Parkinson's Disease Research Web: News Archive
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Objective: To study the safety and efficacy of a cholinesterase inhibitor, donepezil hydrochloride, for the treatment of dementia in Parkinson's disease (PD). Methods: This was a randomised double blind, placebo controlled, crossover study in 22 subjects with PD and dementia. Participants were randomised to receive either donepezil followed by identical placebo, or placebo followed by donepezil. Donepezil was administered at 5-10 mg/day. Treatment periods were 10 weeks with a washout period of 6 weeks between the two periods. The primary outcome measure was the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAScog). Results: Donepezil was well tolerated and most adverse events were mild. There was no worsening of PD symptoms as measured by the total or motor sections of the Unified Parkinson's Disease Rating Scale. There was a 1.9 point trend toward better scores on the ADAScog on treatment compared with placebo that was not statistically significant. The secondary cognitive measures showed a statistically significant 2 point benefit on the Mini Mental Status Examination and no change on the Mattis Dementia Rating Scale (MDRS). The Clinical Global Impression of Change (CGI) showed a significant 0.37 point improvement on donepezil. No improvement was observed on the MDRS or the Brief Psychiatric Rating Scale. Carryover between treatment periods was observed but was not statistically significant. Conclusions: Donepezil was well tolerated and did not worsen PD. There may be a modest benefit on aspects of cognitive function. The possible clinical benefit measured by CGI was reflected in only one of the cognitive scales used in this study.
Abnormal folding of a-synuclein (a-syn) is thought to lead to neurodegeneration and the characteristic symptoms of Lewy body disease (LBD). Since previous studies suggest that immunization might be a potential therapy for Alzheimer’s disease, we hypothesized that immunization with human (h)a-syn might have therapeutic effects in LBD. For this purpose, ha-syn transgenic (tg) mice were vaccinated with ha-syn. In mice that produced high relative affinity antibodies, there was decreased accumulation of aggregated ha-syn in neuronal cell bodies and synapses that was associated with reduced neurodegeneration. Further more, antibodies produced by immunized mice recognized abnormal ha-syn associated with the neuronal membrane and promoted the degradation of ha-syn aggregates, probably via lysosomal pathways. Similar effects were observed with an exogenously applied FITC-tagged ha-syn antibody. These results suggest that vaccination is effective in reducing neuronal accumulation of ha-syn aggregates and that further development of this approach might have potential role in the treatment of LBD.
The manifestations of Parkinson's disease are caused by reduced dopaminergic innervation of the striatum. Loss-of-function mutations in the DJ-1gene cause early-onset familial parkinsonism. To investigate a possible role for DJ-1 in the dopaminergic system, we generated a mouse model bearing a germline disruption of DJ-1. Although DJ-1?/? mice had normal numbers of dopaminergic neurons in the substantia nigra, evoked dopamine overflow in the striatum was markedly reduced, primarily as a result of increased reuptake. Nigral neurons lacking DJ-1 were less sensitive to the inhibitory effects of D2 autoreceptor stimulation. Corticostriatal long-term potentiation was normal in medium spiny neurons of DJ-1?/? mice, but long-term depression (LTD) was absent. The LTD deficit was reversed by treatment with D2 but not D1 receptor agonists. Furthermore, DJ-1?/? mice displayed hypoactivity in the open field. Collectively, our findings suggest an essential role for DJ-1 in dopaminergic physiology and D2 receptormediated functions.
Radiotracer imaging (RTI) of the nigrostriatal dopaminergic system is a widely used but controversial biomarker in Parkinson disease (PD). Here the authors review the concepts of biomarker development and the evidence to support the use of four radiotracers as biomarkers in PD: [18F]fluorodopa PET, (+)-[11C]dihydrotetrabenazine PET, [123I]beta-CIT SPECT, and [18F]fluorodeoxyglucose PET. Biomarkers used to study disease biology and facilitate drug discovery and early human trials rely on evidence that they are measuring relevant biologic processes. The four tracers fulfill this criterion, although they do not measure the number or density of dopaminergic neurons. Biomarkers used as diagnostic tests, prognostic tools, or surrogate endpoints must not only have biologic relevance but also a strong linkage to the clinical outcome of interest. No radiotracers fulfill these criteria, and current evidence does not support the use of imaging as a diagnostic tool in clinical practice or as a surrogate endpoint in clinical trials. Mechanistic information added by RTI to clinical trials may be difficult to interpret because of uncertainty about the interaction between the interventions and the tracer.
Familial Parkinson's disease (PD) has been linked to missense and genomic multiplication mutations of the -synuclein gene (SNCA). Genetic variability within SNCA has been implicated in idiopathic PD in many populations. We now confirm and extend these findings, within a Belgian sample, using a high-resolution map of genetic markers across the SNCA locus. Our study implicates the SNCA promoter in susceptibility to PD, and more specifically defines a minimum promoter haplotype, spanning approximately 15.3kb of sequence, which is overrepresented in patients. Our findings represent a biomarker for PD and may have implications for patient diagnosis, longitudinal evaluation, and treatment.
An abundant presynaptic protein, a-synuclein, is centrally involved in the pathogenesis of Parkinson's disease. However, conflicting data exist about the normal function of a-synuclein, possibly because a-synuclein is redundant with the very similar b-synuclein. To investigate the functions of synucleins systematically, we have now generated single- and double-knockout (KO) mice that lack a- and/or b-synuclein. We find that deletion of synucleins in mice does not impair basic brain functions or survival. We detected no significant changes in the ultrastructure of synuclein-deficient synapses, in short- or long-term synaptic plasticity, or in the pool size or replenishment of recycling synaptic vesicles. However, protein quantitations revealed that KO of synucleins caused selective changes in two small synaptic signaling proteins, complexins and 14-3-3 proteins. Moreover, we found that dopamine levels in the brains of double-KO but not single-KO mice were decreased by ~20%. In contrast, serotonin levels were unchanged, and dopamine uptake and release from isolated nerve terminals were normal. These results show that synucleins are not essential components of the basic machinery for neurotransmitter release but may contribute to the long-term regulation and/or maintenance of presynaptic function.
Parkinson's disease (PD; OMIM #168600) is the second most common neurodegenerative disorder in the Western world and presents as a progressive movement disorder. The hallmark pathological features of PD are loss of dopaminergic neurons from the substantia nigra and neuronal intracellular Lewy body inclusions. Parkinsonism is typically sporadic in nature; however, several rare familial forms are linked to genetic loci, and the identification of causal mutations has provided insight into the disease process. PARK8, identified in 2002 by Funayama and colleagues, appears to be a common cause of familial PD. We describe here the cloning of a novel gene that contains missense mutations segregating with PARK8-linked PD in five families from England and Spain. Because of the tremor observed in PD and because a number of the families are of Basque descent, we have named this protein dardarin, derived from the Basque word dardara, meaning tremor.
Human embryonic stem (hES) cells are defined by their extensive self-renewal capacity and their potential to differentiate into any cell type of the human body. The challenge in using hES cells for developmental biology and regenerative medicine has been to direct the wide differentiation potential toward the derivation of a specific cell fate. Within the nervous system, hES cells have been shown to differentiate in vitro into neural progenitor cells, neurons, and astrocytes. However, to our knowledge, the selective derivation of any given neuron subtype has not yet been demonstrated. Here, we describe conditions to direct hES cells into neurons of midbrain dopaminergic identity. Neuroectodermal differentiation was triggered on stromal feeder cells followed by regional specification by means of the sequential application of defined patterning molecules that direct in vivo midbrain development. Progression toward a midbrain dopamine (DA) neuron fate was monitored by the sequential expression of key transcription factors, including Pax2, Pax5, and engrailed-1 (En1), measurements of DA release, the presence of tetrodotoxin-sensitive action potentials, and the electron-microscopic visualization of tyrosinehydroxylase-positive synaptic terminals. High-yield DA neuron derivation was confirmed from three independent hES and two monkey embryonic stem cell lines. The availability of unlimited numbers of midbrain DA neurons is a first step toward exploring the potential of hES cells in preclinical models of Parkinson's disease. This experimental system also provides a powerful tool to probe the molecular mechanisms that control the development and function of human midbrain DA neurons.
An abundant presynaptic protein, a-synuclein, is centrally involved in the pathogenesis of Parkinson's disease. However, conflicting data exist about the normal function of a-synuclein, possibly because a-synuclein is redundant with the very similar b-synuclein. To investigate the functions of synucleins systematically, we have now generated single- and double-knockout (KO) mice that lack a- and/or b-synuclein. We find that deletion of synucleins in mice does not impair basic brain functions or survival. We detected no significant changes in the ultrastructure of synuclein-deficient synapses, in short- or long-term synaptic plasticity, or in the pool size or replenishment of recycling synaptic vesicles. However, protein quantitations revealed that KO of synucleins caused selective changes in two small synaptic signaling proteins, complexins and 14-3-3 proteins. Moreover, we found that dopamine levels in the brains of double-KO but not single-KO mice were decreased by ~20%. In contrast, serotonin levels were unchanged, and dopamine uptake and release from isolated nerve terminals were normal. These results show that synucleins are not essential components of the basic machinery for neurotransmitter release but may contribute to the long-term regulation and/or maintenance of presynaptic function.
