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DOI: 10.1148/radiol.2412051122
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(Radiology 2006;241:492-500.)
© RSNA, 2006

Neuroradiology

Subcortical Damage and Cortical Functional Changes in Men and Women with Fabry Disease: A Multifaceted MR Study1

Cinzia Gavazzi, MD, Walter Borsini, MD, Laura Guerrini, MD, Riccardo Della Nave, MD, Maria Assunta Rocca, MD, Carlo Tessa, MD, PhD, Suzanne Buchner, MD, Giacomo Belli, MSc, Massimo Filippi, MD, Natale Villari, MD and Mario Mascalchi, MD, PhD

1 From the Radiodiagnostic Section, Department of Clinical Physiopathology (C.G., L.G., R.D.N., C.T., N.V., M.M.), and Neurological Clinic, Department of Neurological Sciences (W.B., S.B.), University of Florence, Viale Morgagni 85, Florence, Italy; Neuroimaging Research Unit, San Raffaele Hospital and University, Milan, Italy (M.A.R., M.F.); and Department of Medical Physics, Careggi Hospital, Florence, Italy (G.B.). Received July 4, 2005; revision requested September 6; revision received October 1; accepted October 18; final version accepted January 9, 2006. Address correspondence to M.M. (e-mail: m.mascalchi{at}dfc.unifi.it).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Purpose: To prospectively compare brain magnetic resonance (MR) imaging and hydrogen 1 (1H) MR spectroscopy findings and to use functional MR imaging to explore the patterns of brain activation in men and women with Fabry disease (FD).

Materials and Methods: Eight men and eight women with FD (mean age, 38.8 years ± 13.9 [standard deviation]) with absent or mild neurologic deficit and 16 healthy control subjects (eight men and eight women; mean age, 42.7 years ± 15.3) gave informed consent to participate in the study, which was approved by the local ethical committee. Patients and control subjects underwent MR imaging, 1H MR spectroscopy of the frontal cortex and subcortical white matter, and functional MR imaging during repetitive flexion-extension of the last four fingers of the right hand. Extent of cerebral white matter damage was rated on fluid-attenuated inversion recovery MR images by using a visual score. Areas of activation were identified by using statistical parametric mapping software and the adoption of a height threshold of P < .001 (uncorrected) and an extent threshold of P < .05 (corrected).

Results: Men and women with FD showed a similar distribution of cerebral white matter changes, lacunar and cortical infarcts, small hemorrhages, and vertebrobasilar dolichoectasia. No significant (P > .05) difference was observed between patients with FD and control subjects for concentration of N-acetylaspartate, creatine, and choline. During the motor task, patients showed recruitment of additional cortical areas in comparison with control subjects. Increased activation of the contralateral sensorimotor area correlated (P = .002) with extent of white matter damage.

Conclusion: Subcortical ischemic changes in men and women with FD are similar and are associated with increased recruitment of the sensorimotor network during a simple motor task, which might limit the functional effect of the white matter small-vessel disease.

© RSNA, 2006


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Fabry disease (FD) is an inherited sex-linked disorder caused by deficiency of {alpha}-galactosidase A, with deposit of glycosphingolipids in the lysosomes of many cells, including those of the vascular endothelium (1). This storage causes progressive vasculopathy with renal, cardiac, and brain ischemia and infarction. The affected hemizygous male patients show a reduced level of {alpha}-galactosidase A activity, which, because of random X chromosomal inactivation, can be observed also in heterozygous female patients (1).

In young adult male subjects with FD, magnetic resonance (MR) imaging of the brain shows multiple lesions in the white or gray matter that are typical of a small-vessel disease (2). The lesions are frequently located in the territories of the vertebrobasilar arteries, which often appeared dilated and tortuous (dolichoectasia) (2,3). However, stroke and transient ischemic attack occur in a minority of male subjects with lesions at MR imaging (most lesions are asymptomatic) (2). Hyperintensity of the pulvinar on T1-weighted MR images, which is assumed to be due to calcifications, was reported as very common and pathognomonic in male subjects with FD (4,5). Also, hydrogen 1 (1H) MR spectroscopy, diffusion MR imaging, and perfusion MR imaging were performed almost exclusively in male subjects with FD (6–9). Female carriers of the FD mutation have disease-related morbidity and mortality similar to those of male carriers (10).

