Evaluation of an imaging biomarker, Dixon quantitative chemical shift imaging, in Gaucher disease: lessons learned.

Gaucher disease (GD) is the first lysosomal storage disorder for which specific therapy became available. The infiltration of bone marrow by storage cells plays an important part in the pathophysiology of skeletal complications and can be quantified by measurements of bone marrow fat fraction (Ff). Ff measurements by Dixon quantitative chemical shift imaging (QCSI) are standard for the follow-up care of GD patients at the Academic Medical Center. Several criteria should be met in order for these measurements to qualify as an imaging biomarker. These include: 1) The presence of the imaging biomarker is closely coupled or linked to the presence of the target disease or condition; 2) The detection and/or quantitative measurement of the biomarker is accurate, reproducible, and feasible over time, and; 3) The changes measured over time in the imaging biomarker are closely coupled, or linked, to the success or failure of the therapeutic effect and the true end point for the medical therapy being evaluated. This review assesses the use of Ff measurements by QCSI as a biomarker for GD in light of these criteria. In addition potential pitfalls are discussed including: degenerative disc disease; vertebral collapse and infection; haematological malignancies; focal fatty deposits; age; menopause; phase and repositioning errors, and; fat surrounding the basivertebral vein.QCSI measurements of Ff can be used as an imaging biomarker for GD taking these pitfalls into account. It is one of the first biomarkers, in particular imaging biomarkers, for GD that has been systematically evaluated and could be a valuable tool in clinical trials comparing different treatments or dosing regimens.

Taliglucerase alfa leads to favorable bone marrow responses in patients with type I Gaucher disease.

Taliglucerase alfa (Protalix Biotherapeutics, Israel) is a carrot-cell-expressed recombinant human beta-glucocerebrosidase recently approved in the United States for the treatment of type 1 Gaucher disease (GD). As bone disease is one of the most debilitating features of GD, quantification of bone marrow involvement is important for monitoring the response to treatment. Therefore, bone marrow fat fraction (Ff) measured by quantitative chemical shift imaging (QCSI) was included as exploratory parameter to evaluate bone marrow response in treatment naïve GD patients participating in a double-blind, randomized phase III study. Eight GD patients with intact spleens were treated with 30 or 60U/kg biweekly. Ff results were compared to outcomes in 15 untreated Dutch GD patients with a follow-up interval of 1year. Five taliglucerase alfa treated patients had a Ff below the threshold that relates to complication risk (<0.23) at baseline (median (n=8) 0.19, range 0.11-0.35). Ff significantly increased compared to baseline (p=0.012) and compared to untreated patients (p=0.005), already after 1year of follow-up with further improvement up to 36months. In four patients with the lowest Ff, the higher dose resulted in increases above 0.23 within 1year. All patients had sustained improvements in all other parameters. There was no influence of antibodies on response parameters. Treatment with taliglucerase alfa results in significant increases in lumbar spine fat fractions, which indicates clearance of Gaucher cells from the bone marrow.

Acid sphingomyelinase (Asm) deficiency patients in The Netherlands and Belgium: disease spectrum and natural course in attenuated patients.

Niemann-Pick disease (NPD) is a neurovisceral lysosomal storage disorder caused by acid sphingomyelinase (ASM) deficiency, which can be categorized as either Niemann-Pick disease type A [NPD-A], with progressive neurological disease and death in early childhood, or as Niemann-Pick disease type B [NPD-B], with a more variable spectrum of manifestations. Enzyme replacement therapy (ERT) with recombinant sphingomyelinase is currently studied as potential treatment for NPD-B patients. The objective of this study is to characterize the clinical features of patients with ASM deficiency in the Netherlands and Belgium with focus on the natural disease course of NPD-B patients. Prospective and retrospective data on ASM deficient patients were collected in The Netherlands and part of Belgium. Patients with NPD-B that could be followed prospectively were evaluated every 6-12 months for pulmonary function tests, 6 minute walk test (6 MWT), imaging (bone marrow infiltration measured by QCSI, organ volumes by MRI and CT scan of the lungs) and biochemical markers. Twenty-five patients with ASM deficiency were identified (13 males, 12 females, median age 13years, range 1-59 years). Nine patients had died at the time of the study, including four NPD-A patients at the age of 1,1, 2, 3 and five NPDB patents at the age of 5, 6, 43, 56 and 60 years. There was a high prevalence of homozygosity and compound heterozygosity for the common p.Arg608del mutation in 43% and 19% of NPD-B patients, respectively. In NPD-B patients, thrombocytopenia was present in most, while anemia and leucopenia were less common (33% and 6 % respectively). HDL cholesterol was reduced in most patients. Pulmonary disease was severe in several patients. Follow-up up to 11 years revealed a gradual decrease in platelet count. Detailed investigations in 6 NPD-B patients with follow-up in 4 patients revealed remarkable stable disease parameters up to 6 years, with some decline in pulmonary function and 6 MWT. Bone marrow fat fractions were decreased, indicating the presence of storage macrophages. Lung involvement was not related to the extent of visceromegaly, cytopenia or bone marrow involvement. In conclusion, in NPD-B patients pulmonary disease is the most debilitating feature. Disease manifestations are mostly stable in attenuated patients. Bone marrow infiltration is a less prominent feature of the disease.

