- Email: [email protected]
The relationship between arm dystonia in corticobasal degeneration and handedness
Journal of Clinical Neuroscience 19 (2012) 1134–1136
Contents lists available at SciVerse ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
The relationship between arm dystonia in corticobasal degeneration and handedness Abdul Qayyum Rana ⇑, Hamza Ansari, Ishraq Siddiqui Parkinson’s Clinic of Eastern Toronto and Movement Disorders Center, 404-2863 Ellesmere Road, Toronto, Ontario, Canada M1E5E9
a r t i c l e
i n f o
Article history: Received 12 October 2011 Accepted 18 October 2011
Keywords: Corticobasal degeneration Handedness Laterality
a b s t r a c t Corticobasal degeneration is a progressive neurodegenerative disease involving the cerebral cortex and basal ganglia and leads primarily to motor symptoms and cognitive dysfunction. Unilateral arm dystonia is a common presenting symptom in many patients with corticobasal degeneration. This study attempts to determine if a relationship exists between arm dystonia in corticobasal degeneration and the handedness of the patient. A chart review of 12 right-handed patients (six males and six females) diagnosed with corticobasal degeneration seen in a Parkinson’s disease clinic was conducted. With the exception of a single individual who was afflicted in her dominant arm, all had dystonia in their left arm. The ages of the female patients were substantially lower than their male counterparts. Although the sample size of the patient population is small, the results raise an interesting question: is arm dystonia in corticobasal degeneration more commonly seen on the contralateral side of the dominant hand. Further observation is needed to establish a correlation. Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
1. Introduction Corticobasal degeneration (CBD) is a progressive neurodegenerative disease that involves the cerebral cortex and basal ganglia.1,2 The cerebral cortex mediates the control of voluntary motor executions, sensory perception, memory, and thought. The basal ganglia are a group of nuclei in the brain that are associated with functions that primarily include motor control. Due to the involvement of these areas, the clinical symptoms of CBD involve cognitive and motor deficits.3,4 Motor symptoms include: limb clumsiness, bradykinesia or akinesia, rigidity, postural tremor, and limb dystonia.1,4 A defining feature of the motor symptoms in CBD is unilaterality or strong asymmetry.1 Dystonia occurs commonly in CBD, with studies reporting from 59% to more than 90%.5 Dystonia is a condition characterized by prolonged muscle contractions causing sustained twisting movements and abnormal posture of affected body regions.6 The exact pathophysiology of CBD is still unclear, and the diagnosis may be complicated and difficult due to similarities with other neurodegenerative diseases.1 There is as yet no cure for CBD nor any permanent means of suppressing the dystonia. Although it is well established that CBD presents with asymmetric motor symptoms,7,8 consistent patterns in the observed asymmetry, particularly in the case of arm dystonia, have not been ⇑ Corresponding author. Tel.: +1 416 724 9850. E-mail address: [email protected] (A.Q. Rana).
focused upon previously. The purpose of this study was to identify if there exists a relationship between arm dystonia in CBD and handedness, namely to observe if the side ipsilateral or contralateral to the dominant arm seems particularly predisposed to dystonia. 2. Methods A chart review of 12 patients with CBD was performed regularly and they were then followed in a community-based Parkinson’s Disease and Movement Disorders Clinic. Due to the rarity of the condition, these patients constituted the entire group of individuals with CBD in the clinic over the previous four years. The clinical diagnosis of CBD was based on presence of three of the following: bradykinesia and rigidity that does not respond to levodopa; alien limb phenomena; cortical sensory signs; focal limb dystonia; action tremor; or myoclonus. The diagnostic criteria applied were adapted from those described by Boeve.9 The data of greatest interest were the dominant and dystonic arm for each patient. Also taken into account were potentially relevant factors such as gender and age at diagnosis. The available medical histories were reviewed to identify potential confounds in the diagnosis of CBD and in the presentation of dystonia. Since the sample of patients used for the study was particularly small, no statistical analysis was performed on the findings. Tests were not applicable or otherwise believed to add no value to information ascertainable from descriptive statistics alone.
0967-5868/$ - see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jocn.2011.10.012
A.Q. Rana et al. / Journal of Clinical Neuroscience 19 (2012) 1134–1136 Table 1 Characteristics of 12 patients with corticobasal degeneration with either left or right arm dystonia Patient no.
