Parkinsonism and Related Disorders xxx (2015) 1e5

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Changes of cerebral white matter in patients suffering from Pantothenate Kinase-Associated Neurodegeneration (PKAN): A diffusion tensor imaging (DTI) study P. Stoeter a, *, P. Roa-Sanchez b, H. Speckter a, E. Perez-Then c, B. Foerster d, C. Vilchez a, J. Oviedo a, R. Rodriguez-Raecke e a

Dep. of Radiology, Santo Domingo, Dominican Republic Dep. of Neurology, Santo Domingo, Dominican Republic Dep. of Medical Science, CEDIMAT, Santo Domingo, Dominican Republic d Philips Medical Systems LatAm, Sao Paulo, Brazil e Dep. of Neuroradiology, University Clinic RWTH Aachen, Germany b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 3 November 2014 Received in revised form 24 February 2015 Accepted 8 March 2015

Background: To look for microstructural white matter alterations in patients with dystonia due to Pantothenate Kinase-Associated Neurodegeneration. Material and methods: We examined 21 genetically confirmed patients and an age-matched group of 21 healthy controls by diffusion tensor imaging. Evaluation of data was performed by tract-based spatial statistics analysis and a voxel-wise comparison of calculated maps of fractional anisotropy. Findings were compared between groups and correlated to the dystonia score of the Burke-Fahn-Marsden Scale (p  0.05). Results: Patients showed reductions of fractional anisotropy mainly in the periventricular substance surrounding the third ventricle, in the medial part of both putamina and in the frontal white matter including the anterior limbs of the internal capsules and the corpus callosum. Infratentorially, the cerebellar white matter and dorsal parts of the pons and medulla were affected. Conclusion: In addition to cortical grey matter changes, we now have a second structural finding pointing to a more widespread affection of cerebral tissue in PKAN dystonia than just the lesion and iron accumulation in the globus pallidus. © 2015 Published by Elsevier Ltd.

Keywords: Pantothenate Kinase-Associated Neurodegeneration Diffusion tensor imaging White matter tracts

1. Introduction Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a secondary dystonia due to a known mutation of the PANK2 gene and a known metabolic defect causing the typical lesion in the internal pallidum [1]. The clinical expression is characterized by an early (during childhood) or late onset (during the teens or later), a generalized dystonia with a variable clinical picture, and cognitive decline and degenerative retinopathy in some cases. The hallmark of PKAN, the lesion and iron accumulation in the Globus pallidus is well-known in the Magnetic Resonance Imaging (MRI) literature as the ”eye-of-the-tiger” sign [2,3] showing increased relaxivity and,

* Corresponding author. Dep. de Radiología, CEDIMAT, Plaza de la Salud, Santo Domingo, Dominican Republic. Tel.: þ1 809 565 9989, þ1 829 343 6544 (mobile). E-mail address: [email protected] (P. Stoeter).

probably because of local inhomogeneities of the magnetic field, also an important increase in fractional anisotropy (FA) [4]. However, MRI reports about of structural abnormalities of gray and white matter in this condition outside the basal ganglia are rare. Recently, our group described some age-related grey matter changes of the mid-frontal cortex [5], which could represent a compensatory process to counterbalance the increased activity of the motor system in these patients [6]. The present study is aimed to look for white matter alterations that might accompany these findings. Here we report the results of Diffusion Tensor Imaging (DTI), a method which is generally accepted to allow assessment of white matter integrity [7,8], performed in a group of PKAN patients from the Dominican Republic. 2. Patients and methods The study had been approved by the national ethics committee, and informed consent was given by every individual who entered into the study.

http://dx.doi.org/10.1016/j.parkreldis.2015.03.009 1353-8020/© 2015 Published by Elsevier Ltd.

Please cite this article in press as: Stoeter P, et al., Changes of cerebral white matter in patients suffering from Pantothenate Kinase-Associated Neurodegeneration (PKAN): A diffusion tensor imaging (DTI) study, Parkinsonism and Related Disorders (2015), http://dx.doi.org/10.1016/ j.parkreldis.2015.03.009

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P. Stoeter et al. / Parkinsonism and Related Disorders xxx (2015) 1e5