MR spectroscopy findings in early stages of motor neuron disease.

BACKGROUND AND PURPOSE: Upper motor neuron degeneration varies in different phenotypes of MND. We used single-voxel MR spectroscopy of the primary motor cortex to detect corticomotoneuron degeneration and glial hyperactivity in different phenotypes of MND with a relatively short disease duration, contributing to further delineation of the phenotypes. MATERIALS AND METHODS: We prospectively included patients with ALS-B, ALS-L, and PMA and compared their data with those of patients with PLS and healthy controls. Each cohort consisted of 12 individuals. Disease duration was <1 year in ALS and PMA, but longer in PLS by definition. Follow-up examination was at 6 months. We measured ALSFRS-R, finger- and foot-tapping speed, and levels of the following: 1) NAAx, 2) mIns, and 3) Glx in the primary motor cortex. RESULTS: At baseline, we found significantly decreased NAAx levels and increased mIns levels in PLS. Levels of NAAx and mIns in patients with ALS-L and ALS-B were not significantly different from those in controls, but NAAx levels were significantly lower compared with those in PMA. At follow-up, only in PMA was a decrease of NAAx demonstrated. Glx levels varied widely in all groups. Levels of NAAx and mIns correlated well with clinical variables. CONCLUSIONS: Metabolite changes suggest neuronal dysfunction and active glial involvement in PLS. The corticomotoneuron is affected in early ALS-B and ALS-L, but at a later stage also in PMA. MR spectroscopy data are useful to obtain insight into the disease process at the level of the upper motor neuron in various phenotypes of MND.

Evaluation of the occlusion status of coiled intracranial aneurysms with MR angiography at 3T: is contrast enhancement necessary?

BACKGROUND AND PURPOSE: MR angiography (MRA) is increasingly used as a noninvasive imaging technique for the follow-up of coiled intracranial aneurysms. However, the need for contrast enhancement has not yet been elucidated. We compared 3D time-of-flight MRA (TOF-MRA) and contrast-enhanced MRA (CE-MRA) at 3T with catheter angiography. MATERIALS AND METHODS: Sixty-seven patients with 72 aneurysms underwent TOF-MRA, CE-MRA, and catheter-angiography 6 months after coiling. Occlusion status on MRA was classified as adequate (complete and neck remnant) or incomplete by 2 independent observers. For TOF-MRA and CE-MRA, interobserver agreement, intermodality agreement, and correlation with angiography were assessed by kappa statistics. RESULTS: Catheter-angiography revealed incomplete occlusion in 12 (17%) of the 69 aneurysms; 3 aneurysms were excluded due to MR imaging artifacts. Interobserver agreement was good for CE-MRA (kappa = 0.77; 95% confidence interval [CI], 0.55-0.98) and very good for TOF-MRA (kappa = 0.89; 95% CI, 0.75-1.00). Correlation of TOF-MRA and CE-MRA with angiography was good. The sensitivity of TOF-MRA and CE-MRA was 75% (95% CI, 43%-95%); the specificity of TOF-MRA was 98% (95% CI, 91%-100%) and of CE-MRA, 97% (95% CI, 88%-100%). All 5 incompletely occluded aneurysms, which were additionally treated, were correctly identified with both MRA techniques. Areas under the receiver operating characteristic curve for TOF-MRA and CE-MRA were 0.90 (95% CI, 0.79-1.00) and 0.91 (95% CI, 0.79-1.00). Intermodality agreement between TOF-MRA and CE-MRA was very good (kappa = 0.83; 95% CI, 0.65-1.00), with full agreement in 66 (96%) of the 69 aneurysms. CONCLUSIONS: In this study, TOF-MRA and CE-MRA at 3T were equivalent in evaluating the occlusion status of intracranial aneurysms after coiling. Because TOF-MRA does not involve contrast administration, this method is preferred over CE-MRA.