Human embryonic stem (hES) cells are defined by their extensive self-renewal capacity and their potential to differentiate into any cell type of the human body. The challenge in using hES cells for developmental biology and regenerative medicine has been to direct the wide differentiation potential toward the derivation of a specific cell fate. Within the nervous system, hES cells have been shown to differentiate in vitro into neural progenitor cells, neurons, and astrocytes. However, to our knowledge, the selective derivation of any given neuron subtype has not yet been demonstrated. Here, we describe conditions to direct hES cells into neurons of midbrain dopaminergic identity. Neuroectodermal differentiation was triggered on stromal feeder cells followed by regional specification by means of the sequential application of defined patterning molecules that direct in vivo midbrain development. Progression toward a midbrain dopamine (DA) neuron fate was monitored by the sequential expression of key transcription factors, including Pax2, Pax5, and engrailed-1 (En1), measurements of DA release, the presence of tetrodotoxin-sensitive action potentials, and the electron-microscopic visualization of tyrosinehydroxylase-positive synaptic terminals. High-yield DA neuron derivation was confirmed from three independent hES and two monkey embryonic stem cell lines. The availability of unlimited numbers of midbrain DA neurons is a first step toward exploring the potential of hES cells in preclinical models of Parkinson's disease. This experimental system also provides a powerful tool to probe the molecular mechanisms that control the development and function of human midbrain DA neurons.
Parkinson's disease seems to occur more commonly in men than women based primarily on studies of death rates and prevalence. In recent years, several population based incidence studies of Parkinson's disease that included sex data have been conducted in a variety of populations around the world. To investigate whether these incidence studies suggest an increased risk of Parkinson's disease in men, a meta-analysis was performed of the differences in incidence of Parkinson's disease between men and women reported in seven studies that met the inclusion criteria. A significantly higher incidence rate of Parkinson's disease was found among men with the relative risk being 1.5 times greater in men than women. Possible reasons for this increased risk of Parkinson's disease in men are toxicant exposure, head trauma, neuroprotection by oestrogen, mitochondrial dysfunction, or X linkage of genetic risk factors.
Ten years ago, a glial cell line-derived neurotrophic factor (GDNF) that has prominent actions on nigral dopaminergic neurons, both in vitro and in animal models of Parkinson disease (PD), was discovered. A recently published open-label clinical trial now reports that long-term intracerebral delivery of GDNF may also markedly improve symptoms in patients with PD. Here we review the experimental data underlying the current clinical trial and discuss the types of structural and functional changes induced by GDNF that may provide symptomatic benefit in PD patients. Data obtained in rodent and primate models of PD highlight the importance of how and where the factor is administered, supporting the view that GDNF has to be delivered locally in the brain parenchyma, at the receptive target site, to provide therapeutic benefit in PD patients.
In this paper, we assess the complexity (fractal measure) of body motion during walking in patients with Parkinson's disease. The body motion of 11 patients with Parkinson's disease and 10 healthy elderly subjects was recorded using a triaxial accelerometry technique. A triaxial accelerometer was attached to the lumbar region. An assessment of the complexity of body motion was made using a maximum-likelihood-estimator-based fractal analysis method. Our data suggest that the fractal measures of the body motion of patients with Parkinson's disease are higher than those of healthy elderly subjects. These results were statistically different in the X (anteroposterior), Y (lateral) and Z (vertical) directions of body motion between patients with Parkinson's disease and the healthy elderly subjects (p < 0.01 in X and Z directions and p < 0.05 in Y direction). The complexity (fractal measure) of body motion can be useful to assess and monitor the output from the motor system during walking in clinical practice.
For many years pathophysiological studies on patients with movement disorders were viewed as inferior to those in animal models because, given the complexity of dealing with the complete interconnected CNS, it was difficult to assign any particular physiological abnormality exclusively to the site of a known lesion. More recently this has come to be seen as an advantage. All the articles reviewed below focus on how healthy parts of the CNS react to damage at a distance, with the result that we are now beginning to have much more insight into how these reactions both compensate and exacerbate the primary deficit.
Deep brain stimulation at high frequency was first used in 1997 to replace thalamotomy in treating the characteristic tremor of Parkinson's disease, and has subsequently been applied to the pallidum and the subthalamic nucleus. The subthalamic nucleus is a key node in the functional control of motor activity in the basal ganglia. Its inhibition suppresses symptoms in animal models of Parkinson's disease, and high frequency chronic stimulation does the same in human patients. Acute and longterm results after deep brain stimulation show a dramatic and stable improvement of a patient's clinical condition, which mimics the effects of levodopa treatment. The mechanism of action may involve a functional disruption of the abnormal neural messages associated with the disease. Long-term changes, neural plasticity and neural protection might be induced in the network. Similar effects of stimulation and lesioning have led to the extension of this technique for other targets and diseases.
The role of genetic factors in idiopathic, late-onset Parkinson's disease (PD) remains unclear, in spite of the recent advances in the genetics of early-onset forms of familial parkinsonism. There is increasing interest in using genetically isolated populations to unravel the genetics of complex diseases such as late-onset PD.We have studied genetic and clinical features of 109 patients with parkinsonism from an area comprising a genetically isolated population in the South-West of the Netherlands.Of the 109 patients with ascertained parkinsonism, 41 patients were diagnosed with PD and could be linked to a common founder 14 generations ago. The distribution of ages at onset of PD in the genetically isolated population was significantly bimodal, showing two peaks (one with a mean at age 67 years and another with a mean at 44 years, the former peak being significantly larger than that in a population-based study, the Rotterdam Study). In other clinical features, the only statistically significant difference between early-onset and late-onset PD was a decreased motor and cognitive function in patients with late-onset PD. Involvement of other PD genes including DJ-1, a gene implicated in a kindred with early-onset parkinsonism from the same genetic isolate,was excluded in other PD patients in the population. The finding of a common ancestor in 41 idiopathic-PD patients along with the exclusion of known PD genes and loci suggests the presence of at least one other, yet unknown, susceptibility gene involved in PD in this population.
Loss-of-function mutations in parkin are the major cause of early-onset familial Parkinson's disease. To investigate the pathogenic mechanism by which loss of parkin function causes Parkinson's disease, we generated a mouse model bearing a germline disruption in parkin. Parkin-/- mice are viable and exhibit grossly normal brain morphology. Quantitative in vivo microdialysis revealed an increase in extracellular dopamine concentration in the striatum of parkin-/- mice. Intracellular recordings of medium-sized striatal spiny neurons showed that greater currents are required to induce synaptic responses, suggesting a reduction in synaptic excitability in the absence of parkin. Furthermore, parkin-/- mice exhibit deficits in behavioral paradigms sensitive to dysfunction of the nigrostriatal pathway. The number of dopaminergic neurons in the substantia nigra of parkin-/- mice, however, is normal up to the age of 24 months, in contrast to the substantial loss of nigral neurons characteristic of Parkinson's disease. Steady state levels of CDCrel-1, synphilin-1 and a-synuclein, which were identified previously as substrates of the E3 ubiquitin ligase activity of parkin, are unaltered in parkin-/- brains. Together these findings provide the first evidence for a novel role of parkin in dopamine regulation and nigrostriatal function, and a non-essential role of parkin in the survival of nigral neurons in mice.
Parkinson disease (PD) is the second most common neurodegenerative disorder. We studied 754 affected individuals, comprising 425 sibling pairs, to identify PD susceptibility genes. Screening of the parkin gene was performed in a subset of the sample having earlier age of PD onset or a positive LOD score with a marker in the parkin gene. All subjects were evaluated using a rigorous neurological assessment. Two diagnostic models were considered for genome-wide, nonparametric linkage analyses. Model I included only those individuals with a more stringent diagnosis of verified PD (216 sibling pairs) and resulted in a maximum LOD score of 3.4 on chromosome 2. Model II included all affected individuals (425 sibling pairs) and yielded a LOD score of 3.1 on the X chromosome. Our large sample was then employed to test for gene-by-gene (epistatic) interactions. A genome screen using the 23 families with PD patients having a mutation in only one allele of the parkin gene detected evidence of linkage to chromosome 10 (LOD = 2.3). The 85 families with a very strong family history of PD were employed in a genome screen and, in addition to strong evidence of linkage to chromosome 2 (LOD = 4.9), also produced a LOD of 2.4 on chromosome 14. A genome screen performed in the 277 families without a strong family history of PD detected linkage to chromosomes 10 (LOD = 2.4) and X (LOD = 3.2). These findings demonstrate consistent evidence of linkage to chromosomes 2 and X and also support the hypothesis that gene-by-gene interactions are important in PD susceptibility.
