Second NINDS-DMRF Workshop on Dystonia

Second NINDS-DMRF Workshop on Dystonia
Recent Advances and Future Directions
June 6-7, 2006
Bethesda, MD

• Summary
• Conclusions
• Targeted Areas of Investigation
• Participant List

Meeting Organizers:

• Danilo Tagle, Ph.D., National Institute of Neurological Disorders and Stroke (NINDS),
• Jan K. Teller, Ph.D., Dystonia Medical Research Foundation (DMRF)
• Mahlon DeLong, M.D., Emory University

The Second NINDS-DMRF Workshop on Dystonia, Recent Advances and Future Directions, was held on June 6-7, 2006, in Bethesda, MD. The meeting brought together leading researchers, clinicians, industry scientists, and representatives from patient advocacy groups. Current research approaches to dystonia were reflected in the themes of the workshop sessions.

SUMMARY

Session I: Genetics and Epidemiology

The majority of dystonia patients do not inherit the disease. However, studying the genes that cause a variety of inheritable dystonias provides invaluable knowledge about the mechanism. Identification of genes that cause dystonia is essential for understanding the disease process, discovering molecular drug targets, and enabling early and precise diagnosis. Genetic animal models should facilitate the understanding of the pathophysiology of dystonia and provide tools for drug testing. Discovery of new genes causing other forms of dystonia should shed light on the basic mechanisms of this disease. Finally, understanding the complex interactions between genes and environment should provide answers related to fundamental questions concerning the etiology and progression of dystonia.

Out of fifteen genes linked to dystonia, six have been isolated. They code for structural proteins, enzymes, transcription factors, and proteins of unknown primary function. Genetic and symptomatic heterogeneity is considered a complicating factor in the study of dystonia. More studies on dystonia prevalence and incidence are needed since dystonia remains under-diagnosed or misdiagnosed. Research into the causes of dystonia should first concentrate on new and already identified genes and their products. In addition, studies on environmental and occupational risk factors are also warranted.

Immediate next steps should involve:

• Characterization of brain pathology in inherited forms of dystonia
• Analysis of multiplex families to identify linkages
• More extensive genetic association studies
• Definition and restriction of specific phenotypes and populations
• Using imaging technologies, especially positron emission tomography, to characterize phenotypes and search for defined biomarkers
• Incorporating arising knowledge about phenotypes and biomarkers in association studies
• Establishment of genetic testing for dystonia genes other than DYT1
• Identify and characterize clinical markers
• Identify the genetic basis of focal dystonias
• Investigate the basis of commonly observed reduced penetrance in dystonia
• Conduct more extensive gene expression and proteomic analyses, especially in cases with known genetic linkages, including non-manifesting carriers
• Determine true frequency of all dystonias in multiethnic populations
• Identify and analyze risk factors
• Develop practical guidelines for treatment and prevention based on epidemiology
• Assess early involvement of genes versus later effect of environmental factors
• Reassess the causes of task specific and action induced dystonias

Session II: Pathophysiology of the Dystonias

The basal ganglia is considered to be the primary site of the physiological and biochemical abnormalities observed in dystonia. What are the principles governing the coordination of movement? Is plasticity an underlying principle in the etiology of dystonia? If so, what role does plasticity play? Is dystonia the reaction of the motor systems to a variety of insults? What is the involvement of the cerebellum in human pathophysiology? To answer these fundamental questions, physiological studies of dystonia should be focused on mechanisms leading to the loss of inhibition, increased plasticity, and abnormal sensory function. More research is needed on therapies derived from the understanding of pathophysiology of the dystonias, which are based on motor and sensory retraining, increased inhibition, and normalized plasticity. If disease causing mutations are known, research should be aimed at the identification of physiological substrates directly linked to such mutations - mechanism-based therapies should then be developed. Studies on motor learning and motor adaptation may provide the interpretational framework for dystonia etiology. Studies on corrective strategies for acquired or developmentally disrupted models of sensorimotor patterns in the brain may provide viable treatment options. The use of afferent electric nerve and transcranial magnetic stimulation in the motor cortex, known as paired associative stimulation (PAS), should provide more information on how cortical afferent inhibition is modulated. By using PAS and other techniques one could attempt to reveal the role of the basal ganglia in cortical plasticity.

