Parkinson Disease: Pennsylvania

Weintraub D, Stern MB. · University of Pennsylvania School of Medicine, Department of Psychiatry, 3535 Market Sreet, Room 3003, Philadelphia, PA 19104, USA. · Expert Rev Neurother. · Pubmed #17563252 No free full text.

Abstract: Although Parkinson's disease is considered a movement disorder, it has a wide range and high prevalence of affective, psychotic, cognitive, behavioral and sleep-related features. To treat such features, agents including antidepressants, anxiolytics, antipsychotics and cognition-enhancing agents are commonly prescribed, although the targeted syndromes are often incompletely understood and controlled studies demonstrating a treatment's efficacy and tolerability in Parkinson's disease patients are often lacking. Nevertheless, the available information does suggest the outlines of management methods, pending expanded research to identify optimal strategies specific to Parkinson's disease.

Kashem A, Cross RC, Santamore WP, Bove AA. · Section of Cardiology, Temple University School of Medicine, 3401 North Broad Street, Parkinson Pavilion, Suite 901, Philadelphia, PA 19140, USA. · Curr Cardiol Rep. · Pubmed #17543243 No free full text.

Abstract: Heart failure (HF) continues to place significant demands on health care resources because of the large number of hospital admissions for HF, the growth of the elderly population with HF, and the improved survival of patients with chronic heart disease who develop HF that requires continuous care. Because HF is best managed using a disease management approach, frequent communication is an important component of care. A variety of studies using the telephone to maintain communication have demonstrated reduced hospital admissions and improved morbidity rate. Hardware monitoring systems that can record vital signs and transmit information from the home to a data center have also demonstrated their value in HF care, but such systems become expensive when considered for large populations of HF patients. Most HF patients can transmit their vital signs, weight, and symptoms to a practice data center using the Internet with no specialized hardware other than a sphygmomanometer and a scale. We have used such a system to monitor HF patients and have provided care instructions using the same system. With use of an Internet communication system, it is possible to reduce hospitalizations and maintain a stable HF status without frequent office visits.

Elman LB, Houghton DJ, Wu GF, Hurtig HI, Markowitz CE, McCluskey L. · ALS Association Center, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · J Palliat Med. · Pubmed #17472516 No free full text.

Abstract: BACKGROUND: Amyotrophic lateral sclerosis, Parkinson's disease, atypical parkinsonian syndromes, and multiple sclerosis are progressive neurologic disorders that cumulatively afflict a large number of people. Effective end-of-life palliative care depends upon an understanding of the clinical aspects of each of these disorders. OBJECTIVES: The authors review the unique and overlapping aspects of each of these disorders with an emphasis upon the clinical management of symptoms. Design: The authors review current management and the supporting literature. CONCLUSIONS: Clinicians have many effective therapeutic options to choose from when managing the symptoms produced by these disorders.

Liao S, Arnold RM. · University of California-Irvine, Orange, California 92868, USA. · J Palliat Med. · Pubmed #17472515 No free full text.

This publication has no abstract.

Lippa CF, Duda JE, Grossman M, Hurtig HI, Aarsland D, Boeve BF, Brooks DJ, Dickson DW, Dubois B, Emre M, Fahn S, Farmer JM, Galasko D, Galvin JE, Goetz CG, Growdon JH, Gwinn-Hardy KA, Hardy J, Heutink P, Iwatsubo T, Kosaka K, Lee VM, Leverenz JB, Masliah E, McKeith IG, Nussbaum RL, Olanow CW, Ravina BM, Singleton AB, Tanner CM, Trojanowski JQ, Wszolek ZK, Anonymous00243. · Department of Neurology, Drexel University College of Medicine, Philadelphia, PA 19102, USA. · Neurology. · Pubmed #17353469 No free full text.

