Mahlon R. DeLong - US grants

The proposed studies are designed to clarify the role of the basal ganglia (BG) in the control of normal movement and in the pathophysiology of movement disorders of BG origin, such as dyskinesias (involuntary movements), akinesia and rigidity. The activity of neurons in the BG output nuclei (substantia nigra (SN) and globus pallidus (GP) will be examined. In addition, the presumed modulatory role of the subthalamic nucleus (STN) on these structures will be studied. Also relevant to these issues is the nucleus basalis of Meynert (nbM), which is anatomically continuous with the GP and whose neurons, in fact, are intermingled to some extent with those of the GP. Because of this interdigitation of GP and nbM neurons, it is possible that the widespread cholinergic projections of nbM to all cortical areas, including motor cortex, might represent a non-thalamic projection to cortex of BG influences. We have found that the activity of many nbM neurons is movement-related. Comparison of the neuronal activity in SN, GP, STN and nbM in intact primates and in suitable primate models of human BG disorders should lead to a better understanding of the role of these structures in motor control. Three areas of study are proposed: 1) Normal BG/nbM Activity: To analyze the directional specificity of neuronal activity in GP, STN and nbM, we will examine single neuron activity in these structures during performance on a behavioral paradigm which dissociates the direction of limb movement from the pattern of muscular activity. The effects of microstimulation in GP and STN on task performance and muscle tone will also be studied. 2) Dyskinesia Model: The patterns of neuronal discharge in GP will be examined in the primate model of hemiballismus, a disorder in which involuntary movements result from lesions of the STN. The results should clarify the pathophysiology of hemiballismus and provide a direct measure of the altered BG output in this disorder. 3) Rigidity/Akinesia Model: The activity of BG output neurons (in both GP and SN) will be studied in neuroleptic-induced akinesia and rigidity to determine whether these motor abnormalities are associated with increased or decreased BG output.

The general goals are to examine the relationships between structure and function in the primate neostriatum and to provide a better understanding of the nature and mechanisms of sensorimotor integration in the putamen. Recent studies have revealed physiologic inhomogeneities within the primate putamen in the form of 1) discrete clusters of neurons whose activity is related to movements and/or somatosensory stimulation of individual body parts, or whose activity exhibits instruction-dependent changes in discharge related to "motor set" and 2) discrete foci, "striatal microexcitable zones" (SMZ), from which movements of individual body parts may be evoked by microstimulation. The specific aims are to determine the relationships between these physiologic inhomogeneities and the recently described anatomical inhomogeneities within the striatum, which occur in the form of discontinuous patches of terminal labeling of cortical and thalamic afferents and discontinuities in the distribution of histochemical, histofluorescence and immunocytochemical markers for a variety of neurotransmitter/neuromodulators. These discontinuities appear to reflect an intrinsic organization of the neostriatum in the form of two interdigitating compartments which, in the primate, have been designated the "island" and "matrix" compartments. The studies are designed to evaluate the relationships between the anatomic and physiologic compartments of the primate putamen, and between this intrinsic organization and the patterns of striatal afferent and efferent connections. Specifically, we plan to investigate the patterns of termination of striatal afferents from the motor, premotor and somatosensory cortex and the supplementary cortex and the organization of putamen output neurons projecting to the globus pallidus and the substantia nigra. These studies employ techniques of single cell recordings from behaving primates, anterograde and retrograde transport studies, immunocytochemical and conventional anatomical techniques. These studies should help to clarify the functional organization of the basal ganglia and may lead to a better understanding of the role of these studies in health and disease.

