Introduction

Fabry disease (FD) is a rare X-linked metabolic disorder caused by a deficiency in the lysosomal enzyme α -galactosidase A (α-GLA) 1. Neuropsychological symptoms are common in FD, in particular depression, reported to be clinically significant in up to 50% of the patients 2. Furthermore, existing data suggest an impairment in executive functioning, information processing speed and attention , although with a preservation of global cognitive functioning 3. Abnormalities of the Default Mode Network (DMN) have been demonstrated in several disorders (e.g. Alzheimer’s disease 4, Parkinson's disease 5, Huntington's disease 6 and epilepsy 7). However, to the best of our knowledge no studies have been performed to evaluate the integrity of the DMN in FD, a condition in which alterations of the functional connectivity (FC) have been recently reported 8. Therefore, we aimed to perform an RS-fMRI study in FD to evaluate possible alterations of this network and correlations with neuropsychological scores in FD patients, to help understand the mechanisms underlying the cognitive dysfunction in this condition.

Methods

Thirty-two FD patients with genetically confirmed diagnosis of classical FD (Males=12, mean age 43.3±12.2) were enrolled, along with thirty-five healthy controls (HC) of comparable age and sex (Males=14, mean age 42.1±14.5). MRI data were acquired on a 3 Tesla MR scanner (Trio, Siemens Medical Systems, Erlangen, Germany). Functional data were processed using the functional connectivity toolbox (CONN, v. 16.a, http://www.nitrc.org/projects/conn), which contains libraries for fMRI analysis based on the Statistical Parametric Mapping (SPM8) software package (http://www.fil.ion.ucl.ac.uk/spm). Briefly, pre-processing steps included the removal of the first five time points, to allow for instability of the initial MRI signal, leaving 195 time points, followed by the motion and slice timing correction, the temporal despiking by means of an hyperbolic tangent squashing function to limit outlier values, band-pass filtering (0.008 Hz<f<0.09 Hz), and spatial smoothing (using a 6-mm Full-Width at Half Maximum Gaussian kernel). Studies with a mean relative root-mean-square (RMS) of the translation parameters at each time point of 0.15 or higher (according to 9), or with more than 1.5mm displacement along or 1.5 degrees rotation around any of the three main axes, were discarded from the analysis. For each subject, BOLD signal time course was calculated separately for each of the main hubs of the DMN, namely the posterior cingulate and the ventral portion of the precuneus (PCC), the medial prefrontal cortex (MPFC), and the right (RPL) and left (LPL) inferior parietal lobules, and corresponding correlation maps of the BOLD signal across the brain were generated (Figure 1). Finally, correlations with neuropsychological variables were probed voxelwise over the whole brain.

Results

Clusters of increased functional connectivity emerged in FD patients among the main DMN hubs, as well as between the DMN and the middle temporal gyri, with a reduced anticorrelation between the midline DMN hubs and the right cerebellar Crus I and II (Figure 2). The connectivity between right inferior frontal gyrus and precuneus was significantly correlated with the results of the Corsi block tapping test (P=0.0001) (Figure 3).

Discussion

The variable association of executive dysfunction and depression with the relatively widespread involvement of deep and periventricular white matter is present also in other chronic, although etiopathogenetically different, conditions, such as cerebral small vessel disease, Multiple Sclerosis (MS), late-life depression and mild cognitive impairment, and different DMN changes have been described in the above mentioned conditions. When analyzing the brain FC with reference to the four main hubs of the DMN in FD patients, we found clusters of increased connectivity in the medial frontal cortex, in the precuneus and parietal cortices bilaterally, without a significant correlation with WMH load. This result, however, is only apparently in contrast with those available in other white matter disorders, as WMH were present only in 14 out of 32 patients (43.8%), and with a low lesion load median Fazekas' score: 1). Furthermore, it should be noted that increased FC in cortical areas implicated in the DMN has been indeed previously reported in other conditions such as early stages of MS, Clinically Isolated Syndrome (CIS) and concussion, which share with FD the diffuse, although mild, involvement of WM 10-13.

Conclusion

Widespread DMN changes are present in FD patients, and correlate with cognitive performance. Our results confirm the current view of a cerebral involvement in FD patients not simply associated to major cerebrovascular events, but also related to significant and diffuse functional changes.

Acknowledgements

No acknowledgement found.

References

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