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Topographic pattern of cortical thinning with consideration of motor laterality in Parkinson disease
Parkinsonism and Related Disorders 20 (2014) 1186e1190
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Topographic pattern of cortical thinning with consideration of motor laterality in Parkinson disease Ji Sun Kim a, Jin-ju Yang b, Jong-min Lee b, Jinyoung Youn c, Ju-min Kim c, Jin Whan Cho c, * a
Department of Neurology, Soonchunhyang University Hospital, Soonchunhyang University School of Medicine, Republic of Korea Department of Biomedical Engineering, Hanyang University, Republic of Korea c Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Republic of Korea b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 26 April 2014 Received in revised form 15 July 2014 Accepted 24 August 2014
Background: The asymmetry of Parkinson's disease (PD) may contribute to the unilateral appearance of parkinsonism, as well as its cerebral morphological changes. However, previous studies have not considered that cerebral involvement would probably be asymmetric. Our study aimed to identify whether one-sided symptom dominance has an influence on cortical thinning patterns in early-stage, non-demented PD patients from cortical thickness analyses and cortical thinning patterns are associated with motor functions. Methods: We used cortical thickness analysis in 64 non-demented right-handed subjects: 21 PD patients with left-sided disease onset (LPD), 21 PD patients with right-sided disease onset (RPD) and 22 control subjects. We modeled local cortical thickness as a linear association with each motor symptom. Results: We identified three clusters exhibiting significant cortical thinning (p < 0.01 RFT corrected) in the LPD group compared with the control group: a cluster including the right primary sensory, motor cortex and paracentral lobule, as well as another two clusters in bilateral parahippocampal gyri. In the RPD group, there was only one cluster that exhibited significant cortical thinning compared with the control group, located in the left lingual gyrus. There were no significant correlations between cortical thinning clusters and motor severity, any of the motor subscales including tremor, rigidity, bradykinesia and axial impairment. Conclusions: Our right-handed PD population revealed that significant thinning of motor-related cortical areas in contralateral hemisphere to symptomatic side in LPD, but not in RPD group. Our results support that neuroprotective effect of enhanced physical activity by handedness on contralateral motor cortex. © 2014 Elsevier Ltd. All rights reserved.
Keywords: Cortical thickness Parkinson's disease Asymmetry Functional laterality
1. Introduction Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by the loss of dopamine due to the degeneration of dopaminergic neurons in substantia nigra pars compacta. The pathological process in PD is not confined to the brainstem nuclei but develops to affect various parts of the brain including the cerebral neocortex with an ascending temporal sequence [1]. Infratentorial and subcortical structures such as the brainstem and striatum are primarily affected in PD, and hence past studies have focused on those structures while cortical pathology has received little attention. Recently, various magnetic resonance (MR)
* Corresponding author. Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Irwon-Dong, Gangnam-Gu, Seoul 135-710, Republic of Korea. Tel.: þ82 2 3410 1279; fax: þ82 2 3410 0052. E-mail address: [email protected] (J.W. Cho). http://dx.doi.org/10.1016/j.parkreldis.2014.08.021 1353-8020/© 2014 Elsevier Ltd. All rights reserved.
techniques have become available to describe the morphological changes and patterns of PD during the last decade, suggesting that cortical involvement may be more extensive than previously recognized even in early stages of the disease. However, previous studies revealed discrepancies in reported cortical changes as detected using voxel-based morphometry, volumetric techniques and cortical thickness analysis of MR imaging data collected from PD patients [2e4]. Furthermore, one typical feature of PD is asymmetrical motor feature at the time of diagnosis, and previous studies have not considered that cerebral involvement would probably be asymmetric. Although possible causative mechanisms of asymmetry in PD have been suggested, such as unequal numbers of neurons on each side of the substantia nigra [5], one-sided weakness of the midbrain bloodebrain barrier [6], the neuroprotective effect of enhanced motor exercise [7,8] and hand dominance [9], the exact mechanism of asymmetric manifestation is still unknown. The beneficial effects of exercise from enhanced neuroplasticity have been well
J.S. Kim et al. / Parkinsonism and Related Disorders 20 (2014) 1186e1190
documented by previous studies in both human beings and animal models of PD [10,11], and it is possible that these effects might contribute to the unilateral appearance of motor symptoms [12] and possibly influence on the morphological changes of cerebral structures. Our study aimed to identify whether one-sided symptom dominance has an influence on cortical thinning patterns in earlystage, non-demented PD patients from cortical thickness analyses and whether cortical thinning patterns are associated with motor functions.
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3. Results 3.1. Demographic and clinical features Table 1 presents the demographic characteristics of each group. There were no significant differences of age, sex, disease duration, ICV and MMSE scores among each group. Motor function assessed by UPDRS and H & Y stage did not show differences between LPD and RPD. 3.2. Distribution of focal areas with reduced cortical thickness
2. Methods 2.1. Patients We recruited 64 non-demented, right-handed subjects: 21 patients with PD who had left-sided symptom dominance (LPD), 21 patients with PD who had right-sided symptom dominance (RPD) and 22 control subjects (matched for age and gender). Clinical diagnosis of PD was determined by the UK Brain Bank Criteria for diagnosis of PD [12]. We included patients who scored higher than 26 on the Korean version of the Mini Mental Status Examination (K-MMSE) and with disease duration of less than 4 years. All patients underwent clinical interviews and neurological examinations conducted by experienced neurologists (J.W.C. and J.S.K) in order to evaluate their motor functions. The motor portion of the Unified Parkinson's Disease Rating Scale (UPDRS) and Hoehn and Yahr (H & Y) stage of PD subjects were measured. UPDRS scores were divided into subscores for tremor, rigidity, bradykinesia and axial impairment based on the DATATOP factorial division, using the sum of UPDRS items 20 and 21 for the tremor score, item 22 for the rigidity score, the sum of items 24, 25, 26, and 31 for the bradykinesia score, the sum of items 27, 28, 29 and 30 for the axial impairment score (arising from chair, posture, gait and postural stability) [13]. Patients who had infarction, hemorrhage, tumors, trauma or severe white matter hyperintensity (deep white matter lesion 25 mm and caps or bands 10 mm) were excluded from the study [14,15]. This study was approved by the Institutional Review Board of Samsung Medical Center, Seoul, Korea, and each patient provided informed consent to participate.
