Positron Emission Tomography and Magnetic Resonance Imaging of the Brain in Fabry Disease: A Nationwide, Long-Time, Prospective Follow-Up

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Abstract

Background

Fabry disease is a rare metabolic glycosphingolipid storage disease caused by deficiency of the lysosomal enzyme α-galactosidase A—leading to cellular accumulation of globotriasylceramide in different organs, vessels, tissues, and nerves. The disease is associated with an increased risk of cerebrovascular disease at a young age in addition to heart and kidney failure.

Objective

The objective of this study was to assess brain function and structure in the Danish cohort of patients with Fabry disease in a prospective way using 18-fluoro-deoxyglucose (F-18 FDG) positron emission tomography (PET) and magnetic resonance imaging (MRI).

Patients

Forty patients with Fabry disease (14 males, 26 females, age at inclusion: 10–66 years, median: 39 years) underwent a brain F-18-FDG-PET-scan at inclusion, and 31 patients were followed with FDG-PET biannually for up to seven years. All patients (except one) had a brain MRI-scan at inclusion, and 34 patients were followed with MRI biannually for up to nine years.

Image Analysis

The FDG-PET-images were inspected visually and analysed using a quantitative 3-dimensional stereotactic surface projection analysis (Neurostat). MRI images were also inspected visually and severity of white matter lesions (WMLs) was graded using a visual rating scale.

Results

In 28 patients brain-FDG-PET was normal; in 23 of these 28 patients brain MRI was normal—of the remaining five patients in this group, four patients had WMLs and one patient never had an MRI-scan. In 10 patients hypometabolic areas were observed on brain-FDG-PET; all of these patients had cerebral infarcts/hemorrhages visualized on MRI corresponding to the main hypometabolic areas. In two patients brain-FDG-PET was ambiguous, while MRI was normal in one and abnormal in the other.

Conclusion

Our data indicated that, in patients with Fabry disease, MRI is the preferable clinical modality—if applicable—when monitoring cerebral status, as no additional major brain-pathology was detected with FDG-PET.

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Most cited references 25

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A new rating scale for age-related white matter changes applicable to MRI and CT.

L Wahlund, F. Barkhof, F Fazekas … (2001)

MRI is more sensitive than CT for detection of age-related white matter changes (ARWMC). Most rating scales estimate the degree and distribution of ARWMC either on CT or on MRI, and they differ in many aspects. This makes it difficult to compare CT and MRI studies. To be able to study the evolution and possible effect of drug treatment on ARWMC in large patient samples, it is necessary to have a rating scale constructed for both MRI and CT. We have developed and evaluated a new scale and studied ARWMC in a large number of patients examined with both MRI and CT. Seventy-seven patients with ARWMC on either CT or MRI were recruited and a complementary examination (MRI or CT) performed. The patients came from 4 centers in Europe, and the scans were rated by 4 raters on 1 occasion with the new ARWMC rating scale. The interrater reliability was evaluated by using kappa statistics. The degree and distribution of ARWMC in CT and MRI scans were compared in different brain areas. Interrater reliability was good for MRI (kappa=0.67) and moderate for CT (kappa=0.48). MRI was superior in detection of small ARWMC, whereas larger lesions were detected equally well with both CT and MRI. In the parieto-occipital and infratentorial areas, MRI detected significantly more ARWMC than did CT. In the frontal area and basal ganglia, no differences between modalities were found. When a fluid-attenuated inversion recovery sequence was used, MRI detected significantly more lesions than CT in frontal and parieto-occipital areas. No differences were found in basal ganglia and infratentorial areas. We present a new ARWMC scale applicable to both CT and MRI that has almost equal sensitivity, except for certain regions. The interrater reliability was slightly better for MRI, as was the detectability of small lesions.

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Enzyme replacement therapy in Fabry disease: a randomized controlled trial.

R Schiffmann, J. B. Kopp, H Austin … (2001)

Fabry disease is a metabolic disorder without a specific treatment, caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-gal A). Most patients experience debilitating neuropathic pain and premature mortality because of renal failure, cardiovascular disease, or cerebrovascular disease. To evaluate the safety and efficacy of intravenous alpha-gal A for Fabry disease. Double-blind placebo-controlled trial conducted from December 1998 to August 1999 at the Clinical Research Center of the National Institutes of Health. Twenty-six hemizygous male patients, aged 18 years or older, with Fabry disease that was confirmed by alpha-gal A assay. A dosage of 0.2 mg/kg of alpha-gal A, administered intravenously every other week (12 doses total). Effect of therapy on neuropathic pain while without neuropathic pain medications measured by question 3 of the Brief Pain Inventory (BPI). Mean (SE) BPI neuropathic pain severity score declined from 6.2 (0.46) to 4.3 (0.73) in patients treated with alpha-gal A vs no significant change in the placebo group (P =.02). Pain-related quality of life declined from 3.2 (0.55) to 2.1 (0.56) for patients receiving alpha-gal A vs 4.8 (0.59) to 4.2 (0.74) for placebo (P =.05). In the kidney, glomeruli with mesangial widening decreased by a mean of 12.5% for patients receiving alpha-gal vs a 16.5% increase for placebo (P =.01). Mean inulin clearance decreased by 6.2 mL/min for patients receiving alpha-gal A vs 19.5 mL/min for placebo (P =.19). Mean creatinine clearance increased by 2.1 mL/min (0.4 mL/s) for patients receiving alpha-gal A vs a decrease of 16.1 mL/min (0.3 mL/s) for placebo (P =.02). In patients treated with alpha-gal A, there was an approximately 50% reduction in plasma glycosphingolipid levels, a significant improvement in cardiac conduction, and a significant increase in body weight. Intravenous infusions of alpha-gal A are safe and have widespread therapeutic efficacy in Fabry disease.

