Parkinsonism and Related Disorders 20 (2014) 975e979
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Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Grey matter alterations in patients with Pantothenate Kinase-Associated Neurodegeneration (PKAN) Rea Rodriguez-Raecke a, Pedro Roa-Sanchez b, Herwin Speckter c, Rafael Fermin-Delgado c, Eddy Perez-Then d, Jairo Oviedo c, Peter Stoeter c, * a
Department of Neurology, Medizinische Hochschule, Hannover, Germany Department of Neurology, CEDIMAT, Santo Domingo, República Dominicana Department of Radiology, CEDIMAT, Santo Domingo, República Dominicana d Department of Research, CEDIMAT, Santo Domingo, República Dominicana b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 28 February 2014 Received in revised form 5 May 2014 Accepted 7 June 2014
Background: Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a rare heritable disease marked by dystonia and loss of movement control. In contrast to the well-known “Eye-of-the-Tiger” sign affecting the globus pallidus, little is known about other deviations of brain morphology, especially about grey matter changes. Methods: We investigated 29 patients with PKAN and 29 age-matched healthy controls using Magnet Resonance Imaging and Voxel-Based Morphometry. Results: As compared to controls, children with PKAN showed increased grey matter density in the putamen and nucleus caudatus and adults with PKAN showed increased grey matter density in the ventral part of the anterior cingulate cortex. A multiple regression analysis with dystonia score as predictor showed grey matter reduction in the cerebellum, posterior cingulate cortex, superior parietal lobule, pars triangularis and small frontal and temporal areas and an analysis with age as predictor showed grey matter decreases in the putamen, nucleus caudatus, supplementary motor area and anterior cingulate cortex. Conclusions: The grey matter increases may be regarded as a secondary phenomenon compensating the increased activity of the motor system due to a reduced inhibitory output of the globus pallidus. With increasing age, the grey matter reduction of cortical midline structures however might contribute to the progression of dystonic symptoms due to loss of this compensatory control. © 2014 Elsevier Ltd. All rights reserved.
Keywords: Pantothenate Kinase Associated Neurodegeneration Grey matter alterations Voxel-Based Morphology
1. Introduction Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a genetically determined, autosomal-recessive disease, characterized by a defect in the formation of coenzyme A from vitamin B5 and belongs to the group of Neurodegeneration with Brain Iron Accumulation (NBIA), formerly called Hallervorden-Spatz disease [1,2]. The disease starts during childhood in the classical form or during the teens in the late-onset variety and mainly affects the anterior part of the internal globus pallidus. Patients first present with agitation and frequent falls. Later, they develop dystonic movements which affect the head and neck, various parts of the body
* Corresponding author. Department of Radiology, CEDIMAT, Plaza de la Salud, Santo Domingo, República Dominicana. E-mail address: [email protected] (P. Stoeter). http://dx.doi.org/10.1016/j.parkreldis.2014.06.005 1353-8020/© 2014 Elsevier Ltd. All rights reserved.
and extremities, and may be accompanied by rigidity, spasticity, or tremor. In some cases, there is cognitive decline or disturbed vision due to retinal degeneration [3]. On Magnetic Resonance Imaging (MRI), the primary lesion presents as a bright spot in T2 weighted scans in the pallidum which later is accompanied by a dark area of signal loss due to accumulation of iron known as the “Eye-of-the-Tiger” sign [4]. Otherwise, apart from subtle white matter changes in the anterior parts of the internal capsule, the brain of these patients does not show obvious structural deviations in imaging [5]. Although at least the gliotic part of the “Eye-of-the-tiger” sign is regarded to be present in all PKAN patients in some stage of their disease, including the very early cases, there is a period of delay between its appearance and the clinical manifestation of the dystonic symptoms [6,7]. Because of this symptom-free interval, the primary lesion obviously is not sufficient to lead to symptoms of dystonia
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immediately, raising the question if there are secondary processes or compensatory mechanisms involved. The fact that the functional changes correlate positively with the degree of dystonia [8] points to an increasing functional dysregulation as a secondary process. Changes in function usually are accompanied by some grey matter alterations in the sense of cerebral plasticity [9] and have been described in different subtypes of primary dystonia [10], but not yet in PKAN. To look further into this issue, we performed MRI and Voxel-Based Morphometry (VBM) in a group of PKAN patients from the Dominican Republic and matched healthy controls, and correlated the results of grey matter density measurements to the dystonia scale and age of our patients.
and were analyzed with a two-sample t-test (patients vs. volunteers), using dystonia score and age as covariates. Significance was assumed in case of p 0.001 uncorrected, analyzing the whole brain. Additionally, we performed a non-parametric ttest and correction for multiple comparisons on the cluster level according to the threshold-free cluster enhancement (TFCE) methodology proposed by Smith and Nichols 2009 [12] and implemented in the TFCE-toolbox by Christian Gaser (http:// dbm.neuro.uni-jena.de/tfce/). To detect grey matter alterations due to age and dystonia over the lifespan in patients, we also conducted a multiple regression analysis with age and dystonia score as predictors for the whole group of patients (7e41 years).
