Effect of formalin fixation on measured concentrations of deposited gadolinium in human tissue: an autopsy study.

BACKGROUND: Generally, studies of gadolinium (Gd) deposition in humans measure concentration by analyzing formalin fixed postmortem tissue. However, the effect of formalin fixation on measured Gd concentration has not been well investigated. PURPOSE: To evaluate the effect of fixation by comparing Gd concentration in fresh versus formalin-fixed postmortem human tissues. MATERIAL AND METHODS: Fresh samples of bone and skin were collected from autopsy cases with previous exposure to Gd-based contrast agents (GBCAs). The type of GBCA administered, dose, and estimated glomerular filtration rate were recorded. Each tissue sample was cut into three aliquots. Paired samples were stored fresh frozen while the remaining two were stored in 10% neutral buffered formalin for one and three months, respectively. Gd concentration was measured using ICP-MS. RESULTS: Of 18 autopsy cases studied, 12 were exposed to only macrocyclic GBCA, one to only linear agents, and five received both macrocyclic and linear agents. On average, Gd concentration for bone decreased 30.7% after one month of fixation (P = 0.043) compared to non-fixed values. There was minimal, if any, change in concentration between one and three months (average decrease 1.5%; P = 0.89). The findings were numerically similar for skin tissue with an average decrease of 36.9% after one month (P = 0.11) and 6.0% (P = 0.73) between one and three months. CONCLUSION: Formalin fixation appears to decrease Gd concentration in bone and skin by approximately 30%-40% on average. The largest decrease occurs within the first 30 days of fixation followed by a considerably smaller decrease at 60 days.

Comparison of Human Tissue Gadolinium Retention and Elimination between Gadoteridol and Gadobenate.

Background Linear gadolinium-based contrast agents (GBCAs) are known to be retained at higher levels of gadolinium than macro-cyclic GBCAs. However, very little is known regarding their relative elimination rates and retained fraction of injected gadolinium. Purpose To quantify and compare gadolinium retention and elimination rates in human brain tissue, skin, and bone obtained from cadavers exposed to single-agent administration of either gadoteridol (macrocyclic GBCA) or gadobenate dimeglumine (linear GBCA). Materials and Methods Autopsy cases from August 2014 to July 2019 of patients exposed to a single type of GBCA, either gadoteridol or gadobenate dimeglumine, either single or multiple doses, were included. Gadolinium levels in the brain, skin, and bone were analyzed with inductively coupled plasma mass spectrometry. Linear regression was used to compare gadolinium retention between agents and estimate elimination rates of the retained gadolinium using the time between last injection and death. Results Twenty-eight cadavers with gadoteridol exposure and nine with gadobenate dimeglumine exposure were identified (22 men; age range, 19-83 years). The median gadolinium retention of gadobenate dimeglumine was 3.0-6.5 times higher than that of gadoteridol in the brain (P < .02), 4.4 times higher in bone (P = .002), and 2.9 times higher in skin (P = .05). Gadolinium retention in the globus pallidus (GP), dentate nucleus (DN), white matter (WM), bone, and skin decreased with time elapsed from last administration to death in both the gadobenate dimeglumine (GP: -3% per twofold increase in time, P = .69; DN: -2%, P = .83; WM: -20%, P = .01; bone: -22%, P = .07; skin: -47%, P < .001) and gadoteridol (GP: -17%, P = .11; DN: -16%, P = .15; WM: -30%, P < .001; bone: -11%, P = .16; skin: -24%, P = .01) groups (P values for elimination are compared with a null hypothesis of no elimination). Conclusion The linear agent gadobenate dimeglumine retains several-fold higher levels of gadolinium in the brain and bone compared with the macrocyclic agent gadoteridol. Nonzero elimination of retained gadolinium was detected in the white matter and skin for both agents. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Tweedle in this issue.

Variability in hair gadolinium concentrations among decedents who received gadolinium-based contrast agents.

