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INTRODUCTIONIt remains unclear to which extent vascular burden promotes neurodegeneration and cognitive dysfunction in a cohort spanning low-to-severe small vessel disease (SVD) and amyloid-beta pathology.METHODSIn 120 subjects, we investigated 1) whether vascular burden, quantified as total or lobar white matter hyperintensity (WMH) volumes, is associated with different cognitive domains; and 2) whether the total WMH effect on cognition is mediated by amyloid (18F-AV45-PET), glucose metabolism (18F-FDG-PET), and/or cortical atrophy.RESULTSIncreased total WMH volume was associated with poorer performance in all cognitive domains tested, with the strongest effects observed for semantic fluency. These relationships were mediated mainly through cortical atrophy, particularly in the temporal lobe, and to a lesser extent through amyloid and metabolism. WMH volumes differentially impacted cognition depending on lobar location and amyloid status.DISCUSSIONOur study suggests mainly an amyloid-independent pathway in which vascular burden affects cognitive impairment through temporal lobe atrophy.

Background: Accurate assessment of hepatopulmonary shunting, typically performed by planar scintigraphy, is critical in planning yttrium-90 radioembolization. High lung shunt fractions (LSFs) may alter treatment. Objective: To compare LSFs calculated from planar scintigraphy versus SPECT/CT in patients with high planar LSFs (>15%) and to describe potential clinical and dosimetric implications of SPECT/CT LSF calculations. Methods: This retrospective study included 36 patients (29 male, 7 female; mean age 62.4±9.8 years) who underwent technetium-99m labeled macroaggregated albumin planar scintigraphy for planning hepatic radioembolization, with planar LSF >15% and concurrent SPECT/CT. Clinically reported planar LSFs were recorded. SPECT/CT LSFs were retrospectively calculated using automatically generated volumetric ROIs around the lungs and liver with subsequent manual adjustments. Total lung and perfused liver doses were calculated using a medical internal radiation dose model. Values derived from planar and SPECT/CT data were compared with Mann-Whitney U tests. Multivariable regression analysis was performed of factors associated with LSF discrepancy between techniques. Results: Mean planar LSF was 25.1%±11.6%; mean SPECT/CT LSF was 16.0%±9.3% (p 20%, instead undergoing shunt-reducing embolization with subsequent radioembolization (n=7), transarterial chemoembolization (n=5), or no treatment (n=2). Five of these 14 patients had SPECT/CT LSF

A 54-year-old man with hepatocellular carcinoma from alcohol-induced cirrhosis presented with hepatic encephalopathy and refractory ascites related to decompensated liver disease. MRI confirmed disease progression adjacent the site of prior radiofrequency ablation, performed 2 years prior, with associated right hepatic vein tumor thrombus. 99mTc-labeled macroaggregated albumin lung shunt imaging performed before 90Y radioembolization identified a left lower lobe wedge-shaped defect, confirmed as pulmonary embolism on CT pulmonary angiography and MRI.

Images of DaTscan (ioflupane [123I] SPECT) have been used as an adjunct to clinical diagnosis to facilitate the differential diagnosis of neurodegenerative (ND) Parkinsonian Syndrome (PS) vs. non-dopamine deficiency aetiologies of Parkinsonism. Despite several systematic reviews having summarised the evidence on diagnostic accuracy, the impact of imaging results on clinical utility has not been systematically assessed. Our objective was to examine the available evidence on the clinical utility of DaTscan imaging in changing diagnosis and subsequent management of patients with suspected PS. We performed a systematic review of published studies of clinical utility from 2000 to 2019 without language restrictions. A meta-analysis of change in diagnosis and management rates reported from each study was performed using a random-effects model and logit transformation. Sub-group analysis, meta-regression and sensitivity analysis was performed to explore heterogeneity. Twenty studies met the inclusion criteria. Thirteen of these contributed to the meta-analyses including 950 and 779 patients with a reported change in management and change in diagnosis, respectively. The use of DaTscan imaging resulted in a change in management in 54% (95% CI: 47–61%) of patients. Change in diagnosis occurred in 31% (95% CI: 22–42%) of patients. The two pooled analyses were characterised by high levels of heterogeneity. Our systematic review and meta-analysis show that imaging with DaTscan was associated with a change in management in approximately half the patients tested and the diagnosis was modified in one third. Regardless of time from symptom onset to scan results, these changes were consistent. Further research focusing on specific patient subgroups could provide additional evidence on the impact on clinical outcomes.

