Parkinson Disease: US Mid-Atlantic

Yang JL, Weissman L, Bohr VA, Mattson MP. · Laboratory of Molecular Gerontology, National Institute on Aging Intramural Research Program, Baltimore, MD, USA. · DNA Repair (Amst). · Pubmed #18463003 links to  free full text

Abstract: By producing ATP and regulating intracellular calcium levels, mitochondria are vital for the function and survival of neurons. Oxidative stress and damage to mitochondrial DNA during the aging process can impair mitochondrial energy metabolism and ion homeostasis in neurons, thereby rendering them vulnerable to degeneration. Mitochondrial abnormalities have been documented in all of the major neurodegenerative disorders-Alzheimer's, Parkinson's and Huntington's diseases, and amyotrophic lateral sclerosis. Mitochondrial DNA damage and dysfunction may be downstream of primary disease processes such as accumulation of pathogenic proteins. However, recent experimental evidence demonstrates that mitochondrial DNA damage responses play important roles in aging and in the pathogenesis of neurodegenerative diseases. Therapeutic interventions that target mitochondrial regulatory systems have been shown effective in cell culture and animal models, but their efficacy in humans remains to be established.

Martin LJ. · Department of Pathology, Division of Neuropathology, and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196, USA. · J Neuropathol Exp Neurol. · Pubmed #18431258 links to  free full text

Abstract: DNA damage is a form of cell stress and injury that has been implicated in the pathogenesis of many neurologic disorders, including amyotrophic lateral sclerosis, Alzheimer disease, Down syndrome, Parkinson disease, cerebral ischemia, and head trauma. However, most data reveal only associations, and the role for DNA damage in direct mechanisms of neurodegeneration is vague with respect to being a definitive upstream cause of neuron cell death, rather than a consequence of the degeneration. Although neurons seem inclined to develop DNA damage during oxidative stress, most of the existing work on DNA damage and repair mechanisms has been done in the context of cancer biology using cycling nonneuronal cells but not nondividing (i.e. postmitotic) neurons. Nevertheless, the identification of mutations in genes that encode proteins that function in DNA repair and DNA damage response in human hereditary DNA repair deficiency syndromes and ataxic disorders is establishing a mechanistic precedent that clearly links DNA damage and DNA repair abnormalities with progressive neurodegeneration. This review summarizes DNA damage and repair mechanisms and their potential relevance to the evolution of degeneration in postmitotic neurons.

Weintraub D, Comella CL, Horn S. · Department of Psychiatry and Neurology, University of Pennsylvania, 3615 Chestnut St, Philadelphia, PA 19104, USA. · Am J Manag Care. · Pubmed #18402509 links to  free full text

Abstract: The nonmotor neuropsychiatric symptoms of Parkinson's disease, particularly depression, psychosis, and cognitive impairment/dementia, are major contributors to disability and a decline in quality of life. Their effect on patients may be more disabling than motor symptoms. Increasing awareness of the importance of recognizing and treating neuropsychiatric symptoms of this disease in the medical community is a focus of specialists and organizations. This article looks at useful screening measures to help clinicians recognize neuropsychiatric symptoms and offers suggestions for their effective treatment.

Weintraub D, Comella CL, Horn S. · Department of Neurological Sciences, University of Pennsylvania, 330 S 9th St, Philadelphia, PA 19107, USA. · Am J Manag Care. · Pubmed #18402508 links to  free full text

Abstract: In the absence of a cure, the primary goals in managing Parkinson's disease (PD) are to preserve functionality and health-related quality of life. Meeting these goals can minimize healthcare-resource utilization and long-term healthcare costs. Although effective treatment of motor symptoms of the disease is a central consideration to facilitate improved outcomes, management of nonmotor symptoms is now recognized as an equally important target of intervention, since nonmotor symptoms can contribute greatly to disability. The article addresses the current treatment options of choice for reducing motor symptoms of PD and their most rational use. Cost-effectiveness is a major consideration for managed care and is also analyzed for many available treatment options.