The purpose of our study was to prospectively compare brain MR imaging and 1H MR spectroscopy findings and to use functional MR imaging to explore the patterns of brain activation in men and women with FD.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Patients and Control Subjects
Sixteen consecutive right-handed patients with FD (mean age, 38.8 years ± 13.9 [standard deviation]) were referred to the neurologic clinic of our university (University of Florence); there were eight men (mean age, 34.7 years ± 10) and eight women (mean age, 42.8 years ± 16.6; nonsignificant age difference between male and female patients, P = .48 with the two-tailed Student t test). The patients gave informed consent to participate in the study, which was approved by the local ethical committee.

In all but one patient with FD, the diagnosis was supported by demonstration of decreased {alpha}-galactosidase A activity in fibroblasts or leukocytes. One woman with mutation of the {alpha}-galactosidase A gene had normal enzyme activity. Table 1 details the genetic and clinical findings in the patients. In particular, all women with FD were heterozygous for the gene mutation. Transient ischemic attacks or minor or major strokes had occurred in six patients (neurologically symptomatic patients with FD), whereas there was no history of neurologic disturbances in the other 10 patients (neurologically asymptomatic patients with FD). Because of renal insufficiency, three patients had received renal transplants. Seven patients (four neurologically asymptomatic and two neurologically symptomatic men, with a mean age of 34.6 years ± 11.8, and one neurologically symptomatic 48-year-old woman) were receiving intravenous enzyme replacement therapy.


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  		Table 1. Genetic and Clinical Findings in 16 Patients with FD

 
One neurologist with 25 years of clinical experience (W.B.) evaluated the severity of the neurologic deficit in patients with FD by using the Rankin scale, which has scores that range from 0 (absent) to 5 (maximal). Four patients (two men and two women) had a score of 1, and 12 patients had a score of 0.

To match the sex and handedness distribution of the patients, we recruited 16 healthy right-handed volunteers (mean age, 42.7 years ± 15.3) with no personal or familiar history of neurologic diseases who provided control data for MR imaging and functional MR imaging; there were eight men (mean age, 39.2 years ± 12.9) and eight women (mean age, 40.8 years ± 10.9; nonsignificant age difference between male and female volunteers, P = .6 with the two-tailed Student t test). None of the volunteers underwent genetic investigation for possible mutations typical of FD. Handedness was assessed with the Edinburgh inventory (11). There was no significant difference in age between the 16 patients with FD and the 16 control subjects (P = .47, with the two-tailed Student t test). In 13 of the healthy subjects (mean age, 37.4 years ± 12.1), semiquantitative and quantitative 1H MR spectroscopy control data were also obtained.

To avoid confounding factors in the evaluation of functional MR imaging results, the motor function of the right hand in patients and control subjects was assessed outside the magnet by determining the maximum finger-tapping frequency (12) for two 30-second trial periods, and the nearest 0.5 Hz was entered into the analysis. The maximum finger-tapping rate in each patient (Table 1) was not significantly different (P > .05) between patients with FD (mean, 2.4 Hz ± 0.3) and control subjects (mean, 2.5 Hz ± 0.2), between patients with FD with a history of neurologic disturbances (n = 6; mean, 2.2 Hz ± 0.4) and those without neurologic disturbances (n = 10; mean, 2.5 Hz ± 0.2), and, finally, between patients with FD with neurologic deficit (n = 4; mean, 2.5 Hz ± 0.3) and those without neurologic deficit (n = 12; mean, 2.3 Hz ± 0.3), as assessed with the two-tailed Student t test.

MR Examination
All examinations were performed by using a 1.5-T MR imager (Intera; Philips Medical Systems, Best, the Netherlands) with a gradient capability of 30 mT/m and equipped with a quadrature head coil.

