Recent advances in the diagnostic methods and therapeutic strategies of transthyretin cardiac amyloidosis.

Cardiac amyloidosis is a progressive disease characterized by the buildup of amyloid fibrils in the extracellular space of the heart. It is divided in 2 main types, immunoglobulin light chain amyloidosis and transthyretin amyloidosis (ATTR), and ATTR amyloidosis is further divided in 2 subtypes, non-hereditary wild type ATTR and hereditary mutant variant amyloidosis. Incidence and prevalence of ATTR cardiac amyloidosis is increasing over the last years due to the improvements in diagnostic methods. Survival rates are improving due to the development of novel therapeutic strategies. Tafamidis is the only disease-modifying approved therapy in ATTR amyloidosis so far. However, the most recent advances in medical therapies have added more options with the potential to become part of the therapeutic armamentarium of the disease. Agents including acoramidis, eplontersen, vutrisiran, patisiran and anti-monoclonal antibody NI006 are being investigated on cardiac function in large, multicenter controlled trials which are expected to be completed within the next 2-3 years, providing promising results in patients with ATTR cardiac amyloidosis. However, further and ongoing research is required in order to improve diagnostic methods that could provide an early diagnosis, as well as survival and quality of life of these patients.

Long-Term Prognostic Value of Automated Measurements in Nuclear Cardiology: Comparisons with Expert Scoring.

Background and Objectives: Automated methods for the analysis of myocardial perfusion studies have been incorporated into clinical practice, but they are currently used as adjuncts to the visual interpretation. We aimed to investigate the role of automated measurements of summed stress score (SSS), summed rest score (SRS), and summed difference score (SDS) as long-term prognostic markers of morbidity and mortality, in comparison to the prognostic value of expert reading. Materials and Methods: The study was conducted at the Nuclear Medicine Laboratory of the University of Thessaly, in Larissa, Greece. A total of 378 consecutive patients with known or suspected coronary artery disease were enrolled in the study. All participants were referred to our laboratory for the performance of stress/rest myocardial perfusion single photon emission computed tomography. Automated measurements of SSS, SRS, and SDS were obtained by Emory Cardiac Toolbox (ECTb (Version 3.0), Emory University, Atlanta, GA, USA), Myovation (MYO, Xeleris version 3.05, GE Healthcare, Chicago, IL, USA), and Quantitative Perfusion SPECT (QPS (Version 4.0), Cedars-Sinai Medical Center, Los Angeles, CA, USA) software packages. Follow-up data were recorded after phone contacts, as well as through review of hospital records. Results: Expert scoring of SSS and SDS had significantly greater prognostic ability in comparison to all software packages (p < 0.001 for all comparisons). Similarly, ECTb-obtained SRS measurements had significantly lower prognostic ability in comparison to expert scoring (p < 0.001), while expert scoring of SRS showed significantly higher prognostic ability compared to MYO (p = 0.018) and QPS (p < 0.001). Conclusions: Despite the useful contribution of automated analyses in the interpretation of myocardial perfusion studies, expert reading should continue to have a crucial role, not only in clinical decision making, but also in the assessment of prognosis.

Nuclear medicine in the assessment and prevention of cancer therapy-related cardiotoxicity: prospects and proposal of use by the European Association of Nuclear Medicine (EANM).

Cardiotoxicity may present as (pulmonary) hypertension, acute and chronic coronary syndromes, venous thromboembolism, cardiomyopathies/heart failure, arrhythmia, valvular heart disease, peripheral arterial disease, and myocarditis. Many of these disease entities can be diagnosed by established cardiovascular diagnostic pathways. Nuclear medicine, however, has proven promising in the diagnosis of cardiomyopathies/heart failure, and peri- and myocarditis as well as arterial inflammation. This article first outlines the spectrum of cardiotoxic cancer therapies and the potential side effects. This will be complemented by the definition of cardiotoxicity using non-nuclear cardiovascular imaging (echocardiography, CMR) and biomarkers. Available nuclear imaging techniques are then presented and specific suggestions are made for their application and potential role in the diagnosis of cardiotoxicity.

Multi-center study of inter-rater reproducibility, image quality, and diagnostic accuracy of CZT versus conventional SPECT myocardial perfusion imaging.