3. Results 3.1. Group comparison patients vs. volunteers
2. Material and methods 2.1. Patients and volunteers Probably due to a founder effect, PKAN is unusually frequent in the area around the town of Cabral in the southwest of the Dominican Republic. So far, more than 40 patients of an intermediate and late onset type have been identified. In spite of some differences in the clinical expression of the disease, the genetic basis is identical in all cases (homozygous c.680 A > G, p.Y227C). Having given informed consent, 29 confirmed patients between 7 and 41 years of age (mean age: 18.8 ± 8.5 years, 19 females), and an age-matched control group of nonaffected volunteers (8e41 years, mean age: 18.8 ± 8 years, 21 females) were included in the present study, which had been approved by the national ethics committee of the Dominican Republic. Because of the heterogeneity of age we divided the patients into two groups, one group for adults (patients: 18e41 years, n ¼ 13, 9 females, mean age: 26.1 ± 7.3 years; controls: 18e41 years, n ¼ 13, 9 females, mean age 25.6 ± 6.7 years) and one group for children (patients: 7e17 years, n ¼ 16, 10 females, mean age 12.7 ± 2.5 years; controls: 8e19 years, n ¼ 16, 12 females, mean age 13.3 ± 3.3 years). All participants were examined neurologically including video scan, and signs of dystonia were quantified according to the BurkeeFahneMarsden scale. 2.2. Magnetic Resonance Imaging All examinations were carried out on the same 3 T scanner “Achieva”, release 2.6 (Philips). T1-weighted images with 3-dimensional Turbo Field Echo, TR/TE ¼ 6.73/ 3.11 ms, 180 sagittal slices, voxel size 1 mm3, were acquired. 2.3. Image processing and statistical analysis Grey matter density was calculated using the VBM 8-toolbox (http://dbm.neuro. uni-jena.de/vbm/), implemented in Statistical Parametric Mapping 8 (SPM8, http:// www.fil.ion.ucl.ac.uk/spm). This program is based on high resolution structural 3D MR images and allows for applying voxel-wise statistics to detect regional differences in gray matter density or volumes. In summary, pre-processing involved spatial normalization, gray matter segmentation, non-linear modulation and smoothing with a kernel of 8 8 8 mm. To minimize the effect of age in the analysis (a child's brain may not be comparable to an adult's brain due to brain development in childhood [11]), and to see if effects differ in children and adults, the resulting volumes were divided into children (7e17 years) and adults (18e41 years),
As compared to controls, children with PKAN showed increased grey matter density in the putamen and nucleus caudatus, but not in the pallidum, and decreased grey matter density in small areas of the cerebellum, Superior Parietal Lobule (SPL), temporal and frontal cortex. Adults with PKAN showed increased grey matter density in the ventral part of the Anterior Cingulate Cortex (ACC) with a frontal extension into the paralimbic area 32 and a caudal extension into the infralimbic cortex (area 25). In addition, there were small areas of decreased grey matter density in the SPL, Supplementary Motor Area (SMA) and frontal cortex compared to controls (Table 1, Fig. 1). Regarding the covariate “age” we found a decrease of grey matter along the midline involving the frontomedial and the ACC and Posterior Cingulate Cortex (PCC) including the SMA, parts of the precuneus and the occipital cortex and additionally the midbrain in children compared to agematched controls, and a less extensive grey matter decrease in corresponding areas in adults compared to age-matched controls. Focusing the covariate “dystonia score” we found a grey matter decrease in the most anterior part of the cingulate cortex and further smaller regions in the frontal cortex in adults. Children with PKAN only showed a decrease of grey matter density for the covariate “dystonia score” in small areas of the cerebellum and lateral prefrontal cortex. After correction for multiple comparisons on the cluster level with the TFCE toolbox, the only surviving result is the increase of grey matter density in the right putamen (cluster 1: x ¼ 35, y ¼ 12, z ¼ 3, p ¼ 0.038 FWE corrected, cluster size: 133; and cluster 2: x ¼ 27, y ¼ 6, z ¼ 1, p ¼ 0.04 FWE corrected, cluster size: 99) in the subgroup of children with PKAN compared to controls.