This study utilized laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) to quantify gadolinium in the hair of autopsy cases that had received gadolinium-based contrast agents (GBCAs) before death. Consecutive autopsy cases were reviewed for GBCA injections and subjects who received a single type of GBCA in the year before death were included. Hair samples were analyzed using LA-ICP-MS as a line scan technique and parameters were optimized to maximize instrument sensitivity, accuracy, and precision. Linear regression analyses between hair measures and gadolinium dose were executed. LA-ICP-MS analysis produced a time-resolved record of GCBA exposure, with the position of the gadolinium peak maxima along the hair shaft providing a good estimate for the day that GBCA injection occurred (R2 = 0.46; p = 0.0022); however, substantial within and between subject variation in the position of the GBCA peak was observed. Average area under the curve for gadolinium peaks in the hair samples was a better predictor of gadolinium dose (R2 = 0.41; p = 0.0046), compared to the average of peak maxima concentration. Correlation between area under the curve and dose suggests that LA-ICP-MS analysis of hair may be an effective method to evaluate gadolinium levels in subjects in vivo after exposure to GBCAs. This study demonstrates that analysis of human hair using techniques with high spatial resolution such as LA-ICP-MS has excellent potential to reveal time-dependent signatures of past exposures.

Human Hair as a Possible Surrogate Marker of Retained Tissue Gadolinium: A Pilot Autopsy Study Correlating Gadolinium Concentrations in Hair With Brain and Other Tissues Among Decedents Who Received Gadolinium-Based Contrast Agents.

OBJECTIVES: We used laser ablation inductively coupled plasma mass spectrometry to quantify gadolinium in hair samples from autopsy cases with gadolinium-based contrast agent (GBCA) exposure. Hair gadolinium data were correlated with gadolinium concentrations in brain, skin, and bone tissues from the same case to investigate a potential noninvasive method for gadolinium quantification and monitoring. MATERIALS AND METHODS: Medical records from autopsy cases at our institution were screened for history of GBCA exposure. Cases with exposure to a single type of GBCA with the most recent injection occurring within 1 year were identified and included in the study. The concentration of gadolinium in hair samples was analyzed by laser ablation inductively coupled plasma mass spectrometry, and brain (globus pallidus, dentate nucleus, white matter), bone, and skin tissues were analyzed by bulk inductively coupled plasma mass spectrometry. The mean of the maximum value in the hair samples was used to generate a representative measurement of the hair gadolinium concentration for each case. A linear regression analysis between each tissue type and hair was conducted to assess for possible correlation. RESULTS: Tissue and hair samples from 18 autopsies (16 cases with exposure to GBCA, 2 controls) were included in the study. Comparing the different tissues revealed good correlation between some tissue types. The best model fit occurred between white matter and hair (R = 0.83; P < 0.0001) followed by the comparison between dentate nucleus and hair (R = 0.72; P < 0.0001) and dentate nucleus and skin (R = 0.70; P < 0.0001). CONCLUSIONS: A significant correlation in this study between hair gadolinium concentrations and brain and skin gadolinium concentrations suggests that hair may serve as a safe and effective biomonitoring tissue for patients who receive GBCA injections.

Brain tissue gadolinium retention in pediatric patients after contrast-enhanced magnetic resonance exams: pathological confirmation.

BACKGROUND: Retained gadolinium from gadolinium-based contrast agents (GBCAs) used in MR exams has been inferred based on signal changes on serial brain MRI and subsequently demonstrated pathologically in adults. Retention has been similarly inferred in children but pathological demonstration in pediatric patients is limited. The long-term effects of retained gadolinium are unknown but are potentially of greater concern in children given their increased vulnerability from continuing development and their expected longer period of exposure. Several factors can influence gadolinium retention. In adults as well as in children, greater accumulation has been demonstrated based on MR signal changes with linear compared with macrocyclic gadolinium chelates, attributed to lower chelate affinity with linear agents. Effects of age at exposure on retention are unknown, while differences in GBCA washout rates are still under investigation and might affect gadolinium retention relative to time of GBCA administration. OBJECTIVE: The purpose of this study was to confirm whether gadolinium brain deposits are present in pediatric patients who received GBCAs and to quantify the amounts present. MATERIALS AND METHODS: Brain autopsy specimens from 10 pediatric patients between 1 year and 13 years of age who underwent at least one contrast-enhanced MR exam were analyzed for elemental gadolinium using inductively coupled plasma mass spectrometry. Brain samples included white matter, basal ganglia (putamen, globus pallidus), thalamus, dentate nucleus and tumor tissue as available. Type and dose of contrast agent, number and timing of contrast-enhanced MR exams and renal function (estimated glomerular filtration rate [eGFR]) were documented for each child. RESULTS: Patient exposures ranged from 1 dose to 20 doses of GBCAs including both macrocyclic and linear ionic agents. Gadolinium was found to be present in brain tissue in all children and was generally highest in the globus pallidus. Those who received only macrocyclic agents showed lower levels of gadolinium retention. CONCLUSION: This study demonstrates pathological confirmation of gadolinium retention in brain tissue of a series of pediatric patients exposed to GBCAs including not only linear ionic agents but also macrocyclic agents with both nonionic and ionic compounds. The distribution and deposition levels in this small pediatric population are comparable with the findings in adults. While the clinical significance of these deposits remains unknown, at this point it would be prudent to exert caution and avoid unnecessary use of GBCAs in pediatric patients.