Weintraub D, Comella CL, Horn S. · University of Pennsylvania, Philadelphia, PA, USA. · Am J Manag Care. · Pubmed #18402507 links to  free full text

Abstract: Parkinson's disease (PD) is a chronic neurodegenerative disease associated with substantial morbidity, increased mortality, and high economic burden. Of importance to managed care is that the number of cases of PD are on the rise, paralleling the advancing age of the population, and misdiagnosis is common. Effective management of PD can minimize disability and potentially improve long-term outcomes, which would minimize long-term healthcare costs and medical resource utilization. This article provides a brief review of the epidemiology, pathophysiology, clinical course, and burden of PD.

Niedermeyer E. · Sinai Hospital, Division of Neurology, Baltimore, Maryland, USA. · Clin EEG Neurosci. · Pubmed #18318418 No free full text.

Abstract: A report of severe akinetic episodes in patients with Parkinson disease (PD) has been the stimulus for the following discussion of akinesia and its variants. Severe persistent akinesia may occur in frontal lobe impairment. Therefore, it is likely that extension of the Parkinsonian dysfunction into the frontal lobe causes severe akinesia which should be separated from the very common Parkinsonian hypokinesia. Another very common clinical phenomenon of PD is sudden freezing. Hence the frontal lobe--hardly regarded as a region of special interest in the realm of PD--can be the cause of severe and dangerous complications of PD. The term "arrest reaction" or "motor arrest" denotes a similar freezing. It is recommended to restrict these terms to certain forms of frontal lobe epilepsy. This discussion of hypokinetic and akinetic states should also include catatonia: a form of schizophrenia with a special type of akinesia. Though without major neuropathological substratum, this condition can, in extremely rare cases, lead to severe hyperthermia and fatal outcome (presumably via hypothalamic dysfunction).

Chiocco MJ, Harvey BK, Wang Y, Hoffer BJ. · Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA. · Parkinsonism Relat Disord. · Pubmed #18267258 No free full text.

Abstract: Parkinson's disease (PD) is a slowly progressive disorder with no known etiology. Pathologically, there is a loss of the dopaminergic neurons in the substantia nigra that project to the striatum. Current available therapies for PD are targeted to the restoration of striatal dopamine. These approaches may alleviate symptoms transiently, but fail to slow the progression of disease. One emergent therapeutic approach is the use of neurotrophic factors to halt or reverse the loss of dopaminergic neurons. There have been intensive research efforts both preclinically and clinically testing the efficacy and safety of neurotrophic factors for the treatment of PD. In this review, we discuss the neuroprotective and neuroregenerative properties of various trophic factors, both old and recent, and their status as therapeutic molecules for PD.

Ross CA, Smith WW. · Department of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. · Parkinsonism Relat Disord. · Pubmed #18267256 No free full text.

Abstract: PD is the second most common neurodegenerative disease, and affects 5% of the population by the age of 85. PD is a multi-factorial disease with a complex etiology including genetic risk factors, environmental exposure and aging. The pathogenesis is not fully understood. Here we review research on the genetic and environmental causes of PD and the current research models. None of the single models replicate all the features of PD. Genetic models (possibly including more than one mutation) in combination with toxins or other environmental manipulation may provide better models of PD pathogenesis.

Dawson TM. · Institute for Cell Engineering, Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Parkinsonism Relat Disord. · Pubmed #18267244 No free full text.

Abstract: Parkinson's disease (PD) is a common neurodegenerative disease characterized by the loss of dopaminergic neurons leading to bradykinesia, rest tremor and rigidity. Although the majority of PD is sporadic, rare genetic causes of PD are providing tremendous insight into the pathogenesis of PD. Here I shortly review the major genes implicated in autosomal dominant and autosomal recessive PD. Understanding how mutations in these PD associated genes holds particular promise for development of new therapies to treat PD.