Diseases of the basal ganglia account for many neurologic and neuropsychiatric disorders, such as Parkinson's and Huntington's Diseases. Progress in understanding the functional organization and pathophysiology of the basal ganglia has been rapid. Much of this work has been integrated into a working model of basal ganglia circuitry that can account for both normal and abnormal behavior. The present proposal represents a multi-disciplinary effort, including neuroanatomical, electrophysiological, neuropharmacological, neurosurgical, and behavioral approaches to further our understanding of the structural and functional organization of the basal ganglia within the framework of this model. According to the model there exists a family of 'basal ganglia- thalamocortical circuits' that are organized in a parallel fashion, largely secreted one from another, both structurally and functionally. In the primate, "motor" "Oculomotor", "associative and "limbic" circuits have been described which take origin from specific cortical areas. Within each circuit, there appears to exist even further parallel features, e.g., the striatum, the major input structure of the basal ganglia, influences the internal pallidum, the major output structure, via parallel "direct" and indirect" pathways. Project 1 address the role of recently discovered dopamine and muscarinic acetylcholine receptor gene families with the primate basal ganglia. Using subtype-specific antibodies to the receptors, the molecular pharmacology and anatomy of identified striatal circuits will be delineated. These studies will help identify the best targets for new drugs aimed at the subtypes for better treatment of movement disorders. Project 2 addressed the basis model at the level of brainstem interactions with the basal ganglia-thalamocortical circuitry. This project will help to elucidate the influence of the midbrain tegmentum on movement and basal ganglia-thalamocortical circuits at the level of the internal pallidum (GPi) on parkinsonian signs in monkeys with experimental parkinsonism. Correlation of behavioral changes with lesion sites as determined electrophysiologically and by MRI will help to optimize the outcome and reduce surgical complications. Data from this study will also help to elucidate the pathophysiology of these disorders and will lead to improved surgical treatment strategies. Project 4 explores the issue of segregated functions of the associative/oculomotor and motor circuits as regards the phenomenon of adaption to prism-induced and tendon-induced target displacements. This adaptation involves two additive components - a visual and a proprioceptive shift, both of which appear to depend on the integrity of separate basal ganglia circuits. Together these studies will extend out understanding of basal ganglia function, help to elucidate the pathophysiologic basis of basal ganglia disorders and lead to new innovative therapies for these disorders.

The major aim of this study is to carry out a controlled clinical trial of pallidotomy for the treatment of advanced intractable Parkinson's Disease (PD) and to comprehensively evaluate these patients for changes in motor, cognitive and psychiatric state. Two recent factors have led to a renewed interest in pallidotomy for PD: 1) the demonstration that lesions of the subthalamic nucleus (STN) in the experimental monkey model of PD ameliorates the cardinal signs of this disorders, including akinesia, and 2) the recent report that pallidotomy also that pallidotomy provides significant benefit to patients with PD who no longer derive adequate response to anti-parkinson medications and who suffer from motor fluctuations and drug-induced dyskinesias. At the present time pallidotomy is being performed with increasing frequency in ever more centers. As yet, however, there have been no-well controlled clinical trial of pallidotomy. We propose to carry out a controlled clinical trial of pallidotomy versus best medical therapy in 42 patients with intractable PD. Surgical patients and controls will be monitored for 3 months prior to surgery and every 6 months thereafter. Clinical evaluation will be carried out in the Clinical Research Center. We will perform comprehensive evaluations of motor, cognitive and psychiatric state pre and post operatively. The functional assessments include standard parkinsonian rating systems used for reevaluation of transplant patients as well as quantitative motor testing. Pallidotomy will be carried out under both MRI and microelectrode-guidance. Lesion size and placement will be determined post-operatively using new high resolution MRI imaging techniques. Changes in parkinsonian and behavioral signs will be correlated with lesion location. These studies will serve to: 1) validate the safety and efficacy of pallidotomy in PD, 2) better define the optimal target location and 3) provide important data on the effects of pallidal lesion on motor, cognitive and psychiatric functioning in parkinsonian patients.

The overall aim of the present study is to assess the role of pallidotomy in the treatment of experimental parkinsonism and to explore the mechanism, in the experimental MPTP monkey model of Parkinson's disease (PD), whereby pallidotomy ameliorates the signs of PD. The recent demonstration in the primate model of parkinsonism, of increased levels of neuronal activity in the subthalamic nucleus (STN) and globus pallidus pars intima (GPi) and the finding that inactivation of either the STN of GPi can reverse akinesia, tremor, and rigidity suggests that these abnormalities results from excessive (inhibitory) pallidal output. The finding that akinesia. Furthermore, the recent elucidation of specific subchannels in the sensorimotor portion of GPi related to different precentral motor areas (motor cortex [MC], supplementary motor area [SMA], premotor cortex [PMC]) raises the questions of whether different cardinal features of PD (akinesia, bradykinesia, rigidity, tremor and drug-induced dyskineasias) are related to dysfunction of these specific sub-circuits. As yet, however, there has been little work in the monkey models of PD to explore the effects of GPI lesions on experimental parkinsonism and drug-induced dyskinesias, and whether lesions in regions of GPi which interrupt specific subchannels will have a differential effect of parkinsonian motor signs and drug-induced dyskinesia. Consistent with the hypothesis that the pallido-thalamic "motor" circuits is responsible for the development of parkinsonian motor signs are earlier and recent reports that stereotactic lesions of the posteroventral (probable sensorimotor) portion of GPi in parkinsonian patients, can reverse the major motor abnormalities of PD as well as drug-induced dyskinesia. Thus, there is hope of improving motor function by surgical intervention for parkinsonian individuals who no longer derive benefit from medication or who cannot tolerate the dyskinesia and/or cognitive disturbances associated with drug therapy. Yet, much work remains to be done to determine which normalize activity in GPi while leaving the pallidothalamic projection and fibers passing through GPi intact, may be more effective. The studies in this proposal are directed at answering these questions. Specifically we will: 1) determine the optimal site of lesions in the pallidum for reversing parkinsonian motor signs and drug-induced dyskinesia, 2) determine whether specific subregions of GPi mediate specific parkinsonian signs (akinesia, bradykinesia, tremor and rigidity) and drug-induced dyskinesia, 3) determine whether bilateral lesions in GPi are more or less effective than GPi lesions in reversing parkinsonian motor sign and drug-induced dyskinesia.