Sequential MR imaging changes in nonketotic hyperglycinemia.

Serial diffusion-weighted (DWI) and diffusion tensor imaging (DTI) were performed in a patient with neonatal onset nonketotic hyperglycinemia (NKH). At 3 weeks areas that are normally myelinated at this time showed increased T2-signal intensity and restricted diffusion, consistent with vacuolating myelinopathy. At 3 months, these areas had increased in the topographic pattern of normal myelination, whereas fractional anisotropy was compatible with axonal sparing. At 17 months, diffusion restriction had disappeared, likely because of coalescence of myelin vacuoles. A decrease of fractional anisotropy was observed in the previously myelinated areas indicative of axonal loss. We conclude that DWI and DTI can be used to identify and characterize white matter tract abnormalities in patients with NKH.

Radiology of Gaucher disease (type 1) and bone manifestations: the Dutch experience.

Evaluating bone disease in Gaucher disease is a very important part of monitoring patients on therapy. In the Academic Medical Center (AMC) there is ample experience covering the evaluating of bone marrow involvement. Both state of the art Quantitative Chemical Shift Imaging (QCSI) as well as alternatives have been subject of research protocols. Our experiences are described.

Dixon quantitative chemical shift MRI for bone marrow evaluation in the lumbar spine: a reproducibility study in healthy volunteers.

PURPOSE: The purpose of this work was to explore the reproducibility of fat-fraction measurements using Dixon quantitative chemical shift imaging (QCSI) in the lumbar spine (L3, L4, and L5) of healthy volunteers. METHOD: Sixteen healthy volunteers were examined at 1.5 T two times to obtain a repeated measurement in the same slice and a third time in three parallel slices. Single slice, two point Dixon SE (TR/TE 2,500/22.3) sequences were used, from which fat-fraction images were calculated. The fat-fraction results are presented as averages over regions of interest, which were derived from the contours of the vertebrae. Reproducibility measures related to repeated measurements on different days, slice position, and contour drawing were calculated. RESULTS: The mean fat fraction was 0.37 (SD 0.08). The SD due to repeated measurement was small (sigmaR = 0.013-0.032), almost all of which can be explained by slice-(re)-positioning errors. CONCLUSION: When used to evaluate the same person longitudinally in time, Dixon QCSI fat-fraction measurement has an excellent reproducibility. It is a powerful noninvasive tool in the evaluation of bone marrow composition.

Dixon quantitative chemical shift imaging is a sensitive tool for the evaluation of bone marrow responses to individualized doses of enzyme supplementation therapy in type 1 Gaucher disease.

Type 1 Gaucher disease can be effectively treated with enzyme supplementation therapy. Bone disease is a debilitating feature of the disorder and results from infiltration of the bone marrow by Gaucher cells. The effect of treatment on bone marrow infiltration is difficult to measure, necessitating the development of sensitive techniques to allow adequate dosing. Dixon quantitative chemical shift imaging (Dixon-QCSI) is a MRI technique to measure displacement of fatty marrow by Gaucher cells. Low bone marrow fat fractions have been found in Gaucher disease. We studied the effect of individualized low doses of enzyme therapy on the fat fractions of the lumbar spine in 12 adult Gaucher disease patients before and during treatment and in 9 untreated Gaucher controls. Fat fractions were decreased in 9/12 patients (median 0.20, range 0.08-0.40) and equally low in the untreated Gaucher controls compared to age-matched healthy volunteers (normal values 0.27-0.43, P < 0.01). During treatment, fat fractions increased significantly already after 1 year in 11/12 patients (P = 0.007). After 4 to 5 years, fat fractions normalized in 11/12 patients. Fat fractions remained low in the untreated Gaucher controls (P = 0.5 and 0.6 at 1 and 2 years, respectively). Six of 11 patients had a dose increase, which did not clearly affect fat fractions. Dixon-QCSI is a sensitive tool for the measurement of the response of bone marrow to enzyme therapy.

MRI in clinically asymptomatic neuropathic leprosy feet: a baseline study.