Doty RL. · Smell and Taste Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · Parkinsonism Relat Disord. · Pubmed #18267240 No free full text.

Abstract: It has become increasingly apparent that Parkinson's disease (PD) can no longer be considered purely a motor disease, as numerous sensory alterations accompany this disorder either before or early in its clinical progression. Most notable among such disturbances are decrements in smell function. Such anomalies have been documented in approximately 90% of patients with early-stage sporadic PD and appear to progress little, if at all, with the development of the more classic PD-related motor symptoms. In this paper, I briefly review the nature of the olfactory dysfunction observed in PD and current theories as to its pathological basis.

Doty RL. · Smell and Taste Center and Department of Otorhinolaryngology, Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · Ann Neurol. · Pubmed #18232016 No free full text.

Abstract: Environmental agents, including viruses, prions, and toxins, have been implicated in the cause of a number of neurodegenerative diseases, most notably Alzheimer's and Parkinson's diseases. The presence of smell loss and the pathological involvement of the olfactory pathways in the formative stages of Alzheimer's and Parkinson's diseases, together with evidence that xenobiotics, some epidemiologically linked to these diseases, can readily enter the brain via the olfactory mucosa, have led to the hypothesis that Alzheimer's and Parkinson's diseases may be caused or catalyzed by agents that enter the brain via this route. Evidence for and against this concept, the "olfactory vector hypothesis," is addressed in this review.

Heindel JJ. · Division of Extramural Research and Training, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA. · Basic Clin Pharmacol Toxicol. · Pubmed #18226058 No free full text.

Abstract: There is a major paradigm shift taking place in science that while simple is profound. The new paradigm suggests that susceptibility to disease is set in utero or neonatally as a result of the influences of nutrition and exposures to environmental stressors/toxicants. In utero nutrition and/or in utero or neonatal exposures to environmental toxicants alter susceptibility to disease later in life as a result of their ability to affect the programming of tissue function that occurs during development. This concept, which is still a hypothesis undergoing scientific testing and scrutiny, is called the developmental basis of health and disease. If true, then it says that the focus on disease prevention and intervention must change from the time of disease onset to perhaps decades prior: during the in utero and neonatal period. Perhaps the reason it has been so difficult to link environmental exposure to disease susceptibility is that scientists have been looking at the wrong time! Certainly, not all exposures that result in increased disease or dysfunction occur during development. This paradigm shift just suggests that this is a sensitive window of exposure that should be examined more thoroughly. This overview focuses on animal models for the assessment of this new scientific paradigm and the animal data that now supports it.

Zhang LN, Parkinson JF, Haskell C, Wang YX. · Department of Pharmacology and Immunology, Berlex Bioscience, Richmond, CA 94806, USA. · Curr Vasc Pharmacol. · Pubmed #18220938 No free full text.

Abstract: The murine carotid artery ligation (CAL) model has been widely used in the research of intimal hyperplasia, a major pathological process in vascular diseases, such as atherosclerosis and restenosis after angioplasty. Using a variety of gene knockout or transgenic mice and different pharmacological interventions, these studies have yielded significant new findings that contribute not only to unraveling the basic molecular mechanisms involved in the pathogenesis of intimal hyperplasia, but also to the identification of novel targets for intervention of these diseases. The current review outlines the findings derived from the murine CAL model, including studies run by the authors, covering the impacts of hyperlipidemia, pro-inflammatory factors, endothelial dysfunction, protease activity and growth mediators on neointimal hyperplasia.

Abel T, Zukin RS. · Department of Biology, University of Pennsylvania, 204G Lynch Laboratories, 433 South University Avenue, Philadelphia, PA 19104-6018, USA. · Curr Opin Pharmacol. · Pubmed #18206423 links to  free full text

Abstract: Epigenetic chromatin remodeling and modifications of DNA represent central mechanisms for regulation of gene expression during brain development and in memory formation. Emerging evidence implicates epigenetic modifications in disorders of synaptic plasticity and cognition. This review focuses on recent findings that HDAC inhibitors can ameliorate deficits in synaptic plasticity, cognition, and stress-related behaviors in a wide range of neurologic and psychiatric disorders including Huntington's disease, Parkinson's disease, anxiety and mood disorders, Rubinstein-Taybi syndrome, and Rett syndrome. These agents may prove useful in the clinic for the treatment of the cognitive impairments that are central elements of many neurodevelopmental, neurological, and psychiatric disorders.