The physiological and pathophysiological aspects of dystonia that need to be studied include:

• Assessment of the role of focused selection and surround inhibition in dystonia
• Determination of the GPi involvement in controlling co-contractions and abnormal postures
• Studies on the role of dopamine in spatial and temporal focusing
• The basis of disinhibition of the putamen/pallidum in hand dystonia observed by fMRI
• Hemispheric asymmetry observed in brain microstructures between pallidum and thalamus using diffusion MRI in dystonia patients should be confirmed by other techniques
• Determination if the changes observed by diffMRI are static, congenital, or dynamic
• More MRI studies on basal ganglia are urgently needed - PET and other imaging techniques should be used for verification
• Need for biomarkers

Session III: Neuroimaging the Dystonias

Neuroimaging technologies provide noninvasive visualization of brain structures and functional changes. Rapidly developing neuroimaging techniques have found wide application in dystonia research ranging from clinical diagnosis and determination of pathogenesis to biomarker development. Measurement of the dynamics of different transmitter/receptor systems, measurement of endogenous neurotransmitters metabolism, assessment of effects of drugs on endogenous dopamine are just a few examples. Since novel technologies are being constantly added there is great hope that they can provide a necessary means to integrate our knowledge about dystonia. Imaging may provide the optimal and most accessible readout for therapies and research efforts attempting to correlate genotype with phenotype. Imaging might be the best source of universal biomarkers.

Current areas of interest are as follows:

• Combination of imaging and functional assessment should provide excellent measures in evaluating interventions
• The role of dopamine in dystonia deserves further exploration:
• Is the dopamine receptor expression altered?
• Is dopamine release altered?
• Are there any secondary effects of altered dopamine metabolism?
• What is the role of dopamine in center-surround inhibition and signal/noise ratio maintenance?
• What is the role of dopamine in learning, especially sensorimotor skills?
• What is the role of dopamine in sensorimotor integration? This can be pursued as an imaging project.

• More research on other pathways is worth pursuing with special emphasis on:

• Pallidothalamic projections
• Cerebellum
• Corticostriatal projections

• Circuitry mapping, analysis of other neurotransmitters, and possible gene activity imaging
• Resolving if plasticity is primary or compensatory in dystonia might be critical for understanding the disease pathogenesis
• Comparative analysis of manifesting vs. non-manifesting carriers will be essential
• Imaging/functional mapping of dopamine receptors and analysis of the torsion dystonia-related pattern (TDRP) should be correlated
• In studies of reported brain microstructures asymmetry in dystonia one needs to select the most appropriate imaging modality
• What is the significance of the enlarged putamen in dystonia?
• What is the dopamine D2-like receptor binding/distribution in the dystonias?
• What is the D1-like binding/distribution in the striatum?
• Diffusion Tensor Imaging (DTI) should be used for pathway changes analysis
• More analyses of sensorimotor processing and pharmacological manipulations should be attempted
• What are the contributions of the resting metabolism, brain activation responses, and pathway microstructure?
• Is network activation in DYT1 and DYT6 associated with penetrance?
• Primary dystonia is linked to abnormalities in resting brain function and motor activation responses
• Resting metabolic abnormality may be a functional consequence of microstructural changes in motor circuits and related pathways
• Are brain structural abnormalities primary or secondary in dystonia?
• What is the basis of bilateral abnormalities in unilateral dystonia?
• What is the role of sensorimotor practice in gray matter remodeling?
• Can this remodeling/change be detected by imaging?
• Can DTI fiber tracking be applied to imaging dystonia?
• Can the changes observed by imaging be used as biomarkers?
• How can we use all the information provided by imaging as a guide/interpretation for DBS?
• Can one of the imaging techniques be used as a uniform biomarking technique?
• Do basal ganglia change cortical inhibition and vice versa?
• The thalamo-cortical communication is totally unknown
• The contribution of cerebellar projections to striatum should also be considered

Session IV: Brain Pathology, Brain Banking, and Biomarkers

Very little is known about dystonia brain pathology; we know more about dystonia mouse models pathology than human pathology. Although no overt neurodegeneration has been detected, there might be undiscovered pathological changes. More post-mortem brain specimens are needed to expand and intensify neuropathological studies. Patients, support groups, and brain banks should all be involved. More neuropathological studies are needed on genetically-linked dystonia with the inclusion of non-manifesting carrier and controls. In addition, the neuropathology of focal dystonia cases should be included due to its relatively high prevalence,

The issues to be addressed immediately are:

• Establishment of standard neuropathological protocols for dystonia that include cutting procedures, especially in cases of asymmetric changes
• Although everyone has focused on the basal ganglia, brain stem involvement should be considered
• More biochemical markers should be included in neuropathological analysis
• The basis of the DYT3 putamenal atrophy and patchy loss in matrix requires investigation
• What is the basis of depigmentation observed in dopa-responsive dystonia?
• There are limited studies on secondary dystonia causes by other primary diseases
• Novel markers of subtle signs of protein dysfunction should be widely used
• Quantitative, stereological measurements and markers of inter-neuronal communication should be used
• There is a need to initiate exploratory search for biomarkers in serum and CSF for all dystonias
• Changes in neurotransmitter metabolites should be correlated with pathology
• Asymptomatic carriers should be examined pathologically if available
• Neuropathological changes should be correlated with brain imaging signatures and neurophysiological examinations
• A neuropathology consortium to solidify neuropathology research
• Centralized brain banking should be promoted and preferred, both for sample storage and information
• Every effort should be made to increase prospective brain collection
• Quality control of tissue and extracted RNA must be included
• Survey of neuropathologists to consider centralized collection or formation of a network of brain banks
• DMRF could consider a small grant to establish standard protocols, explore various stains, and antibodies, etc.
• Explore some ideas by using animal models first
• Establish a 'tool chest' of common markers - proceed from there and do it systematically

Session V: Rehabilitation

Rehabilitation remains the most direct and often very effective treatment for all forms of dystonia. Quality of life is improved by reducing general disability, increasing range of motion, recovering normal gait or voice, reduction of tremors and rigidity, and fighting depression. Yet, current dystonia rehabilitation strategies should be more comprehensive and include active exercise, motor, sensory, and cognitive retraining, often combined with other therapeutic interventions. Since assessment of success in rehabilitation therapies is often subjective, more efforts should be devoted to studying design issues: control group selection, study duration, etc.

The immediate needs in this field are:

• More studies on appropriateness of rehab timing (before, during, or after medical or surgical treatment)
• Better definition of rehab outcomes and assessment (What is alleviated impairment, disability, quality of life?)
• Determination and agreement how to measure the above outcomes
• How to determine disability in dystonia?
  • How to assess it?
  • How to identify outcome measures?
  • How to apply these measures in clinical trials and clinical care?
• New rehab approaches based on pathophysiology must answer patient's needs
• Build a bridge between patients' needs and research
• Address the issue of clinical meaningfulness: to people with dystonia and to policymakers
• Prospective placebo-controlled evaluation scales for rehab assessment in focal dystonias must be established
• There is an urgent need for prospective clinical studies with objective scales, placebo arm, evaluations, etc.
• The old view of dystonia has to be revised/challenged - it assumed an initial normal state, an event causing/initiating dystonia. Rehabilitation options were dictated by that view and aimed at cortical retuning/improvement.
• The old view has to be revised since endophenotype data conflict with this model - anatomically and functionally, the hand and face, in case of musician's dystonia, are not designed to do what they do, especially repetitive tasks
• What is the effect of peripheral modifiers on phenotype?
• What is the goal for rehabilitation therapy in musician's dystonia? Is restoration of the normal state the right goal? Are they 'normal' in the first place?
• As re-training can be used for the first two, rTMS and PAS should be more widely applied for the latter
• Find ways of dealing with variability within patients, health care providers, and researchers as the primary problem in rehabilitation and its assessment
• Obtain a quantifiable measure of central control in the disorder. This should include EMG, kinematic, and cortical assessment followed by standardization.
• More efforts should be dedicated to combined treatments
• Robotic therapy should be adopted for dystonia and other movement disorders with learning/relearning components
• Wide support for clinical trials of such robotic therapies should be encouraged
• 'Therapeutic' robots can also be used in recovery, treatment progress, or drug efficacy assessment as demonstrated for DBS patients
• Ultimately, personalized robots can be designed and built for in-home use.

Session VI: TorsinA - Function and Interactions

Since the discovery of the DYT1 gene, the field of torsinA research has matured considerably. The most promising leads to elucidate torsinA function should be pursued: the role of torsinA at the nuclear envelope, the role of the nucleotide binding site, the putative enzymatic activity, and the chaperone function. Several recently identified torsinA binding proteins offer clues as to the protein's function and localization in the cell. Continuous studies on the nuclear envelope structure and function provide the necessary background in this area. One of the primary questions is why and how the torsinA pathogenic mutant protein accumulates in the nuclear envelope. TorsinA has a 'substrate' in the nuclear envelope, thus more efforts should be directed at the identification and understanding of this process. LAP1 and LULL1, two protein binding partners of torsinA, may be crucial to understanding the torsinA function, especially at the nuclear envelope. The idea that the ∆E-torsinA functionally represents a loss of function allele establishes a conceptual framework for research. Studies on torsinA should take into account that torsinA-related nuclear envelope abnormalities are neuronal specific and developmentally depended. What cellular function is regulated by the torsinA pathway? What is the role of the nucleo-skeletal connections and secretory pathways? What is the role of membrane dynamics in this process? More efforts should be directed toward fully understanding the protein-protein interactions in which torsinA and its binding partners participate. At the biochemical/molecular level, the major challenge is to determine the three-dimensional structure of torsinA. One of the fundamental prerequisites for structural studies - high level of torsinA expression - has not been achieved. More insight into the ATP/ADP binding mechanism and kinetics is needed. The role of the redox state dependency of the nucleotide binding could be relevant in vivo. What cellular conditions, from a biochemical perspective, contribute to altered functionality of the torsinA mutant? Are these conditions unique in neurons?