Table 1 Changes in grey matter density in PKAN (patients versus volunteers, t-test, in groups of children and adults). Localization, size and T-value of clusters. Children
Adults
Location
x (mm) y (mm) z (mm) Increase/ Cluster Peak T Location decrease size
Right putamen Left putamen Right caudate nucleus Right cerebellum Right caudate nucleus Right cerebellar vermis Right thalamus Th-temporal Right amygdala Left thalamus Right area 1 Right medial temporal pole Left cerebellum Left superior parietal lobule area 2 Left fusiform gyrus
35 32 20 26 15 3 2
12 12 15 36 15 67 12
3 5 21 44 4 23 2
Increase Increase Increase Increase Increase Increase Increase
909 411 157 98 429 79 49
5.32 5.15 4.49 4.47 4.16 3.67 3.63
Right anterior cingulate cortex 6 Left posterior cingulate cortex 8 Right pars triangularis 47 Left temporal pole 30 Right SMA area 6 12 Left intraparietal sulcus hIP1 35 Left superior parietal lobule 18
29 43 30 11 12 52 28
6 28 12 29 58 31 33
Increase 534 Increase 191 Increase 22 Increase 10 Decrease 86 Decrease 55 Decrease 50
5.16 4.36 3.97 3.88 4.95 4.35 4.31
20 9 62 36
6 30 12 2
14 3 37 35
Increase 14 Increase 21 Increase 8 Decrease 208
3.59 3.53 3.51 4.61
Left inferior temporal gyrus
36
3
38
Decrease
3.84
23 20
52 45
44 51
Decrease 130 Decrease 198
4.57 4.49
33
69
18
Decrease
3.98
14
x (mm) y (mm) z (mm) Increase/ Cluster Peak T decrease size
13
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Fig. 1. Grey matter alterations in patients with PKAN, group comparison of patients and volunteers (two-sample t-test): children's group on the left and adults' group on the right. Grey matter increases compared to controls are depicted in yellow, grey matter decreases in red, p 0.001 uncorrected.
3.2. Prediction of grey matter decreases by age and dystonia A multiple regression analysis of the whole group of patients with age as predictor showed grey matter decreases in the putamen, nucleus caudatus, SMA and ACC. In a separate multiregression analysis in healthy volunteers, decreases of grey matter were less pronounced and mainly affected the pars triangularis and small frontal and temporal areas. These results in patients with PKAN and controls, predicted by age, are significant with FWE correction (p < 0.05). A multiple regression analysis of the whole group of patients with dystonia score as predictor showed grey matter density reduction mainly in the cerebellum, PCA, SPL, pars triangularis and small frontal and temporal areas with p < 0.001 uncorrected (Table 2, Fig. 2). 4. Discussion Regarding the increase of grey matter density in patients with PKAN compared to controls, we see a different signature in children and in adults. Whereas in the early stage, there is some increase of grey matter density mainly in the striatum, this finding is no longer seen in adults, who instead present a density increase of the rostral part of their ACC. Similar enlargements of the striatum have been reported in other types of dystonia like blepharospasm [13,14],
cervical dystonia [14,15] and musician's dystonia [16]. Although there are conflicting reports about striatal volume augmentations and reductions in various types of primary dystonia [17], the majority of VBM studies reported volume increases in the basal ganglia and of other motor system-related cortical and subcortical areas, according to two recent meta-analysis publications about grey matter changes in dystonic patients [10,18]. Sometimes, these increases in volume could be reduced by therapeutic immobilization [19] and therefore have been regarded as a secondary phenomenon. Among others, a malfunction of the basal ganglia-thalamocortical circuit has been postulated as the underlying course of most types of primary dystonia [20e22]. Because in PKAN the first lesion affects the globus pallidus and thus reduces its electrophysiological output, a compensatory density increase of its input areas as the striatum makes sense and may happen already during an early stage of the disease. This grey matter increase may be seen as the morphologic correlate of increased activity leading to increased blood supply and may be new formation of synaptic input in these areas, in the sense of brain plasticity [23]. However, the hypothesis of the increase in striatal density as a compensatory process does not explain why we do not longer see this phenomenon in our adult PKAN patients in spite of a progression of the disease, and why there is no correlation to the degree of their
Table 2 Prediction of grey matter density decreases predicted by dystonia score in PKAN-patients (multiple regression analysis). Localization, size and T-value of clusters. PKAN age
PKAN dystonia
Location
x (mm)
y (mm)
z (mm)
Cluster size
Peak T
Location
x (mm)
y (mm)
z (mm)
Cluster size
Peak T
Left putamen Right caudate nucleus Left pars triangularis area 44 Left supra marginal gyrus OP1 Left postcentral gyrus area 1 Right SMA Left SMA Right anterior cingulate cortex Left fusiform gyrus hOC4 Right middle temporal gyrus Right pars triangularis Right superior medial gyrus Right precuneus Left inferior parietal lobule Left pars opercularis area 44 Right insular lobe Left superior parietal lobule Right parahippocampal gyrus Right middle temporal gyrus Right pars opercularis area 44 Left postcentral gyrus area 1
29 9 54 63 56 2 0 17 21 66 53 6 15 45 60 45 44 29 59 57 20
3 17 15 24 15 7 18 48 78 33 41 66 58 48 11 17 58 22 48 17 28