2.2. Image acquisition and processing for cortical thickness measurement Three-dimensional T1-weighted MR images were acquired with 3.0-T MRI scanner (Philips 3.0T Achieva) from 64 participants using the following imaging parameters: sagittal slice thickness, 1.0 mm, over contiguous slices with 50% overlap; no gap; repetition time (TR), 9.9 ms; echo time (TE), 4.6 ms; flip angle, 8 ; and matrix size of 240 240 pixels, reconstructed to 480 480 over a field of view (FOV) of 240 mm. Images were processed by the standard Montreal Neurological Institute anatomic pipeline. Further image processing for cortical thickness measurement was described in a previous study [16]. Cortical thickness was measured as the Euclidean distance between linked vertices of the inner and outer surfaces that contained 40,962 vertices on each hemisphere for each subject in native space [17]. To compare thickness across subjects, the thicknesses were spatially normalized using surface-based registration, in which the vertices of each subject were nonlinearly registered to a group template by matching sulcal folding pattern [18,19]. To increase the signal to noise ratio and statistical power, each cortical thickness map was blurred by surface-based diffusion smoothing kernel with a full-width halfmaximum of 20 mm [17]. We included intracranial volume (ICV) as a covariate to control the brain size effect in statistical analyses. ICV was calculated by measuring as the total volume of gray matter, white matter, and cerebrospinal fluid.
There were no significant differences of whole brain mean thickness among LPD, RPD group and control group (mean cortical thickness in the LPD group ¼ 3.01 ± 0.03 mm, in the RPD group ¼ 3.03 ± 0.27 mm, in the NC group ¼ 3.06 ± 0.19 mm). We found three clusters exhibiting significant cortical thinning (p < 0.01 RFT corrected) in the LPD group compared with control group: one cluster including the right primary sensory, motor cortex and paracentral lobule, as well as another two clusters in bilateral parahippocampal gyri (Fig. 1). In the RPD group, there was only one cluster exhibiting a significant cortical thinning (p < 0.01 RFT corrected) compared with the control group, located in the left lingual gyrus (Fig. 1). When we analyzed the difference of cortical thickness between 2 PD groups, significant cortical thinning cluster was not found between 2 PD groups. 3.3. Correlation analyses of cortical thinning areas with motor scale and disease-related metrics We conducted additional analyses in PD groups in order to evaluate the correlation of cortical thinning with motor severity assessed by H & Y stage, UPDRS total score and subscales including tremor, rigidity, bradykinesia and axial impairment. We modeled local cortical thickness as a linear correlation of motor severity and subscales with adjustment of age, sex and ICV. There was no significant correlation between cortical thinning clusters and motor severity assessed by UPDRS score and H & Y stage, nor with motor subscales including tremor, rigidity, bradykinesia and axial impairment. 4. Discussion This is the first study to consider the dominant side of symptom in analysis of cortical thickness in early, non-demented PD patients. The results of this study show that global cortical thickness is preserved in the early-stage PD population compared with a Table 1 Demographic characteristics of IPD and normal controls. IPD (n ¼ 42)
p
65.27 ± 8.50 12:10 28.68 ± 0.31 1373.23 ± 117.82
0.962 0.815 0.138 0.969 0.980 0.553 0.119 0.896 0.785 0.198 0.941
Rt sided (n ¼ 21) Lt sided (n ¼ 21)
2.3. Statistical analyses Statistical analyses for the demographic characteristics of subjects were performed with SPSS Statistics 18.0 (Predictive Analysis Software, Chicago, IL). Independent T-test and ANOVA were used to compare means of variables and the Chisquare test was used to compare the frequency of sex. The localized differences in cortical thickness between the NC and PD groups were analyzed using the General Linear Model on a vertex-by-vertex basis with covariates of age, sex and ICV. Statistical significance was assessed by random field theory (RFT) at a corrected probability value of 0.01 to correct the result for multiple comparisons [20]. To evaluate the correlation of motor subscales on significant cortical thinning cluster, multiple linear regression analysis was performed the regression equation was given as follows: Y(significant thinning cluster) ¼ b1(UPDRS) þ b2(HY) þ b3(Disease duration) þ b4(Tremor subscore) þ b5(rigidity subscore) þ b6(bradykinesia subscore) þ b7(axial impairment subscore).
NC (n ¼ 22)
Age (yrs) Sex (M:F) MMSE ICV (cc) Duration (yrs) UPDRS part III Tremor Rigidity Bradykinesia Axial impair H&Y
65.14 ± 9.99 12:9 27.81 ± 1.66 1365.94 ± 146.32 2.33 ± 1.16 18.07 ± 8.00 1.14 ± 1.28 3.45 ± 2.48 6.90 ± 3.27 2.43 ± 2.40 1.67 ± 0.60
64.57 ± 7.67 10:11 27.90 ± 1.55 1363.40 ± 138.44 2.52 ± 1.17 13.31 ± 7.95 0.90 ± 0.99 3.02 ± 2.69 4.88 ± 3.28 1.40 ± 1.53 1.48 ± 0.58
IPD, idiopathic Parkinson's disease; NC, normal controls; yrs, years; MMSE, Mini Mental Status Examination; ICV, intracranial volume; UPDRS, Unified Parkinson's Disease Rating Scale; H & Y, Hoehn and Yahr stage.