Dose Finding Study of Gadopiclenol, a New Macrocyclic Contrast Agent, in MRI of Central Nervous System.

OBJECTIVES: The aim of this study was to determine a safe and effective dose of gadopiclenol, a new high relaxivity macrocyclic gadolinium-based contrast agent. Based on the contrast-to-noise ratio (CNR) as primary criterion, this new agent was compared with gadobenate dimeglumine in patients with contrast-enhancing central nervous system lesions. METHODS AND MATERIALS: This phase IIb international, multicenter, double-blind, randomized, controlled, parallel dose groups, and cross-over study included adult patients with known or highly suspected lesions with disrupted blood-brain barrier. Patients were randomized to 1 of 4 doses of gadopiclenol (0.025, 0.05, 0.1, 0.2 mmol/kg) and to 1 series of 2 magnetic resonance imaging scans: gadopiclenol then gadobenate dimeglumine at 0.1 mmol/kg or vice versa. The qualitative and quantitative efficacy evaluations were performed by 3 independent off-site blinded readers. Adverse events were monitored up to 1 day after second magnetic resonance imaging. RESULTS: The study population included 272 patients (58.5% females) with a mean (SD) age of 53.8 (13.6) years. The superiority of gadopiclenol over gadobenate dimeglumine was statistically demonstrated at 0.2 and 0.1 mmol/kg for all readers with an increase in CNR of more than 30% (P ≤ 0.0007). At 0.05 mmol/kg, gadopiclenol showed a CNR of similar magnitude as gadobenate dimeglumine at 0.1 mmol/kg, with no statistically significant difference. Similar results were obtained for lesion-to-brain ratio and contrast enhancement percentage, as secondary criteria. The relationship between CNR and dose of gadopiclenol was linear for all readers. Mean scores for lesion visualization variables, particularly lesion contrast enhancement, tended to be higher with gadopiclenol at 0.1 and 0.2 mmol/kg compared with gadobenate dimeglumine. All 3 readers mainly expressed an overall diagnostic preference for images with gadopiclenol at 0.1 mmol/kg (45.3%, 50.9%, or 86.8% of images) or expressed no preference (49.1%, 49.1%, or 9.4%, respectively), whereas preference for images with gadobenate dimeglumine was reported by 2 readers for 3.8% and 5.7% of the images. Predominantly, no preference was expressed when comparing images with gadopiclenol at 0.05 mmol/kg to those with gadobenate dimeglumine.Rates of adverse reactions were comparable for gadopiclenol (11.7%) and gadobenate dimeglumine (12.1%). Changes from baseline of more than 25% in serum creatinine and estimated glomerular filtration rate occurred in less than 2% of patients equally for gadopiclenol and gadobenate dimeglumine. Changes from baseline for the values of blood urea nitrogen and cystatin C were also similar between gadopiclenol and gadobenate dimeglumine. No safety concerns were detected on centralized electrocardiography readings. CONCLUSIONS: Between the doses of 0.025 and 0.2 mmol/kg of gadopiclenol, the increase in CNR is linear. Compared with gadobenate dimeglumine at 0.1 mmol/kg, the doses of 0.05 and 0.1 mmol/kg of gadopiclenol gave similar or significantly greater contrast enhancement, respectively, and thus both doses can be considered for future phase III studies.

Radiologic evidence that hypothalamic gliosis is improved after bariatric surgery in obese women with type 2 diabetes.