3 8 31 51 48 70 45 10 11 0 15 12 40 48 6 9 60 23 4 27 69
12596 12596 456 258 258 1835 1835 121 287 699 873 1393 86 178 99 36 35 127 48 50 30
9.78 9.32 8.07 7.27 6.11 6.66 6.61 6.92 6.72 6.70 5.80 6.61 6.59 6.36 6.25 6.2 6.12 6.08 6.07 5.93 5.86
Right cerebellar vermis Left posterior cingulate cortex Right superior parietal lobule Right superior occipital gyrus Right middle frontal gyrus Right pars triangularis Right middle orbital gyrus Left inferior temporal gyrus Right inferior temporal gyrus Right middle frontal gyrus Left area 2 Right superior occipital gyrus Left pars triangularis Right supra marginal gyrus Right middle temporal gyrus Left cerebellum
3 3 41 26 39 42 6 62 63 39 47 27 38 63 47 45
43 43 60 82 42 33 57 37 42 60 27 93 39 39 42 49
12 21 56 42 0 10 9 21 11 4 36 22 3 37 7 50
866 866 192 184 339 339 941 623 611 192 367 101 97 282 183 194
5.48 4.61 4.72 4.65 4.49 3.87 4.35 4.35 4.18 4.12 4.11 3.95 3.93 3.93 3.86 3.80
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Fig. 2. Prediction of grey matter decreases (in red) in both groups (children and adults) of PKAN patients, predicted by dystonia score, (upper images, multiple regression analysis, p 0.001 uncorrected), and of grey matter decreases predicted by age (lower images, separate analysis for controls (left images) and patients (right images), p < 0.05 FWE corrected).
hyperkinetic movements. So we cannot exclude a primary origin as it has been suggested from the results of a family study in adultonset primary distorsion dystonia [24]. The fact that we did not see any reduction of the globus pallidus which is the primary target in PKAN, might mainly be due to methodologic reasons because iron accumulation which is a severe issue in this disease and responsible for the “Eye-of-the-tiger” appearance of this structure, shortens T1 relaxation time and systematically interferes with automated segmentation by degrading the T1 contrast [25]. Segmentation techniques other than SPM like Freesurfer or FSL-FIRST were not applied because their reliability is reduced as well in pathologic brains [26]. In contrary to the increase of grey matter density of the striatum in childhood, the grey matter increase of the ventral part of the ACC was seen in adult patients with PKAN. Here, another compensatory process may well be involved which develops at an intermediate stage of the disease to exhibit some control of hyperkinetic movements. Apart from its well-known role in attention, emotional self-control and focused problem solving, the ACC is involved in error recognition and online monitoring of performance [27,28]. In rats, discrete lesions of pre- and infralimbic areas, which may correspond to the region of increased cortex density in our patients Seamans et al. [29] reproduced a disinhibitory behavior as it is observed in humans with frontal hypoactivity [30]. However, our idea of a compensatory ACC enlargement serving as a control mechanism in PKAN dystonia is not in line with the hyperexitibility and aberrant brain plasticity hypothesis of Kranz et al. [31] who could reduce dystonic blepharospasm by transcranial magnetic stimulation of the ACC. A possible explanation may be that the underlying pathophysiology is different (focal vs. generalized dystonia) and that different areas of the ACC are involved. At a later stage of the disease and together with the general density reduction of midline cortical areas seen in our patients with increasing age, the compensation may no longer be valid, as
indicated by the negative correlation of putamen, nucleus caudatus and frontal areas to the dystonic score. With increasing age the symptoms get worse and the ACC may be a region in the brain that is struggling to compensate the loss of control. Beside areas of increased grey matter density as discussed above, our patients showed tiny areas of grey matter density reductions in the cerebellum, SPL, SMA and prefrontal cortex. Motor system-related density reductions have been observed in primary dystonia in the motor and premotor cortex, basal ganglia and thalamus [10] as well as in the somatosensory cortex progressing over 5 years [32]. In other functional conditions showing cortical reductions as chronic pain, the loss of density could neither be attributed to damage nor to atrophy and were regarded as a secondary phenomenon [33]. A similar mechanism might be causing the density loss of cortical midline structures with increasing age. Because these areas are regarded to exhibit control functions as well [34], their reduction may further aggravate the dystonic symptoms. 5. Conclusion Patients with primary dystonia due to PKAN show increased grey matter density of the striatum during childhood and increased grey matter density of the ventral part of the ACC in adults, which both may be regarded as a secondary phenomenon compensating the reduced inhibitory output of the globus pallidus and the resulting increased and uncontrolled activity of the motor system. In addition, there is an extensive grey matter decrease of cortical midline structures including the SMA and ACC, as well as putamen and nucleus caudatus with increasing age, which might contribute to the progression of dystonic symptoms due to loss of compensatory control. The origin and time course of this grey matter reduction remains unclear, and further studies including follow-up examinations of individual patients are needed.
