dense-cored plaques seems to be the decisive factor for feasibility of amyloidosis models for amyloid PET analysis.

Amyloid positron emission tomography (PET) acquisition timing impacts quantification. In florbetaben (FBB) PET scans of 245 adults with and without cognitive impairment, we investigated the impact of post-injection acquisition time on Centiloids (CLs) across five reference regions. CL equations for FBB were derived using standard methods, using FBB data collected between 90 and 110 min with paired Pittsburgh compound B data. Linear mixed models and t-tests evaluated the impact of acquisition time on CL increases. CL values increased significantly over the scan using the whole cerebellum, cerebellar gray matter, and brainstem as reference regions, particularly in amyloid-positive individuals. In contrast, CLs based on white matter-containing reference regions decreased across the scan. The quantification of CLs in FBB PET imaging is influenced by both the overall scan acquisition time and the choice of reference region. Standardized acquisition protocols or the application of acquisition time-specific CL equations should be implemented in clinical protocols. Acquisition timing affects florbetaben positron emission tomography (PET) scan quantification, especially in amyloid-positive participants. The impact of acquisition timing on quantification varies across common reference regions. Consistent acquisitions and/or appropriate post-injection adjustments are needed to ensure comparability of PET data.

Imaging with β-amyloid (Aβ) positron emission tomography (PET) has the potential to aid the diagnosis of the cause of cognitive impairment affecting people living with HIV (PLWH) when neurodegenerative disorders are considered. We evaluated the clinical utility of [18F]Florbetaben (FBB) in PLWH with cognitive symptoms. Imaging with FBB PET was performed in 20 patients with cognitive concerns about dementia. Neuropsychological testing, plasma neurofilament light protein, plasma Aβ40, Aβ42, and cerebrospinal fluid Aβ42, tau, and HIV RNA were obtained. FBB PET images were assessed visually by 3 readers blinded to the clinical diagnosis and quantitatively by obtaining a composite cortical to cerebellar cortex standardized uptake value ratio (SUVR). FBB SUVR from 10 age-matched healthy controls was compared with SUVR of PLWH. Most participants were men (90%) of white ethnicity (90%) with a median age (interquartile range) of 59 (43-79) years. Median CD4 count was 682 (74-1056). All patients were on combination antiretroviral therapy with plasma and cerebrospinal fluid HIV RNA <40 copies/mL. Fourteen patients had objective cognitive impairment including 2 who met clinical criteria for a diagnosis of dementia. No significant differences in composite SUVRs between PLWH and controls [mean (SD): 1.18 (0.03) vs. 1.16 (0.09); P = 0.37] were observed. Four patients were FBB+ with the highest SUVR in the posterior cingulate, superior temporal, and frontal superior lobe. Amyloid PET results contributed to a change in diagnosis and treatment for 10 patients. [18F]Florbetaben PET has potential as an adjunctive tool in the diagnosis of PLWH with cognitive impairment, increasing diagnostic certainty and optimizing management.

The prognosis for patients affected by light-chain cardiac amyloidosis and acquired transthyretin-related (TTR) amyloidosis is poor. Heart transplantation (HTx) could improve prognosis also enabling autologous stem cell transplantation (ASCT) in the first group. A total of 36 patients affected by systemic amyloidosis have been referred to our centre from 2009 to 2019. Of these, nine had cardiac involvement: seven by light-chain amyloidosis and two by acquired TTR amyloidosis. None died while waiting for HTx. A specific internal protocol useful to select candidates and to monitor the organ involvement after HTx was developed. Median age at diagnosis was 54 years and 66% were male. The most common short-term complication after HTx was renal failure (44%), followed by acute cardiac rejection more than 2R (22%). ASCT was performed in six out of seven light-chain cardiac amyloidosis patients, with a median time of 6 months after HTx. Two patients affected by light-chain cardiac amyloidosis died due to amyloidosis relapse: one before undergoing ASCT. After a median follow-up of 31 (7-124) months, 1- and 5-year survival was 88 and 66% in the cardiac light-chain amyloidosis group. Conversely, 1- and 5-year survival was 100% in the acquired TTR amyloidosis group. HTx may represent a valuable option in carefully selected patients. ASCT after HTx is an effective treatment that could decrease amyloidosis relapse in light-chain cardiac amyloidosis patients. A multidisciplinary approach is mandatory to select the best candidates and to obtain the most effective results with a specific surveillance follow-up protocol.

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. 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 β-amyloid-reactive cells. 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 β-amyloid-immunopositive plaques compared to controls. The therapeutic effect of intravenously injected bone marrow-derived mesenchymal stem cells in a mouse model of Alzheimer's disease was confirmed by β-amyloid positron emission tomography imaging, memory functional studies and histopathological evaluation.