Abstract: For more than a decade, researchers have refined criteria for the diagnosis of dementia with Lewy bodies (DLB) and at the same time have recognized that cognitive impairment and dementia occur commonly in patients with Parkinson disease (PD). This article addresses the relationship between DLB, PD, and PD with dementia (PDD). The authors agreed to endorse "Lewy body disorders" as the umbrella term for PD, PDD, and DLB, to promote the continued practical use of these three clinical terms, and to encourage efforts at drug discovery that target the mechanisms of neurodegeneration shared by these disorders of alpha-synuclein metabolism. We concluded that the differing temporal sequence of symptoms and clinical features of PDD and DLB justify distinguishing these disorders. However, a single Lewy body disorder model was deemed more useful for studying disease pathogenesis because abnormal neuronal alpha-synuclein inclusions are the defining pathologic process common to both PDD and DLB. There was consensus that improved understanding of the pathobiology of alpha-synuclein should be a major focus of efforts to develop new disease-modifying therapies for these disorders. The group agreed on four important priorities: 1) continued communication between experts who specialize in PDD or DLB; 2) initiation of prospective validation studies with autopsy confirmation of DLB and PDD; 3) development of practical biomarkers for alpha-synuclein pathologies; 4) accelerated efforts to find more effective treatments for these diseases.

Zigmond MJ. · Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA. · J Neural Transm Suppl. · Pubmed #17017565 No free full text.

Abstract: Glial cell line-derived neurotrophic factor (GDNF) has been implicated in the protection of dopamine (DA) neurons from oxidative stress in animal models of Parkinson's disease (PD). We have now shown that GDNF can also protect against the effects of 6-hydroxydopamine (6-OHDA) in a dopaminergic cell line and in cultures of primary DA neurons prepared from rat substantia nigra (SN). This appears to involve a rapid and transient increase in the phosphorylation of several isoforms of extracellular signal-regulated kinase (ERK). Our evidence indicates that ERK activation also can be modulated by reactive oxygen species (ROS), including those generated by endogenous DA. Identification of the ways by which these pathways can be triggered should provide insights into the pathophysiology of PD, and may offer useful avenues for retarding the progression of the disorder.

Lee VM, Trojanowski JQ. · Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Institute on Aging, Maloney Building, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. · Neuron. · Pubmed #17015225 No free full text.

Abstract: Classic Parkinson's disease (PD) is characterized by fibrillar alpha-synuclein inclusions known as Lewy bodies in the substantia nigra, which are associated with nigrostriatal degeneration. However, alpha-synuclein pathologies accumulate throughout the CNS in areas that also undergo progressive neurodegeneration, leading to dementia and other behavioral impairments in addition to parkinsonism. Although mutations in the alpha-synuclein gene only cause Lewy body PD in rare families, and although there are multiple other, albeit rare, genetic causes of familial parkinsonism, sporadic Lewy body PD is the most common movement disorder, and insights into mechanisms underlying alpha-synuclein-mediated neurodegeneration provide novel targets for the discovery of disease-modifying therapies for PD and related neurodegenerative alpha-synucleinopathies.

Kleiner-Fisman G, Herzog J, Fisman DN, Tamma F, Lyons KE, Pahwa R, Lang AE, Deuschl G. · Parkinson's Disease Research Education and Clinical Center, Philadelphia VA Hospital, Philadelphia, Pennsylvania 19104, USA. · Mov Disord. · Pubmed #16892449 No free full text.

