Stanley Fahn, M.D. - US grants

Although dopamine (DA) replacement therapy is useful for most of the motor symptoms of Parkinson's disease (PD), some troubling symptoms of the disease are refractory to levodopa therapy and may even worsen with such treatment. These include apathy, depression, memory loss, postural instability and freezing episodes. The data presented here suggest that some of these symptoms may be due to brain norepinephrine (NE) deficiency. Such deficiency is not treatable with levodopa, but may, however, respond to "NE replacement threapy." DL-threo-3,4-dihydroxyphenylserine (DL-threo-DOPS) is a nonphysiological precursor of NE which has been shown to undergo decarboxylation in various mammalian tissues, and to yield NE in a similar way to the formation of DA from levodopa. In preliminary clinical experience DL-threo-DOPS has been shown to improve symptoms of PD which were refractory to levodopa therapy. We are proposing 1) to study the effects of DL-threo-DOPS on DA and NE metabolism in the rat brain and, 2) to evaluate the clinical efficacy of DL-threo-DOPS in the treatment of PD. Results are expected to show the effect of DL-threo-DOPS on NE turnover in the rat brain and the effect of such therapy on the dopaminergic pathway. Clinical studies are expected to show the efficacy of DL-threo-DOPS in the therapy of PD and possible side effects of the drug. If DL-threo-DOPS is proven to be a safe and effective precusor of NE in humans, it may open new approaches for future treatment of several other disorders as well.

The long term objective of the proposed research is to produce valid, sensitive, and economical instrumented tests of tremor, bradykinesia, and cogwheel rigidity for patients with Parkinson's Disease (1). The specific aims of the proposed research are 1) to validate simplified accelerometric measures of resting tremor, 2) to instrument and validate a variation of the Finger Oscillation Test (FOT) of bradykinesia, and 3) to further validate an accelerometric measure of cogwheel rigidity reported by Lance, Schwab, and Peterson (2), and Findley, Gresty, and Halmagyi (3). These three test use the same accelerometer and personal computer and therefore are more efficient and cost effective than using separate equipment for each test as is currently the norm (1). Validation will be economically accomplished by using 30 patients already enrolled in the funded study entitled DEPRENYL AND TOCOPHEROL ANTIOXIDATIVE THERAPY OF PARKINSONISM (DATATOP) (4,5) and 30 spouse/relative control subjects at Month 0, 1, 3, 6, 9, 12, 15, 18, 21, 24, and 25, or until levodopa therapy is begun, where upon their participation in the parent study is terminated after a one month washout period. Clinical status as reflected by the accelerometric measures of tremor, bradykinesia, and cogwheel rigidity will be correlated with the standard clinical assessments of these same symptoms. Positive results will provide valid, sensitive, and economical means of obtaining instrumented tests of tremor, bradykinesia, and rigidity in an outpatient setting.

Dystonia is a disabling neurological disorder characterized by involuntary twisting movements and postures. Dystonia may be idiopathic or secondary to known environmental or metabolic factors. No marker, pathological or biochemical, has been identified in idiopathic dystonia. However based on clinical and ethnic criteria and familial patterns, subtypes have been described and genetic heterogeneity proposed. Included in these subtypes are (1) Ashkenazi Jews, (2) non- Jewish caucasians and (3) non-Ashkenazi caucasians with dopa responsiveness. Because of our rich resource of patients, clinical expertise, and team of experienced geneticists, we are in a unique position to locate and ultimately identify the defective gene(s) underlying idiopathic dystonia and establish whether the same locus is involved in each group through linkage heterogeneity test. We propose to perform linkage studies on families that are representative of the three subtypes of dystonia described above. Detailed and unbiased clinical assessment of informative large and small families will be performed. Blood samples from informative family members will be collected for DNA and protein marker determination. We will search for a linked marker within individual large families ethnic subtype. We will test for genetic heterogeneity both within and between subgroups. Once a linked marker to one or more disease subtypes is found, we will define further the genomic region containing the dystonia gene with the ultimate aim of identification of the defective gene. The results of this study are directly applicable in the clinical setting. Finding a closely linked marker will allow for reliable risk assessment in counseling of families. Further identification of the mutant gene will ultimately elucidate the mechanism(s) underlying this mysterious disorder and could provide a basis for specific treatment.