PURPOSE OF REVIEW Brain banking remains a necessity for the study of neurodegenerative diseases. While the characterization of pathology observed at autopsy confirms clinical diagnosis, the structure and contents of pathological hallmarks are the starting point from which disease pathogenesis may be elucidated. Traditional neuropathology has served to define, characterize, and diagnose neurodegenerative diseases, accompanied by clinical presentation. The pathological substrates are then studied for their role in how they cause dysfunction in disease, or how their accumulation is presumably damaging.RECENT FINDINGS New genetic findings have revolutionized these studies and have prompted a reexamination of traditional pathological definitions of disease. Many familial genetic mutations have been found, encoding proteins such as synuclein, parkin, tau, and others, creating genetic ways to define neurodegenerative diseases. Many of these proteins are components of aggregates, thus the ability to label these proteins has revealed new pathological characteristics that must be standardized. More complicating is that many proteins genetically linked to clinically distinct diseases are involved in overlapping neuropathology of what now appears to be a spectrum of diseases: 'synucleinopathies', 'tauopathies', and so on. Moreover, as genetic discoveries fuel molecular experiments on brain tissue, banking methods must now accommodate these techniques. Lastly, DNA screening involves ethical issues beyond those which were previously considered with postmortem tissue banking.SUMMARY As more proteins are linked to disease, more is revealed about the underlying causative mechanisms, exposing points for interventions. To achieve this end, characterization for neurodegenerative disease in the post genomic era must include genotype, phenotype and clinical characterization, and postmortem brain banking data which includes these.
The goal of this study was to estimate the incidence of Parkinson's disease by age, gender, and ethnicity. Newly diagnosed Parkinson's disease cases in 1994-1995 were identified among members of the Kaiser Permanente Medical Care Program of Northern California, a large health maintenance organization. Each case met modified standardized criteria/Hughes diagnostic criteria as applied by a movement disorder specialist. Incidence rates per 100,000 person-years were calculated using the Kaiser Permanente membership information as the denominator and adjusted for age and/or gender using the direct method of standardization. A total of 588 newly diagnosed (incident) cases of Parkinson's disease were identified, which gave an overall annualized ageand gender-adjusted incidence rate of 13.4 per 100,000 (95% confidence interval (CI): 11.4, 15.5). The incidence rapidly increased over the age of 60 years, with only 4% of the cases being under the age of 50 years. The rate for men (19.0 per 100,000, 95% CI: 16.1, 21.8) was 91% higher than that for women (9.9 per 100,000, 95% CI: 7.6, 12.2). The age- and gender-adjusted rate per 100,000 was highest among Hispanics (16.6, 95% CI: 12.0, 21.3), followed by non-Hispanic Whites (13.6, 95% CI: 11.5, 15.7), Asians (11.3, 95% CI: 7.2, 15.3), and Blacks (10.2, 95% CI: 6.4, 14.0). These data suggest that the incidence of Parkinson's disease varies by race/ethnicity.
Mutations in DJ-1 have been linked to an autosomal recessive form of early-onset parkinsonism. To identify mutations causing Parkinson's disease (PD), we sequenced exons 1 through 7 of DJ-1 in 107 early-onset (age at diagnosis up to 50 years) PD subjects. One subject had a frameshift mutation in the first coding exon and an exon 7 splice mutation both predicted to result in a loss of functional protein. This subject was diagnosed with probable PD at age 24 years with asymmetric onset and an excellent response to levodopa therapy. Our observations suggest that sequence alterations in DJ-1 are a rare cause of early-onset PD.
Mitochondrial (mt) impairment, particularly within complex I of the electron transport system, has been implicated in the pathogenesis of Parkinson disease (PD). More than half of mitochondrially encoded polypeptides form part of the reduced nicotinamide adenine dinucleotide dehydrogenase (NADH) complex I enzyme. To test the hypothesis that mtDNA variation contributes to PD expression, we genotyped 10 single-nucleotide polymorphisms (SNPs) that define the European mtDNA haplogroups in 609 white patients with PD and 340 unaffected white control subjects. Overall, individuals classified as haplogroup J (odds ratio [OR] 0.55; 95% confidence interval [CI] 0.34 0.91; P = .02) or K (OR 0.52; 95% CI 0.30 0.90; P = .02) demonstrated a significant decrease in risk of PD versus individuals carrying the most common haplogroup, H. Furthermore, a specific SNP that defines these two haplogroups, 10398G, is strongly associated with this protective effect (OR 0.53; 95% CI 0.39 0.73; P = .0001). SNP 10398G causes a nonconservative amino acid change from threonine to alanine within the NADH dehydrogenase 3 (ND3) of complex I. After stratification by sex, this decrease in risk appeared stronger in women than in men (OR 0.43; 95% CI 0.27 0.71; P = .0009). In addition, SNP 9055A of ATP6 demonstrated a protective effect for women (OR 0.45; 95% CI 0.22 0.93; P = .03). Our results suggest that ND3 is an important factor in PD susceptibility among white individuals and could help explain the role of complex I in PD expression.
Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor with restorative effects in a wide variety of rodent and primate models of Parkinson disease, but penetration into brain tissue from either the blood or the cerebro-spinal fluid is limited. Here we delivered GDNF directly into the putamen of five Parkinson patients in a phase 1 safety trial. One catheter needed to be repositioned and there were changes in the magnetic resonance images that disappeared after lowering the concentration of GDNF. After one year, there were no serious clinical side effects, a 39% improvement in the off-medication motor sub-score of the Unified Parkinson's Disease Rating Scale (UPDRS) and a 61% improvement in the activities of daily living sub-score. Medication-induced dyskinesias were reduced by 64% and were not observed off medication during chronic GDNF delivery. Positron emission tomography (PET) scans of [(18)F]dopamine uptake showed a significant 28% increase in putamen dopamine storage after 18 months, suggesting a direct effect of GDNF on dopamine function. This study warrants careful examination of GDNF as a treatment for Parkinson disease.
In FY2001, The National Institute of Neurological Disorders and Stroke (NINDS), The Huntington's Disease Society of America (HDSA), The Amyotrophic Lateral Sclerosis Association (ALSA), The Hereditary Disease Foundation (HDF) announced an administrative supplement program intended to facilitate drug screens to identify new treatments for late onset neurodegenerative disorders through evaluation of FDA-approved compounds. A report of the first consortium meeting was recently released in Trends in Neurosciences (October, 2002). For more information, on the program announcement please link to http://www.ninds.nih.gov/funding/research/parkinsonsweb/award_opportunities_archive.htm#notices
The National Institute of Environmental Health Sciences, a component of the National Institutes of Health, today announced five-year grants totaling $20 million for three centers to conduct research on the relationship between exposures to environmental agents and subsequent Parkinson's disease.
Embryonic mouse stem cells transformed into neurons in a lab dish and then transplanted into a rat model for Parkinson's disease (PD) form functional connections and reduce disease symptoms, a new study shows. The finding suggests that embryonic stem (ES) cells may ultimately be useful for treating PD and other brain diseases.
Parkinson's disease is known to cause damage to a specific region of the brain. A new study led by NINDS scientist David S. Goldstein, M.D., Ph.D., shows that the disease also causes widespread damage to the sympathetic nervous system, which controls blood pressure, pulse rate, and many other automatic responses to stress. The study also shows that this damage is unrelated to treatment with the most commonly used Parkinson's drug, levodopa, and may lead to new approaches to identifying the cause of the disease. The study appears in the April 23, 2002, issue of Neurology. Fact Sheet
Scientists, patient advocates, and representatives of nine National Institutes of Health (NIH) components gathered January 9-10 to review progress made in implementing the agency's Parkinson's Disease Research Agenda. In her welcoming remarks, NIH Director Dr. Ruth Kirschstein spoke of the "unprecedented push, unseen ever before," that the NIH has made in Parkinson's disease research since the document was written. Originally released in March 2000, the Agenda describes areas of significant scientific opportunity in Parkinson's research to be explored over the following five years. The January 2002 meeting reviewed progress made towards accomplishing the goals set forth in the Agenda, identified newly emerging areas of interest, and prioritized future research goals.
NIH has posted the NIH Human Embryonic Stem Cell Registry based on the President's criteria in the NIH Guide for Grants and Contracts Notice along with related information in Notice NOT-OD-02-006 and Notice NOT-OD-02-007. The stem cell registry currently lists providers of stem cell lines with web links to their organizations.
The NINDS is undertaking a major research initiative to establish efficacious therapies to slow the progression of Parkinson's disease, a cause of chronic neurologic disability affecting more than a million Americans. Recommendations for neuroprotective drugs for testing in a large clinical trial are sought. Ideas and recommendations are being widely solicited from experts working in Parkinson's disease, academic and pharmaceutical industry-based, as well as from patient advocate groups. This information will be collated and presented to the Oversight Committee. For more information, please go to Request for Neuroprotective Agents.
Sharing of information, ideas, data, experiences, and resources best describes the 3rd annual meeting of the Udall Centers of Excellence for Parkinson's Disease Research. Held August 6-7 in Bethesda, Maryland, the event brought scientists from all eleven Centers together to discuss their current work and future directions, and to brainstorm new ideas and possible solutions to research problems.
The NIH-wide Parkinson's disease research effort recently made another advance in public-private partnership with the launching of a new Parkinson's Disease Research Website (http://www.ninds.nih.gov/parkinsonsweb/). The site, sponsored and maintained by NINDS, is designed for a broad group of users including scientists and clinicians, voluntary agencies, and patients, and provides information ranging from the full-length Parkinson's Disease Research Agenda and descriptions of NIH's funding opportunities and announcements to resources for patients and caregivers such as advocacy contact information. As the site continues to develop during the next several months, NINDS hopes to include information from all NIH Institutes--showcasing their parallel efforts on Parkinson's disease research.