Abstract: Subthalamic nucleus (STN) deep brain stimulation (DBS) is currently the most common therapeutic surgical procedure for patients with Parkinson's disease (PD) who have failed medical management. However, a recent summary of clinical evidence on the effectiveness of STN DBS is lacking. We report the results of such a systematic review and meta-analysis. A comprehensive review of the literature using Medline and Ovid databases from 1993 until 2004 was conducted. Estimates of change in absolute Unified Parkinson's Disease Rating Scale (UPDRS) scores after surgery were generated using random-effects models. Sources of heterogeneity were explored with meta-regression models, and the possibility of publication bias was evaluated. Patient demographics, reduction in medication requirements, change in dyskinesia, daily offs, quality of life, and a ratio of postoperative improvement from stimulation compared to preoperative improvement by medication from each study were tabulated and average scores were calculated. Adverse effects from each study were summarized. Thirty-seven cohorts were included in the review. Twenty-two studies with estimates of standard errors were included in the meta-analysis. The estimated decreases in absolute UPDRS II (activities of daily living) and III (motor) scores after surgery in the stimulation ON/medication off state compared to preoperative medication off state were 13.35 (95% CI: 10.85-15.85; 50%) and 27.55 (95% CI: 24.23-30.87; 52%), respectively. Average reduction in L-dopa equivalents following surgery was 55.9% (95% CI: 50%-61.8%). Average reduction in dyskinesia following surgery was 69.1% (95% CI: 62.0%-76.2%). Average reduction in daily off periods was 68.2% (95% CI: 57.6%-78.9%). Average improvement in quality of life using PDQ-39 was 34.5% +/- 15.3%. Univariable regression showed improvements in UPDRS III scores were significantly greater in studies with higher baseline UPDRS III off scores, increasing disease duration prior to surgery, earlier year of publication, and higher baseline L-dopa responsiveness. Average baseline UPDRS III off scores were significantly lower (i.e., suggesting milder disease) in later than in earlier studies. In multivariable regression, L-dopa responsiveness, higher baseline motor scores, and disease duration were independent predictors of greater change in motor score. No evidence of publication bias in the available literature was found. The most common serious adverse event related to surgery was intracranial hemorrhage in 3.9% of patients. Psychiatric sequelae were common. Synthesis of the available literature indicates that STN DBS improves motor activity and activities of daily living in advanced PD. Differences between available studies likely reflect differences in patient populations and follow-up periods. These data provide an estimate of the magnitude of the treatment effects and emphasize the need for controlled and randomized studies.

Weintraub D, Potenza MN. · Department of Psychiatry, University of Pennsylvania, 3535 Market Street, Room 3003, Philadelphia, PA 19104, USA. · Curr Neurol Neurosci Rep. · Pubmed #16822350 No free full text.

Abstract: There is an increasing awareness that impulse control disorders (ICDs), including pathologic gambling and compulsive sexual behavior, can occur as a complication of Parkinson's disease (PD). Anecdotal experience and case reporting have suggested an association between ICDs in PD and the use of dopamine agonists. Lacking established treatments for ICDs in PD, clinical management should initially consist of modifications to or discontinuation of dopamine replacement therapy, particularly dopamine agonists. It is important that PD patients be aware that dopamine agonist use may lead to the development of an ICD, and that clinicians monitor patients as part of routine clinical care. As empirically validated treatments for ICDs are emerging, it will be important to examine their efficacy and tolerability in individuals with co-occurring PD and ICDs.

Siderowf A, Stern MB. · Parkinson's Disease and Movement Disorders Center, Department of Neurology, University of Pennsylvania, 330 South 9th Street, Philadelphia, PA 19107, USA. · Curr Neurol Neurosci Rep. · Pubmed #16822349 No free full text.

Abstract: Preclinical Parkinson's disease (PD) can be defined as a state that precedes the diagnosis of PD but without the presence of the characteristic motor features of the disorder. In such a situation, subtle non-motor features may be present or subclinical abnormalities may exist that can be detected only by physiologic testing. Alternatively, lifelong traits such as genetic mutations may predict the onset of PD in the absence of any clinical or physiologic abnormalities. A number of diagnostic technologies are currently available that can detect both preclinical states and traits that will lead to PD in the future. The current challenges are to refine these technologies and to determine how they should be employed so that their use is ethical, practical, and meaningful to at-risk individuals.

Nofzinger EA. · Sleep Neuroimaging Research Program, University of Pittsburgh School of Medicine, 3811 O'Hara Street, Pittsburgh, PA 15213, USA. · Curr Neurol Neurosci Rep. · Pubmed #16522269 No free full text.

Abstract: Herein are presented the results of research in the area of sleep neuroimaging over the past year. Significant work has been performed to clarify the basic mechanisms of sleep in humans. New studies also extend prior observations regarding altered brain activation in response to sleep deprivation by adding information regarding vulnerability to sleep deprivation and regarding the influence of task difficulty on aberrant responses. Studies in sleep disorder medicine have yielded significant findings in insomnia, depression, and restless legs syndrome. Extensive advances have been made in the area of sleep apnea where physiologic challenges have been used to probe brain activity in the pathophysiology of sleep apnea syndrome.