BACKGROUND/OBJECTIVES: Hypothalamic neurons play a major role in the control of body mass. Obese subjects present radiologic signs of gliosis in the hypothalamus, which may reflect the damage or loss of neurons involved in whole-body energy homeostasis. It is currently unknown if hypothalamic gliosis (1) differs between obese nondiabetic (ND) and obese diabetic subjects (T2D) or (2) is modified by extensive body mass reduction via Roux-n-Y gastric bypass (RYGB). SUBJECTS/METHODS: Fifty-five subjects (all female) including lean controls (CT; n = 13), ND (n = 28), and T2D (n = 14) completed at least one study visit. Subjects underwent anthropometrics and a multi-echo MRI sequence to measure mean bilateral T2 relaxation time in the mediobasal hypothalamus (MBH) and two reference regions (amygdala and putamen). The obese groups underwent RYGB and were re-evaluated 9 months later. Analyses were by linear mixed models. RESULTS: Analyses of T2 relaxation time at baseline showed a group by region interaction only in the MBH (P < 0.0001). T2D had longer T2 relaxation times compared to either CT or ND groups. To examine the effects of RYGB on hypothalamic gliosis a three-way (group by region by time) mixed effects model adjusted for age was executed. Group by region (P < 0.0001) and region by time (P = 0.0005) interactions were significant. There was a reduction in MBH relaxation time by RYGB, and, although the T2D group still had higher T2 relaxation time overall compared to the ND group, the T2D group had significantly lower T2 relaxation time after surgery and the ND group showed a trend. The degree of reduction in MBH T2 relaxation time by RYGB was unrelated to clinical outcomes. CONCLUSION: T2 relaxation times, a marker of hypothalamic gliosis, are higher in obese women with T2D and are reduced by RYGB-induced weight loss.

Gadolinium Retention: A Research Roadmap from the 2018 NIH/ACR/RSNA Workshop on Gadolinium Chelates.

Gadolinium-based contrast agents (GBCAs) have revolutionized MRI, enabling physicians to obtain crucial life-saving medical information that often cannot be obtained with other imaging modalities. Since initial approval in 1988, over 450 million intravenous GBCA doses have been administered worldwide, with an extremely favorable pharmacologic safety profile; however, recent information has raised new concerns over the safety of GBCAs. Mounting evidence has shown there is long-term retention of gadolinium in human tissues. Further, a small subset of patients have attributed a constellation of symptoms to GBCA exposure, although the association of these symptoms with GBCA administration or gadolinium retention has not been proven by scientific investigation. Despite evidence that macrocyclic GBCAs show less gadolinium retention than linear GBCAs, the safety implications of gadolinium retention are unknown. The mechanism and chemical forms of gadolinium retention, as well as the biologic activity and clinical importance of these retained gadolinium species, remain poorly understood and underscore the need for additional research. In February 2018, an international meeting was held in Bethesda, Md, at the National Institutes of Health to discuss the current literature and knowledge gaps about gadolinium retention, to prioritize future research initiatives to better understand this phenomenon, and to foster collaborative standardized studies. The greatest priorities are to determine (a) if gadolinium retention adversely affects the function of human tissues, (b) if retention is causally associated with short- or long-term clinical manifestations of disease, and (c) if vulnerable populations, such as children, are at greater risk for experiencing clinical disease. The purpose of the research roadmap is to highlight important information that is not known and to identify and prioritize needed research. ©RSNA, 2018 Online supplemental material is available for this article .

Brain iron concentrations in regions of interest and relation with serum iron levels in Parkinson disease.

Brain iron has been previously found elevated in the substantia nigra pars compacta (SNpc), but not in other brain regions, of Parkinson's disease (PD) patients. However, iron in circulation has been recently observed to be lower than normal in PD patients. The regional selectivity of iron deposition in brain as well as the relationship between SNpc brain iron and serum iron within PD patients has not been completely elucidated. In this pilot study we measured brain iron in six regions of interest (ROIs) as well as serum iron and serum ferritin, in 24 PD patients and 27 age- gender-matched controls. Brain iron was measured on magnetic resonance imaging (MRI) with a T2 prime (T2') method. Difference in brain iron deposition between PD cases and controls for the six ROIs were calculated. SNpc/white matter brain iron ratios and SNpc/serum iron ratios were calculated for each study participant, and differences between PD patients and controls were tested. PD patients overall had higher brain iron than controls in the SNpc. PD patients had significantly higher SNpc/white matter brain iron ratios than controls, and significantly higher brain SNpc iron/serum iron ratios than controls. These results indicate that PD patients' iron metabolism is disrupted toward a higher partitioning of iron to the brain SNpc at the expenses of iron in the circulation.

