Practical Overview of 123I-Ioflupane Imaging in Parkinsonian Syndromes.

Parkinsonian syndromes are a heterogeneous group of progressive neurodegenerative disorders involving the nigrostriatal dopaminergic pathway and are characterized by a wide spectrum of motor and nonmotor symptoms. These syndromes are quite common and can profoundly impact the lives of patients and their families. In addition to classic Parkinson disease, parkinsonian syndromes include multiple additional disorders known collectively as Parkinson-plus syndromes or atypical parkinsonism. These are characterized by the classic parkinsonian motor symptoms with additional distinguishing clinical features. Dopamine transporter SPECT has been developed as a diagnostic tool to assess the levels of dopamine transporters in the striatum. This imaging assessment, which uses iodine 123 (123I) ioflupane, can be useful to differentiate parkinsonian syndromes caused by nigrostriatal degeneration from other clinical mimics such as essential tremor or psychogenic tremor. Dopamine transporter imaging plays a crucial role in diagnosing parkinsonian syndromes, particularly in patients who do not clearly fulfill the clinical criteria for diagnosis. Diagnostic clarification can allow early treatment in appropriate patients and avoid misdiagnosis. At present, only the qualitative interpretation of dopamine transporter SPECT is approved by the U.S. Food and Drug Administration, but quantitative interpretation is often used to supplement qualitative interpretation. The authors provide an overview of patient preparation, common imaging findings, and potential pitfalls that radiologists and nuclear medicine physicians should know when performing and interpreting dopamine transporter examinations. Alternatives to 123I-ioflupane imaging for the evaluation of nigrostriatal degeneration are also briefly discussed. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material. See the invited commentary by Intenzo and Colarossi in this issue.

Distinct spatial contributions of amyloid pathology and cerebral small vessel disease to hippocampal morphology.

INTRODUCTION: Cerebral small vessel disease (SVD) and amyloid beta (Aß) pathology frequently co-exist. The impact of concurrent pathology on the pattern of hippocampal atrophy, a key substrate of memory impacted early and extensively in dementia, remains poorly understood. METHODS: In a unique cohort of mixed Alzheimer's disease and moderate-severe SVD, we examined whether total and regional neuroimaging measures of SVD, white matter hyperintensities (WMH), and Aß, as assessed by 18F-AV45 positron emission tomography, exert additive or synergistic effects on hippocampal volume and shape. RESULTS: Frontal WMH, occipital WMH, and Aß were independently associated with smaller hippocampal volume. Frontal WMH had a spatially distinct impact on hippocampal shape relative to Aß. In contrast, hippocampal shape alterations associated with occipital WMH spatially overlapped with Aß-vulnerable subregions. DISCUSSION: Hippocampal degeneration is differentially sensitive to SVD and Aß pathology. The pattern of hippocampal atrophy could serve as a disease-specific biomarker, and thus guide clinical diagnosis and individualized treatment strategies for mixed dementia.

A Pilot Study of F-18 Fluciclovine-PET/CT as a Diagnostic Tool for Bone Metastases in Patients With Castrate Resistant Prostate Adenocarcinoma and Correlative Analysis of Blood and Bone Molecular Testing (The FACT Study).

BACKGROUND: Suspicious F-18 fluciclovine PET/CT findings for osseous metastases from prostate cancer (PC) were targeted for core needle biopsy. We correlated the maximum standardized uptake value (SUVmax) of biopsied lesions, with biopsy results, other diagnostic outcomes, and blood and tissue molecular analysis (TMA). MATERIAL AND METHODS: Patients with castrate resistant prostate cancer (CRPC) were recruited from a university oncology clinic. SUVmax, histology, blood, and TMA were correlated. RESULTS: Fifteen patients were enrolled and 12 underwent bone biopsies. Fifty percent of bone biopsies demonstrated malignancy. Higher SUVmax was associated with positive biopsies for adenocarcinoma (P = .003), and lesions with SUVmax ≥ 5.1 were all positive for malignancy. Significant correlation between blood and somatic TMA (P = .002) was also found. CONCLUSION: Higher uptake of F-18 fluciclovine was associated with higher predictive value for osseous metastasis on biopsy. There was a significant correlation between blood and TMA.

Transcranial Magnetic Stimulation for the Treatment of Chemo Brain.