Marino MJ, Conn PJ. · Neuroscience Drug Discovery - Movement Disorders, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. · Curr Opin Pharmacol. · Pubmed #16368268 No free full text.

Abstract: Metabotropic glutamate receptors (mGluRs) have been proposed as novel targets for the treatment of a variety of disorders. Recently, highly selective allosteric modulators of the mGluRs have been developed by several groups. These allosteric compounds provide an unprecedented degree of selectivity for individual mGluRs, allowing for more detailed functional studies on the roles of these receptors. Furthermore, the allosteric approach avoids many of the hurdles associated with the development of direct agonists as drugs, and provides a clear path forward for clinical proof-of-concept studies. Currently, both positive allosteric modulators of mGluR2 and negative allosteric modulators of mGluR5 hold promise as novel anxiolytics, and positive allosteric modulators of mGluR4 appear to be an exciting new target for the treatment of Parkinson's disease.

Robinson K, Dennison A, Roalf D, Noorigian J, Cianci H, Bunting-Perry L, Moberg P, Kleiner-Fisman G, Martine R, Duda J, Jaggi J, Stern M. · Department of Rehabilitation Medicine, University of Pennsylvania, Philadelphia, PA, USA. · NeuroRehabilitation. · Pubmed #16340098 No free full text.

Abstract: OBJECTIVE: To identify falling risk factors that are potentially modifiable among individuals who have idiopathic Parkinson's disease. DESIGN: A between group comparison of 19 fallers and 21 nonfallers who have Parkinson's disease, across an array of variables that have been identified as falling risk factors among the elderly and among those who have Parkinson's disease. RESULTS: Several variables were demonstrated significantly to distinguish fallers: disease duration and severity; dyskinesias associated with the use of dopaminergic agents; freezing; postural instability; depression; fear of falling; impaired fine motor control and motor planning in the feet; decreased proximal strength and muscular endurance in the legs; and a higher level of disability. CONCLUSIONS: Several of these variables can be viewed a potentially modifiable during a future intervention trial that aims to reduce falls in those who have Parkinson's disease using multidimensional risk factor modification.

Bilen J, Bonini NM. · Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. · Annu Rev Genet. · Pubmed #16285856 No free full text.

Abstract: Among many achievements in the neurodegeneration field in the past decade, two require special attention due to the huge impact on our understanding of molecular and cellular pathogenesis of human neurodegenerative diseases. First is defining specific mutations in familial neurodegenerative diseases and second is modeling these diseases in easily manipulable model organisms including the fruit fly, nematode, and yeast. The power of these genetic systems has revealed many genetic factors involved in the various pathways affected, as well as provided potential drug targets for therapeutics. This review focuses on fruit fly models of human neurodegenerative diseases, with emphasis on how fly models have provided new insights into various aspects of human diseases.

Weintraub D, Stern MB. · Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · Am J Geriatr Psychiatry. · Pubmed #16223962 No free full text.

Abstract: Although Parkinson disease (PD) is primarily considered a movement disorder, the high prevalence of psychiatric complications suggests that it is more accurately conceptualized as a neuropsychiatric disease. Affective disorders, cognitive impairment, and psychosis are particularly common in PD and are associated with excess disability, worse quality of life, poorer outcomes, and caregiver distress. Yet, in spite of this and their frequent occurrence, there is incomplete understanding of the epidemiology, phenomenology, risk factors, neuropathophysiology, and optimal treatment strategies for these disorders. Psychiatric complications are typically comorbid, and there is great intra- and inter-individual variability in presentation. The hallmark neuropathophysiological changes that occur in PD plus the association between exposure to dopaminergic medications and certain psychiatric disorders suggest a neurobiological basis for most psychiatric symptoms, although psychological factors are probably involved in the development of affective disorders. Although antidepressants, antipsychotics, and cognition-enhancing agents are commonly prescribed in PD, controlled studies demonstrating efficacy and tolerability of these drugs are virtually nonexistent. Because of the high prevalence and complexity of psychiatric complications in PD, geriatric psychiatrists are in a position to offer valuable consultation and clinical care to this population. This article provides an overview of the epidemiology, pathophysiology, clinical presentation, and management of the most common psychiatric complications in PD.

