As the U.S. population ages, a priority for primary care providers (PCPs), including nurse practitioners (NPs), will be the acquisition of knowledge and expertise in managing chronic conditions common in older adults, such as Parkinson disease (PD).1,2 PD is the second most common neurodegenerative disease in older adults, affecting at least 500,000 people in the United States, and the projected number of PD patients in 2030 is 610,000.3 About 50,000 people will receive a new diagnosis of PD every year.4 The annual incidence rates of PD ranged from 8.6 to 19.0 per 100,000 population.1,5
PD is a progressive and degenerative neurological condition, which results in the loss of dopamine-producing cells in the brain.6,7 Men are about 1.5 times more likely to develop PD than women.8 People with PD have motor and nonmotor symptoms that frequently affect their ability to carry out tasks for daily living.
Due to its chronic nature, PD can be burdensome to the individual, family, and healthcare delivery system. The total cost of PD in the United States was projected to be $23 billion annually, including direct and indirect costs.2 PD-related early retirement and income loss are parts of the indirect costs of PD.9 Most PD patients (93%) at 10 years of the disease live at home,10 and many report physical debilitations associated with their illness that impair their quality of life.11 Informal caregivers of patients with PD also report increased burden associated with their home caregiving.10 Therefore, management of PD does not equate to patient care alone but also necessitates assistance toward their caregivers. By virtue of being PCPs and the increasing age of people in the United States, NPs should anticipate a rise in the number of patients with PD being followed in their primary care practices. This article provides a discussion about PD with a focus on its management. Both pharmacologic and nonpharmacologic approaches to symptoms are described as well as support strategies for informal caregivers of patients with PD.
The most characteristic pathologic feature of PD is a loss of dopamine-containing neurons in the substantia nigra pars compacta whose axons terminate in the caudate nucleus and putamen (the striatum), which is linked to the motor syndrome (see Neurotransmitter action in PD). Additionally, the development of concentric hyaline inclusions (Lewy bodies) found in the cytoplasm, is a finding associated with neuronal loss.12 (See Lewy bodies in PD.) Nonmotor symptoms and signs are related to the degeneration of other neuronal groups, including serotonergic neurons, noradrenergic neurons, and cholinergic neurons.13
The causes of PD are not clearly identified yet; however, genetic and environmental factors are considered important risk factors for PD. The suggested risk factors of PD reported in the literature include genetic mutations in the parkin gene on chromosome 6 and the alpha-synuclein gene on chromosome 4, as well as exposure to pesticides, and the environmental endotoxin, lipopolysaccharide-produced Salmonella minnesota.12,14 Therefore, the NP should closely assess these risk factors along with family history and list of medications while considering the diagnosis of PD among patients in clinical settings. Additionally, research findings indicate that caffeine intake is associated with a decreased risk of PD.15
PD is a clinical diagnosis based on 2 of 4 cardinal symptoms: resting tremor, bradykinesia, cogwheel rigidity, and postural instability. One of the two symptoms must be resting tremor or bradykinesia, which showed a very high sensitivity of 99%.6,16 Tremor is the most common initial finding in 70% of patients with PD, although some patients do not present resting tremor in the course of the disease.17
Nonmotor symptoms in PD can be divided into four categories: cortical manifestations, such as dementia, mild cognitive impairment, and psychosis; basal ganglial symptoms, such as apathy, restlessness, and impulse control disorders; brainstem-linked symptoms, such as depression, anxiety, and sleep disorders; and peripheral nervous system disturbances, such as orthostatic hypotension, constipation, pain, and sensory disturbances.16,18 In a longitudinal study of patients with PD, the following symptoms were reported: cognitive decline, falls, hallucinations, depression, dysphasia, urinary incontinence, sialorrhea, and symptomatic postural hypotension.19 Dysarthria may be an early feature; dysphagia usually occurs later.12
The clinical manifestation and the rate of progression of PD are variable, so each patient shows heterogeneous presentations.13 Women are more likely than men to experience PD-related complications, including depression and medication-associated dyskinesia.7 In many cases, the most disabling aspects of PD are nonmotor symptoms, especially neuropsychiatric disturbances.8 In a recent review of studies regarding the prevalence of depression in patients with PD, 35% were diagnosed with clinically significant depression and 17% with major depression.20 Therefore, NPs should carefully assess for depression in patients with PD. About 25% to 40% of patients with PD develop dementia in the course of the disease due to degeneration and the development of Lewy bodies in the cerebral cortex and limbic structures,21 which seems related to the reduced life expectancy of patients with PD.1 Lewy body dementia and PD dementia have similar characteristics, including global cognitive deterioration and impairment of self-care and other activities of daily living, so it is beneficial to consider the treatment of the two diseases together.22