For years, researchers studying stem cells have been intrigued by the possibility that these cells might be used to treat brain diseases. Recent studies have suggested that neural stem cells transplanted into the brain can migrate throughout the brain and develop into other types of cells. Now, two new studies show that bone marrow cells transplanted into mice can migrate into the brain and develop into cells that appear to be neurons. The studies suggest that bone marrow may be a readily available source of neural cells with potential for treating such neurological disorders as Parkinson's disease and traumatic brain injury.
For many years, researchers have known that the movement problems associated with Parkinson's disease result from a loss of neurons that produce a nerve-signaling chemical called dopamine in one part of the brain. A new study suggests that Parkinson's disease (PD) also affects nerve endings that produce a related chemical, norepinephrine, in the heart. The finding improves understanding about how Parkinson's disease develops and may lead to a way of predicting the disorder and possibly even preventing it.
The first meeting of the NINDS Parkinson's Disease Implementation Committee (PDIC) was held July 31, 2000 at the National Institutes of Health, Neuroscience Center in Rockville, Maryland. The Committee identified several areas of Parkinson's disease research that will receive the highest priority in the coming weeks, including clinical trials and gene research.
As part of its efforts to defeat Parkinson's disease, the National Institute of Neurological Disorders and Stroke (NINDS) today announced plans to award new grants to eight top universities. The new awards will raise to eleven the number of Parkinson's Disease Research Centers of Excellence the Institute funds and represent a total commitment of $49 million to be spent over the next 5 years. Added to the $24 million committed to three such centers in September of 1998, this brings total Institute funding for the Parkinson's Disease Research Centers of Excellence program to $73 million.
For years, researchers have probed the mysteries of neural stem cells -- immature cells that can differentiate into all the cell types that make up the brain -- with the idea that they might be useful for treating brain disorders such as Parkinson's disease. Important new animal research now suggests that these cells may be effective in treating a much broader array of brain diseases than previously anticipated, including Alzheimer's disease and many childhood brain disorders.
Results from the first randomized, controlled clinical trial of fetal dopamine cell implants for Parkinson's disease show that the surgery helped a small number of Parkinson's patients, but not all who underwent the experimental therapy. These results raise important questions in the search for improved treatments for Parkinson's disease.
Genetic factors do not play a significant role in causing the most common form of Parkinson's disease (PD), according to a study to be published in the January 27, 1999 issue of the Journal of the American Medical Association. This epidemiological study, the largest of its kind to investigate the role of genetic or environmental causes of PD, examined 19,842 white male twins enrolled in a large registry of World War II veteran twins.
Three top university hospitals will receive a total of almost $24 million from the National Institute of Neurological Disorders and Stroke (NINDS) to advance understanding of Parkinson's disease and related movement disorders. Investigators at Emory University, Massachusetts General Hospital, and The Johns Hopkins University School of Medicine will spend the next five years unraveling the cause or causes of Parkinson's disease and seeking new ways to diagnose and treat it. They will also provide state-of-the-art, multidisciplinary training for young scientists preparing for research careers investigating Parkinson's disease and related neurodegenerative disorders.
For decades, researchers have imagined treating human diseases by replacing damaged cells with stem cells - embryonic cells from which all other kinds of cells develop. While the potential benefits are enormous, such strategies have been limited by an uncertain supply of stem cells. Now, scientists have shown that neural stem cells can be multiplied and raised to maturity in the laboratory and that these cells can greatly reduce symptoms in an animal model of Parkinson's disease.
For decades, scientists believed that the adult central nervous system could not repair itself, in part because it lacked fundamental "stem cells," mother cells that can divide to form other kinds of cells. A series of findings has now shown that stem cells are present in the adult brain and spinal cord, and that they can be grown in culture and directed to act in much the same way as fetal stem cells. These findings provide new hope for people with Parkinson's disease, spinal cord injury, and a host of other disorders.
Bethesda, MD - For the first time, scientists have pinpointed the location of a gene they believe is responsible for some cases of Parkinson's disease. Their discovery provides strong evidence that a genetic alteration is capable of causing the disease. The study, published in the November 15 issue of Science,1 sheds light on the mysterious origins of this devastating neurological disease that affects about 500,000 Americans.
Age-old dogma held that the central nervous system could not regrow or recover, dampening hopes for recovery from spinal cord injury and other neurological disorders. But recent results from scientists at the National Institute of Neurological Disorders and Stroke (NINDS) offer a glimpse of how basic research promises approaches for restoring and repairing damaged nerves.
A new drug, when added to standard treatment for Parkinson's disease, prolongs relief of symptoms by more than 60 percent, report scientists from the National Institute of Neurological Disorders and Stroke (NINDS). In announcing their findings today at the annual meeting of the American Academy of Neurology in New York,* scientists said that the drug, called R0 40-7592, could help overcome drawbacks of current drug treatment.
Scientists announced today in the January 21 New England Journal of Medicine the results of a broad, long-term study on the effects of deprenyl and tocopherol (a form of vitamin E) on the progression of early Parkinson's disease. The investigators, who comprise a group known as the Parkinson's Study Group, confirmed that deprenyl is effective in slowing the early progression of Parkinson's disease and delaying the need for initiation of therapy with the drug levodopa. The latest results of the study showed, however, that the beneficial effects of deprenyl were not as lasting in fighting Parkinson's disease as the investigators had anticipated when evaluating the preliminary results in 1989. The clinical trials also showed no evidence that tocopherol was useful in Parkinson's disease.
Animal studies have revealed new knowledge of brain chemistry in Parkinson's disease and suggest new treatment approaches, according to results published in the December 7, 1990 issue of Science.
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2005
Provisional diagnostic criteria for depression in Parkinson's disease: Report of an NINDS/NIMH Work Group
Mov Disord. 2005 Oct 6; [Epub ahead of print]Mood disorders are the most common psychiatric problem associated with Parkinson's disease (PD), and have a negative impact on disability and quality of life. Accurate diagnosis of depressive disturbances in PD is critical and will facilitate the testing and use of new interventions; however, there are no clear diagnostic criteria for depressive disorders in PD. In their current form, strict Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria are difficult to use in PD and require attribution of specific symptoms to PD itself or the depressive syndrome. Additionally, DSM criteria for major depression and dysthymia exclude perhaps half of PD patients with comorbid clinically significant depression. This review summarizes an NIH-sponsored workshop and describes recommended changes to DSM diagnostic criteria for depression for use in PD. Participants also recommended: (1) an inclusive approach to symptom assessment to enhance reliability of ratings in PD and avoid the need to attribute symptoms to a particular cause; (2) the inclusion of subsyndromal depression in clinical research studies of depression of PD; (3) the specification of timing of assessments for PD patients with motor fluctuations; and (4) the use of informants for cognitively impaired patients. The proposed diagnostic criteria are provisional and intended to be defined further and validated but provide a common starting point for clinical research in PD-associated depression. (c) 2005 Movement Disorder Society.
Donepezil for dementia in Parkinson's disease: a randomised, double blind, placebo controlled, crossover study
J Neurol Neurosurg Psychiatry 2005;76:934-939Objective: To study the safety and efficacy of a cholinesterase inhibitor, donepezil hydrochloride, for the treatment of dementia in Parkinson's disease (PD). Methods: This was a randomised double blind, placebo controlled, crossover study in 22 subjects with PD and dementia. Participants were randomised to receive either donepezil followed by identical placebo, or placebo followed by donepezil. Donepezil was administered at 5-10 mg/day. Treatment periods were 10 weeks with a washout period of 6 weeks between the two periods. The primary outcome measure was the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAScog). Results: Donepezil was well tolerated and most adverse events were mild. There was no worsening of PD symptoms as measured by the total or motor sections of the Unified Parkinson's Disease Rating Scale. There was a 1.9 point trend toward better scores on the ADAScog on treatment compared with placebo that was not statistically significant. The secondary cognitive measures showed a statistically significant 2 point benefit on the Mini Mental Status Examination and no change on the Mattis Dementia Rating Scale (MDRS). The Clinical Global Impression of Change (CGI) showed a significant 0.37 point improvement on donepezil. No improvement was observed on the MDRS or the Brief Psychiatric Rating Scale. Carryover between treatment periods was observed but was not statistically significant. Conclusions: Donepezil was well tolerated and did not worsen PD. There may be a modest benefit on aspects of cognitive function. The possible clinical benefit measured by CGI was reflected in only one of the cognitive scales used in this study.
Effects of a-Synuclein Immunization in a Mouse Model of Parkinson's Disease
Neuron, Vol. 46, 857-868, June 16, 2005Abnormal folding of a-synuclein (a-syn) is thought to lead to neurodegeneration and the characteristic symptoms of Lewy body disease (LBD). Since previous studies suggest that immunization might be a potential therapy for Alzheimer’s disease, we hypothesized that immunization with human (h)a-syn might have therapeutic effects in LBD. For this purpose, ha-syn transgenic (tg) mice were vaccinated with ha-syn. In mice that produced high relative affinity antibodies, there was decreased accumulation of aggregated ha-syn in neuronal cell bodies and synapses that was associated with reduced neurodegeneration. Further more, antibodies produced by immunized mice recognized abnormal ha-syn associated with the neuronal membrane and promoted the degradation of ha-syn aggregates, probably via lysosomal pathways. Similar effects were observed with an exogenously applied FITC-tagged ha-syn antibody. These results suggest that vaccination is effective in reducing neuronal accumulation of ha-syn aggregates and that further development of this approach might have potential role in the treatment of LBD.