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Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Grey matter alterations in patients with Pantothenate Kinase-Associated Neurodegeneration (PKAN) Rea Rodriguez-Raecke a, Pedro Roa-Sanchez b, Herwin Speckter c, Rafael Fermin-Delgado c, Eddy Perez-Then d, Jairo Oviedo c, Peter Stoeter c, * a
Department of Neurology, Medizinische Hochschule, Hannover, Germany Department of Neurology, CEDIMAT, Santo Domingo, República Dominicana Department of Radiology, CEDIMAT, Santo Domingo, República Dominicana d Department of Research, CEDIMAT, Santo Domingo, República Dominicana b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 28 February 2014 Received in revised form 5 May 2014 Accepted 7 June 2014
Background: Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a rare heritable disease marked by dystonia and loss of movement control. In contrast to the well-known “Eye-of-the-Tiger” sign affecting the globus pallidus, little is known about other deviations of brain morphology, especially about grey matter changes. Methods: We investigated 29 patients with PKAN and 29 age-matched healthy controls using Magnet Resonance Imaging and Voxel-Based Morphometry. Results: As compared to controls, children with PKAN showed increased grey matter density in the putamen and nucleus caudatus and adults with PKAN showed increased grey matter density in the ventral part of the anterior cingulate cortex. A multiple regression analysis with dystonia score as predictor showed grey matter reduction in the cerebellum, posterior cingulate cortex, superior parietal lobule, pars triangularis and small frontal and temporal areas and an analysis with age as predictor showed grey matter decreases in the putamen, nucleus caudatus, supplementary motor area and anterior cingulate cortex. Conclusions: The grey matter increases may be regarded as a secondary phenomenon compensating the increased activity of the motor system due to a reduced inhibitory output of the globus pallidus. With increasing age, the grey matter reduction of cortical midline structures however might contribute to the progression of dystonic symptoms due to loss of this compensatory control. © 2014 Elsevier Ltd. All rights reserved.
Keywords: Pantothenate Kinase Associated Neurodegeneration Grey matter alterations Voxel-Based Morphology
1. Introduction Pantothenate Kinase-Associated Neurodegeneration (PKAN) is a genetically determined, autosomal-recessive disease, characterized by a defect in the formation of coenzyme A from vitamin B5 and belongs to the group of Neurodegeneration with Brain Iron Accumulation (NBIA), formerly called Hallervorden-Spatz disease [1,2]. The disease starts during childhood in the classical form or during the teens in the late-onset variety and mainly affects the anterior part of the internal globus pallidus. Patients first present with agitation and frequent falls. Later, they develop dystonic movements which affect the head and neck, various parts of the body
* Corresponding author. Department of Radiology, CEDIMAT, Plaza de la Salud, Santo Domingo, República Dominicana. E-mail address: [email protected] (P. Stoeter). http://dx.doi.org/10.1016/j.parkreldis.2014.06.005 1353-8020/© 2014 Elsevier Ltd. All rights reserved.
and extremities, and may be accompanied by rigidity, spasticity, or tremor. In some cases, there is cognitive decline or disturbed vision due to retinal degeneration [3]. On Magnetic Resonance Imaging (MRI), the primary lesion presents as a bright spot in T2 weighted scans in the pallidum which later is accompanied by a dark area of signal loss due to accumulation of iron known as the “Eye-of-the-Tiger” sign [4]. Otherwise, apart from subtle white matter changes in the anterior parts of the internal capsule, the brain of these patients does not show obvious structural deviations in imaging [5]. Although at least the gliotic part of the “Eye-of-the-tiger” sign is regarded to be present in all PKAN patients in some stage of their disease, including the very early cases, there is a period of delay between its appearance and the clinical manifestation of the dystonic symptoms [6,7]. Because of this symptom-free interval, the primary lesion obviously is not sufficient to lead to symptoms of dystonia
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immediately, raising the question if there are secondary processes or compensatory mechanisms involved. The fact that the functional changes correlate positively with the degree of dystonia [8] points to an increasing functional dysregulation as a secondary process. Changes in function usually are accompanied by some grey matter alterations in the sense of cerebral plasticity [9] and have been described in different subtypes of primary dystonia [10], but not yet in PKAN. To look further into this issue, we performed MRI and Voxel-Based Morphometry (VBM) in a group of PKAN patients from the Dominican Republic and matched healthy controls, and correlated the results of grey matter density measurements to the dystonia scale and age of our patients.
and were analyzed with a two-sample t-test (patients vs. volunteers), using dystonia score and age as covariates. Significance was assumed in case of p 0.001 uncorrected, analyzing the whole brain. Additionally, we performed a non-parametric ttest and correction for multiple comparisons on the cluster level according to the threshold-free cluster enhancement (TFCE) methodology proposed by Smith and Nichols 2009 [12] and implemented in the TFCE-toolbox by Christian Gaser (http:// dbm.neuro.uni-jena.de/tfce/). To detect grey matter alterations due to age and dystonia over the lifespan in patients, we also conducted a multiple regression analysis with age and dystonia score as predictors for the whole group of patients (7e41 years).