Rationale We evaluated K-means clustering to classify amyloid brain PETs as positive or negative. Patients and methods Sixty-six participants (31 men, 35 women; age range, 52-81 years) were recruited through a multicenter observational study: 19 cognitively normal, 25 mild cognitive impairment, and 22 dementia (11 Alzheimer disease, 3 subcortical vascular cognitive impairment, and 8 Parkinson-Lewy Body spectrum disorder). As part of the neurocognitive and imaging evaluation, each participant had an 18F-flutemetamol (Vizamyl, GE Healthcare) brain PET. All studies were processed using Cortex ID software (General Electric Company, Boston, MA) to calculate SUV ratios in 19 regions of interest and clinically interpreted by 2 dual-certified radiologists/nuclear medicine physicians, using MIM software (MIM Software Inc, Cleveland, OH), blinded to the quantitative analysis, with final interpretation based on consensus. K-means clustering was retrospectively used to classify the studies from the quantitative data. Results Based on clinical interpretation, 46 brain PETs were negative and 20 were positive for amyloid deposition. Of 19 cognitively normal participants, 1 (5%) had a positive 18F-flutemetamol brain PET. Of 25 participants with mild cognitive impairment, 9 (36%) had a positive 18F-flutemetamol brain PET. Of 22 participants with dementia, 10 (45%) had a positive 18F-flutemetamol brain PET; 7 of 11 participants with Alzheimer disease (64%), 1 of 3 participants with vascular cognitive impairment (33%), and 2 of 8 participants with Parkinson-Lewy Body spectrum disorder (25%) had a positive 18F-flutemetamol brain PET. Using clinical interpretation as the criterion standard, K-means clustering (K = 2) gave sensitivity of 95%, specificity of 98%, and accuracy of 97%. Conclusions K-means clustering may be a powerful algorithm for classifying amyloid brain PET.

We designed a dedicated multi-detector multi-pinhole brain SPECT scanner to generate images of higher quality compared to general-purpose systems. The system, AdaptiSPECT-C, is intended to adapt its sensitivity-resolution trade-off by varying its aperture configurations allowing both high-sensitivity dynamic and high-spatial-resolution static imaging. The current system design consists of 23 detector heads arranged in a truncated spherical geometry. In this work, we investigated the axial and angular sampling capability of the current stationary system design. Two data acquisition schemes using limited rotation of the gantry and two others using axial translation of the imaging bed were also evaluated concerning their impact on image quality through improved sampling. Increasing both angular and axial sampling in the current prototype system resulted in quantitative improvements in image quality metrics and qualitative appearance of the images as determined in studies with specifically selected phantoms. Visual improvements for the brain phantoms with clinical distributions were less pronounced but presented quantitative improvements in the fidelity (normalized root-mean-square error (NRMSE)) and striatal specific binding ratio (SBR) for a dopamine transporter (DAT) distribution, and in NRMSE and activity recovery for a brain perfusion distribution. More pronounced improvements with increased sampling were seen in contrast recovery coefficient, bias, and coefficient of variation for a lesion in the brain perfusion distribution. The negligible impact of the most cranial ring of detectors on axial sampling, but its significant impact on sensitivity and angular sampling in the cranial portion of the imaging volume-of-interest were also determined.