The Alzheimer's Disease Center (ADC) will continue to build upon the resources at Emory to support and foster the growth and quality of Alzheimer's disease (AD). Since its inception in the fall of 1991, the ADC has energized the clinical and research activities of the Emory community. The addition of a Satellite Clinic in urban Atlanta has enabled the ADC to provide research, clinical, and educational opportunities to an underserved, predominantly African American community. The unparalleled clinical and research activities in movement disorders at Emory provide a valuable resource as the ADC examines the overlap and heterogeneity of AD, Parkinson's disease and related dementias. These themes are also synergistic with the unique contributions of Emory investigators in the field of mitochondrial genetics examining mitochondrial abnormalities in neurodegenerative and other disorders. The Administrative and Data Management Core will manage the overall ADC operation and provide the structural foundation for promotion of basic and clinical scientific research. Investigators from Emory Rollins School of Public Health with expertise in study design, data management, and biostatistics will assure quality and integration of data and promote productivity among ADC and other investigators. In a setting of quality patient care, family support, and education, the Clinical Core will provide well characterized groups of AD patients, Parkinson's disease patients with and without dementia, and normal individuals free of cognitive and motor impairment. The high proportion of African American subjects seen through the Clinical Core, paralleling that of our regional population, will enable us to obtain information on dementia in this understudied group. The Neuropathology Core will continue to supply brain and other appropriate tissues from well characterized dementia and control cases to investigators through maintenance of an active brain bank. The Molecular Biology Core will screen for mitochondrial and other genetic abnormalities associated with AD, PD and the overlap syndromes, on well characterized cases seen through the Clinical and Neuropathology cores. The Education and Transfer Core will develop and enhance its innovative educational programs for professionals, caregivers, and other groups. In combination with strong institutional support and the enormous growth of the neuroscience community at Emory, the ADC will serve as increasingly critical role in promoting AD research.

The Alzheimer's Disease Center (ADC) will continue to build upon the resources at Emory to support and foster the growth and quality of Alzheimer's disease (AD). Since its inception in the fall of 1991, the ADC has energized the clinical and research activities of the Emory community. The addition of a Satellite Clinic in urban Atlanta has enabled the ADC to provide research, clinical, and educational opportunities to an underserved, predominantly African American community. The unparalleled clinical and research activities in movement disorders at Emory provide a valuable resource as the ADC examines the overlap and heterogeneity of AD, Parkinson's disease and related dementias. These themes are also synergistic with the unique contributions of Emory investigators in the field of mitochondrial genetics examining mitochondrial abnormalities in neurodegenerative and other disorders. The Administrative and Data Management Core will manage the overall ADC operation and provide the structural foundation for promotion of basic and clinical scientific research. Investigators from Emory Rollins School of Public Health with expertise in study design, data management, and biostatistics will assure quality and integration of data and promote productivity among ADC and other investigators. In a setting of quality patient care, family support, and education, the Clinical Core will provide well characterized groups of AD patients, Parkinson's disease patients with and without dementia, and normal individuals free of cognitive and motor impairment. The high proportion of African American subjects seen through the Clinical Core, paralleling that of our regional population, will enable us to obtain information on dementia in this understudied group. The Neuropathology Core will continue to supply brain and other appropriate tissues from well characterized dementia and control cases to investigators through maintenance of an active brain bank. The Molecular Biology Core will screen for mitochondrial and other genetic abnormalities associated with AD, PD and the overlap syndromes, on well characterized cases seen through the Clinical and Neuropathology cores. The Education and Transfer Core will develop and enhance its innovative educational programs for professionals, caregivers, and other groups. In combination with strong institutional support and the enormous growth of the neuroscience community at Emory, the ADC will serve as increasingly critical role in promoting AD research.