This pilot feasibility study aimed to evaluate the effects of transcranial magnetic stimulation (TMS) on chemotherapy-related cognitive impairment (CRCI), and we report here on the first patient. BACKGROUND: Deleterious cognitive changes due to chemotherapy or CRCI are commonly referred to as "chemo brain". With the increasing survival of cancer patients, this poorly understood and inadequately treated condition will likewise have an increasing toll on individuals and society. Since there is no approved treatment for chemo brain, we have initiated a therapeutic trial using transcranial magnetic stimulation (TMS), a non-invasive brain stimulation technique approved in many countries for the treatment of neurologic and psychiatric conditions like migraine and depression. CASE PRESENTATION: A 58-year-old woman, diagnosed 7 years prior with left breast cancer, underwent partial mastectomy with sentinel lymph node biopsy. She then received four cycles of adjuvant chemotherapy followed by radiation therapy. Afterwards, she was on tamoxifen for 4 years and then switched to aromatase inhibitors. The patient's CRCI started during chemotherapy and severely impaired her quality of life for an additional two years. In the third year after chemotherapy, the CRCI partially cleared to stabilize to the level at the time of presentation for this trial. The patient continues to have memory difficulties and decreased concentration, which makes multi-tasking very difficult to impossible. She is reliant on memory aids at work and at home. The participant underwent 10 consecutive sessions of TMS during weekdays for 2 weeks. Stimulation was directed to the left dorsolateral prefrontal cortex. After TMS, the participant significantly improved in memory function on neuropsychological testing. While she reported no subjective differences in concentration or memory, she did report an improvement in her sleep. Functional magnetic resonance imaging of the brain before and after TMS showed increased resting-state functional connectivity between the stimulation site and several brain regions. Remarkably, after 6 years of chemo brain and remaining in the same position at work due to her inability to concentrate and multi-task, she applied for and received a promotion 5-6 months after her TMS treatments. CONCLUSIONS: This first patient in the phase 1 clinical trial testing of TMS for the treatment of "chemo brain" provided important lessons for feasibility and insights into mechanisms of potential benefit.

Vascular burden and cognition: Mediating roles of neurodegeneration and amyloid PET.

It remains unclear to what extent cerebrovascular burden relates to amyloid beta (Aß) deposition, neurodegeneration, and cognitive dysfunction in mixed disease populations with small vessel disease and Alzheimer's disease (AD) pathology. In 120 subjects, we investigated the association of vascular burden (white matter hyperintensity [WMH] volumes) with cognition. Using mediation analyses, we tested the indirect effects of WMH on cognition via Aß deposition (18 F-AV45 positron emission tomography [PET]) and neurodegeneration (cortical thickness or 18 F fluorodeoxyglucose PET) in AD signature regions. We observed that increased total WMH volume was associated with poorer performance in all tested cognitive domains, with the strongest effects observed for semantic fluency. These relationships were mediated mainly via cortical thinning, particularly of the temporal lobe, and to a lesser extent serially mediated via Aß and cortical thinning of AD signature regions. WMH volumes differentially impacted cognition depending on lobar location and Aß status. In summary, our study suggests mainly an amyloid-independent pathway in which vascular burden affects cognitive function via localized neurodegeneration. HIGHLIGHTS: Alzheimer's disease often co-exists with vascular pathology. We studied a unique cohort enriched for high white matter hyperintensities (WMH). High WMH related to cognitive impairment of semantic fluency and executive function. This relationship was mediated via temporo-parietal atrophy rather than metabolism. This relationship was, to lesser extent, serially mediated via amyloid beta and atrophy.

Pilot Study for Correlation of Heart Rate Variability and Dopamine Transporter Brain Imaging in Patients with Parkinsonian Syndrome.

BACKGROUND: Parkinsonian syndrome (PS) is a broad category of neurodegenerative movement disorders that includes Parkinson disease, multiple system atrophy (MSA), progressive supranuclear palsy, and corticobasal degeneration. Parkinson disease (PD) is the second most common neurodegenerative disorder with loss of dopaminergic neurons of the substantia nigra and, thus, dysfunction of the nigrostriatal pathway. In addition to the motor symptoms of bradykinesia, rigidity, tremors, and postural instability, nonmotor symptoms such as autonomic dysregulation (AutD) can also occur. Heart rate variability (HRV) has been used as a measure of AutD and has shown to be prognostic in diseases such as diabetes mellitus and cirrhosis, as well as PD. I-123 ioflupane, a gamma ray-emitting radiopharmaceutical used in single-photon emission computed tomography (SPECT), is used to measure the loss of dopaminergic neurons in PD. Through the combination of SPECT and HRV, we tested the hypothesis that asymmetrically worse left-sided neuronal loss would cause greater AutD. METHODS: 51 patients were enrolled on the day of their standard of care I-123 ioflupane scan for the work-up of possible Parkinsonian syndrome. Demographic information, medical and medication history, and ECG data were collected. HRV metrics were extracted from the ECG data. I-123 ioflupane scans were interpreted by a board-certified nuclear radiologist and quantified by automated software to generate striatal binding ratios (SBRs). Statistical analyses were performed to find correlations between the HRV and SPECT parameters. RESULTS: 32 patients were excluded from the final analysis because of normal scans, prior strokes, cardiac disorders and procedures, or cancer. Abnormal I-123 ioflupane scans were clustered using T-SNE, and one-way ANOVA was performed to compare HRV and SBR parameters. The analysis was repeated after the exclusion of patients taking angiotensin-converting enzyme inhibitors, given the known mechanism on autonomic function. Subsequent analysis showed a significant difference between the high-frequency domains of heart rate variability, asymmetry of the caudate SBR, and putamen-to-caudate SBR. CONCLUSION: Our results support the hypothesis that more imbalanced (specifically worse left-sided) neuronal loss results in greater AutD.