Romano G. · Department of Neurosurgery, The Farber Institute for the Neurosciences, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA. · Drug News Perspect. · Pubmed #16193103 No free full text.

Abstract: Vectors based on adeno-associated virus (AAV) have recently been used in phase I clinical trials for the treatment of neurological disorders, such as Parkinson's and Canavan's diseases. Indeed, AAV-mediated gene transfer is a promising tool for the delivery of therapeutic gene into the central and peripheral nervous systems. AAV-mediated gene transfer was also applied in phase I and phase II clinical trials for the treatment of cystic fibrosis and in phase I clinical trials for the treatment of hemophilia B. Remarkable progress is being reported in the development of AAV-based vectors; however, the design of AAV-derived vectors needs to be improved. As it stands, AAV-mediated gene transfer has a limited capacity in accommodating foreign genes. In addition, some preclinical studies have shown that AAV-derived vectors can cause tumors in animals due to insertional mutagenesis events. This review will discuss perspectives and drawbacks for AAV-based vector systems.

Richter JE. · Department of Medicine, Temple University School of Medicine, 3401 North Broad Street, 8th Floor, Parkinson Pavilion, Philadelphia, PA, 19140, USA. · Thorac Surg Clin. · Pubmed #16104128 No free full text.

Abstract: Although PPI have revolutionized the treatment of GERD and its complications, many patients continue to have breakthrough symptoms and take antacids and H2RA. Furthermore, acid reflux actually is the innocent bystander, with few drugs available to target the true culprit, a dysfunctional LES. Future development of treatments, such as the GABA(B) agonists, which reduce TLESR, may prove an important advance in the therapy of GERD by controlling acid and nonacid reflux better. The chemical, pharmacodynamic, and clinical limitations of PPI may be addressed by the development of innovative drugs, such as the P-CAB or gastrin vaccine, to control acid secretion. Which of these drugs, if any, will be the new GERD drug for the millennium is unknown. There is no question, however, that improved drug treatments will parallel a better understanding of the complicated pathophysiology of GERD.

Forman MS, Lee VM, Trojanowski JQ. · Department of Pathology and Laboratory Medicine, Institute on Aging, University of Pennsylvania, Philadelphia, PA 19104, USA. · Neuron. · Pubmed #16102530 No free full text.

Abstract: The discovery of SNCA mutations pathogenic for autosomal-dominant Lewy body Parkinson's disease (PD) in 1997 heralded a revolution in understanding the molecular and genetic basis of PD. Indeed, it now is clear that Lewy body PD is one of many neurodegenerative parkinsonian disorders that result from nigrostriatal degeneration caused by diverse mechanisms. However, to capitalize on these new insights and facilitate efforts to improve the diagnosis and therapy of neurodegenerative movement disorders, it is timely to define a nosology for these diseases that is based on their genetic and molecular underpinnings, as proposed here.

Weintraub D, Morales KH, Moberg PJ, Bilker WB, Balderston C, Duda JE, Katz IR, Stern MB. · Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Mov Disord. · Pubmed #15954137 links to  free full text

Abstract: The objective of this study was to determine effect sizes for both antidepressant treatment and placebo for depression in Parkinson's disease (PD), and to compare the findings with those reported in elderly depressed patients without PD. Recent reviews have concluded that there is little empiric evidence to support the use of antidepressants in PD; however, available data has not been analyzed to determine the effect size for antidepressant treatment in PD depression. A literature review identified antidepressant studies in PD. Suitable studies were analyzed using meta-analytic techniques, and effect sizes were compared with those from antidepressant studies in elderly patients without PD. Large effect sizes were found for both active treatment and placebo in PD, but there was no difference between the two groups. In contrast, active treatment was superior to placebo in depressed elderly patients without PD. In PD, increasing age and a diagnosis of major depression were associated with better treatment response. Results also suggest that newer antidepressants are well tolerated in PD. Despite the high prevalence of depression and antidepressant use in PD, controlled treatment research has been almost nonexistent. Meta-analysis results suggest a large but nonspecific effect for depression treatment in PD. In addition, PD patients may benefit less from antidepressant treatment, particularly selective serotonin reuptake inhibitors, than do elderly patients without PD.