The fundamental questions to be answered are:

• What is the function of torsinA at the nuclear envelope?
• What is the function of torsinA in the ER?
• Why is torsinA moving around the cell?
• What is the role of its binding motifs, especially for ATP?
• Does it have any catalytic activity?
• Is this activity ATP-dependent?
• What is the nature and role of torsinA interactions with the cytoskeleton?
• What are the native binding partners of torsinA?
• How do they modulate its function?
• How does mutant torsinA cause dystonia?
• How does mutant torsinA interfere with torsinA function?
  • How does it affect neurons in development?
  • How does it interfere with transcription (no data at all on this)?
  • How does it affect processing of proteins through the secretory pathway?

Session VII: Animal Models

A comprehensive approach to animal modeling of the dystonias is essential. Both etiologic and phenotypic models are indispensable. Animal models implicate two major brain regions involved in dystonia: basal ganglia and cerebellum. Basal ganglia models include animals with drug-induced pathologies as well as episodic dystonia, apparently caused by unknown autosomal recessive mutation(s). Does abnormal cerebellar signaling induce dystonia? Yes, since cerebellar injection of kainate causes dystonia. Recent studies confirm communication between the cerebellum and the basal ganglia. Discoveries of new dystonia-causing genes prompted numerous studies using transgenic, knock-in, knock-down, knock-out, and conditional knock-out animals. DYT1 delta GAG knock-in mice display aggregates in the brainstem; similar aggregates have been seen in DYT1 transgenics. Valid genetic models of dystonia typically demonstrate slip deficits in beam walking tests and hyperactivity in open field tests, abnormal dopaminergic function, brainstem cellular aggregates, and EMG-detectable abnormal co-contraction of agonist and antagonist muscles. The knock-in mice show deficits in motor coordination and balance, in dopaminergic metabolism, and in brainstem neuropathology. However, the mice do not show "dystonia". Animal genetic models appear not to display dystonic phenotype - are these phenotypes masked by unknown factors? Are selected drugs necessary to induce dystonia even in genetic models?

Among the issues that need further study are:

• More experimental models of dystonia are necessary
• Cell culture findings must be confirmed in vivo
• Animal models of other neurological diseases with frequent motor manifestations, especially PD and HD, may provide some additional insight
• Both reverse and forward genetic approaches should be used and cross-verified
• Reliable markers that can be used in HTS should be identified and validated in genetic models
• Animals should be used to understand how DBS works

Session VIII: Surgical Approaches

Deep brain stimulation (DBS) is an effective treatment for torsion dystonia. Why does DBS work? How does it work? How long does it work? Why doesn't it benefit everyone equally? How do lesions compare to DBS? What are the differences in targeting thalamic vs. pallidal sites? Are there any other target sites? We need to consider genetic status, phenotype, lead location, programming parameters, and other factors. Understanding the pathophysiology of the disease will elucidate the mechanism of action of the therapy. These efforts are critical for developing new surgical therapies since parameter selection is currently done by 'clinical intuition' and one can describe DBS as 'one-size-fits-all' technology. Patient-specific DBS can be achieved through complex computer modeling.

The goals of such modeling are to merge neural stimulation modeling techniques with MR/CT imaging data and electrophysiological recording data:

• Anatomical model is based on patient MRI that defines the model geometry, 3D brain atlas is scaled to fit patient anatomy
• Neurophysiological model is created from stereotactic microelectrode recordings
• Electrical model is derived from diffusion tensor MRI that defines tissue conductivity and provides evaluation of the volume of tissue activated

These modeling efforts should also involve:

• Evaluation of more patients: establishing different trajectories and parameter settings, and definition of good and bad responders
• Definition of a therapeutic target volume of tissue activated through development of a probabilistic map of overlapping therapeutic stimulation volumes
• Surgical navigation including pre-operative target/trajectory optimization and intra-operative visualization
• Post-operative programming involving visualization and optimization of stimulation parameter selection
• Re-engineering of DBS systems based on scientific principles