Nigrostriatal Dopaminergic Deficits and Hypokinesia Caused by Inactivation of the Familial Parkinsonism-Linked Gene DJ-1
j.neuron.2005.01.041The manifestations of Parkinson's disease are caused by reduced dopaminergic innervation of the striatum. Loss-of-function mutations in the DJ-1gene cause early-onset familial parkinsonism. To investigate a possible role for DJ-1 in the dopaminergic system, we generated a mouse model bearing a germline disruption of DJ-1. Although DJ-1?/? mice had normal numbers of dopaminergic neurons in the substantia nigra, evoked dopamine overflow in the striatum was markedly reduced, primarily as a result of increased reuptake. Nigral neurons lacking DJ-1 were less sensitive to the inhibitory effects of D2 autoreceptor stimulation. Corticostriatal long-term potentiation was normal in medium spiny neurons of DJ-1?/? mice, but long-term depression (LTD) was absent. The LTD deficit was reversed by treatment with D2 but not D1 receptor agonists. Furthermore, DJ-1?/? mice displayed hypoactivity in the open field. Collectively, our findings suggest an essential role for DJ-1 in dopaminergic physiology and D2 receptormediated functions.
The role of radiotracer imaging in Parkinson disease
NEUROLOGY 2005;64: 208-215Radiotracer imaging (RTI) of the nigrostriatal dopaminergic system is a widely used but controversial biomarker in Parkinson disease (PD). Here the authors review the concepts of biomarker development and the evidence to support the use of four radiotracers as biomarkers in PD: [18F]fluorodopa PET, (+)-[11C]dihydrotetrabenazine PET, [123I]beta-CIT SPECT, and [18F]fluorodeoxyglucose PET. Biomarkers used to study disease biology and facilitate drug discovery and early human trials rely on evidence that they are measuring relevant biologic processes. The four tracers fulfill this criterion, although they do not measure the number or density of dopaminergic neurons. Biomarkers used as diagnostic tests, prognostic tools, or surrogate endpoints must not only have biologic relevance but also a strong linkage to the clinical outcome of interest. No radiotracers fulfill these criteria, and current evidence does not support the use of imaging as a diagnostic tool in clinical practice or as a surrogate endpoint in clinical trials. Mechanistic information added by RTI to clinical trials may be difficult to interpret because of uncertainty about the interaction between the interventions and the tracer.
2004
a-Synuclein promoter confers susceptibility to Parkinson's disease
Ann of Neurol, 2004; 56 (4): 591–595Familial Parkinson's disease (PD) has been linked to missense and genomic multiplication mutations of the -synuclein gene (SNCA). Genetic variability within SNCA has been implicated in idiopathic PD in many populations. We now confirm and extend these findings, within a Belgian sample, using a high-resolution map of genetic markers across the SNCA locus. Our study implicates the SNCA promoter in susceptibility to PD, and more specifically defines a minimum promoter haplotype, spanning approximately 15.3kb of sequence, which is overrepresented in patients. Our findings represent a biomarker for PD and may have implications for patient diagnosis, longitudinal evaluation, and treatment.
Double knockout mice for a- and b-synucleins: Effect on synaptic functions
PNAS October 12, 2004; 10 (41): 14966–14971An abundant presynaptic protein, a-synuclein, is centrally involved in the pathogenesis of Parkinson's disease. However, conflicting data exist about the normal function of a-synuclein, possibly because a-synuclein is redundant with the very similar b-synuclein. To investigate the functions of synucleins systematically, we have now generated single- and double-knockout (KO) mice that lack a- and/or b-synuclein. We find that deletion of synucleins in mice does not impair basic brain functions or survival. We detected no significant changes in the ultrastructure of synuclein-deficient synapses, in short- or long-term synaptic plasticity, or in the pool size or replenishment of recycling synaptic vesicles. However, protein quantitations revealed that KO of synucleins caused selective changes in two small synaptic signaling proteins, complexins and 14-3-3 proteins. Moreover, we found that dopamine levels in the brains of double-KO but not single-KO mice were decreased by ~20%. In contrast, serotonin levels were unchanged, and dopamine uptake and release from isolated nerve terminals were normal. These results show that synucleins are not essential components of the basic machinery for neurotransmitter release but may contribute to the long-term regulation and/or maintenance of presynaptic function.
Cloning of the Gene Containing Mutations that Cause Park8-Linked Parkinson's Disease
Neuron, Published Online October 21, 2004Parkinson's disease (PD; OMIM #168600) is the second most common neurodegenerative disorder in the Western world and presents as a progressive movement disorder. The hallmark pathological features of PD are loss of dopaminergic neurons from the substantia nigra and neuronal intracellular Lewy body inclusions. Parkinsonism is typically sporadic in nature; however, several rare familial forms are linked to genetic loci, and the identification of causal mutations has provided insight into the disease process. PARK8, identified in 2002 by Funayama and colleagues, appears to be a common cause of familial PD. We describe here the cloning of a novel gene that contains missense mutations segregating with PARK8-linked PD in five families from England and Spain. Because of the tremor observed in PD and because a number of the families are of Basque descent, we have named this protein dardarin, derived from the Basque word dardara, meaning tremor.
Derivation of midbrain dopamine neurons from human embryonic stem cell
PNAS August 24, 2004; 101 (34): 12543-12548Human embryonic stem (hES) cells are defined by their extensive self-renewal capacity and their potential to differentiate into any cell type of the human body. The challenge in using hES cells for developmental biology and regenerative medicine has been to direct the wide differentiation potential toward the derivation of a specific cell fate. Within the nervous system, hES cells have been shown to differentiate in vitro into neural progenitor cells, neurons, and astrocytes. However, to our knowledge, the selective derivation of any given neuron subtype has not yet been demonstrated. Here, we describe conditions to direct hES cells into neurons of midbrain dopaminergic identity. Neuroectodermal differentiation was triggered on stromal feeder cells followed by regional specification by means of the sequential application of defined patterning molecules that direct in vivo midbrain development. Progression toward a midbrain dopamine (DA) neuron fate was monitored by the sequential expression of key transcription factors, including Pax2, Pax5, and engrailed-1 (En1), measurements of DA release, the presence of tetrodotoxin-sensitive action potentials, and the electron-microscopic visualization of tyrosinehydroxylase-positive synaptic terminals. High-yield DA neuron derivation was confirmed from three independent hES and two monkey embryonic stem cell lines. The availability of unlimited numbers of midbrain DA neurons is a first step toward exploring the potential of hES cells in preclinical models of Parkinson's disease. This experimental system also provides a powerful tool to probe the molecular mechanisms that control the development and function of human midbrain DA neurons.
Double knockout mice for a- and b-synucleins: Effect on synaptic functions
PNAS October 12, 2004; 10 (41): 14966–14971An abundant presynaptic protein, a-synuclein, is centrally involved in the pathogenesis of Parkinson's disease. However, conflicting data exist about the normal function of a-synuclein, possibly because a-synuclein is redundant with the very similar b-synuclein. To investigate the functions of synucleins systematically, we have now generated single- and double-knockout (KO) mice that lack a- and/or b-synuclein. We find that deletion of synucleins in mice does not impair basic brain functions or survival. We detected no significant changes in the ultrastructure of synuclein-deficient synapses, in short- or long-term synaptic plasticity, or in the pool size or replenishment of recycling synaptic vesicles. However, protein quantitations revealed that KO of synucleins caused selective changes in two small synaptic signaling proteins, complexins and 14-3-3 proteins. Moreover, we found that dopamine levels in the brains of double-KO but not single-KO mice were decreased by ~20%. In contrast, serotonin levels were unchanged, and dopamine uptake and release from isolated nerve terminals were normal. These results show that synucleins are not essential components of the basic machinery for neurotransmitter release but may contribute to the long-term regulation and/or maintenance of presynaptic function.
Derivation of midbrain dopamine neurons from human embryonic stem cell
PNAS August 24, 2004; 101 (34): 12543–12548Human embryonic stem (hES) cells are defined by their extensive self-renewal capacity and their potential to differentiate into any cell type of the human body. The challenge in using hES cells for developmental biology and regenerative medicine has been to direct the wide differentiation potential toward the derivation of a specific cell fate. Within the nervous system, hES cells have been shown to differentiate in vitro into neural progenitor cells, neurons, and astrocytes. However, to our knowledge, the selective derivation of any given neuron subtype has not yet been demonstrated. Here, we describe conditions to direct hES cells into neurons of midbrain dopaminergic identity. Neuroectodermal differentiation was triggered on stromal feeder cells followed by regional specification by means of the sequential application of defined patterning molecules that direct in vivo midbrain development. Progression toward a midbrain dopamine (DA) neuron fate was monitored by the sequential expression of key transcription factors, including Pax2, Pax5, and engrailed-1 (En1), measurements of DA release, the presence of tetrodotoxin-sensitive action potentials, and the electron-microscopic visualization of tyrosinehydroxylase-positive synaptic terminals. High-yield DA neuron derivation was confirmed from three independent hES and two monkey embryonic stem cell lines. The availability of unlimited numbers of midbrain DA neurons is a first step toward exploring the potential of hES cells in preclinical models of Parkinson's disease. This experimental system also provides a powerful tool to probe the molecular mechanisms that control the development and function of human midbrain DA neurons.