3. Results

2.1. Patients and controls In the Dominican Republic lives a group of more than 30 individuals suffering from PKAN which is unique worldwide because all present an identical missense mutation of the PANK2 gene (c.680A > G, p.Y227C). In spite of their homogeneous mutation, which probably is due to a founder effect, the clinical expression of dystonia was different as well as their cognitive decline, which was obvious in some patients only and as a whole, appeared to be less severe than has been reported in other groups of PKAN patients. In most of these patients, the onset of clinical expression was between 8 and 12 years of age. We included all members of this group, where we were able to collect DTI data of sufficient quality to allow for postprocessing as described below, including a 7 year old “preclinical” female, who was scanned as an asymptomatic family member, but showed the typical eye-ofthe-tiger sign and a homogenous mutation of her PANK2 genes. Altogether, 21 persons (16 females and 5 males, mean age 19.0 years) entered into this group of symptomatic and asymptomatic “patients”, who were examined neurologically including video and scoring of the Burke-Fahn-Marsden scale. The mean age of onset was 10.7 years, the mean duration of symptoms 8.2 years and the mean dystonia score 17.6 points. 21 healthy individuals from the general population of Santo Domingo were scanned as age- and gender-matched controls.

2.2. MRI All examinations were performed on a 3 T scanner (Achieva, Philips/ Netherlands, Release 2.6), using an 8 channel SENSE receiver head coil. In addition to T2-, T2*- and 3d T1-weighted images, we measured DTI data by application of a spin echo based sequence: TR/TE ¼ 6542/70 ms, flip angle 90 , 32 gradient directions, b ¼ 0 and 800 s/mm2, measured voxel size 2  2  2 mm, 60 slices covering the whole head, SENSE factor 2, scanning time 4.5 min.

2.3. Postprocessing Using FMRIB Software Library (FSL), we performed eddy current correction and automatic brain extraction and computed Fractional Anisotropy (FA) maps from all subjects. For tract-based spatial statistics (tbss) analysis, these maps were aligned into a common space by non-linear registration and a mean group FA image was created. From this image, a mean FA skeleton was extracted and individual subject's data were projected onto this skeleton. Difference between groups was calculated by unpaired t-test and correlation to grade of dystonia was calculated from the 21 patients only, both adjusted for age, by applying the threshold-free cluster enhancement option (tfce) in the randomize permutation testing tool of FSL. White matter tracts were identified using the white matter atlas contained in FSL. For voxel-wise comparison, we decomposed the mean group image into aligned individual FA maps (DICOM2NII) and performed further postprocessing by the program Statistical Parametric Mapping (SPM, 2nd level): again unpaired t-test between groups and correlation to dystonia grade in the patients' group, both adjusted for age. The level of significance was set to p  0.05 (uncorrected) for the FA skeleton evaluation and to 0.01 for the voxel-based evaluation. These thresholds were chosen to demonstrate the statistically relevant differences of this special rare group of patients and volunteers. However, after FWE correction, the differences were no longer significant. In the same way, maps of Mean Diffusivity (MD), Longitudinal Diffusivity (LD) and Radial Diffusivity (RD) were calculated.

In the patients' group, group comparison of the fiber tract skeletons as extracted by tbss, showed a wide-spread reduction of FA of subcortical white matter tracts, mainly in the frontal lobes and in the cerebellum (t-test, p  0.05), and in general, the FA reduction correlated to the degree of dystonia (p  0.05). The voxel-wise comparison of FA maps showed similar, although less widespread results (p  0.01) (Table 1, Fig. 1). There was no positive or negative correlation of the FA maps to patients' age. An increase of patients' FA values was seen only in the anterior parts of both globi pallidi, and just few of these voxels correlated positively to the degree of dystonia (Table 2). The biggest cluster of voxels showing an FA reduction in patients as compared to volunteers was localized in the periventricular area around the third ventricle bilaterally (“substantia periventriculare“ according to the Schaltenbrand atlas). In the tbss maps, the area of reduction was more confined and localized in the anterior part of the stratum periventriculare behind the foramen of Monroi and roughly in the middle between the floor and roof of this ventricle, whereas the in the FA maps of voxel-wise comparison, it reached a bit more upwards. But only few of these voxels correlated significantly to the degree of dystonia. The second largest area with a significant reduction of FA in the group comparison and a strong negative correlation to the degree of dystonia was localized in the medial part of both putamina, just touching the lateral border of the internal capsule. However, there was no similar finding in the tbss-extracted FA skeletons. In three other areas of the anterior parts of the hemispheres, we saw as well reductions in the FA skeletons as in the voxelwise FA maps: the anterior limbs of the internal capsule, the anterior part of the corpus callosum and the white matter of both frontal lobes, mainly their middle and inferior parts including the subcortical fibers of the left anterior cingular cortex. In the cerebellum, the lateral and inferior-medial areas of the white matter showed a significant reduction of FA in the group comparison in the tbss extraction and voxelwise comparison, with negative correlation to the degree of dystonia mainly of the inferior fibers. We also saw some important FA reduction in the dorsal part of the medulla oblangata with both methods of evaluation, but without correlation to the degree of dystonia, and in the dorsal part of the pons, just underneath the floor of the fourth ventricle, with negative correlation to the dystonia scale, but here in the tbssextracted fiber skeletons only.