The majority of aggressive prostate cancers overexpress the transmembrane protein prostate-specific membrane antigen (PSMA). PSMA is, therefore, an attractive target for drug development. Over the last decade, numerous PSMA-targeted radiopharmaceuticals for imaging and therapy have been developed and investigated in theranostic combination. PSMA-targeted radiopharmaceuticals for imaging have been primarily developed for PET. PSMA PET provides whole-body evaluation of the degree of PSMA expression on tumors and potentially provides a method to better select patients for PSMA-targeted therapy. Numerous PSMA-targeted therapeutic agents using β- or α-particle emitters are under study in clinical trials. In particular, the β-particle-emitting radioisotope 177Lu bound to PSMA-targeted small molecules have ongoing and completed late-stage clinical trials in metastatic castration-resistant prostate cancer. To define the most appropriate patient group for PSMA-targeted therapeutics, multiple studies have investigated PSMA and FDG PET/CT to establish PET parameters as predictive and prognostic biomarkers. This article discusses recent clinical trials that examine the optimal use of PET for the selection of patients for PSMA-targeted therapeutics and provides an integrative overview of choice of PET tracer(s), targeting molecule, therapeutic radioisotope, nonradioactive therapy, and cancer type (prostate or nonprostate).

Key Points Question What is the prognostic value of tau positron emission tomography (PET) for predicting cognitive decline across the clinical spectrum of Alzheimer disease? Findings In this longitudinal, multicenter prognostic study including 1431 participants, baseline tau PET predicted change in Mini-Mental State Examination scores during a mean (SD) follow-up of 1.9 (0.8) years. Moreover, tau PET outperformed established volumetric magnetic resonance imaging and amyloid PET markers in head-to-head comparisons, especially in participants with mild cognitive impairment and cognitively normal individuals who were positive for amyloid-β. Meaning These findings suggest that tau PET is a promising prognostic tool for predicting cognitive decline in preclinical and prodromal stages of Alzheimer disease., Importance Tau positron emission tomography (PET) tracers have proven useful for the differential diagnosis of dementia, but their utility for predicting cognitive change is unclear. Objective To examine the prognostic accuracy of baseline fluorine 18 (18F)–flortaucipir and [18F]RO948 (tau) PET in individuals across the Alzheimer disease (AD) clinical spectrum and to perform a head-to-head comparison against established magnetic resonance imaging (MRI) and amyloid PET markers. Design, Setting, and Participants This prognostic study collected data from 8 cohorts in South Korea, Sweden, and the US from June 1, 2014, to February 28, 2021, with a mean (SD) follow-up of 1.9 (0.8) years. A total of 1431 participants were recruited from memory clinics, clinical trials, or cohort studies; 673 were cognitively unimpaired (CU group; 253 [37.6%] positive for amyloid-β [Aβ]), 443 had mild cognitive impairment (MCI group; 271 [61.2%] positive for Aβ), and 315 had a clinical diagnosis of AD dementia (315 [100%] positive for Aβ). Exposures [18F]Flortaucipir PET in the discovery cohort (n = 1135) or [18F]RO948 PET in the replication cohort (n = 296), T1-weighted MRI (n = 1431), and amyloid PET (n = 1329) at baseline and repeated Mini-Mental State Examination (MMSE) evaluation. Main Outcomes and Measures Baseline [18F]flortaucipir/[18F]RO948 PET retention within a temporal region of interest, MRI-based AD-signature cortical thickness, and amyloid PET Centiloids were used to predict changes in MMSE using linear mixed-effects models adjusted for age, sex, education, and cohort. Mediation/interaction analyses tested whether associations between baseline tau PET and cognitive change were mediated by baseline MRI measures and whether age, sex, and APOE genotype modified these associations. Results Among 1431 participants, the mean (SD) age was 71.2 (8.8) years; 751 (52.5%) were male. Findings for [18F]flortaucipir PET predicted longitudinal changes in MMSE, and effect sizes were stronger than for AD-signature cortical thickness and amyloid PET across all participants (R2, 0.35 [tau PET] vs 0.24 [MRI] vs 0.17 [amyloid PET]; P < .001, bootstrapped for difference) in the Aβ-positive MCI group (R2, 0.25 [tau PET] vs 0.15 [MRI] vs 0.07 [amyloid PET]; P, This prognostic study examines the prognostic accuracy of baseline [18F]flortaucipir and [18F]RO948 (tau) positron emission tomography (PET) in individuals across the Alzheimer disease clinical spectrum and performs a head-to-head comparison with established magnetic resonance imaging and amyloid PET markers.