Brain pathology of a patient 7years after autologous hematopoietic stem cell transplantation for multiple sclerosis.

Aggressive immunosuppression followed by autologous hematopoietic stem cell transplantation (aHSCT) can be an effective treatment for severe multiple sclerosis (MS), but not all stages of disease may benefit equally. The case of a 49-year-old woman with advanced secondary-progressive MS whose clinical course was not improved by aHSCT and who seven years after transplantation succumbed to complications of severe MS disease-related disability is presented. Autopsy findings of ongoing neurodegeneration despite only rare infiltrating T-lymphocytes illustrate that late MS disease may not represent a suitable disease stage for aHSCT.

Gadolinium tissue deposition in brain and bone.

Until recognition of the association of nephrogenic systemic fibrosis (NSF) and gadolinium based contrast agents (GBCA) in 2006, these agents were considered extremely safe and without major adverse effects. Even after the recognition of NSF, most physicians considered all GBCAs to be safe when used in patients with normal renal function. This belief has been called into question with the discovery by Kanda in 2014 that gadolinium (Gd) is deposited in brain tissue in patients with normal kidney function. Since that initial report, there have been a number of important studies analyzing the effects of various GBCAs in brain using MR T1 signal intensity measurements and postmortem tissue analyses with inductively coupled plasma mass spectrometry. From these our knowledge and understanding of some key issues surrounding these observations has rapidly evolved. This report reviews and summarizes many recent human and animal studies in combination with past studies to better understand Gd tissue deposition not only in brain but also in bone and skin. Brain tissue deposition was initially demonstrated to occur with less stable group 1 linear agents but recent postmortem studies now confirm that Gd deposition also occurs with more stable linear agents as well as with macrocyclic agents although at much lower levels. Although no adverse health effects have been documented to date, even for the group 1 agents that deposit Gd in higher amounts, the implications for possible unrecognized toxicity is discussed. Future studies are being pursued that may provide better understanding of the various chemical forms of Gd that are deposited in tissues. This may help elucidate relative risks of different types of agents, mechanisms involved and even recognition of potential downstream toxic effects.

Adverse Reactions to Gadoterate Meglumine: Review of Over 25 Years of Clinical Use and More Than 50 Million Doses.

OBJECTIVE: The aim of this study was to evaluate the safety profile of gadoterate meglumine from clinical trials, postmarketing observational studies, and pharmacovigilance reports of adverse drug reactions (ADRs) encompassing 25 years of clinical use and over 50 million administered doses. MATERIALS AND METHODS: Assessment of the safety of gadoterate meglumine through processing and review of all safety data was collected after magnetic resonance imaging procedures. All ADRs originated from 3 major sources: (1) a clinical study database including 50 phase I to IV studies involving 2822 patients, (2) a safety database including 8 postmarketing safety studies (PMSs) involving 151,050 patients, and (3) a pharmacovigilance database compiling safety experience following over 50 million doses administered between March 1989 and September 2015. RESULTS: Among the 2822 patients receiving gadoterate meglumine in the clinical trials, 241 (8.5%) experienced 405 postinjection adverse events (AEs), considered related to the contrast agent for 113 patients (4.0%). Serious AEs were reported for 27 patients (1.0%) and assessed as related to gadoterate meglumine for 2 patients (0.07%). None of the PMS studies showed evidence of unexpected safety issues, with a very low rate of AEs (<1%). Postmarketing safety experience with over 50 million doses of gadoterate meglumine prescribed for 25 years of approved use worldwide compiled spontaneous reports for 3797 patients who experienced 8397 ADRs, yielding a very low reported incidence of ADRs of 0.007% of patients. There was no single-agent case of confirmed nephrogenic systemic fibrosis with gadoterate meglumine either from clinical development programs or from postmarketing experience. CONCLUSIONS: Based on clinical trials, postmarketing observational studies and pharmacovigilance data, a very low incidence of ADRs was reported with gadoterate meglumine, which has no impact on its favourable benefit-risk ratio.

High Levels of Gadolinium Deposition in the Skin of a Patient With Normal Renal Function.