MR imaging.—All 16 patients with FD and 16 control subjects were examined with a protocol that included scout imaging, transverse three-dimensional T1-weighted turbo gradient-echo imaging (25/4.6 [repetition time msec/echo time msec], flip angle of 30°, field of view of 256 mm, matrix size of 256 x 256, 160 contiguous sections, and section thickness of 1 mm), transverse T2-weighted fluid-attenuated inversion recovery (FLAIR) imaging (6000/100/2100 [repetition time msec/echo time msec/inversion time msec], field of view of 230 mm, matrix size of 256 x 256, 40 contiguous sections, and section thickness of 3 mm), and transverse T2*-weighted echo-planar imaging (1600/102, echo-planar imaging factor of 15, field of view of 230 mm, matrix size of 100 x 256, 20 contiguous sections, section thickness of 6 mm, and peripheral pulse gating).

1H MR spectroscopy.—All 16 patients with FD and 13 healthy control subjects underwent 1H MR spectroscopy. Three control subjects did not complete the 1H MR spectroscopy examination because of claustrophobia. We employed a single-voxel technique and an external phantom calibration method described elsewhere (13) for quantification of metabolite concentrations. Since we wanted to exclude changes secondary to large- and small-vessel disease, we placed the 2 x 2 x 2-cm (8-cm3) voxel for 1H MR spectroscopy in the normal-appearing frontal interhemispheric cortex and subcortical white matter. A point-resolved proton spectroscopy technique was used for acquisition of the proton spectrum, with a repetition time of 2000 msec, 128 measurements, and four different echo times (80, 136, 272, and 350 msec) in order to correct for possible changes in T2 relaxation time in determining the metabolite concentrations. The acquisition time for each spectrum was 4 minutes 56 seconds.

Functional MR imaging.—In all 16 patients with FD and in 16 healthy control subjects, functional MR imaging exploiting the blood oxygenation level–dependent effect was performed by employing a simple motor task (14). Five periods of activation, in which subjects were imaged while performing repetitive flexion-extension of the last four fingers of the right hand moving together, were alternated with six periods of rest. A T2*-weighted single-shot echo-planar imaging sequence (repetition time, 3.0 seconds; echo time, 50 msec; flip angle, 90°; matrix size, 128 x 128; and field of view, 256 x 256 mm) was employed. Twenty-four 5-mm-thick transverse sections parallel to the bicommissural plane were acquired during each measurement and covered the whole brain.

Data Analysis
MR imaging.—Brain changes in patients with FD and in control subjects were assessed by one observer (C.T., with 15 years of experience in brain MR imaging), who was blinded to the clinical, genetic, and other MR data. He rated cerebral white matter signal intensity changes on FLAIR images by using the scale (Table 2) proposed by Fazekas et al (15), which has a maximum score of 6 (ie, a maximum score of 3 for each of the two scales) and has shown a "very good" interobserver reproducibility in a prior study (16). Moreover, the observer noticed the presence and location of lacunar infarcts (cerebrospinal fluid–filled areas outlined by a border of high signal intensity on FLAIR images), infarcts (well-defined areas of high signal intensity on FLAIR images that correspond to an arterial vascular territory, combined or not with low-signal-intensity cerebrospinal fluid–like areas within, or dilation of the nearby cerebrospinal fluid spaces), and old hemorrhages (areas that exhibit low signal intensity on T2*-weighted echo-planar images). Pulvinar hyperintensity was assessed on T1-weighted gradient-echo images. Finally, the observer evaluated the vertebrobasilar arteries exhibiting flow-related enhancement on T1-weighted gradient-echo images for possible dolichoectasia.


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  		Table 2. Fazekas Scale for Cerebral White Matter Signal Intensity

 
Another operator (R.D.N., with 6 years of experience in brain MR imaging), who was blinded to clinical and other MR data, computed brain volumes normalized to head size on T1-weighted images by using structural image evaluation of normalized atrophy for single-time-point estimation, or SIENAX, an automated and accurate technique for brain segmentation (17).