Table 1 Difference of FA values between groups (controls > patients, t-test, p  0.01) and correlation of FA values to dystonia score in patients (multiple regression analysis, p  0.01). Localization, T-value and size of clusters. Anatomical structure

Paraventric. fibers (III) bilat PaePu L PaePu R Ant. caps. int. L Ant. caps. int. R Front. CC (bilateral) WM front L WM front R Lat. cerebellum L Lat. cerebellum R Med. cerebellum/vermis L Med. cerebellum/vermis R Dorsal pons/medulla

Comp. between groups (C > P, t-test, p < 0.01)

Negative correlation to dystonia (multiple regression anal., p < 0.01)

x

y

z

T Max

Cluster

x

y

z

T Max

Cluster

2 24 24 11 14 9 23 17 42 34 7 17 12

8 11 8 13 10 33 32 47 56 55 60 60 49

6 0 4 5 6 8 1 8 35 38 40 34 50

7.3 8.0 7.9 5.5 6.8 4.7 4.0 4.2 5.2 6.0 4.7 6.7 5.7

2670 2321 2308 231 284 135 203 658 2117 1439 1138 453 861

2 35 20 10 15 9 21 23 43 30 16 18 5

14 9 8 10 13 20 41 49 59 42 72 73 32

4 5 1 2 5 16 5 5 27 34 41 41 48

4.2 5.4 5.2 6.4 5.0 5.3 3.6 4.4 5.7 4.1 4.8 5.1 4.1

55 852 390 483 101 535 185 223 467 85 180 257 62

Please cite this article in press as: Stoeter P, et al., Changes of cerebral white matter in patients suffering from Pantothenate Kinase-Associated Neurodegeneration (PKAN): A diffusion tensor imaging (DTI) study, Parkinsonism and Related Disorders (2015), http://dx.doi.org/10.1016/ j.parkreldis.2015.03.009

P. Stoeter et al. / Parkinsonism and Related Disorders xxx (2015) 1e5

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Fig. 1. Results of tbss analysis (p  0.05, a-d and i-l) and of voxel-wise analysis of FA maps (p  0.01, e-h and m-p) of comparison between groups (t-test) of patients and controls (supratentorial: a, b and e, f; infratentorial: i, j and m, n) and of correlation between FA values and dystonia score of corresponding areas in patients (supratentorial: c, d and g, h; infratentorial: k, l and o, p). Deviations above the indicated thresholds are displayed in red/yellow. For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.

The decrease of FA values was paralleled by an increase in MD, mainly in the supratentorial areas (internal capsule and frontal white matter). According to the two other diffusion parameters, RD was more affected than LD (Esupp Figs. 1e3). 4. Discussion The finding of a wide-spread reduction of FA values in PKAN patients is not surprising because this is a general finding in neurodegenerative diseases as well as in various types of dystonia [9]. In PKAN and other varieties of Neurodegeneration with Brain Iron Accumulation (NBIA) however, an increase in FA values has been reported confined to the globus pallidus [4,10,11]. Because of the massive disturbance of field homogeneity in this area due to the accumulation of iron (the “eye of the tiger“-sign), this increase might be regarded as an artifact [12,13]. In this report, it is not further discussed as a finding representing true structural changes, and this means that we unfortunately cannot present reliable results about fiber alterations within the globus pallidus, where the lesions caused by the metabolic deficiencies specific to PKAN, are supposed to start [14]. Apart from the more general reduction of white matter FA values as mentioned above, there are some areas which were specifically affected. The largest cluster showing significantly