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A diagnostic approach in Alzheimer's disease using three-dimensional stereotactic surface projections of fluorine-18-FDG PET.

Björn Kuhl, S Minoshima, N Foster … (1995)

To improve the diagnostic performance of PET as an aid in evaluating patients suspected of having Alzheimer's disease, we developed a fully automated method which generates comprehensive image presentations and objective diagnostic indices. Fluorine-18-fluorodeoxyglucose PET image sets were collected from 37 patients with probable Alzheimer's disease (including questionable and mild dementia), 22 normal subjects and 5 patients with cerebrovascular disease. Following stereotactic anatomic standardization, metabolic activity on an individual's PET image set was extracted to a set of predefined surface pixels (three-dimensional stereotactic surface projection, 3D-SSP), which was used in the subsequent analysis. A normal database was created by averaging extracted datasets of the normal subjects. Patients' datasets were compared individually with the normal database by calculating a Z-score on a pixel-by-pixel basis and were displayed in 3D-SSP views for visual inspections. Diagnostic indices were then generated based on averaged Z-scores for the association cortices. Patterns and severities of metabolic reduction in patients with probable Alzheimer's disease were seen in the standard 3D-SSP views of extracted raw data and statistical Z-scores. When discriminating patients with probable Alzheimer's disease from normal subjects, diagnostic indices of the parietal association cortex and unilaterally averaged parietal-temporal-frontal cortex showed sensitivities of 95% and 97%, respectively, with a specificity of 100%. Neither index yielded false-positive results for cerebrovascular disease. 3D-SSP enables quantitative data extraction and reliable localization of metabolic abnormalities by means of stereotactic coordinates. The proposed method is a promising approach for interpreting functional brain PET scans.

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Author and article information

Contributors

Raphael Schiffmann: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 2 December 2015

Publication date Collection: 2015

Volume: 10

Issue: 12

Electronic Location Identifier: e0143940

Affiliations

[1 ]Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

[2 ]Department of Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

[3 ]Department of Radiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

Baylor Research Institute, UNITED STATES

Author notes

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: UFR LH IL. Performed the experiments: UFR HG BB AKR. Analyzed the data: KK IL. Wrote the paper: KK. Manuscript editing and final approval: KK UFR HG LH BB AKR IL.

* E-mail: korsholmk@ 123456gmail.com

Article

Publisher ID: PONE-D-15-41717

DOI: 10.1371/journal.pone.0143940

PMC ID: 4667906

PubMed ID: 26629990

SO-VID: 78cfbb42-b2fa-461b-9ba0-c57695db75b1

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

History

Date received : 24 September 2015

Date accepted : 11 November 2015

Page count

Figures: 2, Tables: 2, Pages: 13

Funding

The study has been partly sponsored by unrestricted research grants from Genzyme ( https://www.genzyme.com/) and Shire ( https://www.shire.com)/, and UFR has received teaching honoraria and served in advisory boards in Shire, Genzyme and Amicus ( http://www.amicusrx.com/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Custom metadata

Data Availability All relevant data can be found in the manuscript, and the remaining data (PET- and MRI-scans and patient reports) cannot be made publicly available for ethical and legal reasons, as public availability would compromise patient confidentiality, and local (Danish) legislation prohibits public availability of the data. National Ethics Committee, De Videnskabsetiske Komiteer for Region Hovedstaden, Center for Sundhed, Kongens Vænge 2, 3400 Hillerød, Denmark, Website: www.regionh.dk/vek Email: vek@ 123456regionh.dk

Positron Emission Tomography and Magnetic Resonance Imaging of the Brain in Fabry Disease: A Nationwide, Long-Time, Prospective Follow-Up

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Abstract

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Objective

Patients

Image Analysis

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Conclusion

Related collections

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Most cited references 25

A new rating scale for age-related white matter changes applicable to MRI and CT.

Enzyme replacement therapy in Fabry disease: a randomized controlled trial.

A diagnostic approach in Alzheimer's disease using three-dimensional stereotactic surface projections of fluorine-18-FDG PET.

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