Differential diagnoses of PD include Parkinson-like diseases: progressive supranuclear palsy (PSP), multiple system atrophy (MSA), an adverse reaction of numerous medications, Alzheimer disease or multiple cerebral infarction, and fragile X-tremor ataxia syndrome.12,23 In a study by Testa and colleagues,24 all 39 PSP patients had oculomotor palsy, whereas 89% of 74 MSA patients had dysautonomia, bradykinesia, and falls as the most common signs. A careful assessment/exam of the typical symptoms of Parkinson-like diseases (PSP and MSA) is beneficial in differentiating PD.24 Additionally, performing a careful review of medications and their drug-drug interactions would be beneficial in identifying risk factors of PD and ruling out medications as the possible culprits for symptomatic presentations. Alzheimer disease should also be considered by the NP if the extrapyramidal syndrome is ruled out. Multiple cerebral infarctions can be diagnosed with imaging tests, such as brain computerized axial tomography scan and/or magnetic resonance imaging (MRI) scan. Although advanced imaging assessment such as positron emission tomography, functional MRI, and single-photon emission computed tomography would be a possible option to diagnose PD, a reliable and easily applicable diagnostic test or marker for PD is not yet available.1,25
Management: Goals of care
PD currently has no cure. Therefore, long-term care management for patients with PD is essential to monitor progression of the disease. Once diagnosis of PD is established, the NP can provide care to patients with PD by pharmacological therapy and multidisciplinary interventions. Referral for surgical management is also an option for those whose symptoms are uncontrolled by pharmacotherapy.6 The three goals of therapy for patients with PD are to delay disease progression, relieve symptoms, and preserve functional capacity.12 Quality-of-life issues should be considered along with symptom management. In addition, primary caregivers and other family members should be involved in the patient's plan of care.
Pharmacologic management. Symptomatic dopaminergic drug therapy is the most important management for patients with PD due to the loss of dopaminergic pigmented neurons in the substantia nigra pars.6,26 Anti-parkinson medications include levodopa, dopamine agonists, monoamine oxidase (MAO)-B inhibitors, catechol O-methyltransferase (COMT), anticholinergic drugs, and amantadine.6,25 (See Anti-parkinson medications.)
Dopaminergic therapy. Levodopa is the most effective medication for managing symptoms of PD. It is effective in reducing akinesia, tremor, and rigidity, but difficulties with standing and coordination are less likely to improve.27 In the United States, carbidopa is combined with levodopa to improve the efficiency of levodopa; in Asia, Canada, and Europe, levodopa is combined with benserazide.27 Adverse reactions of levodopa include nausea, sleepiness, dizziness, and headache. More severe adverse reactions are confusion, hallucinations, delusion, and psychosis, which are more common in older populations. Long-term use (5 to 10 years) of levodopa is related to motor fluctuations, which is “on-off time” and dyskinesias, which are involuntary movements of the limbs or twisting movements of the limbs, face, or trunk.27 These movements restrict the patient's ability to perform desired activities and hinder ability to communicate. When levodopa is used with a COMT inhibitor (entacapone) and a MAO-B inhibitor (rasagiline), the off time of levopoda can be reduced.28 According to American Academy of Neurology's guideline for medical and surgical treatment of PD with motor fluctuations and dyskinesia, there is no difference between immediate-release levodopa and sustained-release levodopa in the incidence of motor complications.28
Dopamine agonists. These medications work by directly stimulating dopamine receptors in the brain. The medications in this category in the United States are bromocriptine, pramipexole, ropinirole, rotigotine, and apomorphine.28,29 Common adverse reactions of these medications include lightheadedness, somnolence, vivid dreaming, sleepiness, nausea, vomiting, orthostatic hypotension, confusion, hallucinations, and swelling in the lower legs and feet.27 Drug-induced, excessive daytime sleepiness is an adverse reaction of many dopamine agonists.30 Dopaminergic drug-related compulsive behaviors vary, and common symptoms include pathological gambling, hypersexuality, compulsive eating, and compulsive buying.31 Because of the many adverse reactions associated with dopamine agonists, benefits and risks should be considered carefully prior to their use as initial treatment for PD, especially in younger patients.