Dystonia is a disabling neurological disorder characterized by involuntary twisting movements and postures. Dystonia may be idiopathic or secondary to known environmental or metabolic factors. No marker, pathological or biochemical, has been identified in idiopathic dystonia. However based on clinical and ethnic criteria and familial patterns, subtypes have been described and genetic heterogeneity proposed. Included in these subtypes are (1) Ashkenazi Jews, (2) non- Jewish caucasians and (3) non-Ashkenazi caucasians with dopa responsiveness. Because of our rich resource of patients, clinical expertise, and team of experienced geneticists, we are in a unique position to locate and ultimately identify the defective gene(s) underlying idiopathic dystonia and establish whether the same locus is involved in each group through linkage heterogeneity test. We propose to perform linkage studies on families that are representative of the three subtypes of dystonia described above. Detailed and unbiased clinical assessment of informative large and small families will be performed. Blood samples from informative family members will be collected for DNA and protein marker determination. We will search for a linked marker within individual large families ethnic subtype. We will test for genetic heterogeneity both within and between subgroups. Once a linked marker to one or more disease subtypes is found, we will define further the genomic region containing the dystonia gene with the ultimate aim of identification of the defective gene. The results of this study are directly applicable in the clinical setting. Finding a closely linked marker will allow for reliable risk assessment in counseling of families. Further identification of the mutant gene will ultimately elucidate the mechanism(s) underlying this mysterious disorder and could provide a basis for specific treatment.

Dystonia is a disabling neurological disorder characterized by involuntary twisting movements and postures. Dystonia may be idiopathic or secondary to known environmental or metabolic factors. No marker, pathological or biochemical, has been identified in idiopathic dystonia. However based on clinical and ethnic criteria and familial patterns, subtypes have been described and genetic heterogeneity proposed. Included in these subtypes are (1) Ashkenazi Jews, (2) non- Jewish caucasians and (3) non-Ashkenazi caucasians with dopa responsiveness. Because of our rich resource of patients, clinical expertise, and team of experienced geneticists, we are in a unique position to locate and ultimately identify the defective gene(s) underlying idiopathic dystonia and establish whether the same locus is involved in each group through linkage heterogeneity test. We propose to perform linkage studies on families that are representative of the three subtypes of dystonia described above. Detailed and unbiased clinical assessment of informative large and small families will be performed. Blood samples from informative family members will be collected for DNA and protein marker determination. We will search for a linked marker within individual large families ethnic subtype. We will test for genetic heterogeneity both within and between subgroups. Once a linked marker to one or more disease subtypes is found, we will define further the genomic region containing the dystonia gene with the ultimate aim of identification of the defective gene. The results of this study are directly applicable in the clinical setting. Finding a closely linked marker will allow for reliable risk assessment in counseling of families. Further identification of the mutant gene will ultimately elucidate the mechanism(s) underlying this mysterious disorder and could provide a basis for specific treatment.

Negative motor phenomena (lapses in normal muscle tone, manifested by prolonged silence on electromyography) are present in several pathological states and produce major motor disability in patients affected with these problems. Three major neurological disorders in which negative motor phenomena play a devastating role are cataplexy and certain forms of epilepsy and myoclonus. The treatments available for "positive" and typical forms of epilepsy and myoclonus rarely improve those patients in which negative motor phenomena are also present. Sudden loss of motor tone causes the patients to fall down, impair motor coordination, and interfere with activities of daily living. New advances in physiology make this an opportune time to review this entire subject. Asterixis is the most familiar form of negative myoclonus. The type of negative myoclonus affecting thigh muscles, as commonly occurs in patients with post-hypoxic action myoclonus, prevents ambulation. Atonic seizures, that occur in several types of epilepsy syndromes, such as the lennox- Gastaut syndrome. Cataplexy is a dramatic disorder triggered by an emotional stimulus, with the patient suddenly losing motor tone, falling down, and being unable to move. Negative motor phenomena occur in choreic disorders (being called motor impersistence) and account for the dropping of objects.The 'freezing' phenomenon in Parkinson's disease may be a negative motor phenomenon. All of these forms of negative motor phenomena have ben highly resistant to any form of treatment. Negative motor phenomena can appear in normal motor behavior, such as in REM sleep, and possible in silent periods in electromyography. The neural basis for loss of motor tone unknown, and to date, no formal scientific meeting devoted to negative motor phenomena has ever been held. In a three day workshop, invited discussants and participants will review the current state of knowledge in their field of expertise and present their research in those areas. The workshop will bring together neuroscientists and clinicians renowned for work in subspecialties relating to negative motor phenomena, including neurophysiology, neurochemistry, neuroanatomy, epileptology, sleep disorders and movement disorders. Normally, such individuals would not share the same scientific meetings, so this workshop will allow them to learn from one another. The material will encompass all that is known on the subject, and each participant will write a review chapter that will be part of a monograph which should serve as the definitive volume on negative motor phenomena. We hope to achieve a new level of understanding with the expected compilation of current knowledge and anticipate that new research strategies will emerge.