1H MR spectroscopy.—One operator (L.G., with 6 years of experience in 1H MR spectroscopy), who was blinded to the other MR data processed, analyzed the 1H MR spectroscopy data. Semiquantitative evaluation was performed on the spectrum obtained with an echo time of 272 msec. Accordingly, after zero filling, exponential multiplication, Fourier transform, and manual phase correction, the areas of the peaks at 2.01, 3.00, and 3.20 ppm were assigned to N-acetylaspartate (NAA), creatine (Cr), and choline (Cho), and the NAA/Cr and Cho/Cr ratios were calculated. Possible presence of lactate peak at 1.3 ppm was recorded. Quantitative analysis was performed according to a previously reported procedure (13), with determination of T2 relaxation time and concentrations of NAA, Cr, and Cho.

Functional MR imaging.—Postprocessing was performed by one operator (C.G., with 4 years of experience in functional MR imaging) by using statistical parametric mapping software (SPM2; avaliable at www.fil.ion.ucl.ac.uk/spm), according to a previously reported procedure (14). This operator was blinded to the other MR data.

Prior to statistical analysis, all images were (a) realigned to the first image to correct for subject motion, (b) spatially normalized into the standard space of SPM2, and (c) smoothed with an 8-mm three-dimensional Gaussian filter.

T1-weighted images from each subject were coregistered with the corresponding functional MR imaging data sets and were normalized into the same standard space. Then, functional MR imaging results were superimposed onto these high-spatial-resolution images for the cluster-level analysis detailed in the next section.

Statistical Analysis
We used the Mann-Whitney U test to assess differences in the Fazekas scale score (FSS) and 1H MR spectroscopy data between patients and control subjects, between healthy men and men with FD, between healthy women and women with FD, between men and women with FD, between patients with FD with a history of neurologic disturbances and those without such a history, and, finally, between patients with FD with neurologic deficit and those without neurologic deficit. Significance was set at P < .05.

To assess whether the mild age difference between men and women with FD had a relevant influence on the 1H MR spectroscopy data, we calculated correlation coefficients between age and metabolite ratios and concentrations in the patients according to sex.

Changes in the blood oxygenation level–dependent contrast associated with the performance of the motor task were assessed on a pixel-by-pixel basis by using the general linear model (18) and the theory of Gaussian field (19). For each subject, specific effects were tested by applying appropriate linear contrast. Significant hemodynamic changes were assessed by using t statistical parametric maps. The intragroup (patients with FD and healthy subjects) activations and the comparison of the activations between groups (patients with FD vs healthy control subjects) were investigated by using random-effects analysis (20). Intragroup activations were assessed by using a one-sample t test. Intergroup comparisons were performed by using a two-sample t test. Clusters of voxels on resulting z statistical images with a height threshold of P < .001 (uncorrected) and an extent threshold of P < .05 (corrected) were considered significant.

By using a cluster-level inference on a patient-by-patient basis (21), we evaluated the spatial extent and the coordinates of the centers of activation of brain areas with significantly different relative activations at group analysis. Differences in these functional MR imaging metrics between patients and control subjects and between male and female patients were assessed by using a two-tailed Student t test for nonpaired data.

To explore the correlation between functional MR imaging findings and structural findings, only functional MR imaging data from areas with significantly different relative activations at group analysis were considered. To assess the correlation of blood oxygenation level–dependent changes with T2 lesion extent on FLAIR images, the FSS was entered into the statistical parametric mapping design matrix by using basic models and linear regression analysis (20). We also investigated the correlation between FSS and the relative signal intensity changes of those areas with significantly increased activations at group analysis by using the Spearman rank correlation coefficient.

All the statistical analyses were performed with statistical software (Statistica, version 6; Statsoft, Tulsa, Okla).