Are men at greater risk for Parkinson's disase than women?
J Neurol Neurosurg Psychiatry 2004; 75: 637-639Parkinson's disease seems to occur more commonly in men than women based primarily on studies of death rates and prevalence. In recent years, several population based incidence studies of Parkinson's disease that included sex data have been conducted in a variety of populations around the world. To investigate whether these incidence studies suggest an increased risk of Parkinson's disease in men, a meta-analysis was performed of the differences in incidence of Parkinson's disease between men and women reported in seven studies that met the inclusion criteria. A significantly higher incidence rate of Parkinson's disease was found among men with the relative risk being 1.5 times greater in men than women. Possible reasons for this increased risk of Parkinson's disease in men are toxicant exposure, head trauma, neuroprotection by oestrogen, mitochondrial dysfunction, or X linkage of genetic risk factors.
Localized striatal delivery of GDNF as a treatment for Parkinson's disease
Nature Neuroscience (February 2004) 7(2): 105-110Ten years ago, a glial cell line-derived neurotrophic factor (GDNF) that has prominent actions on nigral dopaminergic neurons, both in vitro and in animal models of Parkinson disease (PD), was discovered. A recently published open-label clinical trial now reports that long-term intracerebral delivery of GDNF may also markedly improve symptoms in patients with PD. Here we review the experimental data underlying the current clinical trial and discuss the types of structural and functional changes induced by GDNF that may provide symptomatic benefit in PD patients. Data obtained in rodent and primate models of PD highlight the importance of how and where the factor is administered, supporting the view that GDNF has to be delivered locally in the brain parenchyma, at the receptive target site, to provide therapeutic benefit in PD patients.
Fractal dynamics of body motion in patients with Parkinson's Disease
Journal of Neural Engineering (March 2004) 1: 8-15In this paper, we assess the complexity (fractal measure) of body motion during walking in patients with Parkinson's disease. The body motion of 11 patients with Parkinson's disease and 10 healthy elderly subjects was recorded using a triaxial accelerometry technique. A triaxial accelerometer was attached to the lumbar region. An assessment of the complexity of body motion was made using a maximum-likelihood-estimator-based fractal analysis method. Our data suggest that the fractal measures of the body motion of patients with Parkinson's disease are higher than those of healthy elderly subjects. These results were statistically different in the X (anteroposterior), Y (lateral) and Z (vertical) directions of body motion between patients with Parkinson's disease and the healthy elderly subjects (p < 0.01 in X and Z directions and p < 0.05 in Y direction). The complexity (fractal measure) of body motion can be useful to assess and monitor the output from the motor system during walking in clinical practice.
2003
Systems-level studies of movement disorders in dystonia and Parkinson's disease
Current Opinion in Neurobiology (2003) 13: 691-695For many years pathophysiological studies on patients with movement disorders were viewed as inferior to those in animal models because, given the complexity of dealing with the complete interconnected CNS, it was difficult to assign any particular physiological abnormality exclusively to the site of a known lesion. More recently this has come to be seen as an advantage. All the articles reviewed below focus on how healthy parts of the CNS react to damage at a distance, with the result that we are now beginning to have much more insight into how these reactions both compensate and exacerbate the primary deficit.
Deep brain stimulation for Parkinson's disease
Current Opinion in Neurobiology (2003) 13: 696-706Deep brain stimulation at high frequency was first used in 1997 to replace thalamotomy in treating the characteristic tremor of Parkinson's disease, and has subsequently been applied to the pallidum and the subthalamic nucleus. The subthalamic nucleus is a key node in the functional control of motor activity in the basal ganglia. Its inhibition suppresses symptoms in animal models of Parkinson's disease, and high frequency chronic stimulation does the same in human patients. Acute and longterm results after deep brain stimulation show a dramatic and stable improvement of a patient's clinical condition, which mimics the effects of levodopa treatment. The mechanism of action may involve a functional disruption of the abnormal neural messages associated with the disease. Long-term changes, neural plasticity and neural protection might be induced in the network. Similar effects of stimulation and lesioning have led to the extension of this technique for other targets and diseases.
A Clinical-Genetic Study of Parkinson's Disease in a Genetically Isolated Community
J Neurol (2003) 250: 1056-1062The role of genetic factors in idiopathic, late-onset Parkinson's disease (PD) remains unclear, in spite of the recent advances in the genetics of early-onset forms of familial parkinsonism. There is increasing interest in using genetically isolated populations to unravel the genetics of complex diseases such as late-onset PD.We have studied genetic and clinical features of 109 patients with parkinsonism from an area comprising a genetically isolated population in the South-West of the Netherlands.Of the 109 patients with ascertained parkinsonism, 41 patients were diagnosed with PD and could be linked to a common founder 14 generations ago. The distribution of ages at onset of PD in the genetically isolated population was significantly bimodal, showing two peaks (one with a mean at age 67 years and another with a mean at 44 years, the former peak being significantly larger than that in a population-based study, the Rotterdam Study). In other clinical features, the only statistically significant difference between early-onset and late-onset PD was a decreased motor and cognitive function in patients with late-onset PD. Involvement of other PD genes including DJ-1, a gene implicated in a kindred with early-onset parkinsonism from the same genetic isolate,was excluded in other PD patients in the population. The finding of a common ancestor in 41 idiopathic-PD patients along with the exclusion of known PD genes and loci suggests the presence of at least one other, yet unknown, susceptibility gene involved in PD in this population.
Parkin-Deficient Mice Exhibit Nirgostriatal Deficits but not Loss of Dopaminergic Neurons
J Biol Chem, 2003 Aug 20 [Epub ahead of print]Loss-of-function mutations in parkin are the major cause of early-onset familial Parkinson's disease. To investigate the pathogenic mechanism by which loss of parkin function causes Parkinson's disease, we generated a mouse model bearing a germline disruption in parkin. Parkin-/- mice are viable and exhibit grossly normal brain morphology. Quantitative in vivo microdialysis revealed an increase in extracellular dopamine concentration in the striatum of parkin-/- mice. Intracellular recordings of medium-sized striatal spiny neurons showed that greater currents are required to induce synaptic responses, suggesting a reduction in synaptic excitability in the absence of parkin. Furthermore, parkin-/- mice exhibit deficits in behavioral paradigms sensitive to dysfunction of the nigrostriatal pathway. The number of dopaminergic neurons in the substantia nigra of parkin-/- mice, however, is normal up to the age of 24 months, in contrast to the substantial loss of nigral neurons characteristic of Parkinson's disease. Steady state levels of CDCrel-1, synphilin-1 and a-synuclein, which were identified previously as substrates of the E3 ubiquitin ligase activity of parkin, are unaltered in parkin-/- brains. Together these findings provide the first evidence for a novel role of parkin in dopamine regulation and nigrostriatal function, and a non-essential role of parkin in the survival of nigral neurons in mice.
Genome-Wide Linkage Analysis and Evidence of Gene-by-Gene Interactions in a Sample of 362 Multiplex Parkinson Disease Families
Hum. Mol. Genetics, 2003 Aug 12 [Epub ahead of print]Parkinson disease (PD) is the second most common neurodegenerative disorder. We studied 754 affected individuals, comprising 425 sibling pairs, to identify PD susceptibility genes. Screening of the parkin gene was performed in a subset of the sample having earlier age of PD onset or a positive LOD score with a marker in the parkin gene. All subjects were evaluated using a rigorous neurological assessment. Two diagnostic models were considered for genome-wide, nonparametric linkage analyses. Model I included only those individuals with a more stringent diagnosis of verified PD (216 sibling pairs) and resulted in a maximum LOD score of 3.4 on chromosome 2. Model II included all affected individuals (425 sibling pairs) and yielded a LOD score of 3.1 on the X chromosome. Our large sample was then employed to test for gene-by-gene (epistatic) interactions. A genome screen using the 23 families with PD patients having a mutation in only one allele of the parkin gene detected evidence of linkage to chromosome 10 (LOD = 2.3). The 85 families with a very strong family history of PD were employed in a genome screen and, in addition to strong evidence of linkage to chromosome 2 (LOD = 4.9), also produced a LOD of 2.4 on chromosome 14. A genome screen performed in the 277 families without a strong family history of PD detected linkage to chromosomes 10 (LOD = 2.4) and X (LOD = 3.2). These findings demonstrate consistent evidence of linkage to chromosomes 2 and X and also support the hypothesis that gene-by-gene interactions are important in PD susceptibility.