Beyond modeling, research on DBS should consider the following:

• In selection of patients for DBS, there is a need for reliable outcome predictors likely provided by imaging and assessment of neurophysiological markers
• A multicenter effort mayl be necessary with patient registry and standardized clinical outcome measures
• New targets for DBS should be evaluated, especially for other dystonias. These should include STN, thalamus, brainstem, and cerebellum;
• Existing and newly-developed animal models should be used in testing novel surgical techniques
• New electrodes with improved control should be developed
• New, smaller, and rechargeable batteries should be introduced
• More computational and experimental work is needed to fine-tune DBS programming, specifically in regard to low and high frequency stimulation. Setting should be predicted based on neuronal firing frequency, computational models, chronic vs. cyclic stimulation, and target-specific oscillatory activation.
• Computational and experimental models are necessary to resolve whether electrode stimulation causes local activation or inhibition
• Overriding abnormal patterns of neural activity should be monitored by neurophysiological and imaging markers as well as computer modeling
• More proactive approaches should be undertaken to successfully deliver service to patients by overcoming insurance and other obstacles
• Motor cortical stimulation such as transcranial magnetic stimulation should be explored as an alternative strategy. Experience gained in PD and the apparent critical role of the sensory-motor cortex make this technique an attractive option providing reduced risk and cost related to DBS procedures
• Neurosurgery may facilitate structure targeted gene therapy, i.e. siRNA

Session IX: Experimental Therapeutics

Genetics continues to provide diverse molecular targets, although pathophysiology of the dystonias is not fully understood. Selected brain regions provide the basis for anatomical, physiological, and molecular inquiry. Therapeutics development is further complicated by tremendous heterogeneity of the patient population and lack of uniform outcome measures.

RNA interference (RNAi) offers a new avenue for innovative drug development. Dystonia is a primarily a dominantly inherited disorder with likely dominant negative effect. There is an apparent window of susceptibility and, since there is no neuronal loss, there is potential for reversibility. Sparing wild-type torsinA levels might be important. Therefore the siRNA-based therapy should be allele-specific. Before such therapy can be moved to the clinic, several fundamental questions need to be answered: What to deliver? How, when, and where? Allele-specific silencing of torsinA (delatGAG) is feasible in cells - it leads to rescuing dominant negative effects of torsinA (delatGAG) over the wild type allele. Suppression of endogenous torsinA has been achieved in mammalian neurons. As the feasibility of siRNA-based therapy is now being established in animals, a major challenge will be to develop successful brain delivery methods and safe viral or non-viral methods of targeting selected brain structures. Searches for more conventional drugs use several assays based on torsinA properties. Several such assays have been established in research laboratories: fibroblast adhesion assay, neurite outgrowth assay, membrane abnormalities assessment, and nuclear envelope mislocalization assay.

In another model system, using C. elegans, it has been shown that torsinA has the capacity to function as a molecular chaperone. Wild type torsinA can suppress the aggregation and toxic protein misfolding in vivo. In contrast, mutant torsinA (∆E) or a combination of wild type and mutant torsinA show diminished chaperone function. This system has been used to evaluate the potential of small molecule drugs to affect the chaperone activity of torsinA in suppressing polyglutamine (polyQ)-induced protein aggregation associated with α- synuclein overexpression in dopaminergic neurons of C. elegans. Out of 240 structurally diverse, mostly off-patent FDA-approved drugs, five were identified that exhibit aggregation-suppressing activity by exerting their effects through modulating the function of torsinA. The identified compounds fall into four different therapeutic categories and will be evaluated in other cellular assays and transgenic animals. Medicinal chemistry efforts may potentially expand this family of drugs.

Issues to consider in developing dystonia experimental therapeutics are:

• Concerted efforts should be made to develop animal models of dystonia; such models are central to drug development
• Animal models should be validated and replicate some aspects of dystonia
• Drug testing should be validated at multiple levels of analysis in predictive animal models
• Explore the environment around torsinA - cellular location plus binding partners
• Cross the species barrier: test drugs identified in one species in a different species model