MAO-B inhibitors. Selegiline and rasagiline are MAO-B inhibitors.27 Selegiline increases the duration of levodopa effects by blocking proteins that inactivate dopamine. Rasagiline is used for monotherapy or as adjunct therapy to levodopa. These medications are specific MAOIs, which do not require dietary changes or restrictions, such as tyramine-rich food. However, there is a potential risk for hypertensive reaction with foods that contain high amounts of tyramine, such as aged cheeses. Common adverse reactions associated with this medication include nausea, vomiting, symptomatic orthostatic hypotension, hallucinations, insomnia, and jitteriness.
COMT inhibitors. Tolcapone and entacapone may be used to prolong and enhance the effect of levodopa.28 The primary reason to choose these medications is to decrease motor fluctuations that occur during “wearing-off” periods associated with the use of levodopa. The medication has no effect on its own.27 Adverse reactions include diarrhea, nausea, somnolence, hallucinations, and symptomatic orthostatic hypotension.
Anticholinergic drugs. Trihexyphenidyl, benztropine, and biperiden are anticholinergic drugs, which have comparable effectiveness.27 The effect of these medications is to reduce symptoms of tremor in patients with PD. The most common adverse reactions of anticholinergics include dry mouth, blurred vision, constipation, nausea, difficulty emptying the bladder, impaired sweating, and rapid heart rate.27,28
Other: Antiviral. Amantadine is an antiviral drug developed to prevent influenza; however, it also reduces dyskinesia in patients with advanced PD.28 Adverse reactions include nausea, constipation, dizziness, insomnia, depression, anxiety, somnolence, hallucinations, and symptomatic orthostatic hypotension.
Nonmotor symptom management. Treatment of nonmotor symptoms such as sleep dysfunction, autonomic dysfunction, mood disorders, and cognitive abnormalities is important, as these are disturbing features of PD and a major cause of morbidity.12,32
There is insufficient evidence regarding specific treatments for urinary incontinence and orthostatic hypotension.32 Management of constipation among PD patients uses a similar approach to that of the general population, which includes adequate water intake. Erectile dysfunction management is similar to the general population, such as sildenafil, use with caution in patients with orthostatic hypotension, and do not use in patients taking nitrates. Quetiapine may be considered to treat hallucinations and psychosis.33 The evidence base regarding the therapeutic efficacy of antidepressants in PD is currently insufficient.33,34 Antidepressants have been used to treat depression in patients with PD, including selective serotonin reuptake inhibitors (such as citalopram, paroxetine, sertraline), serotonin-norepinephrine reuptake inhibitors (such as venlafaxine), and the secondary amine tricyclic antidepressants.34 Amitriptyline may be considered to treat depression in PD without dementia33; however, tricyclic antidepressants should be used carefully in older patients with PD due to their adverse reactions. Cholinesterase inhibitors may be effective in treating psychosis in patients with PD who have dementia; however, there is much less evidence for the use of memantine.34
Surgical managements. Surgical procedures may be recommended for patients with PD whose debilitating symptoms persist despite pharmacological management. These procedures are briefly described below.
Surgery and deep brain stimulation (DBS). Unilateral pallidotomy has shown effectiveness in severe dyskinesia and on-off fluctuations.12 DBS is a less-invasive interventional option in which a pacemaker device is inserted in the brain. The pacemaker and electrode stimulate a specific brain structure (the globus pallidus and subthalamic nucleus) with pulses of electricity in order to improve off time and involuntary movement.28
Adverse reactions of DBS may include thought processes and speech disorders, visual and sensory disturbances, abnormal gait, lack of coordination, headaches, and seizures.28 In one randomized controlled trial, patients with advanced PD who have had surgery showed improvements in symptoms at 6 months in comparison to those who received nonsurgical management.35 However, since surgical procedures including DBS are associated with some inherent risks, NPs have the responsibility to ensure that adequate information is received by patients with PD for informed consent.