Brain banking for neurodegenerative disease
Curr. Opin Neurology, 2003 Aug; 16 (4):459-463PURPOSE OF REVIEW Brain banking remains a necessity for the study of neurodegenerative diseases. While the characterization of pathology observed at autopsy confirms clinical diagnosis, the structure and contents of pathological hallmarks are the starting point from which disease pathogenesis may be elucidated. Traditional neuropathology has served to define, characterize, and diagnose neurodegenerative diseases, accompanied by clinical presentation. The pathological substrates are then studied for their role in how they cause dysfunction in disease, or how their accumulation is presumably damaging.RECENT FINDINGS New genetic findings have revolutionized these studies and have prompted a reexamination of traditional pathological definitions of disease. Many familial genetic mutations have been found, encoding proteins such as synuclein, parkin, tau, and others, creating genetic ways to define neurodegenerative diseases. Many of these proteins are components of aggregates, thus the ability to label these proteins has revealed new pathological characteristics that must be standardized. More complicating is that many proteins genetically linked to clinically distinct diseases are involved in overlapping neuropathology of what now appears to be a spectrum of diseases: 'synucleinopathies', 'tauopathies', and so on. Moreover, as genetic discoveries fuel molecular experiments on brain tissue, banking methods must now accommodate these techniques. Lastly, DNA screening involves ethical issues beyond those which were previously considered with postmortem tissue banking.SUMMARY As more proteins are linked to disease, more is revealed about the underlying causative mechanisms, exposing points for interventions. To achieve this end, characterization for neurodegenerative disease in the post genomic era must include genotype, phenotype and clinical characterization, and postmortem brain banking data which includes these.
Incidence of Parkinson's Disease: Variation by Age, Gender, and Race/Ethnicity
Am. J. Epidemiology, 157 (11):1015-1022, 2003The goal of this study was to estimate the incidence of Parkinson's disease by age, gender, and ethnicity. Newly diagnosed Parkinson's disease cases in 1994-1995 were identified among members of the Kaiser Permanente Medical Care Program of Northern California, a large health maintenance organization. Each case met modified standardized criteria/Hughes diagnostic criteria as applied by a movement disorder specialist. Incidence rates per 100,000 person-years were calculated using the Kaiser Permanente membership information as the denominator and adjusted for age and/or gender using the direct method of standardization. A total of 588 newly diagnosed (incident) cases of Parkinson's disease were identified, which gave an overall annualized ageand gender-adjusted incidence rate of 13.4 per 100,000 (95% confidence interval (CI): 11.4, 15.5). The incidence rapidly increased over the age of 60 years, with only 4% of the cases being under the age of 50 years. The rate for men (19.0 per 100,000, 95% CI: 16.1, 21.8) was 91% higher than that for women (9.9 per 100,000, 95% CI: 7.6, 12.2). The age- and gender-adjusted rate per 100,000 was highest among Hispanics (16.6, 95% CI: 12.0, 21.3), followed by non-Hispanic Whites (13.6, 95% CI: 11.5, 15.7), Asians (11.3, 95% CI: 7.2, 15.3), and Blacks (10.2, 95% CI: 6.4, 14.0). These data suggest that the incidence of Parkinson's disease varies by race/ethnicity.
Early-onset Parkinson's disease caused by a compound heterozygous DJ-1 mutation
Annals of Neurology, 30 June 2003Mutations in DJ-1 have been linked to an autosomal recessive form of early-onset parkinsonism. To identify mutations causing Parkinson's disease (PD), we sequenced exons 1 through 7 of DJ-1 in 107 early-onset (age at diagnosis up to 50 years) PD subjects. One subject had a frameshift mutation in the first coding exon and an exon 7 splice mutation both predicted to result in a loss of functional protein. This subject was diagnosed with probable PD at age 24 years with asymmetric onset and an excellent response to levodopa therapy. Our observations suggest that sequence alterations in DJ-1 are a rare cause of early-onset PD.
Mitochondrial Polymorphisms Significantly Reduce the Risk of Parkinson Disease
Am. J. Hum. Genet., 72:804-811, 2003Mitochondrial (mt) impairment, particularly within complex I of the electron transport system, has been implicated in the pathogenesis of Parkinson disease (PD). More than half of mitochondrially encoded polypeptides form part of the reduced nicotinamide adenine dinucleotide dehydrogenase (NADH) complex I enzyme. To test the hypothesis that mtDNA variation contributes to PD expression, we genotyped 10 single-nucleotide polymorphisms (SNPs) that define the European mtDNA haplogroups in 609 white patients with PD and 340 unaffected white control subjects. Overall, individuals classified as haplogroup J (odds ratio [OR] 0.55; 95% confidence interval [CI] 0.34 0.91; P = .02) or K (OR 0.52; 95% CI 0.30 0.90; P = .02) demonstrated a significant decrease in risk of PD versus individuals carrying the most common haplogroup, H. Furthermore, a specific SNP that defines these two haplogroups, 10398G, is strongly associated with this protective effect (OR 0.53; 95% CI 0.39 0.73; P = .0001). SNP 10398G causes a nonconservative amino acid change from threonine to alanine within the NADH dehydrogenase 3 (ND3) of complex I. After stratification by sex, this decrease in risk appeared stronger in women than in men (OR 0.43; 95% CI 0.27 0.71; P = .0009). In addition, SNP 9055A of ATP6 demonstrated a protective effect for women (OR 0.45; 95% CI 0.22 0.93; P = .03). Our results suggest that ND3 is an important factor in PD susceptibility among white individuals and could help explain the role of complex I in PD expression.
Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease
Nat Med. 2003 Mar 31Glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor with restorative effects in a wide variety of rodent and primate models of Parkinson disease, but penetration into brain tissue from either the blood or the cerebro-spinal fluid is limited. Here we delivered GDNF directly into the putamen of five Parkinson patients in a phase 1 safety trial. One catheter needed to be repositioned and there were changes in the magnetic resonance images that disappeared after lowering the concentration of GDNF. After one year, there were no serious clinical side effects, a 39% improvement in the off-medication motor sub-score of the Unified Parkinson's Disease Rating Scale (UPDRS) and a 61% improvement in the activities of daily living sub-score. Medication-induced dyskinesias were reduced by 64% and were not observed off medication during chronic GDNF delivery. Positron emission tomography (PET) scans of [(18)F]dopamine uptake showed a significant 28% increase in putamen dopamine storage after 18 months, suggesting a direct effect of GDNF on dopamine function. This study warrants careful examination of GDNF as a treatment for Parkinson disease.
2002
Drug Screening Meeting Report
September 10, 2002In FY2001, The National Institute of Neurological Disorders and Stroke (NINDS), The Huntington's Disease Society of America (HDSA), The Amyotrophic Lateral Sclerosis Association (ALSA), The Hereditary Disease Foundation (HDF) announced an administrative supplement program intended to facilitate drug screens to identify new treatments for late onset neurodegenerative disorders through evaluation of FDA-approved compounds. A report of the first consortium meeting was recently released in Trends in Neurosciences (October, 2002). For more information, on the program announcement please link to http://www.ninds.nih.gov/funding/research/parkinsonsweb/award_opportunities_archive.htm#notices
NIEHS Announces $20 Million, Three-Center Effort to Pin-point Environmental Triggers of Parkinson's Disease
August 26, 2002The National Institute of Environmental Health Sciences, a component of the National Institutes of Health, today announced five-year grants totaling $20 million for three centers to conduct research on the relationship between exposures to environmental agents and subsequent Parkinson's disease.
Embryonic Mouse Stem Cells Reduce Symptoms in Model for Parkinson's Disease
June 20, 2002Embryonic mouse stem cells transformed into neurons in a lab dish and then transplanted into a rat model for Parkinson's disease (PD) form functional connections and reduce disease symptoms, a new study shows. The finding suggests that embryonic stem (ES) cells may ultimately be useful for treating PD and other brain diseases.
Study Finds Widespread Sympathetic Nerve Damage in Parkinson's Disease
April 22, 2002Parkinson's disease is known to cause damage to a specific region of the brain. A new study led by NINDS scientist David S. Goldstein, M.D., Ph.D., shows that the disease also causes widespread damage to the sympathetic nervous system, which controls blood pressure, pulse rate, and many other automatic responses to stress. The study also shows that this damage is unrelated to treatment with the most commonly used Parkinson's drug, levodopa, and may lead to new approaches to identifying the cause of the disease. The study appears in the April 23, 2002, issue of Neurology. Fact Sheet
Parkinson's Disease Research Agenda Implementation Review Meeting
January 9 - 10, 2002Scientists, patient advocates, and representatives of nine National Institutes of Health (NIH) components gathered January 9-10 to review progress made in implementing the agency's Parkinson's Disease Research Agenda. In her welcoming remarks, NIH Director Dr. Ruth Kirschstein spoke of the "unprecedented push, unseen ever before," that the NIH has made in Parkinson's disease research since the document was written. Originally released in March 2000, the Agenda describes areas of significant scientific opportunity in Parkinson's research to be explored over the following five years. The January 2002 meeting reviewed progress made towards accomplishing the goals set forth in the Agenda, identified newly emerging areas of interest, and prioritized future research goals.
2001
The Stem Cell Registry is Available for Research
Tuesday, November 27, 2001NIH has posted the NIH Human Embryonic Stem Cell Registry based on the President's criteria in the NIH Guide for Grants and Contracts Notice along with related information in Notice NOT-OD-02-006 and Notice NOT-OD-02-007. The stem cell registry currently lists providers of stem cell lines with web links to their organizations.