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Fig. 1. Topographical distribution of cortical thickness in LPD compared to NC (A) and RPD compared to NC (B). The statistical t map (top row) shows a trend of cortical thinning in both comparisons of LPD vs. NC (A) with t-value range of 5.89 to 2.75 and RPD vs. NC (B) with t-value range of 4.46 to 3.33. The p map (bottom row) indicated by the color was corrected using the RFT for multiple comparison at a 0.01 threshold.
healthy population, regardless of the symptomatic side of the body. However, different focal areas exhibiting significant cortical thinning in PD groups were found with consideration of symptomatic side: one cluster including the right primary sensory, motor cortex and paracentral lobule, as well as another two clusters in bilateral parahippocampal gyri, while left lingual gyrus in RPD. Significant cortical thinning cluster was not found between 2 PD groups. We did not find any significant associations between clusters with cortical thinning and the motor symptoms of PD in correlation analyses. The major pathological change in PD is a degeneration of nigrostriatal dopaminergic neurons. However, PD is a network disorder and is known to involve almost the whole brain [1]. Despite less vulnerable cortical structures gradually become affected as the disease progresses, several recent MR-based imaging analyses of PD revealed that cortical atrophy exists even in early stages of disease development [4]. Among several other methods, cortical thickness analysis has been introduced as an effort to overcome the difficulties in analysis of highly convoluted cerebral cortex and have demonstrated focal cortical thinning pattern in neurologic diseases. However, the results using cortical thickness analysis in PD patients were not consistent between the studies and there was no study to consider the motor laterality which is one of the most important features. We identified several focal thinning areas including the right primary sensory, motor cortex, paracentral lobule, bilateral parahippocampal gyri of LPD patients and the left lingual gyrus of RPD patients. We included early stage patients whose duration of symptom is less than 4 years, and it might have an effect on the topographical distribution of cortical thinning pattern. The distribution of cortical thinning clusters is overlapped with the regions where cortical Lewy bodies and Lewy neuritis are found in patients of Braak's stage 4 [1] and almost consistent with the results of previous imaging studies [4,21]. Cortical areas associated with motor functions are known to be damaged in PD even in early stage by recent imaging analyses [22].
Interestingly, we identified significant cortical thinning in motorrelated areas only in LPD, but not in RPD group. These results suggest the possibility that enhanced physical activity by handedness may have a neuroprotective effect on contralateral cerebral structures. The onset of motor symptoms is often exhibited exclusively on either the right or left side of the body, and the unilateral predominance of symptoms often persists long after the disease becomes clinically bilateral [23]. Despite the common recognition of symptom asymmetry in PD, data explaining this phenomenon are sparse. Although the exact etiology of lateralization is not well established, there are a few potential mechanisms and contributory factors that have been suggested to influence the asymmetry of symptom appearance [23e25]. Previous experimental results have demonstrated that enhanced physical activity may have a neuroprotective effect on contralateral motor circuits [7,8]. In an experimental motor rat model, unilateral injection of 6-hydroxydopamine (6-OHDA) with a cast applied to an ipsilateral non-impaired limb, forcing the animal to use the impaired contralateral limbs, caused no detectable impairment or asymmetry of limb use despite a decreased ipsilateral dopamine concentration in the striatum. Another functional neuroimaging study also suggested that enhancing performance by handedness plays a significant role in the reorganization of the contralateral motor system and neuroplasticity [26]. All of the patients in the present study were right-handed, so more strenuous exercise performed by the right side of the body may explain the absence of significant cortical thinning in areas of the motor related cortex in the RPD group. Additionally, Korean culture has a strong tradition of preferring use of right hand in all tasks, and using right hand is thought to be polite manners. So the percentage of left handed people in Korea is lower than in other countries. And hence, cultural feature of encouraging use of right hand would also influence on the results of our study. Our results support the hypothesis of neuroprotective effect by enhanced physical activity on contralateral motor cortex. In linear correlation analysis, the thickness of the cortical area did not show significant correlation with the severity of motor
J.S. Kim et al. / Parkinsonism and Related Disorders 20 (2014) 1186e1190
symptoms including tremor, rigidity, bradykinesia or axial impairment. Another recent study using cortical thickness analysis in advanced PD reported that motor severity was not correlated with cortical thickness, but the associations with subcortical structures (basal ganglia) were robust [22]. Structural and dopamine transporter (DAT) imaging analyses also suggested that cortical change, as well as striatal DAT binding does not seem to be correlated with clinical severity assessed by UPDRS [27e29]. Likewise, the exact nature of the correlation between clinical severity and cortical thickness is not yet well established. The lack of significant correlation between motor symptoms and cortical thickness in our study might suggest that cortical thinning of PD occurs independently of striatonigral dopaminergic neuronal damage. Cortical thinning is reported to be associated with nonmotor symptoms such as cognitive dysfunction [3,30] and we might miss the better correlation of these potential non-motor symptoms with observed cortical thinning in PD patients. However, we analyzed the only patients of early stage to identify existence of cortical thinning in early-stage, non-demented PD patients from cortical thickness analyses and to rule out the influence of non-motor symptoms such as cognitive dysfunctions on cortical structures that may occur in advanced stage. And hence, the short disease duration may not be long enough to significantly change the cortical thickness to detect the association with clinical severity considering that cortical atrophy becomes more defined with increased disease progression. A large-scale study demonstrating this relationship is needed to clarify the nature of this association. 5. Conclusion In summary, our study demonstrated different cortical thinning areas according to side of symptom dominance in early, nondemented PD patients for the first time. Our right-handed PD population revealed significant thinning of motor-related cortical areas in the hemisphere contralateral to the symptomatic side in LPD patients but not in the RPD group. These data support the possibility that enhanced physical activities by handedness may have a neuroprotective effect on contralateral motor cortices. To confirm this, a well-designed prospective study demonstrating this hypothesis is needed. Disclosure This work was supported by a Samsung Medical Center grant (SMO1131541) and Soonchunhyang University Research Fund. Author's role 1. Research project: A. Conception, B. Organization, C. Execution 2. Statistical analysis: A. Design, B. Execution, C. Review and Critique 3. Manuscript preparation: A. Writing of the first draft, B. Review and Critique Ji sun Kim, MD: 1ABC, 2AB and 3A; Jin-ju Yang: 2ABC and 3B; Jong-min Lee, PhD: 2ABC and 3B; Jinyoung Youn, MD: 1ABC, 2C and 3C. Ju-min Kim, MD: 2C and 3B. Jin Whan Cho, M.D., Ph.D.: 1ABC, 2C and 3C. Ethical standards All persons gave their informed consent prior to their inclusion in the study.
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Conflict of interest The authors declare that they have no conflict of interest.
Acknowledgment We thank the members of the KOJYP study group (Wooyoung Jang, Eungseok Oh, Jinse Park) for special comments on our work. J.J Y and J. M. L have received research support from National Research Foundation of Korea (NRF) grant funded by the Korea Government (MEST) (2011-0028333).
