Expert Review of Neurotherapeutics
ISSN: 1473-7175 (Print) 1744-8360 (Online) Journal homepage: http://www.tandfonline.com/loi/iern20
Twentieth WFN World Congress on Parkinson’s disease and related disorders Karen Frei & Erik Ch Wolters To cite this article: Karen Frei & Erik Ch Wolters (2014) Twentieth WFN World Congress on Parkinson’s disease and related disorders, Expert Review of Neurotherapeutics, 14:7, 741-743 To link to this article: http://dx.doi.org/10.1586/14737175.2014.923309
Published online: 22 May 2014.
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iern20 Download by: [Karolinska Institutet, University Library]
Date: 12 September 2015, At: 14:29
Meeting Report
Twentieth WFN World Congress on Parkinson’s disease and related disorders Downloaded by [Karolinska Institutet, University Library] at 14:29 12 September 2015
Expert Rev. Neurother. 14(7), 741–743 (2014)
Karen Frei*1 and Erik Ch Wolters2,3
The 20th World Congress on Parkinson’s Disease and Related Disorders City of Geneva, Switzerland, 8–11 December 2013
1 Loma Linda University Medical Center, Neurology, 11370 Barton Rd, Loma Linda, 92354 USA 2 University Hospital Zurich, Neurology, Zurich, Switzerland 3 University Maastricht, Maastricht, The Netherlands *Author for correspondence: [email protected]
Geneva is home to the Red Cross and the United Nations, a fitting site for this international meeting. Emphasis was both on motor behavioral and behavioral motor disorders, including the physiology of behavior in Parkinson’s disease (PD) and the phenotype of synucleinopathies, as also described in a textbook of the IAPRD published at the occasion of this Congress. The objective of the behavioral talks was to describe theories with respect to the origin of some of the abnormal behaviors observed in PD. These topics along with the physiology of tremor that sought to synthesize known data regarding tremor generation and clinical updates in deep brain stimulation (DBS) therapy are briefly discussed.
The physiology of behavior was presented by Mark Hallett [1]. The posterior part of the brain, the sensory portion, receives visual, somatosensory and auditory information from the environment. This information is then integrated in multisensory regions in the parietal lobe and is the source of external triggering of movement. The front part of the brain receives and integrates information about the body and is considered the source of internal triggering, for example, hunger and thirst from the hypothalamus. Other internal triggers come from the limbic and mesolimbic dopaminergic system. Triggers from the limbic system include vigilance, fear, anxiety and sex and from the mesolimbic dopaminergic system consist of reward. Internal and external inputs are integrated in the mesial frontal areas such as the cingulate, presupplementary motor and premotor areas. Behavior is influenced by environmental stimulation and multiple forces from internal drives. Behavioral abnormalities due to reduced internal triggers include akinesia, hypokinesia and bradykinesia. The basal ganglia support the part of the brain where internal triggering of movement is generated. Basal ganglia dysfunction results in difficulty generating and initiating movement and produces slow and small movements. Greater attention to movement helps to compensate for this change. Externally informahealthcare.com
10.1586/14737175.2014.923309
triggered movements require less basal ganglia support underlying the phenomenon of paradoxical kinesia. Another perspective on the pathophysiology of Parkinsonian behavior was presented by John Caviness [2]. He began with molecular pathology and neurochemical changes and concluded with abnormal behavior. In Parkinson’s disease (PD), misfolded a-synuclein is an example of molecular pathology. It is not known how misfolded a-synuclein leads to neuronal death in PD. Further neurochemical changes lead to site dysfunction in the substantia nigra and circuit dysfunction in the frontostriate circuit. This results in global network activity and the production of abnormal behavior. Executive dysfunction, mood alterations, apathy and poor motivation are behavioral manifestations related to frontal lobe dysfunction in PD. Another theory of behavior in PD based on the associative learning literature was presented by Peter Redgrave (UK). There are two behavioral control systems: goaldirected control (GDC) and habitual control (HC). In GDC, behavioral selections are determined by relative outcome values of competing actions. With HC behavioral selections are based upon previously learned stimulus response associations. GDC behaviors appear to be driven by associative loops located in the anterior dorsomedial striatum.