reduced FA values as compared to the controls, was localized in the anterior portion of the paraventricular substance. In the extracted skeletons, the region of significant deviation is confined to a smaller area midway between the roof and floor of the third ventricle and does not extend down to the corpora mamillaria. If one tries to attribute these fibers to a major tract, which of course remains speculative, we would prefer to attribute them to the inferior thalamic peduncle and not to the mamillo-thalamic tract because of their more anterior localization. This tract contains fibers connecting the thalamus and the orbito-frontal, insular and temporal cortices as well as amygdalo-thalamic fibers [15,16]. In structural connectivity maps, the periventricular area connects mainly to the anterior cingular cortex [17], a structure which in adult patients is negatively correlated to the degree of dystonia [5]. The second largest cluster where the FA values were reduced significantly as compared to controls, was the medial part of the putamen and the outer border of the internal capsule. These areas were not included in the extracted fiber skeletons and only showed up in the voxelwise group comparison maps. Because of the strong efferent connections of the putamen to the globus pallidus, an early lesion in the latter could be responsible for this FA reduction, although - as in the case of the periventricular fibers e we did not see a (negative) correlation to the severity of the clinical symptoms. One might speculate if the structural alterations seen in both areas

Please cite this article in press as: Stoeter P, et al., Changes of cerebral white matter in patients suffering from Pantothenate Kinase-Associated Neurodegeneration (PKAN): A diffusion tensor imaging (DTI) study, Parkinsonism and Related Disorders (2015), http://dx.doi.org/10.1016/ j.parkreldis.2015.03.009

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P. Stoeter et al. / Parkinsonism and Related Disorders xxx (2015) 1e5

Table 2 Difference of FA values between groups (patients > controls, t-test, p  0.01) and correlation of FA values to dystonia score in patients (multiple regression analysis, p  0.01). Localization, T-value and size of clusters. Anatomical structure

Globus pallidus L Globus pallidus R

Comp. of groups (P > C, t-test, p < 0.01)

Pos. corr. to dystonia (mult.regression anal., p < 0.01)

x

y

z

T Max

Cluster

x

y

z

T Max

Cluster

18 17

7 5

3 1

8.4 10.0

1426 1766

21 19

14 4

1 3

4.0 3.54

28 10

are related to the clinical expression of the disease at all. At least, they probably do not contribute much to the progression of the symptoms. This was different in the fibers of the anterior portion of the internal capsule, the anterior part of the corpus callosum and the frontal white matter. All three regions showed significant differences between groups and negative correlations to the degree of dystonia in both methods of evaluation. As far as the internal capsule is concerned, we could replicate ROI-based results reported previously from a subgroup of our patients [12]. However, in contrast to the density reduction of frontal grey matter [5], there was no significant correlation of these structural white matter changes to age. Wide-spread reductions of FA values in the lateral and inferior parts of the cerebellum and the dorsal parts of the pons and medulla oblongata were seen in the group comparison of extracted fiber skeletons and the voxelwise comparison of FA maps, but their correlation to the clinical picture was not as strong as with the frontal white matter alterations. Some correlation between the reduction of cerebellar grey matter density and the dystonia score has been reported previously [5] so that these infratentorial findings were not completely unexpected. Previously, involvement of the dentate nuclei has been described in PKAN in terms of hypointensities suggesting accumulation of iron [18,19], a mild cerebellar atrophy without further specification [14] and a reduction of the cerebral blood flow in the pons around the fourth ventricle and in the cerebellar vermis [20,21]. Because the increase in MD, which paralleled the decrease of FA, was mainly accompanied by an increase in RD and not to the same extent by a reduction of LD, these changes might more be related to alterations of myelination than to axonal damage [22,23]. Reduced levels of certain sphingomyelin species, which are the principal component of the myelin sheath, have been recorded in PKAN patients [24]. One major drawback of the study is the lack of significant differences after FWE correction, which is probably due to the limited number of subjects included. But due to the rareness of the disease and the difficulties to record MR data without movement artifacts in some cases, we were not able to increase the number of participants. Although in PKAN the primary lesion without doubt is localized in the pallidum and reduced pallidal output is seen as a key factor as well in primary dystonia as DTY1 [25], a more generalized network model assumes that alterations of cerebello-thalamicocortical pathways may also play a role [26]. In fact, a reduced integrity of the thalamic-prefrontal connections [27] and of the cerebello-thalamico-cortical tracts have been demonstrated, the latter correlating with increased motor responses in nonmanifesting mutation carriers [28]. Metabolic changes (increases as well as reductions) have been shown in the cerebellum of DTY1and DTY6-carriers, and in the former case, were interpreted as a compensation of the impairment of frontal-striatal connectivity in DTY1 gene carriers [29]. Our findings of a reduced white matter integrity affecting mainly the connections between the basal ganglia and the frontal regions as well as the involvement of the cerebellar white matter