Sex-limited penetrance of lymphedema to females with CELSR1 haploinsufficiency: A second family.

A second multigeneration family with hereditary lymphedema (LE) secondary to a variant in the planar polarity gene, CELSR1, is described. Dominant inheritance of the variant was discovered using whole-exome sequencing and confirmed by Sanger sequencing. In contrast to heterozygous males, all heterozygous females showed LE during physical examination albeit variable in severity and age of onset. Lymphscintigraphy in affected females showed previously undescribed lymphatic abnormalities consistent with lymphangiectasia, valve dysfunction, and thoracic duct reflux.

Optimizing the Diagnosis of Parkinsonian Syndromes With 123I-Ioflupane Brain SPECT.

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.

PET/CT of Dementia.

OBJECTIVE: In this article, we review the literature on PET/CT in the management of dementia, present evidence for best clinical practices, and discuss recent advances in the field. CONCLUSION: Standard-of-care imaging for dementia includes CT and MRI, primarily for excluding vascular lesions or masses, detecting atrophy, and monitoring disease severity. PET/CT is a powerful functional modality that can differentiate dementia types and influence management. Fluorine-18-FDG PET/CT reveals the spatial pattern of glucose metabolism in the brain. More recently, radiotracers for PET have been developed that bind to amyloid protein, tau protein, and neuroinflammatory markers.

Signs and Artifacts in Amyloid PET.

Establishing a diagnosis of Alzheimer dementia can be challenging, particularly early in the course of the disease. However, with disease-modifying therapies on the horizon, it is becoming increasingly important to achieve the correct diagnosis as soon as possible. In challenging presentations of dementia, such as patients with clinically atypical features or early-age onset of mild cognitive impairment, amyloid PET is a valuable tool in determining the diagnosis of Alzheimer dementia. Furthermore, preliminary data show that amyloid PET findings alter clinical management in patients who meet the appropriate use criteria. There are currently three U.S. Food and Drug Administration (FDA)-approved fluorine 18 (18F)-labeled radiopharmaceuticals that allow in vivo detection of cerebral amyloid deposition, which is a hallmark pathologic feature of Alzheimer dementia. Knowledge of the common imaging features among these three 18F-labeled radiopharmaceuticals in the normal and abnormal brain will enable the radiologist to more accurately interpret amyloid PET studies. As in other subspecialties of radiology, imaging signs in amyloid PET are helpful to distinguish if a region is normal or abnormal. This article reviews appropriate use criteria for amyloid PET, introduces the properties of the radiopharmaceuticals, explains the algorithmic approach to interpretation with examples of normal and abnormal amyloid PET scans with MRI correlation, and provides an atlas of regional amyloid PET signs and common artifacts. ©RSNA, 2018.

Recurrent Osteosarcoma Presenting as an Isolated Bone Marrow Relapse.

Osteosarcoma (OS) is a malignant bone tumor which is found primarily in adolescents, with the distal femur as the most common location. OS with a jaw primary is present in only about 10% of cases and the risk of recurrence is considered to be decreased in the jaw versus other primary locations. We present a unique case of a patient with localized OS of the jaw with an isolated recurrence in her bone marrow almost 5 years after completion of initial treatment.

Evaluations of extracellular pH within in vivo tumors using acidoCEST MRI.