2014 Informa UK Ltd
ISSN 1473-7175
741
Downloaded by [Karolinska Institutet, University Library] at 14:29 12 September 2015
Meeting Report
Frei & Wolters
HC behaviors are driven by sensorimotor loops located in the posterior putamen. In PD, there is preferential dopamine loss in the sensorimotor territories associated with HC behaviors. With the loss of HC behaviors there is reliance upon GDC behaviors that are slower, involve more effort and are volitional. Therefore, walking becomes a task requiring much attention and patients cannot execute simultaneous or sequential motor programs. Moving from behavior to disorders of synuclein aggregation; the different phenotypes of synucleinopathies were presented by Glenda Halliday [3]. There are three genes that produce synuclein and several isoforms of synuclein that can easily change conformation. Abnormal accumulation of a-synuclein insoluble aggregates found in neuronal or glial cells characterize a-synucleinopathy. Primary a-synucleinopathies include PD, diffuse Lewy body dementia (DLBD) and multisystem atrophy (MSA). Secondary forms comprise Alzheimer’s disease and neuroaxonal dystrophy. A rare mutation in b-synuclein has been found in DLBD. There is no accumulation of b-synuclein, but those with pure DLBD have reduced b-synuclein in the cortex. Mutations in g-synuclein cause breast cancer. a-Synuclein has the ability to self aggregate and is the major protein found in Lewy body inclusions, glial cytoplasmic inclusions and axonal spheroids. The finding of Lewy bodies present in grafted dopaminergic neurons together with pathological observations of anatomical spread endorsed the hypothesis that a-synuclein pathology could be propagated from region to region in a prion-like fashion. However, we do not know if this happens in humans. b-Synuclein lacks aggregation properties, but can form oligomers. The b-synuclein oligomers can bind to oligomeric a-synuclein and this complex becomes insoluble but is stable and does not propagate. Normal functioning b-synuclein inhibits the aggregation of a-synuclein and formation of a/b oligomeric complex. DLBD has deposition of a-synuclein and a and b oligomeric complexes with a greater amount of a-synuclein deposition compared with PD. DLBD has a faster rate and greater spread of neurodegeneration than PD. It is thought that reduced b-synuclein function contributes to these differences. a-Synuclein aggregates are found in oligodendrocytes in MSA. Oligodendrocytes do not produce a-synuclein normally. There is substantially increased amount of a-synuclein in MSA compared with PD. MSA has a faster rate of progression and greater spread of neurodegeneration compared with PD. Reduced growth factor function is thought to be implicated in these differences. A synthesis of current theories regarding tremor pathophysiology was presented by Mark Hallett [4]. The basal ganglia network is linked to the cerebellothalamocortical network. A theory behind the Parkinsonian tremor includes
742
dysfunction in the basal ganglia triggering tremor driving the cerebellothalamocortical network. In essence the basal ganglia act as the light switch turning on the tremor and the cerebellothalamocortical network acts as the dimmer controlling the amplitude of the tremor. However, the specific generator node in the basal ganglia has not been identified. The network oscillates at rest and in stable posture and motor commands coming through the network disrupts the tremor oscillations. Essential tremor (ET) occurs in posture or with movement and is generated by the cerebellothalamocortical circuit. Initiation of the tremor may involve a cerebellar abnormality of GABA, possibly involvement of the inferior olive or spontaneous activity in the VIM thalamic cells. Studies have been controversial. Both PD and ET share the cerebellothalamocortical network as the generator of the tremor. However, in ET, it appears as though the motor controller of the cerebellum is dysfunctional setting off oscillations triggered by movement. Current studies of b oscillations and closed loop deep brain stimulation (DBS) were discussed by Peter Brown [5] and Andres Lozano [6]. b oscillations, the ~20 Hz waveforms found on EEG, are ubiquitous throughout the cortical-basal ganglia circuitry in PD. Increased b oscillations are associated with slowing of spontaneous movement and corrective responses to postural perturbation. Overall b levels are correlated with rigidity and bradykinesia at rest. b-Activity is likely controlled by the level of dopaminergic activity in response to internal and external cues and serves to modulate the stability of the current motor state. Closed loop DBS with high-frequency stimulation given only when b activity is high appears to be effective, with control of PD symptoms including tremor and uses less energy, thereby extending battery life. Finally, alternative DBS sites that have been studied recently include the pedunculopontine nucleus to improve gait and the Nucleus Basalis of Meynert to improve memory. Future developments in the field of DBS include new electrode designs for spatial current steering, more physiological patterns of stimulation and improvement in imaging modalities to better visualize the brain target and better MRI compatibility with DBS hardware. The reader is referred to the textbook published at the occasion of this congress [7]. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
Expert Rev. Neurother. 14(7), (2014)
Twentieth WFN World Congress on PD & related disorders
References 1.