Dystonia is a disabling neurological disorder characterized by involuntary twisting movements and postures. Dystonia may be idiopathic or secondary to known environmental or metabolic factors. No marker, pathological or biochemical, has been identified in idiopathic dystonia. However based on clinical and ethnic criteria and familial patterns, subtypes have been described and genetic heterogeneity proposed. Included in these subtypes are (1) Ashkenazi Jews, (2) non- Jewish caucasians and (3) non-Ashkenazi caucasians with dopa responsiveness. Because of our rich resource of patients, clinical expertise, and team of experienced geneticists, we are in a unique position to locate and ultimately identify the defective gene(s) underlying idiopathic dystonia and establish whether the same locus is involved in each group through linkage heterogeneity test. We propose to perform linkage studies on families that are representative of the three subtypes of dystonia described above. Detailed and unbiased clinical assessment of informative large and small families will be performed. Blood samples from informative family members will be collected for DNA and protein marker determination. We will search for a linked marker within individual large families ethnic subtype. We will test for genetic heterogeneity both within and between subgroups. Once a linked marker to one or more disease subtypes is found, we will define further the genomic region containing the dystonia gene with the ultimate aim of identification of the defective gene. The results of this study are directly applicable in the clinical setting. Finding a closely linked marker will allow for reliable risk assessment in counseling of families. Further identification of the mutant gene will ultimately elucidate the mechanism(s) underlying this mysterious disorder and could provide a basis for specific treatment.

This research is to perform a placebo-controlled, double blind study of embryonic implants into patients with intractable Parkinson's disease. Patients will be monitored at least 3 months prior to surgery and for a minimum of 1 year after surgery. Study is now in extension and open label phase.

Levodopa is the most effective and widely used drug in ameliorating the signs and symptoms of Parkinson's disease (PD). In recent years, an increasing number of scientific reports find both levodopa and dopamine to be toxic to catecholaminergic neurons both in vitro and in vivo animal models of PD. This has led to a growing concern among neurologists and neuroscientists that levodopa treatment may be hastening the growing concern among neurologists and neuroscientists that levodopa treatment may be hastening the underlying progressive degeneration of nigral dopaminergic neurons, the pathological hallmark of PD. Since levodopa is the major drug used to treat PD, it is important to determine whether levodopa does or does not aggravate PD. The investigators in this study have a great deal of uncertainty (clinical equipoise) about the possible toxicity of levodopa. On one hand, early introduction of levodopa could lead to immediate symptomatic benefit and a higher quality of life. Alternatively, if levodopa hastens progression of dopaminergic cell loss, it will more rapidly lead to advanced disease, which ultimately fails to respond to levodopa or other anti-PD drugs. The main goal of this controlled clinical trial is to answer the question: does the early introduction of levodopa provide improved quality of life to PD patients or does it enhance the underlying progression of PD? We will enroll 360 patients with early, untreated PD into this randomized, placebo-controlled, double blinded, multi-center clinical trial. Subjects will be randomized into one of four equally sized treatment arms: carbidopa/levodopa (12.5/50, 25/100, 50/200 mg tid) and matching placebo. They will be treated for 9 months, a duration which is clinically meaningful and feasible in minimizing premature withdrawal from the trial. The primary outcome variable is the rate of PD clinical progression based on a dose-response curve, comparing baseline to post- treatment measures. PD progression will be measured by the change in total Unified Parkinson's Disease Rating Scale (UPDRS) between untreated baseline and final visit. The final visit will take place 14 days after withdrawal from experimental treatments subsequent to 9 months of follow-up on treatment. The blinded institutional primary rater, who will otherwise not be involved in clinical evaluations or medication adjustments during the trial, will perform these baseline and final UPDRS evaluations. The blinded institutional treating investigator will evaluate subjects at 3-month intervals and may adjust the frequency of dosings or add specified antidote drugs to overcome complications from study drug when judged to be clinically required. No symptomatic anti- PD drug will be openly added during the trial. Knowledge gained from this study will address the most common concern of patients, families and clinicians, namely should levodopa be delayed as long as clinically feasible or be used as early as possible.