Transplantation of fetal tissue stem cells. Presently, there is insufficient evidence to support transplantation of fetal tissue stem cells to manage PD. However, the idea of transplantation of fetal substantia nigra tissue into the striatum has been receiving attention as a potential option for PD. Depending on future research in transplanting fetal tissue and stem cells, more treatment options may be available in the future.12,36
Patient and family education. Patient and family education is an essential feature of successful management of PD.12 NPs are in a unique position to develop relationships with patients with PD, caregivers, and specialists.37 Patients and caregivers would benefit from a multidisciplinary approach, including nursing, occupational therapy, physical therapy, speech, and swallowing therapy to manage the physical limitations brought about by PD. At the initial stage of the disease, the NP should set the goals of treatment with the patient and family members and reevaluate the goals at each visit. Education should be given to a patient and his/her family members, including information about the progression of PD and the management of its symptoms, information about resources available in the community, support groups for the patient and family members, and palliative care at the end of life. The NP should reinforce the teaching that was provided at previous office visits and ask if the patient or family members have any additional questions or concerns. Relevant websites that informal caregivers and patients can access for information about PD should also be provided (see Web resources for Parkinson disease). Keeping a PD medication diary at home would be the best way to monitor the effectiveness and adverse reactions of drug therapy and to increase medication adherence among patients with PD.38,39 Surgical management such as DBS might be an option in the later stage of PD. Treatment approaches including surgical management, such as DBS, should be discussed in the early stages of the disease to keep the patient informed on possible options for disease management.
Physical activity/exercise and safety. In recent studies, physical activity/exercise programs showed effectiveness in decreasing the degree of motor-related symptoms in patients with PD.1,40 In a meta-analysis by de Dreu and colleagues, music-based therapies showed a significant improvement in gait and gait-related activities.41 In addition, a tailored Tai Chi program in a randomized, controlled trial showed reduced balance impairments and falls in patients with mild-to-moderate PD.42 Along with these findings, a positive association between level of physical activity and fatigue was reported in another study.43 Therefore, there may be substantial benefits in encouraging adequate physical activity/exercise among patients with PD during each clinical encounter.
Support group and community resources. There are many organizations providing information regarding PD. The patient and family members should be given information regarding available resources in the community. Additionally, many organizations' websites are available, so this information should be shared with patients with PD. In many cases, family members provide homecare for patients with PD, and they report a declined health-related quality of life.44 If PCPs cannot provide their own educational programs in a clinical setting, they can refer family caregivers to available community resources.
Palliative care. Palliative care should be arranged for patients with PD and their family members throughout the course of the illness.45 According to the Parkinson's Disease Model of Care developed by Bunting-Perry, palliative care can be given throughout all stages of the disease, including early disease, moderate disease, advanced disease, hospice, and bereavement.45 The NP should address the idea of palliative care once a patient is diagnosed with the disease. As advanced care planning is the cornerstone of palliative care, it can provide an opportunity to develop a longitudinal plan of care.45
Evaluate the effectiveness of PD management
A patient's self-report using a daily log of medications, symptom manifestation, and functional levels should be utilized to evaluate patient responses to pharmacological therapies. In addition, surrogate reports from family members can be helpful to obtain additional data on patients' responses and should be solicited during each visit if possible. Providers' observations at each visit are also a good way to evaluate the effectiveness of treatment. Finally, utilization of Parkinson-specific tools developed by the CDC, Parkinson's Disease Common Data Elements Standards, and by Movement Disorder Society, Unified Parkinson Disease Rating Scale (MDS-UPDRS) is a good way to assess and evaluate patients' progress of illness, including effectiveness of treatments.46,47
Follow-up by PCPs
NP follow-up care of patients with PD should be based on the CDC's guidelines46 and advanced care planning along with palliative care. If the patient does not see a specialist (neurologist) on a regular basis, the NP should see the patient more frequently in order to evaluate the progress of the treatment of PD in the office and adapt “10 Quality Measures for PD Improvement” developed by the American Academy of Neurology as follows48: Annual PD diagnosis review; psychiatric disorders or disturbances assessment; cognitive impairment or dysfunction assessment; asking about symptoms of autonomic dysfunction; asking about sleep disturbances; asking about falls; rehabilitative therapy options for PD; counseling for safety issues related to PD; asking about PD medication-related motor complications; and reviewing medical and surgical treatment options for PD.