Caviness JN. Pathophysiology of Parkinson’s disease behavior – a view from the network. Parkinsonism Relat Disord 2014;20(S1): 39-44
3.
McCann H, Stevens CH, Cartwright H, Halliday G. Alpha Synuclein phenotypes. Parkinsonism Relat Disord 2014;20(S1): 62-7
6.
Strauss I, Kalia SK, Lozano AM. Where are we with surgical therapies for Parkinson’s disease? Parkinsonism Relat Disord 2014; 20(S1):187-91
4.
Hallett M. Tremor: pathophysiology. Parkinsonism Relat Disord 2014;20(S1): 118-22
7.
5.
Little S, Brown P. The functional role of beta oscillations in Parkinson’s disease. Parkinsonism Relat Disord 2014;20(S1): 44-8
Parkinson disease and other movement disorders: motor behavioural disorders and behavioural motor disorders. Wolters E, Baumann C. editors. Vu University Press; Amsterdam, The Netherlands: 2014. p. 1-832
Downloaded by [Karolinska Institutet, University Library] at 14:29 12 September 2015
2.
Hallett M. The physiology of behaviour. In: Baumann C, Wolters E, editors. Parkinsonism and other movement disorders. Vu University Press; Amsterdam, The Netherlands: 2014. p. 35-43
Meeting Report
informahealthcare.com
743
ISSN: 1473-7175 (Print) 1744-8360 (Online) Journal homepage: http://www.tandfonline.com/loi/iern20
Twentieth WFN World Congress on Parkinson’s disease and related disorders Karen Frei & Erik Ch Wolters To cite this article: Karen Frei & Erik Ch Wolters (2014) Twentieth WFN World Congress on Parkinson’s disease and related disorders, Expert Review of Neurotherapeutics, 14:7, 741-743 To link to this article: http://dx.doi.org/10.1586/14737175.2014.923309
Published online: 22 May 2014.
Submit your article to this journal
Article views: 8
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iern20 Download by: [Karolinska Institutet, University Library]
Date: 12 September 2015, At: 14:29
Meeting Report
Twentieth WFN World Congress on Parkinson’s disease and related disorders Downloaded by [Karolinska Institutet, University Library] at 14:29 12 September 2015
Expert Rev. Neurother. 14(7), 741–743 (2014)
Karen Frei*1 and Erik Ch Wolters2,3
The 20th World Congress on Parkinson’s Disease and Related Disorders City of Geneva, Switzerland, 8–11 December 2013
1 Loma Linda University Medical Center, Neurology, 11370 Barton Rd, Loma Linda, 92354 USA 2 University Hospital Zurich, Neurology, Zurich, Switzerland 3 University Maastricht, Maastricht, The Netherlands *Author for correspondence: [email protected]
Geneva is home to the Red Cross and the United Nations, a fitting site for this international meeting. Emphasis was both on motor behavioral and behavioral motor disorders, including the physiology of behavior in Parkinson’s disease (PD) and the phenotype of synucleinopathies, as also described in a textbook of the IAPRD published at the occasion of this Congress. The objective of the behavioral talks was to describe theories with respect to the origin of some of the abnormal behaviors observed in PD. These topics along with the physiology of tremor that sought to synthesize known data regarding tremor generation and clinical updates in deep brain stimulation (DBS) therapy are briefly discussed.