Pollard JR. · Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA. · Curr Opin Investig Drugs. · Pubmed #18183537 No free full text.

Abstract: UCB SA was developing the high-affinity synaptic vesicle glycoprotein 2A ligand, seletracetam, an analog of levetiracetam, for the potential oral treatment of epilepsy. Phase II epilepsy trials were underway, but in July 2007, the company stated that development of seletracetam had been put on hold and it is unknown whether planned phase IIb/III trials will begin.

Muthane UB, Ragothaman M, Gururaj G. · Departments of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India. · J Assoc Physicians India. · Pubmed #18173026 No free full text.

Abstract: Improving economy and health in developing countries like India, has increased the life span and changed the emphasis from communicable to noncommunicable diseases. This is likely to increase the prevalence of movement disorders and, age-related diseases like Parkinson's disease (PD). We review Indian epidemiological studies to describe: a) Prevalence of movement disorders, b) methodological issues and c) potential of epidemiological research in a country with multiple ethnic races and environmental risks for PD. Most Indian epidemiological studies do not specifically assess PD and figures are from studies evaluating all neurological diseases. Well-designed Indian studies on PD and essential tremors estimate prevalence rates in Parsis who are ethnically different from Indians. We compare Indian prevalence studies with other parts of the world to examine the role of ethnicity in PD. Lack of accurate epidemiological data on PD and movement disorders creates an urgent need for properly designed and conducted epidemiological studies in India. This will help find out their load, identify areas of focus, create public health policies for elderly Indians and, possibly, provide etiological clues to the pathogenesis of PD.

Giasson BI, Van Deerlin VM. · Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104-6084, USA. · Neurosignals. · Pubmed #18097165 No free full text.

Abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common known cause of late-onset Parkinson's disease (PD). Clinical and pathological studies have demonstrated that in the majority of cases LRRK2 mutations lead to PD with classical clinical and pathological features. However, in some patients the pathological features can be distinct and/or more extensive than typically seen in PD. Collectively, these findings provide important clues into the mechanisms by which LRRK2 mutations can lead to demise of dopaminergic neurons. The understanding of LRRK2 protein function and its gene regulation and the consequences of mutations are still at their infancy, but scientific findings are progressing at a rapid pace. Although more detailed information on LRRK2 is still needed in the quest for therapeutic intervention that could halt or slow the progression of disease, here we summarize the current information on the biological and pathological properties of LRRK2.

Kranick SM, Duda JE. · Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. · Neurosignals. · Pubmed #18097158 No free full text.

Abstract: Prior to the onset of the cardinal motor features of idiopathic Parkinson's disease (PD), other manifestations of neurodegeneration such as olfactory dysfunction are often apparent. Characterizing these potential biomarkers of preclinical PD is particularly important in identifying individuals who will go on to develop disabling symptoms, and thus be good candidates for new neuroprotective strategies. As shown by the Braak neuropathologic staging of PD, the olfactory system is among the first neuronal populations to display Lewy body pathology. Clinically, loss of smell can be easily tested in the office using several validated techniques and is often helpful to the physician in distinguishing idiopathic PD from other forms of parkinsonism. Recent findings have indicated that a decline in olfaction may be observed in selected at-risk patients, which has significant implications for identifying potential study populations. Ongoing studies of olfactory dysfunction may also reveal potential for use as a medication-independent biomarker of disease progression in addition to use as a biomarker for the diagnosis of PD.