Barrett AM. · Pennsylvania State College of Medicine, Hershey, USA. · Postgrad Med. · Pubmed #15948369 No free full text.

Abstract: Patients who have the classic combination of progressive memory loss and problems retrieving stored knowledge that is characteristic of Alzheimer's disease may actually have another, treatable disorder. In these cases, appropriate evaluation can reveal the true diagnosis and guide therapy to stabilize or improve thinking and avert other complications. In this article, Dr Barrett explores 10 conditions that may be mistaken for Alzheimer's disease.

Norris EH, Giasson BI. · Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · Antioxid Redox Signal. · Pubmed #15890012 No free full text.

Abstract: Parkinson's disease, the most common movement disorder, is characterized by the loss of brainstem neurons, specifically dopaminergic neurons in the substantia nigra, as well as the accumulation of neuronal cytoplasmic filamentous proteinaceous inclusions comprised of polymerized alpha-synuclein. It was reported recently that alpha-synuclein can induce the formation of filamentous tau inclusions, which are characteristic of disorders like Alzheimer's disease and Lewy body variant of Alzheimer's disease, suggesting that a similar mechanism may exist between alpha-synuclein fibrillogenesis and tau polymerization. Pathological brain inclusions comprised of alpha-synuclein or tau proteins are associated with a spectrum of neurodegenerative disorders, and oxidative and nitrative injury has been implicated in all of these diseases. However, the role of oxidative damage in alpha-synuclein and tau polymerization and pathological inclusion formation is complex. Differences in the level, type, and temporal sequence of the oxidative alterations appear to result in both inhibitory and stimulatory effects on the fibrillogenesis of these proteins.

Newberg AB, Alavi A. · Division of Nuclear Medicine, Department of Radiology, Hospital of the University of Pennsylvania, 3400 Spruce Street, 110 Donner Building, Philadelphia, PA 19104, USA. · Radiol Clin North Am. · Pubmed #15693647 No free full text.

Abstract: PET will continue to play a critical role in both clinical and research applications with regard to CNS disorders. PET is useful in the initial diagnosis of patients presenting with CNS symptoms and can help clinicians determine the best course of therapy. PET studies can also be useful for studying the response to therapy. From the research perspective, the various neurotransmitter and other molecular tracers currently available or in development will provide substantial information about pathophysiologic process in the brain. As such applications become more widely tested, their introduction into the clinical arena will further advance the use of PET imaging in the evaluation and management of CNS disorders.

Kadane JB. · Department of Statistics, Carnegie Mellon University, Pittsburgh, PA 15213, USA. · Stat Med. · Pubmed #15678444 No free full text.

Abstract: This article reviews the basics of Bayesian decision theory, and comments on its use in medical decision making. It emphasizes the subjectivity of the probability and utility inputs, and the desirability, in certain contexts, of representing several decision makers, each with his or her own probabilities and utilities. Applications and ethical considerations are also discussed. A brief bibliography gives pointers to the literature.

Stern MB. · Penn Neurologic Institute, 330 S. 9th Street, Philadelphia, PA 19107, USA. · Arch Neurol. · Pubmed #15596624 links to  free full text

This publication has no abstract.

Giasson BI. · Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · Sci Aging Knowledge Environ. · Pubmed #15576821 No free full text.

Abstract: The recent identification of genes (parkin, DJ-1, and PINK1) involved in recessive autosomal parkinsonism, and the indications that these proteins may have protective effects on the mitochondria, has led to the reemergence of the notion that mitochondrial dysfunction might play a central role in the etiology of sporadic Parkinson's disease (PD). This idea has previously been supported by biochemical analyses showing reduced mitochondrial activity in PD patients and in animal models of PD generated by the selective inhibition of mitochondria activity. However, the involvement of DJ-1 or PINK1 loss of function in classical idiopathic PD, characterized by pathological inclusions composed of aggregated alpha-synuclein protein, has still not been evaluated. More detailed studies of the possible interactions between parkin, DJ-1, PINK1, and alpha-synuclein and their effects on mitochondria are needed to more adequately define the biological pathways that may convergently or independently lead to parkinsonism.