The physiology of behavior was presented by Mark Hallett [1]. The posterior part of the brain, the sensory portion, receives visual, somatosensory and auditory information from the environment. This information is then integrated in multisensory regions in the parietal lobe and is the source of external triggering of movement. The front part of the brain receives and integrates information about the body and is considered the source of internal triggering, for example, hunger and thirst from the hypothalamus. Other internal triggers come from the limbic and mesolimbic dopaminergic system. Triggers from the limbic system include vigilance, fear, anxiety and sex and from the mesolimbic dopaminergic system consist of reward. Internal and external inputs are integrated in the mesial frontal areas such as the cingulate, presupplementary motor and premotor areas. Behavior is influenced by environmental stimulation and multiple forces from internal drives. Behavioral abnormalities due to reduced internal triggers include akinesia, hypokinesia and bradykinesia. The basal ganglia support the part of the brain where internal triggering of movement is generated. Basal ganglia dysfunction results in difficulty generating and initiating movement and produces slow and small movements. Greater attention to movement helps to compensate for this change. Externally informahealthcare.com
10.1586/14737175.2014.923309
triggered movements require less basal ganglia support underlying the phenomenon of paradoxical kinesia. Another perspective on the pathophysiology of Parkinsonian behavior was presented by John Caviness [2]. He began with molecular pathology and neurochemical changes and concluded with abnormal behavior. In Parkinson’s disease (PD), misfolded a-synuclein is an example of molecular pathology. It is not known how misfolded a-synuclein leads to neuronal death in PD. Further neurochemical changes lead to site dysfunction in the substantia nigra and circuit dysfunction in the frontostriate circuit. This results in global network activity and the production of abnormal behavior. Executive dysfunction, mood alterations, apathy and poor motivation are behavioral manifestations related to frontal lobe dysfunction in PD. Another theory of behavior in PD based on the associative learning literature was presented by Peter Redgrave (UK). There are two behavioral control systems: goaldirected control (GDC) and habitual control (HC). In GDC, behavioral selections are determined by relative outcome values of competing actions. With HC behavioral selections are based upon previously learned stimulus response associations. GDC behaviors appear to be driven by associative loops located in the anterior dorsomedial striatum.
2014 Informa UK Ltd
ISSN 1473-7175
741
Downloaded by [Karolinska Institutet, University Library] at 14:29 12 September 2015
Meeting Report
Frei & Wolters
HC behaviors are driven by sensorimotor loops located in the posterior putamen. In PD, there is preferential dopamine loss in the sensorimotor territories associated with HC behaviors. With the loss of HC behaviors there is reliance upon GDC behaviors that are slower, involve more effort and are volitional. Therefore, walking becomes a task requiring much attention and patients cannot execute simultaneous or sequential motor programs. Moving from behavior to disorders of synuclein aggregation; the different phenotypes of synucleinopathies were presented by Glenda Halliday [3]. There are three genes that produce synuclein and several isoforms of synuclein that can easily change conformation. Abnormal accumulation of a-synuclein insoluble aggregates found in neuronal or glial cells characterize a-synucleinopathy. Primary a-synucleinopathies include PD, diffuse Lewy body dementia (DLBD) and multisystem atrophy (MSA). Secondary forms comprise Alzheimer’s disease and neuroaxonal dystrophy. A rare mutation in b-synuclein has been found in DLBD. There is no accumulation of b-synuclein, but those with pure DLBD have reduced b-synuclein in the cortex. Mutations in g-synuclein cause breast cancer. a-Synuclein has the ability to self aggregate and is the major protein found in Lewy body inclusions, glial cytoplasmic inclusions and axonal spheroids. The finding of Lewy bodies present in grafted dopaminergic neurons together with pathological observations of anatomical spread endorsed the hypothesis that a-synuclein pathology could be propagated from region to region in a prion-like fashion. However, we do not know if this happens in humans. b-Synuclein lacks aggregation properties, but can form oligomers. The b-synuclein oligomers can bind to oligomeric a-synuclein and this complex becomes insoluble but