Goldmann Gross R, Siderowf A, Hurtig HI. · Parkinson's Disease and Movement Disorders Center, Department of Neurology, University of Pennsylvania Health System, Philadelphia, PA, USA. · Neurosignals. · Pubmed #18097157 No free full text.

Abstract: Parkinson's disease (PD) is classically thought of as a movement disorder characterized by tremor, rigidity and postural instability. Nevertheless, there is growing recognition of prominent cognitive impairment in PD and related disorders, which is responsible for substantial disability in these patients. This review will focus on cognitive impairment associated with Lewy body pathology, including PD with dementia (PDD) and dementia with Lewy bodies (DLB). We will review the epidemiology, clinical evaluation, underlying mechanisms and treatment of cognitive impairment in these patients. Despite differences between PDD and DLB, there is clinical, neuropathological and radiological overlap between these disorders, supporting the view that they represent a spectrum of disease. These observations suggest that common targets for diagnosis and treatment of these disorders can be identified.

Dobkin RD, Menza M, Bienfait KL. · Department of Psychiatry, UMDNJ/Robert Wood Johnson Medical School, 675 Hoes Lane, Room D-317, Piscataway, NJ 08854, USA. · Expert Rev Neurother. · Pubmed #18088199 No free full text.

Abstract: Depression is very common in Parkinson's disease (PD) and linked with a faster progression of physical symptoms, greater cognitive decline and poorer quality of life. Nonpharmacological approaches, such as cognitive-behavioral therapy (CBT), for the treatment of depression in PD (dPD) have received little experimental attention despite strong demonstrated efficacy in other geriatric and medical populations. Depressed PD patients often differ from the depressed non-PD elderly in that they present with increased rates of both executive dysfunction and comorbid psychiatric diagnoses, may differ in their depressive symptom presentation and typically have caregivers who are highly involved in their treatment. Therefore, it is not possible to conclude that empirically validated treatments in the depressed aged will generalize to those with PD. In order to be most effective for PD patients, CBT should be tailored to their unique needs. Additional controlled research is needed to further explore the efficacy of CBT for dPD.

Greggio E, Singleton A. · Cell Biology & Gene Expression Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20982, USA. · Expert Rev Proteomics. · Pubmed #18067416 No free full text.

Abstract: Parkinson's disease (PD) is a severe, progressive, age-associated, neurodegenerative disorder. Current therapies are symptomatic and not effective at halting or significantly slowing the disease progress. The search for etiologic-based therapies has focused largely on genetic findings made in familial forms of this disease. Mutations of five genes have been unequivocally linked to PD; two of these, LRRK2 and PINK1, encode kinases and as such are attractive tools with which to understand the disease process; furthermore, preliminary functional data suggests that these proteins, or the pathways in which they are involved, are viable therapeutic targets. Here we explore the current data and thoughts regarding LRRK2 and PINK1 and discuss further avenues of research to understand the pathologic effects of mutations at these loci and potential points of therapeutic intervention, such as within these kinases or in associated pathways such as Jun N-terminal kinase and Akt pathways.

Maguire-Zeiss KA, Mhyre TR, Federoff HJ. · Department of Neuroscience, Georgetown University, Washington, DC 20007, USA. · Exp Neurol. · Pubmed #18035353 No free full text.

Abstract: PD gene therapy clinical trials have primarily focused on increasing the production of dopamine (DA) through supplemental amino acid decarboxylase (AADC) expression, neurotrophic support for surviving dopaminergic neurons (DAN) or altering brain circuitry to compensate for DA neuron loss. The future of PD gene therapy will depend upon resolving a number of important issues that are discussed in this special issue. Of particular importance is the identification of novel targets that are amenable to early intervention prior to the substantial loss of DAN. However, for the most part the etiopathogenesis of PD is unknown making early intervention a challenge and the development of early biomarker diagnostics imperative.