fits well into this network pattern of dystonic movements “suggesting defects in neural inhibitory processes, sensimotor integration, and maladaptive plasticity“ [30]. 5. Conclusion A similar constellation as in primary dystonia e impairment of frontal and cerebellar white matter tracts e is seen in the present study in PKAN patients. In addition to the reduction of frontal and to a lesser degree also cerebellar grey matter density as described by our group previously, we now present a second structural finding pointing to a more widespread affection of cerebral tissue in PKAN dystonia than just the lesion and iron accumulation in the globus pallidus. However, in contrast to grey matter, the white matter alterations showed no progression with age, and thus we cannot be sure if we are dealing with primary or with secondary and more adaptive or compensatory changes. In future, a combined evaluation of structural and functional connectivity might tell us more about this network and its alterations in specific conditions. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.parkreldis.2015.03.009. References [1] Hayflick SJ, Westaway SK, Levinson B, Zhou B, Johnson MA, Ching KH, et al. Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. N Engl J Med 2003;348:33e40. [2] Gregory A, Hayflick SJ. Neurodegeneration with brain iron accumulation. Folia Neuropathol 2005;43:286e96. [3] Fermin-Delgado R, Roa-Sanchez P, Speckter H, Perez-Then E, Rivera-Mejia D, Foerster B, et al. Involvement of globus pallidus and midbrain nuclei in pantothenate kinase-associated neurodegeneration : measurement of T2 and T2* time. Clin Neuroradiol 2013;23:11e5. [4] Awasthi R, Gupta RK, Trivedi R, Singh JK, Paliwal VK, Rathore RK. Diffusion tensor MR imaging in children with pantothenate kinase-associated neurodegeneration with brain iron accumulation and their siblings. AJNR Am J Neuroradiol 2010;31:442e7. [5] Rodriguez-Raecke R, Roa-Sanchez P, Speckter H, Perez-Then E, Oviedo J, Stoeter P. Grey matter alterations in patients with Pantothenate KinaseAssociated Neurodegeneration (PKAN). Park Relat Disord 2014;20:975e9. [6] Stoeter P, Rodriguez-Raecke R, Vilchez C, Perez-Then E, Speckter H, Oviedo J, et al. Motor activation in patients with pantothenate kinase-associated neurodegeneration: a functional magnetic resonance imaging study. Park Relat Disord 2012;18:1007e10. [7] Assaf Y, Pasternak O. Diffusion tensor imaging (DTI)-based white matter mapping in brain research: a review. J Mol Neurosci 2008;34:51e61. [8] Chanraud S, Zahr N, Sullivan EV, Pfefferbaum A. MR diffusion tensor imaging: a window into white matter integrity of the working brain. Neuropsychol Rev 2010;20:209e25. [9] Ramdhani RA, Simonyan K. Primary dystonia: conceptualizing the disorder through a structural brain imaging lens. Tremor Other Hyperkinet Mov (N Y) 2014 Jan;8(4). http://dx.doi.org/10.7916/D8MG7MFC. pii: tre-04-213-4821-1. [eCollection 2014 Jan 8]. [10] Shah SO, Mehta H, Fekete R. Late-onset neurodegeneration with brain iron accumulation with diffusion tensor magnetic resonance imaging. Case Rep Neurol 2012;4:216e23. [11] Kimura Y, Sato N, Sugai K, Maruyama S, Ota M, Kamiya K, et al. MRI, MR spectroscopy, and diffusion tensor imaging findings in patient with static encephalopathy of childhood with neurodegeneration in adulthood (SENDA). Brain Dev 2013;35:458e61. [12] Delgado RF, Sanchez PR, Speckter H, Then EP, Jimenez R, Oviedo J, et al. Missense PANK2 mutation without “Eye of the tiger” sign: MR findings in a

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Please cite this article in press as: Stoeter P, et al., Changes of cerebral white matter in patients suffering from Pantothenate Kinase-Associated Neurodegeneration (PKAN): A diffusion tensor imaging (DTI) study, Parkinsonism and Related Disorders (2015), http://dx.doi.org/10.1016/ j.parkreldis.2015.03.009

Changes of cerebral white matter in patients suffering from Pantothenate Kinase-Associated Neurodegeneration (PKAN): A diffusion tensor imaging (DTI) study.

To look for microstructural white matter alterations in patients with dystonia due to Pantothenate Kinase-Associated Neurodegeneration...
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