Request for Neuroprotective Agents for Parkinson's Disease in NINDS-sponsored Clinical Trial
Friday, August 24, 2001The NINDS is undertaking a major research initiative to establish efficacious therapies to slow the progression of Parkinson's disease, a cause of chronic neurologic disability affecting more than a million Americans. Recommendations for neuroprotective drugs for testing in a large clinical trial are sought. Ideas and recommendations are being widely solicited from experts working in Parkinson's disease, academic and pharmaceutical industry-based, as well as from patient advocate groups. This information will be collated and presented to the Oversight Committee. For more information, please go to Request for Neuroprotective Agents.
"Sharing" is central theme for the Third Annual Udall Centers of Excellence for Parkinson's Disease Research Meeting
Friday, August 17, 2001Sharing of information, ideas, data, experiences, and resources best describes the 3rd annual meeting of the Udall Centers of Excellence for Parkinson's Disease Research. Held August 6-7 in Bethesda, Maryland, the event brought scientists from all eleven Centers together to discuss their current work and future directions, and to brainstorm new ideas and possible solutions to research problems.
NINDS Parkinson's Disease Research Web Site Unveiled
Friday, May 11, 2001The NIH-wide Parkinson's disease research effort recently made another advance in public-private partnership with the launching of a new Parkinson's Disease Research Website (http://www.ninds.nih.gov/parkinsonsweb/). The site, sponsored and maintained by NINDS, is designed for a broad group of users including scientists and clinicians, voluntary agencies, and patients, and provides information ranging from the full-length Parkinson's Disease Research Agenda and descriptions of NIH's funding opportunities and announcements to resources for patients and caregivers such as advocacy contact information. As the site continues to develop during the next several months, NINDS hopes to include information from all NIH Institutes--showcasing their parallel efforts on Parkinson's disease research.
2000
Turning Blood into Brain: New Studies Suggest Bone Marrow Stem Cells Can Develop into Neurons in Living Animals
Thursday, November 30, 2000For years, researchers studying stem cells have been intrigued by the possibility that these cells might be used to treat brain diseases. Recent studies have suggested that neural stem cells transplanted into the brain can migrate throughout the brain and develop into other types of cells. Now, two new studies show that bone marrow cells transplanted into mice can migrate into the brain and develop into cells that appear to be neurons. The studies suggest that bone marrow may be a readily available source of neural cells with potential for treating such neurological disorders as Parkinson's disease and traumatic brain injury.
Parkinson's Disease Is More Than a Brain Disorder
Monday, September 04, 2000For many years, researchers have known that the movement problems associated with Parkinson's disease result from a loss of neurons that produce a nerve-signaling chemical called dopamine in one part of the brain. A new study suggests that Parkinson's disease (PD) also affects nerve endings that produce a related chemical, norepinephrine, in the heart. The finding improves understanding about how Parkinson's disease develops and may lead to a way of predicting the disorder and possibly even preventing it.
NINDS Hosts First Parkinson's Disease Implementation Committee Meeting to Establish Priorities for Parkinson's Research
Monday, July 31, 2000The first meeting of the NINDS Parkinson's Disease Implementation Committee (PDIC) was held July 31, 2000 at the National Institutes of Health, Neuroscience Center in Rockville, Maryland. The Committee identified several areas of Parkinson's disease research that will receive the highest priority in the coming weeks, including clinical trials and gene research.
1998
NINDS to Support Eight New Parkinson's Disease Research Centers of Excellence
Tuesday, September 28, 1999As part of its efforts to defeat Parkinson's disease, the National Institute of Neurological Disorders and Stroke (NINDS) today announced plans to award new grants to eight top universities. The new awards will raise to eleven the number of Parkinson's Disease Research Centers of Excellence the Institute funds and represent a total commitment of $49 million to be spent over the next 5 years. Added to the $24 million committed to three such centers in September of 1998, this brings total Institute funding for the Parkinson's Disease Research Centers of Excellence program to $73 million.
Transplanted Neural Stem Cells Migrate Throughout the Abnormal Brain, Reduce Disease Symptoms
Monday, June 07, 1999For years, researchers have probed the mysteries of neural stem cells -- immature cells that can differentiate into all the cell types that make up the brain -- with the idea that they might be useful for treating brain disorders such as Parkinson's disease. Important new animal research now suggests that these cells may be effective in treating a much broader array of brain diseases than previously anticipated, including Alzheimer's disease and many childhood brain disorders.
Fetal Cell Therapy Benefits Some Parkinson's Patients: First Controlled Clinical Trial Shows Mixed Results
Wednesday, April 21, 1999Results from the first randomized, controlled clinical trial of fetal dopamine cell implants for Parkinson's disease show that the surgery helped a small number of Parkinson's patients, but not all who underwent the experimental therapy. These results raise important questions in the search for improved treatments for Parkinson's disease.
Genetics Not Significant to Developing Typical Parkinson's Disease
Tuesday, January 26, 1999Genetic factors do not play a significant role in causing the most common form of Parkinson's disease (PD), according to a study to be published in the January 27, 1999 issue of the Journal of the American Medical Association. This epidemiological study, the largest of its kind to investigate the role of genetic or environmental causes of PD, examined 19,842 white male twins enrolled in a large registry of World War II veteran twins.
NINDS Awards Almost $24 Million to Support Parkinson's Disease Research Centers of Excellence
Friday, December 04, 1998Three top university hospitals will receive a total of almost $24 million from the National Institute of Neurological Disorders and Stroke (NINDS) to advance understanding of Parkinson's disease and related movement disorders. Investigators at Emory University, Massachusetts General Hospital, and The Johns Hopkins University School of Medicine will spend the next five years unraveling the cause or causes of Parkinson's disease and seeking new ways to diagnose and treat it. They will also provide state-of-the-art, multidisciplinary training for young scientists preparing for research careers investigating Parkinson's disease and related neurodegenerative disorders.
Cultured Neural Stem Cells Reduce Symptoms in Model of Parkinson's Disease
Monday, July 20, 1998For decades, researchers have imagined treating human diseases by replacing damaged cells with stem cells - embryonic cells from which all other kinds of cells develop. While the potential benefits are enormous, such strategies have been limited by an uncertain supply of stem cells. Now, scientists have shown that neural stem cells can be multiplied and raised to maturity in the laboratory and that these cells can greatly reduce symptoms in an animal model of Parkinson's disease.
1996
Scientists Gain New Understanding of CNS Stem Cells: Findings May Lead to Improved Treatment for Parkinson's Disease, Other Disorders
Thursday, April 03, 1997For decades, scientists believed that the adult central nervous system could not repair itself, in part because it lacked fundamental "stem cells," mother cells that can divide to form other kinds of cells. A series of findings has now shown that stem cells are present in the adult brain and spinal cord, and that they can be grown in culture and directed to act in much the same way as fetal stem cells. These findings provide new hope for people with Parkinson's disease, spinal cord injury, and a host of other disorders.
Scientists Locate Parkinson's Gene
Monday, November 11, 1996Bethesda, MD - For the first time, scientists have pinpointed the location of a gene they believe is responsible for some cases of Parkinson's disease. Their discovery provides strong evidence that a genetic alteration is capable of causing the disease. The study, published in the November 15 issue of Science,1 sheds light on the mysterious origins of this devastating neurological disease that affects about 500,000 Americans.
1994
No documents posted for 1994-1995
1992
NINDS Research Offers Hope for Transplantation and Regeneration
Wednesday, November 10, 1993Age-old dogma held that the central nervous system could not regrow or recover, dampening hopes for recovery from spinal cord injury and other neurological disorders. But recent results from scientists at the National Institute of Neurological Disorders and Stroke (NINDS) offer a glimpse of how basic research promises approaches for restoring and repairing damaged nerves.
New Drug Prolongs Symptom Relief in Parkinson's Disease
Thursday, April 29, 1993A new drug, when added to standard treatment for Parkinson's disease, prolongs relief of symptoms by more than 60 percent, report scientists from the National Institute of Neurological Disorders and Stroke (NINDS). In announcing their findings today at the annual meeting of the American Academy of Neurology in New York,* scientists said that the drug, called R0 40-7592, could help overcome drawbacks of current drug treatment.
DATATOP Study Confirms Deprenyl's Efficacy in Fighting the Progression of Parkinson's Disease
Wednesday, January 20, 1993Scientists announced today in the January 21 New England Journal of Medicine the results of a broad, long-term study on the effects of deprenyl and tocopherol (a form of vitamin E) on the progression of early Parkinson's disease. The investigators, who comprise a group known as the Parkinson's Study Group, confirmed that deprenyl is effective in slowing the early progression of Parkinson's disease and delaying the need for initiation of therapy with the drug levodopa. The latest results of the study showed, however, that the beneficial effects of deprenyl were not as lasting in fighting Parkinson's disease as the investigators had anticipated when evaluating the preliminary results in 1989. The clinical trials also showed no evidence that tocopherol was useful in Parkinson's disease.
1990
Mounting knowledge of Parkinson's disease leads to new treatment theories
Thursday, December 06, 1990Animal studies have revealed new knowledge of brain chemistry in Parkinson's disease and suggest new treatment approaches, according to results published in the December 7, 1990 issue of Science.
Last updated August 04, 2006
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