Results were displayed by using the neurologic convention whereby the right side of the image is on the right of the observer.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
MR Imaging
No lesions were detected on the FLAIR images of the healthy volunteers (mean FSS, 0). All but one of the patients with FD had an FSS greater than 0 (Fig 1, Table 3). The mean FSS in patients with FD was significantly higher than that in healthy control subjects when considered as a whole (mean, 2.18 ± 1.7, P < .001) and when separated by sex (men with FD: mean, 2.3 ± 1.6 [95% confidence interval: 1.21, 3.53], P < .001; women with FD: mean, 2.2 ± 2.1 [95% confidence interval: 0.74, 3.65], P = .002). The FSS was not significantly different (P = .89) between male and female patients. The FSS in the six patients with a history of neurologic disturbances (mean, 3.5 ± 1.7) was higher (P = .04) than that in the 10 patients without such a history (mean, 1.6 ± 1.5), whereas the FSS in the four patients with neurologic deficit (mean, 3.2 ± 2.2) was not significantly different from that in the 12 patients without neurologic deficit (mean, 2.0 ± 1.7) (P = .2). The correlation between maximum finger-tapping rate and FSS was not significant (r = –0.4; P = .08).


Figure 1
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  		Figure 1: Transverse FLAIR MR (6000/100/2100) images in patients with FD show examples of varying extent of white matter changes (leukoaraiosis, increased signal intensity) according to the FSS, with a score of 2 in a 36-year-old man (left), a score of 5 in a 52-year-old man (middle), and a score of 6 in a 57-year-old woman (right).

 

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  		Table 3. Findings at MR Imaging in 16 Patients with FD

 
Eight patients (two men and six women) showed lacunar infarcts. Pontine infarcts in the territory of the perforating arteries were observed in one male and one female patient. The former also showed a cerebellar infarct. Three tiny old hemorrhages were seen in two patients (two hemorrhages in the thalami and one in the cerebellum). Hyperintensity of the right pulvinar on T1-weighted images was observed in a 36-year-old man with FD (not shown). Vertebrobasilar dolichoectasia was present in two men and one woman with FD.

No significant difference was observed for the normalized brain volume between men with FD (1327 mL ± 96 [95% confidence interval: 1260, 1393]), women with FD (1390 mL ± 67 [95% confidence interval: 1343, 1436]), male control subjects (1353 mL ± 105 [95% confidence interval: 1284, 1421]), and female control subjects (1395 mL ± 82 [95% confidence interval: 1341, 1448]).

1H MR Spectroscopy
No significant difference was observed for NAA/Cr and Cho/Cr ratios, T2 relaxation times, or concentrations of NAA, Cr, and Cho between patients with FD and healthy control subjects (Fig 2, Table 4). Also, no difference was observed between healthy men and men with FD, between healthy women and women with FD, between men and women with FD, between patients with a history of neurologic disturbances and those without, and, finally, between patients with neurologic deficit and those without (data not shown).


Figure 2
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  		Figure 2a: (a) Transverse FLAIR MR (6000/100/2100) image shows location of the 2 x 2 x 2-cm voxel (box) in the frontal interhemispheric regions for 1H MR spectroscopy. (b) Example of proton spectrum obtained with a point-resolved proton spectroscopy technique (2000/272) in a patient with FD shows lack of overt abnormalities.

 

Figure 2
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  		Figure 2b: (a) Transverse FLAIR MR (6000/100/2100) image shows location of the 2 x 2 x 2-cm voxel (box) in the frontal interhemispheric regions for 1H MR spectroscopy. (b) Example of proton spectrum obtained with a point-resolved proton spectroscopy technique (2000/272) in a patient with FD shows lack of overt abnormalities.

 

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  		Table 4. Mean Metabolite Ratios, Metabolite Concentrations, and T2 Relaxation Times in Patients with FD and Healthy Volunteers

 
No significant correlation was observed between age and metabolite ratios and concentrations in men or women with FD.

No lactate peak was present in patients or control subjects.

Functional MR Imaging
Intragroup analysis demonstrated a similar pattern of cortical activation of several supra- and infratentorial structures in healthy volunteers and patients with FD (data not shown). Intergroup analysis revealed that compared with healthy subjects, patients with FD showed increased activation of the primary sensorimotor cortex, bilaterally (ipsilateral statistical parametric mapping space coordinates: 26, –38, 50, with cluster extent = 324 and Z = 4.02; contralateral statistical parametric mapping space coordinates: –28, –42, 48, with cluster extent = 77 and Z = 3.68); the contralateral intraparietal sulcus (coordinates: –28, –48, 34, with cluster extent = 15 and Z = 3.68); the cingulated motor area, bilaterally (ipsilateral coordinates: 8, –4, 46, with cluster extent = 73 and Z = 3, 58; contralateral coordinates: –10, –22, 54, with cluster extent = 8 and Z = 3.59); and the contralateral secondary motor area (coordinates: –56, –40, 34, with cluster extent = 9 and Z = 3.34) (Figs 3 and 4). At cluster-level analysis, no significant differences between groups were found in the spatial extent or in the coordinates of the center of activation of these brain areas. There were no areas where patients with FD showed significantly less activation than control subjects.