Parkinson's disease; education evaluation /planning; training; continuing education; biomedical facility;

The proposed studies of this Center grant are focused on basic issues concerning the pathophysiology of Parkinson's disease (PD) and their therapeutic implications. These studies are, in part, concerned with animal models of PD and key aspects of the current basal ganglia- thalamocortical circuit models of parkinsonism. Project 1 is focused on the development of a more appropriate model of PD, in particular, one that exhibits the progressive nature of PD. The proposed model employs chronic systemic inhibition of complex I by rotenone in rodents with possible extension to primates. The conceptual connective framework for projects 2-5 is the exploration and testing of the current circuit model in both animal models and patients with PD. The studies in Project 2 explore in patients with PD the effects of deep brain stimulation (DBS) of the internal pallidum (GPi) and subthalamic nucleus (TN) on behavior and brain activation of 0-15 PET. These studies will help clarify functional correlates of the amelioration of specific parkinsonian symptoms by DBS of GPi and STN. Project 3 explores, in the primate metabolism in the thalamocortical circuit using a combination of single cell recording and FDG PET. Microdialysis combined with DBS of the STN will help to clarify the mode of action of DBS. This project will also examine the potential neuroprotective effects of STN inactivation. Project 4 explores key controversial issues regarding the pathophysiology of PD using microdialysis in primates. Metabotrophic glutamate receptors are abundant in STN and GPi and specific subtypes may be promising therapeutic targets. Project 5 will test the hypothesis that specific subtypes of metabotrophic glutamate receptors may play a therapeutically relevant role in PD. The Center will also provide state-of-the-art, multi-disciplinary training of fellows in research into parkinsonism and related conditions with an emphasis on translational.

neural degeneration; nervous system disorder; alternative medicine; biomedical facility; degenerative motor system disease;

The major aim of this study is to carry out a sequential Phase I trial of prefrontal transcranial disease (PD) and severe depression. Depression complicates PD in up to 50 percent of cases, leading to further deterioration of motor performance and quality of life; but antidepressant medication fails or produces intolerable side effects in 25-30 percent of patients. Case reports and uncontrolled trials suggest that ect is effective in ameliorating simultaneously the mood and motor symptoms of PD. Only a few small studies of ECT in PD have been prospective or randomized, the assessment protocols have been limited, and the results have been variable. TMS is a new, promising, alternative treatment for refractory depression, which appears to be easier and safer that ETC. Requiring no hospitalization, anesthesia, or recovery time, TMS is now being investigated as an alternative therapy for mood disorders. TMS has not been studied in depressed patients with PD or in other serious central nervous system diseases. This study extends our past and present research in PD, depression, ECT, and TMS. We will comprehensively evaluate the effects of left prefrontal TMS on mood, motor, and neuropsychological function together with quality of life indices in depressed PD patients. All patients will initially receive treatment with TMS. Those who fail to benefit will proceed to ETC. Comprehensive evaluation will be continued for another eight weeks in both the TMS-only and ECT groups. The key issues addressed by these studies include (1) the potential benefit of TMS on mood and movement in depressed PD patient, and (2) the tightness of the association between mood and motor function after TMS and ETC. Overall, these studies will provide important preliminary data on the relationships among mood, cognitive and motor function in PD, and their influence on quality of life. The results will help in directing future applications of TMS as an alternative therapy for brain disorders, and will further elucidate the relative benefits of both TMS and ECT in depressed PD patients. A positive effects from TMS should be an impetus towards randomized, placebo-controlled trials.

[unreadable] DESCRIPTION (provided by applicant): Dystonia is a neurologic syndrome characterized by involuntary muscle contractions and/or abnormal postures. It can be quite painful and debilitating. Primary dystonia cases involve no known pathologic changes in the brain, and the condition, though progressive, does not appear to be degenerative. As a neurochemical disorder the path to development of a successful therapy may be relatively straightforward for any of the dystonias, much as is the case now for dopa-responsive dystonia which responds remarkably well to I-dopa replacement therapy. Early-onset dystonia has a poor prognosis; it starts in childhood, typically in a limb and spreads to involve most limbs and the trunk (generalized dystonia.) The gene for this condition was discovered several years ago by DMRF-funded investigators and mutation of this gone (DYT1) with the deletion of a single pair of GAG triplets leads to an altered gene product, torsin A. At present, the function of torsin A remains obscure but it is clearly a major basis of the pathophysiology of dystonia in carriers who do show symptoms (30% penetrance of the dominant DYT1 gene.) The planned series of workshops will include both basic and clinical topics, all germane to the dystonia field. The overarching theme will emphasize the pathophysiology with emphasis on new findings that are rapidly showing that the centers of the brain responsible to dystonia and other movement disorders may be much more malleable than previously recognized. The workshops will be planned jointly by the DMRF Scientific Advisory Board in partnership with its Directions Committee, with a goal of each year focusing on a topic that offers the greatest potential for rapid progress towards the development of new therapies. [unreadable] [unreadable] [unreadable]