Prophylactic cranial irradiation (PCI) is used to decrease the probability of developing brain metastases in patients with small cell lung cancer and has been linked to deleterious cognitive effects. Although no well-established imaging markers for these effects exist, previous studies have shown that structural and metabolic changes in the brain can be detected with MRI and PET. This study used an image processing technique called texture analysis to explore whether global changes in brain glucose metabolism could be characterized in PET images. Methods:18F-FDG PET images of the brain from patients with small cell lung cancer, obtained before and after the administration of PCI, were processed using texture analysis. Texture features were compared between the pre- and post-PCI images. Results: Multiple texture features demonstrated statistically significant differences before and after PCI when texture analysis was applied to the brain parenchyma as a whole. Regional differences were also seen but were not statistically significant. Conclusion: Global changes in brain glucose metabolism occur after PCI and are detectable using advanced image processing techniques. These changes may reflect radiation-induced damage and thus may provide a novel method for studying radiation-induced cognitive impairment.

After nearly disappearing, invasive lymphangiography not only has resurged, but new approaches have been developed to guide lymphatic interventions. At the same time, noninvasive lymphatic imaging is playing a larger role in the evaluation of lymphatic pathologies. Lymphangioscintigraphy, computed tomography lymphangiography, and magnetic resonance lymphangiography are increasingly being used as alternatives to invasive diagnostic lymphangiography. The purpose of this article is to review current invasive and noninvasive lymphatic imaging techniques.

Dopamine transporter SPECT with I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (I-ioflupane) aids in the diagnosis of parkinsonian syndrome by demonstrating loss of striatal dopamine transporters, proportional to nigrostriatal dopaminergic neuronal loss. Quantitative software analysis (QSA) is a helpful adjunct to visual interpretation. An atlas of pearls and pitfalls of QSA is presented. Examples include correction for head tilt/orientation, scaling artifacts, and detection of balanced loss of activity. Additional examples are provided where QSA can potentially fail such as patient variation and vascular disease.

This report describes a technique for measuring lung shunt fraction (LSF) twice in a single session during planning arteriography for radioembolization using low and standard dose technetium-99m macroaggregated albumin (99mTc-MAA). A patient with a 16.0 cm hepatocellular carcinoma and LSF of 70% was treated with lenvatinib for 4 weeks. Planning arteriography with administration of 0.5 millicuries of 99mTc-MAA was then performed. Arterial access was maintained while the LSF was calculated, which was persistently elevated at 54%. Embolization of arteriovenous shunts was performed during the same session and 5.0 millicuries of 99mTc-MAA were administered. The repeat LSF was 29%. Successful radioembolization was subsequently performed.

Background Perivascular epithelioid cell tumors are defined by the World Health Organization as “a collection of rare mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular epithelioid cells.” Whereas localized perivascular epithelioid cell tumor is typically benign and treated successfully with surgical resection, prognosis for patients with advanced or metastatic perivascular epithelioid cell tumor is unfavorable, and there is no standard curative treatment. Case presentation We report a Caucasian case of metastatic perivascular epithelioid cell tumor previously treated with chemotherapy and surgery with elevated surface expression of programmed cell death ligand 1. Based on this result, treatment via immune checkpoint inhibition with the monoclonal antibody pembrolizumab was pursued. After 21 cycles, the patient sustained a complete response. Therapy was stopped after the 40th cycle, and she was moved to surveillance. She remained disease free 19 months off treatment. Conclusions This case report of a patient with perivascular epithelioid cell tumor treated successfully with programmed cell death protein-1 targeted therapy suggests that programmed cell death ligand-1 levels should be measured in patients with perivascular epithelioid cell tumor and immunotherapy considered for recurrent or metastatic patients. Future phase II/III studies in this disease should focus on sequencing of surgery and immunotherapy with a design of curative intent.