References [1] Braak H, Tredici KD, Rüb U, Vos RAId, Steur ENHJ, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003;24: 197e211. [2] Dalaker TO, Larsen JP, Bergsland N, Beyer MK, Alves G, Dwyer MG, et al. Brain atrophy and white matter hyperintensities in early Parkinson's disease(a). Mov Disord 2009;24:2233e41. [3] Nagano-Saito A, Washimi Y, Arahata Y, Kachi T, Lerch JP, Evans AC, et al. Cerebral atrophy and its relation to cognitive impairment in Parkinson disease. Neurology 2005;64:224e9. [4] Jubault T, Gagnon JF, Karama S, Ptito A, Lafontaine AL, Evans AC, et al. Patterns of cortical thickness and surface area in early Parkinson's disease. Neuroimage 2011;55:462e7. [5] Kempster PA, Gibb WRG, Stern GM, Lees AJ. Asymmetry of substantia nigra neuronal loss in Parkinson's disease and its relevance to the mechanism of levodopa related motor fluctuations. J Neurol Neurosurg Psychiatry 1989;52: 72e6. [6] Kortekaas R, Leenders KL, van Oostrom JC, Vaalburg W, Bart J, Willemsen AT, et al. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann Neurol 2005;57:176e9. [7] Tillerson JL, Cohen AD, Philhower J, Miller GW, Zigmond MJ, Schallert T. Forced limb-use effects on the behavioral and neurochemical effects of 6hydroxydopamine. J Neurosci 2001;15:4427e35. [8] Cohen AD, Tillerson JL, Smith AD, Schallert T, Zigmond MJ. Neuroprotective effects of prior limb use in 6-hydroxydopamine-treated rats: possible role of GDNF. J Neurochem 2003;85:299e305. [9] Uitti RJ, Baba Y, Whaley NR, Wszolek ZK, Putzke JD. Parkinson disease: handedness predicts asymmetry. Neurology 2005;64:1925e30. [10] Petzinger GM, Fisher BE, McEwen S, Beeler JA, Walsh JP, Jakowec MW. Exercise-enhanced neuroplasticity targeting motor and cognitive circuitry in Parkinson's disease. Lancet Neurol 2013;12:716e26. [11] Petzinger GM, Fisher BE, Van Leeuwen JE, Vukovic M, Akopian G, Meshul CK, et al. Enhancing neuroplasticity in the basal ganglia: the role of exercise in Parkinson's disease. Mov Disord 2010;25(Suppl. 1):S141e5. [12] Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181e4. [13] Uc EY, McDermott MP, Marder KS, Anderson SW, Litvan I, Como PG, et al. Incidence of and risk factors for cognitive impairment in an early Parkinson disease clinical trial cohort. Neurology 2009;73:1469e77. €ntyla € R, Erkinjuntti T, Salonen O, Aronen HJ, Peltonen T, Pohjasvaara T, [14] Ma et al. Variable agreement between visual rating scales for white matter hyperintensities on MRI. Stroke 1997;28:1614e23. [15] Scheltens P, Barkhof F, Leys D, Pruvo JP, Nauta JJP, Vermersch P, et al. A semiquantative rating scale for the assessment of signal hyperintensities on magnetic resonance imaging. J Neurol Sci 1993;114:7e12. [16] Kim JS, Youn J, Yang JJ, Lee DK, Lee JM, Kim ST, et al. Topographic distribution of cortical thinning in subtypes of multiple system atrophy. Parkinsonism Relat Disord 2013;19:970e4. [17] Lerch JP, Evans AC. Cortical thickness analysis examined through power analysis and a population simulation. Neuroimage 2005;24:163e73. [18] Robbins S, Evans AC, Collins DL, Whitesides S. Tuning and comparing spatial normalization methods. Med Image Anal 2004;8:311e23. [19] Lyttelton O, Boucher M, Robbins S, Evans A. An unbiased iterative group registration template for cortical surface analysis. Neuroimage 2007;34:1535e44. [20] Worsley KJ, Marrett S, Neelin P, Vandal AC, Friston KJ, Evans AC. A unified statistical approach for determining significant signals in images of cerebral activation. Hum Brain Mapp 1996;4:58e73. [21] Pellicano C, Assogna F, Piras F, Caltagirone C, Pontieri FE, Spalletta G. Regional cortical thickness and cognitive functions in non-demented Parkinson's disease patients: a pilot study. Eur J Neurol 2012;19:172e5. [22] Zarei M, Ibarretxe-Bilbao N, Compta Y, Hough M, Junque C, Bargallo N, et al. Cortical thinning is associated with disease stages and dementia in Parkinson's disease. J Neurol Neurosurg Psychiatry 2013;84:875e81. [23] Djaldetti R, Ziv I, Melamed E. The mystery of motor asymmetry in Parkinson's disease. Lancet Neurol 2006;5:796e802.
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[24] Piccini P, Burn DJ, Ceravolo R, Maraganore D, Brooks DJ. The role of inheritance in sporadic Parkinson's disease: evidence from a longitudinal study of dopaminergic function in twins. Ann Neurol 1999;45:577e82. [25] Ward CD, Duvoisin RC, Ince SE, Nutt JD, Eldridge R, Calne DB. Parkinson's disease in 65 pairs of twins and in a set of quadruplets. Neurology 1983;33: 815e24. [26] Kalmar Z, Kovacs N, Perlaki G, Nagy F, Aschermann Z, Kerekes Z, et al. Reorganization of motor system in Parkinson's disease. Eur Neurol 2011;66: 220e6. [27] Berti V, Pupi A, Ramat S, Vanzi E, De Cristofaro MT, Pellicano G, et al. Clinical correlation of the binding potential with 123I-FP-CIT in de novo idiopathic Parkinson's disease patients. Eur J Nucl Med Mol Imaging 2008;35:2220e6.
[28] Vogt T, Kramer K, Gartenschlaeger M, Schreckenberger M. Estimation of further disease progression of Parkinson's disease by dopamin transporter scan vs clinical rating. Parkinsonism Relat Disord 2011;17:459e63. [29] Du G, Lewis MM, Sen S, Wang J, Shaffer ML, Styner M, et al. Imaging nigral pathology and clinical progression in Parkinson's disease. Mov Disord 2012;27:1636e43. [30] Burton EJ, McKeith IG, Burn DJ, Williams ED, O'Brien JT. Cerebral atrophy in Parkinson's disease with and without dementia a comparison with Alzheimer's disease, dementia with Lewy bodies and controls. Brain 2004;127:791e800.