OBJECTIVE: The aim of this study was to assess gadolinium deposition in the skin of a patient with normal renal function, based on estimated glomerular filtration rate values greater than 59 mL/min/1.73 m(2) after exposure to large cumulative doses of gadolinium-based contrast agents (GBCAs). MATERIALS AND METHODS: The patient underwent 61 contrasted brain MRI scans over the course of 11 years. Skin biopsies from the forearm and lower extremity were analyzed with inductively coupled plasma mass spectrometry (ICP-MS), laser ablation ICP-MS, and hydrophilic interaction liquid chromatography ICP-MS. RESULTS: The ICP-MS demonstrated high levels of gadolinium deposition (14.5 ± 0.4 µg/g), similar to previously reported gadolinium levels within the skin of patients with nephrogenic systemic fibrosis. The laser ablation ICP-MS demonstrated deposition of gadolinium within the deep layers of skin. Speciation analysis using hydrophilic interaction liquid chromatography ICP-MS demonstrated the presence of intact gadolinium-chelate species, although most of the gadolinium present could not be further characterized. Light microscopy demonstrated increased CD34 immunoreactivity in the connective tissue septations of the subcutaneous adipose tissue. The patient had no history of skin disorders and did not have a history of nephrogenic systemic fibrosis but did have severe joint contractures of unknown etiology. CONCLUSIONS: Our results, in contradiction to published literature, suggest that in patients with normal renal function, exposure to GBCAs in extremely high cumulative doses can lead to significant gadolinium deposition in the skin. This finding is in line with more recent reports of gadolinium deposition in the brain of patients with normal renal function. Future studies are required to address possible clinical consequences of gadolinium deposition in the skin, brain, and potentially other organs in patients with normal renal function. We recommend, in addition to following current US Food and Drug Administration and American College of Radiology guidelines based on estimated glomerular filtration rate values, that caution be used when administering large cumulative doses of GBCAs and that total cumulative dose of each agent administered is recorded in the patient's medical record.

Macrocyclic and Other Non-Group 1 Gadolinium Contrast Agents Deposit Low Levels of Gadolinium in Brain and Bone Tissue: Preliminary Results From 9 Patients With Normal Renal Function.

OBJECTIVE: The purpose of this study was to determine whether gadolinium (Gd) is deposited in brain and bone tissues in patients receiving only non-Group 1 agents, either macrocyclic or linear protein interacting Gd-based contrast agents, with normal renal function. Group 1 agents are linear agents most associated with nephrogenic systemic fibrosis that the US Federal Drug Administration has defined as contraindicated in patients at risk for this disease. MATERIALS AND METHODS: This study was institutional review board approved and Health Insurance Portability and Accountability Act compliant for retrospective review of records and also had signed autopsy consent authorizing use of decedent's tissue in research studies. Tissue samples were collected from 9 decedents undergoing autopsy who had contrast-enhanced magnetic resonance imaging (MRI) with only single agent exposure to a non-Group 1 Gd-based contrast agent. Decedents with only noncontrast MRI or no MRI served as controls. Multiple brain areas, including globus pallidus and dentate nucleus, as well as bone and skin, were sampled and analyzed for Gd using inductively coupled plasma mass spectrometry. Gadolinium levels were compared between groups of decedents using the Mann-Whitney test and between brain and bone tissues of the same cases using the Wilcoxon signed-rank test. RESULTS: Of the 9 decedents, 5 received gadoteridol (ProHance; Bracco Diagnostics, Princeton, NJ), 2 received gadobutrol (Gadovist; Bayer Healthcare, Whippany, NJ), and 1 each had gadobenate (MultiHance; Bracco Diagnostics) and gadoxetate (Eovist; Bayer Healthcare). Gadolinium was found with all agents in all brain areas sampled with highest levels in globus pallidus and dentate. Bone levels measured 23 times higher (median) than brain levels (P = 0.008 for bone vs globus pallidus) and showed a significant correlation (r = 0.81, P = 0.022). In controls, Gd levels in the brain were at or below limits of measurement and were significantly lower compared with study cases (P = 0.005 for globus pallidus). CONCLUSION: Gadolinium deposition in normal brain and bone tissue occurs with macrocyclic and linear protein interacting agents in patients with normal renal function. Deposition of Gd in cortical bone occurs at much higher levels compared with brain tissue and shows a notable correlation between the two. Thus, the bone may serve as a surrogate to estimate brain deposition if brain Gd were to become a useful clinical or research marker.

Brain regulation of appetite in twins.