BACKGROUND The lymphatic system is essential for maintaining the balance of interstitial fluid in tissues and for returning protein rich fluids (lymph) to the bloodstream. Congenital lymphatic defects lead to accumulation of lymph in peripheral tissues and body cavities, termed primary lymphedema. To date, only a limited number of individual genes have been identified in association with primary lymphedema. However, variability of age of onset and severity of lymphatic abnormalities within some families suggests that multiple mutations and/or genes may be responsible, thus hampering efforts to identify individual associated genes. METHODS Whole Exome Sequencing (WES) was performed in four members of a large multigeneration family with highly variable lymphedema and followed by Sanger sequencing for identified mutations in 34 additional family members. Genotypes were correlated with clinical and lymphangioscintigraphic phenotypes. RESULTS WES uncovered two different mechanotransducer PIEZO1 mutations and one FOXC2 transcription factor mutation in various combinations. Sanger sequencing confirmed the presence/absence of the three variants in affected and unaffected family members and co-segregation of one or more variants with disease. Genetic profiles did not clearly correlate with the highly variable severity of lymphatic abnormalities. CONCLUSIONS WES in lymphedema families can uncover unexpected combinations of several lymphedema-associated mutations. These findings provide essential information for genetic counseling and reveal complex gene interactions in lymphatic developmental pathways. These can offer insights into the complex spectrum of clinical and lymphatic lymphedema phenotypes and potential targets for treatment.

A 74-year-old woman with primary hyperparathyroidism diagnosed from routine laboratory tests described symptoms of fatigue and difficulty with concentration. During surgical consultation, the cervical and thoracic spine MRI scans from the preceding 10-year period, performed for relapsing-remitting multiple sclerosis, were reviewed. In this clinical context, the slowly enlarging left upper paraesophageal lesion, reported as a lateral proximal esophageal (Killian-Jamieson) diverticulum, was reevaluated for a potential parathyroid adenoma. 99mTc-sestamibi SPECT/CT demonstrated focal uptake in the paraesophageal lesion with surgical resection, confirming it to be a large parathyroid adenoma.

Racial and ethnic disparities in the prevalence of neurodegenerative diseases exist. This study examined the agreement between gold standard diagnosis and visual assessment of dopamine transporter (DaT) imaging in Hispanic and non-Hispanic patients being evaluated for Parkinsonian syndromes (PS). Methods: A retrospective review of DaT imaging and demographic data was performed with institutional review board approval. Documented interpretation by visual assessment was used to classify scans as normal or abnormal. The gold standard for the final diagnosis of PS was determined by a neurologist after 2 or more years of clinical follow-up. Data were analyzed with a z-test for uncorrelated samples. Results: In 30 Hispanic patients, DaT imaging was abnormal in 17, normal in 12, and nondiagnostic in 1. Of those with abnormal imaging, PS was confirmed in 16 of 17. Of those with normal imaging, no PS was confirmed in any patient. Sensitivity was 100%, and specificity was 92%. The single patient with nondiagnostic imaging was excluded. Of 77 non-Hispanic patients, visual assessment of DaT imaging was abnormal in 51. Of those with abnormal imaging, PS was confirmed in 48 of 51. Of those with normal imaging, no PS was confirmed in 22 of 26. Sensitivity was 92%, and specificity was 88%. There was no statistically significant difference (z = 0.34) in the rates of agreement between the gold standard and DaT imaging in Hispanic versus non-Hispanic patients. The study sample size afforded a power of 0.60. Conclusion: No significant difference was found in the accuracy of DaT imaging between Hispanic and non-Hispanic patients. Accuracy was high for both groups.