Summary and concluding discussion
PD is a progressive, degenerative neurologic disease. This disease is prevalent among older adults and requires prolonged treatment. As there are no available distinctive tests or biomarkers of PD, the patient who presents with signs and symptoms of PD should be referred to a neurologist for definitive diagnosis. When monitoring pharmacological treatment, the NP should evaluate effectiveness of medications based on a patient's motor and nonmotor symptoms. The Parkinson's Disease Model of Care based on advanced care planning could be beneficial for the patient, family members, and provider in terms of setting goals for treatment and preparing for the advanced stage of PD.45
Web resources for Parkinson disease
National Parkinson Foundation
The National Parkinson Foundation provides funding for research and support services in the care and treatment of people with Parkinson disease.
Parkinson's Disease Foundation
The Parkinson's Disease Foundation is a leading national presence in Parkinson disease research, education, and public advocacy.
National Institute of Neurological Diseases and Stroke
Created by the U.S. Congress in 1950, the National Institute of Neurological Disorders and Stroke (NINDS) conducts and supports research on brain and nervous system disorders including Parkinson disease.
American Parkinson Disease Association
Founded in 1961 and headquartered in New York, the American Parkinson Disease Association focuses its energies on research, patient services, education, and raising public awareness about Parkinson disease.
1. de Lau LML, Breteler MMB. Epidemiology of Parkinson's disease. Lancet Neurology
2. Huse D, Schulman K, Orsini L, et al. Burden of illness in Parkinson's disease. Movement disorders
3. Dorsey ER, Constantinescu R, Thompson JP, et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030
. 2007; 69:223–224.
5. Twelves D, Perkins KS, Counsell C. Systematic review of incidence studies of Parkinson's disease. Mov Disord
6. McCance KL, Huether SE. Pathophysiology. The biologic basis for disease in adults and children
. 6th ed. St. Louis: Mosby; 2010.
7. Pavon JM, Whitson HE, Okun MS. Parkinson's disease in women: a call for improved clinical studies and for comparative effectiveness research. Maturitas
8. Taylor KS, Cook JA, Counsell CE. Heterogeneity in male to female risk for Parkinson's disease. J Neurol Neurosurg Psychiatry
9. Johnson S, Davis M, Kaltenboeck A, et al. Early retirement and income loss in patients with early and advanced Parkinson's disease. Appl Health Econ Health Policy
10. Hassan A, Wu SS, Schmidt P, et al. What are the issues facing Parkinson's Disease patients at ten years of disease and beyond?: Data from the NPF-QII Study. Parkinsonism & Related Disorders
. 2012: Jul.
11. Findley LJ. The economic impact of Parkinson's disease. Parkinsonism and Related Disorders
12. Goroll AH, Mulley Jr. AG. (Eds.). Primary care medicine: Office evaluation and management of the adult patient
. 6th ed. Philadelphia: Lippincott Williams & Wilkins;2009: 1223–1225.
13. Linazasoro G. A global view of Parkinson's disease pathogenesis: Implications for natural history and neuroprotection. Parkinsonism and Related Disorders
14. Allam MF, Del Castillo AS, Navajas RF. Parkinson's disease risk factors: Genetic, environmental, or both. Neurolo Res
15. Ross GW, Abbott RD, Petrovitch H., et al. Association of coffee and caffeine intake with the risk of Parkinson disease
16. Hughes AJ, Ben-Shlomo Y, Daniel SE, Lees AJ. What features improve the accuracy of clinical diagnosis in Parkinson's disease: A clinicopathologic study. Neurology
17. Hughes AJ, Daniel SE, Blankson S, Lees AJ. A clinicopathologic Study of 100 Cases of Parkinson's Disease. Arch Neurol
18. Stacy M. Nonmotor symptoms in Parkinson's disease. Int J Neeurosic
19. Hely MA, Morris JG, Reid WG, Trafficante R. Sydney multicenter study of Parkinson's disease: non-L-dopa-response problems dominate at 15 years. Mov Disorder
20. Reijnders JSAM, Ehrt U, Weber WEJ, et al. A systematic review of prevalence studies of depression in parkinson's disease. Movement Disorders
21. Emre M. Dementia associated with Parkinson's disease. Lancet Neuroloy
22. Ballard C, Kahn Z, Corbett A. Treatment of Dementia with Lewy Bodies and Parkinson's Disease Dementia. Drugs & Aging
. 2011; 28(10): 769–777
23. Massano J., Kailash P.B. Clinical approach to Parkinson's Disease: Features, diagnosis, and principles of management. Cold Spring Harbor Perspectives in Medicine
24. Testa D, Monza D, Ferrarini M, et al. Comparison of natural histories of progressive supranuclear palsy and multiple system atrophy. Neurol Sci
25. Ignatavicius DD, Workman ML. Medical-surgical nursing: Patient-centered collaborative care
. St. Louis, MO: Elsevier;2010.