Sex
Age at diagnosis (years)
Dominant arm
Dystonic arm
1 2 3 4 5 6 7 8 9 10 11 12
F F M F M M M F M M F F
76 66 85 54 91 78 63 52 60 67 83 66
Right Right Right Right Right Right Right Right Right Right Right Right
Left Left Left Left Left Left Left Right Left Left Left Left
1135
reported prevalence rate, further supported by our observations, encourages the study of dystonia in CBD. In another study of the clinical signs of CBD in 10 patients, eight were right-handed and two were left-handed.2 Most individuals were reported as having the side opposite their dominant being most affected by CBD. These findings suggest that there may be an inverse relationship between the handedness of a patient and the side where the motor symptoms are most prevalent. However, dystonia was not specifically focused upon. The dystonia of the arm is of particular importance as it is a highly disabling symptom that renders a limb useless. What makes dystonia additionally unique is its tendency to only affect one side of the body. Most other motor symptoms manifest disproportionately, but bilaterally nonetheless. 4.2. Dystonia
3. Results 3.1. Dystonia and CBD All patients reviewed were right-hand dominant and had unilateral arm dystonia. A single individual had dystonia of the dominant arm, but the remaining 11 had dystonia of the left upper extremity. The details pertaining to all patients are presented in Table 1. The level of asymmetry between limbs was clear for all patients. Patients had motor disruptions characteristic of CBD other than dystonia such as rigidity, bradykinesia, and apraxia, which also favoured the side with dystonia. In some instances these effects were seen only unilaterally, while others were bilateral but highly disproportionate. The severity of these symptoms always coincided with the dystonia, but dystonic features remained easily distinguishable. The dystonic arm in all patients was stiff, rigid and functionless. Furthermore, there was dystonic posturing of the fingers of the dystonic hand whereas this did not occur on the other hand. Some individuals had additional comorbidities, but these were clearly separable from the symptoms of interest and confirmed to have no confounding effect on the observation of dystonia. The single patient who had dystonia on the right arm showed the same motor symptom trends of other individuals, except consistently on the opposite limb. Despite this exception, the tendency for dystonia to affect the arm opposite the dominant seems highly significant.
3.2. Age and gender A trend that was not being sought but which became evident after analysis was the apparent difference between the ages of male and female patients when CBD and dystonia were diagnosed. The males had an average age of 74 years (range: 60–91 years) while the females were an average of 66.2 years of age (range: 52–83 years). Although the sample does not meet the criteria for statistical testing for probabilistic quantification of this difference, it is certainly notable. The disparity in age is indicative of a potential difference between men and women in the manifestation of dystonia in CBD.
The tendency of dystonia to impact only one side of the body was quite evident. More interesting was the near-perfect consistency in this sample in terms of which arm was affected. The arm contralateral to the dominant seems particularly predisposed to developing dystonia in CBD. From another standpoint, it may be suggested that the dominant arm is particularly resistant to dystonia. Like all motor symptoms in CBD, dystonia originates from the involvement of the contralateral side of the brain. It is possible that the unilateral presentation of dystonia indicates to what extent particular neural networks are affected by CBD. Individuals use their dominant arm preferentially for most general tasks, and almost exclusively for intricate tasks. Due to the disproportionate use of the dominant arm, it is most likely that the neural networks governing the arm movements are disproportionately strengthened. The contralateral arm’s weakness in this regard may explain the observed tendency of dystonia to manifest unilaterally. Parkinson’s disease (PD) is the main condition which mimics CBD in asymmetrical motor symptoms, particularly at disease onset.10 However, the asymmetry of motor symptoms seen in PD decreases with the progression of the disease, whereas CBD maintains its asymmetry throughout its course.1 The neurodegenerative aspects of CBD seem more related to Alzheimer’s disease, in terms of the cortical atrophy and implied involvement of tau protein.11 This is worthy of discussion as there has been much effort put towards determining risk factors and prevention of Alzheimer’s disease. Although no firm conclusion has yet been reached, there have been suggestions that the progression and level of neural deterioration are somewhat dependent on the strength of neural networks involved.12 A background of higher education and cognitive stimulation has been inversely related to cognitive decline.12,13 If indeed dystonia is dependent on the stability of some neural networks, and if these neural networks can be reinforced by experience, it stands to reason that greater use of a limb will make it less prone to dystonia. Although there remains no cure for this condition, it may be helpful to advise patients with early signs of impending dystonia to make more use of their affected arm. Reminding patients to consciously use their affected arm may have a significant effect, considering that otherwise the use of the affected arm would likely be even less than usual due to emergence of difficulty once dystonia is apparent. This suggestion is however based on a great deal of speculation.