Contents lists available at ScienceDirect
Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis
Topographic pattern of cortical thinning with consideration of motor laterality in Parkinson disease Ji Sun Kim a, Jin-ju Yang b, Jong-min Lee b, Jinyoung Youn c, Ju-min Kim c, Jin Whan Cho c, * a
Department of Neurology, Soonchunhyang University Hospital, Soonchunhyang University School of Medicine, Republic of Korea Department of Biomedical Engineering, Hanyang University, Republic of Korea c Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Republic of Korea b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 26 April 2014 Received in revised form 15 July 2014 Accepted 24 August 2014
Background: The asymmetry of Parkinson's disease (PD) may contribute to the unilateral appearance of parkinsonism, as well as its cerebral morphological changes. However, previous studies have not considered that cerebral involvement would probably be asymmetric. Our study aimed to identify whether one-sided symptom dominance has an influence on cortical thinning patterns in early-stage, non-demented PD patients from cortical thickness analyses and cortical thinning patterns are associated with motor functions. Methods: We used cortical thickness analysis in 64 non-demented right-handed subjects: 21 PD patients with left-sided disease onset (LPD), 21 PD patients with right-sided disease onset (RPD) and 22 control subjects. We modeled local cortical thickness as a linear association with each motor symptom. Results: We identified three clusters exhibiting significant cortical thinning (p < 0.01 RFT corrected) in the LPD group compared with the control group: a cluster including the right primary sensory, motor cortex and paracentral lobule, as well as another two clusters in bilateral parahippocampal gyri. In the RPD group, there was only one cluster that exhibited significant cortical thinning compared with the control group, located in the left lingual gyrus. There were no significant correlations between cortical thinning clusters and motor severity, any of the motor subscales including tremor, rigidity, bradykinesia and axial impairment. Conclusions: Our right-handed PD population revealed that significant thinning of motor-related cortical areas in contralateral hemisphere to symptomatic side in LPD, but not in RPD group. Our results support that neuroprotective effect of enhanced physical activity by handedness on contralateral motor cortex. © 2014 Elsevier Ltd. All rights reserved.
Keywords: Cortical thickness Parkinson's disease Asymmetry Functional laterality
1. Introduction Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by the loss of dopamine due to the degeneration of dopaminergic neurons in substantia nigra pars compacta. The pathological process in PD is not confined to the brainstem nuclei but develops to affect various parts of the brain including the cerebral neocortex with an ascending temporal sequence [1]. Infratentorial and subcortical structures such as the brainstem and striatum are primarily affected in PD, and hence past studies have focused on those structures while cortical pathology has received little attention. Recently, various magnetic resonance (MR)
* Corresponding author. Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Irwon-Dong, Gangnam-Gu, Seoul 135-710, Republic of Korea. Tel.: þ82 2 3410 1279; fax: þ82 2 3410 0052. E-mail address: [email protected] (J.W. Cho). http://dx.doi.org/10.1016/j.parkreldis.2014.08.021 1353-8020/© 2014 Elsevier Ltd. All rights reserved.
techniques have become available to describe the morphological changes and patterns of PD during the last decade, suggesting that cortical involvement may be more extensive than previously recognized even in early stages of the disease. However, previous studies revealed discrepancies in reported cortical changes as detected using voxel-based morphometry, volumetric techniques and cortical thickness analysis of MR imaging data collected from PD patients [2e4]. Furthermore, one typical feature of PD is asymmetrical motor feature at the time of diagnosis, and previous studies have not considered that cerebral involvement would probably be asymmetric. Although possible causative mechanisms of asymmetry in PD have been suggested, such as unequal numbers of neurons on each side of the substantia nigra [5], one-sided weakness of the midbrain bloodebrain barrier [6], the neuroprotective effect of enhanced motor exercise [7,8] and hand dominance [9], the exact mechanism of asymmetric manifestation is still unknown. The beneficial effects of exercise from enhanced neuroplasticity have been well
J.S. Kim et al. / Parkinsonism and Related Disorders 20 (2014) 1186e1190
documented by previous studies in both human beings and animal models of PD [10,11], and it is possible that these effects might contribute to the unilateral appearance of motor symptoms [12] and possibly influence on the morphological changes of cerebral structures. Our study aimed to identify whether one-sided symptom dominance has an influence on cortical thinning patterns in earlystage, non-demented PD patients from cortical thickness analyses and whether cortical thinning patterns are associated with motor functions.
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3. Results 3.1. Demographic and clinical features Table 1 presents the demographic characteristics of each group. There were no significant differences of age, sex, disease duration, ICV and MMSE scores among each group. Motor function assessed by UPDRS and H & Y stage did not show differences between LPD and RPD. 3.2. Distribution of focal areas with reduced cortical thickness
2. Methods 2.1. Patients We recruited 64 non-demented, right-handed subjects: 21 patients with PD who had left-sided symptom dominance (LPD), 21 patients with PD who had right-sided symptom dominance (RPD) and 22 control subjects (matched for age and gender). Clinical diagnosis of PD was determined by the UK Brain Bank Criteria for diagnosis of PD [12]. We included patients who scored higher than 26 on the Korean version of the Mini Mental Status Examination (K-MMSE) and with disease duration of less than 4 years. All patients underwent clinical interviews and neurological examinations conducted by experienced neurologists (J.W.C. and J.S.K) in order to evaluate their motor functions. The motor portion of the Unified Parkinson's Disease Rating Scale (UPDRS) and Hoehn and Yahr (H & Y) stage of PD subjects were measured. UPDRS scores were divided into subscores for tremor, rigidity, bradykinesia and axial impairment based on the DATATOP factorial division, using the sum of UPDRS items 20 and 21 for the tremor score, item 22 for the rigidity score, the sum of items 24, 25, 26, and 31 for the bradykinesia score, the sum of items 27, 28, 29 and 30 for the axial impairment score (arising from chair, posture, gait and postural stability) [13]. Patients who had infarction, hemorrhage, tumors, trauma or severe white matter hyperintensity (deep white matter lesion 25 mm and caps or bands 10 mm) were excluded from the study [14,15]. This study was approved by the Institutional Review Board of Samsung Medical Center, Seoul, Korea, and each patient provided informed consent to participate.