PURPOSE: A practical, noninvasive method is needed to measure the extracellular pH (pHe) within in vivo tumors to longitudinally monitor tumor acidosis. We have optimized a biomedical imaging method, termed acidoCEST MRI, to provide noninvasive assessments of tumor pHe in preclinical models of mammary carcinoma. METHODS: A CEST-FISP MRI method was optimized to detect the chemical exchange saturation transfer (CEST) of two amide protons of a clinically approved CT contrast agent, iopromide. The ratio of the two CEST effects was used to measure pH. Routes of administration of iopromide were evaluated to ensure sufficient delivery of the agent to the tumor. The optimized acidoCEST MRI method was then used to evaluate the change in tumor pHe following alkalinizing bicarbonate treatment. RESULTS: The acidoCEST MRI protocol measured pH between 6.2 and 7.2 pH units. Greater delivery of iopromide was shown to improve the precision of the measurement of tumor pHe, but the agent did not influence the tumor pHe. AcidoCEST MRI was used to longitudinally monitor the effect of bicarbonate treatment on the pHe of tumors and bladders. CONCLUSION: This study demonstrates that an optimized acidoCEST MRI method is a practical, noninvasive method for assessing changes in tumor acidosis.

Quantitative and Qualitative Assessment of Urinary Activity of 18F-Flotufolastat-PET/CT in Patients with Prostate Cancer: a Post Hoc Analysis of the LIGHTHOUSE and SPOTLIGHT Studies.

PURPOSE: To evaluate the impact of urinary activity on interpretation of 18F-flotufolastat (18F-rhPSMA-7.3) PET/CT, we conducted a post hoc qualitative and quantitative analysis of scans acquired in two phase 3 studies of 18F-flotufolastat. PROCEDURES: Newly diagnosed or recurrent prostate cancer patients enrolled in LIGHTHOUSE (NCT04186819) or SPOTLIGHT (NCT04186845), respectively, underwent PET/CT 50-70 min after intravenous administration of 296 MBq 18F-flotufolastat. For the present analysis, 718 18F-flotufolastat scans (352 from LIGHTHOUSE and 366 from SPOTLIGHT) were re-evaluated by three board-certified nuclear medicine physicians. Reader 1 performed a quantitative assessment (SUVmax and SUVmean) of bladder activity in a circular region-of-interest over the maximum diameter of bladder activity in the transverse plane. All three readers qualitatively assessed the impact of any urinary activity in the bladder on image interpretation using a three-point scale (0 = no/minimal visible urinary activity, 1 = urinary activity visible but distinction between urine and disease possible and 2 = assessment inhibited by urinary activity) and the presence/absence of ureteric activity and halo artifacts. RESULTS: In total, 712/718 scans were evaluable. Reasons for exclusion were cystectomy, renal failure, or urinary catheter in situ (n = 2 each). The median bladder SUVmax and SUVmean were 17.1 and 12.5, respectively. By majority read, 682/712 (96%) patients had either no urinary activity (score = 0) or visible activity that could be distinguished from disease uptake (score = 1). In the minority of patients (24, 3.4%) where urinary activity did impact assessment (score = 2), the median bladder SUVmean was higher (20.5) than those scored 0 (3.8) or 1 (14.0). Ureteric activity was absent in 401 (56%) patients. Halo artifacts were observed in only two (0.3%) patients (majority read). CONCLUSIONS: 18F-Flotufolastat urinary activity did not influence disease assessment for the majority of patients. While this study was not designed as a head-to-head comparison, the median bladder SUVs are lower than previously reported values for other renally cleared PSMA-PET radiopharmaceuticals.

Correction of multiplexing artefacts in multi-pinhole SPECT through temporal shuttering, de-multiplexing of projections, and alternating reconstruction.

Objective.Single-photon emission computed tomography (SPECT) with pinhole collimators can provide high-resolution imaging, but is often limited by low sensitivity. Acquiring projections simultaneously through multiple pinholes affords both high resolution and high sensitivity. However, the overlap of projections from different pinholes on detectors, known as multiplexing, has been shown to cause artefacts which degrade reconstructed images.Approach.Multiplexed projection sets were considered here using an analytic simulation model of AdaptiSPECT-C-a brain-dedicated multi-pinhole SPECT system. AdaptiSPECT-C has fully adaptable aperture shutters, so can acquire projections with a combination of multiplexed and non-multiplexed frames using temporal shuttering. Two strategies for reducing multiplex artefacts were considered: an algorithm to de-multiplex projections, and an alternating reconstruction strategy for projections acquired with a combination of multiplexed and non-multiplexed frames. Geometric and anthropomorphic digital phantoms were used to assess a number of metrics.Main results.Both de-multiplexing strategies showed a significant reduction in image artefacts and improved fidelity, image uniformity, contrast recovery and activity recovery (AR). In all cases, the two de-multiplexing strategies resulted in superior metrics to those from images acquired with only mux-free frames. The de-multiplexing algorithm provided reduced image noise and superior uniformity, whereas the alternating strategy improved contrast and AR.Significance.The use of these de-multiplexing algorithms means that multi-pinhole SPECT systems can acquire projections with more multiplexing without degradation of images.