Parkinson's disease (P-D) is a common neurodegenerative disorder characterized by bradykinesia, rigidity and tremor; current treatments neither slow progression nor adequately control the most disabling symptoms. Most of PD's clinical features result from the loss of dopamine (DA) neurons in the substantia nigra pars compacta (Snpc). Thus far, the cause and pathogenesis of PD are unknown. This knowledge is critical to learn how to prevent PD's inexorable progression. The unifying theme of this PD Center relates to neurodegeneration in PD; our goal is to unravel its pathogenesis in lab projects 1-4 and quantify its progression in clinical projects 5&6. Project 1 investigates two animal models of PD, i.e., loss of Snpc neurons in the MPTP mouse and in the transgenic mouse expressing mutant Cu/Zn superoxide dismutase (Msod1). We explore our observation that MPTP stimulates the production of hypochlorous acid, a highly reactive tissue damaging species. Through a series of DNA strand breakage and poly (ADP-ribose) polymerase (PARP) activation in the MPTP model. It will also explore the increased cytosolic DA pool leads to degeneration of Snpc neurons and produces cytoplasmic ubiquitinated inclusions reminiscent of Lewy bodies, a hallmark of PD. Project 2 investigates how altering intracellular DA in cultures of SN neurons from genetically engineered mice triggers molecular mechanisms to initiate degeneration of DA neurons. Project 3 evaluates the hypothesis that abnormally re-activated programmed cell death (PCD) (which occurs normally during development) plays a role in pathogenesis of PD. Project 3 examines the role of the signaling molecule c-jun, its kinase, JNK, the death effector caspase-3, and a tau and neurofilament kinase cdk5 in paradigms of PCD in dopaminergic Snpc neurons. Project 4 will identify genes that play roles in the 6-OHDA-induced degeneration of monoaminergic PC12 cells utilizing a new technique, Serial Analysis of Gene Expression (SAGE) and then will determine the expression of such genes in animal models and in POD brains. TO develop a biologic marker to quantify DA neurodegeneration in humans, Project 5 will correlate longitudinal clinical evaluations and positron emission tomography (PET)-generated metabolic findings in a cohort of early PD patients. Development of a biomarker is necessary to assess disease progression in future clinical trials testing potential neuroprotective therapies. Project 6 is an epidemiological study designed to explain the lower prevalence rates of PD in Blacks and women; it will evaluate, among other hypotheses, the possibility that biological differences may affect rates of progression.

DESCRIPTION (Applicant's Abstract): The goal of this application is to plan, execute and publish the proceedings of a 3-day international symposium on new developments in the area of myoclonus and paroxysmal dyskinesias. The meeting will be open to the public and will be advertised at major neurology meetings and journals. It has been 15 years since the last comprehensive meeting on myoclonus, and to our knowledge no open meeting has focused attention on the paroxysmal dyskinesias. There have been tremendous advances in understanding the etiology and mechanisms of these disorders. By presenting recent developments in both fields together, we hope to illustrate the underlying similarities between the two areas. The symposium will include an international roster of 35 invited speakers who will give plenary talks, and approximately 25 poster presentations chosen by the organizing committee on the basis of submitted abstracts. It will occur over 3 days and be divided into 6 half-day sessions, including: 1) Clinical features of myoclonic syndromes; 2) Neurophysiology of myoclonus; 3) Genetics of myoclonus; 4) Neuropharmacology and animal models of myoclonus; 5) Paroxysmal dyskinesias and their relationship to epilepsy; 6) The genetics of paroxysmal disorders. During each day's lunch break, participants will briefly present their posters, reviewing the latest developments in these fields. Each invited speaker will be required to submit a brief abstract and a full-length chapter summarizing their presentation. Poster presenters will submit a brief abstract. The collected abstracts will be published in the journal Movement Disorders. The chapters will be published in full in a single volume, probably in the Advances in Neurology series. Many of the speakers may present videotapes of animal models or patients. These will be edited and accompany the single volume in CD-ROM format.