2.2. Image acquisition and processing for cortical thickness measurement Three-dimensional T1-weighted MR images were acquired with 3.0-T MRI scanner (Philips 3.0T Achieva) from 64 participants using the following imaging parameters: sagittal slice thickness, 1.0 mm, over contiguous slices with 50% overlap; no gap; repetition time (TR), 9.9 ms; echo time (TE), 4.6 ms; flip angle, 8 ; and matrix size of 240 240 pixels, reconstructed to 480 480 over a field of view (FOV) of 240 mm. Images were processed by the standard Montreal Neurological Institute anatomic pipeline. Further image processing for cortical thickness measurement was described in a previous study [16]. Cortical thickness was measured as the Euclidean distance between linked vertices of the inner and outer surfaces that contained 40,962 vertices on each hemisphere for each subject in native space [17]. To compare thickness across subjects, the thicknesses were spatially normalized using surface-based registration, in which the vertices of each subject were nonlinearly registered to a group template by matching sulcal folding pattern [18,19]. To increase the signal to noise ratio and statistical power, each cortical thickness map was blurred by surface-based diffusion smoothing kernel with a full-width halfmaximum of 20 mm [17]. We included intracranial volume (ICV) as a covariate to control the brain size effect in statistical analyses. ICV was calculated by measuring as the total volume of gray matter, white matter, and cerebrospinal fluid.
There were no significant differences of whole brain mean thickness among LPD, RPD group and control group (mean cortical thickness in the LPD group ¼ 3.01 ± 0.03 mm, in the RPD group ¼ 3.03 ± 0.27 mm, in the NC group ¼ 3.06 ± 0.19 mm). We found three clusters exhibiting significant cortical thinning (p < 0.01 RFT corrected) in the LPD group compared with control group: one cluster including the right primary sensory, motor cortex and paracentral lobule, as well as another two clusters in bilateral parahippocampal gyri (Fig. 1). In the RPD group, there was only one cluster exhibiting a significant cortical thinning (p < 0.01 RFT corrected) compared with the control group, located in the left lingual gyrus (Fig. 1). When we analyzed the difference of cortical thickness between 2 PD groups, significant cortical thinning cluster was not found between 2 PD groups. 3.3. Correlation analyses of cortical thinning areas with motor scale and disease-related metrics We conducted additional analyses in PD groups in order to evaluate the correlation of cortical thinning with motor severity assessed by H & Y stage, UPDRS total score and subscales including tremor, rigidity, bradykinesia and axial impairment. We modeled local cortical thickness as a linear correlation of motor severity and subscales with adjustment of age, sex and ICV. There was no significant correlation between cortical thinning clusters and motor severity assessed by UPDRS score and H & Y stage, nor with motor subscales including tremor, rigidity, bradykinesia and axial impairment. 4. Discussion This is the first study to consider the dominant side of symptom in analysis of cortical thickness in early, non-demented PD patients. The results of this study show that global cortical thickness is preserved in the early-stage PD population compared with a Table 1 Demographic characteristics of IPD and normal controls. IPD (n ¼ 42)
p
65.27 ± 8.50 12:10 28.68 ± 0.31 1373.23 ± 117.82
0.962 0.815 0.138 0.969 0.980 0.553 0.119 0.896 0.785 0.198 0.941
Rt sided (n ¼ 21) Lt sided (n ¼ 21)
2.3. Statistical analyses Statistical analyses for the demographic characteristics of subjects were performed with SPSS Statistics 18.0 (Predictive Analysis Software, Chicago, IL). Independent T-test and ANOVA were used to compare means of variables and the Chisquare test was used to compare the frequency of sex. The localized differences in cortical thickness between the NC and PD groups were analyzed using the General Linear Model on a vertex-by-vertex basis with covariates of age, sex and ICV. Statistical significance was assessed by random field theory (RFT) at a corrected probability value of 0.01 to correct the result for multiple comparisons [20]. To evaluate the correlation of motor subscales on significant cortical thinning cluster, multiple linear regression analysis was performed the regression equation was given as follows: Y(significant thinning cluster) ¼ b1(UPDRS) þ b2(HY) þ b3(Disease duration) þ b4(Tremor subscore) þ b5(rigidity subscore) þ b6(bradykinesia subscore) þ b7(axial impairment subscore).
NC (n ¼ 22)
Age (yrs) Sex (M:F) MMSE ICV (cc) Duration (yrs) UPDRS part III Tremor Rigidity Bradykinesia Axial impair H&Y
65.14 ± 9.99 12:9 27.81 ± 1.66 1365.94 ± 146.32 2.33 ± 1.16 18.07 ± 8.00 1.14 ± 1.28 3.45 ± 2.48 6.90 ± 3.27 2.43 ± 2.40 1.67 ± 0.60
64.57 ± 7.67 10:11 27.90 ± 1.55 1363.40 ± 138.44 2.52 ± 1.17 13.31 ± 7.95 0.90 ± 0.99 3.02 ± 2.69 4.88 ± 3.28 1.40 ± 1.53 1.48 ± 0.58
IPD, idiopathic Parkinson's disease; NC, normal controls; yrs, years; MMSE, Mini Mental Status Examination; ICV, intracranial volume; UPDRS, Unified Parkinson's Disease Rating Scale; H & Y, Hoehn and Yahr stage.
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Fig. 1. Topographical distribution of cortical thickness in LPD compared to NC (A) and RPD compared to NC (B). The statistical t map (top row) shows a trend of cortical thinning in both comparisons of LPD vs. NC (A) with t-value range of 5.89 to 2.75 and RPD vs. NC (B) with t-value range of 4.46 to 3.33. The p map (bottom row) indicated by the color was corrected using the RFT for multiple comparison at a 0.01 threshold.