Figure 3
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  		Figure 3a: (a) Sagittal, (b) coronal, and (c) transverse projections of the t value maps related to "patients with FD versus healthy control subjects" during repetitive flexion-extension of the last four fingers of the right hand. Dark areas represent clusters of voxels of significantly increased activations in patients, with a height threshold of P < .001 (uncorrected) and an extent threshold of P < .05 (corrected).

 

Figure 3
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  		Figure 3b: (a) Sagittal, (b) coronal, and (c) transverse projections of the t value maps related to "patients with FD versus healthy control subjects" during repetitive flexion-extension of the last four fingers of the right hand. Dark areas represent clusters of voxels of significantly increased activations in patients, with a height threshold of P < .001 (uncorrected) and an extent threshold of P < .05 (corrected).

 

Figure 3
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  		Figure 3c: (a) Sagittal, (b) coronal, and (c) transverse projections of the t value maps related to "patients with FD versus healthy control subjects" during repetitive flexion-extension of the last four fingers of the right hand. Dark areas represent clusters of voxels of significantly increased activations in patients, with a height threshold of P < .001 (uncorrected) and an extent threshold of P < .05 (corrected).

 

Figure 4
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  		Figure 4: Statistical parametric maps color-coded for t values superimposed on high-spatial-resolution, A, B, transverse and, C, D, sagittal T1-weighted (25/4.6, flip angle of 30°) turbo gradient-echo MR images show areas of increased cortical activations in patients with FD in comparison with healthy control subjects during a simple motor task of the right hand. Images show primary sensorimotor cortex, bilaterally (A); contralateral intraparietal sulcus (B); contralateral (A, C) and ipsilateral (A) cingulated motor area; and contralateral secondary motor area (D).

 
In patients, a significant correlation (R = 0.70, P = .002) was found between increased activation in the contralateral sensorimotor cortex and FSS (Fig 5). The correlation between other areas of increased activation and FSS were not significant: ipsilateral cingulated motor area, R = 0.01, P = .9; contralateral cingulated motor area, R = –0.16, P = .5; contralateral secondary motor area, R = –0.21, P = .4; and ipsilateral sensorimotor cortex, R = –0.3, P = .89.


Figure 5
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  		Figure 5: Graph shows correlation in patients with FD between increased activation of the contralateral primary sensorimotor cortex (SMC) during finger tapping of the right hand and extent of cerebral white matter changes evaluated with the FSS.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 References
 
Renal, cardiac, and cerebrovascular complications predispose patients with FD to early death in comparison with the general population (22,23). Availability of laboratory assays (1) and molecular genetic tests to detect mutations of the gene encoding for the {alpha}-galactosidase A enzyme (24) have considerably enhanced the capability to make an early diagnosis in asymptomatic individuals. This is clinically relevant especially in view of the enzyme replacement therapy, which is expected to slow the storage of the toxic metabolites and was reported to reverse increased urine protein excretion rate and to stabilize the renal function (25).

Female subjects can develop the clinical features of FD even though this usually occurs at an older age than for male subjects (10,23,26). The brain changes we observed on MR images in men with FD are consistent with results in prior reports (2,3). At variance with prior reports, which dealt with single cases of female subjects with FD (3,8,27), we used MR to examine a series of women with FD. The lack of substantial differences in MR imaging findings between men and women in our study confirms that women should not be viewed as simply carriers of the FD gene (10) and suggests that they could be enrolled in prospective trials investigating treatments for brain changes associated with this disease. The rarity of the pulvinar T1 hyperintensity in our series was unexpected and can be attributed to mildness of the central nervous system involvement in our patients, reflected in their absent or mild clinical impairment.