3. Results 3.1. Group comparison patients vs. volunteers
2. Material and methods 2.1. Patients and volunteers Probably due to a founder effect, PKAN is unusually frequent in the area around the town of Cabral in the southwest of the Dominican Republic. So far, more than 40 patients of an intermediate and late onset type have been identified. In spite of some differences in the clinical expression of the disease, the genetic basis is identical in all cases (homozygous c.680 A > G, p.Y227C). Having given informed consent, 29 confirmed patients between 7 and 41 years of age (mean age: 18.8 ± 8.5 years, 19 females), and an age-matched control group of nonaffected volunteers (8e41 years, mean age: 18.8 ± 8 years, 21 females) were included in the present study, which had been approved by the national ethics committee of the Dominican Republic. Because of the heterogeneity of age we divided the patients into two groups, one group for adults (patients: 18e41 years, n ¼ 13, 9 females, mean age: 26.1 ± 7.3 years; controls: 18e41 years, n ¼ 13, 9 females, mean age 25.6 ± 6.7 years) and one group for children (patients: 7e17 years, n ¼ 16, 10 females, mean age 12.7 ± 2.5 years; controls: 8e19 years, n ¼ 16, 12 females, mean age 13.3 ± 3.3 years). All participants were examined neurologically including video scan, and signs of dystonia were quantified according to the BurkeeFahneMarsden scale. 2.2. Magnetic Resonance Imaging All examinations were carried out on the same 3 T scanner “Achieva”, release 2.6 (Philips). T1-weighted images with 3-dimensional Turbo Field Echo, TR/TE ¼ 6.73/ 3.11 ms, 180 sagittal slices, voxel size 1 mm3, were acquired. 2.3. Image processing and statistical analysis Grey matter density was calculated using the VBM 8-toolbox (http://dbm.neuro. uni-jena.de/vbm/), implemented in Statistical Parametric Mapping 8 (SPM8, http:// www.fil.ion.ucl.ac.uk/spm). This program is based on high resolution structural 3D MR images and allows for applying voxel-wise statistics to detect regional differences in gray matter density or volumes. In summary, pre-processing involved spatial normalization, gray matter segmentation, non-linear modulation and smoothing with a kernel of 8 8 8 mm. To minimize the effect of age in the analysis (a child's brain may not be comparable to an adult's brain due to brain development in childhood [11]), and to see if effects differ in children and adults, the resulting volumes were divided into children (7e17 years) and adults (18e41 years),
As compared to controls, children with PKAN showed increased grey matter density in the putamen and nucleus caudatus, but not in the pallidum, and decreased grey matter density in small areas of the cerebellum, Superior Parietal Lobule (SPL), temporal and frontal cortex. Adults with PKAN showed increased grey matter density in the ventral part of the Anterior Cingulate Cortex (ACC) with a frontal extension into the paralimbic area 32 and a caudal extension into the infralimbic cortex (area 25). In addition, there were small areas of decreased grey matter density in the SPL, Supplementary Motor Area (SMA) and frontal cortex compared to controls (Table 1, Fig. 1). Regarding the covariate “age” we found a decrease of grey matter along the midline involving the frontomedial and the ACC and Posterior Cingulate Cortex (PCC) including the SMA, parts of the precuneus and the occipital cortex and additionally the midbrain in children compared to agematched controls, and a less extensive grey matter decrease in corresponding areas in adults compared to age-matched controls. Focusing the covariate “dystonia score” we found a grey matter decrease in the most anterior part of the cingulate cortex and further smaller regions in the frontal cortex in adults. Children with PKAN only showed a decrease of grey matter density for the covariate “dystonia score” in small areas of the cerebellum and lateral prefrontal cortex. After correction for multiple comparisons on the cluster level with the TFCE toolbox, the only surviving result is the increase of grey matter density in the right putamen (cluster 1: x ¼ 35, y ¼ 12, z ¼ 3, p ¼ 0.038 FWE corrected, cluster size: 133; and cluster 2: x ¼ 27, y ¼ 6, z ¼ 1, p ¼ 0.04 FWE corrected, cluster size: 99) in the subgroup of children with PKAN compared to controls.