Quantitative Brain Amyloid PET.

Since the development of amyloid tracers for PET imaging, there has been interest in quantifying amyloid burden in the brains of patients with Alzheimer disease. Quantitative amyloid PET imaging is poised to become a valuable approach in disease staging, theranostics, monitoring, and as an outcome measure for interventional studies. Yet, there are significant challenges and hurdles to overcome before it can be implemented into widespread clinical practice. On November 17, 2022, the U.S. Food and Drug Administration, Society of Nuclear Medicine and Molecular Imaging, and Medical Imaging and Technology Alliance cosponsored a public workshop comprising experts from academia, industry, and government agencies to discuss the role of quantitative brain amyloid PET imaging in staging, prognosis, and longitudinal assessment of Alzheimer disease. The workshop discussed a range of topics, including available radiopharmaceuticals for amyloid imaging; the methodology, metrics, and analytic validity of quantitative amyloid PET imaging; its use in disease staging, prognosis, and monitoring of progression; and challenges facing the field. This report provides a high-level summary of the presentations and the discussion.

Interreader and Intrareader Reproducibility of 18F-Flotufolastat Image Interpretation in Patients with Newly Diagnosed or Recurrent Prostate Cancer: Data from Two Phase 3 Prospective Multicenter Studies.

Interreader and intrareader reproducibility of 18F-flotufolastat PET/CT scans in newly diagnosed and recurrent prostate cancer patients was assessed from masked image evaluations from two phase 3 studies. Methods: 18F-flotufolastat PET/CT images of newly diagnosed (n = 352) or recurrent (n = 389) patients were evaluated by 3 masked readers. Cohen κ was used to assess pairwise patient- and region-level interreader agreement. Agreement among all readers was assessed using Fleiss κ. Intrareader agreement between the first and repeat read (20% of images, ≥4 wk later) was assessed using Cohen κ. Results: Pairwise interreader agreement was 95% or better (newly diagnosed) and 75% or better (recurrent). The κ coefficients were impacted by the high-agreement-low-κ paradox: Cohen κ ranged from not estimable to 0.55, whereas Fleiss κ was 0.50 (newly diagnosed) and 0.41 (recurrent). Agreement was highest in the prostate of newly diagnosed patients (≥95%) and in the pelvic lymph nodes in recurrent patients (≥87%). Intrareader agreement was 86% or better across both populations. Conclusion: 18F-flotufolastat PET/CT images can be reliably interpreted, with a high degree of inter- and intrareader agreement.

ACR Appropriateness Criteria® Dizziness and Ataxia: 2023 Update.

Diagnostic evaluation of a patient with dizziness or vertigo is complicated by a lack of standardized nomenclature, significant overlap in symptom descriptions, and the subjective nature of the patient's symptoms. Although dizziness is an imprecise term often used by patients to describe a feeling of being off-balance, in many cases dizziness can be subcategorized based on symptomatology as vertigo (false sense of motion or spinning), disequilibrium (imbalance with gait instability), presyncope (nearly fainting or blacking out), or lightheadedness (nonspecific). As such, current diagnostic paradigms focus on timing, triggers, and associated symptoms rather than subjective descriptions of dizziness type. Regardless, these factors complicate the selection of appropriate diagnostic imaging in patients presenting with dizziness or vertigo. This document serves to aid providers in this selection by using a framework of definable clinical variants. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Neurotheranostics: The Next Frontier for Health Span.

With an aging U.S. population, advancements in the treatment of Alzheimer disease (AD) and other neurodegenerative diseases are key to the maximization of health span. The recent approval of 2 antiamyloid antibodies, which decrease brain amyloid load, places us on the cusp of breakthrough therapies that target the mechanism of the disease rather than just treating the symptoms. Although the trials that led to these approvals studied patients with mild early symptoms, multiple ongoing trials have enrolled cognitively normal patients screened for AD biomarkers including risk factors for amyloid positivity, family history, and genetic markers. Thus, amyloid PET can help identify an at-risk population that can be enrolled for antiamyloid therapy to prevent AD symptoms from ever developing. In this review, we examine the paradigm of neurotheranostics and how PET biomarkers of amyloid, tau, inflammation, and neurodegeneration could characterize the pathologic stage of AD and therefore allow for personalized therapy.