Parkinson's disease (P-D) is a common neurodegenerative disorder characterized by bradykinesia, rigidity and tremor; current treatments neither slow progression nor adequately control the most disabling symptoms. Most of PD's clinical features result from the loss of dopamine (DA) neurons in the substantia nigra pars compacta (Snpc). Thus far, the cause and pathogenesis of PD are unknown. This knowledge is critical to learn how to prevent PD's inexorable progression. The unifying theme of this PD Center relates to neurodegeneration in PD; our goal is to unravel its pathogenesis in lab projects 1-4 and quantify its progression in clinical projects 5&6. Project 1 investigates two animal models of PD, i.e., loss of Snpc neurons in the MPTP mouse and in the transgenic mouse expressing mutant Cu/Zn superoxide dismutase (Msod1). We explore our observation that MPTP stimulates the production of hypochlorous acid, a highly reactive tissue damaging species. Through a series of DNA strand breakage and poly (ADP-ribose) polymerase (PARP) activation in the MPTP model. It will also explore the increased cytosolic DA pool leads to degeneration of Snpc neurons and produces cytoplasmic ubiquitinated inclusions reminiscent of Lewy bodies, a hallmark of PD. Project 2 investigates how altering intracellular DA in cultures of SN neurons from genetically engineered mice triggers molecular mechanisms to initiate degeneration of DA neurons. Project 3 evaluates the hypothesis that abnormally re-activated programmed cell death (PCD) (which occurs normally during development) plays a role in pathogenesis of PD. Project 3 examines the role of the signaling molecule c-jun, its kinase, JNK, the death effector caspase-3, and a tau and neurofilament kinase cdk5 in paradigms of PCD in dopaminergic Snpc neurons. Project 4 will identify genes that play roles in the 6-OHDA-induced degeneration of monoaminergic PC12 cells utilizing a new technique, Serial Analysis of Gene Expression (SAGE) and then will determine the expression of such genes in animal models and in POD brains. TO develop a biologic marker to quantify DA neurodegeneration in humans, Project 5 will correlate longitudinal clinical evaluations and positron emission tomography (PET)-generated metabolic findings in a cohort of early PD patients. Development of a biomarker is necessary to assess disease progression in future clinical trials testing potential neuroprotective therapies. Project 6 is an epidemiological study designed to explain the lower prevalence rates of PD in Blacks and women; it will evaluate, among other hypotheses, the possibility that biological differences may affect rates of progression.

DESCRIPTION (provided by applicant): The major goal is to organize and execute a 3-day symposium on torsion dystonia, covering current status, new research advances, and prospective new ideas for investigation. The symposium will bring together investigators from around the world to discuss this topic. It has been 5 years since the last International Dystonia Symposium; it was published as Dystonia 3 in Advances of Neurology. The wealth of research, particularly in genetics, PET scans, and surgery in the dystonias that have occurred in the past five years make this an opportune time to review the entire field. The 3-day symposium is divided into the six "hottest" topics in dystonia, two topics per day, one in the morning session and one in the afternoon session. These six topics are: 1) Pathophysiology, 2) Oppenheim's (DYT1), 3) Other Genetic Dystonias (Dopa-responsive Dystonia, Myoclonus-Dystonia, Mennonite Dystonia, and X-linked Dystonia-Parkinsonism), 4) PET and Biochemistry, 4) Musician's Cramps and Other Focal Dsytonias, and 6) Therapeutics. Invited experts will deliver the plenary talks, reviewing the current state of knowledge in their field of expertise and present their research in those areas. Following the plenary talks in each half-day session will be shorter platform presentations by active investigators willing to present new data. These presentations will be selected by the organizing committee from submitted abstracts. Other accepted abstract presentations, unable to be accommodated by platform talks, will be assigned to the poster sessions, which will be verbally discussed during lunch. The symposium is open to all those who wish to attend. Announcements of the symposium will be widely circulated. Another aim is to publish a monograph of the proceedings. Each plenary speaker will write a review chapter, and each scientific presenter a scientific paper. This monograph will serve as an up-to-date single-source volume on dystonia. The abstracts will be distributed to the participants at the time of the symposium, we plan to publish the abstracts from this symposium in the journal Movement Disorders.