Table 1 Changes in grey matter density in PKAN (patients versus volunteers, t-test, in groups of children and adults). Localization, size and T-value of clusters. Children
Adults
Location
x (mm) y (mm) z (mm) Increase/ Cluster Peak T Location decrease size
Right putamen Left putamen Right caudate nucleus Right cerebellum Right caudate nucleus Right cerebellar vermis Right thalamus Th-temporal Right amygdala Left thalamus Right area 1 Right medial temporal pole Left cerebellum Left superior parietal lobule area 2 Left fusiform gyrus
35 32 20 26 15 3 2
12 12 15 36 15 67 12
3 5 21 44 4 23 2
Increase Increase Increase Increase Increase Increase Increase
909 411 157 98 429 79 49
5.32 5.15 4.49 4.47 4.16 3.67 3.63
Right anterior cingulate cortex 6 Left posterior cingulate cortex 8 Right pars triangularis 47 Left temporal pole 30 Right SMA area 6 12 Left intraparietal sulcus hIP1 35 Left superior parietal lobule 18
29 43 30 11 12 52 28
6 28 12 29 58 31 33
Increase 534 Increase 191 Increase 22 Increase 10 Decrease 86 Decrease 55 Decrease 50
5.16 4.36 3.97 3.88 4.95 4.35 4.31
20 9 62 36
6 30 12 2
14 3 37 35
Increase 14 Increase 21 Increase 8 Decrease 208
3.59 3.53 3.51 4.61
Left inferior temporal gyrus
36
3
38
Decrease
3.84
23 20
52 45
44 51
Decrease 130 Decrease 198
4.57 4.49
33
69
18
Decrease
3.98
14
x (mm) y (mm) z (mm) Increase/ Cluster Peak T decrease size
13
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Fig. 1. Grey matter alterations in patients with PKAN, group comparison of patients and volunteers (two-sample t-test): children's group on the left and adults' group on the right. Grey matter increases compared to controls are depicted in yellow, grey matter decreases in red, p 0.001 uncorrected.
3.2. Prediction of grey matter decreases by age and dystonia A multiple regression analysis of the whole group of patients with age as predictor showed grey matter decreases in the putamen, nucleus caudatus, SMA and ACC. In a separate multiregression analysis in healthy volunteers, decreases of grey matter were less pronounced and mainly affected the pars triangularis and small frontal and temporal areas. These results in patients with PKAN and controls, predicted by age, are significant with FWE correction (p < 0.05). A multiple regression analysis of the whole group of patients with dystonia score as predictor showed grey matter density reduction mainly in the cerebellum, PCA, SPL, pars triangularis and small frontal and temporal areas with p < 0.001 uncorrected (Table 2, Fig. 2). 4. Discussion Regarding the increase of grey matter density in patients with PKAN compared to controls, we see a different signature in children and in adults. Whereas in the early stage, there is some increase of grey matter density mainly in the striatum, this finding is no longer seen in adults, who instead present a density increase of the rostral part of their ACC. Similar enlargements of the striatum have been reported in other types of dystonia like blepharospasm [13,14],
cervical dystonia [14,15] and musician's dystonia [16]. Although there are conflicting reports about striatal volume augmentations and reductions in various types of primary dystonia [17], the majority of VBM studies reported volume increases in the basal ganglia and of other motor system-related cortical and subcortical areas, according to two recent meta-analysis publications about grey matter changes in dystonic patients [10,18]. Sometimes, these increases in volume could be reduced by therapeutic immobilization [19] and therefore have been regarded as a secondary phenomenon. Among others, a malfunction of the basal ganglia-thalamocortical circuit has been postulated as the underlying course of most types of primary dystonia [20e22]. Because in PKAN the first lesion affects the globus pallidus and thus reduces its electrophysiological output, a compensatory density increase of its input areas as the striatum makes sense and may happen already during an early stage of the disease. This grey matter increase may be seen as the morphologic correlate of increased activity leading to increased blood supply and may be new formation of synaptic input in these areas, in the sense of brain plasticity [23]. However, the hypothesis of the increase in striatal density as a compensatory process does not explain why we do not longer see this phenomenon in our adult PKAN patients in spite of a progression of the disease, and why there is no correlation to the degree of their
Table 2 Prediction of grey matter density decreases predicted by dystonia score in PKAN-patients (multiple regression analysis). Localization, size and T-value of clusters. PKAN age
PKAN dystonia
Location
x (mm)
y (mm)
z (mm)
Cluster size
Peak T
Location
x (mm)
y (mm)
z (mm)
Cluster size
Peak T
Left putamen Right caudate nucleus Left pars triangularis area 44 Left supra marginal gyrus OP1 Left postcentral gyrus area 1 Right SMA Left SMA Right anterior cingulate cortex Left fusiform gyrus hOC4 Right middle temporal gyrus Right pars triangularis Right superior medial gyrus Right precuneus Left inferior parietal lobule Left pars opercularis area 44 Right insular lobe Left superior parietal lobule Right parahippocampal gyrus Right middle temporal gyrus Right pars opercularis area 44 Left postcentral gyrus area 1
29 9 54 63 56 2 0 17 21 66 53 6 15 45 60 45 44 29 59 57 20
3 17 15 24 15 7 18 48 78 33 41 66 58 48 11 17 58 22 48 17 28