Regadenoson is an adenosine A2A receptor agonist widely used as a pharmacologic stress agent for myocardial perfusion imaging. Approximately 3.4 million regadenoson pharmacologic stress tests were performed annually as of 2011. Caffeine is a competitive antagonist of all adenosine receptor subtypes; thus, caffeine is typically withheld 12-24 h before stress with regadenoson. However, the effects of daily caffeine intake on regadenoson stress are unknown. This study assessed the effects of daily caffeine intake on symptoms and hemodynamic changes during stress testing with regadenoson. Methods: Patients presenting for regadenoson stress myocardial perfusion imaging were asked their amounts of daily caffeine intake. Chart review was used to collect data on demographics, comorbidities, and use of β-blockers. Data collected from the regadenoson stress test included symptoms, administration of aminophylline, heart rate, blood pressure, and arrhythmias. χ2 testing and ANOVA were used to analyze data divided into 3 categories of caffeine intake ( 400 mg daily). χ2 testing was used for nominal data, and unpaired t testing was used for continuous data. Results: In total, 101 patients were enrolled: 53% men and 47% women. Of the 101 patients, 89% reported caffeine intake, with 13% reporting heavy caffeine intake (>400 mg daily). The last intake of caffeine was at least 12 h before the test. During the test, 63% of patients reported symptoms, but the test was completed successfully in all patients. Compared with those who do not use caffeine, intake for caffeine users was associated with less chest pain (P = 0.0013), less aminophylline administration (P = 0.0371), lower resting and peak heart rate (P = 0.0497 and 0.0314, respectively), and lower diastolic blood pressure response (P = 0.0468). No associations were found between caffeine intake and arrhythmia or systolic blood pressure response. Conclusion: The use of regadenoson stress for myocardial perfusion imaging in caffeine consumers is very common, safe, and associated with a lower incidence of certain symptoms than in non-caffeine consumers. Specifically, caffeine intake was associated with less aminophylline use and chest pain.

OBJECTIVE. The purpose of this article is to provide a review of 123I-ioflupane SPECT in the evaluation of suspected parkinsonian syndromes (PSs). This collection of diseases presents frequent diagnostic challenges, even by movement disorder and dementia specialists. CONCLUSION. The 123I-ioflupane scan serves as an imaging biomarker of the status of presynaptic dopamine transporters (DATs) in the striatum. As a result of neuronal death, DATs are greatly reduced in patients with PS neurodegenerative disorders, whereas clinical mimics generally do not show striatal DAT loss. This provides a tremendous opportunity for 123I-ioflupane to aid in the accurate and timely diagnosis of these patients and optimize their management.

To evaluate random forests (RFs) as a supervised machine learning algorithm to classify amyloid brain PET as positive or negative for amyloid deposition and identify key regions of interest for stratification.The data set included 57 baseline F-florbetapir (Amyvid; Lilly, Indianapolis, IN) brain PET scans in participants with severe white matter disease, presenting with either transient ischemic attack/lacunar stroke or mild cognitive impairment from early Alzheimer disease, enrolled in a multicenter prospective observational trial. Scans were processed using the MINC toolkit to generate SUV ratios, normalized to cerebellar gray matter, and clinically read by 2 nuclear medicine physicians with interpretation based on consensus (35 negative, 22 positive). SUV ratio data and clinical reads were used for supervised training of an RF classifier programmed in MATLAB.A 10,000-tree RF, each tree using 15 randomly selected cases and 20 randomly selected features (SUV ratio per region of interest), with 37 cases for training and 20 cases for testing, had sensitivity = 86% (95% confidence interval [CI], 42%-100%), specificity = 92% (CI, 64%-100%), and classification accuracy = 90% (CI, 68%-99%). The most common features at the root node (key regions for stratification) were (1) left posterior cingulate (1039 trees), (2) left middle frontal gyrus (1038 trees), (3) left precuneus (857 trees), (4) right anterior cingulate gyrus (655 trees), and (5) right posterior cingulate (588 trees).Random forests can classify brain PET as positive or negative for amyloid deposition and suggest key clinically relevant, regional features for classification.

Research applications of human brain positron emission tomography (PET) imaging have been in place for over 40 years. The unique combination of quantitative PET instrumentation and reconstruction, novel radiotracers, and kinetic modeling has led to the development and application of a huge number of imaging paradigms. These have been applied to the understanding of normal function and pathophysiology, the development of drugs for neuropsychiatric disorders, and the study of drug interactions with the brain. I have had been fortunate to be part of this great endeavor throughout my research career, using brain-dedicated PET scanners, such as the HRRT [item [1] in the Appendix]. Over time, these systems have offered important advantages over whole-body systems. However, due to the limited clinical market for brain PET imaging, scanner manufacturers have focused exclusively on large field-of-view systems for the past two decades [item [2] in the Appendix]. The goal of this perspective is to share a viewpoint on the utility of brain-dedicated PET systems for human research, particularly in the context of novel radiotracers with dynamic studies using kinetic modeling.