BACKGROUND: Cadmium-zinc-telluride (CZT)-based detectors exhibit higher diagnostic sensitivity in myocardial perfusion imaging (MPI) than conventional Anger-MPI for detection of coronary artery disease (CAD); however, reduced specificity and diagnostic accuracy of CZT-MPI were observed. This study aims to compare these different camera systems and to examine the degree of inter-rater reproducibility among readers with varying experience in MPI. METHODS: 83 patients who underwent double stress/rest examinations using both a CZT and conventional SPECT cameras within one visit were included. Anonymized and randomized MPI-images were distributed to 15 international readers using a standardized questionnaire. Subsequent coronary angiography findings of ten patients served as a reference for analysis of sensitivity and specificity. RESULTS: Image quality was significantly better in CZT-MPI with significantly lower breast attenuation (P < 0.05). CZT-MPI exhibited higher sensitivity than Anger-MPI (87.5% vs. 62.5%) and significantly reduced specificity (40% vs. 100%). Readers experienced with both camera systems had the highest inter-rater agreement indicating higher reproducibility (CZT 0.54 vs. conv. 0.49, P < 0.05). CONCLUSIONS: Higher diagnostic sensitivity of CZT-MPI offers advantages in detection of CAD yet potentially of at the cost of reduced specificity, therefore it requires special training and a differentiated evaluation approach, especially for non-experienced readers with such camera systems.

Automated Analysis vs. Expert Reading in Nuclear Cardiology: Correlations with the Angiographic Score.

Background and Objectives: Myocardial perfusion imaging (MPI) has an important role in the non-invasive investigation of coronary artery disease. The interpretation of MPI studies is mainly based on the visual evaluation of the reconstructed images, while automated quantitation methods may add useful data for each patient. However, little evidence is currently available regarding the actual incremental clinical diagnostic performance of automated MPI analysis. In the present study, we aimed to assess the correlation between automated measurements of Summed Stress Score (SSS), Summed Rest Score (SRS) and Summed Difference Score (SDS), with the corresponding expert reading values, using coronary angiography as the gold standard. Materials and Methods: The study was conducted at the Nuclear Medicine Laboratory of the University Hospital of Larissa, Larissa, Greece, οver an one-year period (January 2019-January 2020). 306 patients, with known or suspected coronary artery disease, were enrolled in the study. Each participant underwent a coronary angiography, prior to or after the scintigraphic study (within a three-month period). Either symptom-limited treadmill test, or pharmacologic testing using adenosine or regadenoson, was performed in all participants, and the scintigraphic studies were carried out using technetium 99m (99mTc) tetrofosmin (one-day stress/rest protocol). Coronary angiographies were scored according to a 4-point scoring system (angiographic score; O: normal study, 1: one-vessel disease, 2: two-vessel disease, 3: three-vessel disease). Moreover, automated measurements of SSS, SRS and SDS were derived by three widely available software packages (Emory Cardiac Toolbox, Myovation, Quantitative Perfusion SPECT). Results: Interclass Correlation Coefficients of SSS, SRS and SDS between expert reading and software packages were moderate to excellent. Visually defined SSS, SRS and SDS were significantly correlated with the corresponding results of all software packages. However, visually defined SSS, SRS and SDS were more strongly correlated with the angiographic score, indicating a better performance of expert reading when compared to automated analysis. Conclusions: Based on our results, visual evaluation continues to have a crucial role for the interpretation of MPI images. Software packages can provide automated measurements of several parameters, particularly contributing to the investigation of cases with ambiguous scintigraphic findings.

Anosognosia in Dementia: Evaluation of Perfusion Correlates Using 99mTc-HMPAO SPECT and Automated Brodmann Areas Analysis.

(1) Background: Considerable inconsistency exists regarding the neural substrates of anosognosia in dementia in previous neuroimaging studies. The purpose of this study was the evaluation of anosognosia perfusion correlates across various types of dementia using automated Brodmann areas (BAs) analysis and comparison with a database of normal subjects. (2) Methods: We studied 72 patients: 32 with Alzheimer's disease, 26 with frontotemporal dementia-FTD (12 behavioral FTD, 9 semantic FTD, 5 Progressive Non-Fluent Aphasia), 11 with corticobasal syndrome, and 3 with progressive supranuclear palsy. Addenbrook's Cognitive Examination-Revised (ACE-R) mean(±SD) was 55.6(±22.8). For anosognosia measurement, the Anosognosia Questionnaire-Dementia was used. Total anosognosia score mean(±SD) was 22.1(±17.9), cognitive anosognosia score mean(±SD) was 18.1(±15.1) and behavioral-mood anosognosia score mean(±SD) was 3.3(±4.7). (3) Results: Higher anosognosia total score was associated with hypoperfusion in the inferior temporal, anterior cingulate, and inferior frontal cortices of the right hemisphere (BAs 20R, 24R, 32R, 45R). Higher anosognosia cognitive score was correlated with hypoperfusion in the left middle and anterior temporal cortices, and right dorsal anterior cingulate cortex (BAs 21L, 22L, 32R). No association was found with behavioral-mood anosognosia. (4) Conclusions: Automated analysis of brain perfusion Single Photon Emission Computed Tomography could be useful for the investigation of anosognosia neural correlates in dementia.