26. Lindskov S, Westergren A, Hagell P. A controlled trial of an educational programme for people with Parkinson's disease. Journal of Clinical Nursing
29. Pahwa R, Factor SA, Lyons KE, et al. Practice parameter: Treatment of Parkinson Disease
with motor fluctuations and dyskinesia (an Evidence-Based Review). Neurology
30. Knie B, Mitra MT, Logishetty K, Chaudhuri R. Excessive daytime sleepiness in patients with Parkinson's Disease. CNS Drugs
. 2011; 25(3):203–212.
31. Evans AH, Strafella AP, Weintraub D, Stacy M. Impulsive and compulsive behaviors in parkinson's disease. Movement Disorders
32. Zesiewicz TA, Sullivan KA, Arnulf I, et al. Practice parameter: Treatment of nonmotor symptoms of Parkinson Disease
33. Miyasaki JM, Shannon K, Voon V, et al. Practice parameter: Evaluation and treatment of depression, psychosis, and dementia in Parkinson Disease
(an Evidence-Based Review). Neurology
. 2006;66(7): 996–1002.
34. Gallagher DA, Schrag A. Psychosis, apathy, depression and anxiety in parkinson's disease. Neurobiol Dis
35. Weaver FM, Follett K, Stern M, et al. Bilateral deep brain stimulation vs. best medical therapy for patients with advanced Parkinson Disease
: A randomized controlled trial. JAMA
36. Politis M, Lindvall O. Clinical application of stem cell therapy in Parkinson's disease. BMC Medicine
37. Welsh M. Treatment challenges in Parkinson's disease. The Nurse Practitioner
. 2008;33(7): 32–38.
38. Hauser RA, Friedlander J, Zesiewicz TA, et al. A home diary to assess functional status in patients with Parkinson's disease with motor fluctuations and dyskinesia. Clinical Neuropharmacology
39. Hauser RA, Deckers F, Lehert P. Parkinson's disease home diary: Further validation and implications for clinical trials. Movement Disorders
40. Suchowersky O, Gronseth G, Perlmutter J, et al. Practice parameter: Neuroprotective strategies and alternative therapies for Parkinson Disease
(an Evidence-Based Review). Neurology
41. de Dreu MJ, van der Wilk ASD, Poppe E, et al. Rehabilitation, exercise therapy and music in patients with Parkinson's disease: A meta-analysis of the effects of music-based movement therapy on walking ability, balance and quality of life
. Parkinsonism & Related Disorders
42. Li F, Harmer P, Fitzgerald K, et al. Tai Chi and postural stability in patients with Parkinson's disease. N Engl J Med
43. Abrantes AM, Friedman JH, Brown RA, et al. Physical activity and neuropsychiatric symptoms of Parkinson Disease
. Journal of Geriatric Psychiatry and Neurology
44. Schulz R, Beack SR. Caregiving as a risk factor for mortality: The Caregiver Health Effects Study. Journal of the American Medical Association
45. Bunting-Perry L. Palliative care in Parkinson's disease: Implications for neuroscience nursing. Journal of Neuroscience Nursing
47. The Unified Parkinson's Disease Rating Scale (UPDRS): status and recommendations. Move Disorder
48. Cheng EM, Tonn S, Swain-Eng R, et al. “Quality Improvement in Neurology: AAN Parkinson Disease
Quality Measures: Report of the Quality Measurement and Reporting Subcommittee of the American Academy of Neurology.” Neurology
. 2010;75(22): 2021–2027.
50. Gutierrez K. Pharmacotherapeutics: Clinical reasoning in primary care. 2nd ed. St. Louis, MO: Saunders, Elsevier; 2008.