The purpose of the Emory CCPDER is to perform cutting-edge collaborative research on PD pathogenesis, with a focus on gene-environment interactions. The CCPDER brings together 3 established investigators - Drs. Greenamyre, Levey and Miller - who are each individually interested in the pathogenesis of PD and the roles that gene-environment interactions play in this disorder. Drs. Greenamyre and Levey bring both clinical and basic research perspectives to the Center. Dr. Miller brings an environmental toxicologist's point of view to the group. The proposed research will take place under the auspices of the new Center for Neurodegenerative Diseases (CND) in the recently completed Whitehead Research Building, where the investigators will share contiguous lab space and core equipment and facilities. The Emory CCPDER will capitalize on the expertise of each individual project leader in a truly collaborative, multidisciplinary endeavor in which the investigators will literally interact on a daily basis. The CCPDER consists of 3 integrative research projects supported by a Research Development Core. There are no Scientific Cores because the CND was conceived as a facility that would contain most necessary core facilities within its walls, with free access to all facilities by all CND investigators. Project 1 expands the rotenone model of PD into mice and organotypic slice cultures in order to examine geneenvironment interactions in this model. It will also screen other similar pesticides for their ability to cause PD, and it will screen neuroprotective strategies. Project 2 examines the vesicular monoamine transporter (VMAT2) as a target of environmental toxicants, such as organochlorines. Genetic approaches will be used to manipulate VMAT2 and examine its interactions with genes important in PD pathogenesis, such as alpha-synuclein. Project 3 is a genetic and pathological study of a new genetic linkage to PD, PARK10, which has been associated with increased risk of 'sporadic' PD in Iceland. Sporadic PD patients will be evaluated at Emory and high-density genome scans will be performed. Candidate genes have been identified and antibodies raised to the gene products. These will be assessed in human postmortem brain specimens and in experimental models of PD. The projects and administrative core involve molecular neurobiology, human genetics, clinical research, education, and collaboration with a PD epidemiologist. Common themes of the interactive projects include pesticides, gene-environment interactions, the ubiquitin/proteasome system, and dopamine. Each of the projects capitalizes on one or more existing funded projects. This fact, together with the core facilities of the CND allows us to leverage the requested funds for maximal effect.

nervous system disorder therapy; human therapy evaluation; electrostimulus; lenticular nucleus; brain electronic stimulator; Parkinson's disease; thalamic nuclei; longitudinal human study; clinical trials; patient oriented research; clinical research; human subject;

[unreadable] DESCRIPTION (provided by applicant): [unreadable] [unreadable] Dystonia is a neuorologic syndrome characterized by involuntary muscle contractions and/or abnormal postures. The majority of patients with dystonia have primary dystonia with no known pathologic changes identified in the brain. Primary Dystonia is thus, viewed as a neurochemical disorder with a great potential for successful treatment if the pathophysiologic basis were better understood. Young-onset dystonia has a poor prognosis typically beginning in a limb and spreading to involve most limbs and trtmk (generalized dystonia). The gene for this young-onset, limb-onset dystonia has been named DYT1, is due to the deletion of one of a pair of GAG triplets in the gene for torsin A located on the long arm of chromosome 9. Little is known about the function of torsin A. Torsi A is a member of the AA+ family of proteins, a group that includes heat shock proteins and chaperones. The purpose of this proposed workshop is to bring together leading researchers with expertise in areas specifically relevant to elucidating the pathophysiology of primary dystonia. Critical aspects to be discussed at this workshop include: possible functions of torsin A in stress, protein folding and degradation and cellular polarity; cellular and molecular aspects of neuronal plasticity during development and motor learning; and neuronal systems involved in motor learning. Researchers in these disparate areas, as well as clinicians/scientists treating dystonia patients, will be able to cross fertilize each other in order to identify the most promising research directions and opportunities as well as the major gaps remaining in our understanding. Discussion will focus on understanding the neuronal events that take place during motor learning which could be disrupted by mutant torsin A during childhood, that is the susceptible period for onset of young onset torsion dystonia, and by repetitive movement and sensory insults that can trigger adult onset dystonia. Data from animal and cellular models as wells as data from human subjects undergoing electrophysiologic, and neuroimaging studies and neurosurgical procedures will be discussed. Emphasis will be given to means of reprogramming the nervous system to reverse the physiologic impact of changes in circuitry associated with dystonia. The conference is scheduled to take place in Atlanta, GA on January 10-11, 2004. [unreadable] [unreadable]