3 8 31 51 48 70 45 10 11 0 15 12 40 48 6 9 60 23 4 27 69
12596 12596 456 258 258 1835 1835 121 287 699 873 1393 86 178 99 36 35 127 48 50 30
9.78 9.32 8.07 7.27 6.11 6.66 6.61 6.92 6.72 6.70 5.80 6.61 6.59 6.36 6.25 6.2 6.12 6.08 6.07 5.93 5.86
Right cerebellar vermis Left posterior cingulate cortex Right superior parietal lobule Right superior occipital gyrus Right middle frontal gyrus Right pars triangularis Right middle orbital gyrus Left inferior temporal gyrus Right inferior temporal gyrus Right middle frontal gyrus Left area 2 Right superior occipital gyrus Left pars triangularis Right supra marginal gyrus Right middle temporal gyrus Left cerebellum
3 3 41 26 39 42 6 62 63 39 47 27 38 63 47 45
43 43 60 82 42 33 57 37 42 60 27 93 39 39 42 49
12 21 56 42 0 10 9 21 11 4 36 22 3 37 7 50
866 866 192 184 339 339 941 623 611 192 367 101 97 282 183 194
5.48 4.61 4.72 4.65 4.49 3.87 4.35 4.35 4.18 4.12 4.11 3.95 3.93 3.93 3.86 3.80
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Fig. 2. Prediction of grey matter decreases (in red) in both groups (children and adults) of PKAN patients, predicted by dystonia score, (upper images, multiple regression analysis, p 0.001 uncorrected), and of grey matter decreases predicted by age (lower images, separate analysis for controls (left images) and patients (right images), p < 0.05 FWE corrected).
hyperkinetic movements. So we cannot exclude a primary origin as it has been suggested from the results of a family study in adultonset primary distorsion dystonia [24]. The fact that we did not see any reduction of the globus pallidus which is the primary target in PKAN, might mainly be due to methodologic reasons because iron accumulation which is a severe issue in this disease and responsible for the “Eye-of-the-tiger” appearance of this structure, shortens T1 relaxation time and systematically interferes with automated segmentation by degrading the T1 contrast [25]. Segmentation techniques other than SPM like Freesurfer or FSL-FIRST were not applied because their reliability is reduced as well in pathologic brains [26]. In contrary to the increase of grey matter density of the striatum in childhood, the grey matter increase of the ventral part of the ACC was seen in adult patients with PKAN. Here, another compensatory process may well be involved which develops at an intermediate stage of the disease to exhibit some control of hyperkinetic movements. Apart from its well-known role in attention, emotional self-control and focused problem solving, the ACC is involved in error recognition and online monitoring of performance [27,28]. In rats, discrete lesions of pre- and infralimbic areas, which may correspond to the region of increased cortex density in our patients Seamans et al. [29] reproduced a disinhibitory behavior as it is observed in humans with frontal hypoactivity [30]. However, our idea of a compensatory ACC enlargement serving as a control mechanism in PKAN dystonia is not in line with the hyperexitibility and aberrant brain plasticity hypothesis of Kranz et al. [31] who could reduce dystonic blepharospasm by transcranial magnetic stimulation of the ACC. A possible explanation may be that the underlying pathophysiology is different (focal vs. generalized dystonia) and that different areas of the ACC are involved. At a later stage of the disease and together with the general density reduction of midline cortical areas seen in our patients with increasing age, the compensation may no longer be valid, as
indicated by the negative correlation of putamen, nucleus caudatus and frontal areas to the dystonic score. With increasing age the symptoms get worse and the ACC may be a region in the brain that is struggling to compensate the loss of control. Beside areas of increased grey matter density as discussed above, our patients showed tiny areas of grey matter density reductions in the cerebellum, SPL, SMA and prefrontal cortex. Motor system-related density reductions have been observed in primary dystonia in the motor and premotor cortex, basal ganglia and thalamus [10] as well as in the somatosensory cortex progressing over 5 years [32]. In other functional conditions showing cortical reductions as chronic pain, the loss of density could neither be attributed to damage nor to atrophy and were regarded as a secondary phenomenon [33]. A similar mechanism might be causing the density loss of cortical midline structures with increasing age. Because these areas are regarded to exhibit control functions as well [34], their reduction may further aggravate the dystonic symptoms. 5. Conclusion Patients with primary dystonia due to PKAN show increased grey matter density of the striatum during childhood and increased grey matter density of the ventral part of the ACC in adults, which both may be regarded as a secondary phenomenon compensating the reduced inhibitory output of the globus pallidus and the resulting increased and uncontrolled activity of the motor system. In addition, there is an extensive grey matter decrease of cortical midline structures including the SMA and ACC, as well as putamen and nucleus caudatus with increasing age, which might contribute to the progression of dystonic symptoms due to loss of compensatory control. The origin and time course of this grey matter reduction remains unclear, and further studies including follow-up examinations of individual patients are needed.
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