MRI-visible perivascular spaces as an imaging biomarker in Fabry disease

D Lyndon,L Cipolotti,H R Jager,R Lachmann,F Jichi,D J Werring,F Bolsover,D Hughes,I Davagnanam,C Wheeler-Kingshott,A Merwick,E Murphy,D Wilson

doi:10.1007/s00415-020-10209-7

Abstract

IntroductionFabry disease (FD) is an X-linked lysosomal storage disorder resulting in vascular glycosphingolipid accumulation and increased stroke risk. MRI findings associated with FD include white matter hyperintensities (WMH) and cerebral microbleeds (CMBs), suggesting the presence of cerebral small vessel disease. MRI-visible perivascular spaces (PVS) are another promising marker of small vessel disease associated with impaired interstitial fluid drainage. We investigated the association of PVS severity and anatomical distribution with FD.Patients and methodsWe compared patients with genetically proven FD to healthy controls. PVS, WMH, lacunes and CMBs were rated on standardised sequences using validated criteria and scales, blinded to diagnosis. A trained observer (using a validated rating scale), quantified the total severity of PVS. We used logistic regression to investigate the association of severe PVS with FD.ResultsWe included 33 FD patients (median age 44, 44.1% male) and 20 healthy controls (median age 33.5, 50% male). Adjusting for age and sex, FD was associated with more severe basal ganglia PVS (odds ratio (OR) 5.80, 95% CI 1.03–32.7) and higher total PVS score (OR 4.03, 95% CI 1.36–11.89). Compared with controls, participants with FD had: higher WMH volume (median 495.03 mm3 vs 0, p = 0.0008), more CMBs (21.21% vs none, p = 0.04), and a higher prevalence of lacunes (21.21% vs. 5%, p = 0.23).ConclusionsPVS scores are more severe in FD than control subjects. Our findings have potential relevance for FD diagnosis and suggest that impaired interstitial fluid drainage might be a mechanism of white matter injury in FD.

Highlights

Fabry disease (FD) is an X-linked lysosomal storage disorder resulting in vascular glycosphingolipid accumulation and increased stroke risk
On the right panel (a) a perivascular spaces (PVS) is shown by black arrows; on the left panel (b) a PVS is shown by white arrows. c and d phase sensitive inversion recovery (PSIR) and T2-weighted axial images of a subject with a mild PVS score in our control group
Two patients in the FD group had a history of ischaemic stroke and another patient had a previous transient ischaemic attack (TIA) compared to none of the control group

Summary

Introduction

Fabry disease (FD) is an X-linked lysosomal storage disorder resulting in vascular glycosphingolipid accumulation and increased stroke risk. MRI findings associated with FD include white matter hyperintensities (WMH) and cerebral microbleeds (CMBs), suggesting the presence of cerebral small vessel disease. MRI-visible perivascular spaces (PVS) are another promising marker of small vessel disease associated with impaired interstitial fluid drainage. PVS, WMH, lacunes and CMBs were rated on standardised sequences using validated criteria and scales, blinded to diagnosis. Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency in the α-galactosidase A (GLA) enzyme, leading to the accumulation of globotriaosylceramide (Gb3) in multiple organ tissues and blood vessels, with increased stroke risk [1]. Cerebral small-vessel disease (SVD) is common, causing clinical subcortical ischaemic stroke or asymptomatic brain imaging changes, white matter hyperintensities (WMH), lacunes and cerebral microbleeds (CMBs) [3]. Laboratory testing for FD is guided by clinical and radiological suspicion, including the presence of SVD markers; in males, FD can be diagnosed by measuring alpha-galactosidase A activity, while in females, only the identification of a pathogenic mutation in the GLA gene allows a definite diagnosis

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