By using a multivoxel 1H MR spectroscopy technique, a diffuse decrease in the NAA/Cr and NAA/Cho ratios was reported in the cerebral cortex and centrum semiovalis in neurologically asymptomatic male patients with FD (6) and was assumed to reflect the intraneuronal storage of glycosphingolipids. On the other hand, a decrease in the NAA/Cr ratio was observed in only one of five subjects with FD examined with a single voxel placed in the normal-appearing periventricular white matter (8). 1H MR spectroscopy changes were reported in the normal-appearing white matter of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (28), an inherited condition that shares with FD the involvement of cerebral small vessels (29). Since we wanted to exclude changes secondary to large- and small-vessel disease, to further explore the spectroscopic features of FD we performed a single-voxel 1H MR spectroscopy study of the normal-appearing frontal interhemispheric cortex and subcortical white matter. We did not observe any 1H MR spectroscopy change in patients with FD versus control subjects. Our data are in line with the neuropathologic observation that intraneuronal deposits of glycosphingolipids are not ubiquitous in the brain of patients with FD and with the view that their clinical significance remains to be defined (30).

Functional MR imaging is a noninvasive technique to investigate cortical brain activations in healthy subjects and patients with diffuse diseases of the central nervous system, such as multiple sclerosis (31).

Like CADASIL and other rarer conditions, FD is an inherited disease caused by accumulation in the cerebral vessels of a toxic metabolite that leads to brain ischemia and infarct (29). In patients with FD, there is a dissociation between the severity of MR imaging changes and clinical findings (2). To evaluate the possible occurrence of modifications of the brain activation pattern in patients with FD, we used functional MR imaging to investigate men and women with absent or mild neurologic impairment. In our patients with FD, we observed an abnormal pattern of activation for a simple motor task with recruitment of the same rather distributed sensorimotor network, including the primary sensorimotor cortex, the intraparietal sulcus, the cingulated motor area, and the secondary motor area, which, by using the same motor task, was activated in patients with nondisabling multiple sclerosis (14). Similar ipsilateral and contralateral motor activations were also reported in patients with CADASIL in performing a simple hand-tapping task (32).

One may speculate on the significance of the activation of this sensorimotor network in FD.

Since, for at least one area (contralateral sensorimotor cortex), a correlation was present between the functional change and the extent of the white matter signal intensity change on MR images, we submit that, as proposed for nondisabling multiple sclerosis (14) and CADASIL (32), the increased activation in the cortical sensorimotor network might have a possible adaptive role in limiting the clinical effect of white matter small-vessel disease in male and female patients with FD.

We recognize limitations of our study. First, our control subjects were not genotyped for FD. However, because of the rarity of the relevant mutations, it is unlikely that one or more of the control subjects is an asymptomatic carrier. Second, we did not evaluate possible effects of hypertension and renal insufficiency, which are frequent comorbidities that can potentially cause brain changes in these patients. Third, a minority of our patients were examined while undergoing enzyme replacement therapy, which may modify the MR findings. However, all of them have started therapy recently, and preliminary data indicate that a 12-month course of enzyme replacement therapy does not prevent progression of cerebral white matter MR signal intensity changes (8).

In conclusion, results of our investigation indicate that subcortical white matter damage due to small-vessel disease is similar in men and women with FD and is associated with modification of the cortical activation pattern during a simple motor task.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
References
 


   FOOTNOTES
 

Abbreviations: CADASIL = cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy • Cho = choline • Cr = creatine • FD = Fabry disease • FLAIR = fluid-attenuated inversion recovery • FSS = Fazekas scale score • NAA = N-acetylaspartate

Authors stated no financial relationship to disclose.

Author contributions: Guarantors of integrity of entire study, N.V., M.M; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, S.B.; clinical studies, C.G., W.B., L.G., R.D.N., M.A.R., C.T., S.B., G.B.; statistical analysis, C.G., R.D.N., M.A.R., G.B.; and manuscript editing, M.F., M.M.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 

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