4. Discussion 4.3. Age and gender significance 4.1. Manifestation of dystonia in CBD patients Unilateral arm dystonia is a very common symptom in patients with CBD.1 All 12 patients analyzed in this study who were diagnosed with CBD presented with unilateral arm dystonia. The high
The difference in age between the genders is less explicable. Although the significance of age at which dystonia takes hold is not clear, one interpretation is that it may be an indication of how prone an individual is to having this motor disorder. This
1136
A.Q. Rana et al. / Journal of Clinical Neuroscience 19 (2012) 1134–1136
would suggest that someone who acquires dystonia at a younger age is somehow predisposed. If the above speculation that dystonia is related to the strength of neural networks holds merit, it may be extended further to explain the gender differences. It has been noted that the nature of cortical asymmetry is variant by age and gender.14,15 Males generally tend to have greater hemispheric asymmetry in favor of the dominant hemisphere. While females also have such asymmetry, the two hemispheres are more alike than in males.15 The disparity in the relative strengths of different neural networks between men and women may play a role in making women more prone to experiencing dystonia from a younger age. This is, however, a highly speculative hypothesis. The small sample size, being the major limitation of this study, makes it difficult to generalize the findings. However, CBD is a rare disease. Such consistency in the results, even in a small population with numerous potential cofactors, cannot be ignored. Further research is required to confirm the consistency of these findings. It would be particularly beneficial to examine a larger group of individuals with a greater variety in age and handedness for both genders. Perhaps more important still is identifying more specifically the connecting factors between the neural degeneration in CBD and the manifestation of arm dystonia and other motor symptoms. 5. Conclusions Our observations suggest that there may be an inverse correlation between handedness and the manifestation of arm dystonia in patients with CBD. Also evident were differences in age of onset of CBD between genders. If these are indeed true effects, it is posited that they are a reflection of how CBD affects brain regions differentially, and may be important for understanding the disease and its cure. Conflict of Interest The authors declare that no funding was received for this project. We attest herein that there are no relevant personal relationships with parties or organizations.
Acknowledgment The authors acknowledge Dr Abdul Fattah’s help in reviewing and formatting the study. References 1. Mahapatra R, Edwards M, Schott J, et al. Corticobasal degeneration. Lancet Neurol 2004;3:736–43. 2. Monza D, Ciano C, Scaioli V, et al. Neurophysiological features in relation to clinical signs in clinically diagnosed corticobasal degeneration. Neurol Sci 2003;24:16–23. 3. Murray R, Neumann M, Forman MS, et al. Cognitive and motor assessment in autopsy-proven corticobasal degeneration. Neurology 2007;68:1274–83. 4. Peigneux P, Salmon E, Garraux G, et al. Neural and cognitive bases of upper limb apraxia in corticobasal degeneration. Neurology 2001;57:1259–68. 5. Vanek Z, Jankovic J. Dystonia in corticobasal degeneration. Mov Disord 2001;16:252–7. 6. Berardelli A, Rothwell JC, Hallett M, et al. The pathophysiology of primary dystonia. Brain 1998;121:1195–212. 7. Hassan A, Whitwell JL, Boeve BF, et al. Symmetric corticobasal degeneration (SCBD). Parkinsonism Relat Disord 2009;16:208–14. 8. Rinne JO, Lee MS, Thompson PD, et al. Corticobasal degeneration. A clinical study of 36 cases. Brain 1994;117:1183–96. 9. Boeve BF, Lang AE, Litvan I. Corticobasal degeneration and its relationship to progressive supranuclear palsy and frontotemporal dementia. Ann Neurol 2003;54:S15–9. 10. Poewe W, Wenning G. The differential diagnosis of Parkinson’s disease. Eur J Neurol 2002;9:23–30. 11. Goedert M, Jakes R. Mutations causing neurodegenerative tauopathies. Biochim Biophys Acta 2005;1739:240–50. 12. Garibotto V, Borroni B, Kalbe E, et al. Education and occupation as proxies for reserve in aMCI converters and AD: FDG-PET evidence. Neurology 2008;71:1342–9. 13. Leibovici D, Ritchie K, Ledésert B, et al. Does education level determine the course of cognitive decline? Age Ageing 1996;25:392–7. 14. Takahashi R, Ishii K, Kakigi T, Yokoyama K. Gender and age differences in normal adult human brain: voxel-based morphometric study. Hum Brain Mapp 2010;32:1050–8. 15. McGlone J. Sex differences in human brain asymmetry: a critical survey. Behav Brain Sci 1980;3:215–27.