healthy population, regardless of the symptomatic side of the body. However, different focal areas exhibiting significant cortical thinning in PD groups were found with consideration of symptomatic side: one cluster including the right primary sensory, motor cortex and paracentral lobule, as well as another two clusters in bilateral parahippocampal gyri, while left lingual gyrus in RPD. Significant cortical thinning cluster was not found between 2 PD groups. We did not find any significant associations between clusters with cortical thinning and the motor symptoms of PD in correlation analyses. The major pathological change in PD is a degeneration of nigrostriatal dopaminergic neurons. However, PD is a network disorder and is known to involve almost the whole brain [1]. Despite less vulnerable cortical structures gradually become affected as the disease progresses, several recent MR-based imaging analyses of PD revealed that cortical atrophy exists even in early stages of disease development [4]. Among several other methods, cortical thickness analysis has been introduced as an effort to overcome the difficulties in analysis of highly convoluted cerebral cortex and have demonstrated focal cortical thinning pattern in neurologic diseases. However, the results using cortical thickness analysis in PD patients were not consistent between the studies and there was no study to consider the motor laterality which is one of the most important features. We identified several focal thinning areas including the right primary sensory, motor cortex, paracentral lobule, bilateral parahippocampal gyri of LPD patients and the left lingual gyrus of RPD patients. We included early stage patients whose duration of symptom is less than 4 years, and it might have an effect on the topographical distribution of cortical thinning pattern. The distribution of cortical thinning clusters is overlapped with the regions where cortical Lewy bodies and Lewy neuritis are found in patients of Braak's stage 4 [1] and almost consistent with the results of previous imaging studies [4,21]. Cortical areas associated with motor functions are known to be damaged in PD even in early stage by recent imaging analyses [22].
Interestingly, we identified significant cortical thinning in motorrelated areas only in LPD, but not in RPD group. These results suggest the possibility that enhanced physical activity by handedness may have a neuroprotective effect on contralateral cerebral structures. The onset of motor symptoms is often exhibited exclusively on either the right or left side of the body, and the unilateral predominance of symptoms often persists long after the disease becomes clinically bilateral [23]. Despite the common recognition of symptom asymmetry in PD, data explaining this phenomenon are sparse. Although the exact etiology of lateralization is not well established, there are a few potential mechanisms and contributory factors that have been suggested to influence the asymmetry of symptom appearance [23e25]. Previous experimental results have demonstrated that enhanced physical activity may have a neuroprotective effect on contralateral motor circuits [7,8]. In an experimental motor rat model, unilateral injection of 6-hydroxydopamine (6-OHDA) with a cast applied to an ipsilateral non-impaired limb, forcing the animal to use the impaired contralateral limbs, caused no detectable impairment or asymmetry of limb use despite a decreased ipsilateral dopamine concentration in the striatum. Another functional neuroimaging study also suggested that enhancing performance by handedness plays a significant role in the reorganization of the contralateral motor system and neuroplasticity [26]. All of the patients in the present study were right-handed, so more strenuous exercise performed by the right side of the body may explain the absence of significant cortical thinning in areas of the motor related cortex in the RPD group. Additionally, Korean culture has a strong tradition of preferring use of right hand in all tasks, and using right hand is thought to be polite manners. So the percentage of left handed people in Korea is lower than in other countries. And hence, cultural feature of encouraging use of right hand would also influence on the results of our study. Our results support the hypothesis of neuroprotective effect by enhanced physical activity on contralateral motor cortex. In linear correlation analysis, the thickness of the cortical area did not show significant correlation with the severity of motor
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symptoms including tremor, rigidity, bradykinesia or axial impairment. Another recent study using cortical thickness analysis in advanced PD reported that motor severity was not correlated with cortical thickness, but the associations with subcortical structures (basal ganglia) were robust [22]. Structural and dopamine transporter (DAT) imaging analyses also suggested that cortical change, as well as striatal DAT binding does not seem to be correlated with clinical severity assessed by UPDRS [27e29]. Likewise, the exact nature of the correlation between clinical severity and cortical thickness is not yet well established. The lack of significant correlation between motor symptoms and cortical thickness in our study might suggest that cortical thinning of PD occurs independently of striatonigral dopaminergic neuronal damage. Cortical thinning is reported to be associated with nonmotor symptoms such as cognitive dysfunction [3,30] and we might miss the better correlation of these potential non-motor symptoms with observed cortical thinning in PD patients. However, we analyzed the only patients of early stage to identify existence of cortical thinning in early-stage, non-demented PD patients from cortical thickness analyses and to rule out the influence of non-motor symptoms such as cognitive dysfunctions on cortical structures that may occur in advanced stage. And hence, the short disease duration may not be long enough to significantly change the cortical thickness to detect the association with clinical severity considering that cortical atrophy becomes more defined with increased disease progression. A large-scale study demonstrating this relationship is needed to clarify the nature of this association. 5. Conclusion In summary, our study demonstrated different cortical thinning areas according to side of symptom dominance in early, nondemented PD patients for the first time. Our right-handed PD population revealed significant thinning of motor-related cortical areas in the hemisphere contralateral to the symptomatic side in LPD patients but not in the RPD group. These data support the possibility that enhanced physical activities by handedness may have a neuroprotective effect on contralateral motor cortices. To confirm this, a well-designed prospective study demonstrating this hypothesis is needed. Disclosure This work was supported by a Samsung Medical Center grant (SMO1131541) and Soonchunhyang University Research Fund. Author's role 1. Research project: A. Conception, B. Organization, C. Execution 2. Statistical analysis: A. Design, B. Execution, C. Review and Critique 3. Manuscript preparation: A. Writing of the first draft, B. Review and Critique Ji sun Kim, MD: 1ABC, 2AB and 3A; Jin-ju Yang: 2ABC and 3B; Jong-min Lee, PhD: 2ABC and 3B; Jinyoung Youn, MD: 1ABC, 2C and 3C. Ju-min Kim, MD: 2C and 3B. Jin Whan Cho, M.D., Ph.D.: 1ABC, 2C and 3C. Ethical standards All persons gave their informed consent prior to their inclusion in the study.
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Conflict of interest The authors declare that they have no conflict of interest.
Acknowledgment We thank the members of the KOJYP study group (Wooyoung Jang, Eungseok Oh, Jinse Park) for special comments on our work. J.J Y and J. M. L have received research support from National Research Foundation of Korea (NRF) grant funded by the Korea Government (MEST) (2011-0028333).