Positron emission tomography (PET) scanning with florbetaben (FBB) was approved in the US in 2014 after validation in histopathological studies for imaging of amyloid plaques in individuals being evaluated for Alzheimer’s disease (AD). The current abstract incorporates real-world evidence of FBB’s clinical and research use, including results from visual and quantitative assessment of amyloid PET images. The objectives of this work included 1) Evaluating the efficacy of the approved visual assessment method in the routine clinical practice and 2) Presenting results of 15 quantitative pipelines to underscore reliability and added value of quantification. The studies’ results confirmed that, both experts and naïve readers accurately assess FBB PET scans and maintain these abilities over time (correct assessments: 96% at baseline and 92% at 6 months follow-up). Quantitative methods, including 510(k) approved software, consistently demonstrated robust and homogeneous performance (accuracy 96.4±1.1%), offering valuable support for visual assessments. Since its approval, visual assessment and quantification of FBB images have undergone additional validation across diverse settings including clinical routine. FBB PET imaging is a validated, reliable, and available tool in the diagnostic pathway of AD, as indicated within the Alzheimer’s Association’s (AA) Updated Criteria for AD Diagnosis and Staging and the AA/Society for Nuclear Medicine’s Appropriate Use Criteria for PET. With the approval of amyloid-targeting therapies, standardized quantification approaches, such as the Centiloid scale, are becoming increasingly important for patient selection and treatment monitoring.

Introduction and importanceCardiac amyloidosis (CA) is a rare condition, characterized by fibrillary proteins infiltration in the extracellular space of the heart. Even though many types of cardiac amyloidosis exist, light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR) remain the most described forms. The diagnosis of amyloidosis represents a real challenge for clinicians, requiring both invasive and non-invasive investigations. Conduction defects and atrial arrhythmias are well known complications of cardiac amyloidosis. However, only a few studies have reported junctional rhythm a primary presentation of light chain cardiac amyloidosis (AL). An early diagnosis and proper management are crucial to improve the prognosis of this disease. Case presentationHere, we report a rare case of a 48 year-old patient, in acutely decompensated heart failure, presenting an accelerated junctional rhythm (AJR) as initial presentation of light-chain cardiac amyloidosis. The diagnosis was made based on clinical, biological, radiological and histological findings. This case shows diagnostic difficulties and management of this rare disease.

In Alzheimer disease (AD), neuroinflammation is an important process related to the deposition of beta-amyloid plaques and the activation of microglia. The inflammatory process can occur in both the gray matter and the white matter. We evaluated glucose metabolism of the white matter in AD patients and compared the value with cognitive parameters of the patients.Eighteen AD patients and 18 healthy subjects underwent F-18 fluorodeoxyglucose (FDG) and F-18 florbetaben positron emission tomography (PET). After segmentation of the white matter in both PET images, the specific binding ratio (SBR) of the global and regional cerebral white matter was checked. We evaluated the differences in SBR of the global and regional white matter between AD patients and healthy subjects. Then, we assessed the correlation between SBR and cognitive parameters in AD patients.In F-18 FDG PET images, the global white matter SBR was significantly higher in AD patients than in healthy subjects. In the regional analysis, the white matter SBR was significantly higher for the frontal, temporal, and parietal areas in AD patients. In the correlation analysis with F-18 FDG PET, SBR was significantly correlated with the Global Deterioration Scale, Mini-Mental State Examination scores, and amyloid deposition.Glucose metabolism of the white matter was significantly higher in AD patients than in healthy subjects and it was related to the scores of cognitive parameters. We suggest that F-18 FDG PET, like 18-kDa translocator protein PET, could be used as an indicator of neuroinflammation; however, further research is needed for a direct comparison between the 2 tests.

Background:[18F]Florbetaben is a positron emission tomography (PET) tracer that specifically binds to amyloid beta‐pleated structure. Diagnosis of immunoglobulin light‐chain amyloidosis in patients with multiple myeloma (MM) is clinically important to manage symptoms and signs associated with amlyoidosis.Aims:We aimed to evaluate the feasibility of [18F]Florbetaben PET for detecting amyloid deposits in MM patients and to explore the most optimal method for PET analysis.Methods:Fourteen patients with multiple myeloma were prospectively enrolled (6 patients with amyloidosis and 8 controls) between Aug 2018 and Nov 2018. After injection of 300 MBq of [18F]Florbetaben, dynamic imaging of the kidneys was acquired for 20 minutes. Time‐activity curve was generated by using a region of interest placed over the kidney and retention index (RI) was obtained. At 90 minutes post‐injection, PET image was acquired, with a scan field from the vertex to mid‐thigh. All images were assessed both qualitatively and quantitatively. Comparison between amyloidosis and non‐amyloidosis groups was performed, regarding SUVmax, SUVmean, and SUV ratio (SUVR = tissue of interest/reference region), which were obtained from both sphere and manually drawn volumes of interest (VOI). Amyloid deposition was confirmed according to international consensus guidelines.Results:All patients in the control group did not show any abnormal amyloid uptake on 18F‐Florbetaben PET/CT (0/8), while those in the amyloid group had amyloid positive findings in more than one organ (6/6, 100%). Among 15 organs confirmed to have amyloidosis involvement prior to PET/CT, 9 were positive on 18F‐Florbetaben PET/CT. The detection rates of amyloidosis involvement in the heart, stomach, and tongue were excellent (100%), whereas those of the liver, esophagus, and colon were poor. 18F‐Florbetaben PET/CT found 12 unexpected abnormal amyloid uptakes in the tongue, thyroid, heart, lung, stomach, and spleen. Three of these 12 unexpected uptakes were later clinically determined to be amyloidosis (1 tongue, 1 heart, and 1 lung).Summary/Conclusion:[18F]Florbetaben PET can be one of the tool to detect systemic amyloid deposits in MM patients, especially in the heart, stomach, and tongue.