Cookson MR, Dauer W, Dawson T, Fon EA, Guo M, Shen J. · Cell Biology and Gene Expression Unit, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland 20892-3707, USA. · J Neurosci. · Pubmed #17978026 links to  free full text

Abstract: The purpose of this mini-symposium is to discuss some of the inherited forms of Parkinson's disease (PD) in view of recent data suggesting that some of the proteins affect cellular signaling pathways. As an illustration, we shall focus on two different kinases associated with recessive and dominant forms of PD. Mutations in the mitochondrial kinase PTEN (phosphatase and tensin homolog)-induced kinase 1 (PINK1) are loss-of-function mutations in a normally neuroprotective protein. Loss-of-function mutations in model organisms have variable effects, from dramatic muscle and spermatid defects in Drosophila to more subtle neurophysiological abnormalities in mice. Several lines of evidence relate these to the action of a second gene for familial PD, parkin, an E3 ubiquitin ligase shown recently to have effects on Akt signaling. Mutations in leucine-rich repeat kinase 2 (LRRK2), a cytosolic kinase, are dominant and have the opposite effect of causing neuronal damage. The mechanism(s) involved are uncertain at this time because LRRK2 is a large and complex molecule with several domains. Increased kinase activity accounts for the action of at least some of the mutations, suggesting that hyperactive or misregulated kinase activity may lead to the damaging effects of LRRK2 in neurons. For both PINK1 and LRRK2, the following key question that needs to be answered: what are the physiological substrates that mediate effects in cells? Here, we will discuss some of the recent thinking about physiological and pathological roles for signaling in PD and how these may have therapeutic implications for the future.

Fishman PS. · Department of Neurology, University of Maryland, School of Medicine and The Baltimore VAMC, Baltimore, Maryland 21201, USA. · Mov Disord. · Pubmed #17973325 No free full text.

Abstract: Although resting tremor is the most identifiable sign of Parkinson's disease, its underlying basis appears to be the most complex of the cardinal signs. The variable relationship of resting tremor to other symptoms of PD has implications for diagnosis, prognosis, medical and surgical treatment. Structural lesions very rarely cause classic resting tremor, with likely contributions to tremor by a network of neurons both within and outside the basal ganglia. Patients with only resting tremor show dopaminergic deficits with radioligand imaging, but severity of tremor correlates poorly in such dopamine imaging studies. Correlation of tremor severity to changes in radioligand studies is also limited by the use of mostly qualitative measures of tremor severity. A complex pharmacologic basis of parkinsonian resting tremor is supported by treatment studies. Although levodopa is clearly effective for resting tremor, several agents have shown efficacy that appears to be superior or additive to that of levodopa including anticholinergics, clozapine, pramipexole, and budipine. Although the thalamus has the greatest body of evidence supporting its role as an effective target for surgical treatment of tremor, recent studies suggest that the subthalamic nucleus may be a reasonable alternative target for patients with Parkinson's disease and severe tremor as the predominant symptom.

Miller L, Vegesna A, Kalra A, Besetty R, Dai Q, Korimilli A, Brasseur JG. · Department of Gastroenterology, Temple University Hospital, Gastroenterology Section, 8th Floor, Parkinson Pavilion, Philadelphia, PA 19043, USA. · Gastroenterol Clin North Am. · Pubmed #17950440 No free full text.

Abstract: The use of high-frequency ultrasound transducers combined with manometry in the gastrointestinal (GI) tract has yielded important findings concerning the anatomy, physiology, and pathophysiology of the high-pressure zone of the gastroesophageal junction and the sphincteric muscles within. These transducers have made previously invisible portions of the GI tract accessible to investigation. Three distinct high-pressure zones have been identified and correlated with anatomic structures: the extrinsic sphincter (crural diaphragm) and the two components of the intrinsic sphincter (an upper LES and a lower LES [the gastric sling fiber/clasp fiber complex]). This article discusses the possible underlying pathophysiology of gastroesophageal reflux disease; the biomechanics of the gastroesophageal junction high-pressure zone; and the mechanism of action of standard surgical and newer endoscopic therapies for gastroesophageal reflux disease.