Differences of apathy perfusion correlates between Alzheimer's disease and frontotemporal dementia. A 99mTc-HMPAO SPECT study with automated Brodmann areas analysis.

OBJECTIVES: To explore differences of apathy perfusion correlates between Alzheimer's disease (AD) and Frontotemporal dementia (FTD) using perfusion SPECT. METHODS: We studied 75 FTD and 66 AD patients. We evaluated apathy using Neuropsychiatric Inventory (NPI). We compared perfusion of BAs on left (L) and right (R) hemisphere in AD and FTD. RESULTS: Apathy in AD was significantly and negatively correlated with dorsolateral prefrontal cortex bilaterally, right anterior prefrontal cortex, inferior frontal cortex bilaterally, especially on the right, orbital part of inferior frontal gyrus bilaterally, left dorsal anterior cingulate cortex, right primary and secondary visual cortex, and with bilateral anterior and dorsolateral prefrontal cortex, inferior frontal cortex and orbital part of inferior frontal gyrus, bilaterally, bilateral anterior -ventral and dorsal- cingulate cortex, left posterior ventral cingulate cortex, right inferior, middle and anterior temporal gyri, entorhinal and parahippocampal cortex in FTD. CONCLUSIONS: Significant overlapping of apathy perfusion correlates between AD and FTD is seen in frontal areas and anterior cingulate. Right occipital cortex is also involved in AD, while right temporal cortex and left posterior cingulate are involved in FTD. Nuclear imaging could be a useful biomarker for revealing apathy underlying mechanisms, resulting in directed treatments.KEYPOINTSUnderlying neural networks and clinical manifestation of apathy may differ between AD and FTD.Apathy in AD is correlated with hypoperfusion in bilateral frontal areas, more prominent on the right, left anterior cingulate and right occipital cortex.Apathy in FTD is correlated with hypoperfusion in bilateral frontal areas, bilateral anterior cingulate, left posterior cingulate and right temporal cortex.Brain perfusion SPECT with automated BAs analysis and comparison with normal healthy subjects may provide significant information for apathy mechanisms in neurodegenerative disorders, affecting patients' treatment.

Correlation of Neuropsychiatric Symptoms in Dementia with Brain Perfusion: A 99mTc-SPECT-HMPAO Study with Brodmann Areas Analysis.

BACKGROUND: Neuropsychiatric symptoms (NPSs) are common in dementia. Their evaluation is based on Neuropsychiatric Inventory (NPI). Neuroimaging studies have tried to elucidate the underlying neural circuits either in isolated NPSs or in specific forms of dementia. OBJECTIVE: The objective of this study is to evaluate the correlation of NPS in the NPI with Brodmann areas (BAs) perfusion, for revealing BAs involved in the pathogenesis of NPSs in dementia of various etiologies. METHODS: We studied 201 patients (82 with Alzheimer's disease, 75 with Frontotemporal dementia, 27 with Corticobasal Syndrome, 17 with Parkinson Disease/Lewy Body Dementia). Exploratory factor analysis was carried out to evaluate underlying groups of BAs, and Principal Component analysis was chosen as extraction method using Varimax rotation. Partial correlation coefficients were computed to explore the association of factors obtained from analysis and NPI items controlling for age, educational yeas, and ACE-R. RESULTS: We found 6 BAs Factors(F); F1 (BAs 8,9,10,11,24,32,44,45,46,47, bilaterally), F2 (BAs 4,5,6,7,23,31, bilaterally), F3 (BAs 19,21,22,37,39,40, bilaterally), F4 (BAs 20,28,36,38, bilaterally), F5 (BAs 25, bilaterally) and F6 (BAs 17,18, bilaterally). Significant and negative correlation was found between NPI1 (delusions) and F3,F6, NPI2 (hallucinations) and F6, NPI7 (apathy) and F1,F4,F5, NPI3 (agitation) - NPI10 (aberrant motor behavior) - NPI12 (eating disorders) and F1. We did not find any significant correlation for NPI4,5,6,8,9,11 (depression, anxiety, euphoria, disinhibition, irritability, sleep disorders, respectively). CONCLUSION: Several NPSs share the same BAs among different types of dementia, while the manifestation of the rest may be attributed to different neural networks. These findings may have an impact on patients' treatment.