DESCRIPTION (provided by applicant): This double-blind, placebo-controlled, parallel-design multi-center clinical trial was developed to determine the impact, if any, of levodopa on the natural history of Parkinson's disease (PD). In essence, there is a serious question whether levodopa, the most important and powerful drug available to treat the symptoms of PD, hastens the underlying progression of the disease in spite of its symptomatic benefit or whether it has no effect, or even slows the rate of progression. The design is that of a dose-response test of levodopa and matching placebo in patients with PD at its earliest stage, i.e., a stage where the symptoms are so mild that symptomatic treatment is not required. Enrolled subjects are assigned placebo or one of three doses (12.5/50, 25/100, 50/200 mg tid) of carbidopa/levodopa which they take for 40 weeks (9 months), followed by a two-week washout period. No other anti-Parkinson medication is allowed in the study. At the end of the washout period the blinded Primary Rater, who examined the subject at baseline and who has had no other contact with the subject over the next 42 weeks, re-examines the patient. The primary outcome variable is the rate of change of severity of PD in the four treatment arms based on a dose-response curve. Severity is measured clinically using the Unified Parkinson's Disease Rating Scale (UPDRS). The blinded institutional treating investigator evaluates subjects throughout the study and adjusts the frequency of dosings or adds specified antidote drugs to overcome complications from study drug when judged to be clinically required. No symptomatic anti-PD drug will be openly added during the trial. There are a number of secondary outcome variables as well: monitoring the longduration and the short-duration benefit of levodopa, studying fatigue in PD, the effect of levodopa on depression, the effect of caffeine on PD, and the development of adverse effects of levodopa. Knowledge gained from this study will address the most common concern of patients, families and clinicians, namely should levodopa be delayed as long as clinically feasible or be used as early as possible. NIH funding for this clinical trial began on January 1, 1998, and is scheduled to be completed on December 3 1, 2000. We are not able to complete this clinical trial within this time frame, and with this application we are requesting an extension of the deadline with additional ftinding to complete the study.

DESCRIPTION (provided by applicant): The major goal is to organize and execute a 4-day international congress on Parkinson's disease (PD) that brings together neuroscientists, physicians, patients, families, health-care providers, and voluntary organizations involved with PD. The majority of invited speakers will be professionals from academia, government and industry from around the world to review and discuss the multifaceted problems of PD and propose solutions. In addition to the invited speakers in both the plenary sessions and the parallel symposia, there will be scientific poster sessions each day of the Congress. The poster sessions will be composed of submitted abstracts accepted by the Program Committee. The selected 3 most outstanding posters each day will also be presented in a plenary platform session at the end of each day. The daily schedule of platform presentations corresponds to the theme of that day. Each day will begin with 2 invited plenary talks, followed by parallel symposia. These parallel sessions will allow separate topics to cover 1) new developments in science, 2) concepts on clinical care, and 3) issues related to quality of life; these separate topics will provide day-long discussions to hold the diverse interest of scientists, clinicians, patients and care-providers. At the end of the day, these distinct groups will come together for a final plenary session to present the 3 hottest topics from that day's poster session, to be followed by summations from the day's parallel sessions. The 2006 World' Parkinson Congress will be held in the Washington Convention Center from February 22- 26, 2006. The Congress is conceived as a scientific and educational forum where all constituencies can meet collectively and in smaller groups to address all topics relevant to PD, particularly to discuss the latest in research and to suggest new solutions for unmet needs. We anticipate that novel ideas and approaches will be generated from such interchanges, leading to better therapies for PD.