Contents lists available at SciVerse ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
The relationship between arm dystonia in corticobasal degeneration and handedness Abdul Qayyum Rana ⇑, Hamza Ansari, Ishraq Siddiqui Parkinson’s Clinic of Eastern Toronto and Movement Disorders Center, 404-2863 Ellesmere Road, Toronto, Ontario, Canada M1E5E9
a r t i c l e
i n f o
Article history: Received 12 October 2011 Accepted 18 October 2011
Keywords: Corticobasal degeneration Handedness Laterality
a b s t r a c t Corticobasal degeneration is a progressive neurodegenerative disease involving the cerebral cortex and basal ganglia and leads primarily to motor symptoms and cognitive dysfunction. Unilateral arm dystonia is a common presenting symptom in many patients with corticobasal degeneration. This study attempts to determine if a relationship exists between arm dystonia in corticobasal degeneration and the handedness of the patient. A chart review of 12 right-handed patients (six males and six females) diagnosed with corticobasal degeneration seen in a Parkinson’s disease clinic was conducted. With the exception of a single individual who was afflicted in her dominant arm, all had dystonia in their left arm. The ages of the female patients were substantially lower than their male counterparts. Although the sample size of the patient population is small, the results raise an interesting question: is arm dystonia in corticobasal degeneration more commonly seen on the contralateral side of the dominant hand. Further observation is needed to establish a correlation. Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
1. Introduction Corticobasal degeneration (CBD) is a progressive neurodegenerative disease that involves the cerebral cortex and basal ganglia.1,2 The cerebral cortex mediates the control of voluntary motor executions, sensory perception, memory, and thought. The basal ganglia are a group of nuclei in the brain that are associated with functions that primarily include motor control. Due to the involvement of these areas, the clinical symptoms of CBD involve cognitive and motor deficits.3,4 Motor symptoms include: limb clumsiness, bradykinesia or akinesia, rigidity, postural tremor, and limb dystonia.1,4 A defining feature of the motor symptoms in CBD is unilaterality or strong asymmetry.1 Dystonia occurs commonly in CBD, with studies reporting from 59% to more than 90%.5 Dystonia is a condition characterized by prolonged muscle contractions causing sustained twisting movements and abnormal posture of affected body regions.6 The exact pathophysiology of CBD is still unclear, and the diagnosis may be complicated and difficult due to similarities with other neurodegenerative diseases.1 There is as yet no cure for CBD nor any permanent means of suppressing the dystonia. Although it is well established that CBD presents with asymmetric motor symptoms,7,8 consistent patterns in the observed asymmetry, particularly in the case of arm dystonia, have not been ⇑ Corresponding author. Tel.: +1 416 724 9850. E-mail address: [email protected] (A.Q. Rana).
focused upon previously. The purpose of this study was to identify if there exists a relationship between arm dystonia in CBD and handedness, namely to observe if the side ipsilateral or contralateral to the dominant arm seems particularly predisposed to dystonia. 2. Methods A chart review of 12 patients with CBD was performed regularly and they were then followed in a community-based Parkinson’s Disease and Movement Disorders Clinic. Due to the rarity of the condition, these patients constituted the entire group of individuals with CBD in the clinic over the previous four years. The clinical diagnosis of CBD was based on presence of three of the following: bradykinesia and rigidity that does not respond to levodopa; alien limb phenomena; cortical sensory signs; focal limb dystonia; action tremor; or myoclonus. The diagnostic criteria applied were adapted from those described by Boeve.9 The data of greatest interest were the dominant and dystonic arm for each patient. Also taken into account were potentially relevant factors such as gender and age at diagnosis. The available medical histories were reviewed to identify potential confounds in the diagnosis of CBD and in the presentation of dystonia. Since the sample of patients used for the study was particularly small, no statistical analysis was performed on the findings. Tests were not applicable or otherwise believed to add no value to information ascertainable from descriptive statistics alone.
0967-5868/$ - see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jocn.2011.10.012
A.Q. Rana et al. / Journal of Clinical Neuroscience 19 (2012) 1134–1136 Table 1 Characteristics of 12 patients with corticobasal degeneration with either left or right arm dystonia Patient no.
Sex
Age at diagnosis (years)
Dominant arm
Dystonic arm
1 2 3 4 5 6 7 8 9 10 11 12
F F M F M M M F M M F F
76 66 85 54 91 78 63 52 60 67 83 66
Right Right Right Right Right Right Right Right Right Right Right Right
Left Left Left Left Left Left Left Right Left Left Left Left
1135
reported prevalence rate, further supported by our observations, encourages the study of dystonia in CBD. In another study of the clinical signs of CBD in 10 patients, eight were right-handed and two were left-handed.2 Most individuals were reported as having the side opposite their dominant being most affected by CBD. These findings suggest that there may be an inverse relationship between the handedness of a patient and the side where the motor symptoms are most prevalent. However, dystonia was not specifically focused upon. The dystonia of the arm is of particular importance as it is a highly disabling symptom that renders a limb useless. What makes dystonia additionally unique is its tendency to only affect one side of the body. Most other motor symptoms manifest disproportionately, but bilaterally nonetheless. 4.2. Dystonia
3. Results 3.1. Dystonia and CBD All patients reviewed were right-hand dominant and had unilateral arm dystonia. A single individual had dystonia of the dominant arm, but the remaining 11 had dystonia of the left upper extremity. The details pertaining to all patients are presented in Table 1. The level of asymmetry between limbs was clear for all patients. Patients had motor disruptions characteristic of CBD other than dystonia such as rigidity, bradykinesia, and apraxia, which also favoured the side with dystonia. In some instances these effects were seen only unilaterally, while others were bilateral but highly disproportionate. The severity of these symptoms always coincided with the dystonia, but dystonic features remained easily distinguishable. The dystonic arm in all patients was stiff, rigid and functionless. Furthermore, there was dystonic posturing of the fingers of the dystonic hand whereas this did not occur on the other hand. Some individuals had additional comorbidities, but these were clearly separable from the symptoms of interest and confirmed to have no confounding effect on the observation of dystonia. The single patient who had dystonia on the right arm showed the same motor symptom trends of other individuals, except consistently on the opposite limb. Despite this exception, the tendency for dystonia to affect the arm opposite the dominant seems highly significant.
3.2. Age and gender A trend that was not being sought but which became evident after analysis was the apparent difference between the ages of male and female patients when CBD and dystonia were diagnosed. The males had an average age of 74 years (range: 60–91 years) while the females were an average of 66.2 years of age (range: 52–83 years). Although the sample does not meet the criteria for statistical testing for probabilistic quantification of this difference, it is certainly notable. The disparity in age is indicative of a potential difference between men and women in the manifestation of dystonia in CBD.
The tendency of dystonia to impact only one side of the body was quite evident. More interesting was the near-perfect consistency in this sample in terms of which arm was affected. The arm contralateral to the dominant seems particularly predisposed to developing dystonia in CBD. From another standpoint, it may be suggested that the dominant arm is particularly resistant to dystonia. Like all motor symptoms in CBD, dystonia originates from the involvement of the contralateral side of the brain. It is possible that the unilateral presentation of dystonia indicates to what extent particular neural networks are affected by CBD. Individuals use their dominant arm preferentially for most general tasks, and almost exclusively for intricate tasks. Due to the disproportionate use of the dominant arm, it is most likely that the neural networks governing the arm movements are disproportionately strengthened. The contralateral arm’s weakness in this regard may explain the observed tendency of dystonia to manifest unilaterally. Parkinson’s disease (PD) is the main condition which mimics CBD in asymmetrical motor symptoms, particularly at disease onset.10 However, the asymmetry of motor symptoms seen in PD decreases with the progression of the disease, whereas CBD maintains its asymmetry throughout its course.1 The neurodegenerative aspects of CBD seem more related to Alzheimer’s disease, in terms of the cortical atrophy and implied involvement of tau protein.11 This is worthy of discussion as there has been much effort put towards determining risk factors and prevention of Alzheimer’s disease. Although no firm conclusion has yet been reached, there have been suggestions that the progression and level of neural deterioration are somewhat dependent on the strength of neural networks involved.12 A background of higher education and cognitive stimulation has been inversely related to cognitive decline.12,13 If indeed dystonia is dependent on the stability of some neural networks, and if these neural networks can be reinforced by experience, it stands to reason that greater use of a limb will make it less prone to dystonia. Although there remains no cure for this condition, it may be helpful to advise patients with early signs of impending dystonia to make more use of their affected arm. Reminding patients to consciously use their affected arm may have a significant effect, considering that otherwise the use of the affected arm would likely be even less than usual due to emergence of difficulty once dystonia is apparent. This suggestion is however based on a great deal of speculation.
4. Discussion 4.3. Age and gender significance 4.1. Manifestation of dystonia in CBD patients Unilateral arm dystonia is a very common symptom in patients with CBD.1 All 12 patients analyzed in this study who were diagnosed with CBD presented with unilateral arm dystonia. The high
The difference in age between the genders is less explicable. Although the significance of age at which dystonia takes hold is not clear, one interpretation is that it may be an indication of how prone an individual is to having this motor disorder. This
1136
A.Q. Rana et al. / Journal of Clinical Neuroscience 19 (2012) 1134–1136
would suggest that someone who acquires dystonia at a younger age is somehow predisposed. If the above speculation that dystonia is related to the strength of neural networks holds merit, it may be extended further to explain the gender differences. It has been noted that the nature of cortical asymmetry is variant by age and gender.14,15 Males generally tend to have greater hemispheric asymmetry in favor of the dominant hemisphere. While females also have such asymmetry, the two hemispheres are more alike than in males.15 The disparity in the relative strengths of different neural networks between men and women may play a role in making women more prone to experiencing dystonia from a younger age. This is, however, a highly speculative hypothesis. The small sample size, being the major limitation of this study, makes it difficult to generalize the findings. However, CBD is a rare disease. Such consistency in the results, even in a small population with numerous potential cofactors, cannot be ignored. Further research is required to confirm the consistency of these findings. It would be particularly beneficial to examine a larger group of individuals with a greater variety in age and handedness for both genders. Perhaps more important still is identifying more specifically the connecting factors between the neural degeneration in CBD and the manifestation of arm dystonia and other motor symptoms. 5. Conclusions Our observations suggest that there may be an inverse correlation between handedness and the manifestation of arm dystonia in patients with CBD. Also evident were differences in age of onset of CBD between genders. If these are indeed true effects, it is posited that they are a reflection of how CBD affects brain regions differentially, and may be important for understanding the disease and its cure. Conflict of Interest The authors declare that no funding was received for this project. We attest herein that there are no relevant personal relationships with parties or organizations.
Acknowledgment The authors acknowledge Dr Abdul Fattah’s help in reviewing and formatting the study. References 1. Mahapatra R, Edwards M, Schott J, et al. Corticobasal degeneration. Lancet Neurol 2004;3:736–43. 2. Monza D, Ciano C, Scaioli V, et al. Neurophysiological features in relation to clinical signs in clinically diagnosed corticobasal degeneration. Neurol Sci 2003;24:16–23. 3. Murray R, Neumann M, Forman MS, et al. Cognitive and motor assessment in autopsy-proven corticobasal degeneration. Neurology 2007;68:1274–83. 4. Peigneux P, Salmon E, Garraux G, et al. Neural and cognitive bases of upper limb apraxia in corticobasal degeneration. Neurology 2001;57:1259–68. 5. Vanek Z, Jankovic J. Dystonia in corticobasal degeneration. Mov Disord 2001;16:252–7. 6. Berardelli A, Rothwell JC, Hallett M, et al. The pathophysiology of primary dystonia. Brain 1998;121:1195–212. 7. Hassan A, Whitwell JL, Boeve BF, et al. Symmetric corticobasal degeneration (SCBD). Parkinsonism Relat Disord 2009;16:208–14. 8. Rinne JO, Lee MS, Thompson PD, et al. Corticobasal degeneration. A clinical study of 36 cases. Brain 1994;117:1183–96. 9. Boeve BF, Lang AE, Litvan I. Corticobasal degeneration and its relationship to progressive supranuclear palsy and frontotemporal dementia. Ann Neurol 2003;54:S15–9. 10. Poewe W, Wenning G. The differential diagnosis of Parkinson’s disease. Eur J Neurol 2002;9:23–30. 11. Goedert M, Jakes R. Mutations causing neurodegenerative tauopathies. Biochim Biophys Acta 2005;1739:240–50. 12. Garibotto V, Borroni B, Kalbe E, et al. Education and occupation as proxies for reserve in aMCI converters and AD: FDG-PET evidence. Neurology 2008;71:1342–9. 13. Leibovici D, Ritchie K, Ledésert B, et al. Does education level determine the course of cognitive decline? Age Ageing 1996;25:392–7. 14. Takahashi R, Ishii K, Kakigi T, Yokoyama K. Gender and age differences in normal adult human brain: voxel-based morphometric study. Hum Brain Mapp 2010;32:1050–8. 15. McGlone J. Sex differences in human brain asymmetry: a critical survey. Behav Brain Sci 1980;3:215–27.