Τhe Greek Variant in APP Gene: The Phenotypic Spectrum of APP Mutations.

Mutations in the gene encoding amyloid precursor protein (APP) cause autosomal dominant inherited Alzheimer's disease (AD). We present a case of a 68-year-old female who presented with epileptic seizures, neuropsychiatric symptoms and progressive memory decline and was found to carry a novel APP variant, c.2062T>G pLeu688Val. A comprehensive literature review of all reported cases of AD due to APP mutations was performed in PubMed and Web of Science databases. We reviewed 98 studies with a total of 385 cases. The mean age of disease onset was 51.3 ± 8.3 (31-80 years). Mutations were most often located in exons 17 (80.8%) and 16 (12.2%). The most common symptoms were dementia, visuospatial symptoms, aphasia, epilepsy and psychiatric symptoms. Mutations in the ß-amyloid region, and specifically exon 17, were associated with high pathogenicity and a younger age of disease onset. We describe the second reported APP mutation in the Greek population. APP mutations may act variably on disease expression and their phenotype is heterogeneous.

Effect of adiponectin on estradiol and progesterone secretion from human luteinized granulosa cells in vitro.

Ιnformation on the role of adiponectin in human ovarian steroidogenesis is limited. The present study aimed to investigate the effect of different doses of adiponectin on the secretion of estradiol and progesterone by human luteinized granulosa cells in culture. Granulosa cells, obtained from women undergoing in vitro fertilization (IVF) treatment, were pre-incubated for 24 h and then cultured for 48 h. Adiponectin was used in 3 doses, i.e., 5, 10, and 100 µg/ml alone and in combinations with FSH (10 and 100 ng/ml). Estradiol and progesterone were measured by radioimmunoassays in culture supernatants at 24 h and 48 h. Adiponectin after 48 h of culture stimulated the secretion of estradiol and, to a lesser extent, progesterone in a dose-dependent manner. FSH showed a variable effect on steroidogenesis. However, when the low dose FSH was combined with adiponectin, estradiol, and progesterone secretion were increased disproportionally to the dose of adiponectin. With the high dose FSH, the positive effect of adiponectin on FSH-induced estradiol secretion was less pronounced, while the effect on progesterone secretion was negligible. This study shows for the first time a stimulatory effect of adiponectin on the secretion of estradiol and progesterone by human luteinized granulosa cells in vitro. It is suggested that adiponectin plays a paracrine role in human ovarian steroidogenesis by sensitizing the granulosa cells to FSH.

Position paper of the EACVI and EANM on artificial intelligence applications in multimodality cardiovascular imaging using SPECT/CT, PET/CT, and cardiac CT.

In daily clinical practice, clinicians integrate available data to ascertain the diagnostic and prognostic probability of a disease or clinical outcome for their patients. For patients with suspected or known cardiovascular disease, several anatomical and functional imaging techniques are commonly performed to aid this endeavor, including coronary computed tomography angiography (CCTA) and nuclear cardiology imaging. Continuous improvement in positron emission tomography (PET), single-photon emission computed tomography (SPECT), and CT hardware and software has resulted in improved diagnostic performance and wide implementation of these imaging techniques in daily clinical practice. However, the human ability to interpret, quantify, and integrate these data sets is limited. The identification of novel markers and application of machine learning (ML) algorithms, including deep learning (DL) to cardiovascular imaging techniques will further improve diagnosis and prognostication for patients with cardiovascular diseases. The goal of this position paper of the European Association of Nuclear Medicine (EANM) and the European Association of Cardiovascular Imaging (EACVI) is to provide an overview of the general concepts behind modern machine learning-based artificial intelligence, highlights currently prefered methods, practices, and computational models, and proposes new strategies to support the clinical application of ML in the field of cardiovascular imaging using nuclear cardiology (hybrid) and CT techniques.

Eating Disorders in Frontotemporal Dementia and Alzheimer's Disease: Evaluation of Brain Perfusion Correlates Using 99mTc-HMPAO SPECT with Brodmann Areas Analysis.