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Conclusions

1. There are various forms of dystonia - multiple etiologies will require multiple pathways to drug and treatment discovery.
2. Identified genetic causes of dystonia hold promise for refining diagnostic and predictive aspects and developing new specifically targeted therapeutics.
3. Animal models of dystonia enhance our understanding of disease mechanisms and provide tools for testing experimental therapeutics.
4. Cellular and molecular models of the dystonias will provide tools needed to test basic principles of disease mechanisms as well as the means to utilize them in large-scale search and testing of new drugs.
5. Deeper understanding of cell signaling mechanisms pertinent to dystonia will help identify novel therapeutic targets and facilitate the assessment of efficacy/shortcomings of therapeutics currently in use.
6. Epidemiological studies will provide information necessary to advance research aimed at identifying environmental and other non-genetic factors that influence penetrance and progression.
7. Comprehensive studies of the pathophysiology of the dystonias will facilitate our understanding of these disorders and provide an overarching scientific basis for interpretation of therapeutic effectiveness.
8. Although our ultimate goal is to cure and prevent dystonia, major efforts should be targeted toward the improvement of patients' quality of life through effective rehabilitation, development of novel drug therapies, and other forms of treatment.
9. Identification, characterization, and validation of multimodal biomarkers of dystonia will be critical for clinical evaluations, trials, and drug testing.

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Targeted Areas of Investigation

Epidemiological Studies

• Dystonia remains underdiagnosed and misdiagnosed. Further research is urgently necessary to provide uniform clinical criteria which will help define the population-dependent differences and factors that determine these differences.
• Research into the etiology of the dystonias should concentrate on previously and newly identified genes and the proteins they encode.
• Coordination of efforts to gather, store, and analyze genetic and epidemiological information will facilitate discovery of genetic background of the dystonias as well as environmental and occupational factors that initiate and drive pathology.

Genetic Studies

• Identification and isolation of all dystonia genes identified thus far through linkage analysis.
• Analysis of regulation of these genes in development will help in understanding the age-dependence of the dystonia progression.
• Molecular analysis of mutant proteins that are encoded by the dystonia-causing genes will provide fundamental information about the cellular and biochemical basis of dystonia.
• Improved diagnostic criteria should be combined with brain imaging and biomarkers to differentiate individual phenotypes of genetic forms of dystonia in order to understand their common and unique mechanisms.

Pathophysiology

• We need to understand the basic mechanisms of movement control in the central nervous system, how these mechanisms are disrupted in dystonia, and how to correct them.
• The current circuit models of dystonia should be further tested and refined.
• Basic questions related to brain plasticity and its role in dystonia and other movement disorders remain unanswered.
  • Is plasticity an underlying factor in the etiology of dystonia?
  • Is dystonia the reaction of the brain motor system to different insults?
  • What is the nature of these insults?
  • How can we test disturbed plastic changes at the brain level?
  • How can we model such changes in animals?
• The role of cerebellum in dystonia should be explored in both animal models and patients.
• The neural and biochemical role of center-surround inhibition in dystonia should be addressed.

Neuroimaging

• Brain imaging should be considered as a source of not only diagnostic (trait) biomarkers but also as functional (state) biomarkers that provide a measure of efficacy for different therapies and treatments.
• More detailed studies of dystonia will be needed to dissect the neural networks critically involved in dystonia.
• The role of neurotransmitters in dystonia should be pursued as an imaging project.
  • Analysis of dopamine, anticholinergics, and other transmitters and their receptors and metabolism should be initiated and placed in the context of the overall circuit functions.
• Imaging of selected brain circuitries that are involved in dystonia and possible gene and protein visualization in the brain should be priority areas.

Neuropathology

• It is of fundamental importance to search for morphological and biochemical markers of dystonia pathology in the human brain.
• Prospective brain collection from both manifesting and non-manifesting patients and controls should facilitate comprehensive neuropathological studies.
  • Specific brain areas, molecules, and genes should be targeted in such studies, especially in cases with the identified genetic background.

Functional Rehabilitation and Quality of Life

• Dystonia rehabilitation strategies should go beyond functional rehabilitation. Achieving well-defined quality of life measures should be the ultimate goal for rehabilitation.
• There is a need to build a bridge between patients' needs and research-driven, innovative approaches to treatment.
• TorsinA/DYT1 torsion dystonia remains the best studied genetic form of dystonia since the discovery of the gene and its mutation in 1997.
• The cellular function of torsinA is still unknown. Its presence at the nuclear envelope and in the endoplasmic reticulum suggests several functions in cell secretion and protein trafficking.
• TorsinA interactions with the cytoskeleton may lead to identification of other targets.

Modeling

• More experimental animal models of dystonia are needed.
• Mechanistic questions about dystonia pathophysiology should be addressed in the broader context of the motor system and the sensorimotor pathways involvement in motor learning. Solving the dystonia mechanism could provide a better understanding of these systems in general.
• Cell and cell-free models of dystonia will be needed to dissect elementary steps in cellular mechanisms and to test drugs.
• Mechanism-based assays for high-throughput screening will be vital for drug discovery and development efforts.