BACKGROUND: Neural responses to highly energetic food cues are robust and are suppressed by eating. It is not known if neural responsiveness to food cues is an inherited trait and possibly even one that mediates the genetic influences on body weight that have been previously observed. OBJECTIVE: We investigated the inherited influence on brain responses to high-calorie visual food cues before and after a meal. DESIGN: With the use of a monozygotic twin study design, 21 healthy monozygotic twin pairs consumed a standardized breakfast and, 3.5 h later, underwent the first of 2 functional MRI (fMRI) scans with the use of visual food cues. After the first fMRI session, twins consumed a standardized meal, which was followed by the second fMRI. Serial ratings of appetite and food appeal were obtained. An ad libitum buffet was used to measure total caloric and macronutrient intakes. Intraclass correlations (ICCs) were used to test for inherited influences by comparing whether intrapair similarity was greater than interpair similarity. RESULTS: Body mass index was highly correlated within twin pairs (ICC: 0.96; P < 0.0001). ICCs also showed a strong intrapair similarity for the meal-induced change in hunger (ICC: 0.41; P = 0.03), fullness (ICC: 0.39; P = 0.04), and the appeal of fattening food (ICC: 0.57; P < 0.001). Twins ate a similar number of kilocalories at the buffet (ICC: 0.43; P = 0.02). Before the meal, the global brain activation across regions involved in satiety processing was not more similar in twins than in unrelated individuals. However, significant ICCs were present after the meal (ICC: 0.39; P = 0.04) and for the meal-induced change in activation by high-calorie visual food cues (ICC: 0.52; P < 0.01). CONCLUSION: Inherited factors influence both satiety perception and the effect of a meal to alter regional brain responses to images of highly energetic food. This trial was registered at clinicaltrials.gov as NCT02483663.

Alterations in Connectivity on Functional Magnetic Resonance Imaging with Provocation of Lower Urinary Tract Symptoms: A MAPP Research Network Feasibility Study of Urological Chronic Pelvic Pain Syndromes.

PURPOSE: Urological chronic pelvic pain syndromes have refractory bladder or pelvic pain as the dominant symptom. This has been attributed to changes in the central nervous system caused by a chronic barrage of noxious stimuli. We developed what is to our knowledge a novel challenge protocol that induced bladder distention in study participants to reproduce pain and urinary symptoms. We tested to see whether it could discriminate between persons with urological chronic pelvic pain syndrome-like symptoms and asymptomatic controls. MATERIALS AND METHODS: We recruited 10 female twin pairs who were discordant for urological chronic pelvic pain syndrome-like symptoms. Before scanning each twin urinated to completion and then consumed 500 cc water. Each twin was scanned with our resting state functional magnetic resonance imaging protocol immediately and approximately 50 minutes after consumption. Time series were extracted from the right and left periaqueductal gray, and the right and left amygdala subregions. We performed the repeated measures 2-sample t-test to assess differences in connectivity between symptomatic and asymptomatic twins before and after bladder distention. RESULTS: Group by condition interaction effects were found from the periaqueductal gray to the right cerebellum VIIIa, the amygdala, the right premotor cortex/supplementary motor area and the insular cortex, and between the amygdala and the frontal pole/medial orbital frontal cortex, the hypothalamus, the insular cortex, the thalamus and the anterior cingulate cortex. CONCLUSIONS: These findings demonstrate that our noninvasive bladder distention protocol can detect differences in the processing of urinary sensation between twins discordant for lower urinary tract pain.

Radiologic evidence that hypothalamic gliosis is associated with obesity and insulin resistance in humans.

OBJECTIVE: To use quantitative magnetic resonance imaging (MRI) to test whether mediobasal hypothalamic (MBH) gliosis is associated with obesity and insulin resistance in humans. METHODS: Sixty-seven participants underwent a fasting blood draw and MRI. Cases with radiologic evidence of MBH gliosis (N = 22) were identified as the upper tertile of left MBH T2 relaxation time and were compared to controls (N = 23) from the lowest tertile. In a separate postmortem study, brain slices (N = 10) through the MBH were imaged by MRI and stained for glial fibrillary acidic protein (GFAP). RESULTS: In all participants, longer T2 relaxation time in the left MBH was associated with higher BMI (P = 0.01). Compared with controls, cases had longer T2 relaxation times in the right MBH (P < 0.05), as well as higher BMI (P < 0.05), fasting insulin concentrations (P < 0.01), and HOMA-IR values (P < 0.01), adjusted for sex and age. Elevations in insulin and HOMA-IR were also independent of BMI. In the postmortem study, GFAP staining intensity was positively associated with MBH T2 relaxation time (P < 0.05), validating an MRI-based method for the detection of MBH gliosis in humans. CONCLUSIONS: These findings link hypothalamic gliosis to insulin resistance in humans and suggest that the link is independent of the level of adiposity.