References [1] Braak H, Tredici KD, Rüb U, Vos RAId, Steur ENHJ, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003;24: 197e211. [2] Dalaker TO, Larsen JP, Bergsland N, Beyer MK, Alves G, Dwyer MG, et al. Brain atrophy and white matter hyperintensities in early Parkinson's disease(a). Mov Disord 2009;24:2233e41. [3] Nagano-Saito A, Washimi Y, Arahata Y, Kachi T, Lerch JP, Evans AC, et al. Cerebral atrophy and its relation to cognitive impairment in Parkinson disease. Neurology 2005;64:224e9. [4] Jubault T, Gagnon JF, Karama S, Ptito A, Lafontaine AL, Evans AC, et al. Patterns of cortical thickness and surface area in early Parkinson's disease. Neuroimage 2011;55:462e7. [5] Kempster PA, Gibb WRG, Stern GM, Lees AJ. Asymmetry of substantia nigra neuronal loss in Parkinson's disease and its relevance to the mechanism of levodopa related motor fluctuations. J Neurol Neurosurg Psychiatry 1989;52: 72e6. [6] Kortekaas R, Leenders KL, van Oostrom JC, Vaalburg W, Bart J, Willemsen AT, et al. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo. Ann Neurol 2005;57:176e9. [7] Tillerson JL, Cohen AD, Philhower J, Miller GW, Zigmond MJ, Schallert T. Forced limb-use effects on the behavioral and neurochemical effects of 6hydroxydopamine. J Neurosci 2001;15:4427e35. [8] Cohen AD, Tillerson JL, Smith AD, Schallert T, Zigmond MJ. Neuroprotective effects of prior limb use in 6-hydroxydopamine-treated rats: possible role of GDNF. J Neurochem 2003;85:299e305. [9] Uitti RJ, Baba Y, Whaley NR, Wszolek ZK, Putzke JD. Parkinson disease: handedness predicts asymmetry. Neurology 2005;64:1925e30. [10] Petzinger GM, Fisher BE, McEwen S, Beeler JA, Walsh JP, Jakowec MW. Exercise-enhanced neuroplasticity targeting motor and cognitive circuitry in Parkinson's disease. Lancet Neurol 2013;12:716e26. [11] Petzinger GM, Fisher BE, Van Leeuwen JE, Vukovic M, Akopian G, Meshul CK, et al. Enhancing neuroplasticity in the basal ganglia: the role of exercise in Parkinson's disease. Mov Disord 2010;25(Suppl. 1):S141e5. [12] Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson's disease a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181e4. [13] Uc EY, McDermott MP, Marder KS, Anderson SW, Litvan I, Como PG, et al. Incidence of and risk factors for cognitive impairment in an early Parkinson disease clinical trial cohort. Neurology 2009;73:1469e77. €ntyla € R, Erkinjuntti T, Salonen O, Aronen HJ, Peltonen T, Pohjasvaara T, [14] Ma et al. Variable agreement between visual rating scales for white matter hyperintensities on MRI. Stroke 1997;28:1614e23. [15] Scheltens P, Barkhof F, Leys D, Pruvo JP, Nauta JJP, Vermersch P, et al. A semiquantative rating scale for the assessment of signal hyperintensities on magnetic resonance imaging. J Neurol Sci 1993;114:7e12. [16] Kim JS, Youn J, Yang JJ, Lee DK, Lee JM, Kim ST, et al. Topographic distribution of cortical thinning in subtypes of multiple system atrophy. Parkinsonism Relat Disord 2013;19:970e4. [17] Lerch JP, Evans AC. Cortical thickness analysis examined through power analysis and a population simulation. Neuroimage 2005;24:163e73. [18] Robbins S, Evans AC, Collins DL, Whitesides S. Tuning and comparing spatial normalization methods. Med Image Anal 2004;8:311e23. [19] Lyttelton O, Boucher M, Robbins S, Evans A. An unbiased iterative group registration template for cortical surface analysis. Neuroimage 2007;34:1535e44. [20] Worsley KJ, Marrett S, Neelin P, Vandal AC, Friston KJ, Evans AC. A unified statistical approach for determining significant signals in images of cerebral activation. Hum Brain Mapp 1996;4:58e73. [21] Pellicano C, Assogna F, Piras F, Caltagirone C, Pontieri FE, Spalletta G. Regional cortical thickness and cognitive functions in non-demented Parkinson's disease patients: a pilot study. Eur J Neurol 2012;19:172e5. [22] Zarei M, Ibarretxe-Bilbao N, Compta Y, Hough M, Junque C, Bargallo N, et al. Cortical thinning is associated with disease stages and dementia in Parkinson's disease. J Neurol Neurosurg Psychiatry 2013;84:875e81. [23] Djaldetti R, Ziv I, Melamed E. The mystery of motor asymmetry in Parkinson's disease. Lancet Neurol 2006;5:796e802.
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J.S. Kim et al. / Parkinsonism and Related Disorders 20 (2014) 1186e1190
[24] Piccini P, Burn DJ, Ceravolo R, Maraganore D, Brooks DJ. The role of inheritance in sporadic Parkinson's disease: evidence from a longitudinal study of dopaminergic function in twins. Ann Neurol 1999;45:577e82. [25] Ward CD, Duvoisin RC, Ince SE, Nutt JD, Eldridge R, Calne DB. Parkinson's disease in 65 pairs of twins and in a set of quadruplets. Neurology 1983;33: 815e24. [26] Kalmar Z, Kovacs N, Perlaki G, Nagy F, Aschermann Z, Kerekes Z, et al. Reorganization of motor system in Parkinson's disease. Eur Neurol 2011;66: 220e6. [27] Berti V, Pupi A, Ramat S, Vanzi E, De Cristofaro MT, Pellicano G, et al. Clinical correlation of the binding potential with 123I-FP-CIT in de novo idiopathic Parkinson's disease patients. Eur J Nucl Med Mol Imaging 2008;35:2220e6.
[28] Vogt T, Kramer K, Gartenschlaeger M, Schreckenberger M. Estimation of further disease progression of Parkinson's disease by dopamin transporter scan vs clinical rating. Parkinsonism Relat Disord 2011;17:459e63. [29] Du G, Lewis MM, Sen S, Wang J, Shaffer ML, Styner M, et al. Imaging nigral pathology and clinical progression in Parkinson's disease. Mov Disord 2012;27:1636e43. [30] Burton EJ, McKeith IG, Burn DJ, Williams ED, O'Brien JT. Cerebral atrophy in Parkinson's disease with and without dementia a comparison with Alzheimer's disease, dementia with Lewy bodies and controls. Brain 2004;127:791e800.