Neurosurgery and Brain Stimulation

• Deep brain stimulation (DBS) is not only an extremely effective treatment for severe dystonia but also a source of invaluable electrophysiological data that can be used in mapping and functional analysis of brain regions involved in dystonia.
• Research into the optimal targets for the different types of dystonia (primary vs. secondary, focal vs. generalized, etc.) is a high priority.
• As functional tests are necessary to evaluate DBS success, the availability of biomarkers, both biochemical and imaging, will help in assessing therapeutic effectives.
• Transcranial magnetic stimulation of different cortical sensory and motor areas should be further explored.
• Neurosurgical techniques will facilitate targeted drug delivery, including siRNA.

Experimental Therapeutics

• Two fundamental approaches should be pursued: one based on the classic gene-protein-target-hit paradigm, which involves combinatorial chemistry and high throughput screening; the other on the old 'magic bullet' concept.
• At this point, the DYT1 mutant gene and torsinA appear to be ideal candidates - success with the siRNA approach and chemical screens in C. elegans fully attest to this notion.
• The 'hit to lead' transition might be the most difficult and costly phase, which will require extensive external collaborations and target validation to reach the point where they can be transferred to commercial entities for further development and clinical trials.

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Participant List

Ron Alterman, M.D.
Director of Functional & Restorative Neurosurgery
Mount Sinai School of Medicine

Ioanna Armata, M.S.
Graduate Student
Mount Sinai School of Medicine

Craig Blackstone, M.D., Ph.D.
Chief, Cellular Neurology Unit
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Anne Blood, Ph.D.
Athinoula Martinos Center for Biomedical Imaging
Massachusetts General Hospital
Department of Neurology

Xandra Breakefield, Ph.D. Professor & Genecist
Massachusetts General Hospital & Harvard Medical School

Susan Bressman, M.D.
Chairman and Professor
Beth Israel Medical Center

Kim Caldwell, Ph.D.
Assistant Professor
The University of Alabama

Guy Caldwell, Ph.D.
Associate Professor of Biological Sciences
The University of Alabama
Department of Biological Sciences

Claire Centrella
President
Dystonia Medical Research Foundation

A. Ray Chaudhuri, Ph.D., M.B.A.
Program Analyst
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Daofen Chen, Ph.D.
Program Director
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Cynthia Comella, M.D.
Professor
Rush University Medical Center

Mark Corrigan, M.D.
Executive Vice President of Research & Development
Sepracor Inc.

Jan Craig
Vice President of Science
Dystonia Medical Research Foundation

William Dauer, M.D.
Assistant Professor of Neurology & Pharmacology
Columbia University

Mahlon DeLong, M.D.
Professor and Director of Neuroscience
Emory University School of Medicine
Department of Neurology

Dennis Dickson, M.D.
Professor
Mayo Clinic College of Medicine

David Eidelberg, M.D.
Director
The Feinstein Institute for Medical Research
Center for Neurosciences

Glen Estrin, B.M.
President
Dystonia Medical Research Foundation

Craig Evinger, Ph.D.
Professor
SUNY Stony Brook

Stanley Fahn, M.D.
Professor of Neurology
Columbia University College of Physicians and Surgeons

Steven Frucht, M.D.
Assistant Professor of Neurology
Columbia University Medical Center

Wendy Galpern, M.D., Ph.D.
Program Director
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Clinical Trials Division

Pedro Gonzalez-Alegre, M.D.
Assistant Professor
University of Iowa

Steve Groft, M.D.
Director
Office of Rare Diseases
National Institutes of Health

Mark Hallett, M.D.
Chief, Medical Neurology Branch
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Phyllis Hanson, M.D., Ph.D.
Associate Professor
Washington University School of Medicine
Department of Cell Biology

Ellen Hess, Ph.D.
Associate Professor
Johns Hopkins University

Jeff Hewett
Senior Laboratory Manager
Massachusetts General Hospital
Neuroscience Center

Janet Hieshetter
Executive Director
Dystonia Medical Research Foundation

Ross Hoffman, M.D.
Western Slope Cardiology

Neville Hogan, Ph.D.
Professor
Massachusetts Institute of Technology

Hans-Christian Jabusch, M.D.
Assistant Director
University of Music and Drama, Hannover

Teresa Jacobson Kimberley, Ph.D.
Assistant Professor
University of Minnesota

Hyder Jinnah, M.D., Ph.D.
Associate Professor
Johns Hopkins University

Melinda Kelley, Ph.D.
Senior Science Advisor
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Art Kessler
Dystonia Medical Research Foundation