Absent cavum septum pellucidum: a review with emphasis on associated commissural abnormalities.

The cavum septum pellucidum (CSP) is an important fetal midline forebrain landmark, and its absence often signifies additional underlying malformations. Frequently detected by prenatal sonography, absence of the CSP requires further imaging with pre- or postnatal MRI to characterize the accompanying abnormalities. This article reviews the developmental anatomy of the CSP and the pivotal role of commissurization in normal development. An understanding of the patterns of commissural abnormalities associated with absence of the CSP can lead to improved characterization of the underlying spectrum of pathology.

Brain White Matter Abnormalities in Female Interstitial Cystitis/Bladder Pain Syndrome: A MAPP Network Neuroimaging Study.

PURPOSE: Several chronic pain conditions may be distinguished by condition specific brain anatomical and functional abnormalities on imaging, which are suggestive of underlying disease processes. We present what is to our knowledge the first characterization of interstitial cystitis/bladder pain syndrome associated white matter (axonal) abnormalities based on multicenter neuroimaging from the MAPP Research Network. MATERIALS AND METHODS: We assessed 34 women with interstitial cystitis/bladder pain syndrome and 32 healthy controls using questionnaires on pain, mood and daily function. White matter microstructure was evaluated by diffusion tensor imaging to model directional water flow along axons or fractional anisotropy. Regions correlating with clinical parameters were further examined for gender and syndrome dependence. RESULTS: Women with interstitial cystitis/bladder pain syndrome showed numerous white matter abnormalities that correlated with pain severity, urinary symptoms and impaired quality of life. Interstitial cystitis/bladder pain syndrome was characterized by decreased fractional anisotropy in aspects of the right anterior thalamic radiation, the left forceps major and the right longitudinal fasciculus. Increased fractional anisotropy was detected in the right superior and bilateral inferior longitudinal fasciculi. CONCLUSIONS: To our knowledge we report the first characterization of brain white matter abnormalities in women with interstitial cystitis/bladder pain syndrome. Regional decreases and increases in white matter integrity across multiple axonal tracts were associated with symptom severity. Given that white matter abnormalities closely correlated with hallmark symptoms of interstitial cystitis/bladder pain syndrome, including bladder pain and urinary symptoms, brain anatomical alterations suggest that there are neuropathological contributions to chronic urological pelvic pain.

Increased brain gray matter in the primary somatosensory cortex is associated with increased pain and mood disturbance in patients with interstitial cystitis/painful bladder syndrome.

PURPOSE: Interstitial cystitis is a highly prevalent pain condition estimated to affect 3% to 6% of women in the United States. Emerging data suggest there are central neurobiological components to the etiology of this disease. We report the first brain structural imaging findings from the MAPP network with data on more than 300 participants. MATERIALS AND METHODS: We used voxel based morphometry to determine whether human patients with chronic interstitial cystitis display changes in brain morphology compared to healthy controls. A total of 33 female patients with interstitial cystitis without comorbidities and 33 age and gender matched controls taken from the larger sample underwent structural magnetic resonance imaging at 5 MAPP sites across the United States. RESULTS: Compared to controls, females with interstitial cystitis displayed significant increased gray matter volume in several regions of the brain including the right primary somatosensory cortex, the superior parietal lobule bilaterally and the right supplementary motor area. Gray matter volume in the right primary somatosensory cortex was associated with greater pain, mood (anxiety) and urological symptoms. We explored these correlations in a linear regression model, and found independent effects of these 3 measures on primary somatosensory cortex gray matter volume, namely clinical pain (McGill pain sensory total), a measure of urgency and anxiety (HADS). CONCLUSIONS: These data support the notion that changes in somatosensory gray matter may have an important role in pain sensitivity as well as affective and sensory aspects of interstitial cystitis. Further studies are needed to confirm the generalizability of these findings to other pain conditions.