BACKGROUND: Eating disorders (ED) in dementia represent a significant impairment affecting patients' and caregivers' lives. In frontotemporal dementia (FTD), ED include overeating, sweet food preference, stereotypical eating, and hyperorality, while in Alzheimer's disease (AD), anorexia and appetite loss are the most common ED. OBJECTIVE: The aim of our study was to highlight Brodmann areas (BAs) implicated specifically in the appearance of ED in FTD and AD. METHODS: We studied 141 patients, 75 with FTD and 66 with AD. We used the NeuroGamTM software on the reconstructed single photon emission computed tomography-SPECT data for the automated comparison of BAs perfusion on the left (L) and right (R) hemisphere with perfusion in corresponding BAs of a normal database. RESULTS: The FTD group included 27 men and 48 women, age (mean±SD) 65.8±8.5 years, duration of disease 3.4±3.3 years, Mini-Mental State Examination (MMSE) 17.9±8.6, ED score on Neuropsychiatric Inventory (NPI) 4.7±8.5. ED in FTD were correlated with hypoperfusion in right anterior and dorsolateral prefrontal cortices (BAs 10R, 46R), left orbitofrontal cortex (BA 12L), orbital part of the right inferior frontal gyrus (BA 47R), and left parahippocampal gyrus (BA 36L). The AD group included 21 men and 45 women, age (mean±SD) 70.2±8.0 years, duration of disease 3.3±2.4 years, MMSE 20.2±6, ED-NPI score 2.7±3.9. ED in AD were correlated with hypoperfusion in left inferior temporal cortex (BA 20L). CONCLUSION: SPECT imaging with automated mapping of brain cortex could contribute to the understanding of the neural networks involved in the manifestation of ED in dementia.

Fahr's syndrome due to hypoparathyroidism revisited: A case of parkinsonism and a review of all published cases.

INTRODUCTION: Fahr's syndrome due to hypoparathyroidism refers to bilateral basal ganglia (BG) calcifications and manifests with movement disorders, seizures, cognitive and behavioral symptoms. CASE PRESENTATION: We report a case of a 74-year-old woman, who presented with parkinsonism due to post-surgical hypoparathyroidism and normal DaT scan, despite extensive calcifications of the BG, periventricular white matter, and cerebellum. METHODS: A comprehensive literature review of all reported cases of Fahr's syndrome due to hypoparathyroidism was conducted in the electronic databases PubMed and Web of science. Moreover, demographic and clinical characteristics of the patients overall were calculated and associated with radiological findings. RESULTS: We reviewed a total of 223 cases with Fahr's syndrome due to hypoparathyroidism (124 female, 99 male). Mean age on presentation was 44.6 ± 17.7 years. Thirty nine percent of patients had idiopathic hypoparathyroidism, 35.4 % acquired and 25.6 % pseudohypoparathyroidism. Almost half of the patients had tetany, seizures or a movement disorder and approximately 40 % neuropsychiatric symptoms. The patients with a movement disorder had a 2.23 likelihood of having neuropsychiatric symptoms as well (OR 2.23, 95 % CI 1.29-3.87). Moreover, there was a statistically significant association between the phenotype severity (i.e. the presence of more than one symptom) and the extent of brain calcifications (χ2 = 32.383, p = 0.009). CONCLUSION: Fahr's syndrome is a rare disorder, which nonetheless manifests with several neurological symptoms. A head CT should be considered for patients with hypoparathyroidism and neurological symptoms. More studies using DaT scan are needed to elucidate the effects of calcifications on the dopaminergic function of the BG.

EANM procedural guidelines for PET/CT quantitative myocardial perfusion imaging.

The use of cardiac PET, and in particular of quantitative myocardial perfusion PET, has been growing during the last years, because scanners are becoming widely available and because several studies have convincingly demonstrated the advantages of this imaging approach. Therefore, there is a need of determining the procedural modalities for performing high-quality studies and obtaining from this demanding technique the most in terms of both measurement reliability and clinical data. Although the field is rapidly evolving, with progresses in hardware and software, and the near perspective of new tracers, the EANM Cardiovascular Committee found it reasonable and useful to expose in an updated text the state of the art of quantitative myocardial perfusion PET, in order to establish an effective use of this modality and to help implementing it on a wider basis. Together with the many steps necessary for the correct execution of quantitative measurements, the importance of a multiparametric approach and of a comprehensive and clinically useful report have been stressed.