Dennis Kessler

Christine Klein, M.D.
Professor of Clinical and Molecular Neurogenetics
University of Luebeck

Kimberly Kuman
Executive Director
National Spasmodic Dysphonia Association

Story Landis, Ph.D.
Director
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Anthony Lang, M.D., F.R.C.P.C.
Director, Movement Disorders Unit
University of Toronto, Toronto Western Hospital

Mark LeDoux, M.D., Ph.D.
Professor
University of Tennessee Health Science Center

Stephane Lehericy, Ph.D.
Professor
University Pierre and Marie Curie

Rosalie Lewis
Vice President of Public Policy
Dystonia Medical Research Foundation

Yuqing Li, Ph.D.
Member
University of Illinois at Urbana-Champaign
NeuroTech Group, Beckman Institute for Advanced Science and Technology

Steven Lo, M.D.
Clinical Fellow in Movement Disorders
Columbia University Medical Center

David Lovinger, Ph.D.
Chief, Laboratory for Integrative Neuroscience
National Institute on Alcohol Abuse and Alcoholism
National Institutes of Health

Christy Ludlow, Ph.D.
Chief, Laryngeal and Speech Section
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Charles Markham, M.D.
Research Professor
University of California

Cameron McIntyre, Ph.D.
Assistant Professor
Cleveland Clinic Foundation

Sabine Meunier, M.D.
Clinical Fellow
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Helen Miller, M.S.S.W.
Executive Director
Mt. Sinai Medical Center
Bachmann-Strauss Dystonia Parkinson Foundation

Jonathan Mink, M.D., Ph.D.
Associate Professor
University of Rochester

Flavia Nery, Ph.D.
Massachusetts General Hospital

Tan Nguyen, M.D., Ph.D.
Medical Officer
U.S. Food and Drug Administration

Laurie Ozelius, Ph.D.
Associate Professor
Albert Einstein College of Medicine

Henry Paulson, M.D., Ph.D.
Professor
University of Iowa

Audrey Penn, M.D.
Deputy Director
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Joel Perlmutter, M.D.
Professor of Neurology and Radiology
Washington Hospital

Jody Roosevelt
Manager of Science and Technology
Dystonia Medical Research Foundation

John Rothwell, Ph.D.
Professor of Human Neurophysiology
Institute of Neurology

Terence Sanger, M.D., Ph.D.
Assistant Professor
Stanford University

Nutan Sharma, M.D., Ph.D.
Assistant Professor of Neurology
Massachusetts General Hospital

Pullanipally Shashidharan, Ph.D.
Associate Professor of Neurology
Mount Sinai School of Medicine

Lisa Shulman, M.D.
Associate Professor of Neurology
University of Maryland

Mary Smith
Board Secretary and Office Manager
Benign Essential Blepharospasm Research Foundation, Inc.

David Standaert, M.D., Ph.D.
Associate Professor
Massachusetts General Hospital

A. Jon Stoessl, M.D., F.R.C.P.C.
Professor and Director
University of British Columbia

Bonnie Strauss
President
MT Sinai Medical Center
Bachmann-Strauss Dystonia Parkinson Foundation

Danilo Tagle, Ph.D.
Program Director
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Michele Tagliati, M.D.
Associate Professor
Mount Sinai School of Medicine

Caroline Tanner, M.D., Ph.D.
Director
The Parkinson's Institute

Jan Teller, M.A., Ph.D.
Science Officer
Dystonia Medical Research Foundation

Philip Thomas, Ph.D.
Professor
University of Texas Southwestern Medical Center at Dallas

Gonzalo Torres, Ph.D.
Assistant Professor
University of Pittsburgh

Jerrold Vitek, M.D., Ph.D.
Director, Functional Neurosciences
The Cleveland Clinic Foundation
Department of Neurosciences

Ruth Walker, M.D., Ch.B., Ph.D.
Assistant Professor
James J. Peters VAMC/Mount Sinai School of Medicine

Benjamin Walter, M.D.
Movement Disorder Specialist
The Cleveland Clinic Foundation

Howard Worman, M.D.
Associate Director
Columbia University Medical Center

H. Ronald Zielke, Ph.D.
Director, Brain and Tissue Bank
University of Maryland at Baltimore

Onsite Participants:

Ted Dawson, Bachmann-Strauss Dystonia Parkinson Foundation
Joseph Pancrazio, NINDS
Rucha Vyas, Dystonia Medical Research Foundation

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