This study was undertaken to analyze the magnetic resonance imaging (MRI) findings in the clinically asymptomatic neuropathic feet of leprosy patients. Since in the literature no MRI data are available concerning the asymptomatic neuropathic foot in leprosy, the interpretation of MRI examinations in clinically suspected neuropathic feet in leprosy is difficult. We examined 10 adult leprosy patients with clinically asymptomatic neuropathic feet. Inclusion criteria were a normal or near normal neuropathic foot, without signs of inflammation. All patients underwent an MRI protocol with the inclusion of two-point Dixon chemical shift imaging as fat suppression sequence. We found MRI changes in almost all patients. The most striking were the changes located in the region of the first metacarpophalangeal (MTP) joint. These changes ranged from degradation and interruption of the subcutaneous fat to effusion/synovitis in the first MTP joint. This study reveals significant MRI changes in clinically asymptomatic neuropathic feet in patients with leprosy. These changes may relate to the development of ulcerations. MRI may play an important role in detecting feet at risk and may influence clinical decision making.

Uniform fat suppression in hands and feet through the use of two-point Dixon chemical shift MR imaging.

PURPOSE: To assess the potential of two-point Dixon chemical shift magnetic resonance imaging to achieve uniform fat suppression in the distal parts of the extremities. MATERIALS AND METHODS: Two-point Dixon chemical shift imaging was performed in 31 consecutive patients clinically suspected to have bone marrow disease. In some patients, Dixon studies were performed before and after the intravenous administration of gadopentetate dimeglumine, and in some patients follow-up examinations were performed, for a total of 64 studies. Areas of interest were the hand, wrist, foot, ankle, and lower leg. There was a special interest in the neuropathic foot and osteomyelitis. The uniformity of fat suppression in the entire field of view, the frequency of displacement artifacts, and the applicability of the technique in routine patient treatment were evaluated. RESULTS: In 64 (100%) Dixon studies, uniform fat suppression was achieved. In 59 (92%) studies, there were no displacement artifacts. In five (8%) studies, displacement artifacts occurred; however, in only one (2%) study did they severely hamper the reading. Thus, in 63 (98%) studies, adequate diagnostic quality was obtained. CONCLUSION: Two-point Dixon chemical shift imaging is a good technique for achieving uniform fat suppression in the distal parts of the extremities. Because the frequency of displacement artifacts is low, the technique is applicable in a routine clinical setting.

Aspects of ketogenesis: control and mechanism of ketone-body formation in isolated rat-liver mitochondria.

The synthesis of ketone bodies by intact isolated rat-liver mitochondria has been studied at varying rates of acetyl-CoA production and of acetyl-CoA utilization in the Krebs cycle. Factors which enhanced the rate of acetyl-CoA production caused an increase in the fraction of acetyl-CoA which was incorporated into ketone bodies. On the other hand, it was found that factors which stimulated the formation of citrate lowered the relative rate of ketogenesis. It is concluded that acetyl-CoA is preferentially used for citrate synthesis, if the level of oxaloacetate in the mitochondrial matrix space is adequate. The intramitochondrial level of oxaloacetate, which is determined by the malate concentration and the ratio of NADH over NAD+, is the main factor controlling the rate of citrate synthesis. The ATP/ADP ratio per se does not affect the activity of citrate synthase in this in vitro system. Ketogenesis can be described as an overflow of acetyl-groups: Ketone-body formation is stimulated only when the rate of acetyl-CoA production increases beyond the capacity for citrate synthesis. The interaction between fatty acid oxidation and pyruvate metabolism and the effects of long-chain acyl-CoA on mitochondrial metabolism are discussed. Ketone bodies which were generated during the oxidation of [1-14C] fatty acids were preferentially labelled in their carboxyl group. This carboxyl group had the same specific activity as the acetyl-CoA pool, whereas the specific activity of the acetone moiety of acetoacetate was much lower, especially at low rates of ketone-body formation. The activities of acetoacetyl-CoA deacylase and the hydroxymethylglutaryl-CoA (HMG-CoA) pathway were compared in soluble and mitochondrial fractions of rat- and cow-liver in different ketotic states. In rat-liver mitochondria, both pathways of acetoacetate synthesis were stimulated upon starvation or in alloxan diabetes. In cow liver, only the HMG-CoA pathway was increased during ketosis in the mitochondrial as well as in the soluble fraction.