is stable and does not propagate. Normal functioning b-synuclein inhibits the aggregation of a-synuclein and formation of a/b oligomeric complex. DLBD has deposition of a-synuclein and a and b oligomeric complexes with a greater amount of a-synuclein deposition compared with PD. DLBD has a faster rate and greater spread of neurodegeneration than PD. It is thought that reduced b-synuclein function contributes to these differences. a-Synuclein aggregates are found in oligodendrocytes in MSA. Oligodendrocytes do not produce a-synuclein normally. There is substantially increased amount of a-synuclein in MSA compared with PD. MSA has a faster rate of progression and greater spread of neurodegeneration compared with PD. Reduced growth factor function is thought to be implicated in these differences. A synthesis of current theories regarding tremor pathophysiology was presented by Mark Hallett [4]. The basal ganglia network is linked to the cerebellothalamocortical network. A theory behind the Parkinsonian tremor includes
742
dysfunction in the basal ganglia triggering tremor driving the cerebellothalamocortical network. In essence the basal ganglia act as the light switch turning on the tremor and the cerebellothalamocortical network acts as the dimmer controlling the amplitude of the tremor. However, the specific generator node in the basal ganglia has not been identified. The network oscillates at rest and in stable posture and motor commands coming through the network disrupts the tremor oscillations. Essential tremor (ET) occurs in posture or with movement and is generated by the cerebellothalamocortical circuit. Initiation of the tremor may involve a cerebellar abnormality of GABA, possibly involvement of the inferior olive or spontaneous activity in the VIM thalamic cells. Studies have been controversial. Both PD and ET share the cerebellothalamocortical network as the generator of the tremor. However, in ET, it appears as though the motor controller of the cerebellum is dysfunctional setting off oscillations triggered by movement. Current studies of b oscillations and closed loop deep brain stimulation (DBS) were discussed by Peter Brown [5] and Andres Lozano [6]. b oscillations, the ~20 Hz waveforms found on EEG, are ubiquitous throughout the cortical-basal ganglia circuitry in PD. Increased b oscillations are associated with slowing of spontaneous movement and corrective responses to postural perturbation. Overall b levels are correlated with rigidity and bradykinesia at rest. b-Activity is likely controlled by the level of dopaminergic activity in response to internal and external cues and serves to modulate the stability of the current motor state. Closed loop DBS with high-frequency stimulation given only when b activity is high appears to be effective, with control of PD symptoms including tremor and uses less energy, thereby extending battery life. Finally, alternative DBS sites that have been studied recently include the pedunculopontine nucleus to improve gait and the Nucleus Basalis of Meynert to improve memory. Future developments in the field of DBS include new electrode designs for spatial current steering, more physiological patterns of stimulation and improvement in imaging modalities to better visualize the brain target and better MRI compatibility with DBS hardware. The reader is referred to the textbook published at the occasion of this congress [7]. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
Expert Rev. Neurother. 14(7), (2014)
Twentieth WFN World Congress on PD & related disorders
References 1.
Caviness JN. Pathophysiology of Parkinson’s disease behavior – a view from the network. Parkinsonism Relat Disord 2014;20(S1): 39-44
3.
McCann H, Stevens CH, Cartwright H, Halliday G. Alpha Synuclein phenotypes. Parkinsonism Relat Disord 2014;20(S1): 62-7
6.
Strauss I, Kalia SK, Lozano AM. Where are we with surgical therapies for Parkinson’s disease? Parkinsonism Relat Disord 2014; 20(S1):187-91
4.
Hallett M. Tremor: pathophysiology. Parkinsonism Relat Disord 2014;20(S1): 118-22
7.
5.
Little S, Brown P. The functional role of beta oscillations in Parkinson’s disease. Parkinsonism Relat Disord 2014;20(S1): 44-8
Parkinson disease and other movement disorders: motor behavioural disorders and behavioural motor disorders. Wolters E, Baumann C. editors. Vu University Press; Amsterdam, The Netherlands: 2014. p. 1-832
Downloaded by [Karolinska Institutet, University Library] at 14:29 12 September 2015
2.
Hallett M. The physiology of behaviour. In: Baumann C, Wolters E, editors. Parkinsonism and other movement disorders. Vu University Press; Amsterdam, The Netherlands: 2014. p. 35-